Cardiovascular benefits of GLP-1 agonists in type 2 diabetes: a comparative review

Aug 18, 2018Clinical science (London, England : 1979)

Heart health benefits of GLP-1 drugs in type 2 diabetes: a comparison

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Abstract

GLP-1 receptor agonists may confer cardiovascular benefits, but this effect is specific to agents that provide longer acting agonism at the GLP-1 receptor.

Four large cardiovascular outcome trials have compared GLP-1 agonists with placebo and standard care over 2-4 years.
LEADER and SUSTAIN-6 demonstrated reductions in major adverse cardiovascular events with active GLP-1 treatment.
ELIXA and EXSCEL trials did not show reductions in cardiovascular events with GLP-1 agonists.
The cardiovascular benefits may be linked to mechanisms such as weight loss, lower blood pressure, and reduced LDL cholesterol.
Additional effects, including decreased low-grade inflammation and improved blood vessel function, could also be important.

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Type 2 diabetes (T2D) carries risks of both cardiovascular (CV) (myocardial infarction, stroke, and peripheral vascular disease) and microvascular (retinopathy/nephropathy/neuropathy) complications. Glucose-lowering is an effective strategy for preventing microvascular complications, but the extent to which it can reduce CV complications is less certain. Glucagon-like peptide-1 (GLP-1) agonists are potent glucose-lowering agents but also have potentially beneficial effects on other traditional (body weight, blood pressure (BP), and LDL cholesterol) and non-traditional risk factors (low grade inflammation and endothelial dysfunction). The results of four large CV outcome trials with GLP-1 agonists are now available. These have compared lixisenatide (ELIXA), liraglutide (LEADER), semaglutide (SUSTAIN-6), and long-acting exenatide (EXSCEL) with placebo and standard of care over 2-4 years; four others (including with dulaglutide and albiglutide) are ongoing. LEADER and SUSTAIN-6 have demonstrated reductions in rates of major adverse CV events with active GLP-1 treatment but ELIXA and EXSCEL have not. In this review, we discuss the mechanisms by which GLP-1 receptor agonists act on the CV system and the design and conduct of these trials. Contrary to the assertions that (a) all GLP-1 agonists reduce CV disease in T2D but to different extents or (b) the magnitude of CV protection is predominantly related to glucose-lowering, we argue that CV benefit is specific to agents that provide longer acting agonism at the GLP-1 receptor. The mechanisms involve reduction in body weight and BP, and lowering of LDL-cholesterol and glucose, but pleiotropic effects-including suppression of low grade inflammation, vasodilation, and natriuresis-are also likely relevant.

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Cardiovascular benefits of GLP-1 agonists in type 2 diabetes: a comparative review

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