Book a Call
MDside
Book a Call

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

  • MDside
  • October 9, 2026

Key points

  • In SELECT, with 17,604 patients without diabetes and prior cardiovascular disease, semaglutide was associated with a 20% reduction in major adverse cardiovascular events (HR 0.80) [1].
  • In FLOW, in type 2 diabetes with chronic kidney disease, semaglutide showed a 24% reduction in major kidney events and a 20% reduction in all-cause mortality [3].
  • Tirzepatide is the first FDA-approved drug for moderate-to-severe obstructive sleep apnea in adults with obesity (December 2024) [4][5].
  • Semaglutide received FDA accelerated approval for MASH with F2 to F3 fibrosis in August 2025, based on histology data from ESSENCE [6][7].
  • The limits are real: more discontinuations for adverse events than with placebo, 64.8% one-year discontinuation in real-world patients without diabetes, and a price that is not currently cost-effective in the US [1][11][12].

US status (October 2026): Semaglutide is approved as Ozempic, Rybelsus and Wegovy, and tirzepatide as Mounjaro and Zepbound. Compounding is limited to named-patient 503A preparations inside FDA’s essentially-a-copy limits. See the semaglutide and tirzepatide status pages.

These trials answer the old objection

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 [1][3][4][6][8][9][10]. When your patients ask what these drugs do besides weight, these six programs are the answer that rests on evidence. Effects on muscle, rebound and the eyes are reviewed in GLP-1s: muscle, rebound, eyes and pancreas.

  • HR 0.80: major adverse cardiovascular events with semaglutide in SELECT [1]
  • 24% reduction: major kidney events with semaglutide in FLOW [3]
  • 62.9% vs 34.3%: steatohepatitis resolution in ESSENCE [6]

SELECT and FLOW cover the heart and kidney

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 to 0.90), over a mean follow-up of 39.8 months [1]. 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 overweight [2].

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 to 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].

SURMOUNT-OSA made tirzepatide a sleep apnea drug

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 improved [4]. On December 20, 2024 the FDA approved tirzepatide for this indication, calling it “the first drug treatment option for certain patients with obstructive sleep apnea” [5].

ESSENCE produced 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 fibrosis [7].

Heart failure and knee osteoarthritis also moved

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 protein [8]. 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 to 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 deserve the same weight

  • Tolerability. In SELECT, 16.6% stopped semaglutide because of adverse events vs 8.2% on placebo [1]. In SUMMIT it was 6.3% vs 1.4%, mainly gastrointestinal [9]. 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 discontinuation [11].
  • Cost. A lifetime model found that neither drug met a common US cost-effectiveness threshold at current net prices. Tirzepatide’s cost per quality-adjusted life-year was less than half of semaglutide’s, and reaching the threshold would require discounts of 30.5% and 81.9% off net price, respectively [12].
  • What has not been shown. SELECT studied secondary prevention, not people without cardiovascular disease [1]. FLOW enrolled only type 2 diabetes [3]. In SUMMIT, cardiovascular death alone was not lower (2.2% vs 1.4%; HR 1.58; 95% CI 0.52 to 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 2029 [6][7]. In STEP 9, the placebo group also improved substantially [10].

What this means in your clinic

The message the data support is precise. In specific populations, these drugs were associated with fewer cardiovascular events, less kidney progression, fewer apneas and better liver histology [1][3][4][6]. Each benefit belongs to the population, molecule and dose of the trial that showed it. Extending it to other patients is a hypothesis. Plan for persistence: in one large US cohort, 64.8% of patients without diabetes stopped within a year [11]. For how MDside structures GLP-1 programs, see weight management, and for sourcing rules after the shortage, see compounded GLP-1s after the shortage. Newer molecules are discussed in After semaglutide.

References

  1. Lincoff AM, et al. Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med. 2023;389(24):2221-2232. PMID 37952131. Link
  2. U.S. Food and Drug Administration. FDA approves first treatment to reduce risk of serious heart problems specifically in adults with obesity or overweight. 8 March 2024. Link
  3. Perkovic V, et al. Effects of semaglutide on chronic kidney disease in patients with type 2 diabetes. N Engl J Med. 2024;391(2):109-121. PMID 38785209. Link
  4. Malhotra A, et al. Tirzepatide for the treatment of obstructive sleep apnea and obesity. N Engl J Med. 2024;391(13):1193-1205. PMID 38912654. Link
  5. U.S. Food and Drug Administration. FDA approves first medication for obstructive sleep apnea. 20 December 2024. Link
  6. Sanyal AJ, et al. Phase 3 trial of semaglutide in metabolic dysfunction-associated steatohepatitis. N Engl J Med. 2025;392(21):2089-2099. PMID 40305708. Link
  7. Novo Nordisk A/S. Wegovy approved in the US for the treatment of MASH. Form 6-K, U.S. Securities and Exchange Commission. 15 August 2025. Link
  8. Kosiborod MN, et al. Semaglutide in patients with heart failure with preserved ejection fraction and obesity. N Engl J Med. 2023;389(12):1069-1084. PMID 37622681. Link
  9. Packer M, et al. Tirzepatide for heart failure with preserved ejection fraction and obesity. N Engl J Med. 2025;392(5):427-437. PMID 39555826. Link
  10. Bliddal H, et al. Once-weekly semaglutide in persons with obesity and knee osteoarthritis. N Engl J Med. 2024;391(17):1573-1583. PMID 39476339. Link
  11. Rodriguez PJ, et al. Discontinuation and reinitiation of dual-labeled GLP-1 receptor agonists among US adults with overweight or obesity. JAMA Netw Open. 2025;8(1):e2457349. PMID 39888616. Link
  12. Hwang JH, et al. Lifetime health effects and cost-effectiveness of tirzepatide and semaglutide in US adults. JAMA Health Forum. 2025;6(3):e245586. PMID 40085108. Link

This is general information, not medical or legal advice. Rules vary by state and change. Confirm your own facts with counsel.

Share this article with a friend

Medical direction. Victor D. Cruz, MD, Systems Medical Director, licensed in Florida (ME117105) and New York, directs structure, corporate practice of medicine, delegation and good faith exams. This states who carries clinical responsibility for this subject area. It is not a page-level review: pages that have been reviewed name the reviewer and show the date. How this site is written and checked.