The rising star of GLP-1 receptor agonists: Keeping up with the cardiovascular outcomes

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have gone Hollywood. In 2024, Oprah produced a special about the “weight-loss revolution” that included a discussion of GLP-1RAs. Influential celebrities have talked openly about their use of GLP-1RAs, from Khloé Kardashian to Sharon Osbourne to Dr. Phil. The two most “famous” GLP-1RAs currently are liraglutide and semaglutide. Both are approved by Health Canada for glycemic control in patients with type 2 diabetes (T2D) and for chronic weight management in patients with obesity (body mass index [BMI] ≥ 30 kg/m2), or BMI ≥ 27 kg/m2 and weight-related comorbidity (e.g., T2D, hypertension, dyslipidemia, obstructive sleep apnea). A related agent, tirzepatide, is gaining in popularity. Are GLP-1RAs deserving of their new-found fame? Celebrity endorsement often does not coincide with robust clinical evidence. This column focuses on the cardiovascular outcome data for these agents thus far.GLP-1RAs for type 2 diabetesBoth liraglutide and semaglutide have demonstrated a reduction in major adverse cardiovascular events (MACE) in patients with T2D and established, or at high-risk of, atherosclerotic cardiovascular disease. In the LEADER trial, liraglutide 1.8 mg subcutaneously (SC) daily reduced MACE (cardiovascular death, myocardial infarction or stroke) versus placebo for a number needed to treat (NNT) of 53 over 3.8 years, as well as cardiovascular death (NNT 77) and all-cause death (NNT 72).1 Semaglutide 1 mg SC weekly reduced MACE (NNT 44) and nonfatal stroke (NNT 91), compared to placebo, over 2.1 years in the SUSTAIN-6 trial.2 However, it did not lower the risk of cardiovascular or all-cause death.Semaglutide also showed a cardio-vascular benefit in patients with T2D and chronic kidney disease (estimated glomerular filtration rate of 25–75 mL/min/1.73 m2 with albuminuria) in the FLOW trial.3 Among 3,533 participants, semaglutide 1 mg SC weekly reduced the primary outcome of major kidney disease events, as well as all-cause death, compared to placebo over 3.4 years. In addition, death from cardiovascular causes (NNT 39) and MACE (NNT 42) were both significantly lower with semaglutide.GLP-1RAs for obesityIn a recent landmark trial, semaglutide had a beneficial cardiovascular effect in patients without T2D. The SELECT trial randomized 17,604 patients with established atherosclerotic cardiovascular disease who were overweight or obese (BMI ≥ 27 kg/m2) but did not have T2D.4 Most were men (72%) with a mean age of 62 years, mean BMI of 33 kg/m2, and mean glycated hemoglobin (A1C) of 5.8%. Compared to placebo, semaglutide 2.4 mg SC weekly reduced the primary composite endpoint of MACE (6.5% vs 8%, hazard ratio 0.80, 95% confidence interval 0.72–0.90) for a NNT of 67 over 3.3 years. Cardiovascular death was slightly lower with semaglutide (2.5% vs 3%), but did not reach statistical significance (p=0.07). Mean body weight was ~8.5% lower with semaglutide versus placebo at two years. Permanent drug discontinuation due to an adverse event was higher with semaglutide (16.6% vs 8.2%, p