Key points Does subcutaneous tirzepatide once weekly with diet and physical activity affect the maintenance of body weight reduction in people who are obese or overweight? Results After 36 weeks of open-label treatment with the maximum tolerated dose of tirzepatide (10 or 15 mg), adults (n = 670) with obesity or overweight (without diabetes) experienced a mean weight loss of 20.9%. Since randomization (at week 36), those who switched to placebo experienced a 14% weight regain and those who continued on tirzepatide experienced an additional 5.5% weight loss over the 52-week double-blind period. Meaning In obese/overweight participants, withdrawal of tirzepatide led to substantial regain of lost weight , while continuation of treatment maintained and increased the initial weight reduction. |
Obesity is a serious, chronic, progressive and recurring disease. Lifestyle interventions are a cornerstone of obesity control; However, maintaining the weight reduction achieved through lifestyle-based calorie restriction is challenging.
Therefore, current guidelines recommend complementary anti-obesity medications to promote weight loss, facilitate weight maintenance, and improve health outcomes in people with obesity. Randomized anti-obesity drug withdrawal studies conducted to date have consistently demonstrated clinically significant body weight regain upon discontinuation of treatment. There is also evidence that anti-obesity medications, including the long-acting glucagon-like peptide-1 (GLP-1) receptor agonists naltrexone/bupropion, phentermine/topiramate, and orlistat, may help maintain the weight reduction achieved. .
Tirzepatide is a unique molecule that combines glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor 13 agonism, producing 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 obese or overweight participants without diabetes, tirzepatide produced mean reductions in body weight of up to 20.9% after 72 weeks of treatment.
The objective of the SURMOUNT-4 trial was to investigate the effect of continued treatment with the maximum tolerated dose (i.e., 10 or 15 mg) of tirzepatide once weekly, compared with placebo, on maintenance of weight loss after of an open-label initial treatment in the initial treatment period in participants with obesity or overweight.
Importance
The effect of continuing treatment with tirzepatide on maintaining initial weight loss is unknown.
Aim
To evaluate the effect of tirzepatide, with diet and physical activity, on the maintenance of weight loss.
Design, environment and participants
This phase 3, randomized withdrawal clinical trial was conducted at 70 sites in 4 countries with a 36-week open-label lead-in period of tirzepatide followed by a 52-week, double-blind, placebo-controlled period.
It 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 initial period received the maximum tolerated dose subcutaneously once weekly (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 results and measures
The primary endpoint was the mean percent change in weight from week 36 (randomization) to week 88.
Key secondary endpoints included the proportion of participants at week 88 who maintained at least 80% weight loss during the baseline period. -in period.
Results
Participants (n = 670; mean age, 48 years; 473 [71%] women; mean weight, 107.3 kg) who completed the 36-week baseline period experienced a mean weight loss of 20.9%.
The mean percent weight change from week 36 to week 88 was −5.5% with tirzepatide versus 14.0% with placebo (difference, −19.4% [95% CI, −21.2% to −17.7%]; P < 0.001).
Overall, 300 participants (89.5%) who received tirzepatide at 88 weeks maintained at least 80% of their weight loss during the baseline period compared with 16.6% who received placebo (P < 0.001).
The overall mean weight reduction from weeks 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 frequently with tirzepatide than with placebo.
Conclusions and relevance
In obese or overweight participants, withdrawal of tirzepatide led to substantial regain of lost weight, while continuation of treatment maintained and increased the initial weight reduction.
Trial Registration ClinicalTrials.gov Identifier: NCT04660643
