GLP-1RAs in type 2 diabetes: mechanisms that underlie cardiovascular effects and overview of cardiovascular outcome data

Abstract

Patients with type 2 diabetes (T2DM) have a substantial risk of developing cardiovascular disease. The strong connection between the severity of hyperglycaemia, metabolic changes secondary to T2DM and vascular damage increases the risk of macrovascular complications. There is a challenging demand for the development of drugs that control hyperglycaemia and influence other metabolic risk factors to improve cardiovascular outcomes such as cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina and heart failure (major adverse cardiovascular events). In recent years, introduction of the new drug class of glucagon-like peptide-1 receptor agonists (GLP-1RAs) has changed the treatment landscape as GLP-1RAs have become well-established therapies in T2DM. The benefits of GLP-1RAs are derived from their pleiotropic effects, which include appetite control, glucose-dependent secretion of insulin and inhibition of glucagon secretion. Importantly, their beneficial effects extend to the cardiovascular system. Large clinical trials have evaluated the cardiovascular effects of GLP-1RAs in patients with T2DM and elevated risk of cardiovascular disease and the results are very promising. However, important aspects still require elucidation, such as the specific mechanisms involved in the cardioprotective effects of these drugs. Careful interpretation is necessary because of the heterogeneity across the trials concerning the definition of cardiovascular risk or cardiovascular disease, baseline characteristics, routine care and event rates. The aim of this review is to describe the main clinical aspects of the GLP-1RAs, compare them using data from both the mechanistic and randomized controlled trials and discuss potential reasons for improved cardiovascular outcomes observed in these trials. This review may help clinicians to decide which treatment is most appropriate in reducing cardiovascular risk in patients with T2DM.

Glucagon-Like Peptide-1 Receptor Agonists in Type 2 Diabetes: Their Use and Differential Features

“…Native GLP-1 has a very short half-life, as it is rapidly degraded by proteases, namely the dipeptidyl peptidase (DPP)-4 enzyme [17][18][19]. To overcome this, GLP-1RAs have been developed that are structurally similar to GLP-1 with regard to their amino-acid sequences, but with modifications that provide stabilization against DPP-4 degradation and/or minimise their renal clearance, thereby increasing their duration of activity (Table 1).…”

Coagulatory Defects in Type-1 and Type-2 Diabetes

“…GLP-1 receptor agonists inhibit platelet aggregation and thrombus formation through enhanced nitric oxide production by activating endothelial nitric oxide synthase, thereby also reducing endothelial dysfunction. [206,207]. They also lower postprandial dyslipidaemia [207].…”

“…[206,207]. They also lower postprandial dyslipidaemia [207]. SGLT2 inhibitors are mostly beneficial in decreasing heart failure as they enhance cardiac cell metabolism, reduce cardiac fibrosis, inhibit Na + /H + exchange in myocardial cells, modulate adipokine and cytokine production, improve ventricular loading conditions and decrease blood pressure [208,209].…”

Changes in SGLT2i and GLP-1RA real-world initiator profiles following cardiovascular outcome trials: A Danish nationwide population-based study

“…These agents currently include 4 agents: dapagliflozin, canagliflozin, empagliflozin, ertugliflozine, and combinations of these SGLT2i with metformin or other antihyperglycemic drugs [2][3][4]. Similarly, glucagonlike peptide-1 receptor agonists (GLP-1RAs), currently including exenatide, liraglutide, dulaglutide, lixisenatide, semaglutide, and paired injectables in combinations with other antihyperglycemic drugs, as a class are increasingly used in the treatment of T2D over the last decade [5][6][7]. While metformin has remained the recommended initial antihyperglycemic drug for most patients with T2D, international (and Danish) guidelines until now have recommended a free choice among several second or third line treatment options, based on an individualised treatment approach [8].…”

“…There are scarce population-based data on how the initiation rates and clinical profiles of initiators of SGLT2i or GLP-1RA have evolved in real-world settings before and after publication of key trial results [3][4][5][6][7]9]. Linked Danish population-based healthcare databases provide a unique opportunity to characterize recent SGLT2i and GLP-1RAs utilization trends in Denmark, and to clinically describe all individuals with incident use of these drugs.…”