Adults with obesity maintain weight loss at 88 weeks with continued tirzepatide therapy
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Key takeaways:
- Adults who received tirzepatide for 36 weeks and then stopped therapy regained some of the weight at 88 weeks.
- Continued weight loss was observed for adults receiving tirzepatide for 88 weeks.
Continued treatment with the GIP/GLP-1 dual agonist tirzepatide is necessary to maintain weight loss for adults with obesity, according to findings from the SURMOUNT-4 trial published in JAMA.
As Healio previously reported, tirzepatide (Zepbound, Eli Lilly) was approved by the FDA for chronic weight management in November based on findings from the SURMOUNT trials. In SURMOUNT-4, adults with obesity or overweight plus one weight-related comorbidity received tirzepatide for 36 weeks during an open-label lead-in period. At 36 weeks, participants who reached the maximum tolerated dose of 10 mg or 15 mg were randomly assigned to continue receiving tirzepatide or to switch to placebo for an additional 52 weeks. At the end of the study, continued weight loss was observed for those randomly assigned to tirzepatide, whereas adults who switched to placebo regained some of the weight they lost during the lead-in period.
“Evidence shows that the weight-regulating parts of the brain become resistant to the key hormones that regulate weight. That’s why it’s so hard to lose weight,” Louis J. Aronne, MD, FACP, DABOM, Sanford I. Weill Professor of Metabolic Research and professor of clinical medicine at Weill Cornell Medicine, told Healio. “These medications mimic the effect of the hormones like GLP-1 and GIP, and when you remove the effect, weight goes back to where it started, like your blood pressure, cholesterol or blood sugar would if you stopped treatments for those. Tirzepatide is highly effective at producing weight loss and improvements in cardiometabolic parameters. The patients regained about half of the weight they had lost over the 1-year time on placebo. That’s more gradual regain than I think most people would have expected. Metabolic parameters also went back toward baseline, but improvement in some parameters was still evident.”
In the SURMOUNT-4 trial, 670 adults who received tirzepatide for 36 weeks and reached the maximum tolerated dose were randomly assigned, 1:1, to continue receiving tirzepatide or to switch to placebo for 1 year (mean age, 48 years; 70.6% women; 80.1% white). All adults were encouraged to adhere to a 500 kcal per day deficit diet and to participate in at least 150 minutes of physical activity per week. The primary outcome of the study was the percent change in body weight from 36 weeks to 88 weeks. Secondary endpoints included the percentage of adults at 88 weeks who maintained at least 80% of the weight they lost at 36 weeks and the percentage of adults achieving at least a 5%, 10%, 15% and 20% weight loss from baseline to 88 weeks. Cardiometabolic risk factors were also assessed. Safety data included treatment-emergent adverse events, serious adverse events and early discontinuation of the study due to adverse events.
Findings from the SURMOUNT-4 trial were initially presented at the European Association for the Study of Diabetes annual meeting in October.
Weight regain with switch to placebo
During the open-label portion of the study, participants lost a mean 20.9% of their body weight. From 36 to 88 weeks, adults randomly assigned to tirzepatide lost an additional 5.5% of body weight, whereas the placebo group had a 14% weight gain (mean difference, –19.4 percentage points; 95% CI, –21.2 to –17.7; P < .001). At 88 weeks, 89.5% of the tirzepatide group maintained at least 80% of the weight they lost vs. 16.6% of the placebo group. The tirzepatide group also had greater improvements in BMI, HbA1c, fasting glucose, insulin, lipid levels and systolic and diastolic BP compared with placebo.
From baseline to 88 weeks, a greater percentage of adults receiving tirzepatide achieved at least 5% weight loss (97.3% vs. 70.3%), at least 10% weight loss (92.1% vs. 46.2%), at least 15% weight loss (84.1% vs. 25.9%) and at least 20% weight loss (69.5% vs. 12.6%) compared with placebo (P < .001 for all).
“Continued treatment [with tirzepatide] is necessary as we expected, but it is not certain if a lower dose or a more intensive behavioral program or other strategy will help with maintenance,” Aronne said.
Gastrointestinal adverse events common
During the lead-in period, 81% of adults reported at least one treatment-emergent adverse event. Gastrointestinal events were most common, with the most frequent events being nausea, diarrhea, constipation and vomiting. During the double-blind portion of the study, 60.3% of the tirzepatide group and 55.8% of the placebo group reported a treatment-emergent adverse event. Gastrointestinal events were more common in the tirzepatide group compared with placebo. Serious adverse events were reported by 2% of adults in the lead-in period. A similar percentage of participants in the tirzepatide and placebo groups reported serious adverse events during the double-blind portion of the study.
During the lead-in period, 7% of adults discontinued the study due to a treatment-emergent adverse event. The percentage of adults discontinuing the study due to an adverse event in the double-blind period was 1.8% in the tirzepatide group and 0.9% in the placebo group.
Aronne said future studies are needed to assess whether tirzepatide at a lower dose or with a more intensive lifestyle intervention could assist adults with maintaining weight loss.
For more information:
Louis J. Aronne, MD, FACP, DABOM, can be reached at ljaronne@med.cornell.edu.
Perspective
Back to TopJamy D. Ard, MD, FTOS and Priya Patel, DO
The SURMOUNT-4 trial results for the use of tirzepatide in managing obesity highlight the remarkable treatment effects seen in the other SURMOUNT trials, but leave some questions about long-term treatment unanswered. After a 36-week open-label treatment period with tirzepatide, the study randomly assigned adults with obesity to continue tirzepatide or placebo for 52 weeks. This study design allows us to understand if continued therapy is clinically better than discontinuation of treatment after an initial exposure.
In this study, the average weight loss during the open-label phase was 20.9%; however, during the randomized phase, the tirzepatide group had an additional 5.5% weight loss by 88 weeks, while the placebo group experienced weight regain of 14%. Notably, nearly 90% of the tirzepatide treatment group maintained at least 80% of their initial weight loss, showcasing the long-term efficacy. The placebo group only had 16.6% of participants achieve this target outcome.
SURMOUNT-4 is another demonstration that weight recurrence is the predictable average response when obesity treatment is discontinued. Obesity is a chronic disease that requires ongoing treatment; however, for about 15% to 20% of the study population — a proportion that has been consistently observed in other trials of similar design — ongoing drug treatment may not be required. We do not know what defines this group and why they respond differently.
In addition to better understanding this population, we need additional research to determine if alternative strategies for weight loss maintenance are viable. In the meantime, our best evidence, which now includes SURMOUNT-4, suggests that chronic treatment is most effective.
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