Chapter 14 - Glucagon-like peptide-1 receptor agonists: role in the prevention and treatment of diabetes-related cardiovascular complications

Abstract

Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RAs) have been used in the treatment of patients with type 2 diabetes since 2005 and are increasingly being used because of their efficacy and durability with respect to glycemic control without hypoglycemia and weight loss. Today (2022), seven GLP-1 RAs are available for treatment of type 2 diabetes. However, their efficacy with respect to reduction of hemoglobin (Hb)A1c and body weight, as well as tolerability and dosing frequency, differ markedly, and the GLP-1 RAs cannot be considered equal. The cardiovascular outcome trials were designed to exclude adverse effects, and none of the GLP-1 RAs have been associated with any imminent adverse events. Rather, they have shown reductions in adverse cardiovascular events and/or cardiovascular mortality. The short-acting agonist (lixisenatide) showed no cardiovascular benefits, while the long-acting agonists, once daily liraglutide and the weekly agonists, semaglutide, dulaglutide, exenatide, and efpeglenatide, all lowered the incidence of major adverse cardiovascular events. Liraglutide, oral semaglutide and exenatide once weekly also reduced mortality. GLP-1 RAs have minimal or no effect on existing heart failure but nevertheless reduce the risk of incident heart failure and reduce the progression of diabetic kidney disease. Importantly, the GLP-1 RAs also reduce the incidence of stroke. Compared to the sodium-glucose cotransporter (SGLT)-2 inhibitors, the GLP-1 RAs may act mainly to prevent progression of atherosclerotic cardiovascular disease (ASCVD). In a 2019 consensus report from European Association for the Study of Diabetes/American Diabetes Association, GLP-1 RAs with demonstrated cardio-renal benefits (liraglutide, semaglutide, and dulaglutide) are recommended after metformin to patients with established cardiovascular diseases or with multiple cardiovascular risk factors. The European Society of Cardiology now proposes starting with a SGLT-2 inhibitor or a GLP-1 RA in drug-naïve patients with type 2 diabetes and ASCVD or high cardiovascular risk. However, since the GLP-1 RAs differ considerably, the choice of agent should be weighed on the basis of the patients’ specific needs and the GLP-1 RAs’ documented effects.