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What Causes What
MECHANISM− DECREASES

GLP-1 receptor agonist → Insulin resistance (HOMA-IR)

Higher GLP-1 receptor agonist decreases Insulin resistance (HOMA-IR).

In 1,879 people with type 2 diabetes, weekly tirzepatide cut HOMA2 insulin resistance by about 16 to 24 percent, more than weekly semaglutide 1 mg (Frias 2024). A clamp study found the same direction versus placebo (Heise 2022).

Randomized trial · Moderate · N=1879

Supported by an experiment or a tightly identified design. Read the caveats.

Mechanism

These drugs raise insulin when glucose is high and cut glucagon. Weight then falls. Both paths can make insulin work better. A clamp measures that directly. HOMA2-IR is a fasting worksheet. Heise, Mari, DeVries and colleagues (2022) assigned adults with type 2 diabetes on metformin to weekly tirzepatide 15 mg, semaglutide 1 mg, or placebo for 28 weeks. The primary end point was change in the clamp disposition index versus placebo. Insulin sensitivity (M value) and secretion both moved. abstract_only. A meal-test look at the same trial (Mather 2024) found a larger gain in model insulin sensitivity on tirzepatide than on semaglutide, with less total insulin secreted for the glucose that remained. abstract_only. Frias, De Block, Brown and colleagues (2024) looked back at SURPASS-2: 1,879 people assigned to tirzepatide 5, 10, or 15 mg or semaglutide 1 mg for 40 weeks. HOMA2-IR fell 15.5 to 24.0 percent on tirzepatide versus 5.1 percent on semaglutide. full_text. Kosiborod 2023 found HOMA-IR fell more on semaglutide 2.4 mg than on placebo in STEP 1, people with overweight or obesity and no diabetes. full_text.

Caveats

Someone was assigned a pen, so the stamp is an RCT stamp. The living page is named for HOMA-IR. Heise used a clamp. SURPASS-2 used HOMA2-IR and had no placebo arm. These are people with type 2 diabetes (Heise, SURPASS-2) or obesity without diabetes (STEP). The kilograms that fall with the pen carry a large share of the HOMA change. Did not hang the SELECT adiposity-and-events file (p-pmid-41138739): that is waist and MACE, not HOMA. Did not hang Chen 2025 (p-pmid-40713699): semaglutide stacked on metformin in PCOS. Did not hang the SURMOUNT weight-loss-bin HOMA look or the four-trial PCOS meta-analysis. This page is a journal entry. It is not medical advice and not a reason to start or stop a drug.

Effect

percent_change = -24. SURPASS-2 HOMA2-IR -15.5 to -24.0% tirzepatide vs -5.1% semaglutide 1 mg, N=1879 T2D. Heise 2022 clamp M vs placebo. STEP 1 HOMA-IR vs placebo.

Nodes

Lifestyle & environmentGLP-1 receptor agonistBiology & endocrinologyInsulin resistance (HOMA-IR)

Named confounders

Cite this page

What Causes What. “GLP-1 receptor agonist → Insulin resistance (HOMA-IR).” https://whatcauseswhat.org/edges/e-glp1-insulin (atlas updated 2026-09-02).

https://whatcauseswhat.org/edges/e-glp1-insulin

Papers