Discussion
SURMOUNT-3, weight loss, overweight or obesity
Tirzepatide substantially increased the magnitude of weight loss when administered following an initial 12-week intensive lifestyle intervention that reduced baseline body weight by an average of 6.9% in successful program completers. As measured from randomization (week 0) to week 72, participants who received tirzepatide MTD of 10 or 15 mg lost an additional 18.4% of body weight, compared with a gain of 2.5% for placebo. In total, 87.5% of tirzepatide-treated participants lost an additional 5% or more of their randomization weight compared with 16.5% of placebo-treated participants, with tirzepatide also demonstrating superiority in the achievement of all other categorical weight losses. These findings indicate that individuals with overweight or obesity who have lost approximately 5–10% of their body weight with supervised lifestyle intervention—or potentially through their own self-directed diet and exercise efforts—could expect to achieve further clinically meaningful weight loss with the addition of tirzepatide.The strength of tirzepatide is underscored by comparison with a similarly designed trial of liraglutide (3.0 mg), approved for chronic weight management. After losing an average 6.0% of baseline weight in a comparable lead-in program, participants who received liraglutide achieved an additional 6.2% reduction in randomization weight at 56 weeks compared with a 0.2% reduction for placeboThe cumulative 24.3% reduction in body weight achieved with intensive lifestyle intervention, followed by tirzepatide, approximates the 1 year weight loss induced with sleeve gastrectomyThe safety profile of tirzepatide in this trial was consistent with findings from previous trials of tirzepatide when evaluated for the treatment of obesityMuch remains to be learned about how lifestyle intervention and the new incretin-based antiobesity medications can be optimally used together. If the goal of combining these therapies is to increase total weight loss, results of the present trial and SCALE-MAINTENANCEThe suggestion of additivity with sequential therapy, however, may be challenged by findings from preclinical studies. These studies have demonstrated that caloric restriction alone does not address the underlying physiology regulating body weight or fat mass, and antiobesity medication has the same overall ultimate effect regardless of whether or not caloric restriction preceded the medicationAnother major treatment issue concerns the intensity (that is, frequency) and scope of lifestyle intervention required with antiobesity medications. Weekly lifestyle visits and daily monitoring of food and energy intake historically have been required to help patients achieve and maintain the 500–750 kcal per day deficit needed to induce clinically meaningful weight lossThe strengths of this study, which included an intensive lifestyle lead-in, include the fact that it had a relatively large sample size in which over one-third of the randomized population were men and over half were of Hispanic ethnicity. In addition, a 72-week treatment period facilitated at least 52 weeks of treatment with tirzepatide at MTD. The allowance of dose de- and re-escalation during the titration phase helped to maximize tolerability and reflected dose adjustment strategies that may be relevant for clinical practice.The study’s limitations include that it was geographically restricted to North and South America and that the study population was predominantly white, thus potentially limiting the generalizability of the findings. In addition, the 17.5% of participants who did not lose at least 5% of baseline weight in the intensive lifestyle intervention were not randomized to medication. To the extent that response to lifestyle intervention may predict response to medication, exclusion of these participants may have resulted in a higher mean weight loss with tirzepatide MTD than would have been observed if lifestyle nonresponders had been included. Trials of the response to antiobesity medications in persons who are unsuccessful with intensive lifestyle intervention are needed, because lack of success with lifestyle interventions has been a common prerequisite for initiation of pharmacotherapy or bariatric surgery. Future studies evaluating both genetic and behavioral predictors of response to lifestyle intervention and pharmacotherapy will help inform clinical management even earlier in the course of treatment.In conclusion, in the SURMOUNT-3 trial, tirzepatide demonstrated clinically meaningful additional body weight reductions in adults with overweight or obesity following initial weight loss with intensive lifestyle intervention.