Semaglutide

What it is

Semaglutide is a prescription glucagon-like peptide-1 receptor agonist, given as a weekly injection (Wegovy, Ozempic) or taken as a tablet. Wegovy is approved to reduce cardiovascular events in adults with heart disease and overweight, for long-term weight reduction, and for a form of fatty liver disease (MASH).

What the research says

Large randomised trials show substantial weight loss (about 15% at 68 weeks versus 2.4% on placebo) and fewer heart attacks, strokes and cardiovascular deaths in people with heart disease (6.5% versus 8.0% over about 3 years). In type 2 diabetes they show fewer major cardiovascular events and slower kidney decline. Stomach and bowel side effects are very common, gallbladder problems are more frequent, and more people stop the drug because of side effects. Most of the lost weight returns within a year of stopping. The thyroid C-cell tumour warning rests on rodent studies, and large human cohorts mostly find no increase. A small risk of a sudden optic nerve problem (NAION) is now recognised.

Evidence grade: Well established.

How it works

Drug class: Glucagon-like peptide-1 (GLP-1) receptor agonist

Semaglutide mimics the gut hormone GLP-1. It lowers blood glucose and slows how fast the stomach empties. The label states both effects. (Source 1)

Boxed warning

In rodents, semaglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures. It is unknown whether WEGOVY causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as human relevance of semaglutide-induced rodent thyroid C-cell tumors has not been determined. WEGOVY is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk for MTC with the use of WEGOVY and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with WEGOVY.

(Source 1)

What it is used for

• In STEP 1, weight fell 14.9% with semaglutide 2.4 mg against 2.4% with placebo over 68 weeks. Continued treatment is needed to keep the weight off. Evidence: established. (Source 2)
• In SELECT (17,604 patients, about 40 months), 6.5% on semaglutide had a heart attack, stroke or cardiovascular death against 8.0% on placebo. Evidence: established. (Source 3)
• In SUSTAIN-6, 6.6% on semaglutide against 8.9% on placebo had a major cardiovascular event over 104 weeks, but retinopathy complications were more common. Evidence: established. (Source 4)
• In FLOW, major kidney disease events were 24% lower (331 against 410 first events among about 1,770 per group, median 3.4 years). We did not confirm the approval status for this use from a label in this run. Evidence: established. (Source 5)

Interactions

• Insulin and sulfonylureas (label): Together they raise the risk of low blood sugar. (Source 1)
• Oral medicines taken by mouth (including levothyroxine), which may include oral supplements (label): Slower stomach emptying can change how other medicines taken by mouth are absorbed. Whether this applies to supplements has not been studied; that extension is theoretical. (Source 1)
• General anaesthesia or deep sedation (case reports): Rare reports of stomach contents being inhaled during anaesthesia, despite fasting. (Source 1)

Stopping it

• When semaglutide and the lifestyle program were stopped after 68 weeks, participants regained about two-thirds of the weight they had lost within a year, and blood pressure and other cardiometabolic gains largely reversed. (Source 6)
• In a randomised withdrawal trial, people switched to placebo regained 6.9% of body weight over 48 weeks. (Source 7)

What goes wrong

In SELECT, twice as many people stopped semaglutide because of adverse events, mostly gastrointestinal, as stopped placebo. Gallbladder disorders were slightly more common. (Source 3)

• Randomized trial, High certainty.
• Size: 17,604 patients.
• Who: Adults with cardiovascular disease and overweight, no diabetes.
• How long: Mean follow-up 39.8 months.
• Result: Discontinuation for adverse events 16.6% against 8.2%; GI disorders leading to discontinuation 10.0% against 2.0%; gallbladder-related disorders 2.8% against 2.3% (P=0.04).
• Funding: Industry-funded (Novo Nordisk)

Gallbladder-related disorders occurred in 246 patients (2.8%) and 203 patients (2.3%), respectively (P=0.04).

In STEP 1, gastrointestinal side effects affected about three in four people on semaglutide against about half on placebo. Gallbladder disorders, mostly gallstones, roughly doubled. (Source 8)

• Randomized trial, High certainty.
• Size: 1,961 adults.
• Who: Adults with obesity, without diabetes.
• How long: 68 weeks.
• Result: GI disorders 74.2% against 47.9%; gallbladder-related disorders 2.6% against 1.2%; serious adverse events 9.8% against 6.4%; 3 cases of mild acute pancreatitis on semaglutide.
• Funding: Industry-funded (Novo Nordisk)

Gallbladder-related disorders (mostly cholelithiasis) were reported in 2.6% and 1.2% of participants in the semaglutide and placebo groups, respectively.

The thyroid C-cell tumour warning rests on rodent studies. In mice and rats, lifelong semaglutide raised thyroid C-cell tumours with dose and duration, and human relevance has not been determined. (Source 1)

• Animal study, Certainty not rated.
• Size: Not applicable.
• Who: Mice and rats.
• How long: Lifetime exposure.
• Result: Dose- and duration-dependent increase in C-cell adenomas and carcinomas at clinically relevant exposures.
• Funding: Manufacturer studies reported in the FDA label.

In mice and rats, semaglutide caused a dose-dependent and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas) after lifetime exposure at clinically relevant plasma exposures.

A French nested case-control study found GLP-1 drug use for 1 to 3 years was associated with more thyroid cancer, including medullary thyroid cancer. As an observational study it shows an association, not a cause, and closer thyroid checking of people on these drugs could explain part of it. (Source 9)

• Case-control study, Low certainty.
• Size: 2,562 thyroid cancer cases and 45,184 matched controls.
• Who: People with type 2 diabetes on second-line diabetes drugs, France, 2006 to 2018.
• How long: Exposure over the 6 years before diagnosis.
• Result: All thyroid cancer adjusted HR 1.58 (95% CI 1.27 to 1.95); medullary adjusted HR 1.78 (95% CI 1.04 to 3.05).
• Funding: Not stated in the extracted text.

Use of GLP-1 RA for 1–3 years was associated with increased risk of all thyroid cancer (adjusted hazard ratio [HR] 1.58, 95% CI 1.27–1.95) and medullary thyroid cancer (adjusted HR 1.78, 95% CI 1.04–3.05).

The European Medicines Agency's safety committee concluded that the optic nerve condition NAION is a very rare side effect of semaglutide. Epidemiological studies suggest about a two-fold risk, roughly one extra case per 10,000 person-years. (Source 10)

• Official position, Low certainty.
• Size: Several large epidemiological studies plus trial data.
• Who: Adults with type 2 diabetes (epidemiological studies)
• How long: Not applicable.
• Result: About 2-fold relative risk; about 1 additional case per 10,000 person-years; classed as very rare (up to 1 in 10,000).
• Funding: Regulator (EMA PRAC, June 2025)

Results from several large epidemiological studies suggest that exposure to semaglutide in adults with type 2 diabetes is associated with an approximately two-fold increase in the risk of developing NAION compared with people not taking the medicine.

The FDA received reports of overdoses with compounded semaglutide from multi-dose vials, where patients drew up 5 to 20 times the intended dose. Reported harms included vomiting, fainting, dehydration, pancreatitis and gallstones, and some patients were hospitalised. (Source 11)

• Case series, Very low certainty.
• Size: Adverse event reports (number not given in the extracted text)
• Who: Patients using compounded injectable semaglutide.
• How long: Not applicable.
• Result: 5 to 20 times the intended dose in the majority of reports.
• Funding: Regulator (FDA alert, 2024)

In these instances, patients administered five to 20 times more than the intended dose of semaglutide.

What the evidence supports

In STEP 1, adults with obesity and no diabetes lost 14.9% of body weight on semaglutide 2.4 mg weekly against 2.4% on placebo over 68 weeks. (Source 2)

• Randomized trial, High certainty.
• Size: 1,961 adults.
• Who: Adults with BMI 30 or more (or 27 or more with a weight-related condition), without diabetes.
• How long: 68 weeks.
• Result: Treatment difference -12.4 percentage points (95% CI -13.4 to -11.5); -15.3 kg against -2.6 kg; 50.5% against 4.9% lost at least 15%.
• Funding: Industry-funded (Novo Nordisk)

The mean change in body weight from baseline to week 68 was -14.9% in the semaglutide group as compared with -2.4% with placebo, for an estimated treatment difference of -12.4 percentage points (95% confidence interval [CI], -13.4 to -11.5; P<0.001).

In SELECT, among people with heart disease and overweight but no diabetes, semaglutide reduced cardiovascular death, heart attack or stroke from 8.0% to 6.5% over about 3 years. (Source 3)

• Randomized trial, High certainty.
• Size: 17,604 patients.
• Who: Adults 45 or older with established cardiovascular disease, BMI 27 or more, no diabetes.
• How long: Mean follow-up 39.8 months.
• Result: HR 0.80 (95% CI 0.72 to 0.90); 569/8803 (6.5%) against 701/8801 (8.0%), an absolute difference of about 1.5 percentage points.
• Funding: Industry-funded (Novo Nordisk)

A primary cardiovascular end-point event occurred in 569 of the 8803 patients (6.5%) in the semaglutide group and in 701 of the 8801 patients (8.0%) in the placebo group (hazard ratio, 0.80; 95% confidence interval, 0.72 to 0.90; P<0.001).

In STEP 4, people switched to placebo after a 20-week run-in regained 6.9% of body weight over 48 weeks, while those who stayed on semaglutide lost a further 7.9%. (Source 7)

• Randomized trial, High certainty.
• Size: 803 randomised participants.
• Who: Adults with obesity or overweight, no diabetes, who reached 2.4 mg during run-in.
• How long: 48 weeks after a 20-week run-in.
• Result: Difference -14.8 percentage points (95% CI -16.0 to -13.5); GI events 49.1% against 26.1%.
• Funding: Industry-funded (Novo Nordisk)

With continued semaglutide, mean body weight change from week 20 to week 68 was -7.9% vs +6.9% with the switch to placebo (difference, -14.8 [95% CI, -16.0 to -13.5] percentage points; P <.001).

In FLOW, among people with type 2 diabetes and chronic kidney disease, semaglutide 1.0 mg cut major kidney disease events by 24%. (Source 5)

• Randomized trial, High certainty.
• Size: 3,533 participants.
• Who: Adults with type 2 diabetes and chronic kidney disease.
• How long: Median 3.4 years (stopped early for efficacy)
• Result: 331 against 410 first events; HR 0.76 (95% CI 0.66 to 0.88); cardiovascular death HR 0.71 (0.56 to 0.89); death from any cause HR 0.80 (0.67 to 0.95).
• Funding: Industry-funded (Novo Nordisk)

The risk of a primary-outcome event was 24% lower in the semaglutide group than in the placebo group (331 vs. 410 first events; hazard ratio, 0.76; 95% confidence interval [CI], 0.66 to 0.88; P=0.0003).

What the evidence does not support

Adjudicated acute pancreatitis was no more common with semaglutide than placebo in SELECT: 17 cases against 24. (Source 3)

• Randomized trial, Moderate certainty.
• Size: 17,604 patients.
• Who: Adults with cardiovascular disease and overweight, no diabetes.
• How long: Mean follow-up 39.8 months.
• Result: 17 (0.2%) against 24 (0.3%), P=0.28. The label still warns about pancreatitis, including fatal cases, seen with GLP-1 drugs.
• Funding: Industry-funded (Novo Nordisk)

Acute pancreatitis¶ 17 (0.2) 24 (0.3) 0.28

One year after semaglutide and the lifestyle program stopped in the STEP 1 extension, participants regained about two-thirds of the weight they had lost, and most cardiometabolic gains went back toward baseline. (Source 6)

• Randomized trial, Moderate certainty.
• Size: 327 participants.
• Who: STEP 1 completers from selected sites.
• How long: 52 weeks off treatment after 68 weeks on.
• Result: Regained 11.6 percentage points of lost weight, leaving a net loss of 5.6% at week 120 against 0.1% for placebo. All extension analyses were exploratory.
• Funding: Industry-funded (Novo Nordisk)

Following treatment withdrawal, semaglutide and placebo participants regained 11.6 (SD: 7.7) and 1.9 (SD: 4.8) percentage points of lost weight, respectively, by week 120, resulting in net losses of 5.6% (SD: 8.9%) and 0.1% (SD: 5.8%), respectively, from week 0 to week 120.

A Scandinavian cohort study (Pasternak et al., BMJ 2024), reported here through a CancerNetwork news summary, found no association between GLP-1 drug use and thyroid cancer compared with DPP-4 inhibitors. Peter Ueda of Karolinska Institutet, quoted in the report, said a higher risk for some subtypes in smaller patient groups could not be ruled out. (Source 12)

• Cohort study, Moderate certainty.
• Size: 145,410 GLP-1 users and 291,667 DPP-4 inhibitor users.
• Who: Adults in Denmark, Norway and Sweden.
• How long: Mean follow-up 3.9 years (GLP-1)
• Result: HR 0.93 (95% CI 0.66 to 1.31); 76 against 184 cases.
• Funding: Not stated in the extracted text.

Therefore, investigators did not find an association between GLP1 use and thyroid cancer (HR, 0.93; 95% CI, 0.66-1.31).

A multinational new-user cohort study of more than 4 million people with type 2 diabetes found no increase in thyroid tumours with GLP-1 drugs compared with three other diabetes drug classes. (Source 13)

• Cohort study, Moderate certainty.
• Size: 460,032 GLP-1 users; 3.9 million comparators.
• Who: Adults with type 2 diabetes starting second-line drugs (only US cohorts passed diagnostics)
• How long: Not stated in the abstract.
• Result: Hazard ratios ranged from 0.78 to 1.03 across comparators; thyroid tumour incidence 0.88 to 1.03 per 1,000 person-years.
• Funding: Not stated in the extracted text.

GLP-1RA exposure was not associated with an increased risk of thyroid tumors compared with SGLT2is, DPP-4is, or SUs

Where the evidence is mixed

In the STEP 1 DXA body-composition subset, lean soft tissue made up about 40% of the weight lost (6.9 kg lean against 10.4 kg fat). These figures are from STEP 1 as summarised by Tinsley et al. in a 2025 case series, not quoted from the STEP 1 paper itself. The STEP 1 authors themselves reported that lean mass fell in kilograms but rose as a proportion of body mass. (Source 14)

• Randomized trial, Low certainty.
• Size: 95 semaglutide-treated participants in the DXA subset (140 in the subset overall)
• Who: Adults with obesity in STEP 1.
• How long: 68 weeks.
• Result: STEP 1 figures as summarised by Tinsley et al. 2025: about 6.9 kg lean soft tissue and 10.4 kg fat mass lost, roughly 40% of weight lost as lean soft tissue. Whether this lean-tissue loss matters clinically was not measured.
• Funding: Trial industry-funded; the summarising paper is a case series.

In the STEP 1 trial, 95 participants treated with semaglutide in the DXA subset lost 6.9 kg (~13%) LST alongside 10.4 kg (~25%) FM, corresponding to ~40% of weight loss as LST.

In SUSTAIN-6, people with type 2 diabetes on semaglutide had fewer major cardiovascular events than those on placebo, but serious diabetic eye (retinopathy) complications were significantly more common. (Source 4)

• Randomized trial, Moderate certainty.
• Size: 3,297 patients.
• Who: Adults with type 2 diabetes at high cardiovascular risk.
• How long: 104 weeks.
• Result: Primary outcome 6.6% against 8.9% (HR 0.74, 95% CI 0.58 to 0.95); retinopathy complications HR 1.76 (95% CI 1.11 to 2.78). The trial was designed to test noninferiority.
• Funding: Industry-funded (Novo Nordisk)

rates of retinopathy complications (vitreous hemorrhage, blindness, or conditions requiring treatment with an intravitreal agent or photocoagulation) were significantly higher (hazard ratio, 1.76; 95% CI, 1.11 to 2.78; P=0.02).

Where the research disagrees

Whether GLP-1 drugs such as semaglutide raise thyroid cancer risk in humans

• Bezin et al., French nested case-control study, 2023, Nested case-control study, French national claims: In the current study we found increased risk of all thyroid cancer and medullary thyroid cancer with use of GLP-1 RA, in particular after 1–3 years of treatment. (Source 9)
• Morales et al., multinational new-user cohort, Diabetes Care 2025, Active-comparator new-user cohort study: In patients with T2DM initiating second-line treatments, we observed no increased risk of thyroid tumors with GLP-1RA exposure. (Source 13)
• FDA label (Wegovy, June 2026), Rodent carcinogenicity studies: It is unknown whether WEGOVY causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans (Source 1)

How much

• Reference intake: The prescriber sets the dose. As a position, the Wegovy label (revised June 2026) gives the adult maintenance dose for weight reduction as either 1.7 mg or 2.4 mg (recommended) once weekly by injection, and the same two options for cardiovascular risk reduction. (Source 1)
• Upper limit: The Wegovy label (revised June 2026) allows up to 7.2 mg once weekly for patients who have tolerated 2.4 mg for at least 4 weeks and need more weight reduction. (Source 1)
• Studied: STEP 1, STEP 4 and SELECT used 2.4 mg once weekly by subcutaneous injection. (Source 3)
• Studied: SUSTAIN-6 used 0.5 mg or 1.0 mg once weekly in type 2 diabetes. (Source 4)
• Studied: FLOW used 1.0 mg once weekly. (Source 5)

A common belief, and what the research shows

The belief: A course of semaglutide takes the weight off for good.

What the research shows: In the STEP 1 extension, "participants regained two-thirds of their prior weight loss" within a year of stopping. The authors concluded the findings "suggest ongoing treatment is required to maintain improvements in weight and health."

Questions and answers

What is it?

Semaglutide is a prescription GLP-1 receptor agonist, sold as Wegovy and Ozempic injections and Rybelsus tablets. It is used for type 2 diabetes, weight reduction, lowering cardiovascular risk and some other conditions. (Source 3)

What does it do in the body?

It mimics the gut hormone GLP-1. It lowers blood glucose and slows how fast the stomach empties. In trials, weight fell by about 15% over 68 weeks. (Source 1)

Is it good or bad for you?

In large trials it produced major weight loss and fewer heart attacks, strokes and cardiovascular deaths in people with heart disease. It also slowed kidney decline in type 2 diabetes. The costs are frequent stomach and bowel side effects, more gallbladder disease, a very rare optic nerve problem (NAION), loss of some lean tissue along with fat, and weight regain after stopping. The benefit depends on the person's condition and risk. (Source 3)

How do you get more of it?

Does not apply in the usual sense. Semaglutide is a prescription medicine. The label position is 2.4 mg weekly for maintenance, with up to 7.2 mg weekly in some patients. Compounded versions have led to overdoses from measuring errors. (Source 11)

If it is harmful, what reduces it?

Semaglutide stays in the body for weeks after the last dose; people stop it by discontinuing it with their prescriber. Stopping usually brings the weight back: about two-thirds of the lost weight returned within a year in STEP 1. (Source 6)

Why might someone be low in it or missing it?

Does not apply. Semaglutide is a synthetic drug, not a nutrient. The trial authors describe obesity as a chronic condition that returns when treatment stops, not as a shortage of the drug. (Source 6)

Which whole foods contain it or feed it?

No food contains semaglutide. Its only food-related point in the label is that it slows stomach emptying, which can change how other medicines taken by mouth are absorbed. (Source 1)

What happens if you do not have it?

For someone who stops it, weight and cardiometabolic markers tend to drift back toward where they were before treatment. (Source 6)

How can you test for it?

There is no routine blood test for semaglutide levels. The label says routine calcitonin testing or thyroid ultrasound is of uncertain value for early detection of thyroid cancer in people taking it. (Source 1)

References

1. US FDA / Novo Nordisk via DailyMed (revised June 2026). WEGOVY (semaglutide) prescribing information, DailyMed. 2026. Read the source
2. The New England Journal of Medicine. Once-Weekly Semaglutide in Adults with Overweight or Obesity. 2021. PMID 33567185, DOI 10.1056/NEJMoa2032183. Read the source
3. The New England Journal of Medicine. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. 2023. PMID 37952131, DOI 10.1056/NEJMoa2307563. Read the source
4. The New England Journal of Medicine. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes (SUSTAIN-6). 2016. PMID 27633186, DOI 10.1056/NEJMoa1607141. Read the source
5. The New England Journal of Medicine. Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes (FLOW). 2024. DOI 10.1056/NEJMoa2403347. Read the source
6. Diabetes, Obesity and Metabolism. Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension. 2022. PMID 35441470, DOI 10.1111/dom.14725. Read the source
7. JAMA. Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity: The STEP 4 Randomized Clinical Trial. 2021. PMID 33755728, DOI 10.1001/jama.2021.3224. Read the source
8. The New England Journal of Medicine. Once-Weekly Semaglutide in Adults with Overweight or Obesity (full text, adverse events and body composition). 2021. PMID 33567185, DOI 10.1056/NEJMoa2032183. Read the source
9. Diabetes Care. GLP-1 Receptor Agonists and the Risk of Thyroid Cancer (Bezin J, Gouverneur A, Pénichon M, et al. Diabetes Care 2023;46(2):384-390). 2023. DOI 10.2337/dc22-1148. Read the source
10. European Medicines Agency. PRAC concludes eye condition NAION is a very rare side effect of semaglutide medicines Ozempic, Rybelsus and Wegovy. 2025. Read the source
11. US Food and Drug Administration. FDA alerts health care providers, compounders and patients of dosing errors associated with compounded injectable semaglutide products. 2024. Read the source
12. CancerNetwork. Increased Thyroid Cancer Risk Not Observed After Use of GLP1 Receptor Agonist (news report of Pasternak et al., BMJ 2024, Scandinavian cohort study). 2024. PMID 38683947. Read the source
13. Diabetes Care. Risk of Thyroid Tumors With GLP-1 Receptor Agonists: A Retrospective Cohort Study (Morales DR, et al. Diabetes Care 2025;48(8):1386-1394). 2025. DOI 10.2337/dc25-0154. Read the source
14. SAGE Open Medical Case Reports. Preservation of lean soft tissue during weight loss induced by GLP-1 and GLP-1/GIP receptor agonists: A case series. 2025. PMID 41122508, DOI 10.1177/2050313X251388724. Read the source