HbA1c reduction with tirzepatide in people with type 2 diabetes: The contribution of weight loss assessed by a mediation analysis

Aug 1, 2025Diabetes, obesity & metabolism

How weight loss may contribute to blood sugar improvement with tirzepatide in type 2 diabetes

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Abstract

The difference in mean HbA1c change from baseline at 40 weeks between tirzepatide and placebo ranged from -20.0 to -14.6 mmol/mol.

  • Mediation analysis showed 12%-27% of the HbA1c reduction difference between tirzepatide and placebo was linked to weight loss when tirzepatide was used alone.
  • When tirzepatide was used alongside insulin with or without metformin, 25%-45% of the HbA1c difference was associated with weight loss.
  • Comparing tirzepatide with semaglutide, weight loss accounted for 54%-71% of the observed difference in HbA1c changes.
  • Tirzepatide's effects on HbA1c reduction were associated with both weight loss-dependent and weight loss-independent mechanisms.
  • The contribution of weight loss to glycaemic efficacy varied depending on the comparator, being more significant against semaglutide than placebo.

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Key numbers

-20.0 to -14.6 mmol/mol
HbA1c Reduction vs. Placebo
Difference in mean HbA1c change at Week 40.
12%–27%
Weight Loss Mediation Percentage
Mediation analysis in placebo-controlled trials.
54%–71%
Weight Loss Mediation Percentage vs. Semaglutide
Mediation analysis comparing tirzepatide to semaglutide 1 mg.

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