SURPASS trial programme (revision 21)
Old revision·00:47, 29 Jun 2025·ParentCatPansy
| SURPASS trial programmePhase 3 programme | |
|---|---|
| Drug | Tirzepatide 5, 10 and 15 mg weekly |
| Indication | Type 2 diabetes |
| Notable member | SURPASS-2, head-to-head with semaglutide |
| Topic infobox · conventions | |
The SURPASS trial programme is the phase 3 series that established tirzepatide for type 2 diabetes. Its trials compared tirzepatide at 5, 10 and 15 mg weekly against placebo, semaglutide 1 mg, insulin degludec, insulin glargine and dulaglutide.[1]
Glycated-haemoglobin reductions across the programme were larger than those reported for any comparator, reaching about 2.0–2.6 percentage points at the higher doses depending on trial and baseline. Weight reduction accompanied them at every dose.[1]
SURPASS-2 is the most cited member because it is a direct head-to-head against semaglutide. The comparator dose was 1 mg — the diabetes dose — not the 2.4 mg used in obesity, a distinction routinely omitted when the trial is summarised.[1]
Constituent trials
[edit]| Trial | Comparator | Notes |
|---|---|---|
| SURPASS-1 | Placebo | Monotherapy in drug-naive participants |
| SURPASS-2 | Semaglutide 1 mg | Open-label head-to-head |
| SURPASS-3 | Insulin degludec | Added to metformin ± SGLT2 inhibitor |
| SURPASS-4 | Insulin glargine | High cardiovascular risk population |
| SURPASS-5 | Placebo | Added to insulin glargine |
| SURPASS-CVOT | Dulaglutide | Cardiovascular outcomes, active comparator |
SURPASS-CVOT is unusual among cardiovascular outcome trials in using an active comparator with an established benefit rather than placebo, which changes what a non-inferiority result means: non-inferiority to an agent that itself reduced events is a stronger statement than non-inferiority to placebo.[1]
Open-label design in SURPASS-2 is a limitation for subjective endpoints and adverse-event reporting, though less so for glycated haemoglobin, which is a laboratory measurement.[2]
The head-to-head comparison
[edit]SURPASS-2 randomised 1,879 participants on metformin to tirzepatide 5, 10 or 15 mg or semaglutide 1 mg, for 40 weeks. Glycated-haemoglobin reduction was 2.01, 2.24 and 2.30 percentage points on tirzepatide against 1.86 on semaglutide; weight reduction was 7.6, 9.3 and 11.2 kg against 5.7 kg.[1]
The result is a genuine head-to-head at the doses studied, and the doses studied were the approved diabetes doses of both agents at the time. It is not a comparison of maximal doses, and it is not evidence about the obesity indication, where the relevant comparison is between SURMOUNT and STEP — which are separate trials in separate populations and therefore not a head-to-head at all.[3]
Cross-trial comparison of SURMOUNT-1 with STEP 1 is made constantly and is not sound: the populations, durations, escalation schedules and lifestyle interventions differ.[2]
What the programme establishes
[edit]It establishes glycaemic efficacy in type 2 diabetes across a range of background therapies, superiority to the specific comparators at the specific doses studied, and the adverse-effect profile at those doses.[1]
It does not establish superiority at maximal doses of the comparators, nor efficacy or safety in populations outside those studied, nor cardiovascular superiority — SURPASS-CVOT was designed against an active comparator.
The consistent finding across the programme is a dose–response relationship for both glycaemic and weight endpoints that had not clearly plateaued at 15 mg, which is one reason the obesity programme studied the same top dose rather than a higher one.[3] The dose range itself was set by the receptor pharmacology established preclinically.[4]
See also
References
- ^ a b c d e f Frías JP, Davies MJ, Rosenstock J, et al. "Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes." New England Journal of Medicine 385(6):503–515 (2021). DOI:10.1056/NEJMoa2107519. PMID 34170647.
- ^ a b International Council for Harmonisation, E9(R1): Estimands and Sensitivity Analysis in Clinical Trials (2019).
- ^ a b Jastreboff AM, Aronne LJ, Ahmad NN, et al. "Tirzepatide once weekly for the treatment of obesity." New England Journal of Medicine 387(3):205–216 (2022). PMID 35658024.
- ^ Coskun T, Sloop KW, Loghin C, et al. "LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus." Molecular Metabolism 18:3–14 (2018). PMID 30473097.