Sodium-glucose co-transporter inhibitors: Medications that mimic fasting for cardiovascular prevention

Abstract

Recent evidence that some diabetes drugs can prevent cardiovascular disease (CVD) has profoundly modified the treatment approach to type 2 diabetes mellitus. Sodium-glucose co-transporter-2 (SGLT2) inhibitors and almost all glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been shown, beyond their effect on glucose control, to lead to a significant decrease in the cardiovascular burden of diabetes. Although these results are well known, the mechanisms of action by which they prevent cardiovascular events are still poorly understood. Both GLP-1RAs and SGLT2 inhibitors promote weight loss, although through different mechanisms. SGLT2 inhibitors promote glycosuria, leading to significant caloric deficit and weight loss. Similarly, GLP-1RAs, probably through an anorexic effect on certain brain areas, inhibit calorie intake, with ensuing weight loss. Although it features less prominently in current treatment pathways, pioglitazone has also demonstrated cardiovascular benefits. Pioglitazone profoundly modifies several mechanisms and risk factors responsible for CVD; however, these mechanisms certainly do not include weight loss. Obesity, and consequent insulin resistance, are well known risk factors for CVD, and it would appear logical to attribute the positive cardiovascular effects of these two classes of drugs to weight loss. The direct metabolic effects of these two classes, however, are profoundly different. The present review proposes a unifying hypothesis to explain the reduction in CVD through three different mechanisms of curbing free fatty acid excess, all leading to the common mechanism of cellular caloric restriction. If this hypothesis is correct, the excellent results obtained with SGLT2 inhibitors could be attributed to their close simulation of fasting.

Keywords: GLP-1RA; SGLT; caloric restriction; cardiovascular disease; free fatty acids; personalized medicine; pioglitazone.