Cardiomodulatory Effects of Cardiometabolic and Antihyperglycemic Medications: The Roles of Oxidative and Endoplasmic Reticulum Stress

Uncontrolled hyperglycemia in people with diabetes is an established risk of premature cardiovascular disease. Repeated hypoglycemic events are also associated with increased cardiovascular mortality. Both hyperglycemia and hypoglycemia induce cellular stress, notably endoplasmic reticulum (ER) stress, a known promoter of cardiovascular disease. Contemporary anti-hyperglycemic drugs such as glucagon-like peptide 1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT-2) inhibitors simultaneously inhibit oxidative stress and ER stress in human coronary artery endothelial cells. Similarly, other known cardioprotective drugs, such as statins and inhibitors of the renin-angiotensin-aldosterone system (RAAS) share a common pleiotropic effect of reducing cellular stress. Antioxidants reduce oxidative stress but may aggravate ER stress. This dichotomy of antioxidant effects may underline the unfavorable outcomes of clinical trials with antioxidant vitamin use. The aim of this review is to highlight the potential role of cellular stress reduction in cardioprotective effects of contemporary diabetes drugs. Future clinical trials are needed to test the hypothesis that cellular stress is the fundamental culprit in cardiovascular disease.