Why GLP-1 Drugs Work Like Magic for Some — and Barely Work at All for Others

Posted on 26 September, 2026 by Mehrdad Fathi

The GLP-1 drugs — semaglutide, tirzepatide, and their pharmaceutical cousins — have been called transformative. Clinical trials show that most people taking them lose an average of 25% of their body weight. Real-world results follow a similar arc. But 10 to 15% of users see minimal or no weight loss at all.

Daniel Drucker, an endocrinologist at the University of Toronto whose research contributed to the development of these medications, describes the situation plainly: “There is tremendous heterogeneity in the response to these medications. And we really don’t understand that.”

Understanding why some people don’t respond has become a priority for obesity science. The Endocrine Society flagged it as a key research direction in a March 2026 scientific statement, and investigators are now working through a list of candidate explanations that includes biological sex, genetics, behavioral factors, and differences in how the drugs interact with the central nervous system.

The practical stakes are high. If researchers can identify who will or won’t respond to a given drug before they start taking it, prescriptions could be matched to patients more effectively. And if the mechanisms behind non-response can be mapped, new drugs could be designed to fill the gap.

Sex Hormones: The Oestrogen Connection

One of the clearest patterns so far is that women tend to lose more weight on GLP-1 drugs than men do. That holds true both in randomized trials and in large real-world datasets.

A 2024 study of postmenopausal women taking semaglutide found that those who were also on hormone-replacement therapy lost significantly more weight than those who were not. A February 2026 study found the same effect in women taking tirzepatide, a dual agonist that mimics both GLP-1 and gastric inhibitory polypeptide.

The implication is that oestrogen, a core component of hormone-replacement therapy, might amplify the effects of GLP-1 drugs. Drucker says the molecular mechanism is not yet understood, but animal studies offer clues: oestrogen reduces food intake and acts on overlapping brain regions with GLP-1. When combined, the two have a synergistic effect on weight loss.

Genetics: A Small but Real Effect

Ruth Loos, a genetic epidemiologist at the University of Copenhagen, notes that while researchers know a great deal about the genetics of obesity itself, far less is known about the genetics of drug response. “When it comes to the genetic contribution to the response to weight-loss drugs,” she says, “there’s not a lot of good data available.”

One of the first substantial findings came in April 2026, when a Nature paper analyzed the genomes of nearly 28,000 users of the now-defunct DNA-testing service 23andMe. The study identified a variant in the gene encoding the GLP-1 receptor. People carrying one copy of the variant lost about 0.76 kilograms more than those with none; people with two copies lost around 1.5 kilograms more.

Loos points out that the effect size is comparable to the sex difference observed in clinical data. However, the magnitude is not large enough to guide individual treatment decisions. In other words: statistically significant, but not yet clinically actionable.

Behavior: Impulsivity and Food Intake

Sai Krupa Das, an obesity researcher at Tufts University, is investigating whether behavioral traits help explain variation in treatment response. Her group is running a clinical trial focused on understanding why some people regain weight after losing it through diet and exercise. One of the factors under study is impulsivity — a personality trait that prior research has linked to higher calorie intake and worse diet quality.

Though the trial does not involve GLP-1 drugs, Das believes the findings could still shed light on drug response. “Is it because of personality traits such as being very impulsive?” she asks. “We always look for answers in biology, but there is definitely a connection with psychology, and we should not ignore it.”

Receptor Density and Brain Circuits: The Unknown Room

One of the most plausible but least studied possibilities is that people who respond to GLP-1 drugs have different densities of GLP-1 receptors in the brain circuits that regulate hunger and satiety. It’s also possible that the drugs reach and activate certain neural pathways in some individuals but not others.

Drucker describes the current state of knowledge as frustratingly incomplete. “We measure drug levels, genetics, proteomics, which are very logical things to measure,” he says. “But so far, that has not unlocked the hidden room that explains interindividual variation.”

What Comes Next

Precision medicine for obesity remains, in the Endocrine Society’s phrasing, “largely aspirational.” The tools to predict who will respond to which drug, and why, do not yet exist. But the fact that the question is now being asked systematically — and funded accordingly — suggests that answers are closer than they were even two years ago.

The next generation of obesity drugs might not just be more effective on average. They might be matched to patients based on sex hormones, genetic markers, behavioral profiles, or brain imaging. That outcome depends on whether researchers can solve a problem that, for now, remains mostly opaque: why the same drug produces radically different results in people who, metabolically speaking, should be similar.

Source: Nature 657 (2026). doi: https://doi.org/10.1038/d41586-026-03020-3

References:

1. Aronne, L. J. et al. JAMA 331, 38–48 (2024).

2. Yang, Y. et al. J. Diabetes 17, e70063 (2025).

3. Tchang, B. et al. Obesity 34, 729–737 (2026).

4. Hurtado, M. D. et al. Menopause 31, 266–274 (2024).

5. Castaneda, R. et al. Lancet Obstet. Gynaecol. Women’s Health 2, e118–e128 (2026).

6. Börchers, S. & Skibicka, K. P. Endocrinology 166, bqae165 (2024).

7. Su, Q. J. et al. Nature 653, 770–775 (2026).

8. Marc, B. et al. Am. J. Clin. Nutr. 109, 117–126 (2019).