2024 Top Story in Cardiology: GLP1RA, the “It” Drug Class

Glucagon-like protein 1 receptor agonists (GLP1RAs) have emerged as the “it” drug class of 2024. Few medications have garnered as much attention — both positive and negative — in the mainstream press. Ozempic, Wegovy, and Mounjaro have become social media sensations, symbolizing a cultural moment in medicine. Remarkably, the first GLP1RA was approved nearly 20 years ago, although these drugs were initially confined to the realm of endocrinologists treating type 2 diabetes. While GLP1RAs gained approval for weight loss in 2014, their transformative potential wasn’t fully realized until the introduction of higher doses, such as 2.4-mg semaglutide and tirzepatide, which delivered 15% to 20% weight loss. These breakthroughs propelled GLP1RAs into the center of a national conversation.

The science of GLP1RAs is evolving rapidly, with over 50 new articles appearing in PubMed each week. What do we know so far? GLP1, a gut hormone, is a potent regulator of satiety and metabolism, exerting effects on the brain and multiple organ systems. At pharmacologic doses, GLP1RAs improve hyperglycemia, promote weight loss, and reduce inflammation. In type 2 diabetes, they are a first-line therapy for glucose control and significantly lower cardiovascular event risk. The SELECT trial¹ demonstrated that semaglutide 2.4 mg reduced cardiovascular events in patients with obesity or overweight and atherosclerotic cardiovascular disease (ASCVD), while also improving renal outcomes in patients with chronic kidney disease (CKD). Additionally, semaglutide and tirzepatide have shown benefits in heart failure with preserved ejection fraction (HFpEF), reduced sleep apnea severity, and alleviated osteoarthritis pain. Emerging research suggests these drugs could address a wide range of conditions, including substance use disorders, atrial fibrillation, Alzheimer’s disease, Parkinson’s disease, metabolic-associated liver disease, and polycystic ovary syndrome (PCOS).

Despite these advancements, fundamental questions remain about GLP1RAs and their mechanisms of action. The relationships of weight loss, glucose control, and clinical outcomes are complex and are likely to vary by condition. For instance, some GLP1RAs deliver cardiovascular benefits with only modest glucose-lowering effects. Conversely, weight loss appears to play a larger role in the benefits observed in HFpEF trials.

The next wave of incretin therapies will feature dual or triple agonists, combining GLP1RAs with an agent such as gastric inhibitory polypeptide (GIP), glucagon, amylin, FGF21, or PYY. To succeed clinically, these combinations will likely need to achieve greater than 20% weight loss. Whether they offer superior cardiovascular, renal, or other systemic benefits — or reduce side effects — will be determined by the outcomes of head-to-head trials.

A bigger challenge looms: how to afford these medications in a society grappling with the consequences of poor-quality diets and sedentary lifestyles. GLP1RAs can profoundly enhance life expectancy and quality when used appropriately, but they are no panacea for society’s broken relationship with food. Striking a balance between their promise and practicality will require collaboration across medicine, industry, and society.