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

Abstract

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.

Pharmacokinetics of Exenatide in nonhuman primates following its administration in the form of sustained-release PT320 and Bydureon

“…In the clinical setting for the treatment of T2DM 1,5–8 as well as for other disorders 10–14 , Exenatide is routinely administered chronically; over months to years duration. This would involve once weekly dosing of Bydureon 5–9 and either once weekly or once every other week dosing for PT320 27,30 .…”

“…As the glucose homeostasis actions and enhancement of insulin signaling provided by GLP-1 are largely preserved in type 2 diabetes mellitus (T2DM), agents that activate the GLP-1 receptor (GLP-1R), a class B G protein–coupled receptor (GPCR) that mediates the action of GLP-1, have been developed for the treatment of T2DM; they appear to be well-tolerated, efficacious and widely used 5–9 . Furthermore, as the GLP-1R has been found expressed across a wide variety of other organs, such as on neurons within the brain and peripheral nervous system and within all four chambers of the heart, GLP-1R agonists are currently being evaluated across an increasing number of other diseases 10–15 .…”

Interactions Between Therapeutics for Metabolic Disease, Cardiovascular Risk Factors, and Gut Microbiota

“…This enables the identification of microbial targets that may help these drugs to provide their cardiovascular protective effects. At present, the potential benefits of these drugs in reducing CVD risks mainly include the reduction of multiple cardiovascular risk factors such as hyperglycemia, hypertension and hyperlipidemia, as well as other beneficial effects, including increased insulin sensitivity, weight loss, reduced of oxidative stress and lowgrade inflammation, restored of endothelial function, and the inhibition of key platelet activation pathways (Standl et al, 2014;Boyle et al, 2018;Lahnwong et al, 2018;Zilov et al, 2019). FIGURE 1 | Metabolic therapy drugs reshape the gut microbiota composition, modulate the abundance of specific gut bacteria, and then control the release of the microbial derivative to achieve cardiovascular protection and reduce cardiovascular risk factors.…”

Glucagon-Like Peptide-1 Receptor Agonists in Adult Patients With Type 2 Diabetes: Review of Cardiovascular Outcome Trials

“…GLP-1RA therapies exert important pharmacodynamic effects on several CV risk factors (body weight, blood pressure and low-density lipoprotein cholesterol/triglycerides). Although some of these effects have been proposed to explain some of the benefits observed in GLP-1RA CVOTs (17), further exploratory subgroup analyses have not found significant associations between any of these variables and the CV benefits of GLP-1RAs (39,40). This was evident in the recent HARMONY-Outcomes trial, wherein albiglutide was associated with a significant reduction in MACE without significant changes in body weight or blood pressure-lowering compared with placebo (22).…”

“…The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome (LEADER) trial and the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN-6) (and the ELIXA trial, previously described) have been extensively reviewed elsewhere (17,18); as such, the characteristics and major findings of these trials are only briefly summarized.…”