Semaglutide: Review and Place in Therapy for Adults With Type 2 Diabetes

Open AccessPublished:June 05, 2018DOI:https://doi.org/10.1016/j.jcjd.2018.05.008

      Abstract

      Guidelines increasingly highlight the importance of multifactorial management in type 2 diabetes, in contrast to the more traditional focus on glycemic control. Semaglutide, a recently approved glucagon-like peptide-1 receptor agonist, is indicated in Canada for adults with type 2 diabetes to improve glycemic control as monotherapy with diet and exercise when metformin is inappropriate or as an add-on to either metformin alone or metformin plus a sulfonylurea or basal insulin. The Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) clinical trial program for semaglutide comprises 6 pivotal global phase 3a trials (SUSTAIN 1 through 6) and 2 Japanese phase 3a trials. Phase 3b trials include SUSTAIN 7, and SUSTAIN 8 and 9 (both ongoing). Results from the completed trials support the superiority of semaglutide for reduction of glycated hemoglobin levels and weight loss vs. placebo as well as active comparators, including sitagliptin, exenatide extended-release, dulaglutide and insulin glargine. SUSTAIN 6 trial data confirmed cardiovascular safety and demonstrated significant reductions in major cardiovascular events with semaglutide vs. placebo, an outcome that confirmed the noninferiority of semaglutide. The robust and sustained effects of semaglutide on glycated hemoglobin levels and weight loss vs. comparators, as well as its safety and possible cardiovascular benefit, address an unmet need in the treatment of type 2 diabetes. This article overviews data from across the semaglutide clinical trial program, including efficacy and safety results and findings from post hoc analyses. The potential place of semaglutide in clinical practice is discussed.

      Résumé

      Les lignes directrices insistent de plus en plus sur l'importance de la prise en charge multifactorielle du diabète de type 2 que sur l'importance généralement accordée à la régulation de la glycémie. Le semaglutide, un agoniste des récepteurs GLP–1 (glucagon-like peptide–1) récemment approuvé au Canada, est indiqué en monothérapie associée à un régime alimentaire et la pratique d'une activité physique chez les adultes atteints de diabète de type 2 pour mieux réguler leur glycémie, lorsque la metformine est inappropriée, ou en traitement d'appoint à la metformine seule, ou à la metformine et une sulfonylurée, ou à l'insuline basale. Le programme d'études cliniques SUSTAIN (The Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes) sur le semaglutide regroupe 6 études pivots internationales de phase IIIa (SUSTAIN, de 1 à 6) et 2 études japonaises de phase IIIa. Les études de phase IIIb sont les suivantes : l'étude SUSTAIN 7, et les études SUSTAIN 8 et 9 (qui sont en cours). Les résultats des études complétées confirment la supériorité du semaglutide par rapport au placebo et aux comparateurs actifs, dont la sitagliptine, l'exénatide à libération prolongée, le dulaglutide et l'insuline glargine, dans la réduction des concentrations de l'hémoglobine glyquée et la perte de poids. Les données de l'étude SUSTAIN 6 ont confirmé l'innocuité cardiovasculaire du semaglutide (vs le placebo) et démontré qu'il réduisait de manière significative les événements cardiovasculaires majeurs. Ces résultats confirment la non-infériorité du semaglutide. Les effets importants et prolongés du semaglutide, leur innocuité et leurs avantages cardiovasculaires potentiels par rapport aux comparateurs sur les concentrations de l'hémoglobine glyquée et la perte de poids répondent à un besoin non comblé dans le traitement du diabète de type 2. Le présent article donne un aperçu des données de l'ensemble du programme d'études cliniques sur le semaglutide, y compris les résultats sur l'efficacité et l'innocuité, et les conclusions des analyses post-hoc. Nous traitons de l'utilisation potentielle du semaglutide en pratique clinique.

      Keywords

      Mots clés

      Key Messages
      • Semaglutide is a glucagon-like peptide-1 receptor agonist that was approved in Canada for the treatment of type 2 diabetes on January 4, 2018.
      • Semaglutide is superior to placebo and sitagliptin, exenatide extended-release, dulaglutide and insulin glargine for reduction of glycated hemoglobin levels and weight.
      • SUSTAIN 6 trial data confirmed noninferiority based on significant reductions in major cardiovascular events with semaglutide vs. placebo.

      Introduction

      The focus of type 2 diabetes management has traditionally been on glycemic control, but the importance of multifactorial management is now highlighted in treatment guidelines. This approach includes the optimization of cardiovascular (CV) risk factors, including hyperglycemia, overweight/obesity, hypertension and dyslipidemia (
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      ). Recent guidelines also recommend prioritizing antihyperglycemic agents with demonstrated CV outcome benefit in patients with clinical CV disease (CVD) (
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      Cardiovascular protection in people with diabetes.
      ).
      Despite the range of available treatments for type 2 diabetes, recommended targets are not attained by many patients, leaving them at risk for serious complications (
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      ). In the Diabetes Mellitus Status in Canada study, only half of the 5,123 patients with type 2 diabetes surveyed had met the glycated hemoglobin (A1C) level target of ≤7.0%, despite most (87%) being on at least 1 antihyperglycemic agent (
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      ). Similarly, in the US-based National Health and Nutrition Examination Survey, only 52.2% of people with self-reported diabetes had met an A1C target of <7.0% in 2011 through 2014 (
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      ). Another key target is weight control. The vast majority (≥85%) of people with diabetes are overweight or obese (
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      ), and the risk of having an A1C level ≥7.0% is greater than in those of normal weight (
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      ).
      Addressing CVD risk as part of diabetes management has also been an important focus. People with diabetes are at a 2- to 4-fold increased risk for CVD compared to those without diabetes, and CV events are more likely to occur at an earlier age (
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      Cardiovascular risk factors in confirmed prediabetic individuals: Does the clock for coronary heart disease start ticking before the onset of clinical diabetes?.
      ,
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      ). Although the precise role of glycemic control in CVD risk reduction remains to be elucidated (
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      ), a recent observational study showed that there is a greater risk for a CV event with increasing A1C level (
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      Early glycemic control and magnitude of HbA1c reduction predict cardiovascular events and mortality: Population-based cohort study of 24,752 metformin initiators.
      ). However, other factors contribute to CV risk, as demonstrated in the INTERHEART study involving approximately 30,000 individuals worldwide. Multivariate analysis revealed an increased risk for myocardial infarction (MI) with diabetes (OR 95% CI 2.37 [2.07 to 2.71]); abdominal obesity (OR 95% CI 1.62 [1.45 to 1.80]) for the highest vs. lowest tertile of waist/hip ratio); hypertension (OR 95% CI 1.91 [1.74 to 2.10]); and dyslipidemia (raised apolipoprotein B and A1 ratio (OR 95% CI 3.25 [2.81 to 3.76]) for the highest vs. the lowest quintile) (
      • Yusuf S.
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      • et al.
      Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): Case-control study.
      ).
      Glucagon-like peptide-1 (GLP-1) is an incretin hormone that reduces hyperglycemia through stimulation of glucose-induced insulin secretion, inhibition of glucagon secretion, reduction of hepatic glucose production, slowing of gastric emptying and, possibly, increase of pancreatic beta cell growth and differentiation (
      • Tasyurek H.M.
      • Altunbas H.A.
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      Incretins: Their physiology and application in the treatment of diabetes mellitus.
      ). Currently approved GLP-1 receptor agonists (GLP-1RAs) include the exendin-based therapies (exenatide/exenatide extended-release and lixisenatide) and human GLP-1 analogs (albiglutide [to be withdrawn in 2018] (
      • GlaxoSmithKline
      TANZEUM® (albiglutide) discontinuation — Q&A.
      ), dulaglutide, liraglutide and semaglutide (
      • Health Canada
      OZEMPIC (semaglutide) injection product monograph.
      ,
      • Lovshin J.A.
      Glucagon-like peptide-1 receptor agonists: A class update for treating type 2 diabetes.
      )). Hypoglycemia is not an expected side effect of GLP-1RA agents because of their glucose-dependent mode of action (
      • Inzucchi S.E.
      • Bergenstal R.M.
      • Buse J.B.
      • et al.
      Management of hyperglycemia in type 2 diabetes, 2015: A patient-centered approach: Update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes.
      ). Gastrointestinal (GI) adverse events (AEs), such as diarrhea, nausea and vomiting, are associated with this class of agents (
      • Bettge K.
      • Kahle M.
      • Abd El Aziz M.S.
      • Meier J.J.
      • Nauck M.A.
      Occurrence of nausea, vomiting and diarrhoea reported as adverse events in clinical trials studying glucagon-like peptide-1 receptor agonists: A systematic analysis of published clinical trials.
      ).
      Head-to-head studies of GLP-1RAs have shown similar decreases in A1C levels from baseline with liraglutide 1.8 mg and dulaglutide 1.5 mg (−1.36% vs. −1.42% at 26 weeks; p<0.0001 for noninferiority), and they have reported that liraglutide 1.8 mg reduces A1C levels to a greater extent than exenatide twice daily (−1.12% vs. −0.79% at 26 weeks; p<0.0001); lixisenatide (−0.51% vs. −0.32% at 28 days; p<0.01); albiglutide (−0.99% vs. −0.78% at 32 weeks) (p=0.0846 for noninferiority of albiglutide vs. liraglutide), or exenatide extended release (−1.48% vs. −1.28% at week 26; p=0.02) (
      • Madsbad S.
      Review of head-to-head comparisons of glucagon-like peptide-1 receptor agonists.
      ,
      • Trujillo J.M.
      • Nuffer W.
      • Ellis S.L.
      GLP-1 receptor agonists: A review of head-to-head clinical studies.
      ). Compared with exenatide twice daily, noninferiority criteria were met with lixisenatide (−0.96% vs. −0.79% at 24 weeks; 0.033 to 0.297), a greater reduction from baseline was observed with dulaglutide 0.75 mg (−0.99% vs. −1.30% at 26 weeks; p<0.001), and dulaglutide 1.5 mg (−0.99% vs. −1.51% at 26 weeks; p<0.001), and a significantly greater reduction in A1C levels was observed with exenatide extended-release in 3 studies (−0.9% vs. −1.6% at 24 weeks; p<0.0001; and −1.12% vs. −1.43% at 26 weeks; p<0.001; and −1.5% vs. −1.9% at 30 weeks; p=0.0023) (
      • Madsbad S.
      Review of head-to-head comparisons of glucagon-like peptide-1 receptor agonists.
      ,
      • Trujillo J.M.
      • Nuffer W.
      • Ellis S.L.
      GLP-1 receptor agonists: A review of head-to-head clinical studies.
      ). Head-to-head studies of GLP-1RAs vs. active comparators have suggested that exenatide twice daily results in a reduction in weight from baseline vs. lixisenatide (−3.98 kg vs. −2.96 kg at 24 weeks; 95% CI 0.456 to 1.581), a significant reduction vs. dulaglutide 0.75 mg (−1.07 kg vs. +0.2 kg at 26 weeks; p<0.001); a similar (−3.6 kg vs. −3.7 kg at 30 weeks; p=0.89) and (−1.4 kg vs. −2.3 kg at 24 weeks; 95% CI −1.9 to 0.01) or a significant reduction vs. exenatide extended-release (−2.45 kg vs. −1.63 kg at 26 weeks; p<0.001) and a similar reduction compared with liraglutide 1.8 mg (−2.87 kg vs. −3.24 kg at 26 weeks; p=0.2235) and dulaglutide 1.5 mg (−1.07 kg vs. −1.30 kg at 26 weeks; p=0.474) (
      • Madsbad S.
      Review of head-to-head comparisons of glucagon-like peptide-1 receptor agonists.
      ,
      • Trujillo J.M.
      • Nuffer W.
      • Ellis S.L.
      GLP-1 receptor agonists: A review of head-to-head clinical studies.
      ). Liraglutide 1.8 mg demonstrated a significant reduction in weight from baseline vs. exenatide extended-release (−3.57 kg vs. −2.68 kg at 26 weeks; p=0.0005); dulaglutide 1.5 mg (−3.61 kg vs. −2.90 kg at 26 weeks; p=0.011); and lixisenatide (−2.4 kg vs. −1.6 kg at 28 days; p<0.01) (
      • Madsbad S.
      Review of head-to-head comparisons of glucagon-like peptide-1 receptor agonists.
      ,
      • Trujillo J.M.
      • Nuffer W.
      • Ellis S.L.
      GLP-1 receptor agonists: A review of head-to-head clinical studies.
      ).
      Trials of GLP-1RAs designed to investigate CV endpoints reported CV safety, although not efficacy, with lixisenatide in the Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) or exenatide extended-release in the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) trial (
      • Pfeffer M.A.
      • Claggett B.
      • Diaz R.
      • et al.
      Lixisenatide in patients with type 2 diabetes and acute coronary syndrome.
      ,
      • Holman R.R.
      • Bethel M.A.
      • Mentz R.J.
      • et al.
      Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes.
      ), respectively, compared with placebo. In the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial, liraglutide was found to have a beneficial effect on CV-related outcomes, including the primary composite endpoint of first occurrence of death from CV causes, nonfatal myocardial infarction (MI) or nonfatal stroke, as well as CV death and all-cause mortality, compared with placebo, in people at high CV risk, following a 3.8-year median follow up (
      • Marso S.P.
      • Daniels G.H.
      • Brown-Frandsen K.
      • et al.
      Liraglutide and cardiovascular outcomes in type 2 diabetes.
      ). The Researching Cardiovascular Events With a Weekly Incretin in Diabetes (REWIND) study of the CV effects of dulaglutide (NCT01394952) (
      • Gerstein H.C.
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      • Dagenais G.R.
      • et al.
      Design and baseline characteristics of participants in the Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) trial on the cardiovascular effects of dulaglutide.
      ) and the HARMONY outcomes trial with albiglutide (NCT02465515) are ongoing (
      • GlaxoSmithKline
      TANZEUM® (albiglutide) discontinuation — Q&A.
      ). The Semaglutide Unabated Sustainability In Treatment of Type 2 Diabetes (SUSTAIN) clinical trial program was designed to investigate semaglutide, a GLP-1RA administered once weekly by subcutaneous (s.c.) injection, and included efficacy and safety trials as well as a CV outcomes trial (CVOT) (
      • Sorli C.
      • Harashima S.I.
      • Tsoukas G.M.
      • et al.
      Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): A double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial.
      ,
      • Ahrén B.
      • Masmiquel L.
      • Kumar H.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): A 56-week, double-blind, phase 3a, randomised trial.
      ,
      • Ahmann A.J.
      • Capehorn M.
      • Charpentier G.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus exenatide ER in subjects with type 2 diabetes (SUSTAIN 3): A 56-week, open-label, randomized clinical trial.
      ,
      • Aroda V.R.
      • Bain S.C.
      • Cariou B.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): A randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial.
      ,
      • Rodbard H.W.
      • Lingvay I.
      • Reed J.
      • et al.
      Semaglutide added to basal insulin in type 2 diabetes (SUSTAIN 5): A randomised, controlled trial.
      ,
      • Seino Y.
      • Terauchi Y.
      • Osonoi T.
      • et al.
      Safety and efficacy of semaglutide once weekly vs sitagliptin once daily, both as monotherapy in Japanese people with type 2 diabetes.
      ,
      • Kaku K.
      • Yamada Y.
      • Watada H.
      • et al.
      Safety and efficacy of once-weekly semaglutide vs additional oral antidiabetic drugs in Japanese people with inadequately controlled type 2 diabetes: A randomized trial.
      ,
      • Marso S.P.
      • Bain S.C.
      • Consoli A.
      • et al.
      Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      ,
      • Pratley R.
      • Aroda V.R.
      • Lingvay I.
      • et al.
      Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): A randomised, open-label, phase 3b trial.
      ).
      The SUSTAIN clinical trial program included 5 controlled, phase 3a trials (SUSTAIN 1 through 5), which compared semaglutide with placebo (as monotherapy or add-on to basal insulin) or with the antihyperglycemic agents sitagliptin, exenatide extended-release and insulin glargine (
      • Sorli C.
      • Harashima S.I.
      • Tsoukas G.M.
      • et al.
      Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): A double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial.
      ,
      • Ahrén B.
      • Masmiquel L.
      • Kumar H.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): A 56-week, double-blind, phase 3a, randomised trial.
      ,
      • Ahmann A.J.
      • Capehorn M.
      • Charpentier G.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus exenatide ER in subjects with type 2 diabetes (SUSTAIN 3): A 56-week, open-label, randomized clinical trial.
      ,
      • Aroda V.R.
      • Bain S.C.
      • Cariou B.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): A randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial.
      ,
      • Rodbard H.W.
      • Lingvay I.
      • Reed J.
      • et al.
      Semaglutide added to basal insulin in type 2 diabetes (SUSTAIN 5): A randomised, controlled trial.
      ). Two Japanese phase 3a trials were also conducted (
      • Seino Y.
      • Terauchi Y.
      • Osonoi T.
      • et al.
      Safety and efficacy of semaglutide once weekly vs sitagliptin once daily, both as monotherapy in Japanese people with type 2 diabetes.
      ,
      • Kaku K.
      • Yamada Y.
      • Watada H.
      • et al.
      Safety and efficacy of once-weekly semaglutide vs additional oral antidiabetic drugs in Japanese people with inadequately controlled type 2 diabetes: A randomized trial.
      ). The SUSTAIN 6 phase 3a trial investigated the safety, efficacy and long-term CV outcomes with semaglutide vs. placebo in adults with type 2 diabetes at high risk for CV events (
      • Marso S.P.
      • Bain S.C.
      • Consoli A.
      • et al.
      Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      ). The phase 3b SUSTAIN 7 trial was a head-to-head comparison of semaglutide vs. dulaglutide (
      • Pratley R.
      • Aroda V.R.
      • Lingvay I.
      • et al.
      Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): A randomised, open-label, phase 3b trial.
      ).
      Semaglutide was approved in Canada on January 4, 2018 (
      • Health Canada
      OZEMPIC (semaglutide) injection product monograph.
      ), in the United States on December 5, 2017 (
      • US Food and Drug Administration
      OZEMPIC (semaglutide) injection prescribing information.
      ) and by the European Medicines Agency in early 2018 (
      • Novo Nordisk Company Announcement
      Ozempic® (semaglutide) approved in the EU for the treatment of type 2 diabetes.
      ), and it is approved (
      • Novo Nordisk Company Announcement
      OZEMPIC® approved in Japan for the treatment of type 2 diabetes.
      ) or under review by several other regulatory agencies (). This article communicates practical information for health-care professionals about the GLP-1RA semaglutide, the findings from the semaglutide clinical trial program, including the efficacy and safety results, and the implications of results from comparative studies and a CVOT. It also provides health-care professionals with insights concerning the place of semaglutide in the management of type 2 diabetes.

      Pharmacology

      The semaglutide molecule has >90% homology to human GLP-1 and, structurally, 3 main modifications in comparison with human GLP-1 (
      • Lau J.
      • Bloch P.
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      Discovery of the once-weekly glucagon-like peptide-1 (GLP-1) analogue semaglutide.
      ,
      • Kapitza C.
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      • Flint A.
      Semaglutide, a once-weekly human GLP-1 analog, does not reduce the bioavailability of the combined oral contraceptive, ethinylestradiol/levonorgestrel.
      ): 1) at peptide position 8, alanine was substituted with alpha-aminoisobutyric acid to disrupt the dipeptidyl peptidase 4 cleavage site and extend its systemic half-life, in comparison with native GLP-1; 2) a linker and C18 diacid chain was attached at peptide position 26, resulting in higher binding affinity for albumin (semaglutide has a 5.6-fold increased affinity for albumin compared with liraglutide, which has a shorter diacid chain), and the linker structure impacts the affinity of semaglutide for binding to the GLP-1 receptor; 3) at peptide position 34, lysine was substituted with arginine to ensure that acylation correctly occurs at Lys26.
      Once-weekly dosing of semaglutide was established in preclinical and pharmacokinetic studies of adults with type 2 diabetes (
      • Lau J.
      • Bloch P.
      • Schaffer L.
      • et al.
      Discovery of the once-weekly glucagon-like peptide-1 (GLP-1) analogue semaglutide.
      ,
      • Kapitza C.
      • Nosek L.
      • Jensen L.
      • Hartvig H.
      • Jensen C.B.
      • Flint A.
      Semaglutide, a once-weekly human GLP-1 analog, does not reduce the bioavailability of the combined oral contraceptive, ethinylestradiol/levonorgestrel.
      ,
      • Kapitza C.
      • Dahl K.
      • Jacobsen J.B.
      • Axelsen M.B.
      • Flint A.
      Effects of semaglutide on beta cell function and glycaemic control in participants with type 2 diabetes: A randomised, double-blind, placebo-controlled trial.
      ,
      • Nauck M.A.
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      • Sesti G.
      • et al.
      A phase 2, randomized, dose-finding study of the novel once-weekly human GLP-1 analog, semaglutide, compared with placebo and open-label liraglutide in patients with type 2 diabetes.
      ). The half-life of semaglutide was approximately 7 days (165 h to 184 h) (
      • Kapitza C.
      • Nosek L.
      • Jensen L.
      • Hartvig H.
      • Jensen C.B.
      • Flint A.
      Semaglutide, a once-weekly human GLP-1 analog, does not reduce the bioavailability of the combined oral contraceptive, ethinylestradiol/levonorgestrel.
      ). Exposure of semaglutide was similar for individuals with or without renal or hepatic impairment (
      • Marbury T.C.
      • Flint A.
      • Jacobsen J.B.
      • Derving Karsbøl J.
      • Lasseter K.
      Pharmacokinetics and tolerability of a single dose of semaglutide, a human glucagon-like peptide-1 analog, in subjects with and without renal impairment.
      ,
      • Jensen L.
      • Kupcova V.
      • Arold G.
      • Kvist T.
      • Pettersson J.
      • Hjerpsted J.B.
      Pharmacokinetics and tolerability of semaglutide in subjects with hepatic impairment. Presentation number SUN 621. Orlando, Florida.
      ). Semaglutide excretion occurs in both urine (primarily, in which approximately 3% of the dose is excreted as intact semaglutide) and in feces (
      • Jensen L.
      • Helleberg H.
      • Roffel A.
      • et al.
      Absorption, metabolism and excretion of the GLP-1 analogue semaglutide in humans and nonclinical species.
      ).

      Phase 3 Efficacy and Safety Trials: SUSTAIN 1–5 and SUSTAIN 7

       Methods and baseline characteristics

      In the Phase 3 SUSTAIN 1 through 5 and SUSTAIN 7 trials, 5,098 subjects with type 2 diabetes were randomized to receive semaglutide (0.5 mg or 1.0 mg s.c. once weekly) or comparators and were exposed to at least 1 dose of treatment (i.e. modified intention-to-treat population) (
      • Sorli C.
      • Harashima S.I.
      • Tsoukas G.M.
      • et al.
      Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): A double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial.
      ,
      • Ahrén B.
      • Masmiquel L.
      • Kumar H.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): A 56-week, double-blind, phase 3a, randomised trial.
      ,
      • Ahmann A.J.
      • Capehorn M.
      • Charpentier G.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus exenatide ER in subjects with type 2 diabetes (SUSTAIN 3): A 56-week, open-label, randomized clinical trial.
      ,
      • Aroda V.R.
      • Bain S.C.
      • Cariou B.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): A randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial.
      ,
      • Rodbard H.W.
      • Lingvay I.
      • Reed J.
      • et al.
      Semaglutide added to basal insulin in type 2 diabetes (SUSTAIN 5): A randomised, controlled trial.
      ,
      • Pratley R.
      • Aroda V.R.
      • Lingvay I.
      • et al.
      Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): A randomised, open-label, phase 3b trial.
      ) (Table 1).
      Table 1Overview of the phase 3 SUSTAIN 1 through 5 and SUSTAIN 7 trials
      Table thumbnail jcjd1062-fig-5001
      Note: See references
      • Sorli C.
      • Harashima S.I.
      • Tsoukas G.M.
      • et al.
      Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): A double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial.
      ,
      • Ahrén B.
      • Masmiquel L.
      • Kumar H.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): A 56-week, double-blind, phase 3a, randomised trial.
      ,
      • Ahmann A.J.
      • Capehorn M.
      • Charpentier G.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus exenatide ER in subjects with type 2 diabetes (SUSTAIN 3): A 56-week, open-label, randomized clinical trial.
      ,
      • Aroda V.R.
      • Bain S.C.
      • Cariou B.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): A randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial.
      ,
      • Rodbard H.W.
      • Lingvay I.
      • Reed J.
      • et al.
      Semaglutide added to basal insulin in type 2 diabetes (SUSTAIN 5): A randomised, controlled trial.
      ,
      • Pratley R.
      • Aroda V.R.
      • Lingvay I.
      • et al.
      Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): A randomised, open-label, phase 3b trial.
      .
      A1C, glycated hemoglobin; BW, body weight; ER, extended-release; IGlar, insulin glargine; MET, metformin; mITT, modified intention-to-treat population; OAD, oral antidiabetic drug; s.c., subcutaneous; SU, sulfonylurea; TZD, thiazolidinedione.
      * IGlar (titrated to target) once daily.
      † Mean value. Subjects with type 2 diabetes in the mITT population were those randomized to receive semaglutide (0.5 mg or 1.0 mg s.c. once weekly) or comparators and were exposed to at least 1 dose of treatment (mITT).
      Inclusion and exclusion criteria were similar across the SUSTAIN 1 through 5 (
      • Sorli C.
      • Harashima S.I.
      • Tsoukas G.M.
      • et al.
      Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): A double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial.
      ,
      • Ahrén B.
      • Masmiquel L.
      • Kumar H.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): A 56-week, double-blind, phase 3a, randomised trial.
      ,
      • Ahmann A.J.
      • Capehorn M.
      • Charpentier G.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus exenatide ER in subjects with type 2 diabetes (SUSTAIN 3): A 56-week, open-label, randomized clinical trial.
      ,
      • Aroda V.R.
      • Bain S.C.
      • Cariou B.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): A randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial.
      ,
      • Rodbard H.W.
      • Lingvay I.
      • Reed J.
      • et al.
      Semaglutide added to basal insulin in type 2 diabetes (SUSTAIN 5): A randomised, controlled trial.
      ) and SUSTAIN 7 trials (
      • Pratley R.
      • Aroda V.R.
      • Lingvay I.
      • et al.
      Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): A randomised, open-label, phase 3b trial.
      ). Participants were ≥18 years of age and had type 2 diabetes, with baseline A1C levels of 7.0% to 10.0% (53 to 86 mmol/mol) in SUSTAIN 1, 4, 5 and 7.0% to 10.5% (53 to 91 mmol/mol) in SUSTAIN 2, 3 and 7. Exclusion criteria included personal histories of chronic or idiopathic acute pancreatitis, personal or family histories of medullary thyroid carcinoma/multiple endocrine neoplasia type 2 or a calcitonin level ≥50 ng/L, an acute coronary or cerebrovascular event within 90 days prior to randomization (or, for SUSTAIN 7, MI, stroke or hospitalization for unstable angina and/or transient ischemic attack within 180 days prior to screening), heart failure (New York Heart Association class IV) or any known proliferative retinopathy or maculopathy requiring acute treatment in the opinion of the investigator.
      Baseline characteristics (mean) were similar across the SUSTAIN 1 through 5 and SUSTAIN 7 trials; the mean duration of type 2 diabetes varied across trials (
      • Sorli C.
      • Harashima S.I.
      • Tsoukas G.M.
      • et al.
      Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): A double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial.
      ,
      • Ahrén B.
      • Masmiquel L.
      • Kumar H.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): A 56-week, double-blind, phase 3a, randomised trial.
      ,
      • Ahmann A.J.
      • Capehorn M.
      • Charpentier G.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus exenatide ER in subjects with type 2 diabetes (SUSTAIN 3): A 56-week, open-label, randomized clinical trial.
      ,
      • Aroda V.R.
      • Bain S.C.
      • Cariou B.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): A randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial.
      ,
      • Rodbard H.W.
      • Lingvay I.
      • Reed J.
      • et al.
      Semaglutide added to basal insulin in type 2 diabetes (SUSTAIN 5): A randomised, controlled trial.
      ,
      • Pratley R.
      • Aroda V.R.
      • Lingvay I.
      • et al.
      Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): A randomised, open-label, phase 3b trial.
      ) (Table 1).

       Effect on glycemic control

      By the end of treatment, a significant reduction in mean A1C levels was demonstrated with semaglutide: 0.5 mg and 1.0 mg vs. all comparators across the 5 SUSTAIN trials (
      • Sorli C.
      • Harashima S.I.
      • Tsoukas G.M.
      • et al.
      Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): A double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial.
      ,
      • Ahrén B.
      • Masmiquel L.
      • Kumar H.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): A 56-week, double-blind, phase 3a, randomised trial.
      ,
      • Ahmann A.J.
      • Capehorn M.
      • Charpentier G.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus exenatide ER in subjects with type 2 diabetes (SUSTAIN 3): A 56-week, open-label, randomized clinical trial.
      ,
      • Aroda V.R.
      • Bain S.C.
      • Cariou B.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): A randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial.
      ,
      • Rodbard H.W.
      • Lingvay I.
      • Reed J.
      • et al.
      Semaglutide added to basal insulin in type 2 diabetes (SUSTAIN 5): A randomised, controlled trial.
      ,
      • Bain S.
      • Skrivanek Z.
      • Tahbaz A.
      • Pechtner V.
      • Adetunji O.
      Semaglutide reduces HbA1c and body weight across baseline HbA1c subgroups in the SUSTAIN 1–5 clinical trials. ePoster number 813. Lisbon.
      ) and in SUSTAIN 7 (
      • Pratley R.
      • Aroda V.R.
      • Lingvay I.
      • et al.
      Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): A randomised, open-label, phase 3b trial.
      ) (all p<0.0001; Figure 1a). A1C reduction from baseline ranged from 1.2% to 1.5% with the 0.5 mg dose and from 1.5% to 1.8% with the 1.0 mg dose, with the 1.0 mg dose decreasing A1C 0.1% to 0.4% more than the 0.5 mg dose (Figure 1a) (
      • Pratley R.
      • Aroda V.R.
      • Lingvay I.
      • et al.
      Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): A randomised, open-label, phase 3b trial.
      ,
      • Chudleigh R.
      • Bain S.C.
      Semaglutide.
      ). The target A1C of <7.0% was achieved by up to 78.7% of subjects in the semaglutide groups, compared with up to 24.8% in the placebo (p<0.0001) and 66.6% in the active comparator groups (p≤0.0021) (
      • Sorli C.
      • Harashima S.I.
      • Tsoukas G.M.
      • et al.
      Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): A double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial.
      ,
      • Ahrén B.
      • Masmiquel L.
      • Kumar H.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): A 56-week, double-blind, phase 3a, randomised trial.
      ,
      • Ahmann A.J.
      • Capehorn M.
      • Charpentier G.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus exenatide ER in subjects with type 2 diabetes (SUSTAIN 3): A 56-week, open-label, randomized clinical trial.
      ,
      • Aroda V.R.
      • Bain S.C.
      • Cariou B.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): A randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial.
      ,
      • Rodbard H.W.
      • Lingvay I.
      • Reed J.
      • et al.
      Semaglutide added to basal insulin in type 2 diabetes (SUSTAIN 5): A randomised, controlled trial.
      ,
      • Pratley R.
      • Aroda V.R.
      • Lingvay I.
      • et al.
      Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): A randomised, open-label, phase 3b trial.
      ,
      • Ahmann A.
      • Chow F.
      • Fonseca V.
      • et al.
      Superior glycaemic control with semaglutide across SUSTAIN 1–5 clinical trials. ePoster number 816. Lisbon.
      ). The target A1C of ≤6.5% was met by up to 66.7% of subjects in the semaglutide groups, compared with up to 13.2% with placebo, and up to 47.2% with active comparators (all p<0.0001) (
      • Sorli C.
      • Harashima S.I.
      • Tsoukas G.M.
      • et al.
      Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): A double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial.
      ,
      • Ahrén B.
      • Masmiquel L.
      • Kumar H.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): A 56-week, double-blind, phase 3a, randomised trial.
      ,
      • Ahmann A.J.
      • Capehorn M.
      • Charpentier G.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus exenatide ER in subjects with type 2 diabetes (SUSTAIN 3): A 56-week, open-label, randomized clinical trial.
      ,
      • Aroda V.R.
      • Bain S.C.
      • Cariou B.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): A randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial.
      ,
      • Rodbard H.W.
      • Lingvay I.
      • Reed J.
      • et al.
      Semaglutide added to basal insulin in type 2 diabetes (SUSTAIN 5): A randomised, controlled trial.
      ,
      • Pratley R.
      • Aroda V.R.
      • Lingvay I.
      • et al.
      Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): A randomised, open-label, phase 3b trial.
      ,
      • Ahmann A.
      • Chow F.
      • Fonseca V.
      • et al.
      Superior glycaemic control with semaglutide across SUSTAIN 1–5 clinical trials. ePoster number 816. Lisbon.
      ). Up to 74.3% of the subjects receiving semaglutide achieved the composite endpoint of A1C <7.0% without severe/blood glucose-confirmed symptomatic hypoglycemia or weight gain—a significantly greater proportion than those receiving placebo or active comparator (≤58.4%; all p≤0.0001) (
      • Sorli C.
      • Harashima S.I.
      • Tsoukas G.M.
      • et al.
      Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): A double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial.
      ,
      • Ahrén B.
      • Masmiquel L.
      • Kumar H.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): A 56-week, double-blind, phase 3a, randomised trial.
      ,
      • Ahmann A.J.
      • Capehorn M.
      • Charpentier G.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus exenatide ER in subjects with type 2 diabetes (SUSTAIN 3): A 56-week, open-label, randomized clinical trial.
      ,
      • Aroda V.R.
      • Bain S.C.
      • Cariou B.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): A randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial.
      ,
      • Rodbard H.W.
      • Lingvay I.
      • Reed J.
      • et al.
      Semaglutide added to basal insulin in type 2 diabetes (SUSTAIN 5): A randomised, controlled trial.
      ,
      • Pratley R.
      • Aroda V.R.
      • Lingvay I.
      • et al.
      Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): A randomised, open-label, phase 3b trial.
      ).
      Figure 1
      Figure 1(A) Change in glycated hemoglobin (A1C) levels with semaglutide vs. comparators across the SUSTAIN 1 through 5 and SUSTAIN 7 trials (
      • Pratley R.
      • Aroda V.R.
      • Lingvay I.
      • et al.
      Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): A randomised, open-label, phase 3b trial.
      ,
      • Chudleigh R.
      • Bain S.C.
      Semaglutide.
      ). *p<0.0001 vs. comparator. Calculated using estimated means from a mixed model for repeated measurements analysis using “on-treatment without rescue medication” data from subjects in the full analysis set. (B) Change in body weight with semaglutide vs. comparators across the SUSTAIN 1 through 5 and SUSTAIN 7 trials (
      • Pratley R.
      • Aroda V.R.
      • Lingvay I.
      • et al.
      Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): A randomised, open-label, phase 3b trial.
      ,
      • Chudleigh R.
      • Bain S.C.
      Semaglutide.
      ). *p<0.0001 vs. comparator. Calculated using estimated means from a mixed model for repeated measurements analysis using “on-treatment without rescue medication” data from subjects in the full analysis set. BW, body weight; ER, extended-release; IGlar, insulin glargine; MET, metformin; OAD, oral antidiabetic drug; SU, sulfonylurea; TZD, thiazolidinedione. Adapted with permission from Drugs of the Future 2017;42(8):479. Copyright © 2017 Clarivate Analytics DOI: 10.1358/dof.2017.042.08.2653526.
      A significant reduction in fasting plasma glucose was demonstrated with semaglutide 1.0 mg vs. all comparators (all p≤0.0005) by the end of treatment and with the 0.5 mg semaglutide dose in the SUSTAIN 1, 2 and 5 trials (all p≤0.0002; note that SUSTAIN 3 did not include the 0.5 mg dose) (
      • Sorli C.
      • Harashima S.I.
      • Tsoukas G.M.
      • et al.
      Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): A double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial.
      ,
      • Ahrén B.
      • Masmiquel L.
      • Kumar H.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): A 56-week, double-blind, phase 3a, randomised trial.
      ,
      • Ahmann A.J.
      • Capehorn M.
      • Charpentier G.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus exenatide ER in subjects with type 2 diabetes (SUSTAIN 3): A 56-week, open-label, randomized clinical trial.
      ,
      • Aroda V.R.
      • Bain S.C.
      • Cariou B.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): A randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial.
      ,
      • Rodbard H.W.
      • Lingvay I.
      • Reed J.
      • et al.
      Semaglutide added to basal insulin in type 2 diabetes (SUSTAIN 5): A randomised, controlled trial.
      ,
      • Pratley R.
      • Aroda V.R.
      • Lingvay I.
      • et al.
      Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): A randomised, open-label, phase 3b trial.
      ,
      • Cariou B.
      • Unger J.
      • Jódar E.
      • Birch S.
      • Tadayon S.
      • Aroda V.R.
      Semaglutide consistently reduces both fasting and postprandial glucose levels across SUSTAIN 1–5 clinical trials. ePoster number 818. Lisbon.
      ).

       Effect on body weight

      Statistically significant reductions in weight were found with semaglutide 0.5 mg and 1.0 mg vs. all comparators (p<0.0001) (Figure 1b) (
      • Sorli C.
      • Harashima S.I.
      • Tsoukas G.M.
      • et al.
      Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): A double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial.
      ,
      • Ahrén B.
      • Masmiquel L.
      • Kumar H.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): A 56-week, double-blind, phase 3a, randomised trial.
      ,
      • Ahmann A.J.
      • Capehorn M.
      • Charpentier G.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus exenatide ER in subjects with type 2 diabetes (SUSTAIN 3): A 56-week, open-label, randomized clinical trial.
      ,
      • Aroda V.R.
      • Bain S.C.
      • Cariou B.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): A randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial.
      ,
      • Rodbard H.W.
      • Lingvay I.
      • Reed J.
      • et al.
      Semaglutide added to basal insulin in type 2 diabetes (SUSTAIN 5): A randomised, controlled trial.
      ,
      • Pratley R.
      • Aroda V.R.
      • Lingvay I.
      • et al.
      Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): A randomised, open-label, phase 3b trial.
      ,
      • Chudleigh R.
      • Bain S.C.
      Semaglutide.
      ). Weight loss from baseline ranged from 3.5 to 4.6 kg with the 0.5 mg dose and from 4.5 to 6.5 kg with the 1.0 mg dose, with the 1.0 mg dose lowering weight by 0.8 to 2.7 kg more than the 0.5 mg dose (Figure 1b) (
      • Sorli C.
      • Harashima S.I.
      • Tsoukas G.M.
      • et al.
      Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): A double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial.
      ,
      • Ahrén B.
      • Masmiquel L.
      • Kumar H.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): A 56-week, double-blind, phase 3a, randomised trial.
      ,
      • Ahmann A.J.
      • Capehorn M.
      • Charpentier G.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus exenatide ER in subjects with type 2 diabetes (SUSTAIN 3): A 56-week, open-label, randomized clinical trial.
      ,
      • Aroda V.R.
      • Bain S.C.
      • Cariou B.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): A randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial.
      ,
      • Rodbard H.W.
      • Lingvay I.
      • Reed J.
      • et al.
      Semaglutide added to basal insulin in type 2 diabetes (SUSTAIN 5): A randomised, controlled trial.
      ,
      • Pratley R.
      • Aroda V.R.
      • Lingvay I.
      • et al.
      Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): A randomised, open-label, phase 3b trial.
      ,
      • Chudleigh R.
      • Bain S.C.
      Semaglutide.
      ). Weight loss observed in the groups receiving semaglutide 1.0 mg was 2-fold or greater than that observed in the placebo or active comparator groups (
      • Sorli C.
      • Harashima S.I.
      • Tsoukas G.M.
      • et al.
      Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): A double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial.
      ,
      • Ahrén B.
      • Masmiquel L.
      • Kumar H.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): A 56-week, double-blind, phase 3a, randomised trial.
      ,
      • Ahmann A.J.
      • Capehorn M.
      • Charpentier G.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus exenatide ER in subjects with type 2 diabetes (SUSTAIN 3): A 56-week, open-label, randomized clinical trial.
      ,
      • Aroda V.R.
      • Bain S.C.
      • Cariou B.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): A randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial.
      ,
      • Rodbard H.W.
      • Lingvay I.
      • Reed J.
      • et al.
      Semaglutide added to basal insulin in type 2 diabetes (SUSTAIN 5): A randomised, controlled trial.
      ,
      • Pratley R.
      • Aroda V.R.
      • Lingvay I.
      • et al.
      Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): A randomised, open-label, phase 3b trial.
      ,
      • Chudleigh R.
      • Bain S.C.
      Semaglutide.
      ) (Figure 1b) and, although weight reduction was apparent with semaglutide in the SUSTAIN 4 trial, weight gain was found in the insulin glargine group (Figure 1b) (
      • Aroda V.R.
      • Bain S.C.
      • Cariou B.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): A randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial.
      ,
      • Chudleigh R.
      • Bain S.C.
      Semaglutide.
      ). Up to 65.7% of subjects in both semaglutide dose groups achieved weight-loss responses of ≥5%, compared with up to 11.3% with placebo and up to 30.2% with active comparators (all p<0.0001) (
      • Sorli C.
      • Harashima S.I.
      • Tsoukas G.M.
      • et al.
      Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): A double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial.
      ,
      • Ahrén B.
      • Masmiquel L.
      • Kumar H.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): A 56-week, double-blind, phase 3a, randomised trial.
      ,
      • Ahmann A.J.
      • Capehorn M.
      • Charpentier G.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus exenatide ER in subjects with type 2 diabetes (SUSTAIN 3): A 56-week, open-label, randomized clinical trial.
      ,
      • Aroda V.R.
      • Bain S.C.
      • Cariou B.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): A randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial.
      ,
      • Rodbard H.W.
      • Lingvay I.
      • Reed J.
      • et al.
      Semaglutide added to basal insulin in type 2 diabetes (SUSTAIN 5): A randomised, controlled trial.
      ,
      • Pratley R.
      • Aroda V.R.
      • Lingvay I.
      • et al.
      Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): A randomised, open-label, phase 3b trial.
      ). Up to 26.7% of subjects in both semaglutide groups achieved weight-loss responses of ≥10% compared with up to 3.0% with placebo (p≤0.05) and up to 7.7% with active comparators (all p≤0.0002) (
      • Sorli C.
      • Harashima S.I.
      • Tsoukas G.M.
      • et al.
      Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): A double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial.
      ,
      • Ahrén B.
      • Masmiquel L.
      • Kumar H.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): A 56-week, double-blind, phase 3a, randomised trial.
      ,
      • Ahmann A.J.
      • Capehorn M.
      • Charpentier G.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus exenatide ER in subjects with type 2 diabetes (SUSTAIN 3): A 56-week, open-label, randomized clinical trial.
      ,
      • Aroda V.R.
      • Bain S.C.
      • Cariou B.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): A randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial.
      ,
      • Rodbard H.W.
      • Lingvay I.
      • Reed J.
      • et al.
      Semaglutide added to basal insulin in type 2 diabetes (SUSTAIN 5): A randomised, controlled trial.
      ,
      • Pratley R.
      • Aroda V.R.
      • Lingvay I.
      • et al.
      Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): A randomised, open-label, phase 3b trial.
      ).

       Adverse and serious adverse events

      The proportion of subjects reporting serious AEs in the SUSTAIN 1 through 5 and SUSTAIN 7 trials, respectively, was similar in the semaglutide 0.5 mg and 1.0 mg groups (6.3%; 84/1332 and 7.3%; 127/1734, respectively) vs. comparators (6.4%; 131/2032) (
      • Sorli C.
      • Harashima S.I.
      • Tsoukas G.M.
      • et al.
      Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): A double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial.
      ,
      • Ahrén B.
      • Masmiquel L.
      • Kumar H.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): A 56-week, double-blind, phase 3a, randomised trial.
      ,
      • Ahmann A.J.
      • Capehorn M.
      • Charpentier G.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus exenatide ER in subjects with type 2 diabetes (SUSTAIN 3): A 56-week, open-label, randomized clinical trial.
      ,
      • Aroda V.R.
      • Bain S.C.
      • Cariou B.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): A randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial.
      ,
      • Rodbard H.W.
      • Lingvay I.
      • Reed J.
      • et al.
      Semaglutide added to basal insulin in type 2 diabetes (SUSTAIN 5): A randomised, controlled trial.
      ,
      • Pratley R.
      • Aroda V.R.
      • Lingvay I.
      • et al.
      Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): A randomised, open-label, phase 3b trial.
      ). The AE profile for semaglutide 0.5 mg and 1.0 mg groups was generally consistent with that noted with other GLP-1RAs and the proportion of subjects reporting an event (70.3%, 936/1332 and 70.5%, 1223/1734, respectively) was similar to, or higher than, comparators (68.4%; 1389/2032), mainly because of a higher proportion of subjects who experienced gastrointestinal (GI) disorders with semaglutide (
      • Sorli C.
      • Harashima S.I.
      • Tsoukas G.M.
      • et al.
      Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): A double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial.
      ,
      • Ahrén B.
      • Masmiquel L.
      • Kumar H.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): A 56-week, double-blind, phase 3a, randomised trial.
      ,
      • Ahmann A.J.
      • Capehorn M.
      • Charpentier G.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus exenatide ER in subjects with type 2 diabetes (SUSTAIN 3): A 56-week, open-label, randomized clinical trial.
      ,
      • Aroda V.R.
      • Bain S.C.
      • Cariou B.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): A randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial.
      ,
      • Rodbard H.W.
      • Lingvay I.
      • Reed J.
      • et al.
      Semaglutide added to basal insulin in type 2 diabetes (SUSTAIN 5): A randomised, controlled trial.
      ,
      • Pratley R.
      • Aroda V.R.
      • Lingvay I.
      • et al.
      Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): A randomised, open-label, phase 3b trial.
      ). GI disturbances, particularly nausea, were the most common type of AEs experienced with semaglutide (Figure 2a) (
      • Sorli C.
      • Harashima S.I.
      • Tsoukas G.M.
      • et al.
      Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): A double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial.
      ,
      • Ahrén B.
      • Masmiquel L.
      • Kumar H.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): A 56-week, double-blind, phase 3a, randomised trial.
      ,
      • Ahmann A.J.
      • Capehorn M.
      • Charpentier G.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus exenatide ER in subjects with type 2 diabetes (SUSTAIN 3): A 56-week, open-label, randomized clinical trial.
      ,
      • Aroda V.R.
      • Bain S.C.
      • Cariou B.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): A randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial.
      ,
      • Rodbard H.W.
      • Lingvay I.
      • Reed J.
      • et al.
      Semaglutide added to basal insulin in type 2 diabetes (SUSTAIN 5): A randomised, controlled trial.
      ,
      • Pratley R.
      • Aroda V.R.
      • Lingvay I.
      • et al.
      Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): A randomised, open-label, phase 3b trial.
      ). The proportion of subjects reporting nausea ranged from 11.4% to 23.8% with the semaglutide 0.5 mg and 1.0 mg doses, compared with 4.5% to 7.8% with placebo and 3.6% to 20.1% with active comparators (
      • Sorli C.
      • Harashima S.I.
      • Tsoukas G.M.
      • et al.
      Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): A double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial.
      ,
      • Ahrén B.
      • Masmiquel L.
      • Kumar H.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): A 56-week, double-blind, phase 3a, randomised trial.
      ,
      • Ahmann A.J.
      • Capehorn M.
      • Charpentier G.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus exenatide ER in subjects with type 2 diabetes (SUSTAIN 3): A 56-week, open-label, randomized clinical trial.
      ,
      • Aroda V.R.
      • Bain S.C.
      • Cariou B.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): A randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial.
      ,
      • Rodbard H.W.
      • Lingvay I.
      • Reed J.
      • et al.
      Semaglutide added to basal insulin in type 2 diabetes (SUSTAIN 5): A randomised, controlled trial.
      ,
      • Pratley R.
      • Aroda V.R.
      • Lingvay I.
      • et al.
      Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): A randomised, open-label, phase 3b trial.
      ). The proportion of subjects reporting nausea was similar to or slightly greater with the 1.0 mg dose than with the 0.5 mg dose (Figure 2a) (
      • Sorli C.
      • Harashima S.I.
      • Tsoukas G.M.
      • et al.
      Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): A double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial.
      ,
      • Ahrén B.
      • Masmiquel L.
      • Kumar H.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): A 56-week, double-blind, phase 3a, randomised trial.
      ,
      • Ahmann A.J.
      • Capehorn M.
      • Charpentier G.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus exenatide ER in subjects with type 2 diabetes (SUSTAIN 3): A 56-week, open-label, randomized clinical trial.
      ,
      • Aroda V.R.
      • Bain S.C.
      • Cariou B.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): A randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial.
      ,
      • Rodbard H.W.
      • Lingvay I.
      • Reed J.
      • et al.
      Semaglutide added to basal insulin in type 2 diabetes (SUSTAIN 5): A randomised, controlled trial.
      ,
      • Pratley R.
      • Aroda V.R.
      • Lingvay I.
      • et al.
      Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): A randomised, open-label, phase 3b trial.
      ). Nausea was mainly mild to moderate in severity and usually decreased over time (
      • Sorli C.
      • Harashima S.I.
      • Tsoukas G.M.
      • et al.
      Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): A double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial.
      ,
      • Ahrén B.
      • Masmiquel L.
      • Kumar H.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): A 56-week, double-blind, phase 3a, randomised trial.
      ,
      • Ahmann A.J.
      • Capehorn M.
      • Charpentier G.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus exenatide ER in subjects with type 2 diabetes (SUSTAIN 3): A 56-week, open-label, randomized clinical trial.
      ,
      • Aroda V.R.
      • Bain S.C.
      • Cariou B.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): A randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial.
      ,
      • Rodbard H.W.
      • Lingvay I.
      • Reed J.
      • et al.
      Semaglutide added to basal insulin in type 2 diabetes (SUSTAIN 5): A randomised, controlled trial.
      ,
      • Pratley R.
      • Aroda V.R.
      • Lingvay I.
      • et al.
      Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): A randomised, open-label, phase 3b trial.
      ) (Figure 2b).
      Figure 2
      Figure 2(A) Proportion of subjects reporting nausea with semaglutide vs. comparators across the SUSTAIN 1 through 5 and SUSTAIN 7 trials (
      • Sorli C.
      • Harashima S.I.
      • Tsoukas G.M.
      • et al.
      Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): A double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial.
      ,
      • Ahrén B.
      • Masmiquel L.
      • Kumar H.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): A 56-week, double-blind, phase 3a, randomised trial.
      ,
      • Ahmann A.J.
      • Capehorn M.
      • Charpentier G.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus exenatide ER in subjects with type 2 diabetes (SUSTAIN 3): A 56-week, open-label, randomized clinical trial.
      ,
      • Aroda V.R.
      • Bain S.C.
      • Cariou B.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): A randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial.
      ,
      • Rodbard H.W.
      • Lingvay I.
      • Reed J.
      • et al.
      Semaglutide added to basal insulin in type 2 diabetes (SUSTAIN 5): A randomised, controlled trial.
      ,
      • Pratley R.
      • Aroda V.R.
      • Lingvay I.
      • et al.
      Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): A randomised, open-label, phase 3b trial.
      ). Adverse event proportions are based on the total percentage of subjects experiencing at least 1 event. (B) Occurrence of nausea over time and by severity in the SUSTAIN 3 trial
      (
      • Ahmann A.J.
      • Capehorn M.
      • Charpentier G.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus exenatide ER in subjects with type 2 diabetes (SUSTAIN 3): A 56-week, open-label, randomized clinical trial.
      )
      . SUSTAIN 3 was selected as a representative study from the SUSTAIN trials, which all show similar results. Figure at left: “on-treatment” summary of adverse events. Events are shown until the scheduled follow-up visit. Table at right: treatment-emergent adverse events include events collected from first exposure to the follow-up visit scheduled 5 weeks (+7-day visit window) after the last trial product dose (42 days). Semaglutide was escalated from a starting dose of 0.25 mg, and the dose was doubled every 4 weeks until the trial dose was achieved. © 2018 by the American Diabetes Association® Diabetes Care 2018 Feb; 41(2):258-266. Reprinted with permission from the American Diabetes Association®. ER, extended-release; IGlar, insulin glargine; MET, metformin; OAD, oral antidiabetic drug; SU, sulfonylurea; TZD, thiazolidinedione.
      The number of confirmed malignant neoplasms across the SUSTAIN 1 through 5 trials was low, and in SUSTAIN 7, the events (n=11) were evenly distributed between the semaglutide and dulaglutide groups (
      • Sorli C.
      • Harashima S.I.
      • Tsoukas G.M.
      • et al.
      Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): A double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial.
      ,
      • Ahrén B.
      • Masmiquel L.
      • Kumar H.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): A 56-week, double-blind, phase 3a, randomised trial.
      ,
      • Aroda V.R.
      • Bain S.C.
      • Cariou B.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): A randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial.
      ,
      • Pratley R.
      • Aroda V.R.
      • Lingvay I.
      • et al.
      Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): A randomised, open-label, phase 3b trial.
      ,
      • Novo Nordisk Advisory Committee
      Briefing materials (available for public release): Semaglutide subcutaneous once-weekly treatment to improve glycemic control in adults with type 2 diabetes mellitus. NDA 209637 Briefing Document.
      ). No events of medullary thyroid carcinoma were observed with semaglutide (
      • Pratley R.
      • Aroda V.R.
      • Lingvay I.
      • et al.
      Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): A randomised, open-label, phase 3b trial.
      ,
      • Novo Nordisk Advisory Committee
      Briefing materials (available for public release): Semaglutide subcutaneous once-weekly treatment to improve glycemic control in adults with type 2 diabetes mellitus. NDA 209637 Briefing Document.
      ), nor was there any effect of semaglutide on calcitonin levels (
      • Sorli C.
      • Harashima S.I.
      • Tsoukas G.M.
      • et al.
      Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): A double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial.
      ,
      • Ahrén B.
      • Masmiquel L.
      • Kumar H.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): A 56-week, double-blind, phase 3a, randomised trial.
      ,
      • Aroda V.R.
      • Bain S.C.
      • Cariou B.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): A randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial.
      ,
      • Pratley R.
      • Aroda V.R.
      • Lingvay I.
      • et al.
      Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): A randomised, open-label, phase 3b trial.
      ,
      • Novo Nordisk Advisory Committee
      Briefing materials (available for public release): Semaglutide subcutaneous once-weekly treatment to improve glycemic control in adults with type 2 diabetes mellitus. NDA 209637 Briefing Document.
      ). Few subjects had increased calcitonin levels, and levels >50 ng/L and >100 ng/L were comparable to those found with comparators (
      • Sorli C.
      • Harashima S.I.
      • Tsoukas G.M.
      • et al.
      Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): A double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial.
      ,
      • Ahrén B.
      • Masmiquel L.
      • Kumar H.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): A 56-week, double-blind, phase 3a, randomised trial.
      ,
      • Aroda V.R.
      • Bain S.C.
      • Cariou B.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): A randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial.
      ,
      • Pratley R.
      • Aroda V.R.
      • Lingvay I.
      • et al.
      Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): A randomised, open-label, phase 3b trial.
      ,
      • Novo Nordisk Advisory Committee
      Briefing materials (available for public release): Semaglutide subcutaneous once-weekly treatment to improve glycemic control in adults with type 2 diabetes mellitus. NDA 209637 Briefing Document.
      ).
      Cholelithiasis was reported more frequently in the semaglutide 0.5 mg (n=6) and 1.0 mg groups (n=16) vs. pooled comparators (n=8) across the SUSTAIN 1 through 5 trials (
      • Sorli C.
      • Harashima S.I.
      • Tsoukas G.M.
      • et al.
      Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): A double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial.
      ,
      • Ahrén B.
      • Masmiquel L.
      • Kumar H.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): A 56-week, double-blind, phase 3a, randomised trial.
      ,
      • Ahmann A.J.
      • Capehorn M.
      • Charpentier G.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus exenatide ER in subjects with type 2 diabetes (SUSTAIN 3): A 56-week, open-label, randomized clinical trial.
      ,
      • Aroda V.R.
      • Bain S.C.
      • Cariou B.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): A randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial.
      ,
      • Rodbard H.W.
      • Lingvay I.
      • Reed J.
      • et al.
      Semaglutide added to basal insulin in type 2 diabetes (SUSTAIN 5): A randomised, controlled trial.
      ) and with similar frequency with semaglutide (n=0 for 0.5 mg and n=2 for 1.0 mg, respectively) and dulaglutide (n=1 for 0.75 mg and n=2 for 1.5 mg, respectively) in SUSTAIN 7 (
      • Pratley R.
      • Aroda V.R.
      • Lingvay I.
      • et al.
      Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): A randomised, open-label, phase 3b trial.
      ). Most cholelithiasis events were nonserious, and the absolute risk was low (
      • Pratley R.
      • Aroda V.R.
      • Lingvay I.
      • et al.
      Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): A randomised, open-label, phase 3b trial.
      ,
      • Novo Nordisk Advisory Committee
      Briefing materials (available for public release): Semaglutide subcutaneous once-weekly treatment to improve glycemic control in adults with type 2 diabetes mellitus. NDA 209637 Briefing Document.
      ) (Novo Nordisk, data on file).
      The number of pancreatitis-related events across the SUSTAIN 1 through 5 trials was low and was comparable to semaglutide, placebo or active comparator (semaglutide 0.5 mg [n=5] and 1.0 mg groups [n=3] vs. placebo [n=0] or active comparator groups [n=3, all with exenatide extended release]) (
      • Sorli C.
      • Harashima S.I.
      • Tsoukas G.M.
      • et al.
      Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): A double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial.
      ,
      • Ahrén B.
      • Masmiquel L.
      • Kumar H.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): A 56-week, double-blind, phase 3a, randomised trial.
      ,
      • Ahmann A.J.
      • Capehorn M.
      • Charpentier G.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus exenatide ER in subjects with type 2 diabetes (SUSTAIN 3): A 56-week, open-label, randomized clinical trial.
      ,
      • Aroda V.R.
      • Bain S.C.
      • Cariou B.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): A randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial.
      ,
      • Rodbard H.W.
      • Lingvay I.
      • Reed J.
      • et al.
      Semaglutide added to basal insulin in type 2 diabetes (SUSTAIN 5): A randomised, controlled trial.
      ). In SUSTAIN 7, there were no confirmed cases of pancreatitis with either semaglutide or dulaglutide (
      • Pratley R.
      • Aroda V.R.
      • Lingvay I.
      • et al.
      Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): A randomised, open-label, phase 3b trial.
      ).
      The proportion of subjects across the SUSTAIN 1 through 5 and in the SUSTAIN 7 trials that discontinued treatment due to AEs was up to 8.1% with semaglutide 0.5 mg and up to 10.0% with semaglutide 1.0 mg, compared with up to 7.2% with both placebo and active comparators, with the difference from comparators being due mainly to GI AEs with semaglutide (
      • Sorli C.
      • Harashima S.I.
      • Tsoukas G.M.
      • et al.
      Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): A double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial.
      ,
      • Ahrén B.
      • Masmiquel L.
      • Kumar H.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): A 56-week, double-blind, phase 3a, randomised trial.
      ,
      • Ahmann A.J.
      • Capehorn M.
      • Charpentier G.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus exenatide ER in subjects with type 2 diabetes (SUSTAIN 3): A 56-week, open-label, randomized clinical trial.
      ,
      • Aroda V.R.
      • Bain S.C.
      • Cariou B.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): A randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial.
      ,
      • Rodbard H.W.
      • Lingvay I.
      • Reed J.
      • et al.
      Semaglutide added to basal insulin in type 2 diabetes (SUSTAIN 5): A randomised, controlled trial.
      ,
      • Pratley R.
      • Aroda V.R.
      • Lingvay I.
      • et al.
      Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): A randomised, open-label, phase 3b trial.
      ). In correspondence with the dose-response effects on GI AEs, there was generally a higher proportion of premature treatment discontinuation in subjects who had received semaglutide 1.0 mg vs. 0.5 mg.

      Further Findings Based on SUSTAIN Trials 1 Through 5 Post Hoc Analyses

      Data from the SUSTAIN 1 through 5 trials were assessed to evaluate semaglutide vs. comparators within baseline categories of body mass index (BMI) (<25, 25 to 30, 30 to 35, ≥35 kg/m2) (
      • Leiter L.A.
      • Charpentier G.
      • Chaykin L.
      • et al.
      Semaglutide reduces body weight across baseline BMI subgroups across SUSTAIN 1–5. Poster number 1105-P. San Diego, CA.
      ) or A1C levels (≤7.5, 7.5 to 8.0, 8.0 to 8.5, 8.5 to 9.0 and >9.0%) (
      • Bain S.
      • Skrivanek Z.
      • Tahbaz A.
      • Pechtner V.
      • Adetunji O.
      Semaglutide reduces HbA1c and body weight across baseline HbA1c subgroups in the SUSTAIN 1–5 clinical trials. ePoster number 813. Lisbon.
      ). Across the 5 trials and within each baseline BMI category, a greater reduction in body weight was reported with semaglutide 0.5 mg and 1.0 mg vs. comparators (BMI <25 kg/m2: −2.0 to −6.3 kg vs. −0.5 to +1.4 kg; BMI 25 to 30 kg/m2: −2.5 to −5.1 kg vs. −1.4 to +1.5 kg; BMI 30 to 35 kg/m2: −3.0 to −6.6 kg vs. −2.0 to +1.2 kg; BMI ≥35 kg/m2; −3.6 to −7.9 kg vs.−3.7 to +0.8 kg). Regardless of baseline A1C levels, a greater improvement in A1C levels was evident with semaglutide (−0.7% to −2.8%) vs. all comparators (−1.8 to +0.6%) (
      • Bain S.
      • Skrivanek Z.
      • Tahbaz A.
      • Pechtner V.
      • Adetunji O.
      Semaglutide reduces HbA1c and body weight across baseline HbA1c subgroups in the SUSTAIN 1–5 clinical trials. ePoster number 813. Lisbon.
      ). Subjects with higher baseline A1C values experienced greater reductions in A1C levels (
      • Bain S.
      • Skrivanek Z.
      • Tahbaz A.
      • Pechtner V.
      • Adetunji O.
      Semaglutide reduces HbA1c and body weight across baseline HbA1c subgroups in the SUSTAIN 1–5 clinical trials. ePoster number 813. Lisbon.
      ).
      A minor component of the weight loss (0.07 to 0.5 kg) with semaglutide vs. comparators was attributed to nausea and vomiting in SUSTAIN 1 through 5, and weight loss with semaglutide was significantly greater than with comparators in subjects who did or did not experience these GI AEs (p<0.001) (
      • Atkin S.
      • Woo V.
      • de la Rosa R.
      • et al.
      The impact of gastrointestinal adverse events on weight loss with semaglutide in subjects with type 2 diabetes. ePoster number 821.
      ).
      In the SUSTAIN 1 through 5 trials, a significantly greater proportion of subjects achieved the clinically meaningful composite endpoint of ≥1.0% A1C reduction and ≥5% weight loss with semaglutide 1.0 mg (38% to 56%) or 0.5 mg (25% to 35%) vs. comparators (2% to 13%) (all p<0.0001) (
      • Rodbard H.
      • Bellary S.
      • Hramiak I.
      • et al.
      Responder analysis of subjects achieving HbA1c ≥1% and weight loss ≥5% across SUSTAIN 1–5 clinical trials. ePoster number 802.
      ). Similarly, a significantly greater proportion of subjects achieved the composite endpoint of A1C <7.0% with no weight gain or severe/blood glucose-confirmed symptomatic hypoglycemia or moderate/severe GI AEs with semaglutide 1.0 mg (46% to 64%) or 0.5 mg (40% to 55%) vs. comparators (7% to 25%) (all p<0.0001) (
      • De Vries J.H.
      • Desouza C.
      • Bellary S.
      • et al.
      More semaglutide-treated subjects achieved HbA1c below 7% without weight gain, hypoglycaemia, and gastrointestinal adverse events versus comparators in the SUSTAIN 1–5 trials. ePoster number 815.
      ).
      Two network meta-analyses compared semaglutide trial results with those for the sodium glucose cotransporter-2 inhibitors (SGLT2is) empagliflozin, canagliflozin and dapagliflozin in individuals with type 2 diabetes inadequately controlled on 1 to 2 oral antidiabetes drugs (OADs) (
      • Kanters S.
      • Wilkinson L.
      • Lopes S.
      • et al.
      Semaglutide is more efficacious than SGLT-2is in T2D patients inadequately controlled on 1-2 oral antidiabetics: a network meta-analysis. Poster number P-0531.
      ) or metformin monotherapy (
      • Kanters S.
      • Wilkinson L.
      • Lopes S.
      • et al.
      Semaglutide is more efficacious than SGLT-2 inhibitors in patients with type 2 diabetes inadequately controlled with metformin: a network meta-analysis. Poster number OP-0013.
      ). These analyses suggested that, after 26 weeks of treatment, semaglutide is superior to SGLT2is in regard to A1C level reductions and weight loss, with a significantly greater reduction found in A1C levels with semaglutide 0.5 mg (mean difference in change from baseline [MD]: −0.4% to −0.8%) and 1.0 mg (MD: −0.7 to −1.1%). A significantly greater reduction in body weight (MD: −0.9 to −2.3 kg) was also observed with semaglutide 1.0 mg, in comparison with SGLT2i while, in general, no difference was evident with the semaglutide 0.5 mg dose vs. SGLT2i (
      • Kanters S.
      • Wilkinson L.
      • Lopes S.
      • et al.
      Semaglutide is more efficacious than SGLT-2is in T2D patients inadequately controlled on 1-2 oral antidiabetics: a network meta-analysis. Poster number P-0531.
      ,
      • Kanters S.
      • Wilkinson L.
      • Lopes S.
      • et al.
      Semaglutide is more efficacious than SGLT-2 inhibitors in patients with type 2 diabetes inadequately controlled with metformin: a network meta-analysis. Poster number OP-0013.
      ). SUSTAIN 8, the ongoing phase 3b trial in which semaglutide is being compared with the SGLT2i canagliflozin, should provide more robust data.

      Phase 3 CV Outcomes Trial: SUSTAIN 6

       Methods

      SUSTAIN 6 compared the long-term safety and efficacy of semaglutide with placebo during 2 years in adults with type 2 diabetes at high risk for CV events (
      • Marso S.P.
      • Bain S.C.
      • Consoli A.
      • et al.
      Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      ). Subjects were ≥50 years of age who had established CVD (prior cardio-, cerebro- or peripheral vascular disease, chronic heart failure; New York Heart Association Classes II and III) or had chronic kidney disease stage 3 or higher or were ≥60 years of age with at least one CV risk factor (
      • Marso S.P.
      • Bain S.C.
      • Consoli A.
      • et al.
      Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      ). Of the 3,297 subjects randomized, 17% were in the primary prevention (CV risk factor) strata and 83% in the secondary prevention strata (
      • Marso S.P.
      • Bain S.C.
      • Consoli A.
      • et al.
      Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      ).
      Subjects were randomized to receive semaglutide (0.5 mg and 1.0 mg s.c. once weekly) or placebo, in addition to standard of care (i.e. as add-on to 0 to 2 OADs±basal or premixed insulin) (
      • Marso S.P.
      • Bain S.C.
      • Consoli A.
      • et al.
      Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      ). The primary endpoint was time to first occurrence of a major adverse CV event—i.e. death from CV causes, nonfatal MI or nonfatal stroke. The data were analyzed for noninferiority (the prespecified number of events was ≥122 in 3,260 patients). Superiority testing was not part of the prespecified analysis because the trial was powered for noninferiority.

       Efficacy and safety data

      A 26% reduction was observed in the composite outcome of CV death, nonfatal MI or nonfatal stroke, occurring in 6.6% of semaglutide-treated subjects vs. 8.9% of those receiving placebo (HR 0.74; 95% CI 0.58 to 0.95; p<0.001 for noninferiority; p=0.02 for superiority, not prespecified) (Figure 3a) (
      • Marso S.P.
      • Bain S.C.
      • Consoli A.
      • et al.
      Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      ). Compared with placebo, a significantly lower proportion of semaglutide-treated subjects experienced nonfatal stroke (p=0.04), with no significant difference found in nonfatal MI (p=0.12) or CV death (p=0.92) (
      • Marso S.P.
      • Bain S.C.
      • Consoli A.
      • et al.
      Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      ). There was no significant difference between semaglutide and placebo in regard to the occurrence of all-cause mortality or hospitalization for heart failure (Figure 3b) (
      • Marso S.P.
      • Bain S.C.
      • Consoli A.
      • et al.
      Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      ). Revascularization occurred in a significantly lower proportion of semaglutide-treated subjects vs. placebo (p=0.003) (Figure 3b) (
      • Marso S.P.
      • Bain S.C.
      • Consoli A.
      • et al.
      Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      ). The expanded composite CV outcome (i.e. major adverse cardiac event, revascularization or hospitalization for unstable angina or heart failure) was reported in a significantly lower proportion of subjects treated with semaglutide vs. placebo (p=0.002) (Figure 3b) (
      • Marso S.P.
      • Bain S.C.
      • Consoli A.
      • et al.
      Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      ). In a prespecified subgroup analysis, a benefit in the primary outcome (28% risk reduction) was demonstrated for subjects in the secondary prevention strata. Although there was no statistical heterogeneity among subjects with or without CVD for the primary outcome (p value for interaction=0.49), the HR for the primary prevention subgroup was 1.00 (95% CI 0.41 to 2.46), and this subgroup accounted for only 7.5% of all primary outcome events, precluding any definitive opinion about the CV benefit in the primary prevention strata (
      • Marso S.P.
      • Bain S.C.
      • Consoli A.
      • et al.
      Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      ).
      Figure 3
      Figure 3(A) Primary cardiovascular outcome results in the SUSTAIN 6 trial. Time to first occurrence of CV death or nonfatal MI/stroke
      (
      • Marso S.P.
      • Bain S.C.
      • Consoli A.
      • et al.
      Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      )
      . Events: 108 semaglutide; 146 placebo. Incidence rate per 100 patient years of risk time (time from randomization until first event or censoring): 3.24 semaglutide; 4.44 placebo. Relative risk reduction: 26% lower risk for the primary composite outcome of death from CV causes, nonfatal MI or nonfatal stroke with semaglutide vs. placebo. p value for superiority not prespecified. Kaplan-Meier plot for first event adjudication committee-confirmed CV death, nonfatal MI and nonfatal stroke using in-trial data from subjects in the full analysis set. From The New England Journal of Medicine, Marso, SP, Bain SC, Consoli, A et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. 375:1834–44. Copyright © 2016 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. (B) Summary of cardiovascular outcomes in the SUSTAIN 6 trial
      (
      • Marso S.P.
      • Bain S.C.
      • Consoli A.
      • et al.
      Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      )
      . *Indicates significance (p<0.05). Values are estimated HRs with 95% CIs using in-trial data from subjects in the full analysis set. Nonfatal MI includes 4 (0.2%) silent MIs in the semaglutide group and 7 (0.4%) in the placebo group. Adapted from Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016;375:1834–44. CI, confidence interval; CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction.
      In comparison with placebo, a significantly greater reduction in A1C levels was observed with semaglutide 0.5 mg and 1.0 mg (−0.7% and −1.0%, respectively; p<0.001) and in body weight (−2.9 kg and −4.3 kg, respectively; p<0.001) (
      • Marso S.P.
      • Bain S.C.
      • Consoli A.
      • et al.
      Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      ). Reduction in systolic blood pressure was also significantly greater with semaglutide 1.0 mg vs. placebo (−2.6 mmHg; p<0.001) (
      • Marso S.P.
      • Bain S.C.
      • Consoli A.
      • et al.
      Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      ).
      The proportion of subjects with new or worsening nephropathy complications was significantly lower in the pooled semaglutide groups (3.8%) compared with placebo (6.1%) (HR 0.64; 95% CI 0.46 to 0.88; p=0.005), driven by a reduction in new-onset macroalbuminuria (
      • Marso S.P.
      • Bain S.C.
      • Consoli A.
      • et al.
      Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      ). Diabetic retinopathy (DR) complications (vitreous hemorrhage, blindness or the need for treatment with an intravitreal agent or photocoagulation) were found in more subjects in the semaglutide groups (n=50; 3.0%), compared with the placebo group (n=29; 1.8%) (HR 1.76; 95% CI 1.11 to 2.78; p=0.02) (
      • Marso S.P.
      • Bain S.C.
      • Consoli A.
      • et al.
      Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      ). Subjects with histories of DR at baseline were more likely to experience retinopathy complications (absolute risk: 8.2% with semaglutide and 5.2% with placebo) vs. those without (0.7% with semaglutide and 0.4% with placebo) (
      • US Food and Drug Administration
      OZEMPIC (semaglutide) injection prescribing information.
      ,
      • US Food and Drug Administration
      Endocrinologic and Metabolic Drugs Advisory Committee Meeting (slide presentation).
      ,
      • US Food and Drug Administration
      Briefing document: Endocrinologic and metabolic drugs advisory committee meeting.
      ). In contrast, no statistically significant difference in the development of DR complications was observed with semaglutide vs. placebo in those without preexisting retinopathy at baseline (
      • Vilsbøll T.
      • Bain S.C.
      • Leiter L.A.
      • et al.
      Semaglutide, reduction in glycated haemoglobin and the risk of diabetic retinopathy.
      ). With the exception of DR complications, a similar safety profile was observed for semaglutide in SUSTAIN 6 as in the other SUSTAIN trials.

      Discussion

      Semaglutide can be used to improve glycemic control in adults with type 2 diabetes (
      • Health Canada
      OZEMPIC (semaglutide) injection product monograph.
      ). Advantages of semaglutide include its robust and sustained effects on A1C levels and weight loss vs. comparators across a spectrum of background therapies, as well as CV safety vs. placebo (
      • Sorli C.
      • Harashima S.I.
      • Tsoukas G.M.
      • et al.
      Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): A double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial.
      ,
      • Ahrén B.
      • Masmiquel L.
      • Kumar H.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): A 56-week, double-blind, phase 3a, randomised trial.
      ,
      • Ahmann A.J.
      • Capehorn M.
      • Charpentier G.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus exenatide ER in subjects with type 2 diabetes (SUSTAIN 3): A 56-week, open-label, randomized clinical trial.
      ,
      • Aroda V.R.
      • Bain S.C.
      • Cariou B.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): A randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial.
      ,
      • Rodbard H.W.
      • Lingvay I.
      • Reed J.
      • et al.
      Semaglutide added to basal insulin in type 2 diabetes (SUSTAIN 5): A randomised, controlled trial.
      ,
      • Marso S.P.
      • Bain S.C.
      • Consoli A.
      • et al.
      Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      ,
      • Pratley R.
      • Aroda V.R.
      • Lingvay I.
      • et al.
      Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): A randomised, open-label, phase 3b trial.
      ). The SUSTAIN 6 CVOT in adults with type 2 diabetes at high risk for CV events demonstrated a 26% reduction in the primary (composite) outcome of CV death, nonfatal MI or nonfatal stroke compared with placebo (HR 0.74; 95% CI 0.58 to 0.95; p<0.001 for noninferiority; p=0.02 for superiority, not prespecified) (
      • Marso S.P.
      • Bain S.C.
      • Consoli A.
      • et al.
      Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      ). Although the SUSTAIN 6 trial was not powered to show superiority, the treatment effect of semaglutide and the accrual of more events than estimated meant that a post hoc sensitivity analysis demonstrated a significantly lower risk for the primary outcome in subjects in the semaglutide vs. the placebo group, thereby raising the possibility of CV benefit of semaglutide (
      • Marso S.P.
      • Bain S.C.
      • Consoli A.
      • et al.
      Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      ).
      Glycemic equipoise (i.e. similar A1C values in the experimental and comparator arms) (
      • Kalra S.
      • John M.
      • Unnikrishnan A.G.
      Glycemic equipoise.
      ) was not achieved in the SUSTAIN 6 trial (
      • Marso S.P.
      • Bain S.C.
      • Consoli A.
      • et al.
      Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      ). Rather, the reduction in A1C values was significantly greater in the semaglutide 0.5 mg and 1.0 mg groups compared with placebo (resulting in A1C values of 7.6% and 7.3% vs. 8.3%, respectively) (
      • Marso S.P.
      • Bain S.C.
      • Consoli A.
      • et al.
      Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      ). Lack of glycemic equipoise has been proposed as a limitation of CVOTs because of the difficulty in establishing whether a demonstrated CV safety/benefit has arisen independently from improved glycemia (
      • Kalra S.
      • John M.
      • Unnikrishnan A.G.
      Glycemic equipoise.
      ). However, a recent commentary on the LEADER trial highlighted that, due to the pleiotropic actions of liraglutide, positive CVOT results could arise from the multiple beneficial CV effects ascribed to this agent, rather than simply from a lack of glycemic equipoise (
      • Kalra S.
      • John M.
      • Unnikrishnan A.G.
      Glycemic equipoise.
      ). The pleiotropic effects of GLP-1RAs as a class have been well documented (
      • Cariou B.
      Pleiotropic effects of insulin and GLP-1 receptor agonists: Potential benefits of the association.
      ). The robust lowering of A1C levels with semaglutide may have contributed to the CV results in SUSTAIN 6, in addition to other pleiotropic effects. Furthermore, the significant reduction in the numbers of revascularizations with semaglutide treatment compared with placebo in SUSTAIN 6 is interesting, especially considering the nonsignificant decrease in risk for nonfatal MI and no change in risk for CV death (
      • Marso S.P.
      • Bain S.C.
      • Consoli A.
      • et al.
      Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      ). Such findings may suggest a protective mechanism, perhaps linked to the metabolic effects of semaglutide treatment, as hypothesized elsewhere (
      • Holst J.J.
      • Madsbad S.
      Semaglutide seems to be more effective the other GLP-1Ras.
      ).
      In SUSTAIN 1 through 5 and SUSTAIN 7, in contrast to SUSTAIN 6, no increase in DR complications was evident in the semaglutide groups vs. comparators (
      • Sorli C.
      • Harashima S.I.
      • Tsoukas G.M.
      • et al.
      Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): A double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial.
      ,
      • Ahrén B.
      • Masmiquel L.
      • Kumar H.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): A 56-week, double-blind, phase 3a, randomised trial.
      ,
      • Ahmann A.J.
      • Capehorn M.
      • Charpentier G.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus exenatide ER in subjects with type 2 diabetes (SUSTAIN 3): A 56-week, open-label, randomized clinical trial.
      ,
      • Aroda V.R.
      • Bain S.C.
      • Cariou B.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): A randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial.
      ,
      • Rodbard H.W.
      • Lingvay I.
      • Reed J.
      • et al.
      Semaglutide added to basal insulin in type 2 diabetes (SUSTAIN 5): A randomised, controlled trial.
      ,
      • Pratley R.
      • Aroda V.R.
      • Lingvay I.
      • et al.
      Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): A randomised, open-label, phase 3b trial.
      ,
      • Vilsbøll T.
      • Bain S.C.
      • Leiter L.A.
      • et al.
      Semaglutide, reduction in glycated haemoglobin and the risk of diabetic retinopathy.
      ). A pooled analysis of the SUSTAIN 1 through 5 and the 2 Japanese trials did not show a difference in DR complications between semaglutide and comparators (
      • Vilsbøll T.
      • Bain S.C.
      • Leiter L.A.
      • et al.
      Semaglutide, reduction in glycated haemoglobin and the risk of diabetic retinopathy.
      ). One possible explanation for the discrepancy in DR findings between SUSTAIN 6 and other SUSTAIN trials is the difference in exclusion criteria and baseline demographics (
      • Vilsbøll T.
      • Bain S.C.
      • Leiter L.A.
      • et al.
      Semaglutide, reduction in glycated haemoglobin and the risk of diabetic retinopathy.
      ). The SUSTAIN 1 through 5 and SUSTAIN 7 trials (though not SUSTAIN 6) excluded subjects with baseline A1C levels >10.0/10.5% or any known proliferative retinopathy or maculopathy requiring acute treatment in the opinion of the investigator. Accordingly, subjects in the SUSTAIN 6 trial were more likely than those in SUSTAIN 1 through 5 and SUSTAIN 7 to be older and taking insulin prior to or at the time of the event and to have longer-duration diabetes, higher baseline A1C levels and higher rates of preexisting DR, all of which are risk factors associated with DR (
      • Sorli C.
      • Harashima S.I.
      • Tsoukas G.M.
      • et al.
      Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): A double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial.
      ,
      • Ahrén B.
      • Masmiquel L.
      • Kumar H.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): A 56-week, double-blind, phase 3a, randomised trial.
      ,
      • Ahmann A.J.
      • Capehorn M.
      • Charpentier G.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus exenatide ER in subjects with type 2 diabetes (SUSTAIN 3): A 56-week, open-label, randomized clinical trial.
      ,
      • Aroda V.R.
      • Bain S.C.
      • Cariou B.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): A randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial.
      ,
      • Rodbard H.W.
      • Lingvay I.
      • Reed J.
      • et al.
      Semaglutide added to basal insulin in type 2 diabetes (SUSTAIN 5): A randomised, controlled trial.
      ,
      • Pratley R.
      • Aroda V.R.
      • Lingvay I.
      • et al.
      Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): A randomised, open-label, phase 3b trial.
      ,
      • Vilsbøll T.
      • Bain S.C.
      • Leiter L.A.
      • et al.
      Semaglutide, reduction in glycated haemoglobin and the risk of diabetic retinopathy.
      ). Methodologic considerations may also have contributed to the DR complication findings in SUSTAIN 6, including how retinopathy was assessed (
      • US Food and Drug Administration
      Briefing document: Endocrinologic and metabolic drugs advisory committee meeting.
      ). In the LEADER trial, a nonsignificant trend was found in the incidence of adjudicated DR complications with liraglutide compared with placebo (p=0.33), and no clinically relevant difference in the incidence of DR complications was reported in the EXSCEL study, in which exenatide was compared with placebo (
      • Holman R.R.
      • Bethel M.A.
      • Mentz R.J.
      • et al.
      Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes.
      ,
      • Marso S.P.
      • Daniels G.H.
      • Brown-Frandsen K.
      • et al.
      Liraglutide and cardiovascular outcomes in type 2 diabetes.
      ). The increase in DR risk in SUSTAIN 6 could be attributed to the rapid improvement and large decline in A1C levels, especially in those with preexisting retinopathy and poor glycemic control (
      • Vilsbøll T.
      • Bain S.C.
      • Leiter L.A.
      • et al.
      Semaglutide, reduction in glycated haemoglobin and the risk of diabetic retinopathy.
      ). Previous studies have suggested that a rapid improvement in glycemic control in patients with preexisting retinopathy may result in a temporary worsening of DR (
      • Vilsbøll T.
      • Bain S.C.
      • Leiter L.A.
      • et al.
      Semaglutide, reduction in glycated haemoglobin and the risk of diabetic retinopathy.
      ). In the Diabetes Control and Complications Trial (DCCT), intensive glycemic control in persons with type 1 diabetes demonstrated that despite early transient worsening, retinopathy outcomes were similar or more favourable than conventional treatment in the long term (
      The Diabetes Control and Complications Trial Research Group
      Early worsening of diabetic retinopathy in the Diabetes Control and Comlications Trial.
      ). The SUSTAIN 6 trial duration was too short to detect a possible long-term benefit for retinopathy. Diabetes Canada guidelines recommend screening all adults with type 2 diabetes for retinopathy at diagnosis and every 1 to 2 years thereafter or monitoring for progression at least annually in individuals in whom retinopathy is already present (
      • Altomare F.
      • Kherani A.
      • Lovshin J.
      Committee DCCPGE. Retinopathy.
      ).
      Ongoing investigations within the SUSTAIN clinical trial program include SUSTAIN 8 (NCT03136484) (
      • US National Library of Medicine (clinicaltrials.gov)
      NCT03136484.
      ), to compare semaglutide and the SGLT2i canagliflozin (as add-on to metformin) over 52 weeks, and SUSTAIN 9 (NCT03086330) (
      • US National Library of Medicine (clinicaltrials.gov)
      NCT03086330.
      ), to compare semaglutide with placebo (as add-on to SGLT2i) over 30 weeks in subjects with type 2 diabetes. A well-powered CV outcomes trial, prespecified for superiority testing, would help to establish the overall CV benefit of semaglutide.

      Semaglutide in the Overall Management of Type 2 Diabetes

      GLP-1RAs are 1 of several second-line treatment options in Canadian and international guidelines (
      • Inzucchi S.E.
      • Bergenstal R.M.
      • Buse J.B.
      • et al.
      Management of hyperglycemia in type 2 diabetes, 2015: A patient-centered approach: Update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes.
      ,
      • American Diabetes Association
      Pharmacologic approaches to glycemic treatment: Standards of medical care in diabetes.
      ,
      • Lipscombe L.
      • Booth G.
      • Butalia S.
      • et al.
      Pharmacologic glycemic management of type 2 diabetes in adults.
      ,
      • Chamberlain J.J.
      • Herman W.H.
      • Leal S.
      • et al.
      Pharmacologic therapy for type 2 diabetes: synopsis of the 2017 American Diabetes Association Standards of Medical Care in Diabetes.
      ) and are associated with efficacious glucose lowering, weight loss and low risk for hypoglycemia (
      • Inzucchi S.E.
      • Bergenstal R.M.
      • Buse J.B.
      • et al.
      Management of hyperglycemia in type 2 diabetes, 2015: A patient-centered approach: Update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes.
      ,
      • Madsbad S.
      Review of head-to-head comparisons of glucagon-like peptide-1 receptor agonists.
      ,
      • Trujillo J.M.
      • Nuffer W.
      • Ellis S.L.
      GLP-1 receptor agonists: A review of head-to-head clinical studies.
      ,
      • Cai X.
      • Ji L.
      • Chen Y.
      • et al.
      Comparisons of weight changes between sodium-glucose cotransporter 2 inhibitors treatment and glucagon-like peptide-1 analogs treatment in type 2 diabetes patients: A meta-analysis.
      ). Diabetes Canada guidelines for 2018 recommend incretin agents and/or SGLT2 inhibitors over insulin secretagogues, insulin and thiazolidinediones as add-on agents in people without clinical CVD, if lower risk for hypoglycemia and/or weight gain are priorities (
      • Lipscombe L.
      • Booth G.
      • Butalia S.
      • et al.
      Pharmacologic glycemic management of type 2 diabetes in adults.
      ). The costs associated with GLP-1RA agents are generally within the higher range in comparison with other classes of agents (
      • Inzucchi S.E.
      • Bergenstal R.M.
      • Buse J.B.
      • et al.
      Management of hyperglycemia in type 2 diabetes, 2015: A patient-centered approach: Update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes.
      ,
      • American Diabetes Association
      Pharmacologic approaches to glycemic treatment: Standards of medical care in diabetes.
      ,
      • Chamberlain J.J.
      • Herman W.H.
      • Leal S.
      • et al.
      Pharmacologic therapy for type 2 diabetes: synopsis of the 2017 American Diabetes Association Standards of Medical Care in Diabetes.
      ,
      • Canadian Diabetes Association Clinical Practice Guidelines Expert Committee
      Pharmacologic management of type 2 diabetes: 2016 interim update.
      ), but they should be considered within the context of clinical benefits (
      • Health Canada
      OZEMPIC (semaglutide) injection product monograph.
      ). Results suggest that semaglutide has better efficacy for glycemic control and weight loss than most other antihyperglycemic agents, and it seems to be the most efficacious in the GLP-R1A class for achieving A1C reductions and weight loss (
      • Sorli C.
      • Harashima S.I.
      • Tsoukas G.M.
      • et al.
      Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): A double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial.
      ,
      • Ahrén B.
      • Masmiquel L.
      • Kumar H.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): A 56-week, double-blind, phase 3a, randomised trial.
      ,
      • Ahmann A.J.
      • Capehorn M.
      • Charpentier G.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus exenatide ER in subjects with type 2 diabetes (SUSTAIN 3): A 56-week, open-label, randomized clinical trial.
      ,
      • Aroda V.R.
      • Bain S.C.
      • Cariou B.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): A randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial.
      ,
      • Rodbard H.W.
      • Lingvay I.
      • Reed J.
      • et al.
      Semaglutide added to basal insulin in type 2 diabetes (SUSTAIN 5): A randomised, controlled trial.
      ,
      • Marso S.P.
      • Bain S.C.
      • Consoli A.
      • et al.
      Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      ,
      • Pratley R.
      • Aroda V.R.
      • Lingvay I.
      • et al.
      Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): A randomised, open-label, phase 3b trial.
      ). Current guidelines recommend prioritizing the use of an antihyperglycemic agent with demonstrated CV superiority in patients with clinical CVD (
      • American Diabetes Association
      Pharmacologic approaches to glycemic treatment: Standards of medical care in diabetes.
      ,
      • Stone J.A.
      • Houlden R.L.
      • Lin P.
      • Udell J.A.
      • Verma S.
      Diabetes Canada Clinical Practice Guidelines Expert Committee
      Cardiovascular protection in people with diabetes.
      ). Although there may be a possible CV benefit with semaglutide in those with established CVD, determining a benefit in patients without clinical CVD requires further study.
      Semaglutide dosing is started at 0.25 mg s.c. once weekly for 4 weeks, then 0.5 mg s.c. once weekly for at least 4 weeks, followed by dose escalation to 1.0 mg once weekly if further glycemic control is required (
      • Health Canada
      OZEMPIC (semaglutide) injection product monograph.
      ). It is administered once weekly at any time of day (with or without meals) (
      • Health Canada
      OZEMPIC (semaglutide) injection product monograph.
      ). As with other GLP-1RAs, gradual dose escalation may help to reduce the risk for GI AEs. The occurrence of nausea, vomiting and diarrhea is more common at the start of therapy but generally decreases over time (
      • Health Canada
      OZEMPIC (semaglutide) injection product monograph.
      ).
      Semaglutide can be used in elderly patients (age ≥65 years) because no differences in overall safety and efficacy were found, nor was there a need for dose adjustment, compared with younger individuals. However, a greater sensitivity in some older individuals cannot be ruled out, and data are limited in older patients (age >75 years) (
      • Health Canada
      OZEMPIC (semaglutide) injection product monograph.
      ). Semaglutide has not been investigated in individuals <18 years of age. No dose adjustment is needed in patients with mild, moderate or severe renal impairment, but caution should be exercised in cases of severe renal impairment because of limited experience with its use, and semaglutide is not recommended in end-stage renal disease (
      • Health Canada
      OZEMPIC (semaglutide) injection product monograph.
      ). Semaglutide should be used with caution in patients with hepatic insufficiency, again because of limited experience with its use (
      • Health Canada
      OZEMPIC (semaglutide) injection product monograph.
      ).
      Semaglutide is a welcome addition to the antihyperglycemic agent armamentarium in type 2 diabetes, offering robust A1C lowering and weight loss across a variety of background therapies, as well as CV safety and convenient once-weekly dosing, and it may have a possible CV benefit in those with established CVD. It can be used across a spectrum of patients with type 2 diabetes, both in primary and secondary prevention, as monotherapy with diet and exercise when metformin is inappropriate, or as a first-line add-on to metformin alone or as an add-on to metformin plus sulfonylurea or basal insulin. Semaglutide can also be considered a preferred first injectable option in the management of type 2 diabetes. The additional possible benefit of CV risk reduction in patients with established CVD makes it an excellent option for these high-risk patients.

      Acknowledgments

      The authors thank AXON Communications for writing and providing editorial assistance in the development of this manuscript. Medical writing assistance was funded by Novo Nordisk , which was also provided with the opportunity to perform a medical accuracy review.

      Author Disclosures

      R.M. Goldenberg reports research support from Abbott, AstraZeneca, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Janssen, Medtronic, Merck, Novartis, Novo Nordisk, Roche, Sanofi and Takeda; advisory panelist for AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, Roche, Sanofi and Takeda; speaker bureaus for Abbott, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, Sanofi and Servier; consultancy for AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Novo Nordisk and Takeda.
      O. Steen reports research support from AstraZeneca, Dexcom, Eisai, Gilead, Janssen, Kowa, Lexicon, Merck, Novartis, Novo Nordisk, Pfizer, Sanofi, Valeant and Zealand; speaking bureaus for AstraZeneca, Eli Lilly, Janssen, Merck, Novo Nordisk and Sanofi; and consultancy for Amgen, Eli Lilly, Novo Nordisk and Sanofi.

      Author Contributions

      All authors actively contributed to manuscript preparation. The final submitted manuscript was approved by all authors, who made the decision to submit the manuscript for publication. The authors assume responsibility for the accuracy and completeness of the data.

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