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GLP-1s and muscle, rebound, eyes and pancreas: what the data say

  • MDside
  • October 9, 2026

Key points

  • About 25% of weight lost on GLP-1s is lean mass, a proportion similar to placebo in SURMOUNT-1 [1][2].
  • One year after stopping semaglutide, two-thirds of the lost weight came back in the STEP 1 extension [3].
  • In 2025 the EMA concluded that NAION is a “very rare” side effect of semaglutide, up to 1 in 10,000 people [9].
  • On suicidal ideation, the EMA concluded the evidence does not support a causal association [13].

US status (October 2026): Semaglutide is approved as Ozempic, Rybelsus and Wegovy, and tirzepatide as Mounjaro and Zepbound.

Lean-mass loss is real and proportionate, regain after stopping is the rule, NAION is real and very rare, and the pancreatitis signal does not hold up in randomized trials. Gastrointestinal and gallbladder effects are the consistent findings.

Lean-mass loss is about a quarter of weight lost

It is the most repeated criticism on social media. The body-composition data are more nuanced. In the SURMOUNT-1 DXA substudy (160 adults), tirzepatide was associated at 72 weeks with reductions of 21.3% in body weight, 33.9% in fat mass and 10.9% in lean mass. About 75% of the weight lost was fat and 25% lean mass, the same split as placebo [1].

A network meta-analysis of 22 trials (2,258 people) found an average lean-mass loss of 0.86 kg, also about a quarter of total weight lost, with no change in lean mass relative to body weight [2]. Two caveats. In that analysis, tirzepatide (15 mg) and semaglutide (2.4 mg) were the most effective for weight and fat reduction but among the least effective at preserving lean mass [2]. And DXA lean mass is not the same as muscle function.

  • About 25%: of weight lost is lean mass (SURMOUNT-1) [1]
  • 2/3: of lost weight regained one year after stopping semaglutide [3]
  • Up to 1 in 10,000: NAION frequency according to the EMA [9]

Most of the weight returns when the drug stops

In STEP 1, semaglutide was associated with a 14.9% reduction in body weight at 68 weeks vs 2.4% with placebo [4]. In the trial extension (327 people), one year after stopping, participants regained about two-thirds of the weight they had lost, and cardiometabolic improvements drifted back toward baseline [3].

SURMOUNT-4 tested this with randomization. After 36 weeks on tirzepatide (a 20.9% weight reduction), 670 people either stayed on the drug or switched to placebo. From week 36 to 88 the placebo group regained 14.0% and the continued group lost a further 5.5% [5]. The pattern supports treating obesity as a chronic condition [3][5]. Set that expectation with patients at the start.

NAION is real and very rare

Non-arteritic anterior ischemic optic neuropathy (NAION) is a kind of “stroke” of the optic nerve. The alarm came in 2024 from a single-center study that found more cases among semaglutide users. The authors stressed it did not establish causality [6]. In people with type 2 diabetes, a Danish-Norwegian population study found a hazard ratio of 2.81 vs SGLT-2 inhibitors, but about 1.4 extra cases per 10,000 person-years: “the absolute risk remains low” [7]. A meta-analysis of 78 trials found no increase in eye disorders overall or in diabetic retinopathy. For NAION it found an association (OR 3.92; 95% CI 1.02 to 15.02), but the authors judged the evidence insufficient for definitive conclusions [8].

In June 2025 the EMA’s pharmacovigilance committee concluded its review: NAION is a very rare side effect of semaglutide that may affect up to 1 in 10,000 people, and the EMA recommended updating the product information [9]. In the US, the Wegovy label (June 2026) does not mention NAION [14].

The pancreatitis signal does not hold up in randomized trials

A US insurance-claims study of people without diabetes using GLP-1s for weight loss associated these drugs with more pancreatitis, bowel obstruction and gastroparesis than bupropion-naltrexone, with very few events and wide confidence intervals [10]. A meta-analysis of 21 randomized trials (99,599 patients) found no difference in pancreatitis. It did find more gastrointestinal (63% more) and gallbladder (26% more) disorders, and lower all-cause mortality [11].

The EMA reviewed the question and in April 2024 concluded that “the available evidence does not support a causal association” between GLP-1s and suicidal thoughts or behaviors [13]. A study of more than 240,000 people with overweight or obesity associated semaglutide with lower risk of suicidal ideation compared with other obesity drugs (HR 0.27), although the evidence is observational [12].

What this means for your clinic

Gastrointestinal and gallbladder effects show up consistently in trials [11]. NAION is real but very rare [9]. Lean-mass loss happens, in a proportion similar to other ways of losing weight [1][2]. Regain after stopping is the rule in trials [3][5]. Build those four facts into your consent and your follow-up plan. Our weight management program covers how we structure that, and compounded GLP-1s after the shortage covers the sourcing rules.

References

  1. Look M, et al. Body composition changes during weight reduction with tirzepatide in the SURMOUNT-1 study of adults with obesity or overweight. Diabetes Obes Metab. 2025;27(5):2720-2729. PMID 39996356. Link
  2. Karakasis P, et al. Effect of glucagon-like peptide-1 receptor agonists and co-agonists on body composition: systematic review and network meta-analysis. Metabolism. 2025;164:156113. PMID 39719170. Link
  3. Wilding JPH, et al. Weight regain and cardiometabolic effects after withdrawal of semaglutide: the STEP 1 trial extension. Diabetes Obes Metab. 2022;24(8):1553-1564. PMID 35441470. Link
  4. Wilding JPH, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med. 2021;384(11):989-1002. PMID 33567185. Link
  5. Aronne LJ, et al. Continued treatment with tirzepatide for maintenance of weight reduction in adults with obesity: the SURMOUNT-4 randomized clinical trial. JAMA. 2024;331(1):38-48. PMID 38078870. Link
  6. Hathaway JT, et al. Risk of nonarteritic anterior ischemic optic neuropathy in patients prescribed semaglutide. JAMA Ophthalmol. 2024;142(8):732-739. PMID 38958939. Link
  7. Simonsen E, et al. Use of semaglutide and risk of non-arteritic anterior ischemic optic neuropathy: a Danish-Norwegian cohort study. Diabetes Obes Metab. 2025;27(6):3094-3103. PMID 40098249. Link
  8. Natividade GR, et al. Ocular adverse events with semaglutide: a systematic review and meta-analysis. JAMA Ophthalmol. 2025;143(9):759-768. PMID 40810985. Link
  9. European Medicines Agency. PRAC concludes eye condition NAION is a very rare side effect of semaglutide medicines Ozempic, Rybelsus and Wegovy. 6 June 2025. Link
  10. Sodhi M, et al. Risk of gastrointestinal adverse events associated with glucagon-like peptide-1 receptor agonists for weight loss. JAMA. 2023;330(18):1795-1797. PMID 37796527. Link
  11. Galli M, et al. Cardiovascular effects and tolerability of GLP-1 receptor agonists: a systematic review and meta-analysis of 99,599 patients. J Am Coll Cardiol. 2025;86(20):1805-1819. PMID 40892610. Link
  12. Wang W, et al. Association of semaglutide with risk of suicidal ideation in a real-world cohort. Nat Med. 2024;30(1):168-176. PMID 38182782. Link
  13. European Medicines Agency. Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC) 8-11 April 2024. Link
  14. Novo Nordisk. Wegovy (semaglutide) US prescribing information, revised 06/2026. Link

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

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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.