Cardiovascular effects of the incretin-based therapy: the good, the bad, or the ugly?

Incretin hormones are secreted from enteronendocrine cells mainly upon nutrient absorption from the gut lumen. So far, two genuine incretin hormones are identified: glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). Both GIP and GLP-1 enhances glucosestimulated insulin secretion from pancreatic beta-cells via increase of intracellular cyclic adenosine monophosphate. Unlike GIP, GLP-1 suppresses glucagon secretion, decelerates gastric emptying, decreases appetite, and increases satiety. Both GIP and GLP-1 are rapidly degraded by enzymatic action of dipeptidyl peptidase-4 (DPP-4), which is abundantly expressed throughout the body including the blood compartment. To exploit the anti-diabetic properties of incretin hormones, GLP-1 receptor agonists and DPP-4 inhibitors have been developed and widely used in clinical practice. The benefits of GLP-1 receptor agonists and DPP-4 inhibitors in diabetes management are clear. However, scrutiny has been exercised over safety issues such as acute pancreatitis and increased susceptibility to certain infection. Because the most common cause of death of patients with type 2 diabetes is cardiovascular disease, it is critical that anti-diabetes agents at least should not increase the risk of cardiovascular events or related death. In this regard, enormous efforts have been put on the research on the cardiovascular effects of incretin-based therapy. Incretin-based therapy has favorable effects on cardiovascular risk factors and/or surrogate markers of the progression of cardiovascular disease (for details, please refer to an excellent review). Briefly, GLP-1 decreases body weight by decreasing appetite, increasing satiety, and increasing energy expenditure. GLP-1 increases natriuresis, which may contribute to its blood pressure lowering effect. In animals, GLP-1 increases atrial natriuretic peptide secretion from atrial cardiomyocytes, which in turn increases renal sodium excretion. Moreover, GLP-1 improves endothelial function. In animal models of ischemic heart disease, GLP-1 decreased the extent of myocardial damage. Furthermore, in an animal model of cerebral infarction, GLP-1 receptor activation decreased the infarct size. In recently completed but not yet published the Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) study, lixisenatide did not increase the risk of quadruple major adverse cardiovascular events (MACE: cardiovascular death, non-fatal myocardial infarction, unstable angina, and non-fatal stroke) or hospital admission for heart failure in type 2 diabetes patients with history of recent acute coronary syndrome. Because lixisenatide is a short-acting GLP-1 receptor agonist and may induce antibody development against the drug in some patients, it might be unable to exert its full cardiovascular benefit. In this regard, the results of currently on-going cardiovascular outcome studies with long-acting GLP-1 receptor agonists such as liraglutide (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results [LEADER]), dulaglutide (Researching Cardiovascular Events with a Weekly Incretin in Diabetes [REWIND]), semaglutide (Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes [SUSTAIN 6]), and exenatide once weekly (Exenatide Study of Cardiovascular Event Lowering Trial [EXSCEL]) are highly expecting. DPP-4 inhibitors also showed favorable cardiovascular effects. Because there are many peptide substrates of DPP-4 other than GLP-1 (e.g., GIP and stromal cell-derived factor 1 [SDF-1]), the net cardiovascular effects of DPP-4 inhibitors cannot be explained by the action of GLP-1 alone. For example, GIP not only increases glucose-dependent insulin secretion but also increases glucagon secretion, which may contribute to the decreased risk of hypoglycemia with DPP-4 inhibitors. SDF-1 recruits endothelial progenitor cells to the ischemic tissue and may reduce ischemic injury. In a meta-analysis with 70 studies, which were mostly short-term studies with mean duration of follow-up of 44.1 weeks, DPP-4 inhibitors exhibited a decreased risk of major cardiovascular events (odds ratio, 0.71; 95% CI, 0.59–0.86). The cardiovascular safety of DPP-4 inhibitors has been tested in the context of large, long-term, placebocontrolled trials. In the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-TIMI 53 (SAVOR-TIMI 53) trial, saxagliptin did not increase the triple MACE (non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death) compared to placebo in type 2 diabetes patients with high risk of cardiovascular disease for a median 2.1 years of follow-up (hazard ratio, 1.00; 95% CI, 0.89–1.12). In the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care in Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome (EXAMINE) study with a median follow-up for 18 months, alogliptin did not increase the risk of the triple MACE compared to placebo (hazard ratio, 0.96; upper boundary of the one-sided repeated CI, 1.16) in type 2 diabetes patients who experienced recent acute coronary syndrome. Very recently, the Trial to Evaluate Cardiovascular Outcomes After Treatment with Sitagliptin