Series: Cardiovascular outcome trials for diabetes drugs Semaglutide and SUSTAIN-6
DOI:
https://doi.org/10.15277/bjd.2021.301Keywords:
diabetes, cardiovascular outcome trial, semaglutideAbstract
SUSTAIN-6 (Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes) was a pre-licensing FDA-mandated cardiovascular outcome trial with subcutaneous semaglutide and was the first completed trial with a once-weekly glucagon-like peptide-1 receptor agonist. SUSTAIN-6 compared semaglutide and placebo in 3,297 people with type 2 diabetes and established cardiovascular disease, chronic kidney disease, or both, or who were aged over 60 years and had subclinical evidence of cardiovascular disease (persistent microalbuminuria or proteinuria, hypertension with left ventricular hypertrophy, left ventricular dysfunction by imaging, ankle/brachial index less than 0.9). As SUSTAIN-6 was performed as a pre-licensing safety study, non-inferiority for major cardiovascular events (MACE; cardiovascular death, non-fatal myocardial infarction, non-fatal stroke) was the primary outcome and testing for superiority for MACE was not pre-specified or adjusted for multiplicity. SUSTAIN-6 confirmed non-inferiority for MACE, with nominal superiority, and demonstrated a significant reduction in the risk of non-fatal stroke. There was no significant difference in non-fatal myocardial infarction, cardiovascular death, all-cause mortality or hospitalisation for heart failure. Rates of retinopathy complications were unexpectedly higher in the semaglutide group. Further outcome trials with subcutaneous semaglutide are in progress, including a cardiovascular outcome trial in non-diabetic subjects with overweight or obesity.
References
Chong WH, Yanoff LB, Andraca-Carrera E, Thanh Hai M. Assessing the safety of glucose-lowering drugs – a new focus for the FDA. N Engl J Med 2020;383:1199–202. https://doi.org/10.1056/NEJMp2004889
Marso SP, Bain SC, Consoli A, et al, for the SUSTAIN-6 Investigators. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016;375:1834–44. https://doi.org/10.1056/NEJMoa1607141
Pfeffer MA, Claggett B, Diaz R, et al, for the ELIXA Investigators. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med 2015;373:2247–57. https://doi.org/10.1056/NEJMoa1509225
Marso SP, Daniels GH, Brown-Frandsen K, et al, for the LEADER Steering Committee on behalf of the LEADER Trial Investigators. N Engl J Med 2016;375;311–22. https://doi.org/10.1056/NEJMoa1603827
Holman RR, Bethel MA, Mentz RJ, et al, for the EXSCEL Study Group. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2017;377:1228–39. https://doi.org/10.1056/NEJMoa1612917
Hernandez AF, Green JB, Janmohamed S, et al, for the Harmony Outcomes Committees and Investigators. Albiglutide and cardiovascular outcomes in people with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised, placebo-controlled trial. Lancet 2018;392:1519–29. https://doi.org/10.1016/S0140-6736(18)32261-X
Gertsein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised, placebo-controlled trial. Lancet 2019;394:121–30. https://doi.org/10.1016/S0140-6736(19)31149-3
Vilsboll T, Bain SC, Leiter LA, et al. Semaglutide, reduction in glycated haemoglobin and the risk of diabetic retinopathy. Diabetes Obes Metab 2018;20:889–97. https://doi.org/10.1111/dom.13172
GOV.UK. Diabetic eye screening: cohort management. https://www.gov.uk/government/publications/diabetic-eye-screening-cohort-management-overview/diabetic-eye-screening-cohort-management (accessed 30 April 2021)
Husain M, Birkenfeld AL, Donsmark M, et al, for the PIONEER 6 Investigators. Oral semaglutide and cardiovascular outcomes in people with type 2 diabetes. N Engl J Med 2019;381:841–51. https://doi.org/10.1056/NEJMoa1901118
ClinicalTrials.gov. A research study to see how semaglutide works compared to placebo in people with type 2 diabetes and chronic kidney disease (FLOW). https://clinicaltrials.gov/ct2/show/NCT03819153
ClinicalTrials.gov. A research study to look at how semaglutide compared to placebo affects diabetic eye disease in people with type 2 diabetes (FOCUS). https://clinicaltrials.gov/ct2/show/NCT03811561
Ryan DH, Lingvay I, Colhoun HM, et al. Semaglutide effects on cardiovascular outcomes in people with overweight or obesity (SELECT) rationale and design. Am Heart J 2020;229:61–9. https://doi.org/10.1016/j.ahj.2020.07.008
Leiter LA, Bain SC, Hramiak I, et al. Cardiovascular risk reduction with once-weekly semaglutide in subjects with type 2 diabetes: a post hoc analysis of gender, age, and baseline CV risk profile in the SUSTAIN 6 trial. Cardiovasc Diabetol 2019;18:73. https://doi.org/10.1186/s12933-019-0871-8
Jódar E, Michelsen M, Polonsky W, et al. Semaglutide improves health-related quality of life versus placebo when added to standard of care in patients with type 2 diabetes at high cardiovascular risk (SUSTAIN 6). Diabetes Obes Metab 2020;22:1339–47. https://doi.org/10.1111/dom.14039
Verma S, McGuire DK, Bain SC, et al. Effects of glucagon-like peptide-1 receptor agonists liraglutide and semaglutide on cardiovascular and renal outcomes across body mass index categories in type 2 diabetes: results of the LEADER and SUSTAIN 6 trials. Diabetes Obes Metab 2020;22:2487–92. https://doi.org/10.1111/dom.14160
Verma S, Bain SC, Honore JB, et al. Impact of microvascular disease on cardiovascular outcomes in type 2 diabetes: results from the LEADER and SUSTAIN 6 clinical trials. Diabetes Obes Metab 2020;22:2193–8. https://doi.org/10.1111/dom.14140
Verma S, Bain SC, Fries TM, et al. Duration of diabetes and cardiorenal efficacy of liraglutide and semaglutide: a post hoc analysis of the LEADER and SUSTAIN 6 clinical trials. Diabetes Obes Metab 2019; 21:1745–51. https://doi.org/10.1111/dom.13698
Husain M, Bain SC, Jeppesen OK, et al. Semaglutide (SUSTAIN and PIONEER) reduces cardiovascular events in type 2 diabetes across varying cardiovascular risk. Diabetes Obes Metab 2020;22:442–51. https://doi.org/10.1111/dom.13955
Published
Issue
Section
License
Publish & Transfer of Copyright Agreement
For the mutual benefit and protection of the Author and the Journal Owner/Publisher it is necessary that the Author provides formal written Consent to Publish and Transfer of Copyright before publication of the Work.
