Series: Cardiovascular outcome trials for diabetes drugs Liraglutide and LEADER

Miles Fisher

Abstract


LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) was an FDA-mandated cardiovascular outcome trial with liraglutide and was the first trial with a glucagon-like peptide-1 (GLP-1) receptor agonist to demonstrate a significant reduction in cardiovascular events. It compared liraglutide and placebo in 9,340 people with type 2 diabetes and either existing cardiovascular disease or age >60 years with at least one cardiovascular risk factor. LEADER demonstrated superiority for major cardiovascular events (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke), and cardiovascular deaths were significantly reduced, as was all-cause mortality. Hospitalisation for heart failure, which was a secondary outcome, was not significantly reduced. Compared with the EMPA-REG OUTCOME trial, the curves for major adverse cardiovascular events in LEADER separated later, and the absence of a clear effect on hospitalisation for heart failure or on estimated glomerular filtration rate suggests that the mechanism of cardiovascular benefit for liraglutide was different from that for empagliflozin


Keywords


diabetes, cardiovascular outcome trial, liraglutide

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References


Food and Drug Administration. Guidance for industry. Diabetes mellitus – evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. Silver Spring, MD: US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), 2008. Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/diabetes-mellitus-evaluating-cardiovascular-risk-new-antidiabetic-therapies-treat-type-2-diabetes (accessed 1 March 2020).

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, 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

Scirica BM, Bhatt DL, Braunwald E, et al, for the SAVOR-TIMI 53 Steering Committee and Investigators. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013;369:1317–26. https://doi.org/10.1056/NEJMoa1307684

White WB, Cannon CP, Heller SR, et al, for the EXAMINE Investigators. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013;369:1327–35. https://doi.org/10.1056/NEJMoa1305889

Green JB, Bethel A, Armstrong PW, et al, for the TECOS Study Group. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2015;373:232–42. https://doi.org/10.1056/NEJMoa1501352

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

Zinman B, Wanner C, Lachin JM, et al, for the EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117–28. https://doi.org/10.1056/NEJMoa1504720

Marso SP, Lindsey JB, Stolker JM, et al. Cardiovascular safety of liraglutide assessed in a patient-level pooled analysis of phase 2-3 liraglutide clinical development studies. Diabetes Vasc Dis Res 2011;8:237–40. https://doi.org/10.1177/1479164111408937

Marso SP, Poulter NR, Nissen SE, et al. Design of the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial. Am Heart J 2013;166:823–30. https://doi.org/10.1016/j.ahj.2013.07.012

Mann JFE, Orsted DD, Brown-Frandsen K, et al, for the LEADER Steering Committee and Investigators. Liraglutide and renal outcomes in type 2 diabetes. N Engl J Med 2017;377:839–48. https://doi.org/10.1056/NEJMoa1616011

Wanner C, Inzucchi SE, Lachin JM, et al, for the EMPA-REG OUTCOME Investigators. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 2016;375:323–34. https://doi.org/10.1056/NEJMoa1515920

Mann JFE, Fonseva V, Mosensen O, et al. The LEADER Publication Committee on behalf of the LEADER Trial Investigators. Effects of liraglutide versus placebo on cardiovascular events in patients with type 2 diabetes mellitus and chronic kidney disease results from the LEADER trial. Circulation 2018;138:2908–18. https://doi.org/10.1161/CIRCULATIONAHA.118.036418

Zinman B, Nauck MA, Bosch-Traberg H, et al. The LEADER Publication Committee on behalf of the LEADER Trial Investigators. Liraglutide and glycaemic outcomes in the LEADER trial. Diabetes Ther 2018;9:2383–92. https://doi.org/10.1007/s13300-018-0524-z

Zinman B, Marso SP, Christiansen E, et al, and the LEADER Publication Committee on behalf of the LEADER Trial Investigators. Diabetes Care 2018;41:1783–91. https://doi.org/10.2337/dc17-2677

Dhatariya K, Bain SC, Buse JB, et al, and the LEADER Publication Committee on behalf of the LEADER Trial Investigators. The impact of liraglutide on diabetes-related foot ulceration and associated complications in patients with type 2 diabetes at high risk for cardiovascular events: results from the LEADER trial. Diabetes Care 2018;41:2229–35. https://doi.org/10.2337/dc18-1094

Nauck MA, Buse JB, Mann JFE, et al, and the LEADER Publication Committee on behalf of the LEADER Trial Investigators. Health-related quality of life in people with type 2 diabetes participating in the LEADER trial. Diabetes Obes Metab 2019;21:525–32. https://doi.org/10.1111/dom.13547

Nauck MA, Muus Ghorbani ML, Kreiner E, et al, and the LEADER Publication Committee on behalf of the LEADER Trial Investigators. Effects of liraglutide compared with placebo on events of acute gallbladder or biliary disease in patients with type 2 diabetes at high risk for cardiovascular events in the LEADER randomized trial. Diabetes Care 2019; 42:1912–20. https://doi.org/10.2337/dc19-0415

Steinberg W, Buse JB, Ghorbani MLM, et al, and the LEADER Steering Committee on behalf of the LEADER Trial Investigators. Amylase, lipase, and acute pancreatitis in people with type 2 diabetes treated with liraglutide: results from the LEADER randomized trial. Diabetes Care 2017;40:966–72. https://doi.org/10.2337/dc16-2747




DOI: https://doi.org/10.15277/bjd.2020.267

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