Tirzepatide, a dual GLP-1/GIP receptor agonist, induces substantial weight loss and cardiometabolic improvements in adults with obesity. However, the SURMOUNT-4 trial demonstrated that most participants regain weight upon discontinuation, raising questions about the durability of associated health benefits. The objective is to evaluate changes in cardiometabolic parameters stratified by the extent of weight regain following tirzepatide withdrawal in the SURMOUNT-4 trial.
This post hoc analysis examined 308 participants (71.1% female; mean age, 47.1 years) from a phase 3, multicenter, randomized withdrawal trial conducted from March 2021 to May 2023. All had received open-label tirzepatide (maximum tolerated dose of 10 or 15 mg weekly) for 36 weeks, achieving ≥10% weight reduction, and were subsequently randomized to placebo for 52 weeks (weeks 36-88). Participants had obesity (BMI ≥30) without diabetes. After 36 weeks of tirzepatide plus lifestyle intervention (500 kcal/day deficit diet and ≥150 min/week exercise), participants switched to matching placebo while continuing lifestyle measures.
Percent weight regain at week 88 relative to week 0-36 loss was categorized as <25% (n=54), 25% to <50% (n=77), 50% to <75% (n=103), or ≥75% (n=74). Changes from week 36 to 88 in waist circumference, blood pressure, lipids (triglycerides, non-HDL cholesterol, HDL cholesterol), glycemic markers (HbA1c, fasting glucose, insulin), and insulin resistance (HOMA2-IR) were assessed using mixed models for repeated measures, adjusted for baseline values, sex, country, and tirzepatide dose.
During initial treatment, mean weight decreased by 21.9%, with parallel improvements in cardiometabolic parameters (e.g., waist circumference -18.3 cm; systolic BP -10.8 mm Hg; HbA1c -0.47%). Post-withdrawal, weight increased dose-dependently (3.2% to 22.9%; P<.001). Cardiometabolic reversals escalated with regain: waist circumference rose 0.8 cm (<25%) to 14.7 cm (≥75%; P<.001); systolic BP 6.8 to 10.4 mm Hg (P=.002); non-HDL cholesterol -0.4% to 10.8% (P=.01); HbA1c 0.14% to 0.35% (P<.001); fasting insulin -4.0% to 46.2% (P<.001). Those with <25% regain showed non-significant changes in waist circumference, non-HDL cholesterol, and insulin versus week 36. Overall (week 0-88), ≥75% regainers reverted near baseline, while <50% maintainers retained most benefits. Tirzepatide withdrawal precipitates weight regain in most patients, proportionally eroding cardiometabolic gains. Sustained therapy is essential to maintain obesity-related health improvements.
Link: https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2841273#250656212
