Incretins and selective renal sodium-glucose co-transporter 2 inhibitors in hypertension and coronary heart disease

Abstract

Hyperglycemia is associated with an increased risk of cardiovascular disease, and the consequences of intensive therapy may depend on the mechanism of the anti-diabetic agent(s) used to achieve a tight control. In animal models, stable analogues of glucagon-like peptide-1 (GLP-1) were able to reduce body weight and blood pressure and also had favorable effects on ischemia following coronary reperfusion. In a similar way, dipeptidyl peptidase IV (DPP-IV) showed to have favorable effects in animal models of ischemia/reperfusion. This could be due to the fact that DPP-IV inhibitors were able to prevent the breakdown of GLP-1 and glucose-dependent insulinotropic polypeptide, but they also decreased the degradation of several vasoactive peptides. Preclinical data for GLP-1, its derivatives and inhibitors of the DPP-IV enzyme degradation suggests that these agents may be able to, besides controlling glycaemia, induce cardio-protective and vasodilator effects. Notwithstanding the many favorable cardiovascular effects of GLP-1/incretins reported in different studies, many questions remain unanswered due the limited number of studies in human beings that aim to examine the effects of GLP-1 on cardiovascular endpoints. For this reason, long-term trials searching for positive cardiovascular effects are now in process, such as the CAROLINA and CARMELINA trials, which are supported by small pilot studies performed in humans (and many more animal studies) with incretin-based therapies. On the other hand, selective renal sodium-glucose co-transporter 2 inhibitors were also evaluated in the prevention of cardiovascular outcomes in type 2 diabetes. However, it is quite early to draw conclusions, since data on cardiovascular outcomes and cardiovascular death are limited and long-term studies are still ongoing. In this review, we will analyze the mechanisms underlying the cardiovascular effects of incretins and, at the same time, we will present a critical position about the real value of these compounds in the cardiovascular system and its protection.

Keywords: Incretins, Hypertension, Cardiovascular effects, Dipeptidyl peptidase 4 inhibitors, Sodium-glucose co-transporter 2

Core tip: The dipeptidyl peptidase IV inhibitors prevent the breakdown of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide, but also decrease the degradation of several vasoactive peptides. Dipeptidyl peptidase IV inhibitors have shown to have favorable effects in animal models of ischemia/reperfusion and in hypertension. Clinical studies are most under way and final results could give reliable information on cardiovascular protection. Selective inhibitors of renal sodium glucose transport 2 have been also evaluated in the prevention of cardiovascular outcomes in type 2 diabetes. However, data on cardiovascular outcomes and cardiovascular death are limited and long term studies are on-going, therefore it is premature to draw conclusions.