2024 Top Story in Diabetes: Efficacy of GLP-1 Receptor Agonists for Obesity-Related Complications

In 2024, high-potency GLP-1 receptor agonist trials went beyond glycemic control, weight management, and atherosclerotic cardiovascular disease outcomes to demonstrate efficacy for non-metabolic complications common in type 2 diabetes, particularly those driven by obesity. For example:

• Heart failure with preserved ejection fraction (HFpEF). Both semaglutide and tirzepatide have been shown to improve the quality of life for individuals with heart failure with preserved ejection fraction and obesity, with and without type 2 diabetes.

  1. A pooled analysis of patients with obesity-related HFpEF treated with semaglutide 2.4 mg in the STEP-HFpEF, STEP-HFpEF DM, and SELECT trials, and 1.0 mg in the FLOW trial, showed a reduced risk of cardiovascular death and heart failure (5.4% vs 7.5%; HR, 0.69; 95% CI, 0.52–0.89).¹

  2. The SUMMIT trial, released at the AHA in November 2024, reported that tirzepatide 15 mg vs placebo in people with HFpEF over a median follow-up period of 104 weeks was associated with a reduced rate of cardiovascular death or worsening heart failure (9.9% vs 15.3%; HR, 0.54; 95% CI, 0.34–0.85), largely attributable to reduced heart failure events.² Quality of life measured by the Kansas City Cardiomyopathy Questionnaire–Clinical Summary Score, also improved to a greater degree in the tirzepatide group, as had previously been seen with semaglutide.

• Obstructive sleep apnea. In the SURMOUNT-OSA trial, people with obesity and moderate to severe sleep apnea were randomly assigned to receive tirzepatide 10 or 15 mg as tolerated and had reduced apnea–hypopnea index score, hypoxic burden, systolic blood pressure measurements, and high-sensitivity C-reactive protein levels, and they had improved sleep-related patient-reported outcomes over a period of 52 weeks compared with those receiving placebo.³

• Knee osteoarthritis. In the STEP 9 trial, people with obesity and moderate knee arthritis with at least moderate pain were randomly assigned to semaglutide 2.4 mg or placebo for 68 weeks, during which all participants received diet and activity counseling. Participants treated with semaglutide had greater reductions in the Western Ontario and McMaster University Osteoarthritis Index pain score and SF-36 physical-function score.⁴

There was a weight loss of 12% to nearly 20% with the active agent in each of these trials, depending on the population, agent, and dose. Although GLP-1 receptor agonists likely have agent and class-specific effects that may impact certain outcomes, these trials convincingly demonstrate that obesity-related complications can be significantly ameliorated by potent medications that cause substantial weight loss.