Among participants with obesity who achieved ≥10% weight reduction following 36-week tirzepatide treatment, withdrawing tirzepatide led to a 25% or greater weight regain in most within one year, according to a post hoc analysis of the SURMOUNT-4 trial published in JAMA Internal Medicine. Furthermore, this was associated with a greater reversal of their initial cardiometabolic parameter improvements compared with participants who had maintained the weight reduction.

Following 36 weeks of either 10 or 15 mg tirzepatide treatment, 670 participants were randomized 1:1 to either an additional 52 weeks of treatment continuation or placebo.

Results at one year post withdrawal showed that among the 308 participants in the placebo arm (71% women; mean age, 47 years), 82% had a >25% weight regain. Only 54 participants regained <25% of lost weight, while 77 regained 25 to <50%, 103 regained 50 to <75% and 74 gained ≥75%.

Additionally, in the four categories of <25%, 25-<50%, 50-<75% and ≥75%, there was an increase by weight regain category for mean change in:

• Waist circumference (0.8 cm vs. 5.4 cm vs. 10.1 cm vs. 14.7 cm; p<0.001),
• Systolic blood pressure (6.8 mm Hg vs. 7.3 mm Hg vs. 9.6 mm Hg vs. 10.4 mm Hg; p=0.002),
• Non–HDL-C (–0.4% vs. 1.6% vs. 8.4% vs. 10.8%),
• Hemoglobin A1c (0.14% vs. 0.15% vs. 0.27% vs. 0.35%; p<0.001)
• Fasting insulin (–4.0% vs. 15.4% vs. 46.2% vs. 26.3%).

These one-year changes in waist circumference, non–HDL-C and fasting insulin in those with <25% weight regain were not significantly different compared to the start of tirzepatide withdrawal.

"These findings support the importance of long-term maintenance of weight reduction through lifestyle intervention and obesity management medications to sustain cardiometabolic benefits and improved health-related quality of life," write study authors Deborah B. Horn, DO, MPH, et al. "Together, these results may inform patient-clinician conversations and shared decision-making on long-term weight management focused on sustained health benefits and help counsel patients on the implications of treatment discontinuation."

"There is a common misconception that patients can stop antiobesity medications when they reach their goal weight and maintain the weight that they lost and the cardiometabolic benefits they achieved," Elizabeth Oczypok, MD, PhD, and Timothy S. Anderson, MD, MAS, write of the trial in an accompanying editorial comment. "One way that clinicians can negotiate with patients who are hesitant about continued use is to point out the improved cardiometabolic outcomes that patients may get from these medications."