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Randomized Controlled Trial
. 2025 Mar;27(3):1507-1514.
doi: 10.1111/dom.16159. Epub 2025 Jan 6.

Greater improvement in insulin sensitivity per unit weight loss associated with tirzepatide versus semaglutide: An exploratory analysis

Kieren J Mather  1 , Andrea Mari  2 , Govinda Weerakkody  1 , Tim Heise  3 , J Hans DeVries  3 , Shweta Urva  1 , Tamer Coskun  1 , Zvonko Milicevic  1 , Axel Haupt  1 , Melissa K Thomas  1
Affiliations
Randomized Controlled Trial

Greater improvement in insulin sensitivity per unit weight loss associated with tirzepatide versus semaglutide: An exploratory analysis

Kieren J Mather et al. Diabetes Obes Metab. 2025 Mar.

Abstract

Aims: To explore the relationship between weight loss and insulin sensitivity in response to tirzepatide or semaglutide.

Materials and methods: We conducted a post hoc exploratory analysis of a 28-week, double-blind, randomized trial in people with type 2 diabetes treated with metformin, randomized to tirzepatide 15 mg, semaglutide 1 mg or placebo. We evaluated the relationship between change in body weight and change in insulin sensitivity determined from hyperinsulinemic euglycemic clamp (M value), or from mixed-meal tolerance testing (Matsuda index).

Results: Tirzepatide was associated with a greater improvement than semaglutide in insulin sensitivity assessed using hyperinsulinemic euglycemic clamps (p < 0.001). With tirzepatide, improvements in insulin sensitivity were associated with percent change in weight (R = -0.656, p < 0.0001). With semaglutide, change in insulin sensitivity was less strongly correlated with percent change in weight (R = -0.268, p = 0.0820; p = 0.0242 vs. tirzepatide). In regression analyses, the slope of the relationship between change in M value and change in weight was statistically different between semaglutide and tirzepatide (p = 0.0461). These relationships were also assessed using the Matsuda index as the metric of insulin sensitivity, and using change in fat mass as the determinant of change in insulin sensitivity.

Conclusions: Improvement in insulin sensitivity was proportional to weight and fat loss, with greater strength of association with tirzepatide. In regression analysis, tirzepatide was associated with greater improvement in insulin sensitivity per unit weight loss than semaglutide. The greater improvement in insulin sensitivity following treatment with tirzepatide was not simply attributable to greater weight or fat loss.

Keywords: GIP; GLP‐1; insulin sensitivity; tirzepatide; weight loss.

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References

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