Obesity management: Stopping tirzepatide leads to substantial regain of weight

Tirzepatide (brand name Mounjaro) is now approved in Canada for use in the treatment of type 2 diabetes in adults.1 Although tirzepatide is not yet approved as a weight loss agent in Canada, it recently gained such approval in the United States (brand name Zepbound).2 In the United States, Zepbound is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of ≥ 30 kg/m2 (obesity), or ≥ 27 kg/m2 (overweight) plus at least one weight-related comorbid condition (e.g., hypertension, dyslipidemia, type 2 diabetes, obstructive sleep apnea, cardiovascular disease).2Tirzepatide has proven effective as a weight loss agent, but the effect of continued treatment with tirzepatide on maintenance of initial weight reduction is unknown. In addition, the effects of withdrawing tirzepatide after successful initial weight reduction is not well studied. A new clinical trial was undertaken to examine these issues.3 Read: No more 'food orgy’? New obesity medications change how users think of holiday mealsThe SURMOUNT-4 study assessed the effect of continued treatment with the maximum tolerated dose of once-weekly subcutaneous tirzepatide (i.e., 10 mg or 15 mg), compared with placebo, on the maintenance of weight reduction. The study included adults with a body mass index ≥ 30…or ≥ 27 and a weight-related complication, excluding diabetes. The initial 36-week open-label lead-in treatment period (n=783) was followed by a 52-week, double-blind, placebo-controlled period in which 670 participants were randomized (1:1) to continue receiving tirzepatide (n=335) or switch to placebo (n=335). Throughout the 88-week trial, all participants received lifestyle counselling to encourage adherence to a healthy 500 kcal/d deficit diet and at least 150 minutes of physical activity per week.3Results showed the following:The 670 participants (mean age, 48 years; 71% women; mean weight, 107.3 kg) who completed the 36-week lead-in period experienced a mean weight reduction of 20.9%. The mean percent weight change from week 36 to week 88 was −5.5% with tirzepatide vs +14.0% with placebo (difference, −19.4% [95%CI, −21.2% to −17.7%]; p < 0.001).Overall, 89.5% of participants receiving tirzepatide at week 88 had maintained at least 80% of the weight loss during the lead-in period compared with 16.6% receiving placebo (p < 0.001). The overall mean weight reduction from week 0 to 88 was 25.3% for tirzepatide and 9.9% for placebo. The most frequent adverse effects were mild to moderate gastrointestinal events, which were more common with tirzepatide than placebo.During the 52-week double-blind period of the trial, the most common gastrointestinal events reported with tirzepatide versus placebo were diarrhea (10.7% vs 4.8%), nausea (8.1% vs 2.7%) and vomiting (5.7% vs 1.2%). Most gastrointestinal events decreased over time in the tirzepatide group during the 36-week lead-in period and leveled off during the 52-week double-blind period.3The investigators concluded that withdrawing tirzepatide in patients with obesity or overweight led to substantial regain of lost weight. However, when treatment with tirzepatide was continued, the initial weight reduction was maintained and even augmented.3The authors emphasize the need to continue pharmacotherapy to prevent weight regain and ensure the maintenance of weight reduction and its associated cardiometabolic benefits. Obesity is a chronic metabolic condition similar to hypertension or type 2 diabetes and requires long-term therapy in most patients.3References1. 2. Eli Lilly Canada Inc. Mounjaro (tirzepatide injection) product monograph. Toronto, ON; November 1, 2023. https://pdf.hres.ca/dpd_pm/00073189.PDF (accessed December 12, 2023).2. Eli Lilly and Company. Zepbound (tirzepatide ) prescribing information. Indianapolis, IN; 2023. https://pi.lilly.com/us/zepbound-uspi.pdf (accessed December 12, 2023).3. Aronne LJ, Sattar N, Horn Db, et al; for the SURMOUNT-4 Investigators. Continued treatment with tirzepatide for maintenance of weight reduction in adults with obesity. The SURMOUNT-4 randomized clinical trial. https://jamanetwork.com/journals/jama/fullarticle/2812936 (accessed December 12, 2023).

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