GLP-1 receptor (GLP-1R) agonists were initially developed to treat diabetes and later evolved into medications for weight management. Recent evidence demonstrates their remarkable efficacy in cardiovascular disease, kidney disease, and heart failure with preserved ejection fraction (HFpEF). This review highlights the cardiovascular protective effects of GLP-1R agonists identified through preclinical studies and outcome trials.

Introduction

Glucagon-like peptide 1 (GLP-1) is an incretin hormone secreted by L-cells in the small intestine in response to food intake. GLP-1 stimulates insulin secretion from pancreatic islet beta cells in a glucose-dependent manner and inhibits glucagon secretion from pancreatic islet alpha cells. The GLP-1R agonist exenatide was first approved in the United States in 2005. Subsequently, liraglutide was approved by the U.S. Food and Drug Administration in 2014 for chronic weight management in obese adults.

GLP-1R activation influences multiple tissues and organs, including adipose tissue, the nervous system, liver, pancreas, stomach, heart, blood vessels, and kidneys. Large clinical trials have demonstrated that GLP-1R agonists improve cardiovascular and kidney outcomes, as well as metabolic dysfunction-associated steatohepatitis (MASH).

Mechanism of Action

GLP-1R is expressed in animal and human atrial and ventricular cardiomyocytes, as well as in the sinoatrial node. Protective effects of GLP-1R agonists on the myocardium have been reported. In preclinical studies, GLP-1 treatment reduced cardiomyocyte apoptosis and caspase-3 activation.

GLP-1R agonists also exert indirect effects on cardiovascular disease by influencing systemic inflammation and the quantity and quality of adipose tissue. GLP-1 levels rise in response to various inflammatory stimuli, with interleukin-6 (IL-6) serving as a key cytokine that drives its induction.

Clinical Evidence

In 2016, the LEADER trial reported cardioprotective effects of GLP-1R agonists in patients with type 2 diabetes. In LEADER, liraglutide reduced the composite outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke by 13% compared with placebo.

The STEP-HFpEF trial was the first RCT testing GLP-1R agonists in obesity-related HFpEF. Semaglutide treatment for 52 weeks significantly improved HF-related symptoms and physical limitations.

More recently, the SUMMIT trial showed that tirzepatide reduced the composite risk of worsening heart failure or cardiovascular death and improved health status and exercise capacity in patients with heart failure with preserved ejection fraction (HFpEF) and obesity.

Conclusions

Over the past 2 decades, GLP-1R agonists have rapidly evolved from antidiabetic drugs to weight-loss medications and protective antiatherosclerotic agents, as well as treatments for heart failure. Their benefits extend to all organ systems affected by excess body fat, including the kidneys, liver, and central nervous system.