Last reviewed 30 August 2026
No compounds in this library carry an evidence base like these three. Semaglutide, tirzepatide and retatrutide have been studied in registration programmes enrolling tens of thousands of participants, published in the New England Journal of Medicine and The Lancet, and the results have escalated generation on generation: one receptor produced a landmark, two receptors beat it, and three receptors have now produced the largest weight reductions ever recorded in a phase 3 trial. This article sets the three programmes side by side — what each trial measured, what it found, how the molecules have performed against each other, and where each stands with regulators as of August 2026.
Every statement here is a statement about a named trial, a regulator’s decision or a published figure; none is advice, and none is an offer. NovoVita does not sell semaglutide, tirzepatide or retatrutide — this article explains why — and documents them here because no serious reference to peptide research can leave them out.
One receptor, then two, then three
The three molecules are a deliberate progression. Semaglutide is a GLP-1 receptor agonist — one receptor, engineered for a week-long half-life. Tirzepatide adds a second incretin receptor, GIP, to the same scaffold idea. Retatrutide (Eli Lilly’s LY3437943) is a single peptide that agonises three receptors at once: GIP, GLP-1 and the glucagon receptor. The discovery paper in Cell Metabolism (Coskun et al., 2022) sets out the rationale for the third: in preclinical work, weight reduction combined incretin-driven reduction in intake with GCGR-mediated increases in energy expenditure
— the glucagon component asks the body to spend more energy while the incretin components reduce the appetite to replace it. All three are dosed once weekly by subcutaneous injection in their trials, each carrying a fatty-acid moiety that binds albumin and extends the half-life to roughly a week.
The headline numbers, side by side
Cross-trial comparison is indicative rather than definitive — different populations, durations and statistical estimands — but the published sequence is striking:
| Compound | Receptors | Pivotal trial | Participants | Duration | Weight change, top dose |
|---|---|---|---|---|---|
| Semaglutide 2.4 mg | GLP-1 | STEP 1 (NEJM 2021) | 1,961 | 68 weeks | −14.9% vs −2.4% placebo |
| Tirzepatide 15 mg | GIP + GLP-1 | SURMOUNT-1 (NEJM 2022) | 2,539 | 72 weeks | −20.9% vs −3.1% placebo* |
| Retatrutide 12 mg | GIP + GLP-1 + glucagon | Phase 2 (NEJM 2023) | 338 | 48 weeks | −24.2% vs −2.1% placebo |
| Retatrutide 12 mg | GIP + GLP-1 + glucagon | TRIUMPH-1 phase 3 (topline, May 2026) | 2,339 | 80 weeks | −25.0% to −28.3% vs −2.2% placebo† |
*SURMOUNT-1’s treatment-regimen figure; its efficacy estimand was −22.5%. †Trials report two estimands — “treatment-regimen” (everyone randomised, whether or not they stayed on the dose) and “efficacy” (on treatment as intended). TRIUMPH-1’s 12 mg arm was −25.0% on the first basis and −28.3% on the second. Coverage that quotes a single unlabelled percentage is usually mixing the two.
TRIUMPH-1 carried a further pre-specified extension: 532 participants with a baseline BMI of 35 or more continued to 104 weeks, and the 12 mg group reached −30.3% (efficacy estimand) — a mean of 85 lb, in territory previously associated with bariatric surgery. On the same estimand, 45.3% of the 12 mg arm at 80 weeks had lost at least 30% of body weight, and 65.3% finished with a BMI below 30. In the phase 2 trial, every participant on the two highest doses achieved at least 5% weight reduction — 100%, against 27% on placebo.
Tolerability follows the class pattern: the most common adverse events across all three molecules are gastrointestinal, dose-related and, in the NEJM phase 2 investigators’ words, mostly mild to moderate in severity
. Retatrutide adds one signal of its own — dysesthesia, an abnormal skin sensation, reported by 12.5% of the TRIUMPH-1 12 mg arm against 0.9% on placebo, described as mostly mild-to-moderate and resolving. Discontinuation for adverse events at that dose was 11.3% versus 4.9% on placebo.
In type 2 diabetes
The same ordering holds where the endpoint is glycaemic. In SURPASS-2, tirzepatide 15 mg reduced HbA1c by 2.30 percentage points against 1.86 for semaglutide 1 mg — superiority, in a 1,879-patient head-to-head at diabetes doses. Retatrutide’s phase 2 in The Lancet (2023) reported HbA1c reductions of 2.02 points at 24 weeks with weight reduction of 16.94% at 36 weeks on the top dose, with no severe hypoglycaemia and no deaths. The first phase 3 retatrutide paper in print anywhere is TRANSCEND-T2D-1 (The Lancet, June 2026): 537 adults, 40 weeks, HbA1c down 1.94 points and weight down 15.3% on 12 mg against 0.81 points and 2.6% on placebo. TRIUMPH-2 (topline, July 2026) extended that to 1,152 people with type 2 diabetes and obesity over 80 weeks: weight down up to 20.8% and HbA1c down up to 1.6 points from a 7.7% baseline. Diabetes blunts weight loss for every molecule in the class — the pattern is consistent from SURMOUNT-2 (−15.7% efficacy estimand) to TRIUMPH-2 — and the comparison between trials should be read with that in mind.
Head to head, directly
For semaglutide against tirzepatide the question has been answered in a dedicated trial. SURMOUNT-5 (NEJM 2025) randomised 751 adults with obesity to the maximum tolerated dose of each: tirzepatide produced −20.2% (22.8 kg) against semaglutide’s −13.7% (15.0 kg) at 72 weeks. The trial was open-label and sponsor-run — worth knowing — but a propensity-matched real-world cohort of more than 18,000 US adults (Truveta Research, JAMA Internal Medicine 2024) found the same direction: −15.3% versus −8.3% at twelve months. No published comparison shows the reverse ordering.
Retatrutide’s own head-to-heads are running now: TRIUMPH-5 (NCT06662383) tests it directly against tirzepatide in 800 participants, and TRANSCEND-T2D-2 against semaglutide in 1,250 people with type 2 diabetes. The cross-generation ordering that today rests on separate trials will shortly rest on direct randomised comparison.
Where each stands with regulators
Semaglutide is the most extensively licensed: in the UK it is a prescription-only medicine as Ozempic and Rybelsus (type 2 diabetes) and Wegovy (weight management, launched September 2023), with the licence extended to cardiovascular risk reduction in July 2024, a conditional authorisation for the liver condition MASH in July 2026, and — as of 11 June 2026 — the first GLP-1 tablet licensed for weight loss in the UK. Tirzepatide (Mounjaro) has held a UK weight-management authorisation since 8 November 2023 and became the first medicine the NHS prescribes for obesity in primary care, in a phased rollout that began in June 2025. Retatrutide is licensed nowhere, for anything: it remains an investigational medicine available only inside its trials, and Lilly has said it plans its first regulatory submission — a US filing covering obesity, knee osteoarthritis pain and obstructive sleep apnoea — in the first quarter of 2027. Lilly’s own summary of the programme: Across five positive Phase 3 studies, retatrutide has shown powerful efficacy, and we believe it could be an important future tool in the management of cardiometabolic health.
The regulatory status is why these compounds appear in this library and not in our catalogue: in the UK the first two may only be sold against a prescription, and the third may not lawfully be sold for human use at all. Vials offered online under the name “retatrutide” are a separate subject — examined, with the measured data on what users report, in the companion article on user reports.
What comes next
The field is compounding rather than settling. A 10,000-participant cardiovascular and kidney outcomes trial of retatrutide (TRIUMPH-Outcomes) is under way, alongside trials in weight maintenance, chronic low back pain and chronic kidney disease. Semaglutide’s 7.2 mg dose reached −20.7% in the STEP UP trial; CagriSema, the combination of semaglutide with the amylin analogue cagrilintide, delivered −22.7% in REDEFINE 1 and was filed with the FDA in December 2025; orforglipron, an oral small-molecule GLP-1 agonist, was approved in the US in April 2026; and amycretin advanced straight to phase 3 on early-phase results of −24.3%. The pattern of the last five years — each result exceeded within two — shows no sign of stopping. What the results have produced beyond weight is a story of its own: hearts, kidneys, livers, sleep apnoea and several new licences.
What this article does not settle
The TRIUMPH results are press-release and conference data: no TRIUMPH trial had a peer-reviewed primary paper as of late August 2026 (TRANSCEND-T2D-1 is the only phase 3 in print), so the figures above are Lilly’s reported topline, stated with their estimands. Cross-trial percentages compare different populations over different durations and are an ordering, not a measurement. And none of the trial figures says anything about what happens after treatment stops — the withdrawal and maintenance evidence is covered in the companion articles.
Sources
- Wilding JPH et al., Once-Weekly Semaglutide in Adults with Overweight or Obesity (STEP 1), NEJM 2021 — the −14.9% result.
- Jastreboff AM et al., Tirzepatide Once Weekly for the Treatment of Obesity (SURMOUNT-1), NEJM 2022 — both estimands and thresholds.
- Jastreboff AM et al., Triple-Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial, NEJM 2023 — the −24.2% result, thresholds, adverse-event profile.
- Coskun T et al., LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist, Cell Metabolism 2022 — the mechanism and energy-expenditure rationale.
- Rosenstock J et al., Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes, The Lancet 2023 — phase 2 HbA1c and weight figures.
- Bajaj HS et al., TRANSCEND-T2D-1, The Lancet, June 2026 — the first published phase 3 retatrutide trial.
- Eli Lilly, TRIUMPH-1 topline results (21 May 2026) and TRIUMPH-2 and TRIUMPH-3 topline results (23 July 2026) — phase 3 figures, estimands, safety table, the Q1 2027 filing plan.
- Aronne LJ et al., Tirzepatide as Compared with Semaglutide for the Treatment of Obesity (SURMOUNT-5), NEJM 2025 — the direct head-to-head.
- Truveta Research, real-world comparison published in JAMA Internal Medicine (2024) — the matched-cohort figures.
- Frías JP et al., Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes (SURPASS-2), NEJM 2021 — the HbA1c head-to-head at diabetes doses.
- MHRA, First GLP-1 tablet for weight loss approved in the UK (11 June 2026); MHRA, Mounjaro authorisation for weight management (8 November 2023); NHS England, interim commissioning guidance for tirzepatide — the UK licensing and rollout facts.
- ClinicalTrials.gov, TRIUMPH-5 and TRIUMPH-Outcomes — the running head-to-head and outcomes trials.