Tirzepatide induces more than 19% weight loss for adults with obesity and MC4R deficiency
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Key takeaways:
- Adults with a loss-of-function mutation in the MC4R gene lost 19.3% of their body weight with tirzepatide.
- More research is underway to analyze the effects of tirzepatide with other genetic varients.
DALLAS — Adults with obesity and a genetic mutation that causes deficiency in the melanocortin-4 receptor (MC4R) pathway lost a similar amount of weight with tirzepatide as adults without a genetic mutation, according to a speaker.
As Healio previously reported, adults receiving tirzepatide (Mounjaro, Eli Lilly) in the SURMOUNT-1 trial lost up to 20.9% of their body weight with the 15 mg dose at 72 weeks. However, Lee Kaplan, MD, PhD, section chief of obesity medicine at the Geisel School of Medicine at Dartmouth and director of The Obesity and Metabolism Institute in Boston, said during a presentation at ObesityWeek that weight loss in SURMOUNT-1 varied from person to person.
“Despite the substantial average weight loss [in SURMOUNT-1], the effect of tirzepatide varied substantially across the treatment population,” Kaplan said during a presentation. “The normal distribution of the response is suggestive of a biological response rather than a compliance response. This was a phase 3 trial, so compliance was heavily influenced by the fact that these patients were in the study, and yet you still see that very wide distribution. ... So we sought to determine whether the weight loss response to tirzepatide was influenced by any of the genetic factors. Some of the genetic work is still in progress, so the first focus is looking at variants in the most common cause of polygenic obesity in the MC4R gene.”
Researchers analyzed genetic mutations in 2,291 adults who participated in the SUMOUNT-1 trial. There were nine mutations identified in the study populations that have been reported to change MC4R function, with six of those mutations defined as causing loss of function. Weight loss among adults with a loss-of-function mutation in the MC4R gene was compared with adults who did not have a loss of function MC4R genetic mutation.
There were 19 adults with a heterozygous loss-of-function mutation in the MC4R gene, which encompassed 0.83% of the full study population.
“The prevalence of previously undiagnosed MC4R deficiency was about the same as in the broader population,” Kaplan said.
Of those who were loss-of-function heterozygous carriers, 15 received tirzepatide and four received placebo. Baseline characteristics between adults with a genetic mutation and those who were noncarriers were similar except for systolic blood pressure. Genetic mutation carriers in the tirzepatide group had a lower systolic BP at baseline than noncarriers (116.4 mm Hg vs. 123.7 mm Hg), with a similar finding observed in the placebo group.
Carriers of the MC4R genetic mutation who received tirzepatide lost 19.3% of their body weight at 72 weeks, and noncarriers achieved a mean weight loss of 19.9%. There was no significant difference in weight loss between adults with an MC4R loss-of-function mutation and those who were noncarriers.
Kaplan said more studies need to be conducted to determine whether additional genetics variants are associated with variable response to tirzepatide.
“MC4R pathogenic mutations have been associated with a decrease in the efficacy of bariatric surgery, to the point where homozygous loss of function has been associated with a complete lack of response to gastric bypass,” Kaplan said. “One of the questions is, would these drugs show any differential effect [on weight loss]. That’s the reason why this was the first group of mutations that we looked at.”
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Bhatnagar P, et al. Oral-057. Presented at: ObesityWeek; Oct. 14-17, 2023; Dallas.
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