GLP-1s beyond weight: the hard-outcome trials

Why these trials matter

For years the reasonable objection to GLP-1 agonists in obesity was that losing weight is not the same as living longer or getting sick less. That objection now has a partial answer in randomized, double-blind, placebo-controlled trials published in the New England Journal of Medicine, with prespecified clinical or histological outcomes^13468910. For the physician fielding patient questions about these drugs, knowing these six programs is what separates opinion from evidence. Effects on muscle, rebound and the eyes are reviewed in GLP-1s: muscle, rebound, eyes and pancreas.

Heart and kidney: SELECT and FLOW

SELECT enrolled 17,604 people aged 45 or older with established cardiovascular disease, a body-mass index of 27 or more and no diabetes. With semaglutide 2.4 mg weekly, the composite of cardiovascular death, nonfatal myocardial infarction or nonfatal stroke occurred in 6.5% vs 8.0% with placebo (HR 0.80; 95% CI 0.72–0.90), over a mean follow-up of 39.8 months¹. On the basis of this trial, the FDA approved in March 2024 the indication to reduce the risk of cardiovascular death, heart attack and stroke in adults with cardiovascular disease and obesity or overweight².

FLOW randomized 3,533 patients with type 2 diabetes and chronic kidney disease to semaglutide 1.0 mg weekly or placebo. The trial was stopped early on the recommendation of a prespecified interim analysis (median follow-up 3.4 years). The risk of major kidney events (kidney failure, a decline of at least 50% in eGFR, or kidney or cardiovascular death) was 24% lower (HR 0.76; 95% CI 0.66–0.88). The annual eGFR slope was 1.16 ml/min/1.73 m² less steep, major cardiovascular events fell 18% and all-cause mortality 20% (HR 0.80)³.

Sleep apnea: SURMOUNT-OSA

In two phase 3 trials in adults with moderate-to-severe obstructive sleep apnea and obesity, tirzepatide (10 or 15 mg) reduced the apnea-hypopnea index by 25.3 events per hour in those not using positive airway pressure (vs 5.3 with placebo) and by 29.3 events per hour in those using it (vs 5.5). Hypoxic burden, high-sensitivity C-reactive protein and systolic blood pressure also improved⁴. On 20 December 2024 the FDA approved tirzepatide for this indication, calling it "the first drug treatment option for certain patients with obstructive sleep apnea"⁵.

Liver: ESSENCE and the first MASH approval

ESSENCE randomized 1,197 patients with biopsy-proven metabolic dysfunction-associated steatohepatitis (MASH) and F2 or F3 fibrosis. At the week-72 interim analysis (800 patients), resolution of steatohepatitis without worsening of fibrosis occurred in 62.9% with semaglutide vs 34.3% with placebo, and improvement in fibrosis without worsening of steatohepatitis in 36.8% vs 22.4%⁶. On these data the FDA granted accelerated approval in August 2025 for noncirrhotic MASH with moderate to advanced fibrosis⁷.

Heart failure and the knee

In heart failure with preserved ejection fraction and obesity, STEP-HFpEF (529 patients) showed with semaglutide 2.4 mg an additional 7.8-point improvement in the KCCQ score, 20.3 m more on the 6-minute walk and a 43.5% vs 7.3% reduction in C-reactive protein⁸. SUMMIT (731 patients, tirzepatide) went beyond symptoms: cardiovascular death or worsening heart failure occurred in 9.9% vs 15.3% (HR 0.62; 95% CI 0.41–0.95)⁹.

In knee osteoarthritis with obesity, STEP 9 (407 participants, 68 weeks) associated semaglutide with a 41.7-point reduction in WOMAC pain vs 27.5 with placebo, and better SF-36 physical function (12.0 vs 6.5 points)¹⁰.

The limits, with the same honesty

• Tolerability. In SELECT, 16.6% stopped semaglutide because of adverse events vs 8.2% on placebo¹. In SUMMIT it was 6.3% vs 1.4%, mainly gastrointestinal⁹; in STEP 9, 6.7% vs 3.0%¹⁰.
• Real-world persistence. Among 125,474 adults in US health systems, 64.8% of those without diabetes stopped the GLP-1 within the first year; moderate or severe gastrointestinal events were associated with more discontinuation¹¹.
• Cost. A lifetime model estimated cost-effectiveness ratios of USD 197,023 per quality-adjusted life-year for tirzepatide and USD 467,676 for semaglutide; reaching USD 100,000 would require discounts of 30.5% and 81.9% off net price¹².
• What has not been shown. SELECT studied secondary prevention, not people without cardiovascular disease¹. FLOW enrolled only type 2 diabetes³. In SUMMIT, cardiovascular death alone was not lower (2.2% vs 1.4%; HR 1.58; 95% CI 0.52–4.83)⁹. The MASH approval is accelerated, rests on histology and excludes cirrhosis; part 2 of ESSENCE, with clinical liver events, is expected to read out in 2029⁶⁷. In STEP 9, the placebo group also improved substantially¹⁰.