GLP-1 Drugs and Insulin Resistance: What the HOMA-IR Data Show

Semaglutide and tirzepatide reduce insulin resistance, and in the trials most of the improvement tracked the weight people lost. On tirzepatide, insulin resistance measured by HOMA-IR fell by about 60% in those who lost the most weight, and it began falling even with modest losses.^[4] Insulin resistance on its own is not an approved reason to take either drug, though; the labels cover weight and specific conditions, not this.^[7][8]

What insulin resistance is

Insulin moves sugar from the blood into cells. In insulin resistance, the cells of the muscles, fat and liver do not respond to it well, and over time the pancreas may not make enough insulin to overcome that, so glucose builds up in the blood.^[1] It usually causes no symptoms, which is why many people learn about it only when a blood test shows prediabetes.^[1]

There is no routine clinical test. The test for insulin resistance is used mainly in research studies, and doctors often do not test for it at all.^[1] Trials report either HOMA-IR, a score calculated from fasting glucose and fasting insulin where a lower number means better insulin sensitivity, or the clamp, a laboratory procedure that measures how much glucose the body takes up under a fixed insulin infusion.^[5] A related sign some people notice is dark, velvety skin in body folds, covered in acanthosis nigricans and weight loss.

The first three are the ADA’s tests for prediabetes.^[10] They detect raised blood sugar, and none of them measures insulin resistance directly; the tests that do are used mainly in research.^[1]

What the trials measured

In adolescents the effect was large: fasting insulin fell by a third on semaglutide, and teenagers who lost 20% or more of their BMI improved most.^[6] The bloodwork from that trial is examined in what changed in the teenagers’ bloodwork.

Is it the drug or the weight loss?

Mostly the weight loss, on the evidence so far. When STEP 1 participants were grouped by how much weight they lost, people on semaglutide and people on placebo who lost the same amount had similar changes in fasting insulin and HOMA-IR. The authors concluded the improvement appeared to come mainly from the greater weight loss on the drug.^[2] The tirzepatide analysis likewise found HOMA-IR fell more the more weight people lost, with the steepest change between less than 5% and about 20% loss.^[4]

Tirzepatide may add something beyond weight. In a 28-week trial using clamps, the most precise measure, tirzepatide improved insulin sensitivity more than semaglutide for each unit of weight lost, and the authors wrote that the difference was not simply explained by greater weight or fat loss.^[5] That study was in people with type 2 diabetes, it was exploratory, and it compared the 1 mg diabetes dose of semaglutide rather than the 2.4 mg weight dose. The wider question of how much any GLP-1 benefit depends on weight is taken up in is it just the weight loss?

The improvement lasts only while treatment does. In STEP 4, gains in fasting insulin and blood sugar made during 20 weeks of semaglutide were kept by those who stayed on it and lost by those switched to placebo.^[2]

Is insulin resistance an approved use?

No. Zepbound’s label covers long-term weight management, for people with obesity or for people who are overweight and have a weight-linked health problem, and moderate to severe sleep apnea in people with obesity. Wegovy is approved for weight reduction, for reducing cardiovascular events in people with established heart disease and overweight or obesity, and for a form of fatty liver disease.^[7][8] Neither label mentions insulin resistance. Someone with insulin resistance who also meets the weight criteria can be prescribed one for weight; someone at a lower weight with insulin resistance alone would be taking it off-label.

Guidance on drugs for insulin resistance as such is sparse. The ADA’s 2026 Standards of Care mention it in one recommendation: pioglitazone may be considered in people with a past stroke, evidence of insulin resistance and prediabetes, to lower the risk of another stroke or a heart attack.^[9] For preventing diabetes, metformin is the drug the ADA names, and no medicine is FDA-approved specifically for that purpose.^[9] The comparison with metformin in polycystic ovary syndrome, where insulin resistance is common, is in GLP-1 drugs for PCOS.

What this means for you

• Measure what can be measured. HbA1c and fasting glucose are routine and show whether insulin resistance has reached the point of raising blood sugar. Whether a continuous glucose monitor adds anything for people without diabetes is covered in CGMs without diabetes.
• Weight loss is the main lever, however it is achieved. In the trials, insulin sensitivity improved in proportion to the weight lost, and even modest losses moved HOMA-IR.^[4]
• Eligibility is by weight. The BMI calculator shows whether you meet the label criteria for a weight indication.

Blood pressure, another number that moves with weight on these drugs, is covered in GLP-1 drugs and blood pressure.