You’ve probably heard the frustrating truth: when it comes to diet and exercise, men often see more dramatic weight loss results than women. For every man who sheds 10 pounds by cutting carbs, a woman doing the same might only lose 2. Research consistently backs up this disparity.

But new insights from recent clinical trials on GLP-1 weight loss medications are flipping the script. Surprisingly, these injectable drugs appear to be more effective on average for women than for men.

A Head-to-Head Look at Leading GLP-1s

The latest study, presented at the European Congress on Obesity and published in the New England Journal of Medicine, offered the first direct comparison between semaglutide (Wegovy) and tirzepatide (Zepbound). Roughly 750 individuals with obesity were split into two groups, each receiving the maximum tolerable dose of one of the medications.

It was observed that Zepbound, the newer medication that targets two gut hormones (compared to Wegovy’s one), proved superior for weight loss, with participants losing approximately 50% more weight than those on Wegovy. This finding aligns with many doctors’ observations.

Interestingly, participants in this study, on average, lost slightly less weight than in previous trials for the same medications. This was largely driven by men, who lost about 6% less weight than women. Men constituted a larger portion of this study’s participants (35%) compared to previous trials (20%-25%).

“Why this works better in women, I can’t honestly tell you, but it’s great,” said Dr. Louis Aronne, who led the study. “It has been seen again and again.”

Previous long-term follow-up trials have also shown this trend:

• Women using semaglutide for two years lost an average of 11% of their starting weight, while men lost 8%.
• In tirzepatide trials, women lost up to 28% of their starting weight, compared to men’s 19%.

Untangling the Sex-Specific Effects: The Theories

Researchers are now working to understand why these powerful drugs exhibit such sex-specific differences. Several intriguing theories are emerging:

• Dosing Discrepancy: Dr. Melanie Jay, an obesity expert at NYU Grossman School of Medicine, points out that women, typically weighing less than men, are often prescribed the same doses, effectively receiving a proportionally higher dose for their body size.
• Fat Storage Location: Women tend to store more subcutaneous fat (under the skin) than visceral fat (around organs). It’s possible GLP-1 drugs are more effective at targeting one type of fat over the other.
• Motivation and Adherence: Societal pressures on women to be thin might lead to greater motivation to persist with the medications, even through significant side effects like nausea, vomiting, and constipation. Dr. Jay has observed that women in her practice often find ways to manage these side effects more readily than men.

The Estrogen Connection: A Key Clue?

One of the most compelling explanations involves estrogen, a hormone present in higher amounts in women. Dr. Karolina Skibicka, a professor of molecular medicine at the University of Gothenberg, has been studying the intricate relationship between gut hormones and the brain.

Her research in rats suggests that estrogen directly interacts with GLP-1 and other gut hormones, amplifying their potency in the brain. Studies have shown that co-injecting rats with GLP-1 and estrogen significantly enhances the effects of GLP-1 on feeding behavior and motivated behavior. Conversely, blocking estrogen’s action reduces GLP-1’s effectiveness.

Skibicka explains that estrogen appears to enhance GLP-1’s effects by increasing the number of GLP-1 receptors on cell surfaces. Many tissues have receptors for both estrogen and GLP-1, leading to an amplified effect within the cell.

A Call for More Research

Despite these fascinating theories, they remain educated guesses. “We’re really dealing with paucity of data compared to just sort of the baseline data that you have about what GLP-1 does,” Skibicka noted. Clinical studies often don’t delve into the “why” behind observed sex differences.

While women may experience greater weight loss and report more gastrointestinal side effects, men seem to benefit more from the cardiovascular advantages of these medications. Some studies also suggest sex-specific differences in mood impacts, with women potentially being more prone to depression on these drugs.

Understanding these sex-specific impacts is crucial for optimizing treatment for all patients. If estrogen influences the drugs’ efficacy, it could have implications for women before or after menopause, or those on hormone-blocking therapies. This knowledge could also help develop strategies for non-responders or those who plateau before reaching their weight loss goals.

“Men and women have different biologies, and we can’t treat them always the same,” emphasizes Dr. Jay. Further research into these sex differences could lead to personalized dosing, complementary therapies, and ultimately, more effective and tolerable weight management solutions for everyone.