Weekly tirzepatide confers substantial weight loss in obesity without diabetes: SURMOUNT-1
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NEW ORLEANS — Nearly all participants with obesity without diabetes assigned tirzepatide experienced at least 5% weight loss over 72 weeks compared with placebo, with at least 20% weight loss in more than half with the highest 15 mg dose.
In the SURMOUNT-1 study, presented at the American Diabetes Association Scientific Sessions, researchers also noted a marked improvement in several key cardiometabolic parameters for participants assigned tirzepatide (Mounjaro, Eli Lilly), including 95% of adults with prediabetes reverting to normoglycemia across the three doses analyzed. For the 15 mg dose of tirzepatide, more than one-third of participants experienced at least 25% body weight reduction compared with placebo, an exploratory endpoint of the study.
“To put this into perspective, if someone weighed 200 lb and lost greater than or equal to 25% of their body weight, they would have gone down to 150 lb,” Ania Jastreboff, MD, PhD, associate professor of medicine and pediatrics (endocrinology) at Yale University School of Medicine, director of weight management and obesity prevention at the Yale Stress Center, and co-director of the Yale Center for Weight Management, said during a press conference. “We are in a new era of obesity treatment.”
As Healio previously reported, the FDA approved tirzepatide, an investigational glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist, in May to improve glucose response in adults with type 2 diabetes in addition to diet and exercise, based on data from the SURPASS clinical trial program. The drug is not currently approved to treat obesity.
Study design
The SURMOUNT-1 study included 2,539 adults with a BMI of at least 30 kg/m2 or at least 27 kg/m2 with at least one weight-related complication, excluding diabetes. Researchers randomly assigned participants 5 mg, 10 mg or 15 mg tirzepatide or placebo once weekly for 72 weeks, including a 20-week dose-escalation period. The co-primary endpoints were percentage change in weight from baseline and weight reduction of 5% or more. Researchers used the treatment-regimen estimand to assess effects regardless of treatment discontinuation in the intention-to-treat population.
The results were simultaneously published in The New England Journal of Medicine.
At baseline, mean body weight was 104.8 kg; mean BMI was 38 kg/m2.
At 72 weeks, mean percentage change in weight was –15% with the 5 mg tirzepatide dose (95% CI, –15.9 to –14.2), –19.5% with the 10 mg dose (95% CI, –20.4 to –18.5), –20.9% with the 15 mg dose (95% CI, –21.8 to –19.9) and 3.1% with placebo (95% CI, –4.3 to –1.9; P < .001 for all comparisons with placebo). The placebo-subtracted difference for the 15 mg group was 17.8 percentage points, Jastreboff said during a presentation.
“There was a relatively similar weight reduction for the 10 mg and 15 mg groups, at least on average,” Jastreboff said.
Across dosing groups, 85% (95% CI, 82-89), 89% (95% CI, 86-92) and 91% (95% CI, 88-94) of participants lost at least 5% body weight in the 5 mg, 10 mg and 15 mg tirzepatide groups, respectively, compared with 35% of participants in the placebo group (95% CI, 30-39).
In the 10 mg and 15 mg groups, 50% (95% CI, 46-54) and 57% (95% CI, 53-61) of participants, respectively, experienced at least 20% reduction in body weight compared with 3% of those assigned placebo (95% CI, 1-5; P < .001 for all comparisons with placebo).
“Nearly all participants on the 15 mg dose, 97.7%, lost weight, whereas 2.3% gained weight,” Jastreboff said. “This shows us that nearly all lost weight with 10 mg and 15 mg and that there is heterogeneity in terms of response to tirzepatide, as we see with all therapies for obesity.”
Cardiometabolic improvements
Improvements in all prespecified cardiometabolic measures were observed with tirzepatide, Jastreboff said. Within the cohort, 40% of participants had prediabetes; the mean baseline HbA1c for participants was 5.6%. Despite being in the normoglycemic range, participants in the tirzepatide groups experienced a mean 0.5% decrease in HbA1c, Jastreboff said. More than 95% of those with prediabetes reverted to normoglycemia in the tirzepatide groups.
Similar improvements were observed for lipids, blood pressure and waist circumference.
Jastreboff noted triglyceride levels decreased by more than 27% in the pooled tirzepatide group vs. 6.3% for those assigned placebo.
The most common adverse events with tirzepatide were gastrointestinal and most were mild to moderate in severity, occurring primarily during dose escalation.
Researchers noted the SURMOUNT-1 trial took place in the midst of the COVID-19 pandemic, with recruitment beginning in December 2019. Despite this, 86% of participants overall and 90% of participants across the tirzepatide dosing groups completed the trial.
‘New generation’ of obesity treatments
In discussion after the presentation, Lee M. Kaplan, MD, PhD, FTOS, director of the Obesity, Metabolism and Nutrition Institute at Massachusetts General Hospital, said tirzepatide joins two other impressive options that are part of a “new generation” of effective obesity therapies: bariatric surgery and the GLP-1 receptor agonist semaglutide (Wegovy, Novo Nordisk).
“We are in a new era of treating obesity,” Kaplan said. “That is one of the most important conclusions from what we have seen today. There are now three strikingly effective and adequately safe therapies for obesity. First is bariatric surgery, second is semaglutide and now the third is tirzepatide.”
Kaplan stressed tirzepatide “is not perfect.”
“Two-thirds of patients lost more than 20% of their body weight and 23% lost as much weight as seen with bariatric surgery — 30%,” Kaplan said. “However, at the other extreme, about 3.7% lost less than 5% of their body weight. This variability becomes important. We will not solve everyone’s obesity by treating them all with tirzepatide, even if we could.”
Following the press conference, Jastreboff told Healio subanalyses are ongoing assessing the characteristics of participants who did not respond well to tirzepatide.
“We should also note that the response to the 5 mg dose is remarkable in and of itself,” Jastreboff told Healio. “[That data] was included as a key secondary endpoint because, based on the phase 2 trial for people with type 2 diabetes, researchers could not predict their response to the drug. We need to know which doses and which medicines work best for which patients. Right now, the best thing is for us to work closely with our patients and see what they are responding to. If they are not responding to something, offer them a different therapy and ensure we are getting them to their weight and health goals with whatever treatment works for them.”
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Perspective
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These data are exciting. Now we have obesity drugs that really work. For the average practitioner, he or she must understand that titration is critically important. If you titrate a drug like tirzepatide too quickly, the patient will not want the drug. That is No. 1: Can you get the drug on board?
Second is the question of affordability. That could be a critical barrier to using this drug successfully. Ultimately, we need randomized controlled trials comparing effective pharmacotherapy vs. surgery, looking at the cost-effectiveness and efficacy. We also need to think about other outcomes, like cancer and CVD. I am hopeful that industry could step up to be a comparator to metabolic surgery and a standard of care group. We hold up every other medical indication to randomized controlled trials. Now, it is time.
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Jastreboff AM, et al. 3-CT-SY24. Presented at: American Diabetes Association Scientific Sessions; June 3-7, 2022; New Orleans (hybrid meeting).
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