GLP-1 Drug Cardiovascular Benefits: SELECT Trial and Beyond 2026

What Did the SELECT Trial Show?

The SELECT (Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity) trial was a landmark double-blind, randomized, placebo-controlled trial enrolling 17,604 adults aged 45 and older with a BMI of 27 or greater, established cardiovascular disease (prior heart attack, stroke, or peripheral artery disease), and no history of diabetes. Participants received either subcutaneous semaglutide 2.4 mg weekly (the Wegovy dose) or placebo, with a median follow-up of 39.8 months. The trial was published in the New England Journal of Medicine in November 2023.

The primary endpoint — a composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke (3-point MACE) — occurred in 6.5% of the semaglutide group versus 8.0% of the placebo group, representing a 20% relative risk reduction (hazard ratio 0.80, 95% CI 0.72-0.90, p < 0.001). Benefits were observed across all three individual components, though the reduction in cardiovascular death alone did not achieve statistical significance. All-cause mortality showed a non-significant 19% reduction. The mean body weight loss was 9.4% with semaglutide versus 0.9% with placebo at the 104-week peak.

The SELECT trial was significant because it established cardiovascular benefit of a GLP-1 receptor agonist specifically for obesity-related cardiovascular risk, independent of diabetes. Previous cardiovascular outcomes trials with GLP-1 agonists — including SUSTAIN-6 (semaglutide in type 2 diabetes), LEADER (liraglutide), and REWIND (dulaglutide) — had demonstrated cardiovascular benefit in diabetic populations. Based on SELECT, the FDA approved a new indication for Wegovy (semaglutide 2.4 mg) in March 2024 to reduce the risk of cardiovascular death, heart attack, and stroke in adults with cardiovascular disease and either obesity or overweight.

How Do GLP-1 Drugs Benefit the Heart and Kidneys?

The cardiovascular benefits of GLP-1 receptor agonists appear to extend beyond what can be explained by weight loss and glucose lowering alone. Mediation analyses from the SELECT trial suggested that weight loss accounted for only a portion of the cardiovascular risk reduction, implying direct cardioprotective mechanisms. GLP-1 receptors are expressed in the heart, blood vessels, kidneys, and immune cells. Preclinical studies have demonstrated that GLP-1 agonists reduce arterial inflammation, decrease macrophage accumulation in atherosclerotic plaques, improve endothelial function, reduce oxidative stress, and lower blood pressure (typically by 2-6 mmHg systolic).

For kidney disease, the FLOW trial (published in NEJM in 2024) provided definitive evidence that semaglutide protects kidney function. This trial enrolled 3,533 patients with type 2 diabetes and chronic kidney disease (eGFR 25-75 mL/min and UACR 300-5000 mg/g). Semaglutide 1.0 mg weekly reduced the primary composite kidney outcome (sustained eGFR decline of 50% or more, kidney failure, kidney-related death, or cardiovascular death) by 24% compared to placebo (HR 0.76). The trial was stopped early for efficacy, and semaglutide became the first GLP-1 receptor agonist with a demonstrated kidney-protective indication, complementing established renal benefits of SGLT2 inhibitors.

In heart failure, the STEP-HFpEF trial (published in NEJM in 2023) showed that semaglutide 2.4 mg weekly significantly improved symptoms, physical function, and quality of life in patients with heart failure with preserved ejection fraction (HFpEF) and obesity. Participants on semaglutide had a mean reduction of 7.8 points on the Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score compared to 1.8 points with placebo, alongside a mean 13.3% body weight loss. These findings are particularly notable because HFpEF — which accounts for approximately half of all heart failure cases — has historically had very few effective treatments, and obesity is a major contributing factor.

Can GLP-1 Drugs Treat Liver Disease?

Metabolic dysfunction-associated steatohepatitis (MASH, formerly known as NASH or non-alcoholic steatohepatitis) affects an estimated 6-8% of adults globally and is the fastest-growing indication for liver transplantation. MASH is characterized by hepatic steatosis (fat accumulation), inflammation, and hepatocyte ballooning, which can progress to fibrosis, cirrhosis, and hepatocellular carcinoma. Given that MASH is strongly associated with obesity, insulin resistance, and metabolic syndrome, GLP-1 receptor agonists represent a logical therapeutic approach.

The Phase III ESSENCE trial, presented at the AASLD Liver Meeting in late 2024, evaluated semaglutide 2.4 mg weekly in patients with biopsy-confirmed MASH and significant liver fibrosis (stage F2 or F3). The results were striking: 62.9% of semaglutide-treated patients achieved resolution of steatohepatitis without worsening of fibrosis (the primary endpoint) at 72 weeks, compared to 34.1% on placebo. Additionally, 37.0% of semaglutide-treated patients achieved improvement in fibrosis by at least one stage without worsening of MASH, compared to 22.5% on placebo. Based on these data, Novo Nordisk filed for FDA approval of semaglutide for MASH treatment.

It is worth noting that resmetirom (Rezdiffra), a thyroid hormone receptor beta agonist, became the first FDA-approved treatment specifically for MASH with moderate to advanced fibrosis in March 2024. Resmetirom works through a different mechanism — activating thyroid hormone receptor beta in the liver to increase fatty acid oxidation and reduce hepatic lipid accumulation. The MAESTRO-NASH trial showed 30% resolution of MASH at 52 weeks. The future of MASH treatment may involve combination approaches utilizing GLP-1 agonists alongside liver-targeted therapies like resmetirom, particularly for patients with advanced fibrosis who need both metabolic improvement and direct anti-fibrotic effects.