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Semaglutide: What the Evidence Actually Shows

Also called Ozempic, Wegovy, Rybelsus, NN9535, GLP-1 receptor agonist

Semaglutide is the compound with the most human data behind it on this site, and the record is genuinely strong: 14.9% mean weight reduction at 68 weeks, sustained to 15.2% at 104 weeks, and a 20% relative reduction in major cardiovascular events across 17,604 patients followed for a mean of 39.8 months. The parts worth reading slowly are the newer ones. A liver indication was added under accelerated approval on a planned interim analysis of the first 800 of 1,197 patients. A 7.2 mg dose reached 18.7% at 72 weeks and roughly doubled the rate of a nerve-sensation side effect. And a tablet form now exists at a completely different dose from the injection. Here is what has been measured, under which standard, and where the record stops.

By Grant Delaney, Research Editor
Highest phase reached

Approved

Largest trial

17,604randomized (SELECT)

Longest reported follow-up

39.8months, mean (SELECT)

Liver indication

Acceleratedapproval

Compound

What it is

Semaglutide is a glucagon-like peptide 1 receptor agonist. It has been tested as a once-weekly subcutaneous injection at 2.4 mg in adults with a body-mass index of 30 or greater, or 27 or greater with at least one weight-related coexisting condition and no diabetes; at 7.2 mg once weekly in adults with a body-mass index of 30 or greater and without diabetes; and as a once-daily 25 mg tablet in people without diabetes at the same body-mass index thresholds. Novo Nordisk funded all of those trials.1,4,5,6

Mechanism

How it works

Semaglutide acts on one receptor, and the trials measure the downstream result rather than the receptor event. In the 1,961-participant STEP 1 trial that result was a mean 15.3 kg reduction at 68 weeks against 2.6 kg on placebo, alongside greater improvement in cardiometabolic risk factors and in participant-reported physical functioning. The same mechanism has been tested against an outcome further from body weight: in 1,197 patients with biopsy-defined metabolic dysfunction-associated steatohepatitis and fibrosis stage 2 or 3, resolution of steatohepatitis without worsening of fibrosis occurred in 62.9% of the 534 patients on semaglutide against 34.3% of the 266 on placebo at week 72, with a mean weight change of −10.5% against −2.0%.1,4

Evidence

What the trials found

Randomized trials

Evidence strength: Randomized trials. Randomized controlled trials in humans, at scale.

STEP 1 randomized 1,961 adults without diabetes 2:1 to semaglutide 2.4 mg once weekly or placebo for 68 weeks and reported a mean weight change of −14.9% against −2.4%, with 50.5% of the semaglutide group losing at least 15% of body weight against 4.9% on placebo. STEP 5 extended the question to 104 weeks in 304 participants: −15.2% against −2.6%. SELECT, the largest trial cited here, randomized 17,604 patients aged 45 or older with preexisting cardiovascular disease, a body-mass index of 27 or greater, and no history of diabetes, and found the composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke in 6.5% on semaglutide against 8.0% on placebo over a mean 39.8 months of follow-up. STEP UP tested a higher dose in 1,407 participants: −18.7% on 7.2 mg against −15.6% on 2.4 mg and −3.9% on placebo at 72 weeks. OASIS 4 tested a 25 mg daily tablet in 307 participants and reported −13.6% at week 64 against −2.2% on placebo. In the one randomized head-to-head against tirzepatide, semaglutide at its maximum tolerated dose of 1.7 or 2.4 mg reached −13.7% at 72 weeks against −20.2%.1,2,3,5,6,7

14.9%

Weight loss, 2.4 mg — 68 wk

STEP 1, 1,961 adults without diabetes, against 2.4% on placebo.

18.7%

Weight loss, 7.2 mg — 72 wk

STEP UP: 3.1 percentage points more than 2.4 mg, with roughly four times the dysaesthesia rate.

20%

Relative reduction in major CV events

SELECT: 6.5% against 8.0% over a mean 39.8 months, in people with existing cardiovascular disease.

—

MASH clinical outcomes

ESSENCE's published result is a week-72 histologic interim in the first 800 of 1,197 patients; the trial runs to 240 weeks.

Weight change by trial, dose and timepoint (%)

Oral 25 mg, 64 wk
13.6 %
2.4 mg, 68 wk
14.9 %
2.4 mg, 104 wk
15.2 %
2.4 mg, 72 wk (STEP UP)
15.6 %
7.2 mg, 72 wk
18.7 %
MTD vs tirzepatide, 72 wk
13.7 %

Trial size, participants randomized

STEP 5
304
OASIS 4
307
SURMOUNT-5
751
ESSENCE
1197
STEP UP
1407
STEP 1
1961
SELECT
17604
How to read the evidence meter

How to read the evidence meter

Four steps, weakest to strongest. Most peptides sold for a goal light up one. We show the step the published human evidence actually reaches — not the step the seller implies.

  1. AnecdotalUser reports and forum consensus. No controlled data.
  2. Animal onlyRodent or cell studies. Nothing published in humans.
  3. Early humanSmall, open-label, or phase 1/2 trials. Promising, unproven.
  4. Randomized trialsRandomized controlled trials in humans, at scale.

Timeline

Development pipeline

  1. Complete

    Preclinical

  2. Complete

    Phase 1

  3. Complete

    Phase 2

  4. Complete

    Phase 3

    Weight, cardiovascular outcomes, MASH, higher dose, oral formulation

  5. 5 — Current step

    FDA review & approval

    Ozempic 2017, Rybelsus 2020, Wegovy 2021; MASH indication under accelerated approval

Summary

What the evidence does — and doesn't — support

Approved on interim data

As of August 2026 the Wegovy label states that the noncirrhotic MASH indication is an accelerated approval based on improvement of MASH and fibrosis, with continued approval potentially contingent on verification in a confirmatory trial. The supporting publication is a planned week-72 interim analysis in the first 800 of ESSENCE's 1,197 patients; the trial is designed to run 240 weeks.
What the evidence supports
  • Mean 14.9% weight reduction at 68 weeks, sustained at 15.2% to 104 weeks
  • A placebo-controlled reduction in major cardiovascular events in 17,604 people who already had cardiovascular disease
  • Larger weight reduction at 7.2 mg than at 2.4 mg within a single randomized trial
  • Improvement in liver histology at week 72 in an interim analysis of a MASH trial
  • An approved oral formulation with its own randomized weight data
What it does not support
  • A verified clinical benefit in MASH — the published analysis is a histologic interim in 800 of 1,197 patients
  • Equivalence between the 25 mg tablet and the 2.4 mg injection — they were tested in separate trials
  • A comparison of 7.2 mg against tirzepatide — the head-to-head trials capped semaglutide at 1 mg and at 2.4 mg
  • Cardiovascular benefit in people without established cardiovascular disease — SELECT did not enroll them
  • A 7.2 mg maintenance dose in patients aged 12 to 17 — the label describes that ceiling for adults

Reality check

The catch

Three things get flattened in the retelling. First, the liver indication is not the same kind of approval as the weight indication. As of August 2026 the Wegovy label states that the noncirrhotic MASH indication is approved under accelerated approval based on improvement of MASH and fibrosis, and that continued approval for it may be contingent on verification and description of clinical benefit in a confirmatory trial — and the published ESSENCE result is a planned interim analysis at week 72 involving the first 800 of the trial's 1,197 patients, in a trial designed to run 240 weeks. Second, the higher dose costs something measurable: in STEP UP, gastrointestinal adverse events were reported by 711 of 1,004 participants on 7.2 mg against 123 of 201 on 2.4 mg, and dysaesthesia — altered skin sensation — by 230 of 1,004 on 7.2 mg against 12 of 201 on 2.4 mg, roughly 23% against 6%. Third, the tablet is not the injection at a different frequency: the label's maintenance dosage for Wegovy tablets is 25 mg once daily, against 2.4 mg once weekly for the injection, and the two were tested in separate trials rather than randomized against each other. On generics, a drugsFDA search in August 2026 returns one abbreviated application for semaglutide — Apotex's ANDA 220314, tentatively approved in April 2026. A tentative approval establishes that an application meets the standard; it is not permission to market.

Dosing

Dosing evidence

Each trial ran its own scheme, and the doses are not interchangeable across formulations. STEP 1 and STEP 5 escalated to a 2.4 mg once-weekly subcutaneous maintenance dose. SELECT used 2.4 mg once weekly. STEP UP randomized participants 5:1:1 to 7.2 mg, 2.4 mg, or placebo once weekly for 72 weeks — the first of the trials here to test a dose above 2.4 mg. OASIS 4 used a 25 mg once-daily tablet, a different route at a different order of magnitude. SURMOUNT-5 did not assign a fixed semaglutide dose at all: it used each participant's maximum tolerated dose of 1.7 mg or 2.4 mg. Those are the doses that were randomized in named trials, reported here as trial design. Which dose, formulation, and titration schedule fits a given person is a prescribing decision, and this page does not make it.1,2,3,5,6,7

Already have a dose in mind? Our reconstitution calculator converts it to syringe units. It does not suggest one.

Safety

Safety and side effects

Gastrointestinal adverse events dominate the tolerability picture, and the rates scale with dose: 82.2% against 53.9% on placebo in STEP 5, 74.0% against 42.2% in OASIS 4, and in STEP UP 70.8% on 7.2 mg against 61.2% on 2.4 mg and 42.8% on placebo. In STEP 1, nausea and diarrhea were the most common adverse events on semaglutide, typically transient and mild to moderate. Discontinuation is where the size of that shows: in SELECT, adverse events led to permanent discontinuation of trial product in 16.6% of the semaglutide group against 8.2% on placebo across a mean 39.8 months, and in STEP 1, 4.5% of the semaglutide group stopped for gastrointestinal events against 0.8% on placebo over 68 weeks. STEP UP also reported dysaesthesia in 230 of 1,004 participants on 7.2 mg against one of 201 on placebo, and serious adverse events in 6.8% on 7.2 mg, 10.9% on 2.4 mg, and 5.5% on placebo.1,2,3,5,6

Approved for this use and available by prescription.

Five applications, one molecule

Semaglutide's approval history is not a single event, and the differences matter. A drugsFDA search in August 2026 returns Ozempic under NDA 209637, approved December 5, 2017 as a new molecular entity; Rybelsus under NDA 213182, approved January 16, 2020; Wegovy under NDA 215256, approved June 4, 2021, carrying efficacy supplements approved in December 2022, March 2024, July 2023, November 2024, August 2025, November 2025 and March 2026; and a further Wegovy application, NDA 218316, approved December 22, 2025 as a new dosage form. Novo Nordisk sponsors all of them. The practical consequence is that "is semaglutide approved?" has no single answer — the approved indication depends on which product, at which dose, in which population.

What the current label actually says

As of August 2026 the DailyMed label for Wegovy lists three things for the injection, in combination with a reduced-calorie diet and increased physical activity: reducing the risk of major adverse cardiovascular events in adults with established cardiovascular disease and either obesity or overweight; reducing excess body weight and maintaining that reduction long term in adults and paediatric patients aged 12 and older with obesity, and in adults with overweight plus at least one weight-related comorbid condition; and treating noncirrhotic metabolic dysfunction-associated steatohepatitis with moderate to advanced fibrosis in adults. That third indication is the accelerated one. The tablet form carries the first two indications, in adults, and not the liver one.

The dosing sections are where a careless read goes wrong. The label's maintenance dosage for weight reduction in adults is 1.7 mg or 2.4 mg once weekly, with a route to a maximum of 7.2 mg once weekly for adults who tolerate 2.4 mg for at least four weeks and for whom additional weight reduction is clinically indicated. The maintenance dosages listed for paediatric patients aged 12 and older are 2.4 mg or 1.7 mg — the 7.2 mg option is described for adults. Those two passages sit close together in the label, and quoting the adult ceiling as though it applied to a 13-year-old would be a real error. We report both because the distinction is the point.

The MASH indication, read as evidence rather than as news

ESSENCE randomized 1,197 patients with biopsy-defined MASH and fibrosis stage 2 or 3 in a 2:1 ratio to semaglutide 2.4 mg or placebo for 240 weeks 4. What has been published is part 1: a planned interim analysis at week 72 involving the first 800 patients 4. In that analysis, resolution of steatohepatitis without worsening of fibrosis occurred in 62.9% of 534 patients on semaglutide against 34.3% of 266 on placebo, and reduction in fibrosis without worsening of steatohepatitis in 36.8% against 22.4% 4. Both differences were large and statistically significant. What they are not yet is an outcome: the endpoints are histologic, the analysis is interim, and 397 of the 1,197 randomized patients are not in it. The accelerated-approval language on the label — continued approval contingent on verification of clinical benefit — is the regulator describing the same gap.

Two comparisons people make that no trial ran

The first is 7.2 mg against tirzepatide. Semaglutide has been randomized against tirzepatide twice in the trials cited here: in type 2 diabetes at 1 mg, and in obesity at a maximum tolerated dose of 1.7 or 2.4 mg 7. Neither randomized the 7.2 mg dose, so the comparison people want is being made across trials rather than within one. Our tirzepatide page covers the same head-to-head from the other side.

The second is the tablet against the injection. OASIS 4's 25 mg tablet produced −13.6% at week 64 6; STEP 1's 2.4 mg injection produced −14.9% at week 68 1. Those are different trials, different durations, different populations and different estimands, and the resemblance of the two numbers is not evidence that the formulations are equivalent. A claim that they are would need a trial that randomized people between them.

Where semaglutide sits against the newer molecules

Semaglutide is the reference point the rest of the class is measured against, which is exactly why the comparisons need care. On our weight loss evidence page the pattern repeats: newer compounds post larger phase 2 numbers, and the gap narrows when the phase 3 arrives. Semaglutide is the one compound in this group where the long, boring, expensive part — a 17,604-patient outcomes trial with a mean 39.8 months of follow-up — has actually been done and published 3.

Questions

Frequently asked questions

How much weight do people lose on semaglutide?

In STEP 1, a mean −14.9% at 68 weeks on 2.4 mg once weekly against −2.4% on placebo, with 50.5% of the semaglutide group losing at least 15% of body weight. STEP 5 followed 304 participants to 104 weeks and reported −15.2% against −2.6%. The higher 7.2 mg dose reached −18.7% at 72 weeks in STEP UP, against −15.6% for 2.4 mg in the same trial. The 25 mg daily tablet reached −13.6% at week 64 in a separate 307-participant trial.

Is semaglutide approved for fatty liver disease?

As of August 2026 the Wegovy injection label carries an indication for noncirrhotic metabolic dysfunction-associated steatohepatitis with moderate to advanced fibrosis in adults, and it states that this indication is approved under accelerated approval based on improvement of MASH and fibrosis, with continued approval potentially contingent on a confirmatory trial. The published evidence behind it is a planned week-72 interim analysis of the first 800 of ESSENCE's 1,197 patients, in a trial designed to run 240 weeks.

Does semaglutide reduce heart attacks and strokes?

SELECT randomized 17,604 patients with preexisting cardiovascular disease and overweight or obesity but no diabetes to semaglutide 2.4 mg or placebo. The composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke occurred in 6.5% on semaglutide against 8.0% on placebo over a mean 39.8 months, a hazard ratio of 0.80. That is a placebo-controlled result in a defined population — people who already had cardiovascular disease — and it does not describe people without it.

Is the 7.2 mg dose better?

In STEP UP it produced more weight loss than 2.4 mg — −18.7% against −15.6% at 72 weeks, a difference of 3.1 percentage points — and more side effects: gastrointestinal events in 70.8% against 61.2%, and dysaesthesia in 230 of 1,004 participants against 12 of 201. Whether that trade is worth making is a clinical judgment about a specific person, not something a trial average settles.

Are semaglutide tablets the same as the injection?

They are the same molecule at very different doses by different routes. As of August 2026 the label's maintenance dosage is 25 mg orally once daily for the tablet and 2.4 mg subcutaneously once weekly for the injection, and the tablet is labelled for cardiovascular risk reduction and weight reduction in adults, not for the liver indication. The trials that produced their weight figures were separate trials, so the two numbers cannot be read as a head-to-head.

Is there a generic semaglutide?

A drugsFDA search in August 2026 returns one abbreviated application, Apotex's ANDA 220314, with a tentative approval dated April 7, 2026. Tentative approval means the application met the required standards but cannot be marketed yet. Anything sold today as generic or compounded semaglutide is not that product.

What are semaglutide's side effects?

Gastrointestinal events dominate the tolerability picture and scale with dose — 82.2% against 53.9% on placebo in STEP 5, and 70.8% on 7.2 mg against 42.8% on placebo in STEP UP. In SELECT, 16.6% of the semaglutide group permanently discontinued for adverse events against 8.2% on placebo over a mean 39.8 months. As of August 2026 the Wegovy label carries a boxed warning for thyroid C-cell tumors and warnings covering acute pancreatitis, acute gallbladder disease, hypoglycemia, acute kidney injury from volume depletion, severe gastrointestinal reactions, hypersensitivity, diabetic retinopathy complications in type 2 diabetes, heart rate increase, and pulmonary aspiration under anesthesia or deep sedation. The label is the authoritative list; this is a summary of it.

Glossary

Key terms

GLP-1 receptor agonist
A drug that activates the receptor for glucagon-like peptide 1, a gut hormone that slows stomach emptying and reduces appetite.
Accelerated approval
An FDA pathway that clears a drug on a surrogate marker likely to predict benefit, with full approval contingent on a confirmatory trial.
Interim analysis
A pre-planned look at part of a trial's data before it finishes — here, week 72 of a 240-week trial in the first 800 of 1,197 patients.
MACE
Major adverse cardiovascular events: the composite of cardiovascular death, nonfatal heart attack, and nonfatal stroke that SELECT counted.
Tentative approval
A finding that a generic application meets FDA standards while patent or exclusivity blocks marketing. It is not permission to sell.
Dysaesthesia
Altered or unpleasant skin sensation. Reported in 230 of 1,004 participants on semaglutide 7.2 mg in STEP UP, against 12 of 201 on 2.4 mg.

Sources

References

  1. Wilding JPH, Batterham RL, Calanna S, et al. (2021). Once-Weekly Semaglutide in Adults with Overweight or Obesity. New England Journal of Medicine. https://pubmed.ncbi.nlm.nih.gov/33567185/
  2. Garvey WT, Batterham RL, Bhatta M, et al. (2022). Two-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial. Nature Medicine. https://pubmed.ncbi.nlm.nih.gov/36216945/
  3. Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. (2023). Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. New England Journal of Medicine. https://pubmed.ncbi.nlm.nih.gov/37952131/
  4. Sanyal AJ, Newsome PN, Kliers I, et al. (2025). Phase 3 Trial of Semaglutide in Metabolic Dysfunction-Associated Steatohepatitis. New England Journal of Medicine. https://pubmed.ncbi.nlm.nih.gov/40305708/
  5. Wharton S, Freitas P, Hjelmesæth J, et al. (2025). Once-weekly semaglutide 7·2 mg in adults with obesity (STEP UP): a randomised, controlled, phase 3b trial. The Lancet Diabetes & Endocrinology. https://pubmed.ncbi.nlm.nih.gov/40961952/
  6. Wharton S, Lingvay I, Bogdanski P, et al. (2025). Oral Semaglutide at a Dose of 25 mg in Adults with Overweight or Obesity. New England Journal of Medicine. https://pubmed.ncbi.nlm.nih.gov/40934115/
  7. Aronne LJ, Horn DB, le Roux CW, et al. (2025). Tirzepatide as Compared with Semaglutide for the Treatment of Obesity. New England Journal of Medicine. https://pubmed.ncbi.nlm.nih.gov/40353578/

Medical disclaimer: This content is for general educational purposes only and is not medical advice, diagnosis, or treatment. Always consult a licensed healthcare professional before starting, stopping, or changing any treatment.