SURMOUNT-3: ‘Substantial’ weight loss with tirzepatide after lifestyle intervention
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Key takeaways:
- Adults participating in a 12-week lifestyle intervention followed by 72 weeks of tirzepatide lost a mean 24.3% of their body weight.
- Nearly 45% of adults achieved weights loss of 20% or greater with tirzepatide.
DALLAS — Adults with obesity who received tirzepatide for 72 weeks following a 12-week intensive lifestyle intervention achieved a total mean weight loss greater than 24%, according to data from the SURMOUNT-3 trial.
In findings presented at ObesityWeek and simultaneously published in Nature Medicine, 87.5% of adults who received tirzepatide (Mounjaro, Eli Lilly) after 12 weeks of lifestyle intervention achieved at least a 5% weight reduction from baseline to 72 weeks. Additionally, 94% of adults who received tirzepatide were able to maintain at least 80% of the weight loss they achieved during the intensive lifestyle intervention.
“These findings potentially give patients and their health care providers a new option for continued weight reduction when individuals hit a plateau after losing 10 to 15 lb, whether through their own self-directed efforts or through participating in a commercial program such as WW,” Thomas A. Wadden, PhD, co-principal investigator of the SURMOUNT-3 trial and professor of psychology in psychiatry at the Perelman School of Medicine at the University of Pennsylvania, told Healio. “Tirzepatide can induce additional substantial weight loss needed to achieve optimal control over obesity-related complications such as type 2 diabetes, obstructive sleep apnea, osteoarthritis and nonalcoholic steatohepatitis.”
The SURMOUNT-3 trial included 806 adults with obesity or overweight plus one obesity-related complication who were enrolled in a 12-week intensive lifestyle intervention. The lifestyle intervention included in-person lifestyle counseling, up to two meal replacements per day and at least 150 minutes of moderate-intensity lifestyle therapy per week. Of those enrolled, 579 achieved a 5% or greater weight reduction with the lifestyle intervention and continued to the next phase of the study, during which they were randomly assigned to receive once-weekly tirzepatide or placebo for 72 weeks (mean age, 45.6 years; 62.9% women; 86% white).
The primary endpoints were percent change in body weight and the proportion of adults who achieved a 5% or greater weight reduction from randomization to 72 weeks. Blood pressure, lipids, fasting glucose, HbA1c and fasting insulin were collected as secondary endpoints. Self-reported physical function was obtained from participants.
More than 24% total weight reduction with tirzepatide
In the treatment-regimen estimand, mean weight reduction in the tirzepatide group was 18.4% at 72 weeks compared with a 2.5% weight gain in the placebo group (P < .001). Among the tirzepatide group, 87.5% lost at least 5% of their body weight vs. 16.5% of the placebo group (P < .001).
“Further, 44.7% of participants were able to achieve a 20% or more weight loss from randomization,” Ariana Chao, PhD, CRNP, FNP-BC, co-principal investigator of the SURMOUNT-3 trial and faculty associate at the Johns Hopkins School of Nursing, told Healio.
During the 12-week intensive lifestyle intervention, participants who qualified for randomization lost a mean 6.9% of their body weight. The proportion of adults who maintained at least 80% of the weight they lost during the lifestyle intervention period was 94% in the tirzepatide group vs. 43.8% in the placebo group. Total weight reduction from the start of the lifestyle intervention until the end of the study was 24.3% for the tirzepatide group compared with 4.5% for the placebo group, according to the results.
“I was very pleased, and somewhat surprised, to see that patients who lost weight with intensive lifestyle intervention, followed by tirzepatide, achieved a cumulative reduction in their baseline body weight of 24.3%,” Wadden told Healio. “That’s impressive, closing in on the mean weight loss achieved with sleeve gastrectomy, a procedure commonly used in metabolic and bariatric surgery. These new incretin-based weight-loss medications — and those to follow — could provide important alternatives to bariatric surgery.”
Waist circumference decreased by 14.6 cm from randomization to 72 weeks in the tirzepatide group compared with a 0.2 cm increase in the placebo group (P < .001). The tirzepatide group exhibited declines in blood pressure, improvements in all fasting lipid levels, and greater decreases in the HbA1c and fasting glucose compared with placebo. Adults receiving tirzepatide also had greater improvements in self-reported physical function compared with placebo.
“The cardiometabolic and physical functioning changes were very surprising in a way,” Chao said during a presentation. “Most of the sample was ... metabolically stable. About 34% of the participants had hypertension and only about one-quarter of them had dyslipidemia. ... I think it’s impressive we were able to see the decline during lifestyle intervention and the continued decline in those measures with tirzepatide.”
Treatment-adverse events consistent with prior trials
Eighty-seven percent of participants who received tirzepatide and 76.7% who received placebo reported at least one treatment-emergent adverse event. The most common adverse events were gastrointestinal and were mostly mild to moderate in severity. The percentage of adults who reported serious adverse events was similar in the tirzepatide and placebo groups.
There were two deaths during the study; one occurred in each treatment group. One confirmed case of pancreatitis occurred in each group. Cholelithiasis was reported by four adults who received tirzepatide and three who received placebo. One adult in the tirzepatide group developed acute cholecystitis. There were no malignancies related to the study treatment, according to the researchers.
“The tolerability and safety profile for tirzepatide in this particular trial were consistent with what we see in the category broadly,” Jamy Ard, MD, FTOS, professor in the department of epidemiology and prevention at Wake Forest School of Medicine and co-director of the weight management center for Advocate Health Wake Forest Baptist, said during the presentation. “It’s also what we’ve seen SURMOUNT-1, -2 and -4. Gastrointestinal events were most frequent ... and occurred primarily during the dose-escalation period.”
Reforming the approach to obesity care
Discussion following the presentation focused on the role of lifestyle intervention moving forward. Robert Kushner, MD, MS, FTOS, DABOM, professor in the departments of medicine and medical education at Northwestern University Feinberg School of Medicine and director of the Center for Lifestyle Medicine at Northwestern Medicine, said there are no prospective randomized trials with newer agents that compare intensive lifestyle therapy plus medication with medication alone. Kushner said the mechanisms and magnitude of weight loss with incretin-based drugs could lead to changes in how intensive lifestyle intervention is approached.
“Given the more effective biological impact of incretin-based medications on appetite, I think we need to question then necessity for providing intensive behavioral therapy as a therapeutic adjunct to the newer generation of anti-obesity medications,” Kushner said.
Kushner said new medications such as tirzepatide may allow for a reexamination of the purpose, components and implementation of lifestyle intervention, including a greater focus on health outcomes, more emphasis on dietary protein and healthy eating patterns, and increased attention to the importance of physical activity and resistance exercise. Further, the impact of newer anti-obesity medications may allow for the disease to be treated more at the primary care level, Kushner said.
“You do lose more weight with lifestyle intervention [plus newer medications], but it’s not as necessary as with the first [anti-obesity] medications,” Kushner said. “I hope that will allow obesity care to be provided at the primary care level. ... It doesn’t mean doing nothing [with lifestyle intervention]; it just means doing it differently.”
Ard said he believes future obesity treatment will vary based on the individual patient and how much weight loss they need to achieve.
“If a patient tells me ‘I’m looking for a 30% reduction in weight,’ I can say, ‘Here’s a combination of lifestyle intervention plus medication.’ If you want to start with lifestyle intervention because that’s what you’re motivated to do and we’ve got some things we want to work on, if you can get some benefit out of that and then we can add medication afterward, that might be a combination that helps you get to your treatment goal,’” Ard said.
Reference:
Wadden TA, et al. Nat Med. 2023;doi:10.1038/s41591-023-02597-w.
Perspective
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Beverly Tchang, MD, DABOM
SURMOUNT-3 continues to drive home the message that tirzepatide is effective and safe for long-term weight management. Similar to SURMOUNT-1 and SURMOUNT-2, which also showed impressive weight losses of 15% to 23%, SURMOUNT-3 resulted in an average weight loss of 25%. The side effect profile is consistent with other studies. We’re still seeing that the main side effects are gastrointestinal, like nausea and reflux. The more concerning side effects, like pancreatitis and gall bladder disorders, were very rare. This trial should continue to reassure people that they can consider this medication for obesity treatment.
When we look at the big picture, the weight loss outcomes in SURMOUNT-1 and SURMOUNT-3 had about a 2% difference. We can’t directly compare the two trials, but 2% is not a huge difference, and this should implore us to reexamine the role of intensive lifestyle intervention. The lifestyle intervention in SURMOUNT-3 required eight visits in just 12 weeks; essentially, each participant saw a specialist every 1 to 2 weeks. This is resource intensive and not scalable. We need to consider different roles for intensive lifestyle intervention, perhaps after an anti-obesity medication is discontinued, whether voluntarily or involuntarily, instead of before a medication is started.
SURMOUNT-3 should also inform payer policies. Many insurance companies require a trial of lifestyle intervention before giving access to medication. The degree of weight loss we see in the SURMOUNT trials suggest that such a requirement may not significantly change weight loss outcomes.
There are a lot of people who are skeptical as to whether a person with obesity needs to take medication. Many are still asking, “Why don’t you just do diet and exercise?” This trial helps answer those naysayers. SURMOUNT-3 enrolled a group of people who were highly motivated and who were given all the tools in the toolbox — diet, exercise and behavioral therapy — and at the end of 3 months, they only lost 7% of their weight. Seven percent is still good, but often people want more than that, and it’s certainly not close to the 20% weight loss that we’re seeing with medication.
SURMOUNT-3 shows that even when a patient does everything right, they may still benefit from an anti-obesity medication. People should not think about lifestyle and medication dichotomously. I predict that we will see the benefit of both manifest in non-weight outcomes, like fat mass loss and muscle mass preservation. Lifestyle intervention and medication work together.
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Machineni S, et al. SURMOUNT-3 trial. Presented at: ObesityWeek; Oct. 14-17, 2023; Dallas.
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