Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity: The SURMOUNT-4 Randomized Clinical Trial
Aronne LJ, Sattar N, Horn DB, Bays HE, Wharton S, Lin WY
JAMA (2024) · n=670
Stopping tirzepatide after 36 weeks of successful weight loss produced 14.0% weight regain over the next year versus continued loss of 5.5% on the active drug — the discontinuation curve that frames every clinical conversation about GLP-1 cessation.
SURMOUNT-4 is the tirzepatide-discontinuation trial that the chronic-pharmacotherapy framing of obesity treatment now rests on. The study had a two-phase design: a 36-week open-label lead-in during which 783 enrolled adults with obesity (BMI ≥30, or ≥27 with at least one weight-related complication, without diabetes) received once-weekly tirzepatide titrated to maximum tolerated dose (10 or 15 mg). During the lead-in, mean weight loss was 20.9%. The 670 participants who completed the lead-in were then randomized 1:1 to either continue tirzepatide or switch to placebo for a 52-week double-blind maintenance period (weeks 36-88), with the primary endpoint being mean percent weight change from randomization to week 88. Mean age was 48 years, 71% female, mean baseline weight 107.3 kg. Mean percent weight change from week 36 to week 88 was -5.5% in the continued-tirzepatide arm versus +14.0% in the placebo arm — a treatment difference of -19.4 percentage points (p < 0.001). Eighty-nine point five percent of tirzepatide-continued participants maintained at least 80% of their lead-in weight loss versus 16.6% in the placebo arm. Cumulative weight loss from study baseline to week 88 was 25.3% on continued tirzepatide versus 9.9% on placebo. Adverse events were mostly mild-to-moderate gastrointestinal events, more frequent on tirzepatide than on placebo as expected.
The trial design is a deliberate "randomized withdrawal" pattern — participants who tolerated and responded to 36 weeks of tirzepatide were the population eligible for randomization, which positively selects for both tolerability and efficacy. Real-world discontinuation populations will include patients who stopped earlier for adverse events, cost, or response failure; the 14% weight regain figure should be read as the maintenance-population estimate, not a universal post-stop trajectory. The 52-week post-randomization window captures the steepest part of the regain curve but does not establish the long-term plateau — whether regain continues past 52 weeks toward full pre-treatment weight, partially stabilizes, or plateaus at a new set point is unaddressed. A 2025 post hoc analysis (Horn et al., JAMA Intern Med) extends the analysis to cardiometabolic parameters and reports that the cardiometabolic improvements during the lead-in (blood pressure, lipids, HbA1c) regress in proportion to weight regain in the placebo arm — clinically the more important finding for chronic-care framing. Industry sponsorship by Eli Lilly is disclosed.
07·Member discussion
No member discussion yet.
Member-only conversation lives here — cycle notes, practitioner commentary, pattern-matching. Be the first paying member to start the thread.