Summary: In a post hoc analysis of the SURPASS-2 phase 3 trial (n=1879), once-weekly tirzepatide (5, 10, 15 mg) produced larger increases in HOMA2-B (96.9 to 120.4% vs 84.0%) and larger reductions in HOMA2-IR (15.5 to 24.0% vs 5.1%) than semaglutide 1 mg at 40 weeks (all P<.05). These are biomarker, not hard clinical, endpoints, and the analysis was sponsored by the manufacturer of tirzepatide.
PICO Summary
| Element | Detail |
|---|---|
| Population | 1879 adults with type 2 diabetes; post hoc analysis of the double-blind SURPASS-2 phase 3 randomised trial across 128 sites in 8 countries. |
| Intervention | Once-weekly subcutaneous tirzepatide (dual GIP and GLP-1 receptor agonist) at 5, 10, or 15 mg for 40 weeks. |
| Comparison | Once-weekly subcutaneous semaglutide 1 mg (GLP-1 receptor agonist), the active comparator arm of SURPASS-2. |
| Outcome | At week 40, HOMA2-B increased more with tirzepatide (96.9 to 120.4%) than semaglutide (84.0%), P<.05. HOMA2-IR fell more with tirzepatide (15.5 to 24.0%) than semaglutide (5.1%), P<.05. Tirzepatide 10 and 15 mg reduced fasting C-peptide (5.2 to 6.0%) and fasting glucagon (53.0 to 55.3%), versus a 3.3% C-peptide rise and 47.7% glucagon reduction with semaglutide, P<.05. HbA1c and weight reductions were consistently and significantly greater with tirzepatide across every HOMA2-B and HOMA2-IR baseline quartile. Confidence intervals, absolute risk reduction and number needed to treat were not reported for these biomarker endpoints. |
SURPASS-2: Tirzepatide vs Semaglutide on Beta-Cell Function
Post hoc RCT · type 2 diabetes · 40 weeks
In this manufacturer-sponsored post hoc analysis, tirzepatide improved modelled beta-cell function (HOMA2-B) and insulin sensitivity (HOMA2-IR) more than semaglutide 1 mg. These are surrogate biomarkers, not clinical outcomes, and the signal is hypothesis-generating.
Expert Commentary
This is a post hoc, exploratory analysis of surrogate biomarkers from a trial whose primary purpose was glycaemic and weight efficacy, so the findings are best read as mechanistic, hypothesis-generating signals rather than confirmation of a clinical advantage. Within those limits, the data are internally consistent: across all three doses, tirzepatide moved HOMA2-derived indices of beta-cell function and insulin sensitivity further than semaglutide 1 mg, and the benefit held within every baseline quartile, which argues against the effect being driven by a small subgroup. The central caveat is that HOMA2-B and HOMA2-IR are modelled estimates from fasting glucose, insulin, and C-peptide, not direct measures of insulin secretion or peripheral sensitivity, and they have not been shown to predict long-term outcomes; multiplicity across doses and biomarkers also inflates the chance of spurious significance. Sponsorship by the manufacturer of tirzepatide, with several authors employed by the company, is a further reason for measured interpretation. Can I use this with my patients? Not as a stand-alone reason to choose tirzepatide; the better-established case rests on its head-to-head HbA1c and weight data, with these biomarkers offering supportive mechanistic context. Confirmatory analyses tied to durable clinical endpoints would strengthen the story considerably.
References
Frias JP, De Block C, Brown K, Wang H, Thomas MK, Zeytinoglu M, Maldonado JM. Tirzepatide Improved Markers of Islet Cell Function and Insulin Sensitivity in People With T2D (SURPASS-2). J Clin Endocrinol Metab. 2024;109(7):1745-1753. doi:10.1210/clinem/dgae038
