Originally published June 6, 2025. Revised August 2026 to reflect evidence that was not available when this was first written, including the STEP UP trial of semaglutide 7.2 mg, pharmacovigilance data from VigiBase and EudraVigilance, and a Mayo Clinic case-control study.
Semaglutide, sold as Ozempic and Wegovy, changed how we handle type 2 diabetes and obesity. Tirzepatide, sold as Mounjaro and Zepbound, pushed it further. I prescribe both routinely and the benefits are not in question. What follows applies to the class rather than to any one brand.
What has changed since I wrote this originally is the quality of the evidence underneath the complaints. In June 2025 the nerve and muscle problems I described were a handful of case reports. They are now in three national pharmacovigilance databases and one controlled study, and one of those findings has changed how I dose.
The skin pain is real, and it is a class effect
The original signal was small. Four patients, described by Stark and colleagues, all of whom developed allodynia after reaching the 2.4 mg weekly dose. Pain from light touch. A shirt hurting. Two stopped and resolved, one of the two who continued resolved at about four months, and all four scored as probable on the Naranjo scale.
Three things have happened since.
The first is tirzepatide, the molecule in Mounjaro and Zepbound. Ahern published two cases in October 2025, one on semaglutide and one on tirzepatide, and Chakrabarti and colleagues published the first tirzepatide-specific series in May 2026. Two patients with severe obesity, moderate to severe allodynia, onset tracking with dose escalation, resolution after stopping. So this is not a semaglutide quirk. It follows the receptor.
The second is that the pharmacovigilance data caught up. Laroche and colleagues ran a disproportionality analysis on VigiBase and found semaglutide and tirzepatide both significantly associated with hyperaesthesia, and semaglutide specifically with dysesthesia and burning sensation. Dose dependent, worse with the more potent agents, resolving on discontinuation, and with positive rechallenge in some cases. A separate EudraVigilance analysis found a dysesthesia signal as well.
The third is the detail I find most interesting. The Laroche paper opens by noting that the reports started on social media and medical blogs before they reached the literature, and that the signal was already visible in the trial data for semaglutide, tirzepatide and retatrutide. Patients described this accurately, in public, for a couple of years before anybody wrote it up.
I mention that because of what it means in a visit. When someone tells me their skin burns and nothing is there to see, that is now a recognized adverse effect with a database signal behind it, not a somatic complaint to be reassured away. I was too slow to that conclusion in 2025.
The 7.2 mg dose changes the arithmetic
Everything above came from case reports and spontaneous reporting databases. Those tell you that something happens. They cannot tell you how often. A randomized trial can, and one has now reported.
Wharton and colleagues published STEP UP in Lancet Diabetes and Endocrinology in November 2025. They randomized 1,407 adults with obesity and without diabetes to semaglutide 7.2 mg, semaglutide 2.4 mg, or placebo, in a five to one to one split, for 72 weeks. The weight loss result is the part that got covered: 18.7 percent on the high dose against 15.6 percent on 2.4 mg and 3.9 percent on placebo.
Here is the part that did not get covered. Dysesthesia occurred in 230 of the 1,004 patients on 7.2 mg. That is 22.9 percent. On 2.4 mg it was 6.0 percent. On placebo it was 0.5 percent, which is one person.
Read those three numbers again, because they are a dose-response curve in a randomized double-blind trial with over 1,400 people in it. Everything in the case series literature, and everything the pharmacovigilance databases hinted at, is confirmed by that single line in a phase 3b safety table.
The FDA approved the 7.2 mg dose as Wegovy HD in March 2026, through a 54-day accelerated review under the National Priority Voucher program, and has said it is looking further into the dysesthesia signal. I have written separately about who should actually consider the 7.2 mg dose.
In fairness to the drug, these events generally settled on their own or with a dose reduction, and serious adverse events were actually lower on 7.2 mg than on 2.4 mg, 6.8 percent against 10.9 percent. The trial authors concluded that 7.2 mg retained a favourable risk-benefit profile, and for weight loss that is defensible.
I would still put the sensory finding differently than they did. Almost one in four is not a rare adverse effect. It is a common one. It belongs in the conversation before the first injection, not in a footnote somebody reads after their shirt starts hurting.
The finding that actually changed my practice
Here is the part that was not in the original post, and it is the most clinically useful thing in this update.
Triplett and colleagues at Mayo published a case-control study in Neurology in August 2025 looking at two specific neuropathies in GLP-1 users. Diabetic lumbosacral radiculoplexus neuropathy, which is severe asymmetric leg pain followed by weakness and wasting, and common fibular neuropathy, which is a foot drop.
They found 26 patients with 27 episodes of DLRPN. Median onset was six months after starting the drug, with a range of three to thirty five. At onset those patients had dropped a median of 2.4 percentage points of HbA1c, with a range up to 8.5, and lost a median of 13.9 percent of body weight. Nerve biopsy showed microvasculitis in four of five cases. For common fibular neuropathy there were 77 patients and 82 episodes, with a smaller median HbA1c drop of 1.2 percent and a slightly larger median weight loss of 15.7 percent.
Against matched controls, GLP-1 users were 51 percent more likely to develop DLRPN, odds ratio 1.5 with a confidence interval of 1.2 to 1.9, and 30 percent more likely to develop common fibular neuropathy, odds ratio 1.3 with an interval of 1.0 to 1.5. Every episode in the series occurred after 2015, and cases rose roughly sevenfold and ninefold between the 2015 to 2019 period and 2020 to 2024.
The interesting split is what predicted which neuropathy. DLRPN tracked with the size of the HbA1c reduction. Common fibular neuropathy tracked with weight loss, which makes sense for a nerve that gets compressed at the fibular head once the fat pad over it disappears.
That first association has a name that predates these drugs. Treatment-induced neuropathy of diabetes, described decades ago after aggressive insulin initiation, where a fast correction of chronic hyperglycemia produces an acute, severe, painful small fiber neuropathy. Nobody expected to see much of it from a weekly injection. We are seeing it because these drugs drop an A1c faster than anything we had before.
So the honest reframing is this. Some of what gets called Ozempic nerve pain is probably not a drug toxicity at all. It is the metabolic correction happening faster than the nerve can tolerate.
Rhabdomyolysis and muscle loss
The rhabdomyolysis report stands where it was. Billings and colleagues described a 47-year-old woman with diffuse muscle pain, weakness and a raised creatine kinase after starting semaglutide, improving after discontinuation. It remains a single case.
Muscle mass is the more common problem and it is not rare at all. Mohamad reported a 74-year-old man who used semaglutide for two years, lost eight kilograms, and turned up with fatigue, weakness and visible wasting. Dose reduction and resistance training recovered some of it. Sarcopenia is an expected consequence of large, fast weight loss, and older adults absorb almost all of that risk. I treat this as something to prevent from day one rather than something to detect later. I go through the evidence in more depth in my piece on whether GLP-1 drugs cause muscle loss.
The eye signal has moved, at least outside the United States
The 2024 JAMA Ophthalmology cohort from Hathaway and colleagues reported a markedly higher rate of non-arteritic anterior ischemic optic neuropathy in patients prescribed semaglutide, with a 36-month cumulative incidence of 6.7 percent against 0.8 percent. Subsequent work has been mixed, with a large Danish and Norwegian cohort finding a smaller but real elevation and other analyses finding none.
Regulators have moved since. The European Medicines Agency’s safety committee reviewed it in June 2025 and concluded NAION is a very rare side effect of semaglutide, affecting up to 1 in 10,000 people, and EU product information was updated on 30 September 2025. The WHO issued its own statement in June 2025. As of this revision the FDA has not added NAION to the US labels for Ozempic, Wegovy or Rybelsus and describes the evidence as under evaluation.
Worth noting that the EudraVigilance analysis also picked up optic ischemic neuropathy reports for tirzepatide and liraglutide, so the eye question may not stay a semaglutide question either.
The absolute risk is still low. I tell patients what it is and what sudden painless vision loss in one eye looks like, and I move on.
What I do differently now
I run a telemedicine practice, so all of this happens over video, and none of it needs a physical exam to get right.
The rate of change matters as much as the destination. If someone comes down four points of A1c in three months I now treat that as a reason to slow the titration rather than a win to celebrate. That is a genuine change in how I practice and it comes directly from the Mayo data.
I ask specifically about skin pain rather than waiting for it. The question that finds it is whether clothing or bedsheets hurt, not whether they have numbness or tingling.
Anyone going to 7.2 mg hears the number before they start. Twenty three percent is high enough that being warned about it is much better than being blindsided by it, and a patient who expects the sensation is far more likely to ring me than to quietly stop the drug.
Severe asymmetric leg pain in someone on a GLP-1 is not a titration side effect and it does not get a watchful waiting plan. That is a neurology referral, and the pain usually arrives weeks before the weakness does.
I check B12 in anyone with neurologic complaints, since slowed gastric emptying can reduce absorption.
Protein and resistance training start at the beginning, not after the wasting shows up. Adequate protein means a number I have actually calculated with the patient, not a general encouragement.
And when I do suspect the drug, holding or reducing the dose answers the question faster than any test will.
The Bottom Line
Most patients do well on these medications and the benefits are large. Nothing in the last year changes that.
What the last year changed is that skin pain from these drugs stopped being an oddity. It is a class effect, it is dose dependent, and at the 7.2 mg dose it reached 22.9 percent in a randomized trial. It is not rare at all.
The other change is that some of the serious nerve injury looks like it is driven by how fast we are correcting the metabolic problem rather than by the drug poisoning the nerve. That is the actionable one, because the fix is in the titration, and the titration is entirely under our control.
References
Wharton S, Freitas P, Hjelmesaeth J, et al. Once-weekly semaglutide 7.2 mg in adults with obesity (STEP UP): a randomised, controlled, phase 3b trial. Lancet Diabetes Endocrinol. 2025;13(11):949-963. PMID: 40961952
Stark J, Klass MJ, Owen L. Allodynia (skin tenderness) associated with semaglutide: A case series. Am J Health Syst Pharm. 2025;82(9):e426-e430. PMID: 39862389
Ahern S. Allodynia and Dysesthesia Associated With Semaglutide and Tirzepatide. Cureus. 2025;17(10):e94126. PMID: 41210042
Chakrabarti MP, Han S, Campbell NM. Cutaneous Allodynia Associated With GLP-1RA Tirzepatide for Weight Management: A Case Series. Am J Case Rep. 2026;27:e952158. PMID: 42101979
Laroche ML, Geniaux H, Jardou M. Dysesthesia associated with GLP-1 agonist therapies: data-mining analysis and literature review. Eur J Clin Pharmacol. 2026;82(6):154. PMID: 42168638
Popa Ilie IR, et al. Incretin-Based Drugs for Obesity: Common and Drug-Specific Reporting Patterns of Adverse Drug Reactions. Pharmaceuticals (Basel). 2026;19(6):876. PMID: 42356493
Triplett JD, Pinto MV, Young NP, et al. GLP-1RA-Associated Diabetic Lumbosacral Radiculoplexus and Common Fibular Neuropathies: A Case-Control Evaluation. Neurology. 2025;105(3):e213916. PMID: 40694751
Billings SA, Felix HM, Prier CC, Hedges MS. Rhabdomyolysis Associated With Semaglutide Therapy: A Case Report. Cureus. 2023;15(12):e50227. PMID: 38192938
Mohamad AA. A case report of semaglutide induced sarcopenia: causes of fatigue in older adults. Korean J Fam Med. 2025;46(4):288-291. PMID: 40223309
Hathaway JT, et al. Risk of Nonarteritic Anterior Ischemic Optic Neuropathy in Patients Prescribed Semaglutide. JAMA Ophthalmol. 2024. PMID: 38958939
European Medicines Agency. Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC), 2-5 June 2025. https://www.ema.europa.eu/en/news/meeting-highlights-pharmacovigilance-risk-assessment-committee-prac-2-5-june-2025
World Health Organization. The use of semaglutide medicines and risk of non-arteritic anterior ischemic optic neuropathy (NAION). 27 June 2025. https://www.who.int/news/item/27-06-2025-27-06-2025-semaglutide-medicines-naion
North American Neuro-Ophthalmology Society and American Academy of Ophthalmology. Consensus statement on GLP-1 receptor agonists and the risk of NAION. https://www.aao.org/education/clinical-statement/glucagon-like-peptide-1-receptor-agonists-risk-of-
Board Certified in Obesity Medicine and Family Medicine
This blog is for educational purposes only and does not constitute individual medical advice. Always consult your own physician before making changes to your health, medications, or treatment plan.
Doctor Rennie's Blog 