Publications of the Week: Losing vs maintaining reduced weight with tirzepatide: Which is easier?



Aronne LJ, Sattar N, Horn DB, et al; SURMOUNT-4 Investigators. Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity: The SURMOUNT-4 Randomized Clinical Trial. JAMA. 2024 Jan 2;331(1):38-48. doi: 10.1001/jama.2023.24945. PMID: 38078870; PMCID: PMC10714284.

Background: An increasing number of medications associated with substantial weight loss are available for clinical use, but the effect of their discontinuation on weight regain is unclear. This study examined the effect of discontinuation of tirzepatide, a combined glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist.

Methods: The study included 670 patients (mean age, 48 years; 71% women; mean body mass index [BMI], 38 kg/m2) who initially received tirzepatide for 36 weeks: the starting dose was 2.5 mg weekly and was increased every 4 weeks to a maximum tolerated dose of 10 to 15 mg. After a 36-week open treatment lead-in period, patients who attained the maximum tolerated dose of tirzepatide were randomized to continue active treatment or to receive placebo for 52 weeks.

Results: During the initial 36-week period of active treatment, the participants lost on average 20.9% of their original weight. During the subsequent 52-week treatment period, tirzepatide treatment resulted in an additional weight loss of 5.5% versus a 14% weight regain with placebo. Overall, 92% of patients continuing tirzepatide treatment and 46% of patients switching to placebo achieved >10% weight loss by the end of the study. The improvement in metabolic parameters (hemoglobin A1c, fasting glucose, insulin, lipids, and blood pressure) observed during active treatment was partially lost after treatment discontinuation. Treatment discontinuation during the lead-in phase occurred in 7.0% of patients, mainly due to gastrointestinal adverse effects (nausea, diarrhea, vomiting).

Conclusions: Withdrawal of tirzepatide results in regain of a major portion of the originally lost weight and partial reversal of the originally lowering metabolic parameters.

McMaster editors’ commentary: Similarly to other drug therapies for weight loss, withdrawal of active treatment resulted (unfortunately) in at least partial reversal of the presumably beneficial effects of treatment. The longer-term benefits of persisting changes (legacy effect) are not clear. In the meantime, it appears that in the majority of (but not all) individuals, maintaining weight loss requires continuation of medication use.

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