Abstract
Importance The effect of continued treatment with tirzepatide on maintaining initial weight reduction is unknown.
Objective To assess the effect of tirzepatide, with diet and physical activity, on the maintenance of weight reduction.
Introduction
Obesity is a serious chronic, progressive, and relapsing disease. Lifestyle interventions are a cornerstone of obesity management; however, sustaining weight reduction achieved through lifestyle-based caloric restriction is challenging.
Therefore, current guidelines recommend adjunctive antiobesity medications to promote weight reduction, facilitate weight maintenance, and improve health outcomes in people with obesity. Randomized withdrawal studies of antiobesity medications to date have consistently demonstrated clinically significant body weight regain with cessation of therapy. There is also evidence that antiobesity medications, including long-acting glucagon-like peptide-1 (GLP-1) receptor agonists, naltrexone/bupropion, phentermine/topiramate, and orlistat, may help maintenance of achieved weight reduction.
Tirzepatide is a single molecule that combines glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonism resulting in synergistic effects on appetite, food intake, and metabolic function. Tirzepatide is approved in many countries, including the US, EU, and Japan, as a once-weekly subcutaneous injectable for type 2 diabetes and for the treatment of obesity in the US and UK. In a placebo-controlled trial of participants with obesity or overweight without diabetes, tirzepatide led to mean reductions in body weight up to 20.9% after 72 weeks of treatment.
The aim of the SURMOUNT-4 trial was to investigate the effect of continued treatment with the maximum tolerated dose (ie, 10 or 15 mg) of once-weekly tirzepatide, compared with placebo, on the maintenance of weight reduction following an initial open-label lead-in treatment period in participants with obesity or overweight...
Discussion
The SURMOUNT-4 trial results emphasize the need to continue pharmacotherapy to prevent weight regain and ensure the maintenance of weight reduction and its associated cardiometabolic benefits.At least 5 trials (including the present study) across various classes of medications, including potent antiobesity medications such as semaglutide, have demonstrated that weight is substantially regained after cessation of pharmacotherapy.
The consistency of these data across therapeutic classes spanning more than 2 decades suggests that obesity is a chronic metabolic condition similar to type 2 diabetes and hypertension requiring long-term therapy in most patients.
A notable finding in the SURMOUNT-4 trial is that after switching to placebo for 1 year, participants ended the study with substantial body weight reduction (9.9%). However, much of their initial improvement in cardiometabolic risk factors had been reversed. Further studies are needed to understand the potential long-term benefits and risks (ie, legacy effects) of such short-term therapy.
The health benefits seen with continued treatment with the maximum tolerated dose of tirzepatide during this study were achieved with a safety profile consistent with that previously reported in SURMOUNT and SURPASS trials and in studies of incretin-based therapies approved for the treatment of obesity and overweight.
The strengths of this study include its large sample size and the randomized withdrawal design. The duration of the open-label lead-in period allowed the study to assess the maintenance of body weight reduction. Dose escalation protocols during the open-label lead-in period helped to maximize tolerability and reflect dose adjustment strategies that may be helpful to future prescribers...
Design, Setting, and Participants This phase 3, randomized withdrawal clinical trial conducted at 70 sites in 4 countries with a 36-week, open-label tirzepatide lead-in period followed by a 52-week, double-blind, placebo-controlled period included adults with a body mass index greater than or equal to 30 or greater than or equal to 27 and a weight-related complication, excluding diabetes.
Interventions Participants (n = 783) enrolled in an open-label lead-in period received once-weekly subcutaneous maximum tolerated dose (10 or 15 mg) of tirzepatide for 36 weeks. At week 36, a total of 670 participants were randomized (1:1) to continue receiving tirzepatide (n = 335) or switch to placebo (n = 335) for 52 weeks.
Main Outcomes and Measures The primary end point was the mean percent change in weight from week 36 (randomization) to week 88. Key secondary end points included the proportion of participants at week 88 who maintained at least 80% of the weight loss during the lead-in period.
Results Participants (n = 670; mean age, 48 years; 473 [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 < .001). Overall, 300 participants (89.5%) receiving tirzepatide at 88 weeks maintained at least 80% of the weight loss during the lead-in period compared with 16.6% receiving placebo (P < .001). The overall mean weight reduction from week 0 to 88 was 25.3% for tirzepatide and 9.9% for placebo. The most common adverse events were mostly mild to moderate gastrointestinal events, which occurred more commonly with tirzepatide vs placebo.
Conclusions and Relevance In participants with obesity or overweight, withdrawing tirzepatide led to substantial regain of lost weight, whereas continued treatment maintained and augmented initial weight reduction.