research articles on antidiabetic drugs

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Article Contents

Type 1 diabetes, type 2 diabetes, conclusions, disclosures, data availability, abbreviations.

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New Horizons: Emerging Antidiabetic Medications

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Geltrude Mingrone, Lidia Castagneto-Gissey, Stefan R Bornstein, New Horizons: Emerging Antidiabetic Medications, The Journal of Clinical Endocrinology & Metabolism , Volume 107, Issue 12, December 2022, Pages e4333–e4340, https://doi.org/10.1210/clinem/dgac499

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Over the past century, since the discovery of insulin, the therapeutic offer for diabetes has grown exponentially, in particular for type 2 diabetes (T2D). However, the drugs in the diabetes pipeline are even more promising because of their impressive antihyperglycemic effects coupled with remarkable weight loss.

An ideal medication for T2D should target not only hyperglycemia but also insulin resistance and obesity. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and the new class of GLP1 and gastric inhibitory polypeptide dual RAs counteract 2 of these metabolic defects of T2D, hyperglycemia and obesity, with stunning results that are similar to the effects of metabolic surgery.

An important role of antidiabetic medications is to reduce the risk and improve the outcome of cardiovascular diseases, including coronary artery disease and heart failure with reduced or preserved ejection fraction, as well as diabetic nephropathy, as shown by SGLT2 inhibitors.

This review summarizes the main drugs currently under development for the treatment of type 1 diabetes and T2D, highlighting their strengths and side effects.

In spite of the large number of antidiabetes medications available, including combination therapies, the percentage of people achieving an adequate glycemic control with a glycated hemoglobin A 1c (HbA 1c ) less than 7% remains lower than 60%. A recent analysis of the trends of diabetes treatment and risk-factor control within the National Health and Nutrition Examination Survey (NHANES) shows that the percentage of participants with HbA 1c less than 7% was 44.0% in 1999 to 2002, 57.4% in 2007 to 2010, and 50.5% in 2015 to 2018 ( 1 ). A leading cause of the failure to achieve an adequate glycemic control resides in the poor medication adherence, especially in type 2 diabetes (T2D), which is as low as 60% ( 2 ). The total costs of diagnosed diabetes in the United States increased by 26% in 5 years, from $245 billion in 2012 to $327 billion in 2017 ( 3 ).

In the last few years, pharmaceutical industries sought to identify new pharmacological molecules with improved selectivity and specificity. For instance, targeting the principal defects of insulin action in T2D can improve patient outcomes and reduce the clinical burden of this condition.

An ideal medication for T2D should target not only hyperglycemia but also insulin resistance and obesity. Glucagon-like peptide-1 receptor agonists (GLP1-RAs) and the new class of gastric inhibitory polypeptide (GIP) and GLP1 dual RAs counteract 2 of these metabolic defects in T2D, hyperglycemia and obesity, with stunning results that are similar to the effects of metabolic surgery.

An important role of antidiabetic medications is to reduce the risk and improve the outcomes of cardiovascular diseases, including coronary artery disease and heart failure with reduced or preserved ejection fraction, as well as diabetic nephropathy, as shown by sodium-glucose co-transporter-2 (SGLT2) inhibitors.

Herein we define as “emerging antidiabetic medications” those antidiabetic medications recently approved by the US Food and Drug Administration (FDA) and/or by the European Medicines Agency (EMA), or by other local regulatory agencies, such as the Japanese PMDA, or drugs in the pipeline for type 1 (T1D) or type 2 diabetes with specific and innovative pharmacologic targets.

Oral insulin was always regarded as a mirage since it would avoid injections, which is a particularly painful and hated procedure for young patients. However, until now this aim was difficult to achieve because of the unpredictability of insulin absorption through the oral route.

Immunomodulatory Strategies

Targeting T cells reduces the presence of T cells that migrate from the thymus to the endocrine pancreas, where they destroy islets.

Teplizumab—a fragment crystalline (Fc) receptor–nonbinding anti-CD3 monoclonal antibody—was used in a phase 2, randomized, placebo-controlled, double-blind trial (RCT) to verify whether the elapsed time from randomization to the clinical diagnosis of T1D could have been delayed in relatives of individuals with T1D at high risk for development of clinical disease ( 4 ). The median time to diagnosis was doubled in participants on teplizumab treatment compared with placebo (48.4 vs 24.4 months) and the proportion of participants with diagnosis of diabetes was reduced by about 30% (43% vs 72%).

An ongoing phase 3trial (PROTECT RCT; ClinicalTrials.gov NCT03875729) is in the midst of evaluating the safety and efficacy of teplizumab in children and adolescents with recent-onset T1D.

Alefacept is a fusion protein, which contains two lymphocyte function-associated antigen 3 (LFA-3) molecules bound to the Fc portion of immunoglobulin G1 (IgG1) ( 5 ). It binds the cell surface marker CD2 mainly expressed on CD4+ and CD8+ effector memory T cells that are responsible for the destruction of β cells in T1D ( 6 ). In an RCT involving 49 individuals with new-onset T1D, two 12-week courses of 15 mg/week intramuscular alefacept separated by a 12-week pause were compared with placebo. At 24-month follow-up, alefacept reduced insulin requirements ( P = .002) as well as major hypoglycemic events ( P < .001) when compared with placebo ( 7 ).

The neuroendocrine hormone, amylin, reduces glucagon secretion improving glycemic control in T1D. Pramlintide, an injectable amylin analogue, approved in the United States as an adjunct to meal-time insulin, reduces postprandial glycemic excursions ( 8 ). The modest efficacy associated with side effects, such as nausea and hypoglycemia, precluded its extensive use in clinics.

Sodium-Glucose Co-transporter Inhibitors

Sotagliflozin and dapagliflozin have been approved in the European Union and Japan and are under scrutiny by the FDA for patients with T1D who are overweight.

Sotagliflozin, belonging to the gliflozin class of antidiabetic drugs, blocks both intestinal SGLT1 and renal SGLT2 glucose carriers with consequent reduction of glucose absorption in the intestinal tract and increases renal excretion of glucose with urine, overall reducing the circulatory levels of glucose.

It was shown that 28.6% of patients in the oral sotagliflozin group, receiving 400 mg of the drug daily, met the primary end point of HbA 1c less than 7.0% compared with 15.2% ( P < .001) in the placebo group ( 9 ).

In patients with T1D and chronic diabetic nephropathy, sotagliflozin reduced the risk of the composite end point of cardiovascular deaths, hospitalizations for heart failure, and urgent visits for heart failure in comparison with placebo (5.6 events per 100 patient-years in the sotagliflozin group and 7.5 events per 100 patient-years in the placebo group) ( 10 ).

Hopefully, the use of sotagliflozin as an add-on therapy to insulin can help patients obtain better glycemic control and reduce cardiovascular events in T1D. On May 3, 2021, the FDA approved oral dapagliflozin tablets to “reduce the risk of kidney function decline, kidney failure, cardiovascular death and hospitalization for heart failure in adults with chronic kidney disease who are at risk of disease progression.” However, in addition to an increase in genital mycotic infections, sotagliflozin has shown a 5- to 17-fold risk increase of diabetic ketoacidosis (DKA), which seems to be dose dependent ( 11 ). A consensus report ( 12 ) recommends measuring ketone bodies in the presence of symptoms consistent with DKA, such as nausea or vomiting or malaise and fatigue. Blood levels of β-hydroxybutyrate higher than 0.6 mmol/L or the presence of even bland ketonuria indicate early ketosis.

Glucagon-like Peptide-1 Receptor Agonists

The ADJUNCT 1 and 2 trials demonstrated the efficacy of liraglutide as an adjunct to insulin in reducing the daily need for insulin injections, in improving glycemic control, and in reducing body weight in participants with T1D and overweight ( 13 , 14 ). However, important safety concerns are the increased risk of hypoglycemia (21.3 vs 16.6 events/patient/year; P = .03) as well as of DKA (0.5 vs 0.1 events/patient/year; P = .01).

Insulin Resistance in Type 2 Diabetes

Currently, insulin resistance is considered the primary defect in individuals with T2D, manifesting long before hyperglycemia ( 15 ). Only when insulin secretion decreases does overt diabetes emerge as a result of relative β-cell failure. A finding supporting this paradigm is the preserved insulin secretory capacity of the endocrine pancreas observed in the presence of T2D, particularly in patients with associated obesity, compared with individuals with normal insulin sensitivity ( 16 , 17 ). In other words, individuals with T2D and obesity have insulin hypersecretion but circulating insulin levels are unable to overcome the insulin resistance state. Moreover, the absence of the early phase of insulin secretion associated with a more pronounced compensatory second phase do not permit individuals with T2D to achieve an adequate and quick response to rapidly increased circulating glucose levels ( 18 ).

Skeletal muscle is the major site showing impaired insulin-mediated glucose uptake and utilization with reduced glycogen formation/deposition and impaired glucose oxidation ( 15 ).

Obesity and especially visceral obesity increase cytokine secretion that alters insulin signaling, thus contributing to insulin resistance ( 19 ). Moreover, the increased afflux of free fatty acids (FFAs) to the liver from the intra-abdominal fat compartment increases hepatic glucose production, a major player in insulin resistance ( 20 ).

Hence, drugs targeting insulin resistance and concurrently reducing body fat should represent the best therapeutic candidates for treating T2D.

Unfortunately, only 2 drugs target directly insulin resistance, metformin and the drug class of thiazolidinediones (TZDs). Metformin reduces hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis and by stimulating insulin-mediated glucose uptake and glycogenesis in the skeletal muscle ( 21 ).

TZDs are ligands of the nuclear peroxisome proliferator-activated receptor γ, which becomes activated and increases transcription of insulin-sensitive genes ( 22 ). Unfortunately, TZDs not only do not decrease body weight but rather increase it, although moderately. However, body fat distribution changes with increased subcutaneous fat at the expense of the visceral fat, which decreases with an improvement in insulin sensitivity ( 23 ).

Current American Diabetes Association and European Association for the Study of Diabetes hyperglycemia treatment guidelines for T2D recommend using drugs that reduce body weight, such as GLP-1 RAs and SGLT2 inhibitors (SGLT2i) ( 24 ). By reducing fat accumulation and obesity, in fact, they improve glycemic control.

Emerging Drugs for Type 2 Diabetes

Since 1920 when a guanidine compound, Synthalin, was synthesized in Germany and successively commercialized, and since 1922 when insulin was first used in humans by Banting and Best, a great number of antidiabetic medications entered the market. Over a century, the therapeutic possibilities for the management of diabetes have grown exponentially. However, the drugs in the diabetes treatment pipeline are even more promising because of their impressive antihyperglycemic effects coupled with remarkable weight loss.

The development of SGLT2i and GLP1-RAs has offered new tools for improving not only glycemic control but also cardiovascular and kidney outcomes in people with T2D.

New Members or Doses of Glucagon-like Peptide-1 Receptor Agonists

GLP1-RAs reduce HbA 1c in ranges of 1% to 1.5% when added to the standard of care ( 25 ). This effect is achieved through the simultaneous stimulation of insulin secretion, the suppression of glucagon release, and the delay of gastric emptying time. Gastric emptying delay slows carbohydrate absorption but causes also gastrointestinal side effects, principally nausea, which can affect up to 30% of patients ( 26 ).

Since the first GLP1-RA—Byetta exenatide from AstraZeneca—was approved in the United States in 2005, other short-acting and long-acting GLP1-RAs have been approved both by the FDA and EMA and hence are commercially available in the United States and the European Union.

Efpeglenatide is a modified exendin-4 molecule conjugated with an immunoglobulin G4 at the level of the fragment crystallizable region (IgG4 Fc), which is injected once a week and, potentially, once a month, but it is not yet approved by the FDA or EMA. Efpeglenatide significantly reduces cardiovascular events, occurring in 7.0% of participants assigned to efpeglenatide and in 9.2% of those receiving placebo (hazard ratio, 0.73; 95% CI, 0.58-0.92; P < .001 for noninferiority; P = .007 for superiority) ( 27 ).

A double-blind phase 3 RCT, SUSTAIN FORTE, comparing the efficacy of 2 mg with 1 mg subcutaneous semaglutide once a week, showed the superiority of the 2-mg dose for both the glycemic control and the weight loss effect ( 28 ). In fact, HbA 1c was reduced from baseline by −2.2% with semaglutide 2.0 mg and by −1.9% with semaglutide 1.0 mg with a statistically significant ( P = .0003) estimated treatment difference of −0.23%. The body weight decrease from baseline was −6.9 kg with semaglutide 2.0 mg and −6.0 kg with semaglutide 1.0 mg ( P = .015). In March 2022, the FDA granted the approval to semaglutide 2 mg subcutaneously once a week for the treatment of T2D.

Dual Gastric Inhibitory Polypeptide and Glucagon-like Peptide 1 Receptor Agonists

A new and very promising class of drugs is the dual GIP and GLP1 RAs. SURPASS-1 ( 29 ) was a double-blind, randomized, controlled, phase 3 trial involving 478 participants with T2D and HbA 1c between 7.0% and 9.5%, who were insulin-naive and were receiving metformin alone or in concomitance to SGLT2 inhibitors. Participants were randomly assigned (1:1:1:1) to subcutaneous administration of 5 or 10 or 15 mg tirzepatide once a week or placebo. Tirzepatide was administered following a slow dose escalation regimen with a 2.5-mg dose increment every 4 weeks until reaching the maintenance dose. The primary end point was HbA 1c mean change from baseline at 40 weeks of follow-up.

At 40 weeks, the mean HbA 1c concentrations reached near normal values of 6.08% (43 mmol/mol) with tirzepatide 5 mg, 6.06% (43 mmol/mol) with tirzepatide 10 mg, and 5.88% (41 mmol/mol) with tirzepatide 15 mg. The mean treatment difference with the control group was about −2%.

The effect of tirzepatide on weight loss was remarkable: −7.0 ± 0.52 kg with 5 mg, −7.8 ± 0.53 kg with 10 mg and −9.5 ± 0.54 kg with 15 mg, with an estimated mean treatment difference vs the control group varying from −6.3 to −8.8 kg. Weight loss was dose dependent with 13% to 27% of the participants showing 15% or greater weight loss vs none in the insulin degludec group ( 30 ), Gastrointestinal side effects, in particular nausea, diarrhea, and vomiting, were the most frequent adverse effects reported in 12% to 18% of participants.

SURPASS-2 trial ( 31 ) was designed to show noninferiority of tirzepatide at a dose of 5 mg or 10 mg or 15 mg vs semaglutide at a dose of 1 mg in regard to the change from baseline in HbA 1c at 40 weeks in individuals with T2D inadequately controlled with metformin monotherapy.

Tirzepatide at doses of 5, 10, and 15 mg was found to be superior to semaglutide 1 mg used as an active comparator.

Tirzepatide 5, 10, and 15 mg reduced HbA 1c by −2.01%, −2.24%, and −2.30% compared with −1.89% with semaglutide 1 mg. It is interesting to note that semaglutide 2.0 mg reduces HbA 1c by −2.2% from baseline ( 28 ), which is very close to the effect of tirzepatide. Moreover, while the effect of tirzepatide on glycemic control was more or less similar with the 3 doses, a clear dose response effect on weight loss was evident. In fact, the weight loss obtained was −7.6 kg, −9.3 kg, and −11.2 kg with tirzepatide 5 mg, 10 mg, and 15 mg, respectively compared with −5.7 kg with semaglutide 1 mg.

Although the number of adverse events (AEs) was similar with tirzepatide and semaglutide, a higher number of serious AEs was observed with the former. Mortality was observed among participants treated with tirzepatide but not in those treated with semaglutide, although it was not imputed to the pharmacological treatment.

The SURMOUNT-1 RCT, dedicated to obesity, showed −3.1% (95% CI, −4.3 to −1.9) weight loss with placebo, −15.0% (95% CI, −15.9 to −14.2) with 5-mg weekly dose of tirzepatide, −19.5% (95% CI, −20.4 to −18.5) with 10 mg, and −20.9% (95% CI, −21.8 to −19.9) with 15 mg ( P < .001 for all comparisons with placebo) ( 32 ). Therefore, the maximal weight loss in excess to placebo was about 18% with 15 mg tirzepatide. Fifty percent (95% CI, 46%-54%) and 57% (95% CI, 53%-61%) of participants receiving tirzepatide 10 mg or 15 mg obtained a weight loss exceeding 20%.

Tirzepatide is a single linear peptide composed of 39 amino acids conjugated with a 20-carbon atom fatty dicarboxylic acid at the lysine residue at position 20. This peptide is bound to albumin to obtain a slow release, permitting a once-a-week subcutaneous administration. Tirzepatide has an affinity for GIP receptors close to that of the native GIP, but it binds the GLP1 receptor with about a 5-fold weaker affinity than native GLP-1. Therefore, its action on the GIP receptor is stronger than that on the GLP1 receptor.

GIP stimulates insulin secretion and reduces glucagon secretion in a glucose-dependent manner, thus under hypoglycemic conditions circulating glucagon levels increase maintaining the physiological antihypoglycemic role of glucagon ( 33 ).

On May 13, 2022, the FDA approved Eli Lilly and Co.’s tirzepatide under the commercial name Mounjaro to treat T2D at doses of 5, 10, and 15 mg ( 34 ).

A new class of oral antihyperglycemic medications containing tetrahydrotriazine, the so-called “glimins,” includes imeglimin. At the moment, imeglimin is commercialized only in Japan.

This drug amplifies glucose-stimulated insulin secretion and improves insulin sensitivity both at the level of the liver and the skeletal muscle. These effects are likely mediated by its inhibitory action on the mitochondrial oxidative phosphorylation ( 35 ).

The efficacy and safety of imeglimin was evaluated in the phase 3 TIMES 1 RCT ( 36 ). A total of 213 patients with T2D were randomly assigned 1:1 to oral imeglimin at the dose of 1000 mg twice daily or to placebo. After 24 weeks, the estimated HbA 1c treatment difference with placebo was 20.87% (95% CI, 21.04-20.69) with P less than .0001.

Serious AEs were observed in the 3.8% of participants in the imeglimin group and in 0.9% in the placebo group. No differences between the groups in terms of incidence of gastrointestinal disorders were observed.

Its long-term efficacy is evaluated in the ongoing DIGNITY trial (Durable Effect of Imeglimin on the Glycemic Control in Patients With Type 2 Diabetes Mellitus: a Multicenter, Open-label, Randomized, Controlled Trial) with ClinicalTrials.gov identifier number NCT05366868.

Glucagon Receptor Antagonist RVT-1502

Circulating glucagon levels decrease during GLP1-RA therapy but only by approximately 10% ( 37 , 38 ). It has been shown that glucagon receptor knockout mice do not develop hyperglycemia or other metabolic disorders associated with diabetes ( 39 ). Therefore, glucagon RAs are actively studied as antidiabetic medications.

LGD-6972 is an orally bioavailable glucagon RA that suppresses hepatic glucose production ( 40 ).

A recent phase 2 RCT evaluated the efficacy in terms of change from baseline of HbA 1c levels and safety of RVT-1502 at doses of 5, 10, and 15 mg compared with placebo over 12 weeks ( 41 ).

After 12 weeks of treatment, the mean HbA 1c changes relative to placebo were 20.7% (95% CI, 21.1%-20.4%; P < .001), 20.8% (95% CI, 21.1%-20.4%; P < .001), and 21.1% (95% CI, 21.4%-20.7%; P < .001) with 5, 10, and 15 mg RVT-1502, respectively.

The most frequent mild to moderate AEs observed in 35.5% of patients receiving RVT-1502 were diarrhea, increased aspartate transaminase, proteinuria, and urinary tract infection, and they were not dose related; however, 36.6% of the participants on placebo had AEs.

Transient changes in liver enzymes, which however remained at the high level of normality, and mild increases in blood pressure were also observed.

Pramlintide, an amylin analogue, has been approved in the United States since 2005 in injectable form as an adjunct to insulin treatment in T1D and T2D ( 42 ). It decreases glucagon secretion, reduces gastric emptying, and induces satiety ( 42 ).

Cagrilintide ( 43 ) is a long-acting amylin analogue with agonistic effects on both native amylin and calcitonin receptors. Native amylin is a hormone cosecreted with insulin that delays gastric emptying and suppresses appetite and induces satiety.

The injection of 4.5 mg of cagrilintide reduced body weight from baseline by 6% more than liraglutide 3 mg after 26 weeks of treatment ( 43 ). It reduced also HbA 1c levels by 1.2 ± 2.4 (mean ± SE) %. Another more recent study showed that cagrilintide associated with semaglutide 2.4 mg reduce 15% body weight after 20 weeks of treatment ( 44 ).

11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors

11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is an enzyme catalyzing the transformation of cortisone to its active form cortisol. This NADPH-dependent enzyme is mainly expressed in the liver and adipose tissue ( 45 ).

11β-Hydroxysteroid dehydrogenase type 2 (11β-HSD2) is an NAD+ dependent enzyme mainly present in the kidney, which oxidizes cortisol to inactive cortisone and, thus, counteracts the action of 11β-HSD1 ( 45 ). When 11β-HSD1 is inhibited, the hypothalamic-pituitary-adrenal axis activates to ensure homeostasis ( 46 ).

None of the drugs (BI 187004, BI 135585, RO 5093151/RO-151, RO5027383/RO-838, ABT-384, MK-0916, AZD4017) that showed a statistically significant preclinical effect on glucose metabolism by improving insulin sensitivity and glycemic control arrived to phase 2. The 11β-HSD1 inhibitor, AZD4017, was the only one used in a phase 2 RCT with 2 primary outcomes: the percentage change from baseline to week 12 in liver fat fraction, and the percentage change from baseline to week 12 in the conversion of 13C cortisone to 13C cortisol. It failed the first primary outcome and succeeded only in drastically reducing the formation of cortisol in tissues ( 47 ).

Glycogen Phosphorylase Inhibitors

Glycogen phosphorylase catalyzes the breakdown of glycogen to glucose-1-phosphate at the α-1,4-glycosidic linkage in the liver and other tissues, such as skeletal muscle, to increase glucose availability and meet high energy demand.

The active form of this enzyme is the phosphorylated one obtained through the phosphorylation of serine-14 by phosphorylase kinase ( 48 ).

Together with gluconeogenesis, hepatic glycogenolysis regulates circulating levels of glucose and, therefore, it represents a good target for the treatment of diabetes. Other than competitive inhibitors binding the active site of glycogen phosphorylase, molecules that bind the purine inhibitory site (I site) of the enzyme, such as caffeine and other heteroaromatic analogues, counteract the action of glycogen phosphorylase ( 49 ).

Although promising in rodent models of diabetes, this class of antidiabetic medications did not reach the clinical phase, mainly because of the barriers of targeting the specific hepatic isoform and, thus, avoiding reduced availability of glucose in the skeletal muscle that can limit physical activity ( 50 ).

Glucokinase Activators

Glucokinase (GKA) or hexokinase IV, is an enzyme covering a central metabolic role. GKA promotes glucose uptake and glycogen synthesis in the liver. It phosphorylates glucose to glucose-6-phosphate, which is then oxidized in the glycolysis and produces pyruvate in the mitochondria. In pancreatic β cells, GKA increases the adenosine triphosphate/adenosine diphosphate ratio closing the K + channel with consequent cell membrane depolarization and insulin secretion.

Heterozygous mutations in the GKA gene cause maturity-onset diabetes of the young ( 51 ).

While theoretically promising drugs, some of them, such as AZD6370, piragliatin, DS-7309, and ARRY-403, terminated their clinical development because of toxicity and low effectiveness in the long term ( 52 ).

G Protein–Coupled Receptor Agonists

FFAs activate several G protein–coupled receptors (GPCRs), which are expressed in pancreatic islets, including GPR119, GPR132, GPR84, GPR119, GPR120, GPR43 (FFAR2), GPR40 (FFAR1), and GPR41 (FFAR3) ( 53 ).

GPR119 is a GPCR expressed on the cell membrane of β cells and gut endocrine cells. It stimulates insulin secretion in a glucose-dependent manner and increases intracellular cyclic adenosine 5′-monophosphate (cAMP) levels and incretin release, including GLP-1, GIP, and glucagon-like peptide-2 (GLP-2) ( 54 ).

To date, no drugs belonging to this class have succeeded and entered the market.

DS-8500a enhanced insulin secretory capacity, but not insulin sensitivity ( 55 ).

GlaxoSmithKline's GSK-1292263, which completed a phase 2 trial in May 2010, did not improve glucose control in patients with T2D ( 56 ).

Fasiglifam is a selective GPR40 agonist that significantly reduced HbA 1c and fasting glycemia compared with placebo, but its clinical development was terminated after a phase 3 RCT due to liver toxicity ( 57 ).

Protein Tyrosine Phosphatase 1B Inhibitors

Protein tyrosine phosphatase 1B (PTP1B) is a key cellular enzyme that controls cell growth and metabolism ( 58 ). Importantly, it catalyzes the removal of the phosphate group from tyrosine residues on the activated insulin receptor impairing its action and, thus, reducing insulin-mediated glucose uptake. Consequently, PTP1B inhibitors increase the phosphorylation of insulin receptors and improve glucose disposal.

Unfortunately, PTP1B inhibitors, such as ertiprotafib, ISIS-113715, and trodusquemine, failed in phase 2 clinical trials because of undesirable side effects and/or low selectivity ( 59 ).

GKA is a liver enzyme that phosphorylates glucose to glucose-6-phosphate, this latter representing the hub to 5 major pathways: the glycolysis, gluconeogenesis, glycogenesis, glycogenolysis, and pentose phosphate pathway. GKA activators stimulate β-cell insulin secretion and promote hepatic glycogen synthesis with subsequent reduction of hepatic glucose output ( 60 ). Preclinical animal studies demonstrate that GKAs normalize blood glucose levels, but induce severe hyperlipidemia and hypertension ( 61 ). Many GKAs entered trials, such as RRY-403, AZD1656, PSN010, which have been discontinued. Dorzagliatin is a novel GKA acting both on pancreatic and hepatic GKAs that is in a phase 3 trial, while TTP399 is a compound selective for liver GKA ( 60 ) in a phase 2 trial.

AMP-activated protein kinase (AMPK) is a key energy regulator. Several AMPK activators are registered in trials: Two of them, PXL770 and PBI-4050, completed phase 2 trials ( 62 ).

Fructokinase (FK) is an enzyme located in the liver, intestine, and kidney cortex that catalyzes the conversion of fructose into fructose-1-phosphate. FK activation depletes the cell of phosphates with the consequent activation of AMP deaminase ending in uric acid production. Uric acid is a proinflammatory molecule that can induce insulin resistance ( 63 ). The FK inhibitor, PF-06835919, is currently in phase 2 development. Tolimidone (MLR-1023) is also in phase 2. Tolimidone stimulates Lyn protein, which is a member of the Src family of intracellular membrane-associated tyrosine kinases ( 64 , 65 ). Lyn tyrosine kinase phosphorylates insulin receptor substrates augmenting insulin receptor signaling ( 66 , 67 ). Tolimidone enhances insulin sensitivity and its action is insulin dependent ( 64 ).

Currently we have ample drug choices to treat diabetes, and the antidiabetic armamentarium continues to increase substantially with a relevant pipeline of new medications.

Apart from oral insulin and immunomodulatory strategies in clinical development and sotagliflozin under FDA scrutiny for T1D, the great majority of antidiabetic drugs target T2D. The major defect of T2D is the presence of insulin resistance, which becomes more and more severe as body weight increases up to morbid obesity. Therefore, aside from true insulin secretion failure due to β-cell exhaustion, the insulin secretion impairment observed in T2D is often relative because higher than normal insulin levels are required to overcome reduced insulin-mediated glucose uptake. An ideal antidiabetic medication should target not only hyperglycemia but also insulin resistance and obesity. The GLP1-RA semaglutide in combination with the long-acting amylin analogue cagrilintide and the new class of GIP and GLP1 dual RAs, which at the moment includes only tirzepatide, counteract two of these metabolic defects of T2D, hyperglycemia and obesity, with stunning results that are almost similar to the effects of metabolic surgery.

An important role of antidiabetic medications is to reduce the risk and improve the outcome of cardiovascular diseases, including coronary artery disease and heart failure with reduced or preserved ejection fraction, as well as diabetic nephropathy, as shown by SGLT2i.

We are still waiting for a drug simultaneously targeting hyperglycemia, obesity, and insulin resistance as the Holy Grail of T2D treatment.

However, the major challenges for the adequate treatment of people with diabetes is not the lack of effective therapies but the inequalities in the populations with diabetes. For instance, the insulin cost in the United States is approximately 800% higher than in other developed countries ( 68 ). The net price of insulin increased by 252% in 2016 ( 69 ). Insurance plans with high deductibles obligate the patients to pay out of pocket before the insurance begins to pay for covered costs. Therefore, many people cannot afford buying insulin and this accounts, at least in part, for the poor adherence to antidiabetic medications observed. Tackling economic inequalities and/or improving the health insurance offering may help improve glycemic control in people with diabetes.

G.M. reports consulting fees from Novo Nordisk, Fractyl, and Recor. She is also a scientific advisor for Metadeq, Keyron, GHP Scientific, and Jemyll, these all being unpaid positions. L.C.G. and S.R.B. have nothing to disclose.

Data sharing is not applicable to this article as no data sets were generated or analyzed during the present study.

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Office of the Assistant Secretary for Planning and Evaluation (ASPE). Comparing Insulin Prices in the U.S. to Other Countries. Publication Date Sep 23, 2020 . Accessed July 18, 2022. https://aspe.hhs.gov/reports/comparing-insulin-prices-us-other-countries

Taylor SI . The high cost of diabetes drugs: disparate impact on the most vulnerable patients . Diabetes Care . 2020 ; 43 ( 10 ): 2330 – 2332 .

11β-hydroxysteroid dehydrogenase type 1

11β-hydroxysteroid dehydrogenase type 2

adverse event

adenosine 5′-monophosphate–activated protein kinase

diabetic ketoacidosis

European Medicines Agency

US Food and Drug Administration

free fatty acid

fructokinase

gastric inhibitory polypeptide

glucokinase

glucagon-like peptide-1 receptor agonist

G protein–coupled receptor

glycated hemoglobin A 1c

National Health and Nutrition Examination Survey

protein tyrosine phosphatase 1B

randomized controlled trial

sodium-glucose co-transporter-2

sodium-glucose co-transporter-2 inhibitors

type 1 diabetes

type 2 diabetes

thiazolidinediones

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MINI REVIEW article

Clinical review of antidiabetic drugs: implications for type 2 diabetes mellitus management.

• 1 GIM Foundation, Little Rock, AR, USA
• 2 University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, USA
• 3 Christus Trinity Mother Frances Hospital, Tyler, TX, USA
• 4 University of Arkansas for Little Rock (UALR), Little Rock, AR, USA
• 5 Tutwiler Clinic, Tutwiler, MS, USA
• 6 Vanderbilt University, Nashville, TN, USA
• 7 Arkansas Department of Health, Little Rock, AR, USA
• 8 St. Vincent Infirmary, Little Rock, AR, USA
• 9 Baptist Hospital SpringHill, North Little Rock, AR, USA
• 10 The Wright Center for Graduate Medical Education, Scranton, PA, USA

Type 2 diabetes mellitus (T2DM) is a global pandemic, as evident from the global cartographic picture of diabetes by the International Diabetes Federation ( http://www.diabetesatlas.org/ ). Diabetes mellitus is a chronic, progressive, incompletely understood metabolic condition chiefly characterized by hyperglycemia. Impaired insulin secretion, resistance to tissue actions of insulin, or a combination of both are thought to be the commonest reasons contributing to the pathophysiology of T2DM, a spectrum of disease originally arising from tissue insulin resistance and gradually progressing to a state characterized by complete loss of secretory activity of the beta cells of the pancreas. T2DM is a major contributor to the very large rise in the rate of non-communicable diseases affecting developed as well as developing nations. In this mini review, we endeavor to outline the current management principles, including the spectrum of medications that are currently used for pharmacologic management, for lowering the elevated blood glucose in T2DM.

Introduction

Diabetes mellitus (DM) is a complex chronic illness associated with a state of high blood glucose level, or hyperglycemia, occurring from deficiencies in insulin secretion, action, or both. The chronic metabolic imbalance associated with this disease puts patients at high risk for long-term macro- and microvascular complications, which if not provided with high quality care, lead to frequent hospitalization and complications, including elevated risk for cardiovascular diseases (CVDs) ( 1 ). The clinical diagnosis of diabetes is reliant on either one of the four plasma glucose (PG) criteria: elevated (i) fasting plasma glucose (FPG) (>126 mg/dL), (ii) 2 h PG during a 75-g oral glucose tolerance test (OGTT) (>200 mg/dL), (iii) random PG (>200 mg/dL) with classic signs and symptoms of hyperglycemia, or (iv) hemoglobin A1C level >6.5%. Recent American Diabetes Association (ADA) guidelines have advocated that no one test may be preferred over another for diagnosis. The recommendation is to test all adults beginning at age 45 years, regardless of body weight, and to test asymptomatic adults of any age who are overweight or obese, present with a diagnostic symptom, and have at least an additional risk factor for development of diabetes.

Furthermore, a condition called prediabetes or impaired fasting glucose (IFG), in which the fasting blood glucose is raised more than normal but does not reach the threshold to be considered diabetes (110–126 mg/dL), predisposes patients to diabetes, insulin resistance, and higher risk of cardiovascular (CV) and neurological pathologies ( 2 , 3 ). Type 2 diabetes mellitus (T2DM) can co-occur with other medical conditions, such as gestational diabetes occurring during the second or third trimester of pregnancy or pancreatic disease associated with cystic fibrosis. T2DM may also be iatrogenically induced, e.g., by use of glucocorticoids in the inpatient setting or use of highly active antiretroviral agents like protease inhibitors and nucleoside reverse transcription inhibitors in HIV-positive individuals ( 4 ). Chemical diabetes or impaired glucose tolerance (IGT) may also develop with the use of thiazide diuretics, atypical antipsychotic agents, and statins ( 5 , 6 ).

Type 2 diabetes mellitus is a common and increasingly prevalent disease and is thus a major public health concern worldwide. The International Diabetes Federation estimates that there are approximately 387 million people diagnosed with diabetes across the globe ( 7 ). According to Centers for Disease Control and Prevention, in 2012, 29.1 million adults, or 9.3% of the population, were identified with diabetes in the United States (US). Also in the same year, 86 million people had prediabetes condition and 15–30% of them developed into full-blown diabetes ( 8 ). In general, 1.4 million newly diagnosed cases in the US are being reported every year. If this trend continues, it is projected that in 2050 one in three Americans will have diabetes. Patients with diabetes have increased risk of serious health complications including myocardial infarction, stroke, kidney failure, vision loss, and premature death. Diabetes, with its associated side effects, remains the seventh leading cause of mortality in the US. The World Health Organization estimates that by 2030, mortality related to diabetes will double in number if not given deliberate attention ( 9 ). In addition, epidemiological studies report that diabetes causes more deaths in Americans every year compared to breast cancer and acquired immunodeficiency syndrome (AIDS) combined ( 10 ). The increasing trend in the incidence and prevalence of diabetes is worrisome and poses a great burden on medical costs and in our current healthcare system.

The ADA has released a range of recommendations called Standards of Medical Care in Diabetes to improve diabetes outcomes. The recommendations include cost-effective screening, diagnostic and therapeutic strategies to prevent, delay, or effectively manage T2DM and its life-threatening complications ( 11 ). Per recommendations of ADA and other organizations, modern approaches to diabetes care should involve a multidisciplinary team of health professionals working in tandem with the patient and the family ( 2 ). The primary aim of these approaches is to obtain optimal glycemic control through dietary and lifestyle modifications and appropriate medications along with regular blood glucose level monitoring. The burden of diabetes can be potentially reduced if the standard of care is implemented as well as patients’ compliance and participation is clinically implemented.

The traditional presentations of T2DM occurring only in adults and type 1 diabetes mellitus (T1DM) only in children are not entirely correctly representative, as both diseases occur in both age groups. Occasionally, patients with T2DM may develop the morbid complication of diabetic ketoacidosis (DKA) ( 12 ). Children with T1DM typically present with polyuria and polydipsia and approximately one-third of them present with DKA, which may also be the first presenting feature ( 12 ). The onset of T1DM may be variable in adults, and they may not present with the classic symptoms that are seen in children. The true diagnosis may become apparent with disease progression. The heterogeneity of the presentations should be kept in mind while caring for the patient with T2DM.

The scope of this review encompasses current clinical guidelines on the pharmacological management of T2DM.

Clinical Diagnosis of Type 2 Diabetes

Diabetes may be identified in low-risk individuals who have spontaneous glucose testing during routine primary clinical care, in individuals examined for diabetes risk assessment, and in frankly symptomatic patients. Early diagnosis of T2DM can be accomplished through blood tests that measure PG levels. FPG is the most common test to detect diabetes: a level of ≥126 mg/dL or 7.0 mmol/L confirmed by repeating the test on another clinic visit effectively diagnoses the disease. This test requires fasting for at least the previous 8 h and generates enhanced reliability when blood is drawn in the morning. Another criterion is the 2 h PG of ≥200 mg/dL or 11.1 mmol/L in a patient presenting with the traditional symptoms of diabetes such as polyuria, polydipsia, and/or unexplained weight loss. A positive 2-h OGTT will show a PG level of ≥200 mg/dL or 11.1 mmol/L after a glucose load containing 75 g of glucose solution in water. Two-hour PG OGTT is not commonly used in the clinic because, although it is more sensitive than FPG test, it is less convenient and more expensive for patients. Additionally, this test holds less relevance in routine follow-ups after confirmed diagnosis of diabetes is obtained.

In the past, the glycated hemoglobin (HbA1C) test was used mainly to monitor the adequacy of glycemic management and has strong predictive value for diabetes complications ( 13 ). HbA1C is a chronic marker of hyperglycemia and reflects patient’s blood glucose level over a period of 3–4 months, coinciding with the lifespan of the red blood cells (RBCs). However, in 2009 after its standardization, the International Expert Committee recommended it to be used in diagnosing T2DM but not in T1DM and gestational diabetes ( 2 ). HbA1C level is reported in percentages, and a normal level is below 5.7%. The main advantage of the HbA1C test over other blood glucose tests is the convenience it offers to patients; it does not require fasting and can be done at any time of the day. However, this test is more expensive and may not be readily available in certain locations, which may limit its usefulness ( 14 , 15 ). HbA1C may be inaccurate in conditions such as anemia, hemolysis, and other hemoglobinopathies like sickle cell disease and hemoglobin (Hb) variants like HbC, HbE, and HbD, as well as elevated fetal hemoglobin. Thus, HbA1C assay in people of South Asian, Mediterranean, or African origin merit taking these issues into account ( 16 ). In conditions associated with increased RBC breakdown, such as in the advanced trimesters of pregnancy, recent hemorrhage, intravascular hemolysis or transfusion or erythropoietin treatment, only blood glucose estimation should be used to diagnose diabetes. There are limited data supporting the use of A1C in diagnosing T2DM in children and adolescents. Although A1C is not routinely suggested for diagnosis of diabetes in children with cystic fibrosis or symptoms that portend development of acute onset of T1DM, the ADA recommends HbA1C for diagnosis of T2DM in children and adolescents.

In order to accurately diagnose diabetes and in the absence of frank hyperglycemia (PG > 200 mg/dL) or hyperglycemic crisis, it is useful to repeat the same diagnostic test for confirmation. In situations where there are two different tests with conflicting results, the test which is positive should be repeated and a diagnosis of diabetes is made after a confirmatory test has been done ( 2 ). For individuals whose test result/s returned negative for diabetes, repeat testing at 3-year intervals is suggested ( 17 ).

The ADA and American Association of Clinical Endocrinologists recommend screening for prediabetes beginning at age 45 years or earlier for asymptomatic individuals with strong risk factors such as obesity (BMI ≥ 25 kg/m 2 ), hypertension and family history (first degree relative with diabetes) ( 18 ). IFG level of 100–125 mg/dL (5.6–6.9 mmol/L), IGT with a 2-h OGTT PG level between 140 and 199 mg/dL (7.9–11.0 mmol/L), or an HbA1C of 5.7–6.4% indicates prediabetes. Patients with an HbA1C level of >6% are considered high risk of developing diabetes, and early detection is necessary to prevent adverse outcomes. Patients diagnosed with prediabetes can be retested after a year; however, without proper intervention 70% of individuals diagnosed with prediabetes are most likely to progress to diabetes in 10 years or even less, depending on their risk factors ( 18 ). It is also important to note that prediabetes may be associated with obesity, dyslipidemia, and hypertension; therefore, lifestyle changes such as healthy diet, physical activity, and cessation of smoking, in addition to the introduction of pharmacological agents, are deemed important to stop or delay the timeline of development of diabetes.

Clinical Management of Type 2 Diabetes

Comprehensive care for a patient with diabetes requires an initial evaluation of the patient’s risk factors, the presence or absence of diabetes complications, and initial review of previous treatment/s ( 2 ). This will enable the healthcare providers to optimally manage patients with either prediabetes or diabetes. The cornerstones of diabetes management include lifestyle intervention along with pharmacological therapy and routine blood glucose monitoring.

Lifestyle Measures

Clinical trials have shown that lifestyle modifications are cost-effective in preventing or delaying the onset of diabetes, with approximately 58% reduction in risk in 3 years ( 19 ). It is highly recommended by the ADA that patients with IGT, IFG or HbA1C level of 5.7–6.4% be counseled on lifestyle changes such as diet and exercise. On the other hand, for patients who are already diagnosed with diabetes, nutrition advice provided by a registered dietitian is recommended. A goal of moderate weight loss (≈7% of body weight) is an important component in the prevention and treatment of diabetes, as it can improve blood glucose levels, and can also positively impact blood pressure and cholesterol levels ( 19 ). Weight loss can be achieved through a healthy balanced diet, with control of total calories and free carbohydrates. However, for patients with diabetes adhering to a low carbohydrate diet, they should be informed on possible side effects such as hypoglycemia, headache and constipation ( 20 ). Other studies have suggested consumption of complex dietary fiber and whole grains to improve glycemic control ( 2 , 21 ).

Studies show that exercise can improve glycemic control (lower HbA1C level by 0.66%), with or without significant decrease in body weight, and improve the total well-being of patients ( 22 ). It is considered an integral part in the prevention and management of both prediabetes and diabetes. According to the U.S. Department of Health and Human Services, adults ≥18 years of age should do a minimum of 150 min/week of moderate intensity exercise (e.g., walking at a 15- to 20-min mile pace) or 75 min/week of vigorous physical activity (e.g., running, aerobics) spread over at least 3 days/week with no more than two consecutive days without exercise to achieve maximum benefits ( 2 , 18 ). For patients ≤18 years old, 60 min of physical activity every day is adequate.

Other lifestyle measures that need to be considered in the treatment plan for patients with diabetes are moderate alcohol consumption (≤1 drink for women, ≤2 drinks/men) and reduction in sodium intake especially in patients with comorbidities such as hypertension, habitual tobacco use, and lacking immunizations (influenza, diphtheria, pertussis, tetanus, pneumococcal, and hepatitis B). Consumption of alcohol, especially in a fasted state, can precipitate life-threatening hypoglycemia and coma and should be explicitly counseled to patients during their visits ( 23 ). Moreover, patient education, counseling, and psychosocial support are very important to successfully combat the deleterious effects of diabetes.

Pharmacologic Management

An “ominous octet” that leads to hyperglycemia, which occur in isolation or in combination, has been proposed for eight pathophysiological mechanisms underlying T2DM ( 24 ). These include (i) reduced insulin secretion from pancreatic β-cells, (ii) elevated glucagon secretion from pancreatic α cells, (iii) increased production of glucose in liver, (iv) neurotransmitter dysfunction and insulin resistance in the brain, (v) enhanced lipolysis, (vi) increased renal glucose reabsorption, (vii) reduced incretin effect in the small intestine, and (viii) impaired or diminished glucose uptake in peripheral tissues such as skeletal muscle, liver, and adipose tissue. Currently available glucose-lowering therapies target one or more of these key pathways.

Good glycemic control remains the main foundation of managing T2DM. Such approaches play a vital role in preventing or delaying the onset and progression of diabetic complications. It is important that a patient-centered approach should be used to guide the choice of pharmacological agents. The factors to be considered include efficacy, cost, potential side effects, weight gain, comorbidities, hypoglycemia risk, and patient preferences. Pharmacological treatment of T2DM should be initiated when glycemic control is not achieved or if HbA1C rises to 6.5% after 2–3 months of lifestyle intervention. Not delaying treatment and motivating patients to initiate pharmacotherapy can considerably prevent the risk of the irreversible microvascular complications such as retinopathy and glomerular damage ( 25 ). Monotherapy with an oral medication should be started concomitantly with intensive lifestyle management.

The major classes of oral antidiabetic medications include biguanides, sulfonylureas, meglitinide, thiazolidinedione (TZD), dipeptidyl peptidase 4 (DPP-4) inhibitors, sodium-glucose cotransporter (SGLT2) inhibitors, and α-glucosidase inhibitors. If the HbA1C level rises to 7.5% while on medication or if the initial HbA1C is ≥9%, combination therapy with two oral agents, or with insulin, may be considered ( 2 , 26 ). Though these medications may be used in all patients irrespective of their body weight, some medications like liraglutide may have distinct advantages in obese patients in comparison to lean diabetics (see below). A schematic of currently approved medications for T2DM is summarized in Table 1 . A flowchart for guiding clinical decision making is presented in Figure 1 .

Table 1. Pharmacological agents for glycemic control .

Figure 1. Flow chart depicting an algorithm for use of drug regimen in treating diabetes mellitus Several concepts presented here are adapted from American Diabetes Association/European Association for the Study of Diabetes ( 27 – 30 ) . Medications in green, causes weight loss; in red, causes weight gain.

The discovery of biguanide and its derivatives for the management of diabetes started in the middle ages. Galega officinalis , a herbaceous plant, was found to contain guanidine, galegine, and biguanide, which decreased blood glucose levels ( 31 ). Metformin is a biguanide that is the main first-line oral drug of choice in the management of T2DM across all age groups. Metformin activates adenosine monophosphate-activated protein kinase in the liver, causing hepatic uptake of glucose and inhibiting gluconeogenesis through complex effects on the mitochondrial enzymes ( 31 ). Metformin is highly tolerated and has only mild side effects, low risk of hypoglycemia and low chances of weight gain. Metformin is shown to delay the progression of T2DM, reduce the risk of complications, and reduce mortality rates in patients by decreasing hepatic glucose synthesis (gluconeogenesis) and sensitizing peripheral tissues to insulin ( 31 ). Furthermore, it improves insulin sensitivity by activating insulin receptor expression and enhancing tyrosine kinase activity. Recent evidence also suggest that metformin lowers plasma lipid levels through a peroxisome proliferator-activated receptor (PPAR)-α pathway, which prevents CVDs ( 31 ). Reduction of food intake possibly occurs by glucagon-like peptide-1 (GLP-1)-mediated incretin-like actions. Metformin may thus induce modest weight loss in overweight and obese individuals at risk for diabetes.

Once ingested, metformin (with a half-life of approximately 5 h) is absorbed by organic cation transporters and remains unmetabolized in the body and is widely distributed into different tissues such as intestine, liver, and kidney. The primary route of elimination is via kidney. Metformin is contraindicated in patients with advanced stages of renal insufficiency, indicated by a glomerular filtration rate (GFR) <30 mL/min/1.73 m 2 ( 32 ). If metformin is used when GFR is significantly diminished, the dose should be reduced and patients should be advised to discontinue the medication if nausea, vomiting, and dehydration arises from any other cause (to prevent ketoacidosis). It is important to assess renal function prior to starting this medication.

Metformin has an excellent safety profile, though may cause gastrointestinal disturbances including diarrhea, nausea, and dyspepsia in almost 30% of subjects after initiation. Introduction of metformin at low doses often improve tolerance. Extended release preparations seldom cause any gastrointestinal issues. Very rarely, metformin may cause lactic acidosis, mainly in subjects with severe renal insufficiency. Another potential problem arising from the use of metformin is the reduction in the drug’s efficiency as diabetes progresses. Metformin is highly efficient when there is enough insulin production; however, when diabetes reaches the state of failure of β-cells and resulting in a type 1 phenotype, metformin loses its efficacy.

Metformin can cause vitamin B12 and folic acid deficiency ( 33 ). This needs to be monitored, especially in elderly patients. Though very rare, in patients with metformin intolerance or contraindications, an initial drug from other oral classes may be used. Although trials have compared dual therapy with metformin alone, few directly compare drugs as add-on therapy. A comparative effectiveness meta-analysis suggests that overall each new class of non-insulin medications introduced in addition to the initial therapy lowers A1C around 0.9–1.1%. An ongoing Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) has compared the effect of four major drug classes (sulfonylurea, DPP-4 inhibitor, GLP-1 analog, and basal insulin) over 4 years on glycemic control and other psychosocial, medical, and health economic outcomes ( 34 ). Though it will be a welcome development for introduction of oral agents for metformin for gestational diabetes, current FDA regulations do not support it.

Incretin Mimetics

Incretin effect is the difference in insulin secretory response from an oral glucose load in comparison to glucose administered intravenously. The incretin effect is responsible for 50–70% of total insulin secretion after oral glucose intake ( 35 ). The two naturally occurring incretin hormones that play important roles in the maintenance of glycemic control: glucose-dependent insulinotropic polypeptide (GIP, or incretin) and glucagon-like peptide (GLP-1); these peptides have a short half-life, as these are rapidly hydrolyzed by DPP-4 inhibitors within 1½ min. In patients with T2DM, the incretin effect is reduced or absent. In particular, the insulinotropic action of GIP is lost in patients with T2DM. Incretins decrease gastric emptying and causes weight loss. Because of impact on weight loss, these medications may find increasing use in diabesity.

Targeting the incretin system has become an important therapeutic approach for treating T2DM. These two drug classes include GLP-1 receptor agonists and DPP-4 inhibitors. Clinical data have revealed that these therapies improve glycemic control while reducing body weight (specifically, GLP-1 receptor agonists) and systolic blood pressure in patients with T2DM ( 36 ). Furthermore, hypoglycemia is low (except when used in combination with a sulfonylurea) because of their glucose-dependent mechanism of action.

GLP-1 Receptor Agonists

The currently GLP-1 receptor agonists available are exenatide and liraglutide. These drugs exhibit increased resistance to enzymatic degradation by DPP4. In young patients with recent diagnosis of T2DM, central obesity, and abnormal metabolic profile, one should consider treatment with GLP-1 analogs that would have a beneficial effect on weight loss and improve the metabolic dysfunction. GLP-1 analogs are contraindicated in renal failure.

Exenatide . Exenatide, an exendin-4 mimetic with 53% sequence homology to native GLP-1, is currently approved for T2DM treatment as a single drug in the US and in combination with metformin ± sulfonylurea. Because of its half-life of 2.4 h, exenatide is advised for twice-daily dosing. Treatment with 10 µg exenatide, as an add-on to metformin, resulted in significant weight loss (−2.8 kg) in comparison to patients previously treated with metformin alone. Exenatide is generally well tolerated, with mild-to-moderate gastrointestinal effects being the most common adverse effect.

Liraglutide . Liraglutide is a GLP-1 analog that shares 97% sequence identity to native GLP-1. Liraglutide has a long duration of action (24 h). Liraglutide causes 1.5% decrease in A1C in individuals with type 2 diabetes, when used as monotherapy or in combination with one or more selected oral antidiabetic drugs. Liraglutide decreases body weight; the greatest weight loss resulted from treatment with liraglutide in combination with combined metformin/sulfonylurea (−3.24 kg with 1.8 mg liraglutide). Liraglutide also diminishes systolic pressure (mean decrease −2.1 to −6.7 mmHg) ( 37 ). Liraglutide is well tolerated, with only nausea and minor hypoglycemia (risk increased with use of sulfonylureas).

Serum antibody formation was very low in patients treated with once-weekly GLP-1 receptor agonists. The formation of these antibodies did not decrease efficacy of their actions on blood glucose lowering.

DPP-4 Inhibitors

Dipeptidyl peptidase 4 inhibitors include sitagliptin, saxagliptin, vidagliptin, linagliptin, and alogliptin. These medications may be used as single therapy, or in addition with metformin, sulfonylurea, or TZD. This treatment is similar to the other oral antidiabetic drugs. The gliptins have not been reported to cause higher incidence of hypoglycemic events compared with controls.

Dipeptidyl peptidase 4 inhibitors impact postprandial lipid levels. Treatment with vidagliptin for 4 weeks decreases postprandial plasma triglyceride and apolipoprotein B-48-containing triglyceride-rich lipoprotein particle metabolism after a fat-rich meal in T2DM patients who have previously not been exposed to these medications. In diabetic patients with coronary heart disease, it was demonstrated that treatment with sitagliptin improved cardiac function and coronary artery perfusion.

The three most commonly reported adverse reactions in clinical trials with gliptins were nasopharyngitis, upper respiratory tract infection, and headache. Acute pancreatitis was reported in a fraction of subjects taking sitagliptin or metformin and sitagliptin. An increased incidence of hypoglycemia was observed in the sulfonylurea treatment group.

In the elderly, DPP-4 inhibitors lower blood glucose but have minimal effect on caloric intake and therefore less catabolic effect on muscle and total body protein mass. In decreased doses, DPP-4 inhibitors are considered safe in patients with moderate to severe renal failure.

SGLT2 Inhibitors

Sodium-glucose cotransporter inhibitors are new classes of glucosuric agents: canagliflozin, dapagliflozin, and empagliflozin. SGLT2 inhibitors provide insulin-independent glucose lowering by blocking glucose reabsorption in the proximal renal tubule by inhibiting SGLT2 ( 38 ).

Because of glucose-independent mechanism of action, these drugs may be effective in advanced stages of T2DM when pancreatic β-cell reserves are permanently lost. These drugs provide modest weight loss and blood pressure reduction.

Urinary tract infections leading to urosepsis and pyelonephritis, as well as genital mycosis, may occur with SGLT2 inhibitors. SGLT2 inhibitors may rarely cause ketoacidosis. Patients should stop taking their SGLT2 inhibitor and seek medical attention immediately if they have symptoms of ketoacidosis (frank nausea or vomiting, or even non-specific features like tiredness or abdominal discomfort).

If non-insulin monotherapy like metformin at the maximum tolerated dose does not achieve or maintain the A1C target over 3 months, then a second oral agent may be added to the regimen, a GLP-1 receptor agonist, or basal insulin. Insulin therapy (with or without additional agents) should be introduced in patients with newly identified T2DM and frankly symptomatic (catabolic features like weight loss, ketosis or features of hyperglycemia including polyuria/polydipsia) and/or severely elevated blood glucose levels [≥300–350 mg/dL (16.7–19.4 mmol/L)] or A1C [≥10–12%] ( 11 ).

The clinical picture of T2DM and its therapies should be regularly and objectively elaborated to patients. Many subjects with T2DM shall require insulin therapy sometime during the course of the disease. For patients with T2DM with inadequate target glycemic goals, insulin therapy should not be postponed. Providers should advocate insulin as a therapy in a complete non-judgmental, empathetic, and non-punitive approach to ensure superior quality of adherence. Self-monitoring of blood glucose (SMBG) (discussed below) contributes to significant improvement of glycemic control in patients with T2DM initiating insulin. Close and frequent monitoring of the patient is needed for any dose titration to achieve target glycemic goals, as well as to prevent hypoglycemia.

Basal insulin is the initial insulin regimen, beginning at 10 U or 0.1–0.2 U/kg, depending on the hyperglycemia severity (titrating by 2–3 U every 4–7 days till glycemic goal is reached). Use of basal insulin greater than 0.5 U/kg indicates the need for use of an additional agent. Basal insulin is usually added to oral metformin and possibly one additional non-insulin agent like DPP-4 or SGLT-2 inhibitor. NPH (neutral protamine Hagedorn) insulin carries low risk of hypoglycemia in individuals without any significant past history, and is low cost. Newer, longer acting, basal insulin analogs have superior pharmacodynamic profiles, delayed onset and longer duration of action but low risk of hypoglycemia, albeit at higher costs. Concentrated basal insulin preparations such as U-500 regular is five times more potent per volume of insulin (i.e., 0.01 mL ~5 U of U-100 regular) than U-100 regular . U-300 glargine and U-200 degludec are other potent, ultra-long acting preparations.

If basal insulin contributes to acceptable fasting blood glucose, but A1C persistently remains above target, mealtime insulin may be added. Rapid-acting insulin analog (lispro, aspart, or glulisine) may be used and administered just before meals. The glucose levels should be monitored before meals and after the injections. Another approach to control the periprandial glucose excursions may be to add twice-daily premixed (or biphasic) insulin analogs (70/30 aspart mix, 75/25 or 50/50 lispro mix ). The total present insulin dose may be computed and then one-half of this amount may be administered as basal and the other half during mealtime, the latter split equally between three meals. Regular human insulin and human NPH–Regular premixed formulations (70/30) are less expensive alternatives to rapid-acting insulin analogs and premixed insulin analogs, respectively, but their unpredictable pharmacodynamic profiles make them inadequate to cover postprandial glucose changes.

Sometime, bolus insulin needs to be administered in addition to basal insulin. Rapid-acting analogs are used as bolus formulations due to their prompt onset of action. Insulin pump (continuous subcutaneous insulin infusion) may be used instead to avoid multiple injections. Often, patients and physicians are reluctant to intensify therapy due to the fear of hypoglycemia, regimen complexity, and increased multiple daily injections. There is a need for a flexible, alternative intensification option taking into account individual patient considerations to achieve or maintain individual glycemic targets. An ideal insulin regimen should mimic physiological insulin release while providing optimal glycemic control with low risk of hypoglycemia, weight gain, and fewer daily injections.

Inhaled insulin (Technosphere insulin-inhalation system, Afrezza) is now available for prandial use. However, the dosing range is limited. Use of inhaled insulin requires pulmonary function testing prior to and after starting therapy. It is contraindicated in subjects with asthma or other lung diseases.

During insulin therapy, sulfonylureas, DPP-4 inhibitors, and GLP-1 receptor agonists are stopped once more complex insulin regimens beyond basal insulin are used. In patients with inadequate blood glucose control, especially if requiring escalating insulin doses, TZDs (usually pioglitazone) or SGLT2 inhibitors may be added as adjunctive therapy to insulin.

Insulin injections can cause weight gain or loss. Insulin drives potassium into the cell and can cause hypokalemia. Components of the insulin preparation have the potential to cause allergy. Insulin injections, along with the use of other drugs like TZDs, can precipitate cardiac failure.

Stressful events like illness, surgery, and trauma can impede glycemic control and may lead to development of DKA or non-ketotic hyperosmolar state, life-threatening conditions, which merits immediate medical attention. Any condition that deteriorates glycemic control necessitates more frequent monitoring of blood glucose in an inpatient setting; ketosis-prone patients also require urine or blood ketone monitoring. If accompanied by ketosis, vomiting, or altered mental status, marked hyperglycemia requires hospital admission. The patient treated with non-insulin therapies or medical nutrition therapy alone may require insulin. Patient must be aggressively hydrated and infections should be controlled.

Without adequate treatment, prolonged hyperglycemia can cause glucose toxicity that can progressively impair insulin secretion. Initiation of insulin therapy is critical to reverse the toxic effect of high blood glucose levels on the pancreas. Once persistent glycemic control is achieved, insulin can be tapered off and replaced with oral medications. At some point in the management of T2DM, β-cell reserves are exhausted, with phenotypic reversal to a T1DM kind of pathophysiological situation. Meticulous follow-up may identify such states and then the need for continued reliance on insulin therapy may be carefully explained to the patients.

Weight gain can raise a barrier to the use of insulin in T2DM. In the United Kingdom Prospective Diabetes Study (UKPDS) study, patients gained 6 kg with insulin therapy, when compared with 1.7–2.6 kg weight gain with sulfonylureas ( 39 ). More recently, the combination of GLP-1 receptor agonists and insulin has been useful in tackling the weight gain associated with insulin and circumventing the need for high doses in the presence of significant insulin resistance. Lipoatrophy with insulin injections is not seen now; however, lipohypertrophy due to failure to change the subcutaneous injection sites is still a common cause of poor insulin absorption and suboptimal glycemic control.

In the Action to Control Cardiovascular Risk in Diabetes trial, aggressive treatment of T2DM patients with higher CV risk was associated with higher all-cause and CV mortality. Post hoc analyses could not find correlation with faster rates of reduction of glucose, hypoglycemia, or specific drugs as the causes underlying this finding. Exposure to injected insulin was hypothesized to increase CV mortality. However, after adjustment for baseline covariates, no significant association of insulin dose with CV death remained ( 40 ). Older patients with cognitive dysfunction may not benefit from intensive therapy. Furthermore, hypoglycemia in the elderly may cause cardiac ischemia, arrhythmia, myocardial infarction, and sudden death ( 41 ).

Sulfonylureas

Sulfonylureas lower blood glucose level by increasing insulin secretion in the pancreas by blocking the K ATP channels. They also limit gluconeogenesis in the liver. Sulfonylureas decrease breakdown of lipids to fatty acids and reduce clearance of insulin in the liver ( 42 ). Sulfonylureas are currently prescribed as second-line or add-on treatment options for management of T2DM. They are divided into two groups: first-generation agents, which includes chlorpropamide, tolazamide, and tolbutamide, and second-generation agents, which includes glipizide, glimepiride, and glyburide. The first-generation sulfonylureas are known to have longer half-lives, higher risk of hypoglycemia, and slower onset of action, as compared to second-generation sulfonylureas. Currently, in clinical practice, second-generation sulfonylureas are prescribed and more preferred over first-generation agents because they are proven to be more potent (given to patients at lower doses with less frequency), with the safest profile being that of glimepiride.

Hypoglycemia is the major side effect of all sulfonylureas, while minor side effects such as headache, dizziness, nausea, hypersensitivity reactions, and weight gain are also common. Sulfonylureas are contraindicated in patients with hepatic and renal diseases and are also contraindicated in pregnant patients due to the possible prolonged hypoglycemic effect to infants. Drugs that can prolong the effect of sulfonylureas such as aspirin, allopurinol, sulfonamides, and fibrates must be used with caution to avoid hypoglycemia. Moreover, other oral antidiabetic medications or insulin can be used in combination with sulfonylurea and can substantially increase the risk of hypoglycemia.

Patients on beta-adrenergic antagonists for the management of hypertension can have hypoglycemia unawareness. Sulfonylureas should be used with caution in subjects receiving beta blockers.

Meglitinide

Meglitinides (repaglinide and nateglinide) are non-sulfonylurea secretagogues, which was approved as treatment for T2DM in 1997. Meglitinide shares the same mechanism as that of sulfonylureas; it also binds to the sulfonylurea receptor in β-cells of the pancreas. However, the binding of meglitinide to the receptor is weaker than sulfonylurea, and thus considered short-acting insulin secretagogues, which gives flexibility in its administration. Also, a higher blood sugar level is needed before it can stimulate β-cells’ insulin secretion, making it less effective than sulfonylurea. Rapid-acting secretagogues (meglitinides) may be used in lieu of sulfonylureas in patients with irregular meal schedules or those who develop late postprandial hypoglycemia while using a sulfonylurea.

Thiazolidinedione

Like biguanides, TZDs improve insulin action. Rosiglitazone and pioglitazone are representative agents. TZDs are agonists of PPAR and facilitate increased glucose uptake in numerous tissues including adipose, muscle, and liver. Mechanisms of action include diminution of free fatty acid accumulation, reduction in inflammatory cytokines, rising adiponectin levels, and preservation of β-cell integrity and function, all leading to improvement of insulin resistance and β-cell exhaustion. However, there are high concerns of risks overcoming the benefits. Namely, combined insulin-TZD therapy causes heart failure. Thus, TZDs are not preferred as first-line or even step-up therapy.

Other Glucose-Lowering Pharmacologic Agents

Pramlintide, an amylin analog, is an agent that delays gastric emptying, blunts pancreatic secretion of glucagon, and enhances satiety. It is a Food and Drug Administration (FDA)-approved therapy for use in adults with T1DM. Pramlintide induces weight loss and lowers insulin dose. Concurrent reduction of prandial insulin dosing is required to reduce the risk of severe hypoglycemia. Other medications that may lower blood sugar include bromocriptine, alpha-glucosidase inhibitors like voglibose and acarbose, and bile acid sequestrants like colesevelam. It may be noted that metformin sequesters bile acids in intestinal lumen and thus has a lipid-lowering effect, also the same mechanism may contribute to gas production and gastrointestinal disturbances.

Pharmacologic Management of Diabetes Complications

Important components of the Standards of Medical Care in Diabetes involves taking care of complications of diabetes and comorbidities including hypertension, atherosclerotic cardiovascular disease (ASCVD), dyslipidemia, hypercoagulopathy, endothelial cell dysfunction, nephropathy, and retinopathy. CVD is the most important cause of morbidity and mortality in patients with diabetes. The currently recommended goal blood pressure is ≤140/80 for patients with diabetes and hypertension. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers are the preferred antihypertensive medication ( 2 ). Optimal blood pressure and blood glucose control can effectively delay the progression of nephropathy and retinopathy in these patients. Patients with existing CVD should be continuously managed with aspirin, including providing primary prevention in subjects less than 50 years old. Patients with diabetes are also recommended to undergo annual lipid profile measurement, and those diagnosed with hyperlipidemia should be treated with statins with a low-density lipoprotein goal of <70 mg/dL ( 2 ). Moreover, it should be noted that an important aspect in the success of pharmacotherapy is patient’s adherence and compliance to medications; therefore, close and regular patient follow-up, monitoring, and education are necessary.

Glucose Monitoring

Self-monitoring of blood glucose and HbA1C are integral components of the standards of care in diabetes. They are designed to assess the effectiveness of a treatment plan and provide guidance in selecting appropriate medications and dosage/s ( 2 ). SMBG allows patients to assess their own response to medication, minimize the risk of hypoglycemia, and determine whether they are achieving glycemic control. Optimal glycemic control is achieved when FPG is 70–130 mg/dL, 2 h post prandial <180 mg/dL, and bedtime glucose is 90–150 mg/dL. However, testing six to eight times daily may burden patients and may result in non-compliance. Therefore, it is recommended to ensure that patients are properly instructed and are given regular evaluation and follow-up.

Self-monitoring of blood glucose is essential in patients with diabetes who are on intense insulin regimen (three to four injections of basal and prandial or insulin pump). It monitors and prevents hyperglycemia and possible side effect of hypoglycemia. Blood glucose level is usually checked prior to meals, prior to exercise, prior to driving, and at bedtime. Evidence is insufficient to prescribe SMBG for patients not receiving an intensive insulin regimen ( 26 ).

According to the current guideline, HbA1C level should be assessed regularly in all patients with diabetes. The frequency of HbA1C testing is flexible and depends primarily on the response of patients to therapy and the physician’s judgment. HbA1C testing is performed at least every 6 months for patients who are meeting treatment goals; for patients who are far from their glycemic goals, HbA1C testing may be performed more frequently.

Summary/Conclusion

Type 2 diabetes mellitus is one of the leading causes of renal failure, ASCVD, non-traumatic lower limb amputation, blindness, and death worldwide. It is a serious chronic medical condition that requires a multidisciplinary team approach, consisting of healthcare professionals, dietitians, patient educators, patients, and their families. Lifestyle intervention designed to manage body weight and treat obesity, as well as patient education, are essential for all patients with diabetes. Treatment options may be individualized and medication(s) chosen based on a patient’s risk factors, current HbA1C level, medication efficacy, ease of use, patient’s financial situation/insurance/costs, and risk of side effects such as hypoglycemia and weight gain. Effectiveness of therapy must be evaluated as frequent as possible using diagnostic blood tests (HbA1C), as well as monitoring for development of diabetic complications (e.g., retinopathy, nephropathy, neuropathy). Furthermore, aggressive efforts from physicians and motivating patients for compliance are the two important aspects of the prevention and management of diabetes. Sociocultural issues should be carefully considered. For example, during religious fasting (e.g., during the holy month of Ramadan), the use of pharmacologic agents that induce hypoglycemia should be used with care and insulin doses (for example, premix formulations) should be appropriately titrated and the patient should be educated for blood glucose monitoring and breaking of fast as needed ( 43 ).

By the year 2030, >70% of people with T2DM shall reside in developing countries ( 44 ). Primary prevention of T2DM should be an urgent public health policy. The disease predominantly affects working-age people and therefore has a counterproductive economic impact, compounded by the frequent occurrence and interaction of T2DM with infectious diseases (such as AIDS and tuberculosis) ( 45 ). Evidence from landmark T2DM prevention trials indicates that lifestyle modification is more effective, cheaper, and safer than medication and provides sustained benefits. Lifestyle modification may be promising approach to T2DM prevention in developing countries. This will be useful for many ethnic groups in the U.S. as well, such as South Asian, Latino, Pima Indians, and African-American populations, which may face socioeconomic challenges similar to what is seen in developing countries. Cost-contained strategies to identify at-risk individuals, followed by the implementation of group-based, inexpensive lifestyle interventions (“comfortably uncomfortable” life, as lived by people in blue zones), seem to be the best options for resource-constrained settings. T2DM pathophysiology is increasingly understood as a mix of insulin resistance and secretory defects of β-cells ( 46 ).

Several options for pharmacologic therapy of lowering blood glucose are currently available, which have revolutionized long-term management of DM ( 47 ). Several antidiabetic drugs may have important CV complications, which the provider team should always be aware ( 48 ). The polypharmacy issues, management of diabetes, as well as hypertension, hyperlipidemia, and use of aspirin should be carefully explained to patients to ensure adherence to therapy to prevent significant CV morbidity and mortality. Careful attention should be paid to development of insulinopenic states by clinical assessment of C peptide and lack of control of HbA1C with multiple medications, and complete lack of secreted insulin conditions should be treated by initiation of appropriate insulin regimens. Every clinical encounter should also be utilized to explain the benefit of weight loss and motivated for such. Even though not yet conclusive, clinical trial and data support consideration of bariatric surgery as a possible strategy to monitor blood glucose levels and body weight, especially in morbid obesity ( 49 ). Balanced hypocaloric diets that cause weight loss must be adopted, and regular interactions with dietitian is a useful approach. Aerobic training and resistance training can control increasing lean mass in middle-aged and overweight/obese individuals. Behavioral strategies for weight loss should be encouraged in primary care settings and appropriate maintenance of body weight prior to conception may help after development of gestational diabetes. Weight loss may be particularly challenging for incapacitated patients and subjects with disabilities, so comprehensive approaches should be undertaken. Newer molecular studies have demonstrated the transcriptional link between inflammatory pathways and increased adipose tissue storage, contributing to insulin resistance ( 50 ). Drug repurposing of the anti-inflammatory agent for aphthous stomatitis, amlexanox, is currently undergoing trials as newer agents for management of diabetes ( 51 ).

Author Contributions

AC conceptualized and led project and drafted manuscript. CD checked accuracy of clinical contents and provided numerous clinical pearls. VSRD checked accuracy of clinical contents and numerous clinical discussions. SK contributed to numerous clinical pearls and revisions. AC contributed to important clinical discussions and revisions. RR contributed to important clinical discussions and revisions. AM contributed to important clinical contribution, especially management with coexistent chronic diseases. NSS contributed to clinical concepts and numerous clinical discussions. MTM prepared initial outline of some aspects of the manuscript. KK contributed to numerous clinical discussions. AS contributed to clinical discussions. AB checked grammar and formatted the initial table. NP contributed to initial discussions. CKM checked accuracy of clinical contents. GPL contributed to important clinical contents and numerous clinical guidance. WM contributed to overall senior mentorship and guidance and support to project.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Keywords: diabetes, clinical management, chronic, insulin, primary care

Citation: Chaudhury A, Duvoor C, Reddy Dendi VS, Kraleti S, Chada A, Ravilla R, Marco A, Shekhawat NS, Montales MT, Kuriakose K, Sasapu A, Beebe A, Patil N, Musham CK, Lohani GP and Mirza W (2017) Clinical Review of Antidiabetic Drugs: Implications for Type 2 Diabetes Mellitus Management. Front. Endocrinol. 8:6. doi: 10.3389/fendo.2017.00006

Received: 14 September 2016; Accepted: 09 January 2017; Published: 24 January 2017

Reviewed by:

Copyright: © 2017 Chaudhury, Duvoor, Reddy Dendi, Kraleti, Chada, Ravilla, Marco, Shekhawat, Montales, Kuriakose, Sasapu, Beebe, Patil, Musham, Lohani and Mirza. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Arun Chaudhury, arunchaudhury.boston@gmail.com ; Wasique Mirza, mirzaw@thewrightcenter.org

† These authors have contributed equally to this work.

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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• Benefits and harms of...

Benefits and harms of drug treatment for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials

• Related content
• Peer review
• Kailei Nong , master student 1 ,
• Per Olav Vandvik , professor 2 ,
• Gordon H Guyatt , professor 3 ,
• Oliver Schnell , professor 4 ,
• Lars Rydén , professor 5 ,
• Nikolaus Marx , professor 6 ,
• Frank C Brosius III , professor 7 ,
• Reem A Mustafa , nephrologist 8 ,
• Arnav Agarwal , internist 3 9 ,
• Xinyu Zou , masters student 1 ,
• Yunhe Mao , doctoral student 10 ,
• Aminreza Asadollahifar , methodologist 11 ,
• Saifur Rahman Chowdhury , methodologist 3 ,
• Chunjuan Zhai , cardiologist 12 ,
• Sana Gupta , methodologist 3 ,
• Ya Gao , methodologist 3 13 ,
• João Pedro Lima , methodologist 3 ,
• Kenji Numata , methodologist 14 ,
• Zhi Qiao , medical student 15 ,
• Qinlin Fan , masters student 1 ,
• Qinbo Yang , doctoral student 16 ,
• Yinghui Jin , methodologist 17 ,
• Long Ge , professor 18 ,
• Qiuyu Yang , master student 19 ,
• Hongfei Zhu , master student 20 ,
• Fan Yang , endocrinologist 21 ,
• Zhe Chen , doctoral student 22 ,
• Xi Lu , master student 1 ,
• Siyu He , medical student 23 ,
• Xiangyang Chen , endocrinologist 24 ,
• Xiafei Lyu , radiologist 25 ,
• Xingxing An , endocrinologist 1 ,
• Yaolong Chen , professor 18 ,
• Qiukui Hao , geriatrician 26 ,
• Eberhard Standl , professor 4 ,
• Reed Siemieniuk , methodologist 3 ,
• Thomas Agoritsas , professor 3 27 ,
• Haoming Tian , professor 1 ,
• 1 Department of Endocrinology and Metabolism, Division of Guideline and Rapid Recommendation, Cochrane China Centre, MAGIC China Centre, Chinese Evidence-Based Medicine Centre, West China Hospital, Sichuan University, Chengdu, China
• 2 Department of Medicine, Lovisenberg Diaconal Hospital, Oslo, Norway
• 3 Department of Health Research Methods, Evidence and Impact, McMaster University, ON, Canada
• 4 Forschergruppe Diabetes eV at the Helmholtz Centre, Munich-Neuherberg, Germany
• 5 Department of Medicine K2, Karolinska Institutet, Stockholm, Sweden
• 6 Clinic for Cardiology, Angiology, and Intensive Care Medicine, RWTH Aachen University, University Hospital Aachen, Aachen, Germany
• 7 Division of Nephrology, University of Arizona College of Medicine Tucson, Tucson, AZ, USA
• 8 Department of Internal Medicine, Division of Nephrology and Hypertension, University of Kansas, Kansas City, MI, USA
• 9 Department of Medicine, McMaster University, Hamilton, ON, Canada
• 10 Department of Orthopedics, Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, China
• 11 Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
• 12 Department of Cardiology, Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, China
• 13 Evidence-Based Medicine Centre, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
• 14 Department of Emergency Medicine, St Marianna University School of Medicine, Kawasaki, Japan
• 15 West China School of Medicine, Sichuan University, Chengdu, China
• 16 Department of Nephrology, National Clinical Research Centre for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
• 17 Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China
• 18 Evidence-Based Social Science Research Centre, School of Public Health, Lanzhou University, Lanzhou, China
• 19 Evidence-Based Nursing Centre, School of Nursing, Lanzhou University, Lanzhou, China
• 20 Department of Social Medicine and Health Management, School of Public Health, Lanzhou University, Lanzhou, China
• 21 Department of Endocrinology and Metabolism, Chengdu Fifth People’s Hospital, Chengdu, China
• 22 Evidence-Based Medicine Centre, Tianjin University of Traditional Chinese Medicine, Tianjin, China
• 23 Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu, China
• 24 Department of Endocrinology and Metabolism, First People’s Hospital of Shuangliu District, Chengdu, China
• 25 Department of Radiology, West China Hospital, Sichuan University, Chengdu, China
• 26 School of Rehabilitation Science, McMaster University, Hamilton, ON, Canada
• 27 Division of General Internal Medicine, Division of Clinical Epidemiology, University Hospitals of Geneva, Geneva, Switzerland
• Correspondence to: S Li lisheyu{at}gmail.com (or @LisheyuSheyu on Twitter)
• Accepted 1 March 2023

Objective To compare the benefits and harms of drug treatments for adults with type 2 diabetes, adding non-steroidal mineralocorticoid receptor antagonists (including finerenone) and tirzepatide (a dual glucose dependent insulinotropic polypeptide (GIP)/glucagon-like peptide-1 (GLP-1) receptor agonist) to previously existing treatment options.

Design Systematic review and network meta-analysis.

Data sources Ovid Medline, Embase, and Cochrane Central up to 14 October 2022.

Eligibility criteria for selecting studies Eligible randomised controlled trials compared drugs of interest in adults with type 2 diabetes. Eligible trials had a follow-up of 24 weeks or longer. Trials systematically comparing combinations of more than one drug treatment class with no drug, subgroup analyses of randomised controlled trials, and non-English language studies were deemed ineligible. Certainty of evidence was assessed following the GRADE (grading of recommendations, assessment, development and evaluation) approach.

Results The analysis identified 816 trials with 471 038 patients, together evaluating 13 different drug classes; all subsequent estimates refer to the comparison with standard treatments. Sodium glucose cotransporter-2 (SGLT-2) inhibitors (odds ratio 0.88, 95% confidence interval 0.83 to 0.94; high certainty) and GLP-1 receptor agonists (0.88, 0.82 to 0.93; high certainty) reduce all cause death; non-steroidal mineralocorticoid receptor antagonists, so far tested only with finerenone in patients with chronic kidney disease, probably reduce mortality (0.89, 0.79 to 1.00; moderate certainty); other drugs may not. The study confirmed the benefits of SGLT-2 inhibitors and GLP-1 receptor agonists in reducing cardiovascular death, non-fatal myocardial infarction, admission to hospital for heart failure, and end stage kidney disease. Finerenone probably reduces admissions to hospital for heart failure and end stage kidney disease, and possibly cardiovascular death. Only GLP-1 receptor agonists reduce non-fatal stroke; SGLT-2 inhibitors are superior to other drugs in reducing end stage kidney disease. GLP-1 receptor agonists and probably SGLT-2 inhibitors and tirzepatide improve quality of life. Reported harms were largely specific to drug class (eg, genital infections with SGLT-2 inhibitors, severe gastrointestinal adverse events with tirzepatide and GLP-1 receptor agonists, hyperkalaemia leading to admission to hospital with finerenone). Tirzepatide probably results in the largest reduction in body weight (mean difference −8.57 kg; moderate certainty). Basal insulin (mean difference 2.15 kg; moderate certainty) and thiazolidinediones (mean difference 2.81 kg; moderate certainty) probably result in the largest increases in body weight. Absolute benefits of SGLT-2 inhibitors, GLP-1 receptor agonists, and finerenone vary in people with type 2 diabetes, depending on baseline risks for cardiovascular and kidney outcomes ( https://matchit.magicevidence.org/230125dist-diabetes ).

Conclusions This network meta-analysis extends knowledge beyond confirming the substantial benefits with the use of SGLT-2 inhibitors and GLP-1 receptor agonists in reducing adverse cardiovascular and kidney outcomes and death by adding information on finerenone and tirzepatide. These findings highlight the need for continuous assessment of scientific progress to introduce cutting edge updates in clinical practice guidelines for people with type 2 diabetes.

Systematic review registration PROSPERO CRD42022325948.

Introduction

People with type 2 diabetes face an elevated risk of cardiovascular and kidney disease, resulting in impaired quality of life and reduced life expectancy. In the light of increased recognition of these risks and the failure of intensive glycaemic control to provide substantial risk reduction, regulatory agencies and researchers have increasingly shifted away from a glucose centric paradigm. Instead, reductions in cardiovascular disease and chronic kidney disease are now, through new and effective treatment options, priority treatment objectives. 1 Two classes of drugs, sodium glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, provide cardiovascular and kidney benefits, particularly in patients with established cardiovascular or kidney disease, 2 with trustworthy guidelines providing recommendations stratified by baseline risks. 2 3

Recently, two novel agents have become available to treat patients with type 2 diabetes: finerenone, a non-steroidal mineralocorticoid receptor antagonist, and tirzepatide, a dual glucose dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist. In two randomised trials looking at the cardiovascular outcomes of finerenone, findings suggested cardiovascular and kidney benefits in people with type 2 diabetes and chronic kidney disease, 4 5 while several randomised trials suggested benefits of tirzepatide in weight loss and quality of life. 6 7 8 9 10 A recent large non-industry funded trial has provided insight regarding older drugs for diabetes treatment, including sulfonylureas and basal insulin, by comparing their long term cardiovascular effects with liraglutide, a GLP-1 receptor agonist. 11 12 13

Clinicians now face the challenge of guiding their patients with type 2 diabetes in whether to add SGLT-2 inhibitors, GLP-1 receptor agonists, or finerenone and tirzepatide to their ongoing therapeutic regimens. Expanding on our previous large network meta-analysis 2 that focused on SGLT-2 inhibitors and GLP-1 receptor agonists, this synthesis of the best current evidence on clinically relevant benefits and harms of all available drugs for people with type 2 diabetes included finerenone and tirzepatide, which are new to clinicians. Beyond informing a current update of the BMJ Rapid Recommendations for diabetes drugs, we designed this network meta-analysis to inform professional societies and healthcare systems in updating their health technology assessments, clinical practice guidelines, and other decision support. 2 3

The taskforce of the guideline workshop (represented by OS, LR, NM, FCB, and ES), an international multidisciplinary team including endocrinologists, cardiologists, and nephrologists, 14 helped to formulate the clinical questions and provided input for the study protocol. The reports of this study followed the PRISMA (preferred reporting items for systematic reviews and meta-analyses) 2020 and PRISMA network meta-analysis statement standards. 15 16 A protocol detailing predefined eligibility criteria, which differed slightly from the previously published network meta-analysis, 2 was registered with PROSPERO (CRD42022325948).

Eligibility criteria

Eligible randomised controlled trials compared drugs used to treat adults with type 2 diabetes. We considered the following drug classes: SGLT-2 inhibitors, GLP-1 receptor agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, thiazolidinediones, sulfonylureas, metformin, α-glucosidase inhibitors, meglitinides, insulins, dual GIP/GLP-1 receptor agonists, and non-steroidal mineralocorticoid receptor antagonists. Appendix 1.3 describes the detailed drug names and definitions of control arms (typically standard treatment at the time the trials were conducted, representing the treatment regimens the patient received before the clinician considered adding a new drug). Eligible trials had a follow-up of 24 weeks or longer. Trials systematically comparing combinations of more than one drug treatment class with no drug treatment, subgroup analyses of randomised controlled trials, and non-English language studies were deemed ineligible.

Search strategy and information sources

We used comprehensive literature search strategies from previously published network meta-analyses in Ovid Medline, Embase, and Cochrane Central to 14 October 2022 (see appendix 1.1 for search strategies). The search added terms for non-steroidal mineralocorticoid receptor antagonists and dual GIP/GLP-1 receptor agonists. The search included reference lists of other identified systematic reviews evaluating cardiovascular and kidney outcomes associated with drugs of interest.

Study selection

The study performed a pilot test for the study selection process before screening. Pairs of reviewers (QS, KNo, QF, ZQ, and FY) independently screened identified hits at the title and abstract and full text levels, with discrepancies resolved by a senior reviewer (SL).

Data collection and data items

Using a standardised extraction form, the paired trained reviewers (QS, KNo, YM, QF, ZQ, XZ, XC, ZC, XL, and SH) independently extracted the following data:

Study characteristics (year, countries, setting, funding, length of follow-up);

Baseline characteristics of included participants (personal characteristics, number of participants, age, sex, body mass index, haemoglobin A1c (HbA1c), duration of diabetes, and complications or comorbidities including cardiovascular diseases, chronic kidney diseases, and obesity);

Interventions (drug name, dose, frequency, and cointerventions); and

Outcomes (trial specific definition, number of events and participants for binary outcomes, quality of life score change, and body weight change).

A senior reviewer (SL) resolved discrepancies. We prioritised study reported intention-to-treat results or modified intention-to-treat results over per protocol results.

Risk-of-bias assessment

Pairs of reviewers independently assessed the risk of bias (QS, KNo, LG, YJ, YM, AAs, CZ, JPL, KNu, SRC, SG, YG, HZ, QiuY, XL, QinY, and XA). The Cochrane risk-of-bias tool, modified by the CLARITY group at McMaster University, informed risk-of-bias assessments 17 for the following six domains: random sequence generation, allocation concealment, blinding to allocated interventions, missing outcome data, selective outcome reporting, and other concerns. Response options for each item were definitely yes (low risk of bias), probably yes, probably no, and no (high risk of bias). A third team (KNo, QinY, and QS) cross checked the pairs of assessments and summarised the final results, with residual discrepancies resolved by a senior reviewer (SL).

Outcomes and effect measures

We judged the following outcomes as critical: all cause death, cardiovascular death, non-fatal stroke, end stage kidney disease, and amputation; and the following outcomes as important: non-fatal myocardial infarction, admission to hospital for heart failure, body weight change, health related quality of life, severe hypoglycaemia, severe gastrointestinal events, genital infection, ketoacidosis due to diabetes, and hyperkalaemia leading to admission to hospital. We evaluated the impact on end stage kidney disease using a composite of long term dialysis, kidney transplantation, a sustained estimated glomerular filtration rate <15 mL per minute per 1.73 m 2 , a sustained percentage decline in estimated glomerular filtration rate of at least 40% or a doubling of serum creatinine, or kidney related death. 18 Appendix 1.2 details the definition of outcomes.

We measured the binary outcomes using odds ratios. For continuous outcomes, we measured health related quality of life as standardised mean difference, and body weight in kg as mean difference.

Data synthesis

We conducted random effect network meta-analysis using a frequentist graph theoretical approach with the weighted least square estimator and Moore-Penrose pseudoinverse. 19 In principle, we started with the assumption that relative effects were similar across drugs in the same class unless evidence indicated otherwise, and the network nodes are therefore in most cases grouped into drug classes based on their mechanisms. The sole exception in which evidence suggests the starting assumption is inaccurate is the impact of GLP-1 receptor agonists on body weight change. 20 The analysis used the continuity correction to account for zero event by adding 0.5 to all cells of groups for the trials with at least one zero event. 21 The global heterogeneity was evaluated with generalised methods of moments estimate of variance between studies and tested by the design based decomposition of Cochran’s Q statistic. 22 We calculated indirect estimates from the network by node splitting and back calculation methods. 23 For each network loop, we judged the local incoherence considering the clinical and statistical significance of the ratio of direct and indirect estimates. Comparison adjusted funnel plots evaluated global small study effects, which could reflect publication bias. We judged the intransitivity based on distribution comparisons of potential effect modifiers (ie, baseline age, sex, body mass index, HbA1c, the proportion of cardiovascular disease, and duration of diabetes) for each direct comparison and outcome, as well as meta-regressions of these parameters with the treatment effect for each drug and outcome.

We performed sensitivity analyses, including a bayesian network meta-analysis adjusted by trial duration 24 ; a Mantel-Haenszel fixed effect network meta-analysis for rare events 25 ; a meta-analysis excluding trials with high risks of bias; a meta-analysis for end stage kidney disease that restricted the definition to a composite of long term dialysis, kidney transplantation, and death from kidney failure; a meta-analysis excluding phase 2 or phase 3 trials; and a meta-analysis pooling study reported hazard ratios for the trials with ≥2 years’ follow-up.

Meta-regression

For trial and aggregated patient characteristics measured as continuous variables, we performed the following four meta-regressions:

Proportion of patients with established cardiovascular diseases (hypothesising a larger relative effect in reducing death and cardiovascular and kidney outcomes in trials with a higher proportion of patients with cardiovascular diseases).

Mean patients’ estimated glomerular filtration rate at baseline (hypothesising a larger relative effect in reducing death and cardiovascular and kidney outcomes in patients with lower estimated glomerular filtration rate).

Mean patients’ body mass index at baseline (hypothesising a larger relative effect in reducing death and cardiovascular and kidney outcomes in patients with higher body mass index).

Trial follow-up length (hypothesising a larger relative effect in reducing death and cardiovascular and kidney outcomes in studies with longer follow-up).

The credibility of any apparent subgroup effect (regression coefficient’s credible interval excludes null effect) was rated using the ICEMAN tool. 26 If no credible subgroup effect was indicated, we assumed the constancy of relative effects across populations.

GRADE certainty of evidence assessment

Following GRADE (grading of recommendations assessment, development and evaluation) guidance, evidence from direct comparisons started as high certainty evidence and could be rated down for risk of bias, inconsistency, indirectness, and publication bias. 27 Evidence from indirect comparisons could be further rated down for intransitivity. A contribution matrix quantified the proportional contribution of each direct comparison with each indirect and network comparison using the random walk approach. 28 The final certainty for network evidence was rated down for incoherence or imprecision. 29 We rated imprecision following the GRADE guidance. 30 When point estimates proved less than specified minimal important differences established by a previous guideline panel, 3 we rated certainty in little or no effect, otherwise in non-zero effect (ie, null effect threshold). We rated down for imprecision by two levels when the 95% confidence interval crossed more than one threshold of importance (appendices 1.4 and 5). 31

To categorise the relative impact of interventions, we chose the null effect as the decision threshold and standard treatments as the reference intervention. 32 33 We initially categorised treatments as different or not different from standard treatments, and subsequently as different or not different from at least one of those with an established difference from standard treatments. This process established five categories of interventions from among the best to among the worst. We then separated these drugs as high or moderate versus low or very low certainty of evidence according to the certainty of evidence relative to standard treatments.

Absolute effect estimations

To better inform clinical decision making, we estimated the anticipated absolute effects of all drugs on the cardiovascular, kidney, and safety outcomes. If valid, we adopted baseline risk estimates applied in a clinical practice guideline that included a systematic review of risk prediction models. 34 We calculated the absolute benefits (number of events per 1000 patients in five years) by applying the relative effects to the baseline risks in five tiers of adults with type 2 diabetes at varying risks of cardiovascular and kidney outcomes: three or fewer cardiovascular risk factors, more than three cardiovascular risk factors, established cardiovascular disease but not chronic kidney disease, established chronic kidney disease but not cardiovascular disease, and established cardiovascular disease and chronic kidney disease. For outcomes not included in the guideline we anticipated baseline risks by pooling the incidence rate in the control arm across trials via the random effect single arm meta-analysis (appendix 5.3), not further stratified by individual risk profiles (eg, risk of genital infections).

Given the complexity of presenting 9770 estimates of effect from this network meta-analysis, we elected to primarily present relative and absolute estimates of effect, certainty, and more detailed network meta-analysis results (eg, number of participants and trials for each comparison) through an interactive GRADE summary of findings table, the MATCH-IT tool ( https://matchit.magicevidence.org/230125dist-diabetes ). This tool also allows end users to compare any of the treatment options, including change of comparator (eg, finerenone v SGLT-2 inhibitors or GLP-1 receptor agonists for key cardiovascular and kidney outcomes).

Patient and public involvement

For the outcome selection and importance rating as well as the minimal important difference for each outcome, this systematic review referred to a previous guideline and its company systematic review, where the patient partners informed their values and preferences.

Study selection and study characteristics

The 816 trials that proved eligible enrolled 471 038 participants with a typical mean age in the late 50s, over 50% men, with a mean body mass index of about 30, and a mean HbA1c of about 8.0%. About 60% of the participants had confirmed cardiovascular disease at baseline ( fig 1 , table 1 , appendix 2.1, and appendix 2.2).

Flow diagram for trial screen and selection. MRA=non-steroidal mineralocorticoid receptor antagonists; GIP/GLP-1=glucose dependent insulinotropic polypeptide/glucagon-like peptide-1. *Previous review refers to reference 2

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Baseline characteristics of included trials and participants

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Risk of bias, global inconsistency, global publication bias, intransitivity, and incoherence

Of the 816 trials, 223 proved at high risk of bias for at least one of six domains, most commonly because of lack of blinding (62%), missing outcome data (26%), and allocation concealment (25%) (appendix 3). The evidence did not suggest global publication bias and intransitivity for any outcome (appendix 4.7), nor did the results suggest relevant global inconsistency or incoherence in outcomes except for health related quality of life, body weight change, and amputation (appendices 4.4, 4.5, and 4.6).

Comparative effectiveness of drugs

Figure 2 shows the network plot with connections between each drug in all included trials for any outcome, appendix 4.1 shows other network plots for each outcome, and appendix 4.3 shows the network estimates with certainty of evidence for each comparison for each outcome. Appendix 5 details the assessments of GRADE certainty of evidence for the direct, indirect, and network comparisons. Figure 3 shows the comparative benefits and harms (excluding weight change, see below) of all drugs of interest through their relative estimates of effect, categorised from the most effective to the most harmful, taking certainty of evidence into account. Figure 4 illustrates the anticipated absolute benefits and harms of all drugs for adults with type 2 diabetes and chronic kidney disease (selected because randomised trials on finerenone were restricted to this population). Figure 5 shows the effects of these drugs on weight change.

Network plot for all included studies, by drug treatments. Drug treatments were grouped by their drug classes. Network plots consist of the drug nodes with node size being proportional to the sample size and the comparison edges with line thickness being proportional to the number of trials. MRA=non-steroidal mineralocorticoid receptor antagonists; GLP-1=glucagon-like peptide-1; SGLT-2=sodium glucose cotransporter-2; DPP-4=dipeptidyl peptidase-4

Benefits and harms of drug treatments for type 2 diabetes. Figure shows benefits and harms of the drugs for diabetes with the estimates that represent the comparative effects of the drugs compared with standard treatments. The GRADE (grading of recommendations, assessment, development, and evaluations) approach was used with a null effect threshold to rate and categorise drugs from among the most effective to among the most harmful. Any 95% confidence intervals touching but not crossing the decision threshold (ie, the null effect), were not rated down for imprecision. Drugs that were superior to (or inferior to) standard treatments (ie, point estimate exceeding (or falling below) the null effect and the 95% confidence interval not crossing) were first categorised into the most effective group (or the most harmful group). Drugs among the most effective (or most harmful) but inferior to (ie, point estimate falling below and 95% confidence interval not crossing) at least one drug in that group were then categorised into the intermediate effective group (or the intermediate harmful group). Non-steroidal mineralocorticoid receptor antagonists (MRAs) mainly refer to finerenone. *End stage kidney disease was defined as a composite of a long term dialysis, kidney transplantation, sustained estimated glomerular filtration rate <15 mL per min per 1.73 m 2 for ≥30 days, sustained percent decline in estimated glomerular filtration rate of at least 40% for ≥30 days or a doubling of serum creatinine, or renal death; effects on end stage kidney disease were rated down owing to indirectness. CI=confidence interval; GLP-1=glucagon-like peptide-1; OR=odds ratio; SGLT-2=sodium glucose cotransporter-2

Anticipated absolute effects for patients with type 2 diabetes and chronic kidney disease, by drug treatment. Figure shows absolute benefits and harms of the drugs for patients with type 2 diabetes and chronic kidney disease. Estimates represent risk differences per 1000 patients in five years compared with standard treatments. Absolute effects were anticipated by applying the relative effects to the baseline risks adopted from a previous guideline panel. Figure is restricted to adults with type 2 diabetes and chronic kidney disease as an example, with the full populations in appendix 6 and the online tool ( https://qingys.shinyapps.io/data_visualization ) or the MATCH-IT tool ( https://matchit.magicevidence.org/230125dist-diabetes ). Non-steroidal mineralocorticoid receptor antagonists (MRAs) mainly refer to finerenone. GLP-1=glucagon-like peptide-1; SGLT-2=sodium glucose cotransporter-2

Body weight impact of drug treatment for type 2 diabetes by drug treatment. Figure shows body weight changes of the drugs for diabetes with the estimates that represent the comparative effects of the drugs compared with standard treatments. The GRADE (grading of recommendations, assessment, development, and evaluations) approach was used with a null effect threshold to rate and categorise drugs from among the most effective to among the most harmful. Any 95% confidence intervals touching but not crossing the decision threshold (ie, the null effect) were not rated down for imprecision. Drugs that were superior to (or inferior to) standard treatments (ie, point estimate exceeding (or falling below) the null effect and the 95% confidence interval not crossing) were first categorised into the most effective group (or the most harmful group). Drugs among the most effective (or the most harmful) but inferior to (ie, point estimate falling below and 95% confidence interval not crossing) at least one drug in that group were then categorised into the intermediate effective group (or the intermediate harmful group). CI=confidence interval; DPP-4=dipeptidyl peptidase-4; MD=mean difference; SGLT-2=sodium glucose cotransporter-2

The MATCH-IT tool ( https://matchit.magicevidence.org/230125dist-diabetes ) provides an interactive view of the anticipated absolute effects for all populations at varying risks of cardiovascular and kidney outcomes. These data are also available in appendix 6 and - with even more details, in another interactive online tool ( https://qingys.shinyapps.io/data_visualization ). Below, we summarise the relative effects for cardiovascular, kidney, and harm outcomes for all drugs and provide examples of anticipated absolute effects for selected outcomes; all subsequent estimates refer to the comparison with standard treatments.

All cause death and cardiovascular death

The analysis included 257 trials with 342 237 participants and 15 371 events for all cause mortality, and 144 trials with 275 679 participants and 9120 events for cardiovascular death. SGLT-2 inhibitors (odds ratio 0.88, 95% confidence interval 0.83 to 0.94; high certainty) and GLP-1 receptor agonists (0.88, 0.82 to 0.93; high certainty) reduce all cause mortality, and cardiovascular death (SGLT-2 inhibitors: 0.86, 0.80 to 0.94; GLP-1 receptor agonists: 0.87, 0.81 to 0.94; both high certainty). Non-steroidal mineralocorticoid receptor antagonists probably reduce all cause mortality (0.89, 0.79 to 1.00; moderate certainty) and possibly reduce cardiovascular death (0.88, 0.75 to 1.02; low certainty). Metformin possibly reduces all cause mortality (0.84, 0.67 to 1.04; low certainty) and might have little or no effect on cardiovascular death. DPP-4 inhibitors probably have little or no effect on cardiovascular death (moderate certainty). Sulfonylureas possibly increase all cause mortality (low certainty) and might have little or no effect on cardiovascular death. Other drugs might have little or no or uncertain effect on mortal outcomes (low to very low certainty; fig 3 and appendix 5).

Non-fatal myocardial infarction and non-fatal stroke

This analysis included 209 trials with 293 042 participants and 8906 events for non-fatal myocardial infarction, and 178 trials with 283 728 participants and 4878 events for non-fatal stroke. SGLT-2 inhibitors reduce non-fatal myocardial infarction (odds ratio 0.90, 95% confidence interval 0.82 to 0.98; high certainty)—as, probably, do GLP-1 receptor agonists (0.91, 0.85 to 0.98; moderate certainty) and, possibly, metformin (0.86, 0.68 to 1.09; low certainty). GLP-1 receptor agonists are the only drug class that convincingly reduces non-fatal stroke (0.85, 0.77 to 0.94; high certainty). Other drugs might have little or no or uncertain effects on non-fatal myocardial infarction or stroke, relative to standard treatments (low to very low certainty; fig 3 and appendix 5).

Admission to hospital for heart failure

The analysis included 142 trials with 252 055 participants and 6681 events. SGLT-2 inhibitors (odds ratio 0.66, 95% confidence interval 0.60 to 0.73; high certainty) decrease admission to hospital for heart failure as, probably, do GLP-1 receptor agonists (0.91, 0.83 to 0.99; moderate certainty) and finerenone (0.78, 0.66 to 0.92; moderate certainty). SGLT-2 inhibitors and finerenone are among the most effective drugs in this regard and SGLT-2 inhibitors are probably superior to GLP-1 receptor agonists (moderate certainty). Thiazolidinediones probably increase admission to hospital due to heart failure (1.54, 1.27 to 1.88; moderate certainty). Metformin and other drugs might have little or no effect, or uncertain effects (low or very low certainty; fig 3 and appendix 5).

End stage kidney disease

The analysis included 54 trials with 209 754 participants and 6972 events. Compared with standard treatments, SGLT-2 inhibitors (odds ratio 0.61, 95% confidence interval 0.55 to 0.67; moderate certainty), GLP-1 receptor agonists (0.83, 0.75 to 0.92; moderate certainty), and finerenone (0.83, 0.75 to 0.92; moderate certainty) probably reduce end stage kidney disease. We rated down the certainty of evidence to moderate owing to indirectness, a result of our composite outcome of end stage kidney disease driven by variable reporting of kidney outcomes in the trials. SGLT-2 inhibitors are among the most effective drugs and are possibly superior to GLP-1 receptor agonists and finerenone (low certainty). Other drugs might have little or no effect, or uncertain effects on end stage kidney disease, relative to standard treatment (very low to low certainty; fig 3 and appendix 5).

Health related quality of life

We analysed 33 trials with 18 588 participants using 13 types of questionaries (appendix 1.2). SGLT-2 inhibitors, GLP-1 receptor agonists, and tirzepatide probably improve health related quality of life with standardised mean differences ranging from 0.17 to 0.39 (moderate certainty), which did not surpass the minimal important difference (1.7 to 3.9 points in the 36-item short form survey; minimal important difference 10 points). DPP-4 inhibitors probably have little or no effect, and other drugs might have little or uncertain impact on health related quality of life (low or very low certainty; fig 3 and appendix 5).

Body weight change

We analysed 531 trials with 279 118 participants. Figure 5 shows that tirzepatide is the most effective drug for reducing body weight (mean reduction 8.57 kg, 95% confidence interval 7.75 to 9.40), followed by individual GLP-1 receptor agonists, SGLT-2 inhibitors (class effect), and metformin with intermediate effects (mean reduction, range 4.62 to 0.72 kg), all high to moderate certainty). Two classes of drugs probably have the biggest effect size in increasing body weight: thiazolidinediones (2.81 kg, moderate certainty) and basal insulin (2.15 kg, moderate certainty). A third, basal bolus insulin, may have a similar effect (increase 3.26 kg, low certainty). Another four drugs have intermediate effects on body weight: sulfonylureas probably increase body weight by 1.78 kg (moderate certainty), meglitinides may increase body weight by 1.26 kg (low certainty), bolus insulin probably increases body weight by 1.01 kg (moderate certainty), and DPP-4 inhibitors probably increase body weight minimally by 0.28 kg (moderate certainty). Other drugs might have little or no effect on body weight (low to very low certainty; fig 5 and appendix 5).

Severe hypoglycaemia

We analysed 202 trials with 302 457 participants and 5595 events. Sulfonylureas (odds ratio 5.22, 95% confidence interval 3.88 to 7.01) and basal bolus insulin (4.94, 1.06 to 22.96) probably increase the risk of severe hypoglycaemic events (moderate certainty), with likely smaller increases in risk with basal insulin (2.38, 1.82 to 3.12), bolus insulin (2.46, 1.31 to 4.63), and DPP-4 inhibitors (1.11, 1.00 to 1.23), with and without the contamination of other treatments. Meglitinides and thiazolidinediones may increase the risk of severe hypoglycaemic events (low certainty). SGLT-2 inhibitors and GLP-1 receptor agonists do not increase the risk of severe hypoglycaemic events (high certainty). Finerenone is probably associated with fewer severe hypoglycaemia than the standard treatments (0.64, 0.43 to 0.96, moderate certainty). Other drugs might have little to no effect compared with standard treatments (low to very low certainty; fig 3 and appendix 5).

Severe gastrointestinal events

We analysed 37 trials with 65 283 participants and 1661 events. Tirzapetide (odds ratio 4.59, 95% confidence interval 1.89 to 11.14) and GLP-1 receptor agonists (1.97, 1.39 to 2.80) probably increase the risk of severe gastrointestinal adverse events (moderate certainty). Other drugs might have little or no effects compared with standard treatments (low to very low certainty; fig 3 and appendix 5).

Genital infection

We analysed 94 trials with 103 111 participants and 2396 events. SGLT-2 inhibitors increase genital infection (odds ratio 3.30, 95% confidence interval 2.88 to 3.78; high certainty). Sulfonylureas may reduce the risk of a genital infection (0.52, 0.36 to 0.75; low certainty). Other drugs might have little to no effect compared with standard treatments (low to very low certainty; fig 3 and appendix 5).

We analysed 18 trials with 107 503 participants and 1150 events. SGLT-2 inhibitors probably increase the risk of amputation (odds ratio 1.27, 95% confidence interval 1.01 to 1.61, moderate certainty); other drugs do not (high to very low certainty; fig 3 and appendix 5). With an estimated baseline risk of 1%, treatment with SGLT-2 inhibitors in 1000 patients for five years probably results in three additional amputations (95% confidence interval 0 to 6; fig 4 and appendix 6).

Ketoacidosis due to diabetes

We analysed 36 trials with 138 322 participants and 265 events. SGLT-2 inhibitors increase the risk of ketoacidosis due to diabetes (odds ratio 2.07, 95% confidence interval 1.44 to 2.98; high certainty); other drugs do not (high to very low certainty; fig 3 and appendix 5). With an estimated baseline risk of 0.2%, treatment with SGLT-2 inhibitors in 1000 patients for five years probably results in two more events with ketoacidosis due to diabetes (95% confidence interval 1 to 4; fig 4 and appendix 6).

Hyperkalaemia leading to admission to hospital

We analysed two trials with 12 999 participants and 71 events for the non-steroidal mineralocorticoid receptor antagonists, which probably increase the risk of hyperkalaemia leading to admission to hospital (odds ratio 5.92, 95% confidence interval 3.02 to 11.62; moderate certainty). With an estimated baseline risk of 0.2%, treatment with non-steroidal mineralocorticoid receptor antagonists in 1000 patients for five years probably results in 10 additional events (95% confidence interval 4 to 21; fig 4 and appendix 6).

Subgroup analyses and sensitivity analyses

Our study did not identify any credible subgroup effects (appendix 7) and all sensitivity analyses confirmed the robustness of our findings (appendix 8).

Principal findings

This network meta-analysis comprehensively summarises the benefits and harms of available drug treatments for type 2 diabetes, including the two recently available drugs finerenone and tirzepatide. Among all drug classes, SGLT-2 inhibitors, GLP-1 receptor agonists, and finerenone show benefits in reducing all cause mortality, admission to hospital due to heart failure (SGLT-2 inhibitors and—probably—finerenone are the most effective drug treatments), and end stage kidney disease (SGLT-2 inhibitors are the most effective drug treatments). Only GLP-1 receptor agonists convincingly reduce non-fatal stroke. SGLT-2 inhibitors, GLP-1 receptor agonists, and tirzepatide improve health related quality of life, but did not reach the threshold for minimal important differences, suggesting trivial effects. As illustrated in the MATCH-IT tool, the absolute benefits of these drugs vary greatly in people with type 2 diabetes depending on baseline risks for cardiovascular and kidney outcomes 2 3 (appendix 6). Trustworthy clinical practice guidelines should provide risk stratified recommendations that could differ in direction and strength, reserving these drugs to adults at elevated risk for cardiovascular and kidney outcomes. 3

Strengths and limitations

Our work represents the most comprehensive systematic review and network meta-analysis assessing all pertinent drug classes for type 2 diabetes treatment. An international multidisciplinary team shaped the study question and protocol, optimising its relevance to current clinical practice. Our study incorporated current and rigorous approaches to network meta-analysiss and GRADE assessment. 31 32 Results provide policy makers and healthcare professionals with quick access to summaries of the effectiveness and safety of all available drug classes for diabetes treatments.

Limitations of our systematic review and network meta-analysis are largely driven by the available evidence. Firstly, for many outcomes that are important to patients, we found low to very low certainty evidence for the oldest as well as the newest classes of drugs, including metformin, sulfonylureas, tirzepatide, and non-steroidal mineralocorticoid receptor antagonists. Secondly, this network meta-analysis cannot answer a highly relevant question: what are the benefits and harms of coadministration of SGLT-2 inhibitors, GLP1 receptor agonists, and finerenone? Nevertheless, observational studies and post hoc analyses of trials suggest cardiovascular and kidney benefits of the combination of SGLT-2 inhibitors, finerenone, and GLP-1 receptor agonists. 35 36 Thirdly, owing to sparse direct evidence and limited reporting of outcomes important to patients, we adopted a composite outcome definition for end stage kidney disease that included a surrogate component. This resulted in moderate certainty of evidence for the effects of all drugs on end stage kidney disease, given the inherent indirectness. Fourthly, this study did not consider the dose-response of each drug. In future studies it could be interesting to explore potential dose-response effects for drugs such as GLP-1 receptor agonists. Fifthly, the exclusion of all non-English language literature might introduce potential publication bias, which in this study was adjusted by trim-and-fill analyses.

Clinical interpretation

Finerenone is the first non-steroidal mineralocorticoid receptor antagonist likely to reduce all cause mortality and admission to hospital for heart failure and improve kidney outcomes in people living with type 2 diabetes. Finerenone is an alternative to SGLT-2 inhibitors and GLP-1 receptor agonists in patients with concomitant chronic kidney disease, but results provide only indirect evidence for other populations. 4 5 A recent analysis, however, suggests that the relative effect on all cause mortality of finerenone is not associated with either baseline estimated glomerular filtration rate or urine albumin-creatinine ratio; thus, effects of finerenone could also apply to patients with type 2 diabetes without chronic kidney disease. 37 38 Regarding the use of finerenone in patients without diabetes or kidney disease, an ongoing cardiovascular outcome trial of participants with congestive heart failure with or without type 2 diabetes or chronic kidney disease (FINEARTS-HF) is expected to conclude in 2024 and will provide relevant evidence. 39

Although finerenone results in a fivefold relative increase in hyperkalaemia leading to admission to hospital, the absolute numbers of admissions to hospitals were very low. The absolute effects of hyperkalaemia (10 additional events per 1000 patients treated for five years) are, for most patients with type 2 diabetes and chronic kidney disease, of less importance than the benefits of 16 fewer deaths, 21 fewer admissions to hospital for heart failure, and 14 fewer cases of end stage kidney disease. Nevertheless, for patients at elevated baseline risk of hyperkalaemia, clinicians should closely monitor serum potassium when prescribing finerenone. Such patients include those taking drug treatments that could elevate serum potassium such as angiotensin converting enzyme inhibitors, angiotensin receptor blockers, and angiotensin receptor-neprilysin inhibitors. 40

Tirzepatide, the only dual GIP/GLP-1 receptor agonist currently available, improves quality of life and reduces body weight with a greater effect than any other drugs or drug classes. GLP-1 receptor agonists also reduce body weight, with semaglutide being the most effective drug in people with type 2 diabetes, as previously established in patients with overweight and obesity. 20 Whereas tirzepatide might be particularly attractive for people with type 2 diabetes seeking body weight loss, we could not show its benefits for cardiovascular and kidney outcomes; these are being explored in an ongoing cardiovascular outcome trial with results expected in 2025. 41 GLP-1 receptor agonists are safe except that an average of 40 patients per 1000 withdraw from these drug treatments because of severe gastrointestinal adverse events. Tirzepatide also causes 133 patients per 1000 to withdraw owing to severe gastrointestinal adverse events. These findings exemplify the need to carefully balance benefits and harms across all patient outcomes for new diabetes drugs, individualised to patients’ characteristics, values, and preferences.

Our results raise concerns about the use of some well established drugs for glucose lowering in adults with type 2 diabetes. In particular, sulfonylureas may increase all cause mortality (low certainty), and thiazolidinediones probably increase admission to hospital due to heart failure (moderate certainty). Clinicians should be cautious in prescribing these drugs, especially to those at higher baseline risks for such outcomes. An additional new finding in our review is that DPP-4 inhibitors, in addition to sulfonylurea and insulin, show a probable intermediate increased risk of severe hypoglycaemia (moderate certainty). Since laboratory studies do not support the hypoglycaemic risk caused by the monotherapy of DPP-4 inhibitors, 42 for people receiving combined therapy, clinicians should consider reducing the dose of insulin or sulfonylureas when adding these drugs.

Consistent with previous systematic reviews, 2 43 44 SGLT-2 inhibitors increase the risk of genital infection, ketoacidosis due to diabetes, and, probably, amputation. The minimal absolute increase we have estimated (two additional ketoacidoses and three additional amputations among 1000 people treated with SGLT-2 inhibitors for five years) warrants a trade-off against established cardiovascular and kidney benefits, again most pronounced in patients at increased cardiorenal risk. This finding is in line with the decision made in 2020 by the US Food and Drug Administration to remove the boxed warning for canagliflozin.

Conclusions

Keeping pace with the growing number of published randomised trials in adults with type 2 diabetes, this network meta-analysis finds highly heterogeneous benefits and drug specific harms across 13 drug classes. Beyond confirming the substantial cardiovascular and kidney benefits of SGLT-2 inhibitors and GLP-1 receptor agonists—with absolute effects highly dependent on patient risk profiles—we find that finerenone, the drug recently made available, displays quite similar benefits to SGLT-2 inhibitors and GLP-1 receptor agonists. Tirzepatide shows superior benefits on weight loss than SGLT-2 inhibitors and GLP-1 receptor agonists. These results and other key findings of our comprehensive systematic review highlight the need for continuous assessment of scientific progress to introduce cutting edge updates in clinical practice guidelines for people with type 2 diabetes.

What is already known on this topic

Sodium glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists have proven benefits in cardiovascular and kidney outcomes, with some notable differences in outcomes such as heart failure and stroke

Recent randomised trials report both cardiovascular and kidney benefits with finerenone, a novel non-steroidal mineralocorticoid receptor antagonist, and improvements in quality of life and weight loss with tirzepatide, a dual glucose dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist

What this study adds

Compared with standard treatments, adding finerenone probably reduces all cause mortality, admission to hospital for heart failure, and end stage kidney disease, while adding tirzepatide could reduce body weight

Compared with standard treatments, findings indicate that adding SGLT-2 inhibitors or GLP-1 receptor agonists reduces all cause mortality, cardiovascular death, non-fatal myocardial infarction, admission to hospital for heart failure, and end stage kidney disease, while adding only GLP-1 receptor agonists reduces non-fatal stroke

Compared with standard treatments, adding metformin possibly reduces all cause mortality and non-fatal myocardial infarction, adding sulfonylureas possibly increases all cause mortality, and adding thiazolidinediones probably increases admission to hospital due to heart failure

Ethics statements

Ethical approval.

Not required.

Data availability statement

No additional data available.

Acknowledgments

We thank Suetonia Palmer from the University of Otago for kindly sharing the original data from her previous systematic review to support this study, as well as for her helpful comments on the protocol; the further members of the taskforce of the guideline workshop, who helped formulate the clinical questions and provided input into the study protocol (Tadej Battelino, Antonio Ceriello, Francesco Cosentino, Jennifer Green, Linong Ji, Monika Kellerer, Sue Koob, Mikhail Kosiborod, Nebojsa Lalic, Prashant Nedungadi, and Helena Rodbard); and Frankie Achille for developing the MATCH-IT tool for this network meta-analysis.

Contributors: QS and KNo contributed equally to this study. QS, SL, POV, GHG, OS, FCB, LR, NM, ES, QH, RAM, RS, TA, and HT conceived and designed the study. SL, POV, GHG, OS, FCB, LR, NM, ES, QH, RAM, AAg, and HT discussed and drafted the study protocol. QS, KNo, QF, ZQ, and FY screened and selected the articles. QS, KNo, YM, QF, ZQ, XZ, XC, ZC, XL, and SH extracted the data. QS, KNo, LG, YJ, YM, AAs, CZ, JPL, KNu, SRC, SG, YG, HZ, QiuY, XL, QinY, and XA assessed the risk of bias of included trials. QS analysed the data. QS, KNo, SL, and GHG rated and revised the GRADE certainty of evidence. QS, SL, POV, GHG, OS, FCB, LR, NM, ES, RAM, AAg, RS, YC, and TA interpreted the results. QS, SL, and GHG drafted the manuscript. QS, SL, GHG, POV, OS, FCB, LR, NM, ES, RAM, and AAg critically revised the manuscript. All authors contributed to revising the manuscript. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication. SL, POV, GHG, OS, FCB, LR, NM, ES, QH, RAM, RS, TA, and HT supervised the study. SL is the guarantor. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

Funding: This study is supported by the Sichuan Science and Technology Programme (grant 2022YFH0114) and 1.3.5 Clinical Research Incubation Project, West China Hospital, Sichuan University (grant 2020HXF011). The funders had no role in considering the study design or in the collection, analysis, interpretation of data, writing of the report, or decision to submit the article for publication.

Competing interests: All authors have completed the ICMJE uniform disclosure form at https://www.icmje.org/disclosure-of-interest/ and declare: support from Sichuan Science and Technology Bureau and West China Hospital, Sichuan University for the submitted work; QS, KNo, POV, AAg, TA, RS, QH, QF, ZQ, FY, XZ, XC, YJ, LG, YM, QinY, AAs, CZ, JPL, KNu, SRC, SG, YG, XL, QiuY, HZ, XA, ZC, XL, SH, YC, HT, and GHG received no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work. ES reported personal fees from Oxford Diabetes Trials Unit, Bayer, Berlin Chemie, Boehringer Ingelheim, Menarini, Merck Serono, EXCEMED, Novartis, Novo Nordisk, and Sanofi. LR reported grants or contracts from Swedish Heart Lung Foundation, Stockholm County Council, Erling Perssons Foundation, and Boehringer-Ingelheim, and payment or honorariums for lectures, presentations, speakers bureaus, manuscript writing or educational events from Bayer AG, Boehringer Ingelheim, and Novo Nordisk. FCB reported grants or contracts from National Institutes of Health, and consulting fees from Gilead Sciences. RAM reported grants or contracts from Boehringer Ingelheim. OS reported payment or honorariums for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Abbott Diagnostics, Lilly Deutschland, Boehringer Ingelheim, Bayer, Mannkind, and Lifescan and is a founder and CEO of Sciarc GmbH. NM reported grants or contracts from Boehringer Ingelheim, Merck, Novo Nordisk, Deutsche Forschungsgesellschaft (German Research Foundation; TRR 219), and consulting fees from Boehringer Ingelheim, Merck, Novo Nordisk, AstraZeneca, BMS, and payment or honorariums for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Boehringer Ingelheim, Merck, Novo Nordisk, Lilly, BMS, and AstraZeneca. SL received the fund from the Sichuan Science and Technology Programme and West China Hospital of Sichuan University.

The manuscript’s guarantors (SL) affirm that the manuscript is an honest, accurate and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned and registered have been explained.

Dissemination to participants and related patient and public communities: This study will support the update of a BMJ Rapid Recommendation ( https://www.bmj.com/rapid-recommendations ).

Provenance and peer review: Not commissioned; externally peer reviewed.

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/ .

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Trends in Antidiabetic Drug Discovery: FDA Approved Drugs, New Drugs in Clinical Trials and Global Sales

Affiliations.

• 1 Functional Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden.
• 2 Department of Biology, Lomonosov Moscow State University, Moscow, Russia.
• 3 Russia Institute of Translational Medicine and Biotechnology, I. M. Sechenov First Moscow State Medical University, Moscow, Russia.
• PMID: 35126141
• PMCID: PMC8807560
• DOI: 10.3389/fphar.2021.807548

Type 2 diabetes mellitus (T2DM) continues to be a substantial medical problem due to its increasing global prevalence and because chronic hyperglycemic states are closely linked with obesity, liver disease and several cardiovascular diseases. Since the early discovery of insulin, numerous antihyperglycemic drug therapies to treat diabetes have been approved, and also discontinued, by the United States Food and Drug Administration (FDA). To provide an up-to-date account of the current trends of antidiabetic pharmaceuticals, this review offers a comprehensive analysis of the main classes of antihyperglycemic compounds and their mechanisms: insulin types, biguanides, sulfonylureas, meglitinides (glinides), alpha-glucosidase inhibitors (AGIs), thiazolidinediones (TZD), incretin-dependent therapies, sodium-glucose cotransporter type 2 (SGLT2) inhibitors and combinations thereof. The number of therapeutic alternatives to treat T2DM are increasing and now there are nearly 60 drugs approved by the FDA. Beyond this there are nearly 100 additional antidiabetic agents being evaluated in clinical trials. In addition to the standard treatments of insulin therapy and metformin, there are new drug combinations, e.g., containing metformin, SGLT2 inhibitors and dipeptidyl peptidase-4 (DPP4) inhibitors, that have gained substantial use during the last decade. Furthermore, there are several interesting alternatives, such as lobeglitazone, efpeglenatide and tirzepatide, in ongoing clinical trials. Modern drugs, such as glucagon-like peptide-1 (GLP-1) receptor agonists, DPP4 inhibitors and SGLT2 inhibitors have gained popularity on the pharmaceutical market, while less expensive over the counter alternatives are increasing in developing economies. The large heterogeneity of T2DM is also creating a push towards more personalized and accessible treatments. We describe several interesting alternatives in ongoing clinical trials, which may help to achieve this in the near future.

Keywords: FDA approved; antihyperglycemics; clinical developments; diabetes mellitus; efficacy and safety; global trends.

Copyright © 2022 Dahlén, Dashi, Maslov, Attwood, Jonsson, Trukhan and Schiöth.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

FDA-approved monotherapies and combination regimens.…

FDA-approved monotherapies and combination regimens. (A) The current 59 FDA-approved anti-diabetic agents. The…

Agents in clinical development. (A)…

Agents in clinical development. (A) The ∼100 antihypertensive agents in clinical development include…

FDA-approved drug classes per year.…

FDA-approved drug classes per year. (A) Timeline of the major classes of antihypertensive…

The molecular targets of the…

The molecular targets of the 99 anti-diabetic agents in clinical trials. The phase…

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Research progress on antidiabetic activity of apigenin derivatives

• Review Article
• Published: 29 August 2022
• Volume 31 , pages 1831–1841, ( 2022 )

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• Jingyi Jiang   ORCID: orcid.org/0000-0002-1399-7140 1   na1 ,
• Ting Tang 1   na1 ,
• Yaling Peng 1 ,
• Meiling Liu 1 ,
• Qianwen Liu 1 ,
• Pengbing Mi 1 ,
• Zehua Yang 1 ,
• Hongfei Chen 1 &
• Xing Zheng 1  

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Diabetes has always been a global health issue of great concern. The current treatment methods include oral and injection hypoglycaemia drugs, which have certain toxic and side effects. Therefore, there is a growing need for discovering more effective and safer antidiabetic agents. Great concern has arisen from scientists in these years, due to the finding that apigenin is an edible plant-derived flavonoid with no toxicity. However, the development of apigenin suffers from its low water solubility which leads to its poor bioavailability. Thus, it is of great importance to improve its bioavailability by developing various derivatives through structural modification. In this review, various apigenin derivatives with different modifications and methods of their synthesis have been listed. We also analysed and compared their antidiabetic activity. Meanwhile, some widely studied anti-diabetes mechanisms were summarised for the better understanding of the anti-diabetes effect of apigenin.

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Acknowledgements

The authors thank Natural Science Foundation of Hunan (2021JJ80015), Hunan Provincial Hengyang Joint Fund (2020JJ6052), Laboratory of Tea and Health of Hengyang (202150083704), the Undergraduate Research Learning and Innovative Experiment Project (S202110555237), the Undergraduate Research Learning and Innovative Experiment Project (X20210555468) for financial support.

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Jingyi Jiang, Ting Tang, Yaling Peng, Meiling Liu, Qianwen Liu, Pengbing Mi, Zehua Yang, Hongfei Chen & Xing Zheng

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Jiang, J., Tang, T., Peng, Y. et al. Research progress on antidiabetic activity of apigenin derivatives. Med Chem Res 31 , 1831–1841 (2022). https://doi.org/10.1007/s00044-022-02933-8

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Air Canada and pilots reach tentative deal, AI’s failed hype to revolutionize drug discovery and a productivity slowdown: Business and investing news for Sept. 15

Air Canada and the pilots union reached a tentative deal just after midnight on Sunday. Air Canada pilots stand during an informational picket at Vancouver International Airport in Richmond, B.C., on Aug. 27. DARRYL DYCK/The Canadian Press

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Antidiabetic Phytochemicals From Medicinal Plants: Prospective Candidates for New Drug Discovery and Development

Safaet alam.

1 Department of Pharmacy, State University of Bangladesh, Dhaka, Bangladesh

Md. Moklesur Rahman Sarker

2 Pharmacology and Toxicology Research Division, Health Med Science Research Limited, Dhaka, Bangladesh

Taposhi Nahid Sultana

3 Department of Pharmacy, University of Asia Pacific, Dhaka, Bangladesh

Md. Nafees Rahman Chowdhury

4 Department of Pharmacy, University of Dhaka, Dhaka, Bangladesh

Mohammad A. Rashid

5 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Dhaka, Dhaka, Bangladesh

Nusrat Islam Chaity

6 College of Food Science, Fujian Agriculture and Forestry University, Fuzhou, China

Jianbo Xiao

7 Department of Analytical Chemistry and Food Science, Faculty of Food Science and Technology, University of Vigo, Vigo, Spain

Elsayed E. Hafez

8 Plant Protection and Biomolecular Diagnosis Department, ALCRI (Arid Lands Cultivation Research Institute), City of Scientific Research and Technological Applications, Alexandria, Egypt

Shah Alam Khan

9 College of Pharmacy, National University of Science & Technology, Muscat, Oman

Isa Naina Mohamed

10 Pharmacology Department, Medicine Faculty, Universiti Kebangsaan Malaysia (The National University of Malaysia), Kuala Lumpur, Malaysia

Diabetes, a chronic physiological dysfunction affecting people of different age groups and severely impairs the harmony of peoples’ normal life worldwide. Despite the availability of insulin preparations and several synthetic oral antidiabetic drugs, there is a crucial need for the discovery and development of novel antidiabetic drugs because of the development of resistance and side effects of those drugs in long-term use. On the contrary, plants or herbal sources are getting popular day by day to the scientists, researchers, and pharmaceutical companies all over the world to search for potential bioactive compound(s) for the discovery and development of targeted novel antidiabetic drugs that may control diabetes with the least unwanted effects of conventional antidiabetic drugs. In this review, we have presented the prospective candidates comprised of either isolated phytochemical(s) and/or extract(s) containing bioactive phytoconstituents which have been reported in several in vitro , in vivo , and clinical studies possessing noteworthy antidiabetic potential. The mode of actions, attributed to antidiabetic activities of the reported phytochemicals and/or plant extracts have also been described to focus on the prospective phytochemicals and phytosources for further studies in the discovery and development of novel antidiabetic therapeutics.

Introduction

Diabetes mellitus is a type of chronic metabolic disorder categorized by insufficiency in insulin activity and/or insulin secretion. Anomalies in proteins, carbohydrates and lipids metabolism can arise due to the lack of insulin, an anabolic hormone ( 1 ). These abnormalities in metabolism are caused by low levels of insulin, insulin resistance of target tissues, insulin receptor level, primarily skeletal muscles, and adipose tissue and to a lesser degree, liver, signal transduction system, and/or effector enzymes or genes and/or signal transduction pathway ( 2 ). Diabetes is one of the most abundant metabolic diseases across the world accounting for about 2.8% of the population worldwide and is projected to reach 4.4% by 2030 which has already risen to an unprecedented extent of the epidemic ( 3 ). Despite being a non-communicable disorder, diabetes is considered one of the five biggest morbidities worldwide ( 1 ). Diabetes category and frequency vary depending on the severity of the symptoms. Some patients with diabetes are asymptomatic, particularly patients with type 2 diabetes during the initial periods of illness whereas others have noticeable hyperglycemia. Uncontrolled and unmonitored diabetes can lead to stupor, coma and even death if kept untreated because of ketoacidosis or rare non-ketotic hyperosmolar disorders ( 4 ). The development of diabetes may include the interaction of genetic and non-genetic factors ( 5 ). Despite diabetes classification being crucial and having repercussions for treatment policies, this is somehow ambiguous and many diabetic individuals do not easily accommodate into one class, exclusively younger adults and 10% of the initially classified patients can need revision afterward ( 6 ). The standard classification of diabetes as type 1, type 2 and gestational diabetes mellitus (GDM) as introduced by the American Diabetes Association (ADA) in 1997 remains the best-accepted and adopted by ADA ( 4 ).

Currently, there are many antidiabetic drugs available in the market to treat hyperglycemia which notably works via improvement of insulin sensitivity, complementing insulin, upraising insulin secretion and stimulating glucose uptake. But metformin and sulfonylureas type antidiabetic drugs are compromised with several unwanted side effects such as diarrhea and lactic acidosis (demonstrated by metformin) and hepatic failure, weight gain, tachycardia and hypothyroidism (demonstrated by sulfonylureas) ( 7 ). Plant is always considered as one of the most reliable sources of curing agents of diseases and many of those synthetic drugs are either directly or indirectly derived from them. Plants and plant products can exert promising antidiabetic efficacy based on recent studies ( Figure 1 ). Plant sources of antidiabetic agents are very much popular from the ancient era as they are relatively safer and much cheaper alternatives than synthetic drugs and are also mentioned in many folkloric medicines including the Indian, Korean and Chinese culture. Traditional herbal medicines and functional foods are believed to ameliorate diabetic syndromes via six notable mechanism of actions including enhanced insulin secretion and sensitivity, glucose uptake by muscle cells and adipose tissues and inhibition of glucose absorption from intestine and glucose production from hepatocytes along with demonstrating anti-inflammatory properties ( 7 ). As a result, functional foods and phytotherapies are becoming popular across the world day by day ( 8 ). In the current review, we have compiled most notable medicinal and dietary plants along with their isolated antidiabetic phytochemicals to give distinct insights into the establishment of novel functional foods and drug moieties against diabetes. The graphical abstract of the manuscript has been presented in Figure 2 .

The mechanisms of action of several prospective bioactive secondary metabolites (phytochemicals) obtained from different medicinal plants.

Graphical abstract of prospective antidiabetic phytochemicals from medicinal plants for the discovery and development.

Latest Researches on the Molecular Mechanisms and Pathogenies of Diabetes Mellitus

In type 1 Diabetes, the pancreatic β-cells undergo autoimmune destruction by CD4+ and CD8+ T cells and macrophages which result in insulin deficiency ( 9 , 10 ). Islet cell antibodies are found in nearly 85% of the patients, and most of them act against the glutamic acid decarboxylase (GAD) found inside the β-cells of the pancreas ( 9 ).

The metabolic disorders related to type 1 diabetes mellitus are a result of deficiency of insulin secretion caused by the immune destruction of islets of Langerhans of the pancreas. Besides, pancreatic α-cells start to function abnormally and secrete an excessively large amount of glucagon in patients with type 1 diabetes mellitus, which further aggravates the metabolic disorders already caused by insulin deficiency ( 11 ). A deficiency of insulin causes lipolysis to occur at an uncontrolled rate which causes the amount of free fatty acids in the blood to rise resulting in a reduction of glucose metabolism in the peripheral tissues ( 11 ). The deficit of insulin also causes a reduction of glucokinase enzyme in the liver and the GLUT-4 transporter protein in adipose tissue resulting in an inability of the target tissues to respond normally to insulin.

Impaired secretion of insulin through destruction of the insulin secreting β-cells, and diminished insulin activity through insulin resistance marks the underlying mechanisms of the pathogenesis of type 2 diabetes ( 9 ). The mitochondria- endoplasmic reticulum contacts are known as mitochondria-associated membranes (MAMs) play an important role in the regulation of lipid exchange, signaling of calcium, cell survival, and homeostasis in cellular metabolism. These MAM contacts are known to contain several insulin signaling proteins such as AKT kinase, mTORC2, PP2A, and PTEN and thus participate in insulin signaling. A growing number of studies have shown that these MAMs are involved in causing dysfunction of the insulin producing β cells, resistance to insulin in the peripheral tissues, leading to type 2 diabetes mellitus ( 12 ). miRNAs are small RNA consisting of 20–24 nucleotides that regulates early development, fat metabolism, cell proliferation, differentiation, apoptosis, and death. Recent studies have shown that these miRNAs contribute to the pathogenesis of type 2 diabetes mellitus and may be developed into new biomarkers ( 13 ).

As reactive oxygen species impact chemical changes in all cellular components and produce lipid peroxidation, oxidative stress also causes type 2 diabetes mellitus. As a result, lipid peroxidation is another important cause of type 2 diabetes mellitus ( 14 ). In excess amounts of hydrogen peroxide (H 2 O 2 ), DNA, RNA, and lipids are severely damaged. Catalase (CAT) is the major H 2 O 2 regulator, and it neutralizes H2O2 by catalytically converting it to water and oxygen. When catalases (CAT) are deficient, pancreatic islet-cells are more susceptible to excessive formation of reactive oxygen species (ROS) and oxidative stress, which leads to pancreatic islet dysfunction and overt type 2 diabetes mellitus ( 15 ). In numerous illness states involving oxidative stress as a significant causal factor, such as diabetes and obesity, plasma levels of oxidized low-density lipoprotein (oxLDL) are elevated ( 16 ). Nuclear factor kappa B (NF-B), NH2-terminal Jun kinases, and p53 MAPK are transcriptionally regulated pathways that have been considered one of the most important stress-signaling pathways, and oxidative stress plays a role in the development of type 2 diabetes mellitus through their involvement ( 14 ).

Type 2 diabetes mellitus is linked by decreased physical activity and exercise training, as well as increased sedentary habits, which are linked to elevated indicators of chronic systemic inflammation ( 17 ). Proinflammatory molecules such as interleukin 6 (IL-6), C-Reactive Protein (CRP), tumor necrosis factor-alpha (TNF-) and interleukin 1 (IL-1) are released into the bloodstream and inside specific organs in this scenario, causing metabolic inflammation ( 18 ). IL-1 is involved in the pancreatic autoimmune response, decreasing -cell activity and activating the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-B) transcription factor, inhibiting -cell function and inducing death.

The importance of the gut microbiota in the development of diabetes has been demonstrated, and new studies suggest that dysbiosis can increase type 2 diabetes mellitus ( 19 ). Experiments in animal models showed that a high-fat diet can increase the synthesis of lipopolysaccharide (from Gram-negative bacteria) by up to thrice, contributing to low-grade inflammation and insulin resistance ( 20 , 21 ). Intestinal dysbiosis can also impair short-chain fatty acid production, which is important for gut barrier integrity, pancreatic cell proliferation, and insulin biosynthesis ( 22 , 23 ). Dysbiosis can also affect the production of other metabolites such as branched aminoacids and trimethylamine, causing glucose homeostasis to be disrupted and type 2 diabetes mellitus to develop ( 24 , 25 ). The clinical consequences of the gut microbiome are still being researched, and more study is needed to better understand the link between gut bacteria and type 2 diabetes mellitus ( 26 ).

Articles Search Strategy

An extensive literature search was carried out through the following databases: Web of Science, Scopus, PubMed/Medline, ScienceDirect, ClinicalTrials.gov, Wiley Online Library and Google Scholar. The following keywords were used: ‘Antidiabetic’, ‘Diabetes’, ‘Phytochemical’, ‘Bioactive compound’, ‘Type 2 diabetes’, ‘Pharmacology’, and ‘Clinical trial’. Only peer-reviewed scientific journals were considered during the process. Plants with reported antidiabetic phytochemicals along with mechanism of actions have been considered only for the review work. Of the 598 identified papers and clinical trials records, 295 unique articles were included and reported in this comprehensive review following inclusion criteria.

Anoectochilus roxburghii (Wall.) Lindl.

Anoectochilus roxburghii (Wall.) Lindl. (family: Orchidaceae) is a perennial herb which mainly occurs in China, Taiwan, Japan, Sri Lanka, India, and Nepal. Polysaccharides from A. roxburghii lower blood glucose levels by enhancing the body’s antioxidant capacity, reducing blood lipid levels, modulating the activity of glucose-metabolizing enzymes, minimizing tissue damage such as pancreas, and promoting damaged tissue repair ( 27 ). Kinsenoside, extracted from A. roxburghii was found to demonstrate significant hypoglycemic activity. Previous studies have shown that kinsenoside could help in the restoration of damaged β cells in pancreas and function against oxidative stress and NO factor and also regulates antioxidant enzymes, scavenging of free radicals ( 28 ).

Bacopa monnieri (L.) Wettst.

Bacopa monnieri (L.) Wettst. (family: Scrophulariaceae) is a creeping herb which occurs across India. Several compounds including tetracyclic triterpenoid saponins, Bacosides A and B, Hersaponin, alkaloids viz. Herpestine and Brahmine and flavonoids have been isolated from the plant ( 29 ). Bacosine, a triterpene isolated from the ethyl acetate fraction of the ethanolic extract of B. monnieri showed pronounced reduction in blood glucose levels in diabetic rats in a dose-dependent mode; however, no such effect has been observed on normal rats. Thus, bacosine is known to possess antihyperglycemic properties rather than hypoglycemic activity. It has been suggested that bacosine works in a way similar to insulin and that its antihyperglycemic activity might be attributed to the increase in the consumption of peripheral glucose as well as protect against oxidative damage in alloxan induced diabetes. Bacosine caused a pronounced increase (p < 0.001) of glycogen content in the liver of diabetic rats and consequently proved its insulin-like activity resulting in an increased uptake of glucose ( 29 ).

Berberis aristata DC.

Berberis aristata DC (family: Berberidaceae) is native to Northern Himalayan part and is known locally as ‘Daruhaldi’ or ‘Citra’. Root extract B. aristata regulates glucose homeostasis by reducing gluconeogenesis and oxidative stress and exhibits a strong anti-hyperglycemic activity ( 30 , 31 ). The major antidiabetic compound extracted from this plant is berberine. Berberine is known to act through several mechanisms, including insulin-mimetic activity; improving the action of insulin by triggering AMPK (5′ adenosine monophosphate-activated protein kinase); reducing insulin resistance through protein kinase C-dependent up-regulation of insulin receptor expression; causing glycolysis; and by enhancing GLP-1 (Glucagon-like peptide 1) secretion and regulating its release, and by inhibiting DPP-IV (Dipeptidyl peptidase-4) ( 30 ). According to 32 , berberine extracted from B. aristata in a manner of 0.5 gm thrice a day on type 2 diabetic patients showed equal efficacy to metformin monotherapy in the reduction of fasting blood glucose, HbA1c, postprandial blood glucose, postprandial insulin and basal insulin ( 32 ). Another clinical trial also showed the efficacy of berberine as adjuvant therapy in poorly controlled type 2 diabetic patients ( 32 ). In other clinical trials, berberine also showed promising efficacy compared to rosiglitazone and metformin by reducing HbA1c, fasting blood glucose, postprandial blood glucose despite having some adverse effects on liver ( 33 ). In another 6 months long randomized-controlled trial on 85 type 1 diabetic patients (39 males and 46 females), twice daily intake of a tablet containing 588/105 mg combination of Berberis aristata/Silybum marianum decreased insulin use by the body during insulin therapy. Moreover, there was a decrease in Hb1Ac level in comparison to baseline and in fasting and postprandial plasma glucose levels in comparison to both baseline and placebo ( 34 ). This combination, which is made to improve the low bioavailability of berberine in oral route, has also been reported to show notable antidiabetic effects in 136 obese/overweight type 2 diabetic patients, as per another year-long placebo-controlled study ( 35 ).

Bixa Orellana L.

Bixa Orellana L. (family: Bixaceae) also known by the name ‘Achuete’, is a rapidly growing shrub that can grow upto 3 to 5 meters in height. The plant originated in Brazil but also grows in South and Central America. Besides, it also occurs in tropical countries such as Peru, Mexico, Ecuador, Indonesia, India, Kenya, and East Africa ( 36 ). B. Orellana lowered the blood glucose levels in dogs with streptozotocin-induced diabetes ( 36 , 37 ). It has been suggested that B. Orellana causes a reduction in blood glucose level by increasing peripheral utilization of glucose ( 38 , 39 ), increasing plasma insulin levels and increasing the binding of insulin to insulin receptors ( 40 ). Bixin, a high carotenoid content and a natural pigment found in B. orellana showed prominent hypoglycemic actions. Bixin is commercially named “Annatto” and a very promising wellspring of new medicines as well imperative nutraceuticals ( 36 ).

Bumelia sartorum Mart.

Bumelia sartorum Mart. (family: Sapotaceae) is a large and tall tree commonly known as ‘Quixaba’, ‘Quixabeira’, ‘Tranceporteira’, ‘Sacutiaba’ and ‘Rompe-gibao’ in northeastern Brazil. It naturally grows from north of Minas Gerias to Piaui ( 41 ). An unsaturated triterpene acid named bassic acid, isolated from the ethanol extract of root bark of B. surtorum exhibited significant hypoglycemic activity in alloxan induced diabetic rat models. Moreover, bassic acid was found to significantly increase the glucose uptake and glycogen synthesis process in isolated rat diaphragm. In alloxan-diabetic rats following bassic acid treatment, a significant increase in plasma insulin levels was found. It has been suggested that bassic acid increases insulin secretion from pancreatic beta-cells. This could be the underlying mechanism by which bassic acid shows its hypoglycemic property which was found to be approximately equal to that of chlorpropamide ( 42 ).

Callistemon rigidus R.Br.

Callistemon rigidus R.Br. (family: Myrtaceae) is an evergreen plant which is native to Australia. Noteworthy antidiabetic compounds piceatannol and scirpusin B were isolated from the stem bark of the plant using 1 H- and 13 C-NMR technology ( 43 ). These compounds can suppress the activity of α- amylase in isolated mouse plasma Methanol extract of C. rigidus can also demonstrate prominent repressing activity on α- amylase. Besides, scirpusin B can regulate α-amylase in mouse GIT to demonstrate antidiabetic efficacy. These compounds are also expected to abate increment of postprandial glucose level and can offer a very good wellspring of antidiabetic drug development ( 44 ).

Catharanthus roseus (L.) G.Don

Catharanthus roseus (L.) G.Don (family: Apocynaceae) is a shrub-type plant that can grow up to 30–100 cm in height. The plant originated from Madagascar but is available around the world due to its high survival rate ( 45 ). Its leaf extracts exhibited significant dose-dependent blood sugar-lowering activity in normal and streptozotocin-induced diabetic model rats. The blood sugar-lowering potential of the leaf extract was equivalent to that of the commercially available drug Tolbutamide in the animal models ( 45 , 46 ). Comapred to normal animals, the enzymic activities of glycogen synthase, glucose 6-phosphate-dehydrogenase, succinate dehydrogenase and malate dehydrogenase were found to decrease in the liver of diabetic animals and were significantly increased after treatment with dichloromethane–methanol (DCMM) extract of leaves and twigs of C. roseus at dose 500 mg/kg p.o. for 7 days. It has been suggested that C. roseus exhibits its anti-diabetic activity by increasing glucose metabolism in treated rats ( 47 ). Among isolated compounds, especially alkaloids including vindoline, vindolidine, vindolicine and vindolinine, isolated from Catharanthus roseus leaves induced increased glucose uptake in myoblast C2C12 or pancreatic β-TC6 cells where vindolicine showed maximum efficacy. First three compounds did not exhibit any cytotoxicity towards pancreatic β-TC6 cells even when administered in the maximum dose of 25.0µg/mL. Vindolicine, vindolidine and vindolinine also revealed improved protein tyrosine phosphatase-1B (PTP-1B) inhibition actions which can play a pivotal role in type 2 diabetes management ( 45 ).

Chamaemelum nobile (L.) All.

Chamaemelum nobile (L.) All. (family: Asteraceae) is a native South-eastern Moroccan shrub-type which is locally known as ‘Babounge’. It is very much popular throughout Europe, most notably in France and USA ( 48 ). Its aqueous extract mitigated blood glucose concentration in streptozotocin induced diabetic rat models except changing plasma insulin level which indicated an insulin secretion independent pathway ( 48 ). C. nobile may also exhibit its hypoglycaemic activity in the gastrointestinal tract by slowing down the digestion process and reducing the rate of carbohydrate absorption ( 48 ). Chamaemeloside, 3-hydroxy-3-methylglutaric acid (HMG) containing flavonoid glucoside is the most notable isolated antidiabetic compound from this plant which revealed hypoglycemic activity in Swiss-Webster mice models by reducing plasma glucose concentration. The reduction of fasting glucose level and improved glucose tolerance referred that it might act following more than one mechanism ( 49 ). The underlying mechanism of action may be attributed to the stimulation of the utilization of peripheral, especially in muscle and adipose tissue. In 8 week long clinical study on 26 pre-diabetic volunteers (21 were male and 5 were female; mean age: 50.5 ± 8.5 years), a mixed herbal extract supplementation was made by combining hot water extract of Anthemis nobilis (Roman chamomile), which is a synonym of Chamaemelum nobile and Vitis vinifera in the dose of 1200 mg reportedly reduced abnormal glucose values and thus the risk of developing diabetes ( 50 ).

Cichorium intybus L.

Cichorium intybus L. (family: Asteraceae) is an erect herb-type perennial plant that grows upto 1 m. It is abundantly found in Asia, Africa, Europe, and Southern America. It is well-known as ‘Chicory’ ( 51 ). Its ethanolic extract (CIE) was found to show a marked reduction in the hepatic glucose-6-phosphatase (Glc-6-Pase) activity when compared to the control group. The decrease in the activity of hepatic Glc-6-Pase could lead to a reduction in the production of hepatic glucose, which in turn reduces the blood glucose level in CIE-treated diabetic rats ( 52 ). Chlorogenic acid and chicoric acid are the two most notable antidiabetic phytoconstituents isolated from this plant which can increase glucose uptake in L6 muscular cells. Both phytochemicals can also upraise insulin secretion from the INS-1E insulin-secreting cell line and rat islets of Langerhans. Besides, chicoric acid can exert both insulin-secreting and sensitizing activities ( 53 ). A randomized, double‐blind clinical trial on 100 type 2 diabetic patients (55 were male and 45 were female) reported a reduction in HbA1c value from 8.6% at baseline to 7.42% after 12 weeks and thus indicated the potentiality of Cichorium intybus seed supplementation as an adjunct therapy in type 2 diabetes mellitus ( 54 ). A similar 4 weeks long randomized, double-blind, placebo-controlled study in 47 healthy subjects (8 were male and 39 were female; age range: 33-70 years) reported that the seed supplementation at 300 ml/day dose caused improvement in adiponectin level and fecal properties along with the antihyperglycemic activity, indicating that the supplement, which included inulin-type fructans, is effective in delaying diabetic mellitus onset and helps improving bowel movements ( 55 ).

Cinnamomum verum J. Presl

Cinnamomum verum J. Presl (family: Lauraceae) is an evergreen plant with a height of 10-15 m which is local to Southern India and Srilanka. Apart from these places, it is widely available in other Asian, Australian, Caribbean and African countries but most notably in China, Indonesia, Madagascar, Vietnam and Burma. It is well-known as ‘Ceylon cinnamon’, ‘True cinnamon’, ‘Darchini’, ‘Dalchini’ and ‘Mexican cinnamon’. The name Ceylon came after the former name of Srilanka, its native place. Bark (after drying) is the most important part of the plant with remarkable medicinal values ( 56 ). Methanolic extract from C. verum can suppress the activity of α- glucosidase and α-amylase ( 57 ). According to the study, cinnamon aqueous extract also showed notable antidiabetic activity in alloxan induced diabetic rat models by reducing fasting blood sugar, triglycerides and total cholesterol when tested for thirty days long ( 57 ). Interestingly, a lower dose of cinnamon extract i.e. 200 mg/kg showed maximum antidiabetic efficacy. In another research, it was revealed that hydro-alcoholic extract of Cinnamon can ameliorate postprandial glycemia more than its aqueous extract ( 58 ). Cinnamon can also increase the uptake of glucose by upraising the number of insulin receptors, glucose transporter 4 and activating glycogen synthase to diminish glucose levels ( 56 , 59 ). Cinnamon extract was also co-administered with other herbals to evaluate the synergistic activity on diabetic complications. Again, a combination of methanolic cinnamon extract along with green tea can also decrease blood glucose concentration and body weight significantly in streptozotocin induced diabetic rat models by showing synergism ( 56 , 60 ). Among isolated phytochemicals, it is believed that cinnamon polyphenols like eugenol and pyrogallol can demonstrate antidiabetic properties by renovating beta cells which leads to hypoglycemic and hypolipidemic actions ( 56 ). According to Tulini et al. solid lipid microparticles (SLM) of proanthocyanidin rich cinnamon extract can improve the antidiabetic efficacy of foods ( 61 ). Again, cinnamaldehyde can ameliorate the uptake of glucose by upraising the amount of AKT2 and aortic nitric oxide synthase 3 (eNOS), insulin receptor substrate1 (IRS1) and p-85 regulatory subunit of PI3K (PI3K-P85) while concurrently abating the expression of NADPH oxidase 4 (NOX4) which eventually balance the increased glucose concentration ( 56 , 59 ). Cinnamon supplementation at the dose of 500 mg showed prominent antidiabetic action in a 3 month long randomized, triple-blind placebo-controlled, parallel clinical trial in 138 type 2 diabetic patients (63 were male and 75 were female; age range: 30-80 years) by causing a reduction in all glycemic parameters, namely FPG by -13.1 ± 1.7 mg/dl, HbA1C by -0.27 ± 0.04%, 2HPP by -16.9 ± 2.5 mg/dl, insulin resistance (HOMA-IR) by -1.01 ± 0.11 and fasting insulin by -1.77 ± 0.41 mIU/L) with no side effects while a better glycemic control was observed in patients whose BMI values were greater than 27 ( 59 ). Another phase 1 clinical study on 30 healthy adults (50% were male; mean age: 38.8 ± 10.4 years; age range: range 21–58 years) showed that cinnamon had no significant toxicity or side effects ( 62 ). In a review of 8 randomized-controlled trials, it has been found that sole therapy of powdered or aqueous form of cinnamon, at different doses starting from 0.5 g to 5 g per day, ameliorated glycemic control in type 2 diabetic and prediabetic patients (impaired fasting glycemia or impaired glucose tolerance) ( 63 ).

Costus pictus D. Don

Costus pictus D. Don (family: Zingiberaceae) is a rhizomatous medicinal herb which is popularly known as ‘Insulin plant’ for its strong antidiabetic efficacy. It demonstrated antidiabetic action by the inhibition of α-amylase and α–glucosidase activity ( 64 ). C. pictus can also improve the secretion of insulin in diabetic rat models along with improvement in glucose utilization ( 65 ). It has been found that upon the administration of aqueous extract of C. pictus to diabetic rats, C. pictus causes a marked reduction in blood glucose levels and an increase in plasma insulin level. Regulation of glucose homeostasis by improved peripheral glucose utilization, increased hepatic glycogen synthesis and/or decrease of glycogenolysis, inhibition of intestinal glucose absorption, and lowering of the glycaemic index of carbohydrates might be responsible for the antidiabetic effect of C. pictus ( 66 ). Earlier researchers also found that β-amyrin and methyl tetracosanate are the major bioactive phytoconstituents which exhibited ameliorated glucose uptake in 3T3-L1 adipocytes ( 67 , 68 ). In another study conducted on C. pictus , β- L- Arabinopyranose methyl glycoside was reported responsible for antidiabetic property ( 69 ). Ingestion of the leaves of C. pictus by diabetic patients showed statistically significant reduction in their fasting and postprandial blood glucose levels, as per a cross-sectional clinical study ( 70 ).

Curcuma longa L.

Curcuma longa L. (family: Zingiberaceae) also known as ‘Turmeric’ is a moderately tall perennial plant containing underground rhizomes. It is grown in tropical regions like Pakistan, China, Peru and India. The curcuminoids bisdemethoxycurcumin, curcumin and demethoxycurcumin were isolated from C. longa and were found to exhibit α-glucosidase inhibitory activity ( 71 ). Among the three curcuminoids, bisdemethoxycurcumin showed the most potent α-glucosidase inhibition ( 72 ). Besides, volatile oils extracted from both fresh and dried turmeric rhizomes showed potent glucosidase inhibitory activity in a dose-dependent mode, and dried rhizomes increased the glucosidase inhibitory action significantly. Potent α-glucosidase and α -amylase inhibitory activity was exhibited by Aromatic-Turmerone, the main volatile component in turmeric rhizome ( 73 ). Turmerin, a water-soluble protein found in turmeric rhizomes inhibits α-amylase and α-glucosidase activities. Thus, turmeric rhizomes exert inhibitory action against enzymes related to type 2 diabetes ( 71 ). A combination of Curcuma longa and  Allium sativum  at 2.4 g total dose showed prominent antihyperglycemic action in type 2 diabetic patients by reducing fasting blood glucose, 2 h postprandial glucose, HbA1C and body mass index levels without showing any side effects ( 74 ). In addition, in six clinical trials, treating type 2 diabetic patients with curcuminoids ranging from 0.25 g to 1 g per day also ameliorated glycemic control by decreasing fasting blood glucose, HbA1c, HOMA-IR (insulin resistance) levels and increasing adiponectin level without causing any major side effects. Improvement in diabetes-associated endothelial dysfunction and hyperlipidemia was observed as well ( 75 ).

Cryptolepis sanguinolenta (Lindl.) Schltr.

Cryptolepis sanguinolenta , (Lindl.) Schltr. (family: Apocynaceae) is a scrambling thin-stemmed shrub indigenous to West Africa which is commonly found in tropical rainforests, thickets, and mountainous ecologies ( 76 ). It was found to reduce the intestinal absorption of glucose and its transport from the gut significantly in a dose-dependent mode in the normoglycemic rats ( 76 , 77 ). The study also revealed that treatment with C. sanguinolenta increased the size of β cells which might have improved the production and activity of insulin resulting in reduced blood glucose levels. Additionally, C. sanguinolenta  also increases the uptake of glucose by 3T3-L1 cells, and improves insulin-mediated disposal of glucose. The hypoglycemic activity exhibited by the extract of C. sanguinolenta  may be due to the presence of its alkaloid constituents. It has been reported that insulin resistance is reduced by alkaloids in mice and high fat-fed rats. They can activate AMP-activated protein kinase in 3T3-L1 adipocytes and L6 myotubes and promote the translocation of GLUT4 in L6 myotubes in a manner that is independent of phosphatidylinositol 3-kinase. Besides, they also improve the uptake of glucose in HepG2 and 3T3-L1 cells. In addition, they probably suppress the activity of the α-glucosidase enzyme and cause a reduction in the absorption of glucose. It has also been reported to significantly reduce the plasma levels of IL-6 with increased insulin sensitivity. This mechanism of action might also be responsible for the hypoglycemic activity of alkaloids-containing  C. sanguinolenta  stem extract ( 77 ). Cryptolepine, an indoloquinoline alkaloid purified from C. sanguinolenta , was found to reduce plasma glucose level significantly in a mouse model of diabetes, and in that model, it was approximately as effective as ciglitazone. It was suggested that cryptolepine works directly at the cellular level to enhance the glucose transport in 3T3-L1 cells and thus causes a reduction in blood glucose level ( 78 ).

Euclea undulate Thunb. var. myrtina

Euclea natalensis Thunb. var. myrtina (family: Ebenaceae) is a multi-stemmed, dioecious shrub or little tree growing up to about 6 m height. It is distributed in Botswana, Zimbabwe, Namibia, Swaziland, Mozambique and South Africa. Its crude acetone root bark extract was found to show antidiabetic activity in type 2 induced diabetic rat models ( 79 ). Besides, the plant extract of E. undulata was found to inhibit α-glucosidase and α-amylase activity ( 80 ). Past studies have revealed the presence of epicatechin and α-amyrin-3O-β-(5-hydroxy) ferulic acid in the crude acetone extract of the root bark of E. undulata . It has been reported that epicatechin may have the ability to lower blood glucose levels and α-amyrin-3O-β-(5-hydroxy) ferulic acid can inhibit α –glucosidase ( 81 ).

Gymnema sylvestre R. Br.

Gymnema sylvestre  R. Br. (family: Asclepiadaceae) is an evergreen, woody climber and endogenous plant which is widely available in central and southern India and in the southern part of China, Sri Lanka, Malaysia and tropical Africa, Malaysia ( 82 ). G. sylvestre can improve average blood glucose levels in animal models and can stimulate insulin secretion from the MIN-6, HIT-T15 and RINm5F β-cells by upraising membrane permeability ( 83 ). Gymnema sylvestre is thought to act by several mechanisms including regeneration of islet cells, increase in the secretion of insulin and glucose utilization by insulin-dependent pathway, increase the phosphorylase enzyme activity, decrease in gluconeogenic enzymes and sorbitol dehydrogenase, reduction of glucose absorption from the gut wall ( 84 ). Antihyperglycemic compounds like gymnemagenin and gymnemic acids were discovered by LC/MS analysis from the ethanol extract of G. sylvestre  leaves which demonstrated blood glucose level lowering activity in rat models ( 83 ). Gymnemic acid is a complex mixture of several (more than seventeen) saponins which are mainly dammarene and oleanane. 3-O-β-D-glucopyranosyl (1-6)-β-D-glucopyranosyloleanolic acid 28-O- β-Dglucopyranosyl ester, longispinogenin 3-O-β- D-glucuronopyranoside, oleanolic acid 3-O-β-D-xylopyranosyl(1-6)-β- D-glucopyranosyl(1-6)-β-D-glucopyranoside and 3-O-β-D-glucopyranosyl (1-6)-β-D-glucopyranosyl oleanolic acid 28-β -D-glucopyranosyl (1-6)-β-Dglucopyranosyl ester and 21 β-benzoylsitakisogenin 3-O-β- D-glucuronopyranoside 3-O-β-D-xylopyranosyl (1-6)-β-D-glucopyranosyl (1-6)-β-D-glucopyranosyl oleanolic acid 28-O-β -D-glucopyranosyl ester are contributing to major oleanane-triterpene glycosides. There are also seven novel dammarane saponins from the leaf extract of G. sylvestre  known as gymnemasides I-VII. The introduction of gymnemic acid IV can decrease whose efficacy is comparable to the commercially available drug glibenclamide. A recent study also revealed that crystallographic investigation of gymnemagenin certainely indicated its good gelling with the target protein’s crystallographic constitution (aldose reductase, dipeptidyl peptidases, fructose 1,6-bisphosphate, glucokinase, 11β-hydroxysteroid dehydrogenase, cytochrome 450, protein kinase B, tyrosine phosphatases, Insulin receptor substrate, cholesteryl ester transfer protein, glutamine fructose- 6-phosphate amidotransferase, AMP-activated protein kinase and Glucose transporter) which contribute to its carbohydrate management property ( 83 ). In addition, the leaf extract of Gymnema sylvestre  at 400 mg b.i.d dose lessened fasting blood glucose levels by 11%, postprandial blood glucose levels by 13% and HbA1c value by 0.6% in a 3 month long open-label trial consisting of 65 type 2 diabetic patients ( 85 ). Such lessening of the fasting blood glucose levels and post-prandial blood glucose levels were additionally consolidated by two other open-label trials on diabetic patients where the leaf extract of G. sylvestre  were administered in the dose of 6–10 g for 15–21 days ( 86 , 87 ). Moreover, in a 18-20 month-long controlled, open-label study on 22 subjects suffering from type 2 diabetes, 400 mg/day supplementation of G. sylvestre leaf extract exhibited a better reduction in blood glucose, glycosylated haemoglobin and glycosylated plasma protein levels compared to conventional therapy of tolbutamide or glibenclamide alone. Interestingly, of the total 22 patients participating in the trial, 5 patients could maintain blood glucose homeostasis with 400 mg/day dose of G. sylvestre alone even after ceasing their conventional drug therapy ( 88 ). A similar open-label study on 27 type 1 diabetic patients observed that the leaf extract supplementation reduced the levels of glycosylated plasma protein and serum amylase and increased serum C-peptide levels in contrast to the conventional therapy alone through the possible mechanism of regenerating the residual beta cells of the pancreas ( 89 ).

Gynura divaricate (L.) DC.

Gynura divaricate (L.) DC. (family: Asteraceae) is a traditional Chinese herbal plant locally known as ‘Bai Bei San Qi’. It also cultivates in the eastern and northern Taiwan coasts though is widely found in various part of Asia ( 90 ). G. divaricate can improve glucose metabolism in animal models including mice and rats. A study also revealed its low toxicity profile in both in vivo and in vivo testing along with significant reduction of fasting serum glucose and improved pancreatic damage ( 91 ). Among hypoglycemic phytoconstituents of the plant aerial part, a few major compounds are nystose, β-D-fructofuranose, 1-kestose, sucrose and 1F-β-fructofuranosylnystose which are fructooligosaccharides. The hexose transport assay showed that Nystose delivered the most powerful hypoglycemic activity among these five isolated phytocompounds ( 92 ). PKM1/2, PI3K, p-AKT, and GLUT4 play a vital role in the insulin signaling pathway in diabetes. High blood glucose-induced cell death and senescence in nucleus pulposus cells are inhibited by the activation of the PI3K/AKT signaling pathway. PKM1/2 is involved in glycolysis, and GLUT4 is a glucose transporter which is present on the cell membrane. Past studies also suggested that increasing GLUT4 expression promotes the glucose uptake and utilization. It has been found that Gynura divaricate increases the expression levels of PKM1/2, PI3Kp85, p-AKT, and GLUT4 resulting in the reduction of blood glucose levels ( 93 ).

Hordeum vulgare L.

Hordeum vulgare L. (family: Poaceae) is an annual herbaceous monocotyledonous grass commonly known as ‘Barley’ which originated in the Fertile Crescent including Israel, Jordan, Syria and southern Turkey to Zagros Mountains in Iran ( 94 , 95 ). It contains high levels of dietary fiber such as β-glucans whose oral administration into type 2 diabetic and high‐fat diet induced obese mice resulted in a significant lowering of blood glucose level ( 96 ). The underlying mechanism is thought to be the suppression of sodium‐glucose transporter‐1 expression in the intestinal mucosa. Besides, it also promotes glycogen synthesis and inhibits fat accumulation in the liver, and depresses macrophage infiltration and the production of pro‐inflammatory cytokines ( 97 ). It was also found to promote glucose uptake and reduce gluconeogenesis by downregulating some genes responsible for gluconeogenesis. Barley is also rich in magnesium acting as a co-factor for more than 300 enzymes as well as for those which are involved in glucose metabolism and insulin secretion. It has been observed that regular consumption of whole grains can lower the risk of type II diabetes by 31%. This could be due to its high fiber content ( 98 ). β-glucans from barley also improved glycemic control in diabetic patients, mainly by abating postprandial blood glucose levels, according to multiple clinical studies. It has been suggested through clinical trials that high β-glucans containing foods have lower glycemic index (GI) and diabetic people should substitute the high-GI foods in their diet with low-GI foods in order to control the disease ( 99 , 100 ).

Larrea tridentata (Sessé & Moc. ex DC.) Coville

Larrea tridentata (Sessé & Moc. ex DC.) (family: Zygophyllaceae), known as Coville or ‘Creosote bush’ is a highly brunched and evergreen shrub from Zygophyllaceae which is widely available in North American warm deserts and Mexico ( 101 ). It contains Masoprocol, a lipooxygenase inhibitor as the major antihyperglycemic compound which decreased plasma glucose level in type-2 diabetic mice models without changing the concentration of plasma insulin. Additionally, it has been shown to improve oral glucose tolerance and enhance insulin activity in lowering the plasma glucose levels in masoprocol-treated db/db mice ( 102 ).

Lobelia chinensis Lour.

Lobelia chinensis Lour. (family: Campanulaceae), known as ‘Asian Lobelia’ or ‘Chinese Lobelia’ is distributed throughout China, Taiwan, Korea, and Japan. It is a plant from which two new pyrrolidine-type alkaloids, radicamines A and radicamines B, were found to inhibit α-glucosidase activity and demonstrate antidiabetic efficacy ( 103 ). Besides, it has also been reported that the active ingredients of 5-hydroxymethylfural and acacetin in L. chinensis has been shown to promote the secretion of insulin, improve insulin resistance, and stimulate the utilization of glucose by acting on GSK3B, MAPK, INR, and dipeptidyl peptidase-4 (DPP4) ( 104 ).

Lupinus perennis L.

Lupinus perennis L. (family: Fabaceae) is a perennial herb which is abundantly found in Canada and USA ( 105 ). It is a plant from the leaves of which the compounds lupanine, 13-a-OH lupanine, and 17-oxo-lupanine were extracted and enhanced the secretion of insulin from isolated rat islets in a glucose-dependent manner. It was assumed that these quinolizidine alkaloids can increase insulin release by reducing K + permeability in the β-cell plasma membrane. The fact that 13-a-OH lupanine and 17-oxo-lupanine stimulate insulin secretion only at high glucose concentrations indicates that it would reduce the risk of hypoglycemia which could be of additional value when considering their potential use in the treatment of type 2 diabetes ( 106 ).

Matricaria chamomilla L.

Matricaria chamomilla L. (family: Asteraceae), commonly known as ‘German chamomile’, ‘Hungarian chamomile’ or ‘wild chamomile’, is a herbaceous plant natively distributed in European and West Asian regions ( 107 ). Its aerial part’s ethanol extract dose-dependently lessened postprandial blood glucose levels and showed protective action on pancreatic β-cells of streptozotocin (STZ)-induced diabetic rats. The same study also reported a significant reduction in oxidative stress related to hyperglycemia ( 108 ). A similar study on STZ-induced diabetic rats showed that a 21 day long 200 mg kg- 1 body weight dose of M. chamomilla leaf extract significantly diminished the fasting blood glucose levels by 62.2% ( 109 ). HbA1C and blood glucose values were also reduced in STZ-induced female fertile diabetic rats after administering the plant’s aerial part-derived ethanolic extract ( 110 ). In addition, another animal study reported the effectiveness of M. chamomilla flower extract and the isolated compounds quercetin, esculetin, umbelliferone and luteolin in preventing the progression of hyperglycemia. It was observed that quercetin and esculetin moderately inhibited the enzymatic activity of sucrase in rats and all the compounds halted sorbitol from accumulating in the erythrocytes of humans. Quercetin and the hot water extract also suppressed blood glucose levels in a 21 days long feed test on STZ-induced diabetic rats. Furthermore, esculetin diminished hyperglycemia in a disaccharide loading test on mice. It was also reported that the extract exhibited good inhibitory activity against the aldose reductase enzyme ( 111 ). Apigenin, which is another compound isolated from the plant, showed antihyperglycemic action by causing increment in blood insulin and diminution in blood glucose levels in alloxan induced diabetic mice ( 112 ). In an 8 week long randomized controlled trial on 64 type 2 diabetic patients (12 were male and 52 were female; age range: 30-60 years), chamomile tea in the dose of 3 g/150 mL thrice a day showed a significant diminution in the HbA1C level by 5.01%, HOMA-IR level by 39.76%, and serum insulin level by 32.59% compared to baseline values and caused improvement in antioxidant activity ( 113 ). Another 4 week long randomized-controlled trial on 50 type 2 diabetic patients observed that twice-daily infusion of 10g/100 ml chamomile as a supplementation significantly improved glycemic control by lessening fasting blood glucose and 2h postprandial blood glucose levels. Moreover, lipid profile was also ameliorated in the patients ( 114 ).

Momordica charantia L.

Momordica charantia  L. (family: Cucurbitaceae) is a flowering vine cultivated in Asia including Bangladesh, India and in other regions like East Africa and South America as well. The fruit has a distinct bitter taste for which this plant is known as bitter gourd which is also well known as ‘Korolla’, ‘Karela’, ‘Bitter melon’ or ‘Balsam pear’. The bitterness becomes more intensified when it ripens. The plant produced notable antidiabetic and hypoglycemic actions which ascertain the adjuvant use of the plant along with conventional commercialized drugs ( 115 ). The oral consumption of the juice of M. charantia  seeds showed prominent hypoglycemic activity in streptozotocin induced type 1 diabetic rat models. There are many bioactive phytocompounds isolated from M. charantia  producing remarkable antidiabetic activity. Among saponins, 3-hydroxycucurbita-5, 24-dien-19-al-7, 23- di-O-β-glucopyranoside and Momordicine- II were extracted from corolla exhibiting promising insulin-releasing properties in MIN6 β-cells. Charantin, a cucurbitane type triterpenoid extracted from the same plant has also showed tremendous antidiabetic activity which is even more potent than standard oral hypoglycemic drug tolbutamide ( 115 ). Polypeptide-p or p-insulin, insulin-like hypoglycemic protein type substance which demonstrated blood glucose-lowering activity in human upon subcutaneous administration was isolated from corolla. The insulin mimicking activity of Polypeptide-p can be considered as a plant based alternative of insulin in type 1 diabetic patients ( 115 ). Vicine, a glycol alkaloid is another isolated compound from M. charantia  which can promote hypoglycemia in non-diabetic fasting rat models upon intraperitoneal administration ( 115 ). Among other isolated compounds, Momordicoside U showed moderate activity during in vitro insulin secretion property screening and 5β,19-epoxy-3 β,25-dihydroxycucurbita-6,23(E)-diene and 3 β,7 β,25-trihydroxycucurbita-5,23(E)-dien-19-al both revealed hypoglycemic activity in diabetes induced male mice models ( 116 , 117 ). A meta-analysis study of ten clinical trials conducted in 1045 type 2 diabetic patients observed that M. charantia possessed significant glycemic control improving ability since it lessened FPG, HBA 1c and PPG levels without causing any side effects. In addition, prediabetic subjects also had a reduction in their FPG levels ( 118 , 119 ). Such action is reported to occur because of increased insulin secretion, as per another randomized-controlled trial. Moreover, anthropometric parameters, namely weight, body mass index, waist circumference, fat percentage were also decreased ( 120 ). Another trial on maturity-onset diabetic patients reported the antihyperglycemic action of M. charantia since it decreased mean blood glucose levels in fasting conditions as well as at 1, 2 and 12 hours after oral intake of 50 g glucose ( 121 ).

Moringa oleifera Lam.

Moringa oleifera Lam. (family: Moringaceae) is a perennial angiosperm plant native to Asia and greatly found in Malaysia and other tropical countries. Local name of M. oleifera is ‘Sajna’, ‘Soanjna’ and ‘Sohanjna’ and the english name is ‘Drum stick tree’ ( 122 ). It is a plant whose leaf’s alcoholic extract along with its antidiabetic phytocompounds like flavonoids, alkaloids, tannins, steroids and glycosides is assumed to be effective to treat diabetic complications. Quercetin and kaempferol, two major phytoconstituents, isolated from M. oleifera notably reduced serum glucose (33.34%) along with augmentation in serum insulin level when introduced to diabetic rat models for four weeks ( 123 ). In another study, moringinine, quercetin and chlorogenic acid, notable phytochemicals extracted from this plant were introduced to diabetic rat models to evaluate antidiabetic efficacy. The outcome showed alleviated serum glucose, total cholesterol and triacylglycerol level at a dose of 150 mg/kg after 21 days of care. In addition, in diabetic rats, it also restored the normal histological structure of the pancreas ( 124 ). Past studies have indicated that the glucose uptake in the rat soleus muscle is stimulated by kaempferol via the PI3K and PKC mechanisms. When administered orally, kaempferol was found to reduce fasting blood glucose levels significantly and serum HbA1c levels besides improving insulin resistance. Additionally, Quercetin blocks the transport of fructose and glucose by GLUT2 in the brain and promotes the translocation and expression of GLUT4 in skeletal muscle ( 125 ). In addition, in a randomized control design trial, promising inhibition in the increment of serum glucose after 2h of 75g oral glucose intake was observed after taking capsules processed with M. oleifera leaf in a population pool of 18-55 years old ( 126 ). The efficacy of M. oleifera in twenty diabetic and ten healthy individuals of 35 to 60 years old was evaluated in another clinical trial. The concentration of glucose, triglycerides, glycosylated hemoglobin, total cholesterol and low-density lipoprotein cholesterol decreased significantly while high-density lipoprotein cholesterol was upraised. This hypoglycemic efficacy has been assumed to be attributed to phenols, tannins, flavonoids, alkaloids and carotenoids ( 122 ). In another study, an assessment was conducted to evaluate the ability of M. oleifera leaf powder to inhibit the activity of α-amylase in vitro . The study found that M. oleifera leaf powder decreased α-amylase enzyme activity by 68.2 ± 3.2% ( 127 ). The study also further evaluated in vivo activity of the leaf powder on postprandial blood glucose levels in the subjects of Saharawi refugee camps (17 diabetic and 10 healthy individuals). The study displayed that administration of 20g leaf powder improved postprandial glycemic index at 90, 120 and 150 min. as well as improved the mean glycemic index in diabetic patients compared to the control group which indicates the candidacy of M. oleifera as an antihyperglycemic herbal drug ( 127 ).

Morus alba L.

Morus alba L. (family: Moraceae), known as ‘Mulberry’ is a quickly growing tree growing as long as 20 m. It is native to China though cultivated sporadically in Japan and Korea ( 128 ). Three major compounds, namely Moracin M, steppogenin-4′-O-β-D-glucosiade and mullberroside A showing efficacy in alloxan induced mice models by demonstrating hypoglycemic efficacy and decreasing fasting blood glucose level were isolated from the plant ( 129 ). Moreover, the alkaloids extracted from the leaves of mulberry were found to exhibit hypoglycemic effects in streptozotocin- (STZ-) induced diabetic mice. It has been reported that 1-deoxynojirimycin (DNJ), a mulberry alkaloid, reduces the activity of α-glucosidase by competitive inhibition. Upon oral administration of starch and sucrose in Kunming mice, flavonoids from mulberry leaf reduced blood glucose level and inhibited α-glucosidase activity. In the laboratory experiment, two flavonoids (isoquercitrin and astragalin) were found to inhibit α-glucosidase activity. Polysaccharides isolated from the leaves of mulberry were reported to reduce plasma glucose level, improve glucose tolerance, increase the hepatic glycogen content, and inhibit α-glucosidase activity. The extracted polysaccharides α-arabinose, α-xylose, α-glucose, α-rhamnose, and α-mannose were found to repair pancreatic β-cells, resulting in increased insulin secretion and reduced accumulation of liver fat in diabetic rats ( 130 ). A randomized, placebo-controlled study on 10 type 2 diabetic (age range: 59 –75 years) and 10 healthy subjects (age range: 24 – 61 years) involving the ingestion of 1 g leaf extract of Morus alba showed remarkably reduced blood glucose levels after 2 hours in comparison to the placebo group ( 131 ). Another trial showed the effectiveness of the leaf extract in suppressing insulin and postprandial blood glucose levels ( 132 ). In addition, fasting blood glucose was better reduced by M. alba compared to glibenclamide in 24 type 2 diabetic patients (24 male; age range: 40-60 years), as per a 30 day long randomized controlled trial ( 133 ). Moreover, a 25% inhibition in carbohydrate absorption of healthy subjects was observed in another crossover trial, suggesting that M. alba could also be used as a supplementation in the treatment of type 2 diabetes ( 134 ). 1-Deoxynojirimycin (DNJ) from the leaves of M. alba in 0.8 and 1.2 g doses also notably reduced the postprandial blood glucose levels and insulin secretion of 24 healthy subjects (mean age: 25.3 ± 0.7 years) in a randomized controlled trial. Such efficacy advocates for the use of 1-Deoxynojirimycin as a dietary supplement in the treatment of diabetes mellitus ( 135 ).

Nelumbo nucifera Gaertn.

Nelumbo nucifera Gaertn. (family: Nelumbonaceae), commonly known as ‘Chinese water lily’, ‘Indian lotus’ and ‘Sacred lotus’, is a large aquatic rhizomatous perennial plant ( 136 ). Nuciferine, an alkaloid was extracted from the plant through identifying by NMR spectroscopy and was found to increase insulin secretion in both isolated islets and INS-1E cells. It was found that nuciferine stimulates both the first phase and the second phase of insulin secretion. These results indicated that the nuciferine acts by closing K-ATP channels and also through stimulation of K-ATP channel-independent amplification pathways. Besides, it shows less cytotoxicity than Glibenclamide ( 137 ). In addition, N. nucifera seeds achieved a low glycemic index (GI) in a randomized crossover trial on healthy subjects ( 138 ).

Nigella sativa L.

Nigella sativa L. (family: Ranunculaceae) is a herbaceous plant which occurs in several southern Mediterranean and Middle Eastern countries. The seeds of Nigella sativa are known by the name ‘Black seed’ or ‘Black cumin’. Its seed’s ethanolic extract was found to enhance insulin secretion, stimulate proliferation of pancreatic β-cells, and enhance glucose uptake in muscle and fat cells ( 139 ). It has been suggested that Nigella sativa exhibits its hypoglycemic effect due to the presence of thymoquinone, dithymoquinone, linoleic acid and oleic acid which might be responsible for stimulating pancreatic β-cells causing insulin secretion, reducing hepatic gluconeogenesis, and inducing insulin sensitivity in peripheral tissue. A placebo-controlled participant blinded clinical study on 114 type 2 diabetic patients found that N. sativa supplementation plays an important role in the amelioration of oxidative stress, the latter being responsible for diabetes mellitus pathogenesis. It has been found that the former does so by improving total antioxidant capacity, glutathione and superoxide dismutase values. The same study perceived that reduction in insulin resistance was also significant in the diabetic patients in the group taking N. sativa supplementation compared to the placebo group ( 140 ). Supplementation of Nigella sativa in type 2 diabetes patients was found to improve fasting blood glucose, HbA1c, total- cholesterol, and LDL level significantly ( 33 ). As such, a systematic review done to assess the effect of N. sativa on type 2 diabetes mellitus has also suggested that it could be adjunctively used with other oral antidiabetic medications to manage the disease ( 141 ).

Panax ginseng C. A. Meyer

Panax ginseng C. A. Meyer (family: Araliaceae) is also known as ‘Asian ginseng’. It is a plant that has been reported to modify blood glucose levels by increasing insulin sensitivity, ameliorating the function of pancreatic β-cells, and stimulating glucose uptake by elevating the production of glucose transporters (GLUT). The berry extract of P. ginseng stimulates the β-cell proliferation leading to increased insulin secretion to control the level of blood glucose in streptozotocin (STZ) -induced diabetic mice. Besides, it also results in improved sensitivity to insulin in C57BL/6 mice over 15 months old ( 142 ). Ginseng is known to contain ginsenosides, a group of steroidal saponins, including neutral ginsenosides and malonyl ginsenosides. Ginseng and neutral ginsenosides were found to lower blood glucose, increase insulin sensitivity, regulate lipid metabolism, and reduce body weight ( 143 , 144 ). Administration of malonyl ginsenosides in high fat diet/streptozotocin diabetic rats was found to remarkably reduce fasting blood glucose levels, improve glucose tolerance and insulin sensitivity without affecting body weight ( 143 , 144 ). The study results suggest that malonyl ginsenosides could be used to treat type-2 diabetes. In addition, a meta-analysis of sixteen clinical trials revealed that Ginseng caused a significant reduction in fasting blood glucose levels in both diabetic and non-diabetic patients, while the other glycemic parameters were contradictory in terms of outcomes ( 145 ). Besides, a randomized, placebo‐controlled, double-blind study in 20 type 2 diabetic patients (mean age: 51.5 ± 1.9 years) observed about 45% reduction in HOMA-IR in the group which was given P. ginseng supplementation compared to 12% reduction for the placebo group ( 146 ). Moreover, combinatory administration of Panax ginseng and Panax quinquefolius in a 12 week long randomized controlled trial on 80 type 2 diabetic subjects (49 were male and 31 were female) reduced another glycemic control parameter, namely HbA1c by −0.35 ± 0.1% along with blood lipid parameters (total cholesterol, LDL-C, triglycerides) and 24-hour systolic blood pressure without causing any side effects ( 147 ).

Pandanus amaryllifolius Roxb.

Pandanus amaryllifolius Roxb. (family: Pandanaceae) is a shrub native to Thailand. This plant is also known as Pandanus odorus . Local name of the plant is ‘Toei-hom’ ( 148 ). In recent studies, P. amaryllifolius exhibited very prominent hypoglycemic activities. The root extract of the plant evidently lowered blood glucose levels in streptozotocin induced mice models. The leaf extract could also show promising antihyperglycemic activity by stimulating insulin production and glucose uptake along with inhibition of α-glucosidase enzyme ( 148 ). 4-Hydroxybenzoic acid is the major hypoglycemic phytoconstituents isolated from the aqueous extract of this plant root. Upon oral administration, this moiety upraised serum insulin and liver glycogen level in normal rat models ( 149 ). A clinical study performed on 30 healthy subjects (15 were male and 15 were female; age range: 15-25 years) showed that intake of 30 g of P. amaryllifolius containing tea caused a significant lessening of postprandial blood glucose ( 148 ).

Punica granatum L.

Punica granatum L. (family: Punicaceae) locally known as ‘Dalim plant’ is a plant native to some Asian countries including India, Bangladesh, Iran and Malaysia along with some other countries of America and European continents, such as United States of America, Peru, Turkey, etc. The fruit of the plant (commonly known as ‘Dalim’ in Asian countries) is popularly consumed as fresh form along with processed juice, jam, paste and wine ( 150 ). The fruit aqueous extract of P. granatum can notably decrease fasting glucose level along with promising increment in the expression levels of Glut-4, Glut-2, Akt and IRS-1 followed by improved glucose uptake and its storage in alloxan induced male Wistar rat models ( 151 ). It is blessed with several polyphenolic compounds like punicalagin, valoneic acid dilactone, anthocyanin, phenolic and non-phenolic Acids, Glutenins and Tannins ( 151 ). Among those, valoneic acid dilactone is the main antidiabetic principle which showed its antidiabetic efficacy by inhibiting the activity of aldose reductase enzyme in a dose dependent pattern. Protein tyrosine phosphatase 1B (PTP1B) was also inhibited by valoneic acid dilactone which can also ameliorate the level of blood glucose in alloxan induced diabetic rat models. Other possible mechanisms attributed to antidiabetic action of valoneic acid dilactone may be attributed to improved insulin secretion from rom pancreatic β cells or its release from the bound form along with insulin-mimetic actions or amended glucose utilization technique ( 150 ). In addition, an 8-week long double blind randomized-controlled clinical study on 52 type 2 diabetic patients with obesity (26 were male and 26 were female; age range: 30-50 years) found that supplementation of P. granatum significantly reduced fasting blood glucose from 161.46 mg/dl to 143.50 mg/dl. An increase in GLUT-4 gene expression was also observed in the patients ( 152 ). Furthermore, another single-blind, randomized-controlled clinical study conducted on 44 type 2 diabetic patients (23 were male and 21 were female; age range 56 ± 6.8 years) found that the juice of P. granatum significantly ameliorated oxidative stress, suggesting that it’s consumption could retard the onset of oxidative stress associated diabetes mellitus ( 153 ).

Pongamia pinnata (L.) Pierre

Pongamia pinnata (L.) Pierre (family: Fabaceae) is a medium-sized glabrous tree, commonly known as ‘Karanja’ in Hindi, ‘Indian Beech’ in English, and ‘Pongam’ in Tamil. It occurs throughout India, and mainly found in tidal forests of India. The flowers of P. pinnata reportedly possessed anti-hyperglycemic and anti-lipidperoxidative properties ( 154 ). It has been found that oral administration of the aqueous (PPAE) and ethanolic (PPEE) extracts of the leaves of P. pinnata PPEE in alloxan diabetic rats resulted in a pronounced reduction in the plasma glucose level. This may be attributed to the enhancement of the effect of insulin by increasing the insulin release from the pancreatic β-cells or its release from the bound insulin. The significant glucose-lowering effect of PPAE and PPEE could also result from increased peripheral glucose utilization ( 155 ). Karanjin, one of the isolated compounds from this plant was reported to possess hypoglycemic activity in normal and in alloxan-induced diabetic rats. Pongamol and karanjin extracted from the chloroform-soluble fraction of the ethanolic extract of P. pinnata fruits exhibited significant glucose-lowering activity ( 156 ). The underlying mechanism of anti-hyperglycemic activity of the compounds may be attributed by the inhibition of PTPase-1B, a major mediator of insulin signaling and insulin resistance ( 156 ).

Psacalium peltatum (Kunth) Cass.

Psacalium peltatum (Kunth) Cass. (family: Asteraceae) is a plant natively grown and known as ‘Matarique’ in Mexico. Peltalosa, an ulopyranose compound, has been obtained from the roots and rhizomes of P.peltatum which has showed anti-hyperglycemic activity on mice with mild diabetes, although the efficacy decreased on mice models with severe diabetes ( 157 ). The hypoglycemic effect of the compound was reported to be similar to tolbutamide, and the possible underlying mechanism of action could be attributed to enhanced secretion of insulin from the islets of Langerhans or an increased utilization of glucose by peripheral tissues ( 157 ).

Silybum marianum (L.) Gaertn

Silybum marianum (L.) Gaertn (family: Asteraceae), also known by the common name ‘Milk thistle’ is an annual or biennial herb native to the Mediterranean regions of Europe, North Africa and the Middle East and in some parts of USA ( 158 , 159 ). Its major component is silymarin, a mixture of silibinin (silybins A and B), isosilybin (isosilybins A and B), silychristin and silydianin ( 160 ). Administration of silymarin in patients with type 2 diabetes resulted in a significant reduction in HbA1c level, fasting plasma glucose (FPG), daily blood glucose average and glucosuria, daily insulin requirement, fasting insulin, as well as an increase in serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT) and HDL levels. When silymarin was supplemented with glibenclamide in type 2 diabetes patients, a reduction in postprandial hyperglycemia was also observed ( 33 ). A flavonolignans, silychristin A, extracted from Silybum marianum demonstrated a marked reduction of both postprandial and/or fasting hyperglycemia and improvement of the function of β-cells in STZ-induced T1DM. It has been suggested that silychristin A exerts its glucose-lowering effect by protecting the β-cells from oxidative stress-induced damage and blocking the activity of the α-glucosidase enzyme ( 159 ).

Swertia chirayita Buch Ham.

Swertia chirayita Buch Ham., (family: Gentianaceae) locally named as ‘Chirayata’, ‘Chirayta’ and ‘Chiretta’ is a popular medicinal herb native to temperate Himalayan region ( 161 ). Promising antidiabetic efficacy of S. chirayita with improved insulin secretion was reported during cell line based evaluation technique using insulin secretion from monolayers of BRIN-BD11 clonal pancreatic cells ( 162 ). There are several antidiabetic compounds found in this species exerting prominent antidiabetic efficacy. According to 163 , 1,5,8-trihydroxy-3- methoxyxanthone extracted from the aerial parts and roots of the S. chirata can demonstrate antidiabetic efficacy by lowering blood sugar levels ( 163 ). Gentianine, another antidiabetic compound of this plant is the active metabolite of swertiamarin and is believed to attribute to the efficacy of swertiamarin ( 164 ). Promising amelioration in adipogenesis associated expression of PPAR-γ, GLUT-4 and adiponectin by gentianine administration expressed that the compound is responsible for antidiabetic efficacy of swertiamarin. Magniferin, a potent phytoconstituent found in S. chirata can also exhibit antihyperglycemic potentiality by exhibiting glucosidase and 2,2-diphenyl-1-picrylhydrazyl radical inhibition action. Besides, as a co-therapy with metformin and gliclazide it cured renal injury symptoms due to diabetic neuropathy ( 165 ). Moreover, compounds, found in S. chirata like amarogentin is used in the preparation of different forms of commercially available drugs to treat diabetic complications ( 166 ). A 30 day long clinical study done on 12 type 2 diabetic patients found that ingestion of S. chirayita in grounded powder form caused 14.5% reduction in blood glucose level. A reduction was also noticed in lipid profile (total cholesterol by 8.6%, LDL-c by 14.4% and, tryglycerides by 10.5%) ( 167 ).

Syzygium cumini (L.) Skeels

Syzygium cumini (L.) Skeels (family: Myrtaceae) is known as ‘Jamun’, ‘Jambul’ and ‘Jambol’ in India and Malaya. The seeds of S. cumini are thought to lower blood sugar levels by increasing either insulin secretion from β-cells of the islets of Langerhans of Pancreas or its release from the bound form. Mycaminose, isolated from the seeds of S. cumini was found to produce a remarkable reduction in blood glucose level ( 168 ). It was suggested that the mode of action of mycaminose is similar to Glibenclamide, a commercially available anti-diabetic drug ( 168 ). In a double-blind randomized controlled trial involving 99 type 2 diabetic patients, 10 g daily Syzygium cumini supplementation significantly lessened fasting blood glucose by 30%, post-prandial blood glucose by 22% and HbA1c value from 8.99 ± 1.39% to 8.31 ± 1.40% after 90 days ( 169 ).

Tinospora cordifolia (Willd.) Miers

Tinospora cordifolia (Willd.) Miers (family: Menispermaceae) is commonly known as ‘Guduchi’ or ‘Amrita’ and is found in the Indian subcontinent and China. It has exhibited blood and urinary glucose-lowering activity along with suppression in the increase of blood glucose level in animal models ( 170 , 171 ). It is considered as an antidiabetic herbal drug in the Indian Ayurvedic Pharmacopoeia too due to its alkaloids, diterpenoids and glycosidic constituents. Among the alkaloids, magnoflorine was found to be the most potent α-glucosidase inhibitor ( 172 ). Besides, a norclerodane diterpenonoid, tinosporaside, extracted from T. cordifolia possessed 28% antihyperglycemic activity when it was compared with Metformin 20.6% in diabetic rat models ( 173 ). It has been found that the isoquinoline alkaloid rich fraction (AFTC) isolated from the stem of T. cordifolia (AFTC) significantly reduced the synthesis of glucose in rat hepatocytes like insulin did and it also stimulated secretion of insulin in RINm5F cells like tolbutamide. The underlying mechanism may be attributed to the promotion of insulin release and insulin-mimicking activity ( 174 ). In addition, the powdered stem of T. cordifoia at the oral dose of 50 mg/kg of body weight significantly reduced the fasting blood glucose and HbA1c levels by 9% and 14%, respectively in type 2 diabetic patients ( 175 ).

Trigonella foenum-graecum L.

Trigonella foenum-graecum L. (family: Fabaceae) known as Fenugreek or Methi is a legume and a popular seasoning worldwide to improve the taste and flavor of food ( 176 ). Its seed water-soluble compound GII extract when administered for 15 days in the subdiabetic and moderately diabetic rabbits and for 30 days in the severely diabetic rabbits resulted in the elevation of hepatic and muscle glycogen content, stimulated hexokinase, glucokinase, pyruvate kinase, malic enzyme, glucose-6-phosphate dehydrogenase, superoxide dismutase, glutathione peroxidase, and reduced the activity of glucose-6-phosphatase, sorbitol dehydrogenase, aldose reductase. Partially damaged pancreatic cells were also regenerated following the administration of GII ( 177 ). Trigonelline, nicotinic acid and coumarin are antidiabetic phytochemicals that were isolated from Fenugreek seed. These three antidiabetic compounds extracted from fenugreek showed prominent efficacy in alloxan induced severe and moderate diabetic rabbit models ( 178 ). A meta-analysis on 10 clinical trials conducted on type 2 diabetic patients revealed that fenugreek can significantly improve glycemic control by altering parameters, namely fasting blood glucose level by -0.96 mmol/l, HbA1c value by -0.85% and 2 hour postprandial glucose level by -2.19 mmol/l ( 179 ). As per a 2 month long double blind placebo controlled trial on 25 subjects with type 2 diabetes mellitus, hydroalcoholic extract of fenugreek seed also decreased insulin resistance compared to control which was apprehended by an increase in insulin sensitivity percentage (112.9 ± 67% vs 92.2 ± 57%, respectively) and beta-cell secretion percentage (86.3 ± 32% vs 70.1 ± 52%, respectively) through HOMA-IR test ( 180 ).

Vitis vinifera L.

Vitis vinifera L. (family: Vitaceae), known as ‘Grapevine’ or ‘Red grape’ is native to southern Europe and western Asia. However, it is cultivated worldwide which makes it the largest fruit crop in the world. It contains many active components in its seed and skin, including polyphenols, flavonoids, proanthocyanidins, anthocyanins, procyanidins, and resveratrol, a stilbene derivative ( 181 ). The kir6.2 channel is encoded by the KCNJ11 gene. It has been shown that congenital hyperinsulinism is caused by a mutation in this gene and has a significant role in the development of type-1 diabetes. Pterostilbene has promising inhibitory efficacy on both normal and mutant models of kir6.2 as an active component of V. vinifera . Again, quercetin, myricetin and resveratrol are three other most notable polyphenols found in red grapes to treat diabetic complications. Quercetin can demonstrate improved expression of adiponectin in white adipose tissue and blood concentration, despite inhibition of poly (ADP-ribose) polymerase γ expression followed by improved insulin sensitivity ( 182 ). Quercetin can also inhibit glucose uptake at the level of glucose transporters (GLUTs) ( 183 ). Besides, to treat hyperglycemia, Myricetin is also used as traditional medicine in northern Brazil. Myricetin can promote glucose uptake in the liver and soleus muscles as well as hepatic glycogen synthase ( 184 ). Myricetin can also improve insulin resistance in fructose chow-fed rat models ( 185 ). In addition, it can also halt advanced glycation end products in diabetic conditions ( 184 ). Furthermore, antihyperlipidemic and human pancreatic alpha-amylase inhibitions are a few other promising mechanisms by which myricetin can produce a significant antidiabetic effect ( 186 ). Resveratrol, a phytochemical from stilbene class of polyphenolic compounds isolated from red grape can also demonstrate strong antidiabetic activity. It can also protect against diabetic nephropathy while administration of resveratrol along with protective activities in renal dysfunction and oxidative stress ( 187 ). Resveratrol can effectively restore cellular homeostasis by activating the redox plasma membrane system, which functions as a compensatory mechanism in the cell to preserve redox status ( 184 , 188 ). Besides, resveratrol administration to diabetic rats has resulted in decreased concentration of glycosylated hemoglobin ( 189 ). The antihyperglycemic efficacy of resveratrol, demonstrated in diabetic animals has been suggested to be due to the stimulatory activity on the transportation of intracellular glucose. The involvement of resveratrol can also promote glucose uptake in diabetic rat models ( 190 ). Improved expression of the insulin-dependent glucose transporter (GLUT4) was reported after ingestion of resveratrol in the study conducted on diabetic rat models ( 191 , 192 ). Resveratrol was also reported to modulate the function of sirtuin-1, which ameliorates homeostasis of whole-body glucose and insulin sensitivity in diabetic rats ( 192 ). Moreover, in a 3 month long randomized controlled clinical trial on 62 subjects with type 2 diabetes mellitus (age range: 30-70 years), resveratrol supplementation exhibited antihyperglycemic action by lowering the value of hemoglobin A1c compared to the control (9.65 ± 1.54 vs 9.99 ± 1.50, respectively) ( 193 ). In another 45 days long randomized double-blinded placebo-controlled parallel clinical study on 66 subjects (age range: 20-65 years) with type 2 diabetes mellitus, 1 g daily resveratrol supplementation exhibited antihyperglycemic action by lowering the values of fasting blood glucose, hemoglobin A1c, insulin secretion, and insulin resistance compared to baseline ( 194 ). In another 30 days long randomized, double‐blind, crossover trial, resveratrol supplementation lowered the response of postprandial glucagon in obese type 2 diabetic patients ( 195 ). Quercetin also reduced fasting blood glucose and insulin secretion, as per a meta‐analysis of randomized controlled trials ( 196 ).

Zingiber officinale Roscoe

Zingiber officinale Roscoe (family: Zingiberaceae) also known as ‘Ginger’ is a perennial plant with slender, brightly green, grassy leaves and yellowish green flowers which is grown in the tropics. Rhizome serves as the edible and medicinal part of the plant. Its administration to streptozotocin (STZ)-induced diabetic rats was found to reduce serum glucose, cholesterol and triacylglycerol levels significantly. Besides, raw ginger also exhibited effectivity in reversing diabetic proteinuria in diabetic rats ( 197 ). Several active constituents have been isolated from Ginger including gingerols and their related dehydration products, the shogaols, as well as volatile oils including sesquiterpenes, such as β-bisabolene and monoterpenes, mainly geranial and neral ( 197 ). A previous study revealed that 6-shogaol and 6-gingerol can suppress the development of diabetic complications as well as advanced glycation end products (AGEs) by arresting methylglyoxal, the precursor of AGEs ( 198 ). 6-gingerol can also arrest Nϵ-carboxymethyl-lysine (CML), a marker of AGEs through activation of Nrf2 ( 199 ). 6-paradol and 6-shogaol facilitated glucose consumption by increasing AMPK phosphorylation in 3T3-L1 adipocytes and C2C12 myotubes. Furthermore, 6-paradol considerably decreased the concentration of blood glucose in high-fat diet-fed mouse models ( 200 ). Besides, 6-gingerol, in type 2 diabetic mice, aided glucose-stimulated insulin secretion and improved glucose tolerance by upraising glucagon-like peptide 1 (GLP-1). In addition, 6-gingerol therapy galvanized glycogen synthase 1 and increased glucose transporter type 4 (GLUT-4) cell membrane presentations which amplified skeletal muscles’ glycogen storage ( 201 ). A meta-analysis study on 10 randomized-controlled clinical trials conducted on 490 type 2 diabetic subjects revealed that ginger improves glycemic control by lowering fasting blood glucose and HbA1c levels. Insulin sensitivity was also improved. Lipid profile improved as well ( 202 ). Moreover, the supplementation of ginger improved the recovery of inflammation in type 2 diabetic patients in a randomized-controlled clinical trial, suggesting that the supplementation could help lessen diabetes associated chronic complications ( 203 ).

Other Promising Plants and Phytocompounds

Researchers suggested that there are almost 800 dietary and non-dietary plants with antidiabetic properties ( 77 ). So it is not possible to describe every plant and its isolated bioactive phytochemicals in a single study. However, a few more notable antidiabetic plants along with their phytochemicals and possible antidiabetic actions are summerized in Table 1 in addition to the aforementioned plants.

Table 1

Plants with antidiabetic properties along with responsible phytochemicals and clinical trial studies.

Molecular Mechanisms of Medicinal Plants and/or Extracted Phytochemicals to Treat Diabetes Mellitus

A. inhibition of α glucosidase secreted from brush border of the small intestine.

Mammalian α glucosidase, a membrane-bound hydrolytic enzyme found in the mucosal brush border of the epithelia of the small intestine plays a key role in carbohydrate digestion. Inhibitors of this α glucosidase enzymes delay the cleavage of carbohydrates resulting in reduced glucose absorption and an attenuated postprandial glycemic level. Thus, α glucosidase inhibitors could show a beneficial effect in the management of non-insulin-dependent diabetes mellitus (NIDDM) by causing a reduction in postprandial blood glucose levels ( 265 , 266 ).

b. Inhibition of DPP-4 Enzyme

Glucagon like peptide-1 (GLP-1) and Glucose dependent insulinotropic polypeptide (GIP) are incretin hormones which can initiate the differentiation of β-cells, stimulate the biosynthesis and secretion of insulin and inhibit gastric emptying. However, these hormones are rapidly broken down by a serine peptidase enzyme known as dipeptidyl peptidase-4 (DPP-4). Therefore, inhibitors of DPP-4 can be used in the treatment of type 2 diabetes. These DPP-4 inhibitors exhibit their antidiabetic activity via prolongation of GLP-1 and GIP activity, stimulation of insulin release and inhibition of glucagon secretion which ultimately leads to regulation of the blood glucose level ( 267 , 268 ).

c. Inhibition of α Amylase Secreted From Salivary Gland

Hydrolysis of α-1,4-glucan polysaccharides, such as starch and glycogen is carried out by the enzyme, α-amylase which is found mainly in the saliva and pancreatic juice. Inhibition of this enzyme helps in the prevention of high postprandial blood glucose levels ( 269 ).

d. Increased Insulin Secretion

Past studies have shown that an increase in intracellular calcium ion [Ca2+]i was associated with insulin secretion. Generally, the release of insulin from the vesicles of the pancreatic β-cells is stimulated by a rise in [Ca2+]i. Membrane depolarization caused by the closure of the ATP-sensitive K+ channels of the insulin secreting β-cells leads to activation and opening of the voltage-dependent Ca2+ channels which increases the [Ca2+]i. These increased intracellular calcium levels stimulate the secretion of insulin from pancreatic β-cells. However, a few phytochemicals, for example, p-methoxycinnamic acid, has shown to increase insulin release by acting on the L-type Ca2+ channels rather than the ATP-sensitive K+ channels. This may also lead to a rise in cAMP via the inhibition of phosphodiesterase ( 270 , 271 ).

e. Increased Insulin Sensitivity and Enhanced Glucose Uptake by Muscle Cells and Adipose Tissue

Some phytochemicals improve the sensitivity of non-pancreatic cells to insulin resulting in improved glycemic control. In skeletal muscle and adipose tissue, glucose uptake is enhanced via the activation of a series of events which take place following an increase in insulin levels. When insulin binds to the insulin receptors, it causes phosphorylation of protein substrates leading to the activation of phosphatidylinositol 3-kinase (PI3K) and downstream signaling through PKB/Akt and PKC-λ/ζ. As a result, GLUT4, insulin-regulated glucose transporter protein is recruited to the cell membrane and an increase in the uptake of circulating glucose by the muscle cells and adipose tissue occurs via facilitated diffusion through GLUT4 transporter protein ( 272 ).

f. Nourishment of Pancreatic β-Cells

Survival, restoration and maintenance of the mass/function of pancreatic β-cells can hinder the pathogenesis of diabetes mellitus. β-cells from the pancreas secrete the hormone insulin which is crucially salient in maintaining homeostasis for glucose metabolism in the body. β-cells are impaired in type 1 diabetes due to macrophage, cytokine and T-cell mediated autoimmune reactions. In the case of type 2 diabetes, β-cells could possibly be debilitated or rendered dysfunctional due to factors like oxidative stress, enduringly elevated glucose or lipid levels, and the release of the inflammatory mediators. To inhibit such destruction, β-cells can be fortified against reactive oxygen species (ROS) accretion and lipid peroxidation mediated cell death by augmenting both non-enzymatic (e.g., reduced glutathione) and enzymatic (e.g., superoxide dismutase, glutathione S transferase, glutathione peroxidase, catalase) antioxidants which can enhance the antioxidant capacity of the cell. In addition, increment of the secretion of β-cell anti-apoptotic genes (e.g., Bcl-2 proteins) and minimizing the secretion of pro-apoptotic genes (e.g., caspases) hinders DNA and subsequent cell damage. Inhibition of the pro-inflammatory transcription factor NF-κB reduces the inflammation stimulated production of inducible nitric oxide synthase (iNOS) and NO, hence reducing cell damage through increasing Ca2+ level in ER and mitigating ER stress, inactivating the JNK pathway and thus actuating the PI3K/Akt signaling which supports cell proliferation, survival and growth. Suppression of the deterioration of β-cell through these mechanisms halts reduced insulin secretion, thereby avoiding the state of hyperglycemia ( 273 , 274 ).

g. Reduction of HbA1c and Glycated Plasma Protein Concentration

Since diabetes mellitus is a condition where blood carbohydrate concentration increases, the monosaccharides nonenzymatically react with the proteins in blood (mainly hemoglobin A and albumin) and adheres to form a modified protein complex (Schiff base) through a process called glycation. The produced glycated hemoglobin (HbA1c) and glycated plasma proteins are concerned with much significance in the research. HbA1c value is often examined as it is one of the major markers for the diagnosis of diabetes mellitus. These glycated products can further encounter intramolecular rearrangements followed by other irreversible reactions (condensation, cross-linking, glycoxidation, cyclization, dehydration, etc.) to become advanced glycation end products (AGEs) which can accumulate and cause deleterious effects on metabolic and vascular health, leading to added diabetic complications. Glycation inhibitors hinder this process through various mechanisms, namely competitively binding with the amino group of the protein, binding at the site of glycation, cutting the open chain structure of monosaccharides and, adhering to the intermediaries of the glycation reaction. Hence, the concentration of HbA1c and glycated plasma proteins is lessened and the aftermath of glycation and diabetic complications can be avoided ( 275 – 277 ).

h. Enhancement of GLP-1

Glucagon-like peptide-1 (GLP-1) is a hormone secreted by the L cells in the distal ileum and colon of the gastrointestinal system. Secreted upon nutrient intake, GLP-1 subsequently binds to GLP-1 receptor (a G-protein-coupled receptor) on pancreatic β-cell to exert its effects, namely, raising the glucose-dependent secretion of insulin and lessening the secretion of glucagon, decelerating gastric emptying, subduing of appetite with imparting a feeling of fullness. Circulatory GLP-1 faces immediate degradation by the enzyme dipeptidyl peptidase 4 (DPP-4) and hence has a short half life of about 2 min. As such, alternative compounds with the functionality of serving as agonists to GLP-1 receptor (GLP-1R) and being resistant to degradation by DPP-4 enzyme have been recognized feasible to employ the proper effect of GLP-1. The GLP-1 receptor (GLP-1R) agonists enhance insulin biosynthesis by increasing the transcription of the insulin genes through activating cAMP/PKA-dependent and -independent signaling mechanisms, increasing Ca2+ levels intracellularly, and activating the insulin gene promoting transcription factor pancreas duodenum homeobox 1 (Pdx-1). The agonist binding also results in inhibition of ATP-sensitive K+ channels, leading to depolarization of the membrane and simultaneous influx of extracellular Ca2+. ATP synthesis is also enhanced in mitochondria. The combined effect of surged ATP and intracellular Ca2+ level is the exocytosis of insulin storage granule. As a result, insulin secretion capability and reserve of β-cell is maintained. Glucagon secretion is inhibited by GLP-1R agonists either directly by acting on α-cells of the pancreas, or less likely indirectly along with the stimulated secretion of insulin. This inhibition ameliorates glycemic control as reduced glucagon level diminishes glucose production from the liver, which in turn reduces the required insulin in the bloodstream. Enhancement of GLP-1 also facilitates the indirect suppression of gastric emptying through the vagus nerve and its involvement with the central nervous system (CNS) located GLP-1Rs, thus relaying a sensory message to the brainstem ( 278 , 279 ).

i. Regulation of GLUT-4

Belonging to the group of sugar transporter proteins (GLUT1-GLUT12, and HMIT), glucose transporter type 4 (GLUT-4) is a 12-transmembrane domain containing transporter which allows insulin induced blood glucose influx into skeletal muscle and fat cells through facilitated diffusion process and hence maintains the homeostasis of glucose metabolism in the body. The transporter typically resides intracellularly but relocates to the cell membrane upon stimulation of insulin or during exercise through independent mechanisms. The receptor binding of insulin in target cells activates insulin receptor (IR) tyrosine kinase, thus beginning phoshphorylation of tyrosine moiety of insulin receptor substrate proteins (IRS) followed by phosphoinositide 3-kinase (PI3K) recruitment. Afterward, PI3K catalyzed phosphorylation of phosphatidylinositol-4, 5-bisphosphate (PIP2) produces phosphatidylinositol-3, 4, 5-triphosphate (PIP3), which in turn triggers the phosphorylation mediated activation of other protein kinases (Akt, aPKCλ/ζ) that eventually mobilize the effectors, namely Rab proteins. Rab proteins (Rab8 and Rab14) lead to GLUT-4 translocation into the cell membrane from intracellular GLUT4 storage vesicle (GSV) which increases glucose internalization up to 10-20 times ( 280 , 281 ).

Chemical Class Wise Few Most Prominent Antidiabetic Phytochemicals Along With the Reported Mechanism of Actions

Based on previous research studies, few phytochemicals have been already recognized as the most prominent antidiabetic lead compounds. Those are currently under exclusive assessment so that novel antidiabetic drugs can be introduced in the coming days. In Tables 2 – 5 the few most prominent phytochemicals with the reported mechanism of actions are represented briefly. Alongside these phytochemicals, concerned researchers should also evaluate other aforementioned phytochemicals in this review work to establish absolute safety and toxicity profile as well as the mechanism of antidiabetic actions.

Table 2

Antidiabetic potential of alkaloids extracted from medicinal plants and their mechanism of actions.

Table 5

Antidiabetic potential of other notablephyto compounds extracted from medicinal plants and their mechanism of actions.

Table 3

Antidiabetic potential of phenolics extracted from medicinal plants and their mechanism of action.

Table 4

Antidiabetic potential of terpenes extracted from medicinal plants and their mechanism of actions.

Future Research Directions

Diabetes is conventionally treated and managed by taking synthetic antidiabetic medications commercially available in the market. The major classes among these medicines are sulphonylureas (glibenclamide), biguanides (metformin), thiazolidinediones (pioglitazone), DPP-4 inhibitors (sitagliptin), alpha-glucosidase inhibitors (acarbose), glinides (repaglinide) and GLP-1 agonists (exenatide) ( 7 , 284 ). Despite the mass prevalence and usage, the synthetic drugs accompany various side effects which include hypoglycemia (for sulphonylureas, glinides), weight gain (for sulphonylureas, thiazolidinediones), cardiovascular risk (for sulphonylureas, thiazolidinediones), pancreatitis (for DPP-4 inhibitors, GLP-1 agonists), hepatitis (for thiazolidinediones, DPP-4 inhibitors), cancer risk (for DPP-4 inhibitors, GLP-1 agonists), gastrointestinal effects (for biguanides, GLP-1 agonists), lactic acidosis (for biguanides) ( 285 ). These adversities and constraints associated with the prevailing synthetic medications entail the researchers to search for antidiabetic drugs from plant sources with a better safety and efficacy profile. Along the lines of many other diseases, diabetes mellitus has been treated with plant based medications for a long while owing to factors like marked efficacy, less toxicity and side effects, low cost, and availability ( 286 , 287 ). An exclusive development of plant based drugs has seemingly occurred through evolutionary mechanisms, imparting the capability to interact with biomolecules ( 288 , 289 ). Isolated phytochemicals are either used as drugs or availed as chemical leads or their analogs for synthesizing biologically active compounds. The prevalence of phytochemicals in the pharmaceutical scenario can be perceived by surveying all the authorized drugs registered globally within the time frame of 25 years before 2007, where roughly 50% of the drugs were majorly plant based natural products or their synthetic derivatives ( 285 , 290 ). As an example, metformin, the extensively used drug in treating type 2 diabetes, is a drug derived from the plant Galegine officinalis ( 291 ). Antidiabetic action being one of the most popular fields of use of phytochemicals houses compounds from various chemical classes, namely flavonoids (quercetin), alkaloids (berberine), terpenes (thymoquinone), phenylpropanoids (chlorogenic acid) and others. The phytochemicals reported in this study revealed prominent antidiabetic action through various mechanisms like inhibiting α-glucosidase, α-amylase and DPP-4 enzyme, increasing insulin sensitivity and secretion, increasing glucose uptake by muscle cells and adipose tissue, nourishing pancreatic β-cells, etc. These various ways of phytocompounds to exert antidiabetic action illustrates the effectual diversity they can offer. Thus, potential phytocompound(s), isolated from medicinal plants or dietary materials, with proven preclinical and clinical antidiabetic efficacy can be the prospective and potential candidates for the development of novel antidiabetic drugs. For example, Charantin and Polypeptide-p isolated from Momordica charantia L. have been reported to exhibit potential antidiabetic activities in preclinical and clinical studies which have been included in this manuscript. These two compounds can be prospective candidates for the development of novel antidiabetic medicaments after confirming their toxicitiy and further clinical trials. Traditional medicinal approaches like Ayurveda, Unani and so on also utilized plant based remedies to treat diabetic illness. However, further research is necessary to disclose the absolute and exact mechanism of action of these compounds which would facilitate their outset as drugs or chemical leads. Indeed, serving as drugs or drug templates is not the only purpose of plant derived compounds, rather, they also guide in the recognition and revelation of complex and novel molecular pathways and targets involving the health condition ( 292 ). Hence, further research on these phytochemicals could enable the discovery of several targets for therapeutic intervention against diabetes mellitus. In addition, elucidation of the feasibility and toxicity profile despite the mentioned predating advantage as plant based products is also a salient research concern.

The two most pronounced variations of diabetes are Type 1 diabetes mellitus and Type 2 diabetes mellitus both of which result in a hyperglycemic state. Type 1 diabetes mellitus is an autoimmune illness typified by the demolition of pancreatic β-cells followed by dreadful insulin scarcity. On the other hand, Type 2 diabetes mellitus is more familiar and a major portion of diabetic patients (90 to 95%) are suffering from this dysfunction, which is categorized by peripheral insulin resistance and anomalies in the secretion of insulin ( 284 ). However, it is a non-communicable illness, experts are warning us about a figure of almost 438 million diabetic patients in 2030 ( 7 ) which considers the dreadfulness of this disease. In a broader sense, the causative factors of diabetes can reside in insulin resistance, abnormal insulin secretion and hepatic glucose synthesis along with impaired fat metabolism. Insulin resistance refers to the state where the efficacy of the insulin on target tissues becomes compromised particularly on adipocytes, hepatocytes and skeletal muscles ( 293 ) which leads to hyperglycemia by impairing utilization of glucose and increasing hepatic glucose output ( 294 ). Despite having a good number of commercially available antidiabetic drugs, the side effects delimit their unquestionable implications. In contrast, nutraceuticals and phytomedicines offer a low incidence of adverse effects that can be a fantastic alternative to regular drugs in combating diabetes and its related complications ( 7 ). Plant-derived medicaments have also been mentioned in various ethnic and traditional practices including the Indian, Koran, Chinese and Mexican cultures as well as in Western and Ayurvedic herbalism approaches which accredits their tremendous antidiabetic potential ( 7 , 295 ). Hence, the reported aforementioned phytochemicals in this extensive review can be considered as very promising wellsprings to develop novel antidiabetic therapeutics to heal diabetes and related complications.

A collection of anti-diabetic plants used in the treatment of diabetes mellitus has been reviewed in this article. Several shreds of scientific evidence have proved that those phytochemicals possess antihyperglycemic potentials and can be effectively implicated in the management of diabetic and metabolic complications avoiding notable side effects exerted by conventional drugs. Although dietary and non-dietary plants are always considered as promising avenues of remedies to treat different types of disease states, together with diabetes and others, many plants and plant-derived bioactive phytoconstituents have not yet been researched well. In order to explore and validate proper mechanistic pathways of pharmacological activities demonstrated by the reported antidiabetic phytochemicals, further investigations are warranted. In spite of considering plants and/or dietary plant materials as safe for intake, yet the prospective antidiabetic phytochemicals should also be evaluated for toxicity studies for the establishment of therapeutically effective and safe phytomedicines.

Author Contributions

MMRS and SA conceptualized the study. SA, MNRC and TNS searched in the databases and collected articles. SA, TNS and MNRC wrote the manuscript. MAR, NIC, CZ, JX, EH, SAK, and INM critically revised the manuscript. SA, TNS and NIC edited the final manuscript as per review comments. MMRS and INM critically evaluated, revised the manuscript and supervised the project. All authors contributed to the article and approved the submitted version.

Conflict of Interest

The authors declare that the study was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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