Incretin-based therapy: An update focusing on the major revolution in cardiovascular-kidney-metabolic health.

Abstract

Type 2 diabetes mellitus and obesity have become the rising burden across various geographic and economic regions, and they are also the common causes of chronic kidney disease, which further contributes to the development and progression of cardiovascular disease. The recently proposed cardiovascular-kidney-metabolic syndrome-the new paradigm of recognizing excess or dysfunctional adipose tissue as the shared pathophysiology-has signaled the interconnection of type 2 diabetes mellitus, obesity, chronic kidney disease, and cardiovascular disease beyond the disturbance of glucose homeostasis, for which recently developed incretin-based therapy has offered an avenue of holistic management. Glucagon-like peptide-1 (GLP1) is one of the incretins and potentiates insulin secretion after food intake, additionally offering extra-pancreatic metabolic effects-reduced hepatic gluconeogenesis and steatosis, increased muscular glucose uptake, and increased lipolysis and glucose uptake in the adipose tissue. Seven different GLP1 receptor agonists have been licensed globally. For those with type 2 diabetes mellitus, GLP1 receptor agonists overall reduce major adverse cardiovascular events by 14% (hazard ratio 0.86, 95% confidence interval 0.80-0.93) and all-cause death by 18% (hazard ratio 0.82, 95% confidence interval 0.82-0.94), and semaglutide, a long-acting GLP1 receptor agonist for once weekly injection, reduces major renal events by 24% (hazard ratio 0.76, 95% confidence interval 0.66-0.88). For obese patients without diabetes mellitus, semaglutide results in a 12.4% (95% confidence interval -13.4 to -11.5) reduction in body weight and 20% lower in the risk of major adverse cardiovascular events (hazard ratio 0.80, 95% confidence interval 0.72-0.90), while the burden of heart failure can also be improved by 7.8 points (95% confidence interval 4.8-10.9) in those with heart failure with preserved ejection fraction and obesity. These findings highlight the transformative role of GLP1 receptor agonists in the management of cardiovascular-kidney-metabolic syndrome. We reviewed the updated clinical evidence of incretin-based therapy and summarized its outcome benefits.