Adults with obesity using tirzepatide maintain ‘remarkable’ weight loss at 88 weeks
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Key takeaways:
- Adults with obesity receiving tirzepatide lost a mean 25.3% of body weight at 88 weeks in the SURMOUNT-4 trial.
- More than half of tirzepatide participants lost 25% or more body weight at 88 weeks.
Adults with obesity receiving tirzepatide lost more than 25% of their body weight and were able to maintain their weight loss for up to 88 weeks, according to data from the SURMOUNT-4 trial.
In SURMOUNT-4, all participants received tirzepatide (Mounjaro, Eli Lilly) during a lead-in phase, with the study population achieving a mean weight loss of 20.2% at 36 weeks. At 36 weeks, participants were randomly assigned, 1:1, to continue receiving tirzepatide or switch to placebo for an additional 52 weeks. At 88 weeks, the tirzepatide group achieved an additional 5.5% weight loss, whereas the placebo group had a weight regain of 14%. Adults in the tirzepatide group had a mean 25.3% weight loss from baseline to 88 weeks, with 56.6% of the group achieving a 25% or higher weight reduction.
“It’s really incredible where we are now in the treatment of obesity compared to where we were as recently as 5 or 10 years ago,” Louis Aronne, MD, Sanford I. Weill Professor of Metabolic Research and professor of clinical medicine at Weill Cornell Medicine, said during a presentation at the European Association for the Study of Diabetes annual meeting. “We’re in the middle of a revolution ... in the treatment of cardiometabolic disease with semaglutide and now tirzepatide.”
SURMOUNT-4 was a randomized, double-blind, placebo-controlled trial in which adults aged 18 years and older with a BMI of at least 30 kg/m2 or at least 27 kg/m2 with one weight-related comorbidity and no diabetes were enrolled. Adults were required to have at least one self-reported unsuccessful dietary effort to lose weight to participate in the trial. All participants received tirzepatide once weekly for 36 weeks as an adjunct to a reduced-calorie diet and increased physical activity during a lead-in period. Tirzepatide was titrated up to a maximum dose of 10 mg or 15 mg. At 36 weeks, adults were randomly assigned, 1:1, to tirzepatide or placebo once weekly during a 52-week double-blind period. The primary outcome was the percent change in body weight from randomization at 36 weeks to the end of the trial at 88 weeks. Secondary outcomes included absolute change in body weight and weight circumference from 36 to 88 weeks, the percentage of adults achieving at least a 5%, 10%, 15%, 20% or 25% weight loss from baseline to 88 weeks and the percentage of adults that maintained at least 80% of the body weight they lost during the open-label period.
Tirzepatide confers 25.3% weight loss at 88 weeks
There were 670 adults who completed the open-label portion of the trial and were randomly assigned to tirzepatide or placebo at 36 weeks (mean age, 47.7 years; 70.6% women; 80.1% non-Hispanic white). Naveed Sattar, MD, PhD, professor of metabolic medicine in the Institute of Cardiovascular & Medical Sciences at the University of Glasgow in the U.K., said the baseline clinical characteristics were similar between the participants who were enrolled at baseline and those who continued to randomization at 36 weeks. Additionally, he said the characteristics were well balanced between the placebo and tirzepatide groups.
“The baseline characteristics and the retention of participants during the study reassure us ... that the results may be similar to those in clinical practice,” Sattar said during the presentation.
The full study group lost a mean 20.9% of body weight at 36 weeks during the lead-in portion of the trial. In the treatment-regimen estimand, the tirzepatide group had a mean weight loss of 25.3% from baseline to 88 weeks compared with a 9.9% weight loss in the placebo group (P < .001). In the efficacy estimand at 88 weeks, the absolute weight reduction was 27.6 kg in the tirzepatide group vs. a 10 kg weight loss in the placebo group (P < .001).
In the treatment-regimen estimand, the tirzepatide group had a 5.5% decline in body weight from 36 to 88 weeks compared with a 14% weight gain in the placebo group (P < .001). Adults receiving tirzepatide lost a mean 4.7 kg of body weight from 36 to 88 weeks compared with an 11.1 kg weight gain for the placebo group.
“There was weight regain [in the placebo group], but interestingly, weight after 52 weeks had not returned back to baseline,” Aronne said.
Among those receiving tirzepatide, 98.5% lost at least 5% of their body weight from baseline to 88 weeks, 94% lost at least 10% of their body weight, 87.1% lost at least 15% of their body weight, 72.6% achieved a 20% or higher weight loss and 56.6% had a weight reduction of at least 25%. The percentage of adults who maintained at least 80% of the weight they lost during the 36-week lead-in phase of the trial was 93.4% of the tirzepatide group compared with 13.5% of the placebo group (P < .001).
“What we see here is weight loss that is on par with that achieved with sleeve gastrectomy, the most commonly performed bariatric procedure,” Aronne said. “This has been a goal of many people in the field of medical treatment of obesity, to achieve the same amount of weight loss as achieved by our surgical colleagues. This suggest that we are getting there.”
From 36 to 88 weeks, the tirzepatide group had a 4.3 cm reduction in waist circumference compared with a 7.8 cm increase with placebo (P < .001). Tirzepatide was also associated with greater decreases in systolic and diastolic blood pressure compared with placebo. Improvements in HbA1c and lipids for adults receiving tirzepatide were also observed.
Most adverse events mild or moderate
During the lead-in portion of the trial, 81% of participants reported a treatment-emergent adverse event and 68.2% of adults had adverse events related to tirzepatide. Of those who enrolled at baseline, 7% discontinued using tirzepatide during to an adverse event and 6.5% discontinued the study. The most common adverse events during the lead-in period were nausea, diarrhea, constipation and vomiting, and most events were mild or moderate.
During the randomized period of the study, 26.3% of adults in the tirzepatide group had a treatment-emergent adverse event related to the drug compared with 10.4% of the placebo group. Serious adverse events occurred in 3% of the tirzepatide and placebo groups, and there was one death in each group. The most common adverse events were diarrhea, nausea and vomiting, though incidence were lower than what was reported during the lead-in period of the study.
Pancreatic amylase and lipase levels increased during the study with tirzepatide, but remained in the normal range, according to Aronne. No cases of confirmed pancreatitis occurred. There was no difference in reported cholelithiasis cases between the tirzepatide and placebo groups. Mean hepatic enzymes decreased with tirzepatide and remained in the normal range during a 4-week safety period at the end of the trial. Pulse rate peaked during the lead-in period of the study before declining over the rest of the trial.
“The observed safety data are consistent with the known safety profile of tirzepatide and the GLP-1 receptor agonist class in people with obesity,” Aronne said.
Questions remain on weight-loss maintenance after stopping tirzepatide
In a commentary, Jens Juul Holst, MD, DMSc, professor at the Novo Nordisk Foundation Center for Basic Metabolic Research, department of biomedical sciences at Panum Institute at University of Copenhagen in Denmark, commended the magnitude of weight loss reported in SURMOUNT-4. He said the findings in the trial shared some things in common with what was observed with semaglutide 2.4 mg (Wegovy, Novo Nordisk) in the STEP 4 trial. In SURMOUNT-4, he noted there was a bit of a plateau at 70 weeks in the tirzepatide group, though tirzepatide conferred a greater percentage of weight loss in SURMOUNT-4 than what was observed with semaglutide in STEP 4. Holst also noted the follow-up time was 88 weeks in SURMOUNT-4 and 72 weeks in STEP 1 and said longer studies are needed to determine how long weight loss can be maintained with those drugs.
“We have this very remarkable weight loss, plateauing around 70 weeks,” Holst said. “If 25% [weight loss] is considered a critical line, that was definitely reached here, critical in terms of resembling bariatric surgery.”
Holst said there are a few questions that should be addressed in future studies. Providers must determine what course of action should be taken after adults stop using tirzepatide, and researchers must conduct future studies to analyze tirzepatide’s impact on cardiovascular endpoints. Finally, Holst said experts must understand whether adults will stop taking tirzepatide after a certain period of time and to determine why they may stop taking it.
“We all know that people on drugs will stop taking the drugs ... and they certainly also [stop using] the GLP-1 agonists once nobody pays for it anymore,” Holst said. “But there’s also other reasons. Why is it that you lose weight? Why is it that you stop eating? That’s because you lost your appetite. That’s because you lost the pleasure of eating, that’s because you lost the pleasure and the reward of having a beautiful meal. How long can you stand that? That is the real question.”
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Sattar N, et al. SURMOUNT-4 trial results: The impact of tirzepatide on maintenance of weight reduction and benefits of continued therapy. Presented at: European Association for the Study of Diabetes Annual Meeting; Oct. 2-6, 2023; Hamburg, Germany (hybrid meeting).
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