Semaglutide (Ozempic, Wegovy)

Serious harms

Semaglutide is prescribed for type 2 diabetes, for weight management and to lower cardiovascular and kidney risk ¹².

Condition	How often	Who is at risk	Source
Acute pancreatitis, sometimes fatal	0.3 against 0.2 per 100 patient-years on comparators in diabetes trials	Not specified	¹
Gallstones, cholecystitis	Adults 1.6% against 0.7% and 0.6% against 0.2%; 27 extra per 10,000 patient-years in 76 trials	Adolescents; weight-loss trials; higher doses; longer use	²³
Intestinal obstruction, ileus	Not known; for the drug class, 1 extra per 1223 treated for a year against SGLT2 inhibitors, none in semaglutide users	Use beyond 1.6 years	¹⁴⁵
Acute kidney injury, some needing haemodialysis	0.4 against 0.2 per 100 patient-years in weight trials	Vomiting, diarrhoea or dehydration; prior renal impairment; dose escalation	¹²
Pulmonary aspiration	Rare postmarketing reports	General anaesthesia or deep sedation	¹²
Diabetic retinopathy complications	8.2% against 5.2% with prior retinopathy; 0.7% against 0.4% without	Existing retinopathy	¹²
NAION, ischaemic damage to the optic nerve	Up to 1 in 10,000 users; about 1 extra per 10,000 person-years	Type 2 diabetes	⁶
Severe hypoglycaemia	1.5% against 0% with basal insulin over 30 weeks; 0.8% to 1.2% with a sulfonylurea	Insulin or sulfonylurea; prior bariatric surgery	¹²
Hip or pelvis fracture	Women 24 of 2448 against 5 of 2424; age 75 or more 17 of 703 against 4 of 663	Women; age 75 or more	²
Thyroid C-cell tumours	In mice and rats; human relevance not determined	Personal or family history of medullary thyroid carcinoma or MEN 2: contraindicated	¹²
Embryofetal loss and malformation	In rats, rabbits and monkeys at clinical exposures	Pregnancy; stopping at least 2 months before a planned one is advised	²

Gallbladder disease was more frequent than on placebo even after accounting for weight loss ². In 20 people, GLP-1 infusion suppressed meal-induced cholecystokinin, the gallbladder-contracting hormone, a mechanism the authors propose ⁷. Across 28 observational studies, GLP-1 receptor agonists were associated with residual gastric contents despite fasting (odds ratio 5.96), not with recorded aspiration (1.04) ⁸. In independent cohorts, NAION hazard ratios were 2.19 to 2.81 for semaglutide and 1.85 for the class, with onset a median 22.2 months after the first prescription in Denmark ^9101112; in a 37-million-person network the incidence rate ratio was 1.32 ¹³. The US labels of June 2026 do not mention NAION ¹².

Other pathways it affects

The gene for the receptor that semaglutide activates is expressed in the pancreas, heart, kidney, brain and several glands ¹⁸.

Its RNA is highest in tuft cells (46.1 nCPM), pancreatic islet cells (23.3), lacrimal and pancreatic acinar cells (19.0, 15.5), other brain neurons (10.8) and proximal tubule cells (5.7); the protein is not detected by antibody staining of tissues ¹⁸. In animals, semaglutide activated neurons in brain regions regulating food intake ².

Tissue	Measured in people
Stomach	Delayed emptying; after 12 weeks on 1.0 mg, 37% of a solid meal retained at 4 hours against none on placebo, in 20 women with polycystic ovary syndrome ¹²¹⁹
Brain	Lower calorie intake ²; in 48 adults with alcohol use disorder, fewer drinks per drinking day but not fewer drinking days ²⁰
Heart	Resting rate up 1 to 4 beats per minute; rises of 20 or more in 26% against 16% ²
Bone	With liraglutide, hip density 0.013 g/cm² lower than with exercise at similar weight loss, in a secondary analysis ²¹
Muscle	Median 28.3% of weight lost from muscle-based indices in 35 trials; objective physical function not reported ²²

What it is for and how it works

Semaglutide is a long-acting form of GLP-1, a hormone that raises insulin and lowers glucagon when blood glucose is high ¹²⁴.

The glucagon response to induced hypoglycaemia is preserved ¹.

In the body

Half of a dose remains in the body about a week later ¹.

Albumin binding slows renal clearance, and a position-8 modification stabilises the peptide against DPP-4 ¹. Slower gastric emptying may alter absorption of oral drugs; oral semaglutide raised levothyroxine exposure by 33% ².

Benefit against harm

The heart and kidney indications are limited to people with established cardiovascular disease, or with type 2 diabetes and kidney disease ¹².

Industry-funded results

Group	Benefit	Serious harm
SELECT: 17,604 with cardiovascular disease, BMI 27 or more, no diabetes; mean 3.3 years	Cardiovascular events 6.5% against 8.0%, 1 per 67; cardiovascular death not significantly lower ²⁵	Stopping for adverse events 16.6% against 8.2%, 1 per 12 ²⁵
FLOW: 3533 with type 2 diabetes and kidney disease; median 3.4 years	Kidney composite 18.7% against 23.2%, 1 per 23 ²⁶	Only serious and selected adverse events collected ¹
SUSTAIN-6: 3297 with type 2 diabetes at high cardiovascular risk; median 2.1 years	Cardiovascular events 6.6% against 8.9%, 1 per 45 ²⁷	Retinopathy complications 3.0% against 1.8%, 1 per 78; blindness 5 against 1 ²⁷
STEP 1: 1961 with obesity, no diabetes; 68 weeks	Weight −14.9% against −2.4% ²⁸	Serious adverse events 9.8% against 6.4% ²⁸

Without the medicine

In an independent randomised trial, 68 of 149 people on a programme based on total diet replacement reached diabetes remission at 12 months, against 6 of 149 controls ²⁹.

Thirty years after a 6-year diet and exercise programme for impaired glucose tolerance in Da Qing, cardiovascular events and deaths were fewer (hazard ratio 0.74 each) ³⁰.

How the recommendations were set

Approval was extended from type 2 diabetes in 2017 to weight management in 2021 and cardiovascular risk in 2024 ¹³¹³².

Stopping

Lost weight is regained after stopping: 9.9 kg in the first year after semaglutide or tirzepatide, reaching baseline by about 1.5 years in projections from 37 studies, only one longer than a year ³⁵.

A prescription is changed together with the prescriber.

References

Regulator
US Food and Drug Administration. OZEMPIC (semaglutide) injection, for subcutaneous use: full prescribing information US Food and Drug Administration; DailyMed, US National Library of Medicine, set id adec4fd2-6858-4c99-91d4-531f5f2a2d79, version 20, effective 1 June 2026, 2026.
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=adec4fd2-6858-4c99-91d4-531f5f2a2d79
Funding and finding
Funding
US Food and Drug Administration
Finding
Initial US approval 2017. Indications: glycaemic control in adults with type 2 diabetes; reduction of major adverse cardiovascular events in type 2 diabetes with established cardiovascular disease; reduction of sustained eGFR decline, end-stage kidney disease and cardiovascular death in type 2 diabetes with chronic kidney disease. Boxed warning: semaglutide causes dose- and duration-dependent thyroid C-cell adenomas and carcinomas in mice and rats at clinically relevant exposures; human relevance has not been determined; contraindicated with a personal or family history of medullary thyroid carcinoma or MEN 2; routine calcitonin or ultrasound monitoring is of uncertain value. Warnings: acute pancreatitis, including fatal and non-fatal haemorrhagic or necrotising pancreatitis; in glycaemic trials adjudicated pancreatitis in 7 semaglutide-treated patients (0.3 per 100 patient-years) against 3 on comparators (0.2). Diabetic retinopathy complications in the 2-year SUSTAIN 6 trial 3.0% against 1.8% on placebo, 8.2% against 5.2% with retinopathy at baseline and 0.7% against 0.4% without; the effect of long-term glycaemic control on retinopathy complications has not been studied. Hypoglycaemia with a sulfonylurea: severe in 0.8% and 1.2% on 0.5 and 1 mg; with basal insulin severe in 1.5% on 1 mg against 0% on placebo over 30 weeks. Postmarketing acute kidney injury, in some cases requiring haemodialysis, mostly after nausea, vomiting or diarrhoea with dehydration. Severe gastrointestinal reactions in 0.4% (0.5 mg) and 0.8% (1 mg) against 0% on placebo; not recommended in severe gastroparesis. Anaphylaxis and angio-oedema. Cholelithiasis 1.5% (0.5 mg) and 0.4% (1 mg) against 0% on placebo. Rare postmarketing pulmonary aspiration during general anaesthesia or deep sedation with residual gastric contents despite fasting; data are insufficient to say whether modified fasting or temporary discontinuation reduces retained gastric contents. Gastrointestinal reactions in placebo-controlled trials 32.7% and 36.4% against 15.3%, leading to discontinuation in 3.1% and 3.8% against 0.4%. Mean heart rate increase 2 to 3 beats per minute. Mean lipase rise 22% and amylase 13%. Postmarketing: necrotising pancreatitis sometimes resulting in death, ileus, intestinal obstruction, severe constipation including faecal impaction, cholecystitis, cholecystectomy, acute kidney injury, alopecia. Stop at least 2 months before a planned pregnancy; in rats, rabbits and monkeys embryofetal loss and structural abnormalities occurred at clinical exposures. Mechanism: glucose-dependent stimulation of insulin and lowering of glucagon secretion, delayed early postprandial gastric emptying; the mechanism of kidney risk reduction has not been established. Half-life about 1 week; present in the circulation about 5 weeks after the last dose. In FLOW, safety data collection was limited to serious adverse events and selected predefined categories.
Regulator
US Food and Drug Administration. WEGOVY (semaglutide) injection, for subcutaneous use; WEGOVY (semaglutide) tablets, for oral use: full prescribing information US Food and Drug Administration; DailyMed, US National Library of Medicine, set id ee06186f-2aa3-4990-a760-757579d8f77b, version 19, effective 18 June 2026, 2026.
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ee06186f-2aa3-4990-a760-757579d8f77b
Funding and finding
Funding
US Food and Drug Administration
Finding
Indications: reduction of major adverse cardiovascular events in adults with established cardiovascular disease and obesity or overweight; chronic weight management in adults with BMI of 30 kg/m2 or more, or 27 or more with a weight-related comorbidity, and in patients aged 12 years and older with obesity; non-cirrhotic MASH with F2 to F3 fibrosis under accelerated approval. Recent major changes: Suicidal Behavior and Ideation (5.10) removed 02/2026. Boxed warning for thyroid C-cell tumours as for Ozempic. Cholelithiasis 1.6% against 0.7% on placebo injection and cholecystitis 0.6% against 0.2% in adults; in adolescents cholelithiasis 3.8% and cholecystitis 0.8% against 0%; gallbladder disease exceeded placebo even after accounting for the degree of weight loss. Severe gastrointestinal reactions 4.1% against 0.9%; gastrointestinal reactions 73% against 47%, leading to permanent discontinuation in 4.3% against 0.7%. Adjudicated acute pancreatitis in 4 patients (0.2 per 100 patient-years) against 1 (under 0.1). Acute kidney injury 0.4 against 0.2 cases per 100 patient-years, more frequent with prior renal impairment and during titration. Hypotension 1.3% against 0.4% and syncope 0.8% against 0.2%. Appendicitis 10 (0.5%) against 2 (0.2%). Resting heart rate rose 1 to 4 beats per minute; maximum rises of 20 beats per minute or more at any visit in 26% against 16% of adults and 54% against 39% of adolescents. Hypoglycaemia below 54 mg/dL in type 2 diabetes 6.2% against 2.5%; in trials without diabetes hypoglycaemia was not systematically captured; in SELECT serious hypoglycaemia occurred in 2 of 87 patients with prior bariatric surgery on semaglutide against 0 of 97 on placebo. SELECT: 8803 patients exposed for a median 37.3 months and 8801 for 38.6 months; safety data collection was limited to serious adverse events, adverse events leading to discontinuation and adverse events of special interest; 16% against 8% stopped for an adverse event; hip and pelvis fractures in women 24 of 2448 (1%) against 5 of 2424 (0.2%) and at age 75 or more 17 of 703 (2.4%) against 4 of 663 (0.6%); urolithiasis 1.2% against 0.8%. MASH trial fractures 4.4% (2.6 per 100 patient-years) against 3.3% (2.0). The 7.2 mg dose caused dysaesthesia in 22% against 6% on 2.4 mg and 0.3% on placebo, unresolved during the trial in 18% of those affected. Weight-reduction Study 5 (STEP 4) randomised 803 of 902 patients after a 20-week run-in in which 99 (11%) stopped, 48 (5.3%) for adverse reactions; the label states its results may not reflect patients first starting the drug. Postmarketing: necrotising pancreatitis sometimes resulting in death, ileus, intestinal obstruction, faecal impaction, pulmonary aspiration during anaesthesia, acute kidney injury. Oral tablets raised levothyroxine exposure by 33%. Semaglutide lowers body weight with greater fat mass loss than lean mass loss. Discontinue when pregnancy is recognised and at least 2 months before a planned pregnancy.
Independent research
He L, Wang J, Ping F, Yang N, Huang J, Li Y, et al. Association of glucagon-like peptide-1 receptor agonist use with risk of gallbladder and biliary diseases: a systematic review and meta-analysis of randomized clinical trials JAMA Internal Medicine, 2022.
doi:10.1001/jamainternmed.2022.0338 PubMed 35344001
Funding and finding
Registration
PROSPERO CRD42021271599
Participants
103,371
Funding
Supported by grants from the National Natural Science Foundation of China, the Beijing Municipal Natural Science Foundation, the Chinese Academy of Medical Sciences and the Dongcheng District talent programme. The funders had no role in design, conduct, collection, analysis, interpretation, preparation, review or approval of the manuscript, or the decision to submit.
Finding
Randomisation to a GLP-1 receptor agonist increased gallbladder or biliary disease (relative risk 1.37, 95% CI 1.23 to 1.52), an absolute excess of 27 (17 to 38) events per 10,000 patients per year; cholelithiasis 1.27 (1.10 to 1.47), cholecystitis 1.36 (1.14 to 1.62), biliary disease 1.55 (1.08 to 2.22). The relative risk was 2.29 (1.64 to 3.18) in 13 weight-loss trials against 1.27 (1.14 to 1.43) in other trials, 1.56 (1.36 to 1.78) at higher against 0.99 (0.73 to 1.33) at lower doses, and 1.40 (1.26 to 1.56) with longer against 0.79 (0.48 to 1.31) with shorter use.
Regulator
European Medicines Agency. Wegovy (semaglutide): EPAR product information, Annex I summary of product characteristics European Medicines Agency, EPAR product information for Wegovy, PDF created 13 August 2026; first authorisation 6 January 2022, 2026.
https://www.ema.europa.eu/en/documents/product-information/wegovy-epar-product-information_en.pdf
Funding and finding
Funding
European Medicines Agency
Finding
Section 4.4 warns of pulmonary aspiration with general anaesthesia or deep sedation, dehydration from nausea, vomiting and diarrhoea that in rare cases deteriorates renal function, acute pancreatitis, and non-arteritic anterior ischaemic optic neuropathy (NAION): epidemiological data indicate an increased risk, no time interval after treatment start has been identified, sudden loss of vision should lead to ophthalmological examination and semaglutide should be stopped if NAION is confirmed. Not recommended below an eGFR of 30 mL/min/1.73 m2. Women of childbearing potential are recommended to use contraception; semaglutide should not be used in pregnancy or breast-feeding and should be stopped at least 2 months before a planned pregnancy. Table 3 frequencies: NAION very rare (under 1 in 10,000); intestinal obstruction, covering ileus and small intestinal obstruction, frequency not known, from post-marketing reports; acute pancreatitis and delayed gastric emptying uncommon; cholelithiasis, hair loss, hypoglycaemia and diabetic retinopathy in type 2 diabetes common; anaphylaxis rare. Adjudicated acute pancreatitis 0.2% against under 0.1% on placebo in phase 3a trials and 0.2% against 0.3% in SELECT. Cholelithiasis 1.6% with cholecystitis 0.6%, against 1.1% and 0.3%. Pulse rise of 10 beats per minute or more at any time in 67.0% against 50.1%. Epidemiological studies suggest about a two-fold relative risk of NAION in type 2 diabetes, about one additional case per 10,000 person-years. Cholelithiasis in adolescents 3.8% against 0%. Patients with gastroparesis may have more serious gastrointestinal effects.
Independent research
Faillie JL, Yin H, Yu OHY, Herrero A, Altwegg R, Renoux C, et al. Incretin-based drugs and risk of intestinal obstruction among patients with type 2 diabetes Clinical Pharmacology and Therapeutics, 2022.
doi:10.1002/cpt.2430 PubMed 34587280
Funding and finding
Follow-up
2013 to 2019
Funding
This study was funded by a Foundation Scheme grant (FDN-143328) from the Canadian Institutes of Health Research. No statement on funder role was given.
Finding
Intestinal obstruction requiring hospitalisation occurred at 1.9 per 1000 person-years with GLP-1 receptor agonists against 1.1 with SGLT2 inhibitors (hazard ratio 1.69, 95% CI 1.04 to 2.74), highest after 1.6 years of use (3.48, 1.79 to 6.79); number needed to harm after 1 year 1223. DPP-4 inhibitors: 2.7 against 1.0 per 1000 person-years (2.59, 1.52 to 4.42). Semaglutide users generated no events; with the outcome restricted to the diagnostic codes most related to intestinal obstruction, GLP-1 receptor agonists were no longer associated with it.
Regulator
European Medicines Agency, Pharmacovigilance Risk Assessment Committee. PRAC concludes eye condition NAION is a very rare side effect of semaglutide medicines Ozempic, Rybelsus and Wegovy European Medicines Agency news, 6 June 2025, revised 13 June 2025, 2025.
https://www.ema.europa.eu/en/news/prac-concludes-eye-condition-naion-very-rare-side-effect-semaglutide-medicines-ozempic-rybelsus-wegovy
Funding and finding
Funding
European Medicines Agency
Finding
After reviewing non-clinical studies, clinical trials, post-marketing surveillance and the literature, PRAC concluded that non-arteritic anterior ischaemic optic neuropathy (NAION) is a very rare side effect of semaglutide, affecting up to 1 in 10,000 people taking it. Several large epidemiological studies suggest that semaglutide exposure in adults with type 2 diabetes is associated with an approximately two-fold increase in NAION risk against people not taking it, about one additional case per 10,000 person-years of treatment; clinical trial data also point to a slightly higher risk than placebo. Product information is to list NAION as very rare; patients with sudden loss of vision or rapidly worsening eyesight should contact their doctor, and semaglutide should be stopped if NAION is confirmed. The review was a post-authorisation measure resulting from a periodic safety update report assessment.
Independent research
Rehfeld JF, Knop FK, Asmar A, Madsbad S, Holst JJ, Asmar M. Cholecystokinin secretion is suppressed by glucagon-like peptide-1: clue to the mechanism of the adverse gallbladder events of GLP-1-derived drugs Scandinavian Journal of Gastroenterology, 2018.
doi:10.1080/00365521.2018.1530297 PubMed 30449207
Funding and finding
Participants
20
Follow-up
240-minute infusion during and after a meal
Funding
This study was supported by the Danish Biotechnology Center for Cellular Communication.
Finding
Plasma cholecystokinin rose during the meal with saline, whereas GLP-1 infusion significantly suppressed postprandial cholecystokinin secretion in both healthy subjects and patients with diabetes. The authors propose that suppression of cholecystokinin attenuates gallbladder contraction and explains the gallbladder adverse events of GLP-1-derived drugs.
Independent research
Elkin J, Rele S, Sumithran P, Hii M, Thuraisingam S, Spelman T, et al. Association between glucagon-like peptide-1 receptor agonist use and peri-operative pulmonary aspiration: a systematic review and meta-analysis Anaesthesia, 2025.
doi:10.1111/anae.16601 PubMed 40230298
Funding and finding
Registration
PROSPERO CRD42024532229
Participants
466,373
Funding
The first author was supported by an Australian Government Research Training Program Scholarship; open access publishing was facilitated by the University of Melbourne. No statement on funder role was given.
Finding
In 9 studies of 185,414 patients with 471 aspiration events, GLP-1 receptor agonist exposure was not associated with pulmonary aspiration (odds ratio 1.04, 95% CI 0.87 to 1.25; low certainty). In 18 studies of 165,522 patients with 3831 cases, exposure was associated with residual gastric contents despite appropriate fasting (5.96, 3.96 to 8.98; low certainty). Withholding at least one dose was associated with lower odds of residual gastric contents in 5 studies of 1706 patients (0.51, 0.33 to 0.81; very low certainty).
Independent research
Simonsen E, Lund LC, Ernst MT, Hjellvik V, Hegedüs L, Hamann S, et al. Use of semaglutide and risk of non-arteritic anterior ischemic optic neuropathy: a Danish-Norwegian cohort study Diabetes, Obesity and Metabolism, 2025.
doi:10.1111/dom.16316 PubMed 40098249
Funding and finding
Follow-up
Denmark 2018 to 2024, Norway 2018 to 2022
Funding
This study was funded by the Independent Research Fund Denmark (2025-00052B).
Finding
There were 32 NAION events among semaglutide users. Unadjusted incidence was 2.19 per 10,000 person-years on semaglutide against 1.18 on SGLT2 inhibitors in Denmark and 2.90 against 0.92 in Norway. Pooled adjusted hazard ratio 2.81 (95% CI 1.67 to 4.75); incidence rate difference +1.41 (0.53 to 2.29) per 10,000 person-years; per-protocol hazard ratio 6.35 (2.88 to 14.0). Self-controlled symmetry ratios were 1.14 (0.55 to 2.36) in Denmark and 2.67 (0.91 to 8.99) in Norway. Analyses for semaglutide in obesity were inconclusive.
Independent research
Grauslund J, Taha AA, Molander LD, Kawasaki R, Möller S, Højlund K, et al. Once-weekly semaglutide doubles the five-year risk of nonarteritic anterior ischemic optic neuropathy in a Danish cohort of 424,152 persons with type 2 diabetes International Journal of Retina and Vitreous, 2024.
doi:10.1186/s40942-024-00620-x PubMed 39696569
Funding and finding
Participants
424,152
Follow-up
1,915,120 person-years, 2018 to 2024
Funding
Funding: not applicable.
Finding
218 persons developed NAION, 67 of them exposed to semaglutide. Incidence 0.228 per 1000 person-years with semaglutide exposure against 0.093 without; adjusted hazard ratio 2.19 (95% CI 1.54 to 3.12). Median time from first prescription to NAION 22.2 months (IQR 10.2 to 37.8). Smoking, blood pressure and BMI were not available for adjustment, and ophthalmic examinations were not accessible.
Independent research
Heberer K, Bress AP, Cogill S, Maldonado AI, Kim SH, Nallamshetty S, et al. New-onset nonarteritic anterior ischemic optic neuropathy and initiators of semaglutide in US veterans with type 2 diabetes JAMA Ophthalmology, 2026.
doi:10.1001/jamaophthalmol.2025.6262 PubMed 41678180
Funding and finding
Participants
102,361
Follow-up
median 2.1 years, maximum 7.5 years; March 2018 to July 2025
Funding
The VA authors conducted the study with support from the VA Cooperative Studies Program (CSP#2012); one author is partially funded by NIH/NIDDK. The VA Cooperative Studies Program was involved in design and conduct, data handling, analysis and interpretation, manuscript preparation and the decision to submit.
Finding
173 incident NAION events occurred. Incidence was 123 per 100,000 person-years among semaglutide initiators against 67 per 100,000 among SGLT2 inhibitor initiators; hazard ratio 2.33 (95% CI 1.54 to 3.54). Overlap-weighted incidence 0.29% against 0.13%, an average treatment effect of 0.16 percentage points over a median 2.1 years.
Independent research
Tesfaye H, Paik JM, Wexler DJ, Hathaway JT, Yu EW, Freedman A, et al. GLP-1RA and the risk of non-arteritic anterior ischaemic optic neuropathy in patients with type 2 diabetes: a population-based study Diabetes, Obesity and Metabolism, 2026.
doi:10.1111/dom.70200 PubMed 41104517
Funding and finding
Participants
965,824
Follow-up
median 6.7 months on treatment; January 2016 to August 2024
Funding
Funded by a research grant from the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK138036); authors were also supported by PCORI, FDA and NIH grants. The funders had no role in design, conduct, collection, analysis, interpretation, preparation, review or approval of the manuscript, or the decision to submit.
Finding
Presumed NAION was more frequent after GLP-1 receptor agonist than SGLT2 inhibitor initiation: hazard ratio 1.85 (95% CI 1.51 to 2.27); rate difference 0.29 (0.19 to 0.39) per 1000 person-years. A meta-analysis of the authors' semaglutide analysis with published results gave a hazard ratio of 2.78 (1.39 to 5.56).
Independent research
Cai CX, Hribar M, Baxter S, Goetz K, Swaminathan SS, Flowers A, et al. Semaglutide and nonarteritic anterior ischemic optic neuropathy JAMA Ophthalmology, 2025.
doi:10.1001/jamaophthalmol.2024.6555 PubMed 39976940
Funding and finding
Participants
37,100,000
Follow-up
December 2017 to December 2023
Funding
Supported in part by NIH and NEI grants to individual authors and by Department of Veterans Affairs informatics resources; the funders had no role in design, conduct, collection, analysis, interpretation, preparation, review or approval of the manuscript, or the decision to submit.
Finding
NAION incidence was 14.5 per 100,000 person-years among semaglutide users. With a sensitive NAION definition, hazard ratios against empagliflozin, sitagliptin and glipizide were 1.44 (95% CI 0.78 to 2.68), 1.30 (0.56 to 3.01) and 1.23 (0.66 to 2.28); with a specific definition, 2.27 (1.16 to 4.46) against empagliflozin. The self-controlled case series gave an incidence rate ratio of 1.32 (1.14 to 1.54). The authors describe a modest increase, smaller than previously reported; cup-to-disc ratio was not available.
Independent research
Bezin J, Gouverneur A, Pénichon M, Mathieu C, Garrel R, Hillaire-Buys D, et al. GLP-1 receptor agonists and the risk of thyroid cancer Diabetes Care, 2023.
doi:10.2337/dc22-1148 PubMed 36356111
Funding and finding
Participants
47,746
Follow-up
exposure measured over 6 years before a 6-month lag; cancers identified 2014 to 2018
Funding
This work was supported by the French Medicines Agency (Agence Nationale de Sécurité du Médicament et des Produits de Santé, ANSM, grant 2019S015) in the context of a partnership with the Health Product Epidemiology Scientific Interest Group (EPI-PHARE), as part of the DRUGS-SAFER research programme. The French Medicines Agency played no role in the study design or conduct or results interpretation or discussion.
Finding
Use of GLP-1 receptor agonists for 1 to 3 years was associated with increased risk of all thyroid cancer (adjusted hazard ratio 1.58, 95% CI 1.27 to 1.95) and medullary thyroid cancer (1.78, 1.04 to 3.05). This study prompted the EMA signal assessment.
Independent research
Pasternak B, Wintzell V, Hviid A, Eliasson B, Gudbjörnsdottir S, Jonasson C, et al. Glucagon-like peptide 1 receptor agonist use and risk of thyroid cancer: Scandinavian cohort study BMJ, 2024.
doi:10.1136/bmj-2023-078225 PubMed 38683947
Funding and finding
Participants
437,077
Follow-up
mean 3.9 years (SD 3.5) on GLP-1 receptor agonists and 5.4 years (SD 3.5) on DPP-4 inhibitors; 2007 to 2021
Funding
Supported by the Swedish Cancer Society and the Swedish Research Council; individual authors by Karolinska Institutet, the Novo Nordisk Foundation, the Lundbeck Foundation, the Independent Research Foundation Denmark, Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse and the Danish Cancer Society. The funding sources had no role in design, conduct, collection, analysis, interpretation, preparation, review or approval of the manuscript, or the decision to submit.
Finding
Thyroid cancer developed in 76 of 145,410 GLP-1 receptor agonist users (1.33 per 10,000 person-years) and 184 of 291,667 DPP-4 inhibitor users (1.46): hazard ratio 0.93 (95% CI 0.66 to 1.31), rate difference -0.13 (-0.61 to 0.36) per 10,000 person-years; medullary thyroid cancer 1.19 (0.37 to 3.86); against SGLT2 inhibitors 1.16 (0.65 to 2.05). The upper confidence limit excludes more than a 31% relative increase over a mean 3.9 years.
Regulator
European Medicines Agency, Pharmacovigilance Risk Assessment Committee. Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC) 23-26 October 2023: GLP-1 receptor agonists, available evidence not supporting link with thyroid cancer European Medicines Agency news, 27 October 2023, 2023.
https://www.ema.europa.eu/en/news/meeting-highlights-pharmacovigilance-risk-assessment-committee-prac-23-26-october-2023
Funding and finding
Funding
European Medicines Agency
Finding
PRAC concluded that available evidence does not support a causal association between exenatide, liraglutide, dulaglutide, semaglutide or lixisenatide and thyroid cancer, and that no product information update is warranted. The signal assessment began after publication of Bezin et al. (Diabetes Care 2022); the committee reviewed that study, Alves 2012, Hu 2022 and Bea 2023, and cumulative non-clinical, clinical and post-marketing data submitted by the marketing authorisation holders, who are to keep monitoring and report new evidence in periodic safety update reports.
Industry-funded
Vilsbøll T, Arun Kumar D, Aiello LP, Rönnbäck C, Stellfeld M, Larsen LM. Non-arteritic anterior ischaemic optic neuropathy incidence in placebo-controlled clinical trials of liraglutide or semaglutide British Journal of Ophthalmology, 2026.
doi:10.1136/bjo-2025-328729 PubMed 42049287
Funding and finding
Participants
96,829
Follow-up
205,777 participant-years of observation
Funding
This study was funded by Novo Nordisk A/S. Representatives of Novo Nordisk were involved in the design and conduct of the trial, data collection, data management, data analysis, data interpretation and the preparation, review and approval of the manuscript; medical writing support was funded by Novo Nordisk A/S.
Finding
Three confirmed NAION cases occurred in three treated participants (about 3 per 100,000 participant-years of observation), all on semaglutide, and five in four placebo participants (about 6 per 100,000); Fisher's exact P = 0.12; all ophthalmologist-confirmed cases had one or more risk factors such as age over 50, obesity, smoking, dyslipidaemia or hypertension. Cases were identified only when investigators named NAION or narratives matched search terms, and the authors state that the trials were not powered to detect NAION. The authors conclude that the trial data do not suggest a relationship between GLP-1 receptor agonist use and NAION.
Textbook or database
Karlsson M, Zhang C, Méar L, Zhong W, Digre A, Katona B, et al. A single-cell type transcriptomics map of human tissues Science Advances, 2021.
doi:10.1126/sciadv.abh2169 PubMed 34321199
Funding and finding
Funding
Main funding was provided by the Knut and Alice Wallenberg Foundation and the Erling Persson Foundation; computation was enabled by the Swedish National Infrastructure for Computing, partially funded by the Swedish Research Council.
Finding
Human Protein Atlas entry for GLP1R (ENSG00000112164), read through proteinatlas.org on 2026-10-22. Tissue RNA: tissue enhanced in pancreas (8.6 nTPM) and heart muscle (2.6 nTPM), detected in some tissues; enriched cell types listed for heart muscle cardiomyocytes, eccrine sweat gland cells and testicular spermatids. Single-cell RNA, cell type enhanced (nCPM): tuft cells 46.1, pancreatic islet cells 23.3, lacrimal acinar cells 19.0, pancreatic acinar cells 15.5, other brain neurons 10.8, neuroendocrine cells 8.0, proximal tubule cells 5.7, salivary acinar cells 4.8. Brain expression cluster: hypothalamus, neuropeptide signalling. Not detected in immune cells. Antibody-based protein tissue staining: not detected.
Independent research
Jensterle M, Ferjan S, Ležaič L, Sočan A, Goričar K, Zaletel K, et al. Semaglutide delays 4-hour gastric emptying in women with polycystic ovary syndrome and obesity Diabetes, Obesity and Metabolism, 2023.
doi:10.1111/dom.14944 PubMed 36511825
Funding and finding
Participants
20
Follow-up
12 weeks
Funding
This research did not receive any specific grant from funding agencies; the study was supported by Slovenian Research Agency programme grants P3-0298 and P3-0343, and planning, conduct, interpretation and writing were completely independent of the funder.
Finding
By technetium scintigraphy of a solid meal, the reference method, semaglutide retained 37% of the meal in the stomach at 4 hours against no retention on placebo (P = 0.002); half-emptying time was 171 against 118 minutes. Retention rose from baseline by 3.5% at 1 hour, 25.5% at 2 hours, 38.0% at 3 hours and 30.0% at 4 hours. The authors note that earlier semaglutide studies using paracetamol absorption reported no delay or delay only in the first hour.
Independent research
Hendershot CS, Bremmer MP, Paladino MB, Kostantinis G, Gilmore TA, Sullivan NR, et al. Once-weekly semaglutide in adults with alcohol use disorder: a randomized clinical trial JAMA Psychiatry, 2025.
doi:10.1001/jamapsychiatry.2024.4789 PubMed 39937469
Funding and finding
Registration
NCT05520775
Participants
48
Follow-up
9 weeks of treatment, assessment at week 10
Funding
Supported by National Institute on Alcohol Abuse and Alcoholism grant R21AA026931 and NCATS award UM1TR004406; investigator-initiated. The funders had no role in design, conduct, collection, analysis, interpretation, preparation, review or approval of the manuscript, or the decision to submit.
Finding
Low-dose semaglutide reduced grams of alcohol consumed in a laboratory self-administration task (beta -0.48, 95% CI -0.85 to -0.11) and peak breath alcohol (-0.46, -0.87 to -0.06). It did not change drinks per calendar day or number of drinking days, but reduced drinks per drinking day (-0.41, -0.73 to -0.09) and weekly craving (-0.39, -0.73 to -0.06). Weight fell 5.05% against +0.18%. No serious adverse events or treatment-related discontinuations were recorded.
Independent research
Jensen SBK, Sørensen V, Sandsdal RM, Lehmann EW, Lundgren JR, Juhl CR, et al. Bone health after exercise alone, GLP-1 receptor agonist treatment, or combination treatment: a secondary analysis of a randomized clinical trial JAMA Network Open, 2024.
doi:10.1001/jamanetworkopen.2024.16775 PubMed 38916894
Funding and finding
Registration
EudraCT 2015-005585-32
Participants
195
Follow-up
8-week low-calorie diet, then 52 weeks
Funding
Supported by the Novo Nordisk Foundation Center for Basic Metabolic Research and the Novo Nordisk Foundation Tripartite Immunometabolism grant, Helsefonden, the University of Copenhagen and the Danish Diabetes Academy. The sponsors had no role in design, conduct, collection, analysis, interpretation, preparation, review or approval of the manuscript, or the decision to submit.
In-kind support
Novo Nordisk A/S supplied Saxenda (liraglutide) and placebo pens; Cambridge Weight Plan supplied meal replacement products.
Finding
Total weight loss was 7.03 kg on placebo, 11.19 kg with exercise, 13.74 kg with liraglutide and 16.88 kg with the combination. Against exercise alone, liraglutide alone lowered bone mineral density at the hip (-0.013 g/cm2, 95% CI -0.024 to -0.001) and lumbar spine (-0.016 g/cm2, -0.032 to -0.001) despite similar weight loss; the combination left hip and spine density unchanged against placebo. The drug was liraglutide, not semaglutide.
Independent research
Batsis JA, Gavras A, Gross DC, Cheever CR, Da Silva BR, Meira Filho LF, et al. Effect of incretin-based and nonpharmacologic weight loss on body composition: a systematic review Annals of Internal Medicine, 2026.
doi:10.7326/ANNALS-25-00478 PubMed 41996180
Funding and finding
Registration
Open Science Framework doi 10.17605/OSF.IO/S3A5E
Funding
Primary funding source: none, as stated in the structured abstract. Disclosure forms are available online and were not read.
Finding
Within incretin groups the median share of total weight loss from muscle-based indices was 28.3% (IQR 15.9% to 39.9%), with 65% of interventions exceeding a prespecified benchmark of about 25%; by BIA or DXA about 29% (16.6% to 43.1%), 67% above benchmark; by CT or MRI about 25.3% (16.7% to 27.2%), two thirds above a 15% benchmark. Among 13 lifestyle or placebo comparator groups, with median weight change of -2.5%, 38% exceeded the benchmark. No study reported objective physical function. 42.9% of studies were at low risk of bias and 28.6% prespecified body composition as a primary outcome; heterogeneity precluded meta-analysis.
Industry-funded
Friedrichsen M, Breitschaft A, Tadayon S, Wizert A, Skovgaard D. The effect of semaglutide 2.4 mg once weekly on energy intake, appetite, control of eating, and gastric emptying in adults with obesity Diabetes, Obesity and Metabolism, 2021.
doi:10.1111/dom.14280 PubMed 33269530
Funding and finding
Participants
72
Follow-up
20 weeks
Funding
This study was funded by Novo Nordisk A/S; medical writing was funded by Novo Nordisk A/S. Four authors are Novo Nordisk employees; the fifth is employed by Parexel, paid by Novo Nordisk to assist in conducting the study; the sponsor generated the randomisation schedule.
Finding
Ad libitum lunch energy intake was 35% lower on semaglutide (1736 against 2676 kJ; difference -940 kJ). Hunger and prospective food consumption fell and fullness and satiety rose; food cravings were fewer and weaker. Weight fell 9.9% against 0.4%. Gastric emptying measured indirectly by paracetamol absorption after a standardised breakfast: AUC over 0 to 5 h was 8% higher on semaglutide (P = 0.005), not significant after correction for body weight, with no effect on 0 to 1 h AUC; the authors report no evidence of delayed gastric emptying at week 20.
Textbook or database
UniProt Consortium. UniProt: the Universal Protein Knowledgebase in 2025 Nucleic Acids Research, 2025.
doi:10.1093/nar/gkae1010 PubMed 39552041
Funding and finding
Funding
National Human Genome Research Institute (NHGRI) [HG002273]; Office of the Director, NIH OD [U24HG007822]; National Institute of Allergy and Infectious Diseases (NIAID); National Institute on Aging (NIA); National Institute of General Medical Sciences (NIGMS) [R35GM141873]; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Eye Institute (NEI); National Cancer Institute (NCI); National Heart, Lung, and Blood Institute (NHLBI); Biotechnology and Biological Sciences Research Council (BBSRC) [BB/T015608/1]; National Science Foundation's Directorate for Biological Sciences [BB/X002179/1]; Open Targets; Horizon 2020 - Research and Innovation Framework Programme [825575]; State Secretariat for Education, Research and Innovation (SERI); European Molecular Biology Laboratory (EMBL) Australia. Funding for open access charge: National Institutes of Health.
Finding
Reviewed human UniProtKB entries, release 2026_03, read through rest.uniprot.org on 2026-10-21. INS (P01308): expressed by pancreatic beta cells; decreases blood glucose. GCG (P01275): glucagon is secreted by A cells of the islets, raises plasma glucose and activates GCGR, which couples to Gs and raises cAMP; glucagon release is stimulated by hypoglycaemia and inhibited by hyperglycaemia, insulin and somatostatin; in intestinal L cells PCSK1 releases GLP-1, a potent stimulator of glucose-dependent insulin release that suppresses plasma glucagon. INSR (P06213): receptor tyrosine kinase; PI3K generates PIP3, a lipid second messenger that activates PDPK1 and then AKT; the net effect is translocation of GLUT4 from cytoplasmic vesicles to the cell membrane. GCGR (P47871), GLP1R (P43220) and TSHR (P16473): G-protein-coupled receptors that activate adenylyl cyclase; TSHR couples to Gs, and PKA phosphorylates thyroid peroxidase and the sodium/iodide symporter. ADRB1 (P08588): couples to Gs to activate adenylyl cyclase and stimulates cardiomyocyte contraction. GHSR (Q92847): ghrelin receptor coupled to Gq that modulates phospholipase C and mediates production of diacylglycerol and inositol 1,4,5-trisphosphate. PLCB1 (Q9NQ66): hydrolyses phosphatidylinositol 4,5-bisphosphate into diacylglycerol and inositol 1,4,5-trisphosphate and signals downstream of G-protein-coupled receptors; PLCB3 (Q01970) is activated by G(q) and G(11) G alpha proteins downstream of such receptors. ITPR1 (Q14643): inositol 1,4,5-trisphosphate-gated channel that releases calcium from the endoplasmic reticulum. THRB (P10828): nuclear hormone receptor and transcriptional repressor or activator with high affinity for T3 and T4. LEPR (P48357): type I cytokine receptor that signals through JAK2 and STAT3. LEP (P41159): adipose tissue is the main source; in the hypothalamus it decreases food intake and increases energy consumption; leptin deficiency causes severe hyperphagia and intractable obesity from an early age, and leptin receptor deficiency hyperphagia and severe obesity from an early age with normal serum leptin. GHRL (Q9UBU3): highest expression in stomach; ghrelin stimulates appetite and growth hormone release, and octanoylation, by GOAT/MBOAT4 (Q96T53), is essential for activation of GHSR. Thyroid pathway entries: SLC5A5 (Q92911) moves iodide into the thyroid with 2 Na+, is inhibited by perchlorate and up-regulated by thyrotropin; TPO (P07202), with haem b and H2O2 from DUOX2 (Q9NRD8), iodinates thyroglobulin tyrosines and couples two diiodotyrosines to thyroxine, leaving dehydroalanine; TG (P01266) is iodinated and coupled in the follicle lumen and cleaved by cathepsins B, L and K in the lumen and after endocytosis; DIO1 (P49895) and DIO2 (Q92813) convert T4 to T3 by outer-ring deiodination; DIO3 (P55073) converts T3 to 3,3'-diiodothyronine and T4 to reverse T3 by inner-ring deiodination.
Industry-funded
Lincoff AM, Brown-Frandsen K, Colhoun HM, Deanfield J, Emerson SS, Esbjerg S, et al. Semaglutide and cardiovascular outcomes in obesity without diabetes New England Journal of Medicine, 2023.
doi:10.1056/NEJMoa2307563 PubMed 37952131
Funding and finding
Registration
NCT03574597
Participants
17,604
Follow-up
mean 39.8 months (SD 9.4); mean exposure 34.2 months
Funding
Supported by Novo Nordisk. The protocol was designed by the sponsor and the academic steering committee.
Finding
Death from cardiovascular causes, non-fatal myocardial infarction or non-fatal stroke occurred in 569 of 8803 (6.5%) on semaglutide 2.4 mg weekly against 701 of 8801 (8.0%) on placebo (hazard ratio 0.80, 95% CI 0.72 to 0.90), an absolute difference of 1.5 percentage points over a mean 39.8 months. Cardiovascular death, the first confirmatory secondary end point, 223 (2.5%) against 262 (3.0%) (0.85, 0.71 to 1.01, P = 0.07), so the hierarchy stopped; death from any cause 375 (4.3%) against 458 (5.2%) (0.81, 0.71 to 0.93) was not formally tested. Non-fatal myocardial infarction 234 (2.7%) against 322 (3.7%); non-fatal stroke 154 (1.7%) against 165 (1.9%) (0.93, 0.74 to 1.15). Weight change to week 104 was -9.39% against -0.88%. Adverse events leading to permanent discontinuation 1461 (16.6%) against 718 (8.2%), gastrointestinal 880 (10.0%) against 172 (2.0%); serious adverse events 2941 (33.4%) against 3204 (36.4%); gallbladder disorders 246 (2.8%) against 203 (2.3%) (P = 0.04); adjudicated acute pancreatitis 17 against 24; acute kidney failure 171 (1.9%) against 200 (2.3%). The trial collected safety data in a targeted manner: only serious adverse events, adverse events leading to discontinuation and prespecified adverse events of special interest were systematically recorded. Permanent premature discontinuation of the trial drug 26.7% against 23.6%. Only patients with established cardiovascular disease were included, so primary prevention was not studied; 27.7% of participants were women and 3.8% Black.
Industry-funded
Perkovic V, Tuttle KR, Rossing P, Mahaffey KW, Mann JFE, Bakris G, et al. Effects of semaglutide on chronic kidney disease in patients with type 2 diabetes New England Journal of Medicine, 2024.
doi:10.1056/NEJMoa2403347 PubMed 38785209
Funding and finding
Registration
NCT03819153
Participants
3,533
Follow-up
median 3.4 years; stopped early after a prespecified interim analysis
Funding
Supported by Novo Nordisk. The methods section describing the sponsor's role is behind the publisher's access wall in the archived copy and was not read.
Finding
The composite of kidney failure, at least 50% reduction in eGFR, or death from kidney-related or cardiovascular causes occurred in 331 of 1767 on semaglutide 1.0 mg weekly against 410 of 1766 on placebo (hazard ratio 0.76, 95% CI 0.66 to 0.88), 18.7% against 23.2%, an absolute difference of 4.5 percentage points over a median 3.4 years. Kidney-specific components 0.79 (0.66 to 0.94); cardiovascular death 0.71 (0.56 to 0.89); major cardiovascular events 0.82 (0.68 to 0.98); death from any cause 0.80 (0.67 to 0.95). The mean annual eGFR decline was 1.16 mL/min/1.73 m2 less steep. Serious adverse events 49.6% against 53.8%.
Industry-funded
Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes New England Journal of Medicine, 2016.
doi:10.1056/NEJMoa1607141 PubMed 27633186
Funding and finding
Registration
NCT01720446
Participants
3,297
Follow-up
median observation 2.1 years; planned 104 weeks of treatment and 5 weeks of follow-up
Funding
Funded by Novo Nordisk. The sponsor designed the study and performed site monitoring, data collection and data analysis; a working group including the first and last authors wrote the first draft; editorial support was funded by the sponsor and provided by medical writers from AXON Communications.
Finding
Pre-approval non-inferiority safety trial with a margin of 1.8; superiority testing was not prespecified. Cardiovascular death, non-fatal myocardial infarction or non-fatal stroke occurred in 108 of 1648 (6.6%) on semaglutide 0.5 or 1.0 mg weekly against 146 of 1649 (8.9%) on placebo (hazard ratio 0.74, 95% CI 0.58 to 0.95); the authors report a number needed to treat of 45 over 24 months. Non-fatal stroke 27 (1.6%) against 44 (2.7%) (0.61, 0.38 to 0.99); non-fatal myocardial infarction 47 (2.9%) against 64 (3.9%) (0.74, 0.51 to 1.08); cardiovascular death 44 (2.7%) against 46 (2.8%) (0.98, 0.65 to 1.48). Diabetic retinopathy complications 50 (3.0%) against 29 (1.8%) (1.76, 1.11 to 2.78), appearing early: photocoagulation 38 against 20, intravitreal agent 16 against 13, vitreous haemorrhage 16 against 7, diabetes-related blindness 5 against 1; 42 of the 50 had retinopathy at baseline. New or worsening nephropathy 62 (3.8%) against 100 (6.1%) (0.64, 0.46 to 0.88). Pulse 2.0 and 2.5 beats per minute higher on 0.5 and 1.0 mg. Acute pancreatitis 9 against 12, gallbladder disorders 58 against 61, pancreatic cancer 1 against 4; no medullary thyroid carcinoma was confirmed. Discontinuation because of adverse events, mainly gastrointestinal, was more frequent on semaglutide; serious adverse events were fewer. More placebo patients received additional antihypertensive, lipid-lowering and glucose-lowering drugs, insulin more than twice as often.
Industry-funded
Wilding JPH, Batterham RL, Calanna S, Davies M, Van Gaal LF, Lingvay I, et al. Once-weekly semaglutide in adults with overweight or obesity New England Journal of Medicine, 2021.
doi:10.1056/NEJMoa2032183 PubMed 33567185
Funding and finding
Registration
NCT03548935
Participants
1,961
Follow-up
68 weeks of treatment and 7 weeks off treatment
Funding
Supported by Novo Nordisk. The sponsor designed the trial and oversaw its conduct; investigators collected data and the sponsor undertook site monitoring, data collation and analysis; a sponsor-funded medical writer assisted with drafting.
Finding
With lifestyle counselling every 4 weeks, weight changed by -14.9% on semaglutide 2.4 mg weekly against -2.4% on placebo (difference -12.4 percentage points, 95% CI -13.4 to -11.5), -15.3 kg against -2.6 kg. Weight loss of 15% or more in 612 (50.5%) against 28 (4.9%) of those with week-68 data. Serious adverse events 128 (9.8%) against 42 (6.4%), the difference driven by serious gastrointestinal (1.4% against 0%) and hepatobiliary disorders (1.3% against 0.2%). Discontinuation for adverse events 92 (7.0%) against 20 (3.1%), for gastrointestinal events 59 (4.5%) against 5 (0.8%). Gastrointestinal disorders 74.2% against 47.9%. Gallbladder-related disorders 34 (2.6%) against 8 (1.2%), cholelithiasis 23 (1.8%) against 4 (0.6%). Mild acute pancreatitis in 3 on semaglutide, 2 with gallstones, against none. In a DXA subgroup of 140 participants, total lean body mass fell in kilograms while the lean proportion of body mass rose; the numbers are in a supplementary table. Persons with diabetes were excluded.
Independent research
Lean ME, Leslie WS, Barnes AC, Brosnahan N, Thom G, McCombie L, et al. Primary care-led weight management for remission of type 2 diabetes (DiRECT): an open-label, cluster-randomised trial Lancet, 2018.
doi:10.1016/S0140-6736(17)33102-1 PubMed 29221645
Funding and finding
Registration
ISRCTN03267836
Participants
306
Follow-up
12 months
Funding
Diabetes UK. The ISRCTN registry entry for ISRCTN03267836 names Diabetes UK as funder and Cambridge Weight Plan (UK) as a provider of product and training support, with NHS Greater Glasgow and Clyde as sponsor.
In-kind support
Product and training support from Cambridge Weight Plan (UK), as recorded in the ISRCTN registry entry.
Finding
Practices were randomised to a weight management programme comprising withdrawal of antidiabetic and antihypertensive drugs, total diet replacement at 825 to 853 kcal/day for 3 to 5 months, stepped food reintroduction over 2 to 8 weeks and structured support for weight loss maintenance, or to best-practice care by guidelines. At 12 months, weight loss of 15 kg or more was recorded in 36 of 149 intervention participants (24%) and none of the control participants (p < 0.0001). Remission of diabetes, defined as HbA1c below 6.5% after at least 2 months off all antidiabetic medication, was achieved by 68 of 149 (46%) against 6 of 149 (4%), odds ratio 19.7 (95% CI 7.8 to 49.8, p < 0.0001). Remission varied with weight loss across the whole study population: none of 76 who gained weight, 6 of 89 (7%) who stayed within 5 kg of baseline, 19 of 56 (34%) losing 5 to 10 kg, 16 of 28 (57%) losing 10 to 15 kg and 31 of 36 (86%) losing 15 kg or more. Mean weight fell by 10.0 kg (SD 8.0) against 1.0 kg (3.7), an adjusted difference of -8.8 kg (-10.3 to -7.3, p < 0.0001). Quality of life on the EuroQol 5 Dimensions visual analogue scale improved by 7.2 points (SD 21.3) in the intervention group and fell by 2.9 (15.5) in the control group (adjusted difference 6.4 points, 2.5 to 10.3, p = 0.0012). Nine serious adverse events were reported by 7 of 157 intervention participants (4%) and two by two control participants (1%); two events in one participant, biliary colic and abdominal pain, were deemed potentially related to the intervention, and no serious adverse event led to withdrawal.
Independent research
Gong Q, Zhang P, Wang J, Ma J, An Y, Chen Y, et al. Morbidity and mortality after lifestyle intervention for people with impaired glucose tolerance: 30-year results of the Da Qing Diabetes Prevention Outcome Study Lancet Diabetes and Endocrinology, 2019.
doi:10.1016/S2213-8587(19)30093-2 PubMed 31036503
Funding and finding
Participants
577
Follow-up
up to 30 years; 540 of 576 participants (94%) assessed for outcomes
Funding
The study was supported from 1986 to 1992 by the World Bank, the Ministry of Public Health of the People's Republic of China and Da Qing First Hospital; from 2004 to 2009 by a US Centers for Disease Control and Prevention and WHO cooperative agreement, China-Japan Friendship Hospital and Da Qing First Hospital; and from 2015 to 2018 by a US CDC and Chinese CDC cooperative agreement, the National Center for Cardiovascular Diseases and Fuwai Hospital, China-Japan Friendship Hospital and Da Qing First Hospital. Investigators from the funding organisations were involved in study design, data collection, analysis, interpretation and writing.
Finding
Over 30 years the combined intervention group had a median delay in diabetes onset of 3.96 years (95% CI 1.25 to 6.67, p = 0.0042). Cardiovascular disease events occurred in 195 of 405 intervention participants (48%, cumulative incidence 52.9%, 47.5 to 57.9) and 80 of 135 control participants (59%, cumulative incidence 66.5%, 57.0 to 74.4), 26% fewer events (8 to 41, p = 0.0060), with nine people needing treatment over 30 years to prevent one cardiovascular event (5 to 36). Composite microvascular disease was 35% lower (5 to 55, p = 0.025), cumulative incidence 25.1% against 34.0%, with retinopathy 40% lower (5 to 62, p = 0.032) and nephropathy and neuropathy numerically but not significantly lower. Cardiovascular death fell 33% (6 to 52, p = 0.022), cumulative incidence 25.6% against 35.2%, and all-cause death 26% (11 to 39, p = 0.0015), with ten people needing treatment over 30 years to prevent one death (6 to 25); average life expectancy increased by 1.44 years (0.20 to 2.68, p = 0.023). Reductions in mortality and vascular complications were greater in women than men, and adjusting for the time of diabetes onset nullified the significance of the intervention effect for each primary outcome, which the authors read as showing that much of the benefit follows from the delay in diabetes onset.
Regulator
US Food and Drug Administration. FDA approves new drug treatment for chronic weight management, first since 2014 US Food and Drug Administration, news release, 4 June 2021, 2021.
https://www.fda.gov/news-events/press-announcements/fda-approves-new-drug-treatment-chronic-weight-management-first-2014
Funding and finding
Funding
US Food and Drug Administration
Finding
FDA approved Wegovy (semaglutide 2.4 mg once weekly) for chronic weight management in adults with a BMI of 30 kg/m2 or more, or 27 or more with at least one weight-related condition, with a reduced-calorie diet and increased physical activity; it was the first drug approved for chronic weight management in general obesity or overweight since 2014. Semaglutide 1 mg (Ozempic) had been approved for type 2 diabetes in 2017. Approval rested on four 68-week trials, three placebo-controlled and one randomised withdrawal trial, with more than 2600 patients on Wegovy and more than 1500 on placebo; placebo-adjusted weight loss was 12.4% in adults without diabetes and 6.2% in adults with type 2 diabetes. Labelled warnings at approval included thyroid C-cell tumours, pancreatitis, gallbladder disease, hypoglycaemia, acute kidney injury, diabetic retinopathy, increased heart rate and suicidal behaviour or thinking. Wegovy had not been studied in patients with a history of pancreatitis.
Regulator
US Food and Drug Administration. FDA approves first treatment to reduce risk of serious heart problems specifically in adults with obesity or overweight US Food and Drug Administration, news release, 8 March 2024, 2024.
https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-reduce-risk-serious-heart-problems-specifically-adults-obesity-or
Funding and finding
Funding
US Food and Drug Administration
Finding
FDA approved a new Wegovy indication to reduce the risk of cardiovascular death, heart attack and stroke in adults with cardiovascular disease and either obesity or overweight, on the basis of a trial of more than 17,600 participants in which major adverse cardiovascular events occurred in 6.5% on Wegovy against 8% on placebo, both groups receiving standard care and lifestyle counselling. The indication received Priority Review and was granted to Novo Nordisk A/S.
Expert consensus
National Institute for Health and Care Excellence. Semaglutide for managing overweight and obesity National Institute for Health and Care Excellence, technology appraisal guidance TA875, published 8 March 2023, last updated 4 September 2023, 2023.
https://www.nice.org.uk/guidance/ta875
Funding and finding
Funding
not stated
Finding
Semaglutide is recommended for weight management alongside a reduced-calorie diet and increased physical activity in adults only if used for a maximum of 2 years within a specialist multidisciplinary weight management service, in people with at least one weight-related comorbidity and a BMI of at least 35.0 kg/m2, or 30.0 to 34.9 kg/m2 meeting referral criteria, with thresholds usually 2.5 kg/m2 lower for people of South Asian, Chinese, other Asian, Middle Eastern, Black African or African-Caribbean background, and under the company's commercial arrangement; stopping should be considered if less than 5% of initial weight is lost after 6 months. The committee found no evidence of effectiveness for semaglutide as a stand-alone treatment. The company's model assumed that the weight advantage would be lost 3 years after stopping and that normalised glucose tolerance would revert; the committee called the assumptions on weight regain uncertain. NHS England noted that the risk equations used to model cardiovascular benefit from surrogate outcomes had not been validated by outcome data in people without diabetes; the committee required a high level of confidence that the ICER was near £20,000 per QALY. Company base-case ICER for BMI of 30 or more with a comorbidity was £14,827 per QALY and the review group's £16,337.
Expert consensus
American Diabetes Association Professional Practice Committee for Diabetes. 8. Obesity and Weight Management for the Prevention and Treatment of Diabetes: Standards of Care in Diabetes-2026 Diabetes Care, 2026.
doi:10.2337/dc26-S008 PubMed 41358882
Funding and finding
Funding
Funding statement read in the companion methodology section of the same Standards of Care (doi 10.2337/dc26-SINT, PMID 41358883): the guideline is funded by American Diabetes Association general revenue; no other entity, industry included, provides financial support; committee members received no remuneration.
Finding
Recommendation 8.18: in people with diabetes and overweight or obesity the preferred pharmacotherapy is a GLP-1 receptor agonist or dual GIP and GLP-1 receptor agonist with greater weight loss efficacy, semaglutide or tirzepatide, especially considering added weight-independent benefits (grade A). 8.19: obesity pharmacotherapy indicated for chronic therapy should be continued beyond reaching weight loss goals, as discontinuation often results in recurrence of weight gain and worsening or re-emergence of cardiometabolic risk factors (grade B). 8.20: the optimal dose may not be the maximum approved dose. 8.8a: lifestyle interventions with at least 16 counselling sessions in 6 months targeting a 500 to 750 kcal/day deficit should be recommended when available (grade A). 8.14: monitor to prevent protein insufficiency and micronutrient deficiencies (grade E); to preserve lean mass, optimise protein intake with resistance training. When adding a GLP-1 receptor agonist, sulfonylureas should be stopped or reduced and insulin adjusted to avoid hypoglycaemia. The obesity medication table states for liraglutide and semaglutide: provide guidance on discontinuation before surgical procedures to mitigate pulmonary aspiration; acute pancreatitis has been reported but causality has not been established; evaluate for gallbladder disease; severe constipation and small-bowel obstruction or ileus; close retinopathy monitoring in those at high risk; NAION reported with rare incidence; not recommended in gastroparesis. 8.22: consider metabolic surgery at BMI of 30.0 or more (27.5 or more in Asian American individuals).
Independent research
West S, Scragg J, Aveyard P, Oke JL, Willis L, Haffner SJP, et al. Weight regain after cessation of medication for weight management: systematic review and meta-analysis BMJ, 2026.
doi:10.1136/bmj-2025-085304 PubMed 41500720
Funding and finding
Registration
PROSPERO CRD42024532069
Participants
9,341
Follow-up
mean treatment 39 weeks (range 11 to 176) and mean follow-up after cessation 32 weeks (4 to 104); search to February 2025
Funding
Funded in part by the NIHR Oxford Biomedical Research Centre (IS-BRC-1215-20008); individual authors by NIHR fellowships, the Wellcome Trust and the China Scholarship Council. The funder had no role in design, conduct, collection, analysis, interpretation, preparation, review or approval of the manuscript, or the decision to submit.
Finding
After stopping any weight management medication weight was regained at 0.4 kg per month (95% CI 0.3 to 0.5); for semaglutide and tirzepatide, after a mean loss of 14.7 kg (11.1 to 18.4), regain was 0.8 kg per month (0.7 to 0.9), 9.9 kg (8.4 to 10.8) in the first year, with projected return to baseline weight by 1.5 years (1.0 to 1.9). Cardiometabolic markers were projected to return to baseline within 1.4 years. Regain after medication was faster than after behavioural weight management programmes by 0.3 kg per month (0.22 to 0.34), independent of initial weight loss; body weight after behavioural programmes was projected to return to baseline at 3.9 years against 1.7 years after medication. Only one study followed participants beyond one year. Certainty for the rate of regain was moderate.
Industry-funded
Wilding JPH, Batterham RL, Davies M, Van Gaal LF, Kandler K, Konakli K, et al. Weight regain and cardiometabolic effects after withdrawal of semaglutide: the STEP 1 trial extension Diabetes, Obesity and Metabolism, 2022.
doi:10.1111/dom.14725 PubMed 35441470
Funding and finding
Registration
NCT03548935
Participants
327
Follow-up
68 weeks on treatment, then 52 weeks off treatment to week 120
Funding
The STEP 1 trial was funded by Novo Nordisk A/S. Medical writing and editorial assistance was funded by Novo Nordisk A/S; three authors are Novo Nordisk employees.
Finding
Observed weight loss to week 68 was 17.3% (SD 9.3) on semaglutide and 2.0% (6.1) on placebo. After semaglutide and the lifestyle programme were withdrawn, participants regained 11.6 (SD 7.7) percentage points against 1.9 (4.8), two thirds of the prior loss, and regain continued to week 120, when net loss was 5.6% (8.9) against 0.1% (5.8). At week 120, 95 of 197 (48.2%) previously on semaglutide kept a loss of 5% or more, against 86.4% at week 68. Systolic and diastolic pressure returned to baseline; mean systolic pressure was 129, 121 and 131 mm Hg at weeks 0, 68 and 120 in the semaglutide arm; HbA1c was 5.7%, 5.2% and 5.6%. Of participants with prediabetes at baseline, 93.6% had normoglycaemia at week 68 against 43.3% at week 120 (placebo 41.5% and 34.0%). No systematic collection of adverse events was performed in the extension. Sites were chosen by highest main-phase recruitment and all analyses were exploratory. Data availability: de-identified individual participant data are to be shared with bona fide researchers whose proposal an independent review board approves, after research completion and approval of the product in the EU and USA, through novonordisk-trials.com.

Updated 2026-10-22