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    Semaglutide and tirzepatide: the approved GLP-1 peptides

    Two synthetic molecules copying a hormone your gut already makes. Here is how they act, what is actually approved and when, and what is still at the clinical-trial stage.

    Written and reviewed by Catherine Piault, naturopath · Last reviewed:

    In one sentence

    Semaglutide and tirzepatide are two synthetic peptides approved for type 2 diabetes and, at certain doses, for obesity, backed by some of the most robust randomised clinical trials in the whole peptide class. Semaglutide mimics a single gut hormone, GLP-1; tirzepatide additionally activates the GIP receptor, which explains part of its greater efficacy: 14.9% average weight loss at 68 weeks in STEP 1, against 20.9% at 72 weeks in SURMOUNT-1. Both are prescription medicines, with frequent digestive side effects and documented weight regain after discontinuation.

    Illustration: a single agonist and a dual agonist binding to the GLP-1 and GIP receptors
    Semaglutide activates one receptor (GLP-1); tirzepatide activates two (GLP-1 and GIP).

    How does it work?

    After a meal, the gut's L cells release , a peptide hormone doing three things at once: it stimulates insulin secretion when blood glucose rises, it slows gastric emptying, and it tells the brain's appetite centres that the meal has happened. Natural GLP-1 is broken down within minutes.

    Semaglutide is an of the GLP-1 : a modified copy of the hormone, engineered to resist breakdown and stay active for a whole week instead of a few minutes. The satiety signal, instead of a post-meal spike, becomes a continuous background. That is the entire mechanism of the appetite-suppressing effect.

    Tirzepatide does the same, plus one more thing. It is a dual agonist: it activates the GLP-1 receptor and the receptor, the second incretin hormone, secreted higher up the digestive tract. GIP acts on insulin and on adipose tissue, and adding it appears to amplify the metabolic effect without proportionally multiplying digestive side effects. This difference in target is the main distinction between the two molecules, and one of the proposed explanations for the efficacy gap seen in trials.

    The natural hormone's mechanism, and the dietary levers that amplify it, are detailed in how endogenous GLP-1 works.

    What is approved, and since when?

    Both molecules hold a in Europe and the United States, obtained after covering several tens of thousands of participants in total.

    Regulatory status as of 7 August 2026

    • Semaglutide. Type 2 diabetes: Ozempic (weekly injection, 0.25 to 2 mg) and Rybelsus (daily tablet). Weight management: Wegovy, 2.4 mg weekly, in adults with BMI ≥ 30, or ≥ 27 with a weight-related comorbidity. Authorised by the EMA and the FDA.
    • Tirzepatide. Type 2 diabetes and weight management, as Mounjaro in Europe (2.5 to 15 mg weekly; marketed in the US as Mounjaro and Zepbound depending on the indication). Authorised by the EMA and the FDA.
    • In both cases: a prescription-only medicine, with gradual dose titration and medical follow-up. Neither molecule is a food supplement, and neither can be legally bought outside the pharmaceutical channel.

    What the trials show. STEP 1 (Wilding et al., NEJM 2021, 1,961 adults with obesity): average weight loss of 14.9% at 68 weeks on semaglutide 2.4 mg weekly, against 2.4% on placebo. SURMOUNT-1 (Jastreboff et al., NEJM 2022, 2,539 adults): 20.9% at 72 weeks on tirzepatide 15 mg, against 3.1% on placebo. In people with type 2 diabetes, HbA1c falls by an average of 1.5 points on semaglutide.

    These two figures come from distinct protocols, with different durations and populations: compare them with care, since no head-to-head trial was designed to arbitrate between them on this endpoint.

    What the trials also show. Adverse effects are mostly digestive: nausea (about 25%), diarrhoea (12%), constipation (10%). Rarer and serious: acute pancreatitis, gallstones, sometimes prolonged gastroparesis. A notable share of the weight lost is lean mass. And after stopping, STEP 4 (Rubino et al., JAMA 2021) documents regain of about two thirds of the lost weight within a year.

    The detail of adverse effects, contraindications and the berberine comparison is covered in Ozempic versus berberine, which uses the same trials and the same figures.

    What is still under study?

    The class is expanding beyond diabetes and obesity, but each indication follows its own regulatory timeline. Distinguish what is authorised, what rests on a published phase III trial, and what is still only a phase II signal.

    Level of evidence, indication by indication

    • Cardiovascular risk. SELECT (Lincoff et al., NEJM 2023, 17,604 participants with obesity and no diabetes): a 20% reduction in major cardiovascular events on semaglutide 2.4 mg. Phase III, an indication recognised by regulators.
    • Obstructive sleep apnoea. SURMOUNT-OSA (Malhotra et al., NEJM 2024, 469 participants): a significant reduction in the apnoea-hypopnoea index on tirzepatide. Phase III, modest sample.
    • Addiction, kidney disease, fatty liver, cognition. Programmes ongoing at various stages. For several of these leads, published data remain preliminary or observational: they justify no off-label prescription.
    • Retatrutide. Triple agonist (GLP-1, GIP and glucagon), assessed in a published trial (Jastreboff et al., NEJM 2023, 338 participants) showing average weight loss of 24.2% at 48 weeks at the highest dose. No marketing authorisation: this result, from a sample ten times smaller than SURMOUNT-1, awaits phase III confirmation.

    One practical consequence: molecules still in development, retatrutide foremost, already circulate on the unregulated market under a “research use only” label. They then carry exactly the same risks as the peptides in Path 2: identity, dose and purity guaranteed by nobody.

    Frequently asked questions

    What is the difference between semaglutide and tirzepatide?

    Semaglutide is an agonist of a single receptor, the GLP-1 receptor. Tirzepatide activates two: GLP-1 and GIP, the second gut incretin hormone. This dual action explains part of the observed efficacy gap: 14.9% average weight loss at 68 weeks with semaglutide 2.4 mg in STEP 1, against 20.9% at 72 weeks with tirzepatide 15 mg in SURMOUNT-1. No head-to-head trial was designed to arbitrate between these two figures, obtained under different protocols.

    Are semaglutide and tirzepatide approved in Europe?

    Yes, both, with distinct indications depending on the brand. Semaglutide is EMA-authorised for type 2 diabetes (Ozempic, injectable, and Rybelsus, oral) and, at 2.4 mg weekly, for weight management in adults with obesity or overweight with a comorbidity (Wegovy). Tirzepatide is authorised for type 2 diabetes and weight management as Mounjaro. Both are prescription medicines requiring medical follow-up.

    What happens when treatment stops?

    Most of the weight comes back. STEP 4 (Rubino et al., JAMA 2021) documents that about two thirds of the lost weight is regained within a year of stopping. The mechanism is straightforward: the appetite effect leaves with the molecule, while the lost muscle mass and lowered resting metabolism remain.

    What are the most common adverse effects?

    Chiefly digestive, tied to slowed gastric emptying: nausea (about 25% of trial participants), diarrhoea (12%), constipation (10%), vomiting. Rarer but serious: acute pancreatitis, gallstones favoured by rapid weight loss, sometimes prolonged gastroparesis. A substantial share of the weight lost is lean mass, which makes protein intake and resistance training essential.

    Is retatrutide available?

    No. Retatrutide, which acts on three receptors (GLP-1, GIP and glucagon), has so far only completed a published phase II trial (Jastreboff et al., NEJM 2023, 338 participants). It holds no marketing authorisation. Any product sold under that name outside a clinical trial comes from the unregulated market.

    Go further

    Continue in the peptides dossier

    Peptides watch — monthly update

    This dossier is reviewed monthly. Monitored each month: PubMed-indexed publications on the peptides covered, EMA and FDA communications (alerts, withdrawals, new authorisations), updates to the WADA prohibited list, and ANSM notices on products sold online. Any new data that changes a conclusion is folded into the text and added to the sources.

    Last review: · Next review due:

    Sources

    1. Wilding JPH et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity (STEP 1). New England Journal of Medicine, 2021;384:989-1002. — DOI : 10.1056/NEJMoa2032183
    2. Jastreboff AM et al. Tirzepatide Once Weekly for the Treatment of Obesity (SURMOUNT-1). New England Journal of Medicine, 2022;387:205-216. — DOI : 10.1056/NEJMoa2206038
    3. European Medicines Agency — Wegovy (semaglutide), European public assessment report.
    4. European Medicines Agency — Mounjaro (tirzepatide), European public assessment report.
    5. Lincoff AM et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes (SELECT, N = 17 604). New England Journal of Medicine, 2023;389:2221-2232. — DOI : 10.1056/NEJMoa2307563
    6. Jastreboff AM et al. Triple-Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial (N = 338). New England Journal of Medicine, 2023;389:514-526. — DOI : 10.1056/NEJMoa2301972
    7. Malhotra A et al. Tirzepatide for the Treatment of Obstructive Sleep Apnea and Obesity (SURMOUNT-OSA, N = 469). New England Journal of Medicine, 2024;391:1193-1205. — DOI : 10.1056/NEJMoa2404881
    8. Rubino D et al. Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance (STEP 4). JAMA, 2021;325:1414-1425. — DOI : 10.1001/jama.2021.3224

    Written and reviewed by Catherine Piault, naturopath · Last reviewed:

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