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Pharmacotherapy of type 2 diabetes: An update and future directions

Published:October 11, 2022DOI:https://doi.org/10.1016/j.metabol.2022.155332

      Highlights

      • Type 2 diabetes (T2D) is a widely prevalent disease with significant comorbidities.
      • A personalized treatment approach is recommended.
      • The mechanism of action, administration, indications, side-effects and cost of the available antidiabetic drugs should be considered.
      • GLP-1 RA and SGLT-2 inhibitors offer favorable side-effect profile and excellent cardiovascular and renal outcomes.
      • Targets of novel therapeutic T2D agents currently in development are discussed.

      Abstract

      Type 2 diabetes (T2D) is a widely prevalent disease with substantial economic and social impact for which multiple conventional and novel pharmacotherapies are currently available; however, the landscape of T2D treatment is constantly changing as new therapies emerge and the understanding of currently available agents deepens. This review aims to provide an updated summary of the pharmacotherapeutic approach to T2D. Each class of agents is presented by mechanism of action, details of administration, side effect profile, cost, and use in certain populations including heart failure, non-alcoholic fatty liver disease, obesity, chronic kidney disease, and older individuals. We also review targets of novel therapeutic T2D agent development. Finally, we outline an up-to-date treatment approach that starts with identification of an individualized goal for glycemic control then selection, initiation, and further intensification of a personalized therapeutic plan for T2D.

      Abbreviations:

      T2D (type 2 diabetes), GLP-1 (glucagon-like peptide-1), GLP1RA (GLP-1 receptor agonist), GIP (gastric inhibitory polypeptide), SGLT-2 (sodium-glucose co-transporter 2), SGLT-2i (SGLT-2 inhibitor), CV (cardiovascular), CVD (cardiovascular disease), CVOT (cardiovascular outcome trial), MACE (major adverse cardiac events), CAD (coronary artery disease), FDA (U.S. Food and Drug Administration), DPP-4 (dipeptidyl peptidase-4), GI (gastrointestinal), RCT (randomized controlled trial), AACE (American Association of Clinical Endocrinologists), ESC (European Society of Cardiology), EASD (European Association for the Study of Diabetes), ADA (American Diabetes Association), HF (heart failure), eGFR (estimated glomerular filtration rate), UKPDS (United Kingdom Prospective Diabetes Study), MI (myocardial infarction), DPPOS (Diabetes Prevention Program Outcomes Study), REACH (Reduction of Atherothrombosis for Continued Health), HR (hazard ratio), CI (confidence interval), RR (risk ratio), SAVOR-TIMI 53 (Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus-Thrombolysis in Myocardial Infarction), VA-IMPACT (Veterans Association Investigation of Metformin in Pre-Diabetes on Atherosclerotic Cardiovascular Outcomes), LDL-C (low-density lipoprotein cholesterol), TG (triglycerides), ATP (adenosine triphosphate), NADAC (National Average Drug Acquisition Cost), SU (sulfonylurea), SUR (sulfonylurea receptor), ESRD (end stage renal disease), ADOPT (A Diabetes Outcome Progression Trial), HbA1c (hemoglobin A1c), GRADE (Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study), UGDP (University Group Diabetes Program), ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation), TOSCA.IT (Thiazolidinediones or Sulfonylureas and Cardiovascular Accidents Intervention Trial), CAROLINA (Cardiovascular Outcome Study of Linagliptin versus Glimepiride in Type 2 Diabetes), CARMELINA (Cardiovascular and Renal Microvascular Outcome Study With Linagliptin), NAVIGATOR (Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research), HDL (high density lipoprotein), AGI (alpha-glucosidase inhibitor), RYGBP (Roux-en-Y gastric bypass), STOP-NIDDM (the Study to Prevent Non-Insulin-Dependent Diabetes Mellitus), ACE (Acarbose Cardiovascular Evaluation), IGT (impaired glucose tolerance), BMI (body mass index), TZD (thiazolidinediones), PPAR-gamma (peroxisome proliferator-activated receptor-gamma), TNF (tumor necrosis factor), CKD (chronic kidney disease), ACT NOW (Actos Now for Prevention of Diabetes), NAFLD (nonalcoholic fatty liver disease), NASH (nonalcoholic steatohepatitis), RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes), Proactive (Prospective Pioglitazone Clinical Trial In Macrovascular Events), IRIS (Insulin Resistance Intervention after Stroke), OR (odds ratio), DME (diabetic macular edema), CHICAGO (Carotid Intima-Media Thickness in Atherosclerosis Using Pioglitazone), PERISCOPE (Efficacy Study of Pioglitazone Compared to Glimepiride on Coronary Atherosclerotic Disease Progression in Subjects with Type 2 Diabetes Mellitus), BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes), T1D (type 1 diabetes), BI (basal insulin), NPH (Neutral Protamine Hagedorn), hHF (hospitalization for HF), IGF-1 (insulin-like growth factor 1), ORIGIN (Outcome Reduction with Initial Glargine Intervention trial), RHI (regular human insulin), RAIA (rapid acting insulin analogues), EXAMINE (Examination of Cardiovascular Outcomes With Alogliptin vs. Standard of Care), TECOS (Trial Evaluating Cardiovascular Outcomes with Sitagliptin), EF (ejection fraction), PIONEER (Peptide Innovation for Early Diabetes Treatment), SUSTAIN (Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes), DURATION (Diabetes therapy Utilization: Researching changes in A1c, weight and other factors Through Intervention with exenatide ONce weekly), LEAD (Liraglutide Effect and Action in Diabetes), ETD (estimated treatment difference), SURPASS (Study of Tirzepatide versus Semaglutide Once Weekly as Add-on Therapy to Metformin in Participants with Type 2 Diabetes), ELIXA (Evaluation of Cardiovascular Outcomes in Patients with Type 2 Diabetes After Acute Coronary Syndrome During Treatment with Lixisenatide), LEADER (Liraglutide Effect and Action in Diabetes – Evaluation of Cardiovascular Outcome Results – A Long Term Evaluation), REWIND (Researching cardiovascular Events with a Weekly Incretin in Diabetes for Dulaglutide), LEAN (Liraglutide Safety and Efficacy in Patients with Nonalcoholic Steatohepatitis), LFC (liver fat content), ASCVD (atherosclerotic cardiovascular disease), EMPA REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), DURATION (Safety and Efficacy of Exenatide Once Weekly Plus Dapagliflozin Once Daily Versus Exenatide or Dapagliflozin Alone in Patients with Type 2 Diabetes Inadequately Controlled with Metformin Monotherapy), DAPA-HF (Dapagliflozin in patients with heart failure and reduced ejection fraction), EMPEROR-Reduced (Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure), DECLARE TIMI 58 (Dapagliflozin and cardiovascular outcomes in type 2 diabetes), CANVAS (Canagliflozin and cardiovascular and renal events in type 2 diabetes), CREDENCE (Canagliflozin and renal outcomes in type 2 diabetes and nephropathy), VERTIS-CV (evaluation of Ertugliflozin efficacy and safety Cardiovascular outcomes), DEFINE-HF (Dapagliflozin effects on biomarkers, symptoms, and functional status in patients with heart failure with reduced ejection fraction), NYHA (New York Heart Association), HFrEF (heart failure with reduced EF), HFpEF (heart failure with preserved EF), EMPEROR Preserved (Evaluation of the effects of sodium-glucose co-transporter 2 inhibition with empagliflozin on morbidity and mortality in patients with chronic heart failure and a preserved ejection fraction), DAPA CKD (Dapagliflozin And Prevention of Adverse outcomes in Chronic Kidney Disease), CGM (continuous glucose monitoring), TIR (time in range), SMBG (self-monitored blood glucoses), GMI (glucose management indicator), AGP (ambulatory glucose profile)

      Keywords

      1. Introduction

      The estimated worldwide prevalence of diabetes in 2021 was 537 million, which is projected to increase 46 % to 783 million by 2045. 541 million people are estimated to have impaired glucose tolerance in 2021 [,
      • Saeedi P.
      • Petersohn I.
      • Salpea P.
      • Malanda B.
      • Karuranga S.
      • Unwin N.
      • et al.
      Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: results from the international diabetes federation diabetes atlas.
      ]. Among all diabetes cases, >90 % are type 2 diabetes (T2D) [
      NCD Risk Factor Collaboration NCD
      NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in diabetes since 1980: a pooled analysis of 751 population-based studies with 4.4 million participants (vol 387, pg 1513, 2016).
      ]. Annual progression of prediabetes to T2D ranges from 5 to 10 % [
      • Gerstein H.C.
      • Santaguida P.
      • Raina P.
      • Morrison K.M.
      • Balion C.
      • Hunt D.
      • et al.
      Annual incidence and relative risk of diabetes in people with various categories of dysglycemia: a systematic overview and meta-analysis of prospective studies.
      ].s
      In addition to its mounting prevalence, the costs of diabetes care are substantial, accounting for 1 in 4 health care dollars spent in the US. Medical expenditures for people with diabetes are nearly 2.3 times higher than those without it. Associated intangible costs include pain, suffering and caregiver fatigue [
      American Diabetes Association
      Economic costs of diabetes in the U.S. in 2017.
      ].
      Development of T2D is multifactorial involving environmental and genetic risk factors [
      • Murea M.
      • Ma L.
      • Freedman B.I.
      Genetic and environmental factors associated with type 2 diabetes and diabetic vascular complications.
      ]. Several pathophysiological abnormalities lead to glucose dysregulation: core defects are increased insulin resistance in skeletal muscle, liver and adipose tissue and impaired pancreatic beta-cell insulin secretion. Other perturbations include an increase in fasting glucagon levels, basal hepatic glucose production, lipolysis and fasting free fatty acid levels, all of which fail to decrease postprandially; suppression of gut incretins glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) after a meal; beta-cell resistance to the stimulatory effects of GLP-1 and GIP leading to beta-cell failure; increased renal absorption of glucose by sodium-glucose co-transporter 2 (SGLT-2); neurochemical alterations promoting weight gain including leptin resistance, amylin resistance, and low brain dopamine; chronic inflammation and impaired vasodilation. All of these disorders can lead to hyperglycemia [
      • DeFronzo R.A.
      From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus.
      ,
      • Lee Y.H.
      • Magkos F.
      • Mantzoros C.S.
      • Kang E.S.
      Effects of leptin and adiponectin on pancreatic β-cell function.
      ,
      • Mantzoros C.S.
      • Flier J.S.
      Insulin resistance: the clinical spectrum.
      ].
      Patients with T2D are at an increased risk of microvascular complications including retinopathy, nephropathy, and neuropathy and macrovascular complications including cardiovascular (CV), cerebrovascular and peripheral vascular disease because of hyperglycemia and the metabolic syndrome [
      • Mantzoros C.S.
      • Flier J.S.
      Insulin resistance: the clinical spectrum.
      ,
      • Ricciardi C.A.
      • Gnudi L.
      Kidney disease in diabetes: from mechanisms to clinical presentation and treatment strategies.
      ]. In this context, T2D is associated with an increased incidence of major adverse cardiac events (MACE), arrhythmias, and heart failure [
      The Emerging Risk Factors Collaboration
      Association of cardiometabolic multimorbidity with mortality.
      ,
      • Sardu C.
      • De Lucia C.
      • Wallner M.
      • Santulli G.
      Diabetes mellitus and its cardiovascular complications: new insights into an old disease.
      ,
      • Yang G.
      • Wei J.
      • Liu P.
      • Zhang Q.
      • Tian Y.
      • Hou G.
      • et al.
      Role of the gut microbiota in type 2 diabetes and related diseases.
      ,
      • Jankauskas S.S.
      • Kansakar U.
      • Varzideh F.
      • Wilson S.
      • Mone P.
      • Lombardi A.
      • et al.
      Heart failure in diabetes.
      ,
      • Triposkiadis F.
      • Xanthopoulos A.
      • Bargiota A.
      • Kitai T.
      • Katsiki N.
      • Farmakis D.
      • et al.
      Diabetes mellitus and heart failure.
      ,
      • Yun J.S.
      • Ko S.H.
      Current trends in epidemiology of cardiovascular disease and cardiovascular risk management in type 2 diabetes.
      ]. Of those individuals with established coronary artery disease (CAD), approximately 70–75 % have coexisting overt diabetes or glucose dysregulation [
      • Mastrototaro L.
      • Roden M.
      Insulin resistance and insulin sensitizing agents.
      ]. Furthermore, patients with T2D have a significantly increased rate of hospitalization and death [
      • Sardu C.
      • De Lucia C.
      • Wallner M.
      • Santulli G.
      Diabetes mellitus and its cardiovascular complications: new insights into an old disease.
      ], with CV disease (CVD) being the leading cause of death [
      The Emerging Risk Factors Collaboration
      Association of cardiometabolic multimorbidity with mortality.
      ].
      Previously, T2D treatment focused mainly on lowering blood glucose, but this has shifted toward emphasizing reversal of the pathophysiological defects in T2D and mitigating cardiorenal risk. This can be achieved through a combination of agents addressing the multiple pathophysiological defects noted above [
      • DeFronzo R.A.
      From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus.
      ,
      • Mantzoros C.S.
      • Flier J.S.
      Insulin resistance: the clinical spectrum.
      ,
      • Standl E.
      • Khunti K.
      • Hansen T.B.
      • Schnell O.
      The global epidemics of diabetes in the 21st century: current situation and perspectives.
      ]. Given the multifaceted nature of T2D, several complementary drug therapies are needed to ameliorate hyperglycemia and the risk of end-organ damage.
      Until 2008, antidiabetic therapies were approved based on glucose lowering capacity. Then, the Food and Drug Administration (FDA) mandated that CV outcome trials (CVOTs) be performed to demonstrate CV safety of new agents. Recent CVOTs showing cardiorenal protection conferred by T2D therapies unrelated to glycemic control has resulted in a paradigm shift in T2D pharmacotherapy [
      • Yang G.
      • Wei J.
      • Liu P.
      • Zhang Q.
      • Tian Y.
      • Hou G.
      • et al.
      Role of the gut microbiota in type 2 diabetes and related diseases.
      ,
      • Raji A.
      • Gerhard-Herman M.D.
      • Warren M.
      • Silverman S.G.
      • Raptopoulos V.
      • Mantzoros C.S.
      • Simonson D.C.
      Insulin resistance and vascular dysfunction in nondiabetic Asian Indians.
      ].
      The objective of this review is to provide an overview of the various drugs available for the treatment of T2D.

      2. Medications

      2.1 Older medications

      2.1.1 Biguanides

      Metformin is one of the oldest agents in diabetes treatment; its history begins in the 1920s when the active agents in the French lilac, Galega officinalis, were reported to have anti-hyperglycemic properties. Metformin was registered in the US in 1995, decades after its first introduction in Europe [
      • Salvatore T.
      • Pafundi P.C.
      • Morgillo F.
      • Di Liello R.
      • Galiero R.
      • Nevola R.
      • et al.
      Metformin: an old drug against old age and associated morbidities.
      ,
      • Triggle C.R.
      • Mohammed I.
      • Bshesh K.
      • Marei I.
      • Ye K.
      • Ding H.
      • et al.
      Metformin: is it a drug for all reasons and diseases?.
      ].

      2.1.1.1 Mechanism of action

      Metformin was developed before the era of target-specific drug development and introduced into clinical use notwithstanding that its cellular mechanisms of action were ill-defined. However, over the last decade, understanding of its mechanism has expanded; it is now known as a multifaceted drug with multiple, complex modes of action. Not only does this hydrophilic cation inhibit hepatic gluconeogenesis via modulation of mitochondrial enzymes and hepatic redox state, but it also increases cellular AMP kinase [
      • Rena G.
      • Hardie D.G.
      • Pearson E.R.
      The mechanisms of action of metformin.
      ]. Furthermore, it increases endogenous GLP-1 levels through a mechanism distinct from dipeptidyl peptidase-4 (DPP-4) inhibition, restores insulin secretion and protects pancreatic β cells from lipotoxicity and glucotoxicity [
      • Mannucci E.
      • Ognibene A.
      • Cremasco F.
      • Bardini G.
      • Mencucci A.
      • Pierazzuoli E.
      • et al.
      Effect of metformin on glucagon-like peptide 1 (GLP-1) and leptin levels in obese nondiabetic subjects.
      ,
      • Yang X.
      • Xu Z.
      • Zhang C.
      • Cai Z.
      • Zhang J.
      Metformin, beyond an insulin sensitizer, targeting heart and pancreatic β cells.
      ]. Metformin also increases glucose consumption in the gastrointestinal (GI) tract, which is demonstrated by the efficacy of the delayed-release metformin [
      • Buse J.B.
      • DeFronzo R.A.
      • Rosenstock J.
      • Kim T.
      • Burns C.
      • Skare S.
      • et al.
      The primary glucose-lowering effect of metformin resides in the gut, not the circulation: results from short-term pharmacokinetic and 12-week dose-ranging studies.
      ]. Metformin predominantly improves fasting blood glucose, but it also reduces post-prandial blood glucose comparable to a prandial insulin secretagogue [
      • Lund S.S.
      • Tarnow L.
      • Frandsen M.
      • Smidt U.M.
      • Pedersen O.
      • Parving H.-H.
      • et al.
      Impact of metformin versus the prandial insulin secretagogue, repaglinide, on fasting and postprandial glucose and lipid responses in non-obese patients with type 2 diabetes.
      ]. Apart from improvement in glycemic control, metformin also exerts a range of pleiotropic effects on other organs such as the heart and the nervous system which will be discussed later [
      • Yang X.
      • Xu Z.
      • Zhang C.
      • Cai Z.
      • Zhang J.
      Metformin, beyond an insulin sensitizer, targeting heart and pancreatic β cells.
      ].

      2.1.1.2 Position in the therapeutic armamentarium

      2.1.1.2.1 Dosing, indications and contraindications

      Metformin is initiated at a dose of 500 mg, once or twice a day, and can be increased up to a total dose of 2000 mg/day, beyond which there is a minimal increase in efficacy, but a clinically significant increase in its side effects [
      • Dornan T.L.
      • Heller S.R.
      • Peck G.M.
      • Tattersall R.B.
      Double-blind evaluation of efficacy and tolerability of metformin in NIDDM.
      ,
      Bristol-Myers Squibb Company
      GLUCOPHAGE® (metformin hydrochloride) tablets, GLUCOPHAGE® XR (metformin hydrochloride) extended-release tablets.
      ].
      Despite the advent of new drugs and the lack of randomized controlled trials (RCTs) for metformin versus placebo therapy, metformin endures as the first line agent in T2D management in the American Association of Clinical Endocrinologists (AACE) 2020 executive summary on T2D management [
      • Garber A.J.
      • Handelsman Y.
      • Grunberger G.
      • Einhorn D.
      • Abrahamson M.J.
      • Barzilay J.I.
      • et al.
      Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm – 2020 executive summary.
      ]. This is justified by its low cost, duration of evidence, favorable side effect profile, and background use in all cardiovascular outcomes studies (CVOTs). However, the latest 2019 joint guidelines of the European Society of Cardiology (ESC) and European Association for the Study of Diabetes (EASD) recommend initiating SGLT2 inhibitors (SGLT2i) or GLP-1 receptor agonists prior to metformin for patients with T2D who have established or are at high or very high risk for CVD [
      • Cosentino F.
      • Grant P.J.
      • Aboyans V.
      • Bailey C.J.
      • Ceriello A.
      • Delgado V.
      • et al.
      2019 ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: the Task Force for diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and the European Association for the Study of Diabetes (EASD).
      ]. In these guidelines, metformin is suggested as the first therapeutic option only in overweight T2D patients without CVD and those not at high risk for CVD. This recommendation is made despite metformin's use as baseline therapy among the majority of patients enrolled in the CVOTs and the large amount of human and animal data demonstrating the cardioprotective effects of metformin [
      • Scheen A.J.
      Challenging 2019 ESC guidelines for the management of type 2 diabetes.
      ]. The 2022 American Diabetes Association (ADA) Standards of Medical Care suggest a compromise by stating that for most patients, metformin is the appropriate first line therapy, but that for select high cardiorenal risk patients, SGLT2i or GLP-1 receptor agonists could be considered with or without metformin. They emphasized making this decision using a patient-centered approach [
      American Diabetes Association Professional Practice Committee
      9. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes—2022.
      ].
      In the past, metformin was considered contraindicated among patients with a history of heart failure (HF) due to the risk of lactic acidosis. However, contemporary critical re-evaluation supports using metformin in stable, compensated HF patients, even in patients with New York Heart Association (NYHA) class III or IV HF [
      • Eurich D.T.
      • Weir D.L.
      • Majumdar S.R.
      • Tsuyuki R.T.
      • Johnson J.A.
      • Tjosvold L.
      • et al.
      Comparative safety and effectiveness of metformin in patients with diabetes mellitus and heart failure.
      ,
      • Schernthaner G.
      • Brand K.
      • Bailey C.J.
      Metformin and the heart: update on mechanisms of cardiovascular protection with special reference to comorbid type 2 diabetes and heart failure.
      ]. Similarly, the 2022 ADA guidelines recommend metformin therapy in patients with stable HF, provided that renal function is within the recommended range discussed next [
      • Draznin B.
      • Aroda V.R.
      • Bakris G.
      • Benson G.
      • Brown F.M.
      • et al.
      American Diabetes Association Professional Practice Committee
      10. Cardiovascular disease and risk management: standards of medical care in diabetes-2022.
      ].
      According to the U.S. Food and Drug Administration (FDA) guidelines, metformin should be discontinued if estimated glomerular filtration rate (eGFR) is <30 mL/min/1.73/m2, whereas its initiation is not recommended for eGFR between 30 and 45 mL/min/1.73/m2 [
      Bristol-Myers Squibb Company
      GLUCOPHAGE® (metformin hydrochloride) tablets, GLUCOPHAGE® XR (metformin hydrochloride) extended-release tablets.
      ]. Safe and efficacious metformin doses for chronic kidney disease (CKD) stage 3A (eGFR 45–59 mL/min/1.73/m2), stage 3B (eGFR 30–44 mL/min/1.73/m2) and stage 4 (eGFR 15–29 mL/min/1.73/m2) have been reported to be 1500, 1000 and 500 mg/day, respectively [
      • Lalau J.-D.
      • Kajbaf F.
      • Bennis Y.
      • Hurtel-Lemaire A.-S.
      • Belpaire F.
      • De Broe M.E.
      Metformin treatment in patients with type 2 diabetes and chronic kidney disease stages 3A, 3B, or 4.
      ]. Although metformin use in CKD stage 4 is noted as contraindicated by the FDA, there is evidence that it might be safe at its lowest dose (500 mg/day), but this indication awaits evaluation in larger, prospective studies [
      • Lalau J.-D.
      • Kajbaf F.
      • Bennis Y.
      • Hurtel-Lemaire A.-S.
      • Belpaire F.
      • De Broe M.E.
      Metformin treatment in patients with type 2 diabetes and chronic kidney disease stages 3A, 3B, or 4.
      ]. Notably, eGFR should be re-assessed at a frequency of every 3–6 months for CKD stage 3 and above. Furthermore, metformin should be withdrawn if a single serum lactate level >5 mmol/L or two levels >2.5 mmol/L are recorded [
      • Lalau J.-D.
      • Kajbaf F.
      • Bennis Y.
      • Hurtel-Lemaire A.-S.
      • Belpaire F.
      • De Broe M.E.
      Metformin treatment in patients with type 2 diabetes and chronic kidney disease stages 3A, 3B, or 4.
      ,
      • Lipska K.J.
      • Bailey C.J.
      • Inzucchi S.E.
      Use of metformin in the setting of mild-to-moderate renal insufficiency.
      ]. While serum lactate levels are not usually monitored during routine clinical use, mild elevation of lactate is seen in a minority of asymptomatic patients with chronic metformin use [
      • Huang W.
      • Castelino R.L.
      • Peterson G.M.
      Lactate levels with chronic metformin use: a narrative review.
      ].

      2.1.1.2.2 Safety and tolerability

      The main adverse effect of metformin is GI discomfort (e.g., nausea, anorexia and diarrhea), which is dose-dependent, tends to subside with time and can be mitigated by switching to the extended-release formulation [
      • Fujita Y.
      • Inagaki N.
      Metformin: new preparations and nonglycemic benefits.
      ]. However, 5 % of patients exhibit persistent metformin intolerance typically due to diarrhea, leading to medication discontinuation [
      • McCreight L.J.
      • Bailey C.J.
      • Pearson E.R.
      Metformin and the gastrointestinal tract.
      ]. Metformin can also interfere with vitamin B12 absorption, reducing B12 levels in the long-term, but rarely causes anemia [
      • Bailey C.J.
      • Turner R.C.
      Metformin.
      ]. ADA guidelines recommend periodic measurement of vitamin B12 levels in metformin-treated patients, especially in the presence of anemia or peripheral neuropathy [
      American Diabetes Association Professional Practice Committee
      9. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes—2022.
      ].
      The most serious side effect is Type B lactic acidosis; risk factors for this include moderate-severe renal impairment, age >65 years, contrast medium administration, surgery and other procedures, hypoxic states (e.g., acute HF), excessive alcohol intake and hepatic impairment [
      • Bailey C.J.
      • Turner R.C.
      Metformin.
      ]. Because inpatients are at increased of volume contracture, acidemia, and other renal insults reducing metformin renal elimination, metformin discontinuation is advisable during hospitalization. Withholding metformin during “sick days” can also mitigate the risk, although evidence is lacking [
      • MacCallum L.
      • Senior P.A.
      Safe use of metformin in adults with type 2 diabetes and chronic kidney disease: lower dosages and sick-day education are essential.
      ]. Overall, the latest evidence indicates that the risk of metformin associated lactic acidosis has been overstated and is rare in contemporary clinical practice [
      • Lalau J.-D.
      • Kajbaf F.
      • Bennis Y.
      • Hurtel-Lemaire A.-S.
      • Belpaire F.
      • De Broe M.E.
      Metformin treatment in patients with type 2 diabetes and chronic kidney disease stages 3A, 3B, or 4.
      ].

      2.1.1.3 Cardiovascular and other outcomes

      Prospective data on the CV effects of metformin are heavily reliant on the United Kingdom Prospective Diabetes Study (UKPDS), in which a small subgroup of overweight patients assigned to metformin achieved long-term significant reduction in myocardial infarction (MI) (risk ratio (RR) 0.67, 95 % confidence interval (CI) 0.51–0.89, P-value = 0.005) and all-cause mortality (RR 0.73, 95 % CI 0.59–0.89, P = 0.002) at 30 year follow-up, including up to 10 years of post-trial monitoring [
      • Holman R.R.
      • Paul S.K.
      • Bethel M.A.
      • Matthews D.R.
      • Neil H.A.W.
      10-Year follow-up of intensive glucose control in type 2 diabetes.
      ]. As compared to sulfonylureas and insulin, metformin is associated with fewer episodes of hypoglycemia and has a more favorable effect on weight, justifying its position as a first line agent [
      Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group.
      ].
      Metformin was shown to reduce coronary artery calcium score in men with prediabetes in the Diabetes Prevention Program Outcomes Study (DPPOS) [
      • Goldberg R.B.
      • Aroda V.R.
      • Bluemke D.A.
      • Barrett-Connor E.
      • Budoff M.
      • Crandall J.P.
      • et al.
      Effect of long-term metformin and lifestyle in the diabetes prevention program and its outcome study on coronary artery calcium.
      ]. Other studies examining the effect of metformin versus placebo in patients with T2D are mostly confined to meta-analyses, and data from these has been less conclusive [
      • Selvin E.
      • Bolen S.
      • Yeh H.-C.
      • Wiley C.
      • Wilson L.M.
      • Marinopoulos S.S.
      • et al.
      Cardiovascular outcomes in trials of oral diabetes medications: a systematic review.
      ]. However, it is worth noting that observational data from the Reduction of Atherothrombosis for Continued Health (REACH) registry revealed that metformin use was independently associated with lower rates of CV death (Hazard Ratio (HR) 0.79, 95 % CI 0.65–0.96, P = 0.02) and all-cause mortality (HR 0.76, 95 % CI 0.65–0.89, P < 0.001) [
      • Roussel R.
      • Travert F.
      • Pasquet B.
      • Wilson P.W.F.
      • Smith Jr., S.C.
      • Goto S.
      • et al.
      Metformin use and mortality among patients with diabetes and atherothrombosis.
      ]. Similarly, a post-hoc analysis of the Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus-Thrombolysis in Myocardial Infarction (SAVOR-TIMI 53) trial found that metformin was related to a lower rate of all-cause mortality (HR 0.75, 95 % CI 0.59–0.95), but not to a lower rate of composite end point of CV death, MI or ischemic stroke [
      • Bergmark B.A.
      • Bhatt D.L.
      • McGuire D.K.
      • Cahn A.
      • Mosenzon O.
      • Steg P.G.
      • et al.
      Metformin use and clinical outcomes among patients with diabetes mellitus with or without heart failure or kidney dysfunction: observations from the SAVOR-TIMI 53 trial.
      ]. There is still not a definite biologically plausible explanation for the metformin-related decrease in mortality in the absence of reductions in MI or ischemic stroke. However, it was recently shown that metformin exerts pleotropic effects by restoring endothelial nitric oxide synthase function and favorably modifying myocardial energy metabolism [
      • Sambe T.
      • Mason R.P.
      • Dawoud H.
      • Bhatt D.L.
      • Malinski T.
      Metformin treatment decreases nitroxidative stress, restores nitric oxide bioavailability and endothelial function beyond glucose control.
      ]. Furthermore, metformin has anti-inflammatory, anti-oxidant, and anti-atherogenic properties, and these actions could explain its benefit on mortality [
      • Dziubak A.
      • Wójcicka G.
      • Wojtak A.
      • Bełtowski J.
      Metabolic effects of metformin in the failing heart.
      ,
      • Zilov A.V.
      • Abdelaziz S.I.
      • AlShammary A.
      • Al Zahrani A.
      • Amir A.
      • Assaad Khalil S.H.
      • et al.
      Mechanisms of action of metformin with special reference to cardiovascular protection.
      ]. In this context, the ongoing Veterans Association — Investigation of Metformin in Pre-Diabetes on Atherosclerotic Cardiovascular Outcomes (VA-IMPACT) trial is an RCT in patients with prediabetes and established CVD treated with metformin versus placebo that aims to provide insight into metformin efficacy in reducing both mortality and CV morbidity [NCT02915198] [
      VA Office of Research and Development
      CSP #2002 - investigation of metformin in pre-diabetes on atherosclerotic cardiovascular OuTcomes (VA-IMPACT).
      ].
      Evidence has also accumulated in recent years on beneficial impacts of metformin on obesity, metabolic syndrome, dyslipidemia, blood pressure, cancer, cognitive decline, and aging. Briefly, the use of metformin as a weight loss drug, in the absence of T2D, is off-label and its role is equivocal [
      • Hendricks E.J.
      Off-label drugs for weight management.
      ]. Pooled analysis of the body weight effect of metformin in patients with T2D suggests it is weight-neutral [
      • Golay A.
      Metformin and body weight.
      ].
      Metformin monotherapy can improve dyslipidemia in statin-naïve patients with newly diagnosed T2D [
      • Lin S.H.
      • Cheng P.C.
      • Tu S.T.
      • Hsu S.R.
      • Cheng Y.C.
      • Liu Y.H.
      Effect of metformin monotherapy on serum lipid profile in statin-naïve individuals with newly diagnosed type 2 diabetes mellitus: a cohort study.
      ]. Interestingly, apart from the direct glycemic effect, the CV benefits of metformin may be attributed to improvements in weight, hyperinsulinemia, dyslipidemia [i.e. low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and free fatty acids], vascular reactivity and endothelial function, platelet aggregation, oxidative stress, atherosclerosis and inflammation. Based on the above, there is interest in repurposing metformin to treat CVD, irrespective of diabetes status [
      • Hundal R.S.
      • Inzucchi S.E.
      Metformin: new understandings, new uses.
      ,
      • Isoda K.
      • Young J.L.
      • Zirlik A.
      • MacFarlane L.A.
      • Tsuboi N.
      • Gerdes N.
      • et al.
      Metformin inhibits proinflammatory responses and nuclear factor-kappaB in human vascular wall cells.
      ]. Furthermore, a previous meta-analysis reported improvements in blood pressure in patients without diabetes taking metformin [
      • Zhou L.
      • Liu H.
      • Wen X.
      • Peng Y.
      • Tian Y.
      • Zhao L.
      Effects of metformin on blood pressure in nondiabetic patients: a meta-analysis of randomized controlled trials.
      ].
      Growing evidence has demonstrated that metformin may be a promising chemotherapeutic agent, and multiple studies have delineated several possible antitumor mechanisms of metformin [
      • Daugan M.
      • Dufaÿ Wojcicki A.
      • d’Hayer B.
      • Boudy V.
      Metformin: an anti-diabetic drug to fight cancer.
      ,
      • Zhao B.
      • Luo J.
      • Yu T.
      • Zhou L.
      • Lv H.
      • Shang P.
      Anticancer mechanisms of metformin: a review of the current evidence.
      ]. One mode of action is that metformin inhibits complex I and adenosine triphosphate (ATP) production in the mitochondria of various types of malignant tumor cells [
      • Zhao B.
      • Luo J.
      • Yu T.
      • Zhou L.
      • Lv H.
      • Shang P.
      Anticancer mechanisms of metformin: a review of the current evidence.
      ]. Given the encouraging evidence from basic studies [
      • Tseng H.-W.
      • Li S.-C.
      • Tsai K.-W.
      Metformin treatment suppresses melanoma cell growth and motility through modulation of microRNA expression.
      ,
      • Zhou X.
      • Liu S.
      • Lin X.
      • Xu L.
      • Mao X.
      • Liu J.
      • et al.
      Metformin inhibit lung cancer cell growth and invasion in vitro as well as tumor formation in vivo partially by activating PP2A.
      ,
      • Xue J.
      • Li L.
      • Li N.
      • Li F.
      • Qin X.
      • Li T.
      • et al.
      Metformin suppresses cancer cell growth in endometrial carcinoma by inhibiting PD-L1.
      ], several trials from Phases I to III are currently underway studying metformin as monotherapy or in combination with chemotherapy for endometrial cancer [
      • Tabrizi A.D.
      • Melli M.S.
      • Foroughi M.
      • Ghojazadeh M.
      • Bidadi S.
      Antiproliferative effect of metformin on the endometrium - a clinical trial.
      ], pancreatic cancer [
      • Reni M.
      • Dugnani E.
      • Cereda S.
      • Belli C.
      • Balzano G.
      • Nicoletti R.
      • et al.
      (Ir)relevance of metformin treatment in patients with metastatic pancreatic cancer: an open-label, randomized phase II trial.
      ,
      • Braghiroli M.I.
      • de Celis Ferrari A.C.R.
      • Pfiffer T.E.
      • Alex A.K.
      • Nebuloni D.
      • Carneiro A.S.
      • et al.
      Phase II trial of metformin and paclitaxel for patients with gemcitabine-refractory advanced adenocarcinoma of the pancreas.
      ], colorectal carcinoma [
      • Singh P.P.
      • Shi Q.
      • Foster N.R.
      • Grothey A.
      • Nair S.G.
      • Chan E.
      • et al.
      Relationship between metformin use and recurrence and survival in patients with resected stage III colon cancer receiving adjuvant chemotherapy: results from North Central Cancer Treatment Group N0147 (Alliance).
      ], non-small cell lung cancer [
      • Parikh A.B.
      • Kozuch P.
      • Rohs N.
      • Becker D.J.
      • Levy B.P.
      Metformin as a repurposed therapy in advanced non-small cell lung cancer (NSCLC): results of a phase II trial.
      ], breast cancer [
      • Nanni O.
      • Amadori D.
      • De Censi A.
      • Rocca A.
      • Freschi A.
      • Bologna A.
      • et al.
      Metformin plus chemotherapy versus chemotherapy alone in the first-line treatment of HER2-negative metastatic breast cancer. The MYME randomized, phase 2 clinical trial.
      ], among others. Results thus far suggest that metformin can be used for cancer prevention, improve therapeutic response to androgen deprivation therapy, radiotherapy and chemotherapy and possibly improve survival outcomes, however future results will lead to more definite conclusions [
      • Saraei P.
      • Asadi I.
      • Kakar M.A.
      • Moradi-Kor N.
      The beneficial effects of metformin on cancer prevention and therapy: a comprehensive review of recent advances.
      ].
      In the last decade, metformin has been suggested to counteract neurodegenerative diseases (e.g., dementia, Parkinson's disease), however large-scale long-term trials are needed to establish this [
      • Rotermund C.
      • Machetanz G.
      • Fitzgerald J.C.
      The therapeutic potential of metformin in neurodegenerative diseases.
      ]. There is excitement around metformin's potential in preventing aging as animal experiment studies have revealed that it can extend life [
      • Anisimov V.N.
      • Berstein L.M.
      • Popovich I.G.
      • Zabezhinski M.A.
      • Egormin P.A.
      • Piskunova T.S.
      • et al.
      If started early in life, metformin treatment increases life span and postpones tumors in female SHR mice.
      ,
      • Novelle M.G.
      • Ali A.
      • Diéguez C.
      • Bernier M.
      • de Cabo R.
      Metformin: a hopeful promise in aging research.
      ]. Metformin has properties of a geroprotector that may increase the lifespan and decrease morbidity in people with diabetes taking the drug, even when compared to people without diabetes [
      • Campbell J.M.
      • Bellman S.M.
      • Stephenson M.D.
      • Lisy K.
      Metformin reduces all-cause mortality and diseases of ageing independent of its effect on diabetes control: a systematic review and meta-analysis.
      ]. A meta-analysis showed that individuals with diabetes taking metformin exhibited a 7 % lower all-cause mortality than those individuals without diabetes (HR 0.93, 95 % CI 0.88–0.99) [
      • Campbell J.M.
      • Bellman S.M.
      • Stephenson M.D.
      • Lisy K.
      Metformin reduces all-cause mortality and diseases of ageing independent of its effect on diabetes control: a systematic review and meta-analysis.
      ]. The Targeting Aging with Metformin (TAME) clinical trial is ongoing, evaluating metformin as an anti-aging drug in individuals without diabetes [
      • Barzilai N.
      • Crandall J.P.
      • Kritchevsky S.B.
      • Espeland M.A.
      Metformin as a tool to target aging.
      ]. Another study, the Metformin in Longevity Study (MILES), investigates whether metformin modifies the gene expression profile of older adults with impaired glucose tolerance toward that of young, healthy individuals (NCT02432287).

      2.1.1.4 Cost

      Metformin is a generally inexpensive medication, costing roughly $10/month [
      • Cavaiola T.S.
      • Pettus J.H.
      Management of type 2 diabetes: selecting amongst available pharmacological agents.
      ].
      The median 30-day National Average Drug Acquisition Cost (NADAC) [
      U.S. Centers for Medicare &ampMedicaid Services
      NADAC (National Average Drug Acquisition Cost) 2022. MedicaidGov.
      ] of maximum approved daily dose of metformin in the US is $2 for immediate release and $102 for extended release [
      American Diabetes Association Professional Practice Committee
      9. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes—2022.
      ].

      2.1.1.5 Summary

      Metformin is considered the initial drug of choice in most patients with T2D because of its glycemic efficacy, absence of hypoglycemia, weight loss effect, good tolerability, and favorable cost. In the coming years, exciting possibilities for use of metformin in the areas of anti-aging, cancer prevention, cancer therapeutics, and more await even those individuals without T2D [
      • Salvatore T.
      • Pafundi P.C.
      • Morgillo F.
      • Di Liello R.
      • Galiero R.
      • Nevola R.
      • et al.
      Metformin: an old drug against old age and associated morbidities.
      ].

      2.1.2 Sulfonylureas

      Sulfonylureas (SUs) were discovered in the 1940s when it was found that patients treated with sulfonamides for typhoid fever experienced severe hypoglycemia [
      • Lavabre-Bertrand T.
      • Faillie J.-L.
      The discovery of hypoglycaemic sulphonamides - Montpellier, 1942.
      ]. SUs were approved by the FDA in the 1950s as the first oral antidiabetic medication [
      • Quianzon C.C.L.
      • Cheikh I.E.
      History of current non-insulin medications for diabetes mellitus.
      ]. First generation SUs, such as tolbutamide and chlorpropamide, are rarely prescribed in current practice. Second and third generation SUs, such as glyburide (or glibenclamide), glipizide, gliclazide (not available in the United States), and glimepiride, remain agents currently used in daily practice.

      2.1.2.1 Mechanism of action

      SUs are insulin secretagogues and act by binding to the sulfonylurea receptor 1 (SUR-1) subunit of the ATP-sensitive potassium (K-ATP) channels, leading to channel closure, membrane depolarization, influx of intra-cellular calcium and, finally, insulin secretion. This occurs irrespective of glucose levels [
      • Inagaki N.
      • Gonoi T.
      • Clement J.P.
      • Namba N.
      • Inazawa J.
      • Gonzalez G.
      • et al.
      Reconstitution of IKATP: an inward rectifier subunit plus the sulfonylurea receptor.
      ]. SUR-1, present in pancreatic beta cells, has two different binding sites: the SU site and the meglitinide site. Different SUs have variable binding affinities for these two sites, and also for other SUR isoforms (SUR-2A and SUR-2B) in other tissues including neurons, myocardium and vascular smooth muscle cells, which determine the efficacy and adverse events of each drug in this class [
      • Gribble F.M.
      • Tucker S.J.
      • Seino S.
      • Ashcroft F.M.
      Tissue specificity of sulfonylureas: studies on cloned cardiac and beta-cell K(ATP) channels.
      ]. Therefore, members of the SU drug class vary significantly in their pharmacodynamic, as well as pharmacokinetic, properties [
      • Lebovitz H.E.
      • Melander A.
      Sulfonylureas and meglitinides: insights into physiology and translational clinical utility.
      ].

      2.1.2.2 Position in the therapeutic armamentarium

      2.1.2.2.1 Dosing, indications, and contraindications

      SUs enhance insulin release irrespective of blood glucose levels, and as such, some should be taken with a meal (glyburide, glimepiride, glipizide extended release, gliclazide modified release) and others, whose absorption is delayed by food, about 30 min prior to a meal (glipizide immediate release, gliclazide immediate release) [
      • Costello R.A.
      • Nicolas S.
      • Shivkumar A.
      Sulfonylureas.
      ]. The doses of SUs must be titrated and thus increased every 2 weeks until glycemic control is attained. The starting dose should be low; doses above the half-maximum rarely provide additional glycemic control but increase the risk of hypoglycemia [
      • Sola D.
      • Rossi L.
      • Schianca G.P.C.
      • Maffioli P.
      • Bigliocca M.
      • Mella R.
      • et al.
      Sulfonylureas and their use in clinical practice.
      ]. The daily dose of SUs ranges from 2.5 to 15 mg for glyburide, from 40 to 320 mg for gliclazide, from 1 to 6 mg for glimepiride and from 2.5 to 20 mg for glipizide. SUs can be administered once or twice daily. Their biological activity lasts much longer than plasma half-life due to the formation of active metabolites [
      • Sola D.
      • Rossi L.
      • Schianca G.P.C.
      • Maffioli P.
      • Bigliocca M.
      • Mella R.
      • et al.
      Sulfonylureas and their use in clinical practice.
      ].
      SUs are metabolized by oxidative pathways of glucuronidation and CYP450 enzymes in the liver and for some (glyburide, glimepiride), the metabolites have hypoglycemic properties, while for others (glipizide, gliclazide) the metabolites do not exert such actions [
      • Krentz A.J.
      • Bailey C.J.
      Oral antidiabetic agents.
      ]. The parent drug, along with its metabolites, is excreted by the kidney.
      SUs can be used in combination with any class of antidiabetic medication, apart from meglitinides [
      • Costello R.A.
      • Nicolas S.
      • Shivkumar A.
      Sulfonylureas.
      ,
      • Hermansen K.
      • Kipnes M.
      • Luo E.
      • Fanurik D.
      • Khatami H.
      • Stein P.
      • et al.
      Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin.
      ]. Traditionally, SUs have been first line as add-on therapy to metformin, but this has changed over the last decade with therapeutic goals broadening beyond glycemic control.
      The 2022 ADA Standards of Medical Care in Diabetes guidelines de-emphasize SUs and suggest that they may be added to metformin in patients at low CV risk in whom hypoglycemia is not likely to be an issue, particularly if cost is a factor [
      • Dornan T.L.
      • Heller S.R.
      • Peck G.M.
      • Tattersall R.B.
      Double-blind evaluation of efficacy and tolerability of metformin in NIDDM.
      ].
      SUs are contraindicated in severe hepatic insufficiency and should be used cautiously in moderate-severe renal impairment (Table 1) [
      • Lebovitz H.E.
      • Melander A.
      Sulfonylureas and meglitinides: insights into physiology and translational clinical utility.
      ]. Furthermore, SUs interact with several drugs due to its primarily hepatic metabolism and competition for plasma protein binding sites (e.g., salicylates, warfarin, monoamine oxidase inhibitors) and this can increase the risk of hypoglycemia [
      • Deacon C.F.
      • Lebovitz H.E.
      Comparative review of dipeptidyl peptidase-4 inhibitors and sulphonylureas.
      ]. SUs are also contraindicated in patients in whom it is imperative to minimize hypoglycemia. Risk factors for hypoglycemia are detailed in the next section.
      Table 1Pharmacokinetics of SUs
      • Deacon C.F.
      • Lebovitz H.E.
      Comparative review of dipeptidyl peptidase-4 inhibitors and sulphonylureas.
      .
      DrugMetabolitesDuration of actionUse in renal impairment
      GlyburideActiveLong (12 to >24 h)Use if GFR ≥60 mL/min

      Contraindicated in ESRD
      GliclazideInactiveIntermediate (12 to 24 h)Can be used in renal impairment and ESRD with caution
      GlimepirideActiveIntermediate (12 to 24 h)Use if GFR ≥60 mL/min

      Contraindicated in ESRD
      GlipizideInactiveShort (<12 to 24 h)Can be used in renal impairment and ESRD
      ESRD: end-stage renal disease.

      2.1.2.2.2 Safety and tolerability

      The main side effects of SUs are hypoglycemia and weight gain, which is related to the non-physiological release of insulin [
      • Monami M.
      • Dicembrini I.
      • Kundisova L.
      • Zannoni S.
      • Nreu B.
      • Mannucci E.
      A meta-analysis of the hypoglycaemic risk in randomized controlled trials with sulphonylureas in patients with type 2 diabetes.
      ]. Mean weight gain following SU therapy is 1.6 kg/year but tends to decrease with time as per the A Diabetes Outcome Progression Trial (ADOPT) [
      • Kahn S.E.
      • Haffner S.M.
      • Heise M.A.
      • Herman W.H.
      • Holman R.R.
      • Jones N.P.
      • et al.
      Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy.
      ,
      • Gangji A.S.
      • Cukierman T.
      • Gerstein H.C.
      • Goldsmith C.H.
      • Clase C.M.
      A systematic review and meta-analysis of hypoglycemia and cardiovascular events: a comparison of glyburide with other secretagogues and with insulin.
      ].
      Several studies have shown that different SUs predispose to hypoglycemia by varying degrees, with glyburide exerting the highest risk, glimepiride and glipizide an intermediate risk, and gliclazide the lowest risk [
      • Gangji A.S.
      • Cukierman T.
      • Gerstein H.C.
      • Goldsmith C.H.
      • Clase C.M.
      A systematic review and meta-analysis of hypoglycemia and cardiovascular events: a comparison of glyburide with other secretagogues and with insulin.
      ,
      • Holstein A.
      • Plaschke A.
      • Egberts E.H.
      Lower incidence of severe hypoglycaemia in patients with type 2 diabetes treated with glimepiride versus glibenclamide.
      ,
      • Schopman J.E.
      • Simon A.C.R.
      • Hoefnagel S.J.M.
      • Hoekstra J.B.L.
      • Scholten R.J.P.M.
      • Holleman F.
      The incidence of mild and severe hypoglycaemia in patients with type 2 diabetes mellitus treated with sulfonylureas: a systematic review and meta-analysis.
      ]. Patients who are elderly, malnourished, or have renal or CVD are at a greater risk of hypoglycemia [
      • Lebovitz H.E.
      • Melander A.
      Sulfonylureas and meglitinides: insights into physiology and translational clinical utility.
      ]. SU-mediated hypoglycemia can be severe, resistant to glucose administration and can last up to 72 h requiring treatment for several days [
      • Lebovitz H.E.
      • Melander A.
      Sulfonylureas and meglitinides: insights into physiology and translational clinical utility.
      ]. Furthermore, severe hypoglycemia from SUs has been associated with an increased risk of severe ventricular arrhythmias [
      • Stahn A.
      • Pistrosch F.
      • Ganz X.
      • Teige M.
      • Koehler C.
      • Bornstein S.
      • et al.
      Relationship between hypoglycemic episodes and ventricular arrhythmias in patients with type 2 diabetes and cardiovascular diseases: silent hypoglycemias and silent arrhythmias.
      ], adverse outcomes, and increased mortality [
      • Zoungas S.
      • Patel A.
      • Chalmers J.
      • de Galan B.E.
      • Li Q.
      • Billot L.
      • et al.
      Severe hypoglycemia and risks of vascular events and death.
      ], but whether SUs directly raise CV mortality is controversial and has been debated for decades as discussed below.

      2.1.2.3 Cardiovascular and other outcomes

      SUs can lower hemoglobin A1c (HbA1c) by approximately 1.5–1.6 % and thus are still considered to be more efficacious than newer medications such as DPP-4 inhibitors which lower HbA1c by 0.5–0.9 % [
      • Hirst J.A.
      • Farmer A.J.
      • Dyar A.
      • Lung T.W.C.
      • Stevens R.J.
      Estimating the effect of sulfonylurea on HbA1c in diabetes: a systematic review and meta-analysis.
      ,
      • Nathan D.M.
      Finding new treatments for diabetes — how many, how fast… how good?.
      ]. However, SUs' relatively greater efficacy may be overestimated: the patients in the earlier SU trials had high baseline HbA1c often ≥9 % compared with recent trials of newer agents where baseline HbA1c is approximately 7.5–8.5 % [
      • Deacon C.F.
      • Lebovitz H.E.
      Comparative review of dipeptidyl peptidase-4 inhibitors and sulphonylureas.
      ]. In this context, some studies showed that when the baseline HbA1c levels are similar, DPP-4 inhibitors and SUs are equally effective [
      • Deacon C.F.
      • Lebovitz H.E.
      Comparative review of dipeptidyl peptidase-4 inhibitors and sulphonylureas.
      ,
      • Seck T.
      • Nauck M.
      • Sheng D.
      • Sunga S.
      • Davies M.J.
      • Stein P.P.
      • et al.
      Safety and efficacy of treatment with sitagliptin or glipizide in patients with type 2 diabetes inadequately controlled on metformin: a 2-year study.
      ]. In a recent meta-analysis, gliclazide reduced HbA1c by 1.04 %, which was only slightly greater than HbA1c reduction of 0.58–0.72 % achieved by DPP-4 inhibitors [
      • Maloney A.
      • Rosenstock J.
      • Fonseca V.
      A model-based meta-analysis of 24 antihyperglycemic drugs for type 2 diabetes: comparison of treatment effects at therapeutic doses.
      ].
      Observational studies suggest that the extended use of SUs can accelerate beta-cell decline [
      • Shin M.-S.
      • Yu J.H.
      • Jung C.H.
      • Hwang J.Y.
      • Lee W.J.
      • Kim M.-S.
      • et al.
      The duration of sulfonylurea treatment is associated with β-cell dysfunction in patients with type 2 diabetes mellitus.
      ]. Indeed, SUs have lower durability compared with thiazolidinediones (TZD) and metformin; monotherapy failure at 5 years was 15 % with rosiglitazone, 21 % with metformin and 34 % with glyburide [
      • Kahn S.E.
      • Haffner S.M.
      • Heise M.A.
      • Herman W.H.
      • Holman R.R.
      • Jones N.P.
      • et al.
      Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy.
      ]. The preliminary results of the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) trial revealed that over 5 years, glimepiride was less durable than insulin glargine or liraglutide, but not less durable than sitagliptin [
      ADA 2021: GRADE preliminary findings suggests superiority of liraglutide and insulin glargine for type 2 diabetes. PracticeUpdate.
      ].
      The University Group Diabetes Program (UGDP) study performed in the 1960s found that patients treated with tolbutamide, a first-generation SU, increased all-cause and CV mortality compared with placebo [
      • Meinert C.L.
      • Knatterud G.L.
      • Prout T.E.
      • Klimt C.R.
      A study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes.II. Mortality results.
      ]. However, this was an underpowered and poorly conducted study [
      • Leiter L.A.
      Latest evidence on sulfonylureas: what's new?.
      ]. Since then, studies and meta-analyses regarding SU-related CV safety have produced conflicting results [
      • Leiter L.A.
      Latest evidence on sulfonylureas: what's new?.
      ,
      • Abdelmoneim A.S.
      • Eurich D.T.
      • Light P.E.
      • Senior P.A.
      • Seubert J.M.
      • Makowsky M.J.
      • et al.
      Cardiovascular safety of sulphonylureas: over 40 years of continuous controversy without an answer.
      ]. RCTs such as the A Diabetes Outcome Progression Trial (ADOPT), the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial and the Thiazolidinediones or Sulfonylureas and Cardiovascular Accidents Intervention Trial (TOSCA.IT) did not provide any evidence for any increased or decreased CV risk in SU-treated patients, with each trial having its own limitations [
      • Kahn S.E.
      • Haffner S.M.
      • Heise M.A.
      • Herman W.H.
      • Holman R.R.
      • Jones N.P.
      • et al.
      Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy.
      ,
      The ADVANCE Collaborative Group
      Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes.
      ,
      • Vaccaro O.
      • Masulli M.
      • Nicolucci A.
      • Bonora E.
      • Del Prato S.
      • Maggioni A.P.
      • et al.
      Effects on the incidence of cardiovascular events of the addition of pioglitazone versus sulfonylureas in patients with type 2 diabetes inadequately controlled with metformin (TOSCA.IT): a randomised, multicentre trial.
      ]. Metformin has consistently been shown to exert a lower CV risk than SU, but this is likely from lower risk of metformin, rather than higher CV risk of SU [
      • Riddle M.C.
      A verdict for glimepiride: effective and not guilty of cardiovascular harm.
      ].
      Against this background, two recent RCTs provided indirect but strong evidence that newer SUs do not increase CV risk. Briefly, in the Cardiovascular Outcome Study of Linagliptin versus Glimepiride in Type 2 Diabetes (CAROLINA), 6033 metformin-treated patients were randomized to additional therapy with glimepiride or linagliptin and the combined CV endpoint of CV death, non-fatal MI, or non-fatal stroke was similar between the 2 studied groups after a median of 6.3 years of follow-up [
      • Rosenstock J.
      • Kahn S.E.
      • Johansen O.E.
      • Zinman B.
      • Espeland M.A.
      • Woerle H.J.
      • et al.
      Effect of linagliptin vs glimepiride on major adverse cardiovascular outcomes in patients with type 2 diabetes.
      ]. In the Cardiovascular and Renal Microvascular Outcome Study With Linagliptin (CARMELINA) trial, linagliptin was compared with placebo in 6979 patients with CV risk factors, and there were no differences in adverse CV outcomes at a median of 2.2 years of follow-up [
      • Rosenstock J.
      • Perkovic V.
      • Johansen O.E.
      • Cooper M.E.
      • Kahn S.E.
      • Marx N.
      • et al.
      Effect of linagliptin vs placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk.
      ]. Since linagliptin is as safe (from a CV perspective) as placebo and glimepiride is as safe as linagliptin (based on the CAROLINA trial), it can be regarded that glimepiride is as safe as placebo in terms of CV risk [
      • Riddle M.C.
      A verdict for glimepiride: effective and not guilty of cardiovascular harm.
      ].
      Furthermore, glimepiride and gliclazide appear to have a more favorable CV profile compared with glyburide, which might be related pharmacodynamic heterogeneity among these drugs [
      • Riddle M.C.
      A verdict for glimepiride: effective and not guilty of cardiovascular harm.
      ]. Overall, the favorable CV profile of gliclazide along with a lower incidence of side effects such as hypoglycemia, makes it the drug of choice within the SU category. Unfortunately, it is not available in the United States [
      • Sarkar A.
      • Tiwari A.
      • Bhasin P.S.
      • Mitra M.
      Pharmacological and pharmaceutical profile of gliclazide: a review.
      ].
      The UKPDS and ADVANCE trials have shown that SUs exert microvascular benefits: they reduced the incidence and progression of nephropathy and retinopathy without increasing all-cause mortality. However, it is unknown whether this is from a glycemic effect or a drug specific effect of SUs [
      The ADVANCE Collaborative Group
      Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes.
      ,
      • King P.
      • Peacock I.
      • Donnelly R.
      The UK Prospective Diabetes Study (UKPDS): clinical and therapeutic implications for type 2 diabetes.
      ]. Last, a recent population-based cohort study concluded that SUs are safe and may be useful for glycemic management in patients with compensated cirrhosis and T2D [
      • Yen F.-S.
      • Lai J.-N.
      • Wei J.C.-C.
      • Chiu L.-T.
      • Hwu C.-M.
      • Hou M.-C.
      • et al.
      Sulfonylureas may be useful for glycemic management in patients with diabetes and liver cirrhosis.
      ].

      2.1.2.4 Cost

      The cost for SUs is low at about $4 to $20/month [
      • Cavaiola T.S.
      • Pettus J.H.
      Management of type 2 diabetes: selecting amongst available pharmacological agents.
      ,
      Sulfonylureas - prices and information. GoodRx.
      ]. The median 30-day NADAC [
      U.S. Centers for Medicare &ampMedicaid Services
      NADAC (National Average Drug Acquisition Cost) 2022. MedicaidGov.
      ] of maximum approved daily dose of sulfonylureas in the US is $3 for glimepiride, $3 for immediate release glipizide, $12 for extended release glipizide, and $12 for glyburide [
      American Diabetes Association Professional Practice Committee
      9. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes—2022.
      ].

      2.1.2.5 Summary

      Despite the proven CV benefits of the newer antidiabetic drugs, SUs are frequently used in clinical practice due to their low cost, wide availability, decades of clinical use, and fast glycemic response [
      • Singh A.K.
      • Singh R.
      Is gliclazide a sulfonylurea with difference? A review in 2016.
      ]. It is yet to be proven if any SU directly increases CV events; in contrast, there is evidence for the CV safety of glimepiride [
      • Deacon C.F.
      • Lebovitz H.E.
      Comparative review of dipeptidyl peptidase-4 inhibitors and sulphonylureas.
      ].

      2.1.3 Meglitinides or glinides

      Decades ago, the non-SU component of glibenclamide was discovered to be insulinotropic [
      • Geisen K.
      • Hübner M.
      • Hitzel V.
      • Hrstka V.E.
      • Pfaff W.
      • Bosies E.
      • et al.
      Acylaminoalkyl substituted benzoic and phenylalkane acids with hypoglycaemic properties (author's transl).
      ]. This was called meglitinide and led to the introduction of 3 drugs in this therapeutic class: nateglinide, repaglinide, and mitiglinide [
      • Geisen K.
      • Hübner M.
      • Hitzel V.
      • Hrstka V.E.
      • Pfaff W.
      • Bosies E.
      • et al.
      Acylaminoalkyl substituted benzoic and phenylalkane acids with hypoglycaemic properties (author's transl).
      ,
      • Dornhorst A.
      Insulinotropic meglitinide analogues.
      ]. Repaglinide was first FDA-approved in 1997; repaglinide and nateglinide are available in the US and Europe, whereas mitiglinide is available in Japan [
      Novo Nordisk Inc.
      PRANDIN® (repaglinide) tablets, for oral use. AccessdataFdaGov.
      ,
      • Black C.
      • Donnelly P.
      • McIntyre L.
      • Royle P.
      • Shepherd J.J.
      • Thomas S.
      Meglitinide analogues for type 2 diabetes mellitus.
      ,
      • Phillippe H.M.
      • Wargo K.A.
      Mitiglinide: a novel agent for the treatment of type 2 diabetes mellitus.
      ].

      2.1.3.1 Mechanism of action

      Meglitinides are insulin secretagogues. Like SUs, meglitinides bind to SUR-1 on islet beta-cells in the pancreas, resulting in the closure of K-ATP channels and insulin secretion. Each meglitinide has a distinct binding site, which is different from the SU site, and this explains the differences in drug properties [
      • Black C.
      • Donnelly P.
      • McIntyre L.
      • Royle P.
      • Shepherd J.J.
      • Thomas S.
      Meglitinide analogues for type 2 diabetes mellitus.
      ,
      • Landgraf R.
      Meglitinide analogues in the treatment of type 2 diabetes mellitus.
      ,
      • Guardado-Mendoza R.
      • Prioletta A.
      • Jiménez-Ceja L.M.
      • Sosale A.
      • Folli F.
      The role of nateglinide and repaglinide, derivatives of meglitinide, in the treatment of type 2 diabetes mellitus.
      ,
      • Gromada J.
      • Dissing S.
      • Kofod H.
      • Frøkjaer-Jensen J.
      Effects of the hypoglycaemic drugs repaglinide and glibenclamide on ATP-sensitive potassium-channels and cytosolic calcium levels in beta TC3 cells and rat pancreatic beta cells.
      ].
      Meglitinides induce early phase postprandial insulin secretion when they are administered prior to meals [
      • Landgraf R.
      Meglitinide analogues in the treatment of type 2 diabetes mellitus.
      ,
      • Keilson L.
      • Mather S.
      • Walter Y.H.
      • Subramanian S.
      • McLeod J.F.
      Synergistic effects of nateglinide and meal administration on insulin secretion in patients with type 2 diabetes mellitus.
      ]. Peak insulin levels occur at 1–2 h and, due to their short half-life (1 to 1.5 h), insulin concentrations return to fasting levels in 6 h, making meglitinides effective in controlling post-prandial glucose excursions [
      • Dornhorst A.
      Insulinotropic meglitinide analogues.
      ,
      • Owens D.R.
      Repaglinide: a new short-acting insulinotropic agent for the treatment of type 2 diabetes.
      ,
      • Scott L.J.
      Repaglinide: a review of its use in type 2 diabetes mellitus.
      ]. Their action is more rapid and shorter than SUs, leading to superior post-prandial control and reduced late onset hypoglycemia [
      • Dornhorst A.
      Insulinotropic meglitinide analogues.
      ,
      • Guardado-Mendoza R.
      • Prioletta A.
      • Jiménez-Ceja L.M.
      • Sosale A.
      • Folli F.
      The role of nateglinide and repaglinide, derivatives of meglitinide, in the treatment of type 2 diabetes mellitus.
      ].
      There is some evidence that nateglinide inhibits DPP-4 levels, leading to an increase in incretin hormone levels, but this has not been firmly established [
      • McKillop A.M.
      • Duffy N.A.
      • Lindsay J.R.
      • Green B.D.
      • Patterson S.
      • O’Harte F.P.M.
      • et al.
      Insulinotropic actions of nateglinide in type 2 diabetic patients and effects on dipeptidyl peptidase-IV activity and glucose-dependent insulinotropic polypeptide degradation.
      ].
      Repaglinide is primarily metabolized by the hepatic cytochrome P450 CYP3A4 and CYP2C9 isoenzymes system, with 90 % excreted in the gut and 8 % in the urine [
      • Owens D.R.
      Repaglinide: a new short-acting insulinotropic agent for the treatment of type 2 diabetes.
      ,
      • Hatorp V.
      Clinical pharmacokinetics and pharmacodynamics of repaglinide.
      ]. Nateglinide is also metabolized by the hepatic cytochrome P450 CYP2C9 and CYP3A4 isoenzymes system, being mostly excreted in the urine [
      • Weaver M.L.
      • Orwig B.A.
      • Rodriguez L.C.
      • Graham E.D.
      • Chin J.A.
      • Shapiro M.J.
      • et al.
      Pharmacokinetics and metabolism of nateglinide in humans.
      ].

      2.1.3.2 Position in the therapeutic armamentarium

      2.1.3.2.1 Dosing, indications and contraindications

      Meglitinides are oral medications, administered three times a day with meals, up to 30 min prior to eating [
      • Blicklé J.
      Meglitinide analogues: a review of clinical data focused on recent trials.
      ]. The dose range for repaglinide is 0.5–4.0 mg and for nateglinide is 60–120 mg, three times daily with meals [
      • Keilson L.
      • Mather S.
      • Walter Y.H.
      • Subramanian S.
      • McLeod J.F.
      Synergistic effects of nateglinide and meal administration on insulin secretion in patients with type 2 diabetes mellitus.
      ,
      • Goldberg R.B.
      • Einhorn D.
      • Lucas C.P.
      • Rendell M.S.
      • Damsbo P.
      • Huang W.C.
      • et al.
      A randomized placebo-controlled trial of repaglinide in the treatment of type 2 diabetes.
      ,
      • Hasslacher C.
      for the Multinational Repaglinide Renal Study Group
      Safety and efficacy of repaglinide in type 2 diabetic patients with and without impaired renal function.
      ].
      Meglitinides can be used as monotherapy when metformin is contraindicated, but they are more commonly used as second or third-line therapy in combination with other drugs [
      • Black C.
      • Donnelly P.
      • McIntyre L.
      • Royle P.
      • Shepherd J.J.
      • Thomas S.
      Meglitinide analogues for type 2 diabetes mellitus.
      ,
      • Guardado-Mendoza R.
      • Prioletta A.
      • Jiménez-Ceja L.M.
      • Sosale A.
      • Folli F.
      The role of nateglinide and repaglinide, derivatives of meglitinide, in the treatment of type 2 diabetes mellitus.
      ]. Fixed dose combination with metformin (PrandiMet) is available in the market and is convenient for patients in whom monotherapy is inadequate [
      • Moses R.G.
      Repaglinide/metformin fixed-dose combination to improve glycemic control in patients with type 2 diabetes: an update.
      ].
      An advantage of repaglinide is that it can be administered in patients with mild to moderate renal insufficiency (eGFR ≥40 mL/min/1.73 m2) without any dose adjustment, as it is primarily metabolized by the liver [
      • Goldberg R.B.
      • Einhorn D.
      • Lucas C.P.
      • Rendell M.S.
      • Damsbo P.
      • Huang W.C.
      • et al.
      A randomized placebo-controlled trial of repaglinide in the treatment of type 2 diabetes.
      ,
      • Hasslacher C.
      for the Multinational Repaglinide Renal Study Group
      Safety and efficacy of repaglinide in type 2 diabetic patients with and without impaired renal function.
      ,
      • Marbury T.C.
      • Ruckle J.L.
      • Hatorp V.
      • Andersen M.P.
      • Nielsen K.K.
      • Huang W.C.
      • et al.
      Pharmacokinetics of repaglinide in subjects with renal impairment.
      ]. In patients with an eGFR 20–40 mL/min/1.73 m2, the dose should be initiated at 0.5 mg before the largest meal, with additional doses prior to other meals as necessary [
      • Hasslacher C.
      for the Multinational Repaglinide Renal Study Group
      Safety and efficacy of repaglinide in type 2 diabetic patients with and without impaired renal function.
      ]. There are no studies in patients with an eGFR <20 mL/min/1.73 m2. Another advantage of repaglinide is that its rapid onset allows for flexible mealtime dosing and eliminates the need to snack between meals to prevent hypoglycemia (as is the case with SUs) [
      • Black C.
      • Donnelly P.
      • McIntyre L.
      • Royle P.
      • Shepherd J.J.
      • Thomas S.
      Meglitinide analogues for type 2 diabetes mellitus.
      ,
      • Moses R.G.
      • Gomis R.
      • Frandsen K.B.
      • Schlienger J.-L.
      • Dedov I.
      Flexible meal-related dosing with repaglinide facilitates glycemic control in therapy-naive type 2 diabetes.
      ].
      On the other hand, nateglinide has active metabolites that are renally excreted; thus, its use in patients with decreased renal function can lead to hypoglycemia. There are no recommended dose adjustments, but careful monitoring of blood glucose levels is warranted [
      • Inoue T.
      • Shibahara N.
      • Miyagawa K.
      • Itahana R.
      • Izumi M.
      • Nakanishi T.
      • et al.
      Pharmacokinetics of nateglinide and its metabolites in subjects with type 2 diabetes mellitus and renal failure.
      ].
      Limitation of meglitinides include their multiple daily dosing schedule making adherence difficult, the potential for weight gain, and drug-drug interactions due to their hepatic metabolism pathway [
      • Black C.
      • Donnelly P.
      • McIntyre L.
      • Royle P.
      • Shepherd J.J.
      • Thomas S.
      Meglitinide analogues for type 2 diabetes mellitus.
      ]. For example, clopidogrel and gemfibrozil can inhibit the hepatic clearance of repaglinide increasing the risk for hypoglycemia and hence it is contraindicated in this setting [
      • Tornio A.
      • Filppula A.M.
      • Kailari O.
      • Neuvonen M.
      • Nyrönen T.H.
      • Tapaninen T.
      • et al.
      Glucuronidation converts clopidogrel to a strong time-dependent inhibitor of CYP2C8: a phase II metabolite as a perpetrator of drug-drug interactions.
      ,
      • Backman J.T.
      • Filppula A.M.
      • Niemi M.
      • Neuvonen P.J.
      Role of cytochrome P450 2C8 in drug metabolism and interactions.
      ]. The use of repaglinide with some antibiotics (i.e., cefditoren, levofloxacin, clarithromycin) has been associated with increased incidence of hypoglycemia [
      • Kennedy K.E.
      • Teng C.
      • Patek T.M.
      • Frei C.R.
      Hypoglycemia associated with antibiotics alone and in combination with sulfonylureas and meglitinides: an epidemiologic surveillance study of the FDA Adverse Event Reporting System (FAERS).
      ]. Due to their metabolism, meglitinides should be used with caution in patients with moderate to severe liver dysfunction [
      • Owens D.R.
      • McDougall A.
      Repaglinide: prandial glucose regulation in clinical practice.
      ].

      2.1.3.2.2 Safety and tolerability

      Meglitinides are well-tolerated drugs, with the most significant side effects being weight gain and hypoglycemia. In this context, the rate of symptomatic hypoglycemia with meglitinide use varies from 17 to 44 % [
      • Goldberg R.B.
      • Einhorn D.
      • Lucas C.P.
      • Rendell M.S.
      • Damsbo P.
      • Huang W.C.
      • et al.
      A randomized placebo-controlled trial of repaglinide in the treatment of type 2 diabetes.
      ,
      • Moses R.G.
      • Gomis R.
      • Frandsen K.B.
      • Schlienger J.-L.
      • Dedov I.
      Flexible meal-related dosing with repaglinide facilitates glycemic control in therapy-naive type 2 diabetes.
      ,
      • Van Gaal L.F.
      • Van Acker K.L.
      • De Leeuw I.H.
      Repaglinide improves blood glucose control in sulphonylurea-naive type 2 diabetes.
      ]. However, the severity and duration of hypoglycemia is lower than with SUs as meglitinides increase the early-phase insulin secretion in contrast to SUs which enhance the late-phase [
      • Scott L.J.
      Repaglinide: a review of its use in type 2 diabetes mellitus.
      ,
      • Moses R.
      A review of clinical experience with the prandial glucose regulator, repaglinide, in the treatment of type 2 diabetes.
      ]. Furthermore, meglitinides may cause a modest weight gain up to 2–3 kg, which is similar to SUs [
      • Black C.
      • Donnelly P.
      • McIntyre L.
      • Royle P.
      • Shepherd J.J.
      • Thomas S.
      Meglitinide analogues for type 2 diabetes mellitus.
      ]. In contrast to metformin, meglitinides do not exert significant GI adverse events [
      • Black C.
      • Donnelly P.
      • McIntyre L.
      • Royle P.
      • Shepherd J.J.
      • Thomas S.
      Meglitinide analogues for type 2 diabetes mellitus.
      ].

      2.1.3.3 Cardiovascular and other outcomes

      Meglitinides improve glycemic control by decreasing HbA1c by 0.2–1.5 % in T2D [
      • Philip J.
      • Fernandez C.J.
      Efficacy and cardiovascular safety of meglitinides.
      ]. Repaglinide is more efficacious than nateglinide (HbA1c reduction of 0.1–2.1%versus 0.2–1.0 %, respectively), with some studies showing that it can be as efficacious as metformin [
      • Black C.
      • Donnelly P.
      • McIntyre L.
      • Royle P.
      • Shepherd J.J.
      • Thomas S.
      Meglitinide analogues for type 2 diabetes mellitus.
      ,
      • Rosenstock J.
      • Hassman D.R.
      • Madder R.D.
      • Brazinsky S.A.
      • Farrell J.
      • Khutoryansky N.
      • et al.
      Repaglinide versus nateglinide monotherapy: a randomized, multicenter study.
      ].
      Post-prandial blood glucose levels are a risk factor for CV disease; thus, its lowering may lead to improved CV outcomes [
      • Gerich J.E.
      Clinical significance, pathogenesis, and management of postprandial hyperglycemia.
      ]. Due to their secretagogue effect, particularly related to early-phase insulin release, meglitinides effectively control post-prandial glucose concentrations, representing another CV advantage of this drug class [
      • Pishdad R.
      • Pishdad P.
      • Pishdad G.R.
      Acarbose versus repaglinide in diabetes treatment: a new appraisal of two old rivals.
      ,
      • Node K.
      • Inoue T.
      Postprandial hyperglycemia as an etiological factor in vascular failure.
      ] especially taking into consideration that other drugs that affect post-prandial glucose levels are expensive injectables (e.g.: short-acting insulin analogs, GLP-1 agonists, pramlintide). Furthermore, meglitinides can reduce the requirement of basal insulin [
      • Pishdad R.
      • Pishdad P.
      • Pishdad G.R.
      Acarbose versus repaglinide in diabetes treatment: a new appraisal of two old rivals.
      ] and do not adversely affect beta-cell survival [
      • Blicklé J.
      Meglitinide analogues: a review of clinical data focused on recent trials.
      ].
      Similar to SUs, there was a concern that meglitinides, via binding to K-ATP channels in the heart, would impair ischemic preconditioning, thus leading to worse outcomes [
      • Quast U.
      • Stephan D.
      • Bieger S.
      • Russ U.
      The impact of ATP-sensitive K+ channel subtype selectivity of insulin secretagogues for the coronary vasculature and the myocardium.
      ]. However, evidence supporting this has not emerged [
      • Derosa G.
      • Mugellini A.
      • Ciccarelli L.
      • Crescenzi G.
      • Fogari R.
      Comparison of glycaemic control and cardiovascular risk profile in patients with type 2 diabetes during treatment with either repaglinide or metformin.
      ].
      Conversely, meglitinide-related postprandial effect led to the hypothesis that these drugs could reduce the risk of IGT progression to T2D, as well as lower CV risk in high-risk patients with IGT. However, the large scale Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) RCT did not demonstrate either of these benefits after 5 years in patients taking nateglinide compared with placebo [
      The NAVIGATOR Study Group
      Effect of nateglinide on the incidence of diabetes and cardiovascular events.
      ].
      Meglitinides do not affect high-density lipoprotein (HDL), LDL or TG [
      • Goldberg R.B.
      • Einhorn D.
      • Lucas C.P.
      • Rendell M.S.
      • Damsbo P.
      • Huang W.C.
      • et al.
      A randomized placebo-controlled trial of repaglinide in the treatment of type 2 diabetes.
      ].

      2.1.3.4 Cost

      The cost for meglitinides are medium at $20–$40/month [
      Glinides - prices and information. GoodRx.
      ]. The median 30-day NADAC [
      U.S. Centers for Medicare &ampMedicaid Services
      NADAC (National Average Drug Acquisition Cost) 2022. MedicaidGov.
      ] of maximum approved daily dose of meglitinides in the US is $28 for nateglinide and $34 for repaglinide [
      American Diabetes Association Professional Practice Committee
      9. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes—2022.
      ].

      2.1.3.5 Summary

      Meglitinides are oral antidiabetic medications that are affordable, though more expensive than SUs, well-tolerated, globally available and affect postprandial glucose levels [
      • Pishdad R.
      • Pishdad P.
      • Pishdad G.R.
      Acarbose versus repaglinide in diabetes treatment: a new appraisal of two old rivals.
      ,
      • Node K.
      • Inoue T.
      Postprandial hyperglycemia as an etiological factor in vascular failure.
      ]. To date, these drugs have not been proven to decrease CV risk. Meglitinides could be considered among T2D patients without overweight or obesity, if seeking low cost, and among those not candidates for SU use given need for more flexible mealtime schedule or a sulfa allergy.

      2.1.4 Alpha-glucosidase inhibitors

      Among the four alpha-glucosidase inhibitors (AGIs), acarbose, miglitol, voglibose, and emiglitate, only acarbose and miglitol are approved by the FDA and are available for use in the US.

      2.1.4.1 Mechanism of action

      These oral drugs are reversible inhibitors of the enzyme alpha-glucosidase present in the small intestinal brush border, leading to a decrease in the absorption of complex polysaccharides, thus lowering post-prandial glucose and insulin levels [
      • van de Laar F.A.
      • Lucassen P.L.
      • Akkermans R.P.
      • van de Lisdonk E.H.
      • Rutten G.E.
      • van Weel C.
      Alpha-glucosidase inhibitors for patients with type 2 diabetes: results from a Cochrane systematic review and meta-analysis.
      ]. Additionally, it has been recently proven that AGIs cause a sustained increase in gut incretin levels via a mechanism distinct from that of DPP-4 inhibitors [
      • Kalra S.
      Incretin enhancement without hyperinsulinemia: α-glucosidase inhibitors.
      ]. Acarbose and voglibose are poorly absorbed from the gut and are excreted in the stool. Miglitol is systemically absorbed and is renally excreted [
      • Pishdad R.
      • Pishdad P.
      • Pishdad G.R.
      Acarbose versus repaglinide in diabetes treatment: a new appraisal of two old rivals.
      ].

      2.1.4.2 Position in the therapeutic armamentarium

      2.1.4.2.1 Dosing, indications and contraindications

      Acarbose is the most prescribed AGI with an initial dose of 25 mg one to three times a day, taken with the first bite of a meal [
      • Derosa G.
      • Maffioli P.
      α-Glucosidase inhibitors and their use in clinical practice.
      ]. The maximum dose for a patient who weighs >60 kg is 100 mg three times a day. However, increasing the dose above 50 mg three times a day only increases side effects without improving glycemic control [
      • van de Laar F.A.
      • Lucassen P.L.
      • Akkermans R.P.
      • van de Lisdonk E.H.
      • Rutten G.E.
      • van Weel C.
      Alpha-glucosidase inhibitors for patients with type 2 diabetes: results from a Cochrane systematic review and meta-analysis.
      ].
      AGIs can be used as monotherapy but are not first line due to their relatively low efficacy, GI side effects, and cost. Thus, they are mainly prescribed in combination with other oral medications or insulin. AGIs are more frequently used as first line therapy in Asia compared with the US [
      • Joshi S.R.
      • Standl E.
      • Tong N.
      • Shah P.
      • Kalra S.
      • Rathod R.
      Therapeutic potential of α-glucosidase inhibitors in type 2 diabetes mellitus: an evidence-based review.
      ]. A unique indication for acarbose compared to other antidiabetic agents is to treat post-bariatric hypoglycemia in those who have undergone Roux-en-Y gastric bypass (RYGBP). It appears to have an overall glucose-stabilizing effect, avoiding postprandial hypoglycemia following RYGBP by decreasing the hyperinsulinemic response. AGIs are contraindicated in patients with chronic intestinal diseases such as inflammatory bowel disease, colonic ulceration, gastroparesis, or patients predisposed to intestinal obstruction [
      • Derosa G.
      • Maffioli P.
      α-Glucosidase inhibitors and their use in clinical practice.
      ].

      2.1.4.2.2 Safety and tolerability

      The main adverse effects are gastrointestinal, including flatulence, diarrhea, and abdominal pain, which can lead to medication non-adherence and discontinuation. The high incidence of GI side effects is one of the main reasons that these drugs are not popular in the US [
      • Isley W.L.
      Review: α glucosidase inhibitors improve glycaemic control but have uncertain effects on patient-important outcomes in type 2 diabetes.
      ]. This can be mitigated by using low doses and titrating the dose slowly [
      • van de Laar F.A.
      • Lucassen P.L.
      • Akkermans R.P.
      • van de Lisdonk E.H.
      • Rutten G.E.
      • van Weel C.
      Alpha-glucosidase inhibitors for patients with type 2 diabetes: results from a Cochrane systematic review and meta-analysis.
      ]. AGIs do not cause hypoglycemia when used as monotherapy [
      • Yang W.
      • Liu J.
      • Shan Z.
      • Tian H.
      • Zhou Z.
      • Ji Q.
      • et al.
      Acarbose compared with metformin as initial therapy in patients with newly diagnosed type 2 diabetes: an open-label, non-inferiority randomised trial.
      ]. There are reports of acute hepatitis with the use of acarbose and thus monitoring of liver enzymes is indicated [
      • Derosa G.
      • Maffioli P.
      α-Glucosidase inhibitors and their use in clinical practice.
      ].

      2.1.4.3 Cardiovascular and other outcomes

      In a meta-analysis of 41 RCTs (7439 participants), acarbose decreased HbA1c levels modestly by 0.8 % (95 % CI 0.7 to 0.9) with a corresponding decrease in fasting glucose (1.1 mmol/L), post-prandial glucose (2.3 mmol/L), and post-prandial insulin levels [
      • van de Laar F.A.
      • Lucassen P.L.
      • Akkermans R.P.
      • van de Lisdonk E.H.
      • Rutten G.E.
      • van Weel C.
      Alpha-glucosidase inhibitors for patients with type 2 diabetes: results from a Cochrane systematic review and meta-analysis.
      ]. Due to their gut-related mechanism of action, they affect post-prandial glucose to a greater degree compared with fasting glucose [
      • van de Laar F.A.
      • Lucassen P.L.
      • Akkermans R.P.
      • van de Lisdonk E.H.
      • Rutten G.E.
      • van Weel C.
      Alpha-glucosidase inhibitors for patients with type 2 diabetes: results from a Cochrane systematic review and meta-analysis.
      ]. Some studies show that AGIs are more efficacious in patients with an Eastern diet (East and South East Asian countries), compared with a Western diet (Europe and North American countries) [
      • Zhu Q.
      • Tong Y.
      • Wu T.
      • Li J.
      • Tong N.
      Comparison of the hypoglycemic effect of acarbose monotherapy in patients with type 2 diabetes mellitus consuming an Eastern or Western diet: a systematic meta-analysis.
      ,
      • Hu R.
      • Li Y.
      • Lv Q.
      • Wu T.
      • Tong N.
      Acarbose monotherapy and type 2 diabetes prevention in Eastern and Western prediabetes: an ethnicity-specific meta-analysis.
      ].
      There is strong, high-quality evidence that AGIs reduce the progression of IGT to T2D and thus they may be used in patients with prediabetes [
      • Coleman R.L.
      • Scott C.A.B.
      • Lang Z.
      • Bethel M.A.
      • Tuomilehto J.
      • Holman R.R.
      Meta-analysis of the impact of alpha-glucosidase inhibitors on incident diabetes and cardiovascular outcomes.
      ]. A Cochrane systematic review, including 10 RCTs (11,814 participants) reported that in patients with IGT treated with acarbose, the risk of developing T2D was decreased by 17 % (RR 0.82, 95 % CI 0.75–0.89, P < 0.0001) [
      • Moelands S.V.
      • Lucassen P.L.
      • Akkermans R.P.
      • De Grauw W.J.
      • Van de Laar F.A.
      Alpha-glucosidase inhibitors for prevention or delay of type 2 diabetes mellitus and its associated complications in people at increased risk of developing type 2 diabetes mellitus.
      ]. Similarly, another meta-analysis of 3 RCTs (9729 participants) found that AGI treatment significantly reduced the risk of incident T2D by 23 % in patients with IGT [
      • Coleman R.L.
      • Scott C.A.B.
      • Lang Z.
      • Bethel M.A.
      • Tuomilehto J.
      • Holman R.R.
      Meta-analysis of the impact of alpha-glucosidase inhibitors on incident diabetes and cardiovascular outcomes.
      ].
      In the Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (STOP-NIDDM) trial, acarbose significantly lowered the risk of cardiovascular (CV) events by 49 % (HR 0.51, 95 % CI 0.28–0.95, P = 0.03) [
      • Coleman R.L.
      • Scott C.A.B.
      • Lang Z.
      • Bethel M.A.
      • Tuomilehto J.
      • Holman R.R.
      Meta-analysis of the impact of alpha-glucosidase inhibitors on incident diabetes and cardiovascular outcomes.
      ,
      • Chiasson J.-L.
      • Josse R.G.
      • Gomis R.
      • Hanefeld M.
      • Karasik A.
      • Laakso M.
      • et al.
      Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose ToleranceThe STOP-NIDDM trial.
      ]. This generated interest in the possible favorable CV impact of these drugs. However, it appears that this was a chance finding as other trials such as the Acarbose Cardiovascular Evaluation (ACE) RCT in China did not show similar results [
      • Holman R.R.
      • Coleman R.L.
      • Chan J.C.N.
      • Chiasson J.-L.
      • Feng H.
      • Ge J.
      • et al.
      Effects of acarbose on cardiovascular and diabetes outcomes in patients with coronary heart disease and impaired glucose tolerance (ACE): a randomised, double-blind, placebo-controlled trial.
      ]. The ACE trial demonstrated that AGIs are neutral with respect to major adverse CV events (HR 0.98, 95 % CI 0.86–1.11, P = 0.73) [
      • Holman R.R.
      • Coleman R.L.
      • Chan J.C.N.
      • Chiasson J.-L.
      • Feng H.
      • Ge J.
      • et al.
      Effects of acarbose on cardiovascular and diabetes outcomes in patients with coronary heart disease and impaired glucose tolerance (ACE): a randomised, double-blind, placebo-controlled trial.
      ]. Furthermore, a recent meta-analysis reported that acarbose did not affect the risk of all-cause mortality (RR 0.98, 95 % CI 0.82–1.18, P = 0.86), CV mortality (RR 0.88, 95 % CI 0.71–1.10, P = 0.26), non-fatal stroke (RR 0.50, 95 % CI 0.09–2.74, P = 0.43) or congestive HF (RR 0.87, 95 % CI 0.63–1.12, P = 0.40) [
      • Moelands S.V.
      • Lucassen P.L.
      • Akkermans R.P.
      • De Grauw W.J.
      • Van de Laar F.A.
      Alpha-glucosidase inhibitors for prevention or delay of type 2 diabetes mellitus and its associated complications in people at increased risk of developing type 2 diabetes mellitus.
      ]. Another meta-analysis also confirmed that in those with IGT or T2D, AGIs showed a neutral CV outcome [
      • Coleman R.L.
      • Scott C.A.B.
      • Lang Z.
      • Bethel M.A.
      • Tuomilehto J.
      • Holman R.R.
      Meta-analysis of the impact of alpha-glucosidase inhibitors on incident diabetes and cardiovascular outcomes.
      ]. Overall, current literature supports that AGIs do not affect CV mortality, morbidity, or quality of life (QOL) [
      • Chiasson J.-L.
      • Josse R.G.
      • Gomis R.
      • Hanefeld M.
      • Karasik A.
      • Laakso M.
      • et al.
      Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose ToleranceThe STOP-NIDDM trial.
      ]. A recent long-term study concluded that AGI use was associated with higher all-cause mortality (HR 1.21, 95 % CI 1.05–1.40, P = 0.01) and non-cardiovascular death (HR 1.27, 95 % CI 1.07–1.50) in T2D patients on insulin, which cautions against adding AGIs to insulin-treated patients [
      • Yen F.-S.
      • Wei J.C.-C.
      • Lin M.-C.
      • Hsu C.-C.
      • Hwu C.-M.
      Long-term outcomes of adding alpha-glucosidase inhibitors in insulin-treated patients with type 2 diabetes.
      ].
      AGIs may modestly decrease bodyweight: one meta-analysis found a significant decrease in body weight compared with placebo in Asian and non-Asian patients with T2D (−0.63 kg, 95 % CI −1.23 to −0.03 kg, P = 0.04; −0.48 kg, 95 % CI −0.92 to −0.05 kg, P = 0.03, respectively) [
      • Gao X.
      • Cai X.
      • Yang W.
      • Chen Y.
      • Han X.
      • Ji L.
      Meta-analysis and critical review on the efficacy and safety of alpha-glucosidase inhibitors in Asian and non-Asian populations.
      ]. A meta-analysis found no statistically significant difference in body weight for acarbose versus placebo, but noted that body mass index (BMI) was slightly reduced by −0.2 kg/m2 (95% CI −0.3 to −0.1 kg/m2) [
      • van de Laar F.A.
      • Lucassen P.L.
      • Akkermans R.P.
      • van de Lisdonk E.H.
      • Rutten G.E.
      • van Weel C.
      Alpha-glucosidase inhibitors for patients with type 2 diabetes: results from a Cochrane systematic review and meta-analysis.