Why some people are likely to get better results

• Tirzepatide, a once-weekly GIP/GLP-1 receptor agonist, is a medicine used for weight reduction in adults with obesity.
• A new analysis of the SURMOUNT clinical trials reveals that the medicine, administered as a once-weekly injection, leads to significant weight reduction.
• Across all doses and trials, women lost up to 24.6% of their body weight compared to 18.1% in men, indicating a potential sex-based difference with regard to drug response.

Obesity is the most common chronic health condition globally, affecting around 650 million adults.

Recent studies have shown that drugs targeting specific hormones involved in energy balance, such as GLP-1, can help people lose weight effectively and safely.

Another hormone, GIP, also plays a role in controlling weight, and a combination treatment that targets both GIP and GLP-1 receptors may be even more effective.

Tirzepatide is a new medication that works on both GIP and GLP-1 receptors and is already approved for treating type 2 diabetes.

Early research showed that it helped mice lose more weight compared to treatments that only target GLP-1. In studies with people who have type 2 diabetes, it also showed promising results for weight loss.

For example, the SURMOUNT-1 (SM-1) trial looked at how well tirzepatide works for weight loss in people with obesity or overweight who do not have diabetes.

To further explore potential differences in how men and women respond to the treatment, researchers conducted a post-hoc analysis of the SURMOUNT (SM) program, which included four clinical trials (SM-1 to SM-4).

Their analysis shows that a weekly injection of tirzepatide results in substantial weight loss for both men and women, with women experiencing greater reductions in weight.

Their findings, presented at the Annual Meeting of the European Association for the Study of Diabetes (EASD) in Madrid (September 9-13), compared tirzepatide to a placebo over 72 to 88 weeks in 4,677 adults (2,999 women and 1,678 men) with obesity.

“This was a post-hoc sub-group data analysis of the SURMOUNT-1, SURMOUNT-2, SURMOUNT-3 and SURMOUNT-4 phase 3 trials that showed tirzepatide injections (5 mg, 10 mg, 15 mg) significantly reduced body weight compared to placebo regardless of sex, with greater body weight reduction associated with tirzepatide in females compared to males.”

— Luis-Emilio García-Pérez, MD

While the SM-1 and SM-2 trials involved randomization immediately after a screening period, SM-3 had a 12-week lead-in phase with intensive lifestyle changes, and SM-4 had a 36-week lead-in with open-label tripeptide treatment.

In this analysis, body weight changes were evaluated in participants who had received at least one dose of tirzepatide (5, 10, or 15 mg) or placebo.

The study used a mixed model to assess differences in average weight change over time (from baseline to the end of the study: 72 weeks for SM-1 to SM-3 and 88 weeks for SM-4).

Logistic regression was used to evaluate whether male and female participants differed in achieving specific weight loss milestones, including reductions of 5%, 10%, and 15% of their body weight.

Across the four trials, women made up 51% to 71% of participants.

And at the start of the trials, women weighed less than men on average. For instance, in SM-1, the average weight of female participants was 99.8 kg, compared to 115.2 kg for men.

However, both men and women had similar body mass index (BMI) levels, indicating similar levels of obesity.

In terms of weight loss, the estimated reduction in body weight for those taking tirzepatide was significantly greater than for those on placebo, regardless of sex.

Women saw a greater percentage of weight loss than men across all doses.

For example, women lost up to 24.6% of their body weight, while men lost up to 18.1%. This difference was statistically significant in all studies.

When looking at specific weight loss thresholds, both men and women were far more likely to achieve reductions of 5%, 10%, and 15% body weight with tirzepatide compared to placebo.

However, in most trials, there was no significant difference between men and women in reaching these thresholds.

An exception was observed in the SM-3 trial, where women were more likely than men to achieve the 5% and 10% weight reduction goals.

The safety outcomes were generally similar for both men and women, though women reported higher rates of nausea and vomiting compared to men.

“The analysis showed that weight reduction happens consistently regardless of sex, however, tirzepatide was associated with greater weight loss in women than in men. Prevalence of obesity and treatment outcomes may differ between males and females as a result of physiological, sociocultural and environmental factors.”
— Luis-Emilio García-Pérez, MD

However, he added that “the results of this post hoc analysis have to be interpreted with caution as they are hypothesis-generating only.”

“The potential mechanisms of this finding need further research,” Dr. García-Pérez explained.

Mark A. Anton, MD, medical director at Slimz Weightloss, not involved in this research, said that this research on body weight reduction with tirzepatide is promising and aligns with our clinical observations.”

“The findings could provide deeper insights into the efficacy of tirzepatide across different demographics, potentially allowing for more personalized treatment plans,” Anton explained.

“These findings could mean more tailored and effective weight loss solutions, enhancing the overall success rates and improving long-term health outcomes,” he added.

Mir B. Ali, MD, board certified bariatric surgeon and medical director of MemorialCare Surgical Weight Loss Center at Orange Coast Medical Center in Fountain Valley, CA, who was also not involved in the research, noted that “this is an interesting study comparing weight loss in males versus females.”

“This is somewhat contrary to what I see in surgical weight loss patients; to me this study demonstrates that females are more responsive to these medications, though both males and females showed significant benefits,” Ali added.

“These findings may help prescribing providers set more realistic expectations based on gender for patients seeking these medications. It would be helpful to see more research in this area and make a consideration for changing dosing based on gender.”

— Mir B. Ali, MD