New data tie GLP-1 weight loss wins and side effects to common DNA variants
Two people can take the same GLP‑1 drug for months, yet one sheds substantial weight while the other barely moves the scale—and genetics may be part of the reason.
According to Healthline, GLP‑1 medications such as Ozempic, Wegovy, Mounjaro and Zepbound have surged in use for type 2 diabetes and obesity because of their strong average weight‑loss results.
Yet both clinical experience and new research show wide variation in how people respond.
A study in Genome Medicine, as reported by Healthline, focused on two genetic variants that affect peptidyl‑glycine alpha‑amidating monooxygenase (PAM), an enzyme that activates several hormones including glucagon‑like peptide‑1 (GLP‑1).
Around 10 percent of people carry PAM variants linked to “GLP‑1 resistance.”
These individuals have higher‑than‑normal GLP‑1 levels but the hormone appears less effective at lowering blood sugar.
When researchers examined people with a PAM variant called p.S539W, they expected lower GLP‑1 levels.
Instead, Healthline said the study found elevated GLP‑1 alongside slower‑than‑expected reductions in blood sugar.
More GLP‑1 was needed to achieve the same biological effect, indicating resistance.
Robert Glatter, MD, an emergency physician at Lenox Hill Hospital in New York City and assistant professor at Zucker School of Medicine, told Healthline that “these findings support the idea that some patients may have partial biologic resistance to incretin-based therapies.”
He added that genetics explains only part of the treatment differences and that routine pharmacogenomic screening is “not yet ready for widespread clinical use.”
The same article noted that this PAM research looked at blood‑sugar control, not weight loss, and GLP‑1 drugs are typically prescribed at higher doses for obesity than for diabetes.
Another large study points to different genetic levers.
A genome‑wide association study from 23andMe, published in Nature, analysed 27,885 people who reported using GLP-1 receptor agonists for weight loss.
The article reported a median pre‑treatment body mass index (BMI) of 35.1 kg m−2 and a median BMI drop of 4.1 kg m−2—about 11.7 percent of starting weight—after a median 8.3 months on treatment.
Within a subset of 15,237 people of European ancestry, the Nature study identified a missense variant in GLP1R, rs10305420, that was significantly associated with greater BMI loss.
Each copy of the effect allele corresponded to an additional 0.641 percentage‑point reduction in BMI, roughly 0.76 kilograms of extra weight loss per allele.
Reuters reported that people with one copy of this variant lost about 1.7 pounds more than non‑carriers over a median eight‑month period, while those with two copies lost about 3.3 pounds more.
The Nature paper also linked variants near GLP1R to higher odds of nausea and vomiting on GLP-1 medications, and found that greater nausea or vomiting aligned with greater BMI loss at this locus.
In tirzepatide users, the researchers reported that a missense variant in GIPR, rs1800437, increased the risk of vomiting, and estimated that people homozygous for risk alleles at both GLP1R and GIPR had a 14.8‑fold higher odds of tirzepatide‑related vomiting than those without risk alleles.
Reuters said people carrying the GIPR variant were 83 percent more likely than non‑carriers to vomit after taking tirzepatide.
Even with these signals, the Nature authors described the overall genetic effects on weight loss as modest and reported that models combining clinical, demographic and genetic variables explained only a quarter of the variance in BMI change, with most of that driven by non‑genetic factors.
Healthline’s experts emphasised those practical factors.
Mir Ali, MD, bariatric surgeon and medical director of MemorialCare Surgical Weight Loss Center at Orange Coast Medical Center said other explanations for poor response include underlying medical conditions or not taking the drugs exactly as prescribed.
Glatter noted that many people labelled “non‑responders” in practice are dealing with incomplete dosing, early discontinuation because of gastrointestinal side effects, short treatment duration, or competing metabolic issues such as severe insulin resistance, sleep disruption, sarcopenia or medication-related weight gain, and that addressing these issues often restores effectiveness.
When GLP‑1 therapy still falls short, Ali told Healthline that surgical weight loss, for those who qualify, “remains the most effective long‑term solution.”
Glatter said metabolic and bariatric surgery—such as sleeve gastrectomy and Roux‑en‑Y gastric bypass—typically produces average weight reductions of 25 to 35 percent and remains the most durable option for severe obesity and obesity‑related metabolic disease, while also altering incretin signalling by increasing GLP‑1 activity and improving insulin sensitivity.
Clinicians, as quoted by Healthline, stressed that lifestyle remains central.
Ali said most weight loss comes from dietary changes—cutting carbohydrates and sugar while prioritising protein and vegetables—supported by aerobic and resistance exercise to burn calories and maintain muscle.
Glatter recommended Mediterranean, DASH or MIND dietary patterns, adequate hydration and strength training alongside aerobic activity, whether or not a person uses a GLP-1.
