Modest weight regain after tirzepatide does not undo its metabolic benefits, study finds

A three-year study reveals that slight weight regain following tirzepatide therapy does not significantly diminish its positive effects on blood sugar and other metabolic markers in individuals with obesity and prediabetes.

A three-year analysis from the SURMOUNT-1 trial suggests that modest weight regain after tirzepatide therapy does not necessarily erase the drug’s broader metabolic benefits. Writing in Obesity Pillars, researchers led by Louis J. Aronne of Weill Cornell Medicine reported that most participants with obesity or overweight and prediabetes who had reached their lowest weight on tirzepatide regained relatively little by the end of the study, while remaining far healthier than they had been at the start.

The analysis looked at 690 participants who had taken at least 75% of their assigned doses and lost at least 5% of their body weight before reaching a nadir, or lowest point, during treatment. They had been assigned to 5 mg, 10 mg or 15 mg once-weekly tirzepatide and were followed for 176 weeks, with an additional 17 weeks after stopping the drug. By week 176, average regain from the nadir was 3.6% of baseline body weight in the 5 mg group, 4.1% in the 10 mg group and 3.5% in the 15 mg group, and 70% of participants across all doses had regained less than 5% of their starting weight, according to the report in Obesity Pillars.

Even among those who regained some weight, the metabolic gains were largely preserved. Participants who had regained less than 5% of baseline weight kept a median 94.8% of the weight they had lost at their nadir, while those in the 5% to less than 10% band retained 69.9% and those who regained at least 10% retained 44.3%. More than 90% of participants converted from prediabetes to normal blood sugar by week 176 regardless of how much weight they had put back on, and even in the group with the largest regain, 91% remained normoglycaemic. Blood pressure improvements weakened somewhat in the highest-regain group, but benefits on lipids and HbA1c were maintained.

That finding builds on the original SURMOUNT-1 trial, which showed that tirzepatide produced substantial weight loss over 72 weeks in adults with obesity. The American College of Cardiology’s trial summary reported mean reductions of 15.0% with 5 mg, 19.5% with 10 mg and 20.9% with 15 mg, compared with 3.1% for placebo, alongside improvements in waist circumference and blood pressure. Lilly’s own report on the study put the 15 mg weight loss even higher, at 22.5%, underscoring how strongly the drug affected body weight before any later regain was considered.

The new analysis is not without limits. It only included people with prediabetes, so the findings may not apply to everyone using tirzepatide for weight management. Waist-to-height ratio was the only cardiometabolic marker tracked at baseline, at weight nadir and at week 176, and the post hoc design means the results should be viewed as hypothesis-generating rather than definitive. Still, the overall message is straightforward: for patients who stay on treatment, a small amount of weight regain may be less clinically important than once assumed, provided the wider metabolic response remains intact.