Landmark head-to-head comparison
The SURMOUNT-5 trial (ClinicalTrials.gov: NCT05822830) is the first large-scale, randomised study to directly compare tirzepatide — Eli Lilly's dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist — against semaglutide, Novo Nordisk's selective GLP-1 receptor agonist, in adults with obesity or overweight with weight-related comorbidities.
Results were published in the New England Journal of Medicine in July 2025 (DOI: 10.1056/NEJMoa2503678). Eli Lilly announced that tirzepatide demonstrated superior weight loss compared to semaglutide at maximum tolerated doses over a 72-week treatment period.
Why this matters
Tirzepatide and semaglutide are the two most widely prescribed incretin-based weight-management therapies globally. Until SURMOUNT-5, no direct head-to-head trial had compared them at obesity-indicated doses. Previous cross-trial comparisons suggested tirzepatide might deliver greater weight reduction, but indirect comparisons are limited by differences in trial populations, dosing, and endpoints.
SURMOUNT-5 eliminates that ambiguity by randomising participants to one agent or the other under identical conditions, providing clinicians and researchers with the first apples-to-apples dataset.
Trial design
SURMOUNT-5 was an open-label, randomised clinical trial enrolling adults with a body mass index (BMI) of 30 or higher, or 27 or higher with at least one weight-related comorbidity (such as hypertension, dyslipidaemia, obstructive sleep apnoea, or cardiovascular disease). Participants were randomised to receive either tirzepatide or semaglutide, titrated to their maximum tolerated dose.
The primary endpoint was the percentage change in body weight from baseline. Key secondary endpoints included the proportion of participants achieving at least 5%, 10%, 15%, and 20% weight reduction.
Key findings
According to the published results and Lilly's announcement, tirzepatide demonstrated statistically superior weight loss compared to semaglutide across the primary endpoint. The full percentage changes and secondary endpoint data are detailed in the NEJM publication.
Both agents showed the adverse-event profiles consistent with their respective classes — predominantly gastrointestinal events such as nausea, diarrhoea, vomiting, and constipation. No new or unexpected safety signals were reported.
UK context
Both tirzepatide (marketed as Mounjaro for type 2 diabetes and Zepbound for weight management) and semaglutide (marketed as Ozempic for type 2 diabetes and Wegovy for weight management) are licensed medicines in the UK. They are classified as prescription-only medicines (POMs) and are regulated by the MHRA.
The National Institute for Health and Care Excellence (NICE) has recommended both agents for use within NHS specialist weight-management services under specific criteria. The SURMOUNT-5 data may inform future NICE technology appraisals and clinical guideline updates, particularly regarding treatment selection and sequencing.
It is important to note that the research-grade peptide forms of these compounds discussed in research communities are not licensed medicines and are not intended for human consumption. They are sold for laboratory and research purposes only.
What comes next
The SURMOUNT-5 results strengthen the evidence base for dual GIP/GLP-1 agonism over selective GLP-1 agonism for weight management. However, clinical decision-making involves factors beyond magnitude of weight loss alone, including tolerability, cost, availability, cardiovascular and metabolic outcomes, and individual patient characteristics.
Researchers and clinicians will be watching for longer-term follow-up data, including cardiovascular outcome trials and real-world evidence, to confirm whether the superiority seen in SURMOUNT-5 translates into sustained clinical benefit.
This article is AI-researched and editorially reviewed. It is provided for research and educational purposes only and is not medical advice. Research peptides are not licensed for human consumption in the UK.