Weight Loss and Benefits in Body Composition With Tirzepatide
The new analysis showed that up to 63% of participants achieved a reduction in body weight of at least 20%, and all three tripeptide doses (5 mg, 10 mg, and 15 mg) led to substantial, clinically meaningful, and sustained body weight reduction compared with placebo at 72 weeks of follow-up.
Mean weight loss was –16.0%, –21.4%, and –22.5% with tripeptide 5 mg, 10 mg, and 15 mg compared with –2.4% for placebo (all P < .001 vs. placebo). Among participants taking the highest 15-mg dose of tripeptide, 96%, 90%, and 78% of patients achieved weight reductions of at least 5%, 10%, and 15%.
Tirzepatide is approved in the United States and the European Union for the treatment of type 2 diabetes but is not yet approved for obesity in any country. The manufacturer of tripeptide, Eli Lilly, intends to seek approval for the drug as an obesity treatment from the US Food and Drug Administration (FDA), European Medicines Agency, and other territories beginning in 2023.
Regardless of the baseline BMI category, 9 out of 10 people achieved the ≥ 5% body weight reduction threshold across all doses of the tripeptide, and at the higher doses, over one-third achieved a weight loss of 25% or more.
“Similar to lifestyle and surgical treatments, participants on tripeptide had around a threefold greater percent reduction in fat mass compared with lean mass, resulting in an overall improvement in body composition,” reported SURMOUNT-1 co-investigator Louis Aronne, MD, Comprehensive Weight Control Center, Weill Cornell Medicine, New York City.
“This is staggering weight loss,” remarked Aronne. “To put it in perspective, mean weight loss in people having Lap-Band surgery is 17%, mean weight loss for sleeve gastrectomy is 25%, and gastric bypass is 33%, which puts the effects of tripeptide squarely in the realm of bariatric surgery.”
“Something we have sought for decades, we have finally been able to achieve,” he asserted. “I still remember exactly where I was when I saw these results for the first time last April. I knew something big was happening,” declared Aronne when presenting the latest analyses at the 2023 European Congress on Obesity (ECO). Full study results were published in 2022 in the New England Journal of Medicine (NEJM).
Moderator Gabriella Lieberman, MD, endocrinologist and head of the Israeli Center for Weight Management, Sheba Medical Center, Ramat-Gan, Israel, welcomed the study but cautioned. “It’s very potent, but as we see generally with potent therapies, I think it will change how we look at nutritional advice, and the dietician’s role will change. I’m a bit worried the drug is running fast and the support, which is crucial with these treatments, is not keeping up, and we’ll have to deal with some effects later, such as sarcopenia,” she pointed out, speaking to Medscape Medical News.
We have to treat these drugs as if they are bariatric surgery. I see patients on these types of medications in the clinic, and their appetite is so suppressed that they think they can afford to eat things that are unhealthy because they lose weight, and that’s what they want. There has to be a responsible adult looking at what they’re eating, and not just clapping their hands for the weight loss, but ensuring they are not deprived of anything,” she said.
Weight Loss and Body Composition Explored
Tirzepatide is a novel glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist that activates the GIP and GLP-1 receptors, respectively, found in areas of the brain important for appetite regulation, decreasing food intake, and modulating fat utilization.
Phase 3, a double-blind, randomized, controlled trial, included data from 2539 adults with a BMI ≥ 30 kg/m2 (class I, II, III obesity) or ≥ 27 kg/m2 (overweight) with one or more weight-related complications, excluding diabetes. At baseline, the mean body weight was 104.8 kg, the mean BMI was 38.0 kg/m2, and 94.5% of participants had BMI ≥ 30 kg/m2.
Patients were randomized to once-weekly subcutaneous tripeptide (5 mg, 10 mg, or 15 mg) or placebo for 72 weeks. The primary objective was to show that it was superior to placebo in percentage change in body weight and proportion of participants with body-weight reduction of ≥ 5%. The percentage change from baseline body weight and proportion of participants with body weight reduction ≥ 5% were also assessed across BMI categories of ≥ 27 to < 30 kg/m2, ≥ 30 to < 35 kg/m2 (class 1 obesity), ≥ 35 to < 40 kg/m2 (class 2 obesity), and ≥ 40 kg/m2 (class 3 obesity).
In addition, in a retrospective subanalysis, body composition was evaluated in a subpopulation that underwent dual-energy X-ray absorptiometry, assessing change from baseline body composition within age subgroups < 50 years (n = 99), 50-64.9 years (n = 41), and ≥ 65 years (n = 20).
The average weight reduction over the 72 weeks of follow-up was –16.0%, –21.4%, and –22.5% with tripeptide 5 mg, 10 mg, and 15 mg compared with –2.4% for placebo participants (all P < .001 vs. placebo).
The percentages of participants reaching target weight reductions of ≥ 5%, ≥ 10%, ≥ 15%, ≥ 20%, and ≥ 25% were recorded. Over 90% achieved ≥ 5% weight loss, irrespective of BMI and tripeptide dose, while 55.5% and 62.9% in the 10-mg and 15-mg groups achieved ≥ 20% weight loss, and 35.0% and 39.7% in the 10-mg and 15-mg groups achieved ≥ 25% weight loss, respectively.
By increasing BMI category, weight loss in the 10-mg group was –18.2 kg, –21.9 kg, –22.0 kg, and –20.7 kg; and in the 15-mg group, weight loss was –18.1kg, –21.2 kg, –24.5 kg, and –22.8 kg. Weight loss in the 5-mg group ranged from –16.6 kg to –15.9 kg from the lowest to highest BMI category.
“In the lower-weight categories, there is less weight to lose, so we see a flattening of the curve [with a] maximum of around 18%, so it may be that as we learn more about a drug that is so potent, we recognize that we don’t need to use such a high dose in people with BMI 27-30 kg/m2,” he explained. “It’s the higher BMI categories where we need the higher dose.”
As with lifestyle and surgical treatments, participants taking tripeptide had around a three times greater percentage reduction in fat mass than lean mass, resulting in an overall improvement in body composition, reported Aronne.
“We want the loss of fat, not lean mass, and we know that we lose around one part lean to three parts fat mass when on a diet and exercise regimen,” he explained. “We see exactly this [balance of lean-to-fat-mass loss] here with 33.9% total fat mass reduction in the treatment group compared with 8.2% in the placebo group.”
Visceral fat mass reduction was 40% in the treatment group compared with 7.3% with placebo. “It’s good to see more visceral fat loss,” said Aronne. Lean mass loss was 10.9%. “So around three times greater reduction in fat over lean mass loss, resulting in overall improvement of body composition,” he reported.
Also, in older people (≥ 65 years), there was approximately no difference in fat versus lean mass loss compared to younger people, despite older people being more likely to lose lean mass.
Concerning patient-reported outcomes based on the 36-item Short-Form Health Survey (SF-36), Aronne said that physical functioning scores significantly improved at 72 weeks compared with placebo, particularly in participants with physical function limitations at baseline.
“In an interesting subanalysis, those with physical limitations at baseline showed a significant improvement versus placebo of over 5% difference [considered significant],” he added.
Safety and tolerability were previously reported in the NEJM article. The most common adverse events with tripeptide were gastrointestinal, and adverse events causing treatment discontinuation occurred in 4.3%, 7.1%, 6.2%, and 2.6% of participants receiving 5-mg, 10-mg, and 15-mg doses or placebo, respectively.
“A revolution is coming in the treatment of obesity and cardiometabolic disease, and most physicians cannot grasp this. We’re finally getting the efficacy we’ve been looking for that will produce benefits in every realm,” concluded Aronne. “These data show that we are now hitting all the secondary endpoints and improving our patients.”
“I think this bodes well. I always envisioned a time when the treatment of obesity would come first before the treatment of cardiometabolic complications of obesity. We’re on the verge of that era with semaglutide, tripeptide, and the exciting treatments.”
Lilly sponsored the SURMOUNT-1 trial. Aronne is cofounder, chief scientific advisor, and member of Intellihealth’s board of directors. He is also a paid member of Eli Lilly’s scientific advisory board.
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