Genetic, age and sex factors challenge the promise of Wegovy as an effective weight-loss solution

Emerging evidence reveals that genetic makeup, age, and sex significantly influence individual responses to obesity drugs like Wegovy, raising questions about their universal efficacy and the need for personalised approaches.

The surge in demand for Wegovy and similar obesity drugs has brought a less comfortable reality into sharper focus: some patients lose little weight at all, and doctors say the shortfall may be more common in men and older adults than the marketing around “miracle” injections suggests. A large Nature study based on 27,885 self-reported GLP-1 users found wide variation in outcomes and reported that people taking semaglutide, the active ingredient in Wegovy, generally lost less body mass than those taking tirzepatide.

That survey, drawn from 23andMe research participants, was heavily female and had a median age of 52. The median starting body mass index was 35.1, and the median reported time on treatment was 8.3 months. Across the full group, participants reported a median loss of 11.3kg, or 11.7% of their pre-treatment weight. But averages conceal a sizeable minority who do not get close to those results. The Associated Press reported that obesity specialists reckon roughly one in five patients may not see strong weight loss, while trials of Wegovy and Mounjaro found about 10% to 15% lost less than 5% of their body weight, a common threshold for a poor response. One Wegovy patient, Danielle Griffin, told AP: “I have been on Wegovy for a year and a half and have only lost 13 pounds,” adding, “I’ve done everything right with no success. It’s discouraging.”

Sex appears to matter. Yale Medicine said women tend to lose more weight than men on GLP-1 medicines, and quoted Dr Imaeda as saying: “Men actually tend to respond worse,” adding, “That’s something we see consistently.” Age complicates the picture further. The Association of American Medical Colleges reported that many clinicians are especially cautious in patients aged 65 and older because frailty, dementia risk and sarcopenia can change the balance of benefit and harm. In that report, physician Rekha Ganta said: “In older adults there is an association between weight loss and all-cause mortality, especially in men who lose more than 10% of body weight.” Another geriatric obesity specialist, John Batsis, said bluntly: “We don’t have data to be able to back up what we’re doing clinically.”

The genetic story is becoming more credible, but it is still far from a tool a GP can use in a consulting room. The Nature paper linked variants near the GLP1R gene to differences in both weight loss and side effects, while variants near GIPR were associated with nausea and vomiting in people using tirzepatide. A separate report highlighted by ScienceDaily, covering a Genome Medicine study, said about 10% of people may carry variants associated with a form of GLP-1 resistance. Anna Gloyn, a Stanford Medicine professor involved in that work, said: “In some of the trials, we saw that individuals who had those variants were unable to lower their blood glucose levels as effectively after six months of treatment.” But that research centred on blood sugar control, not definitive weight-loss outcomes, and the authors did not claim to have produced a practical predictor of who will fail Wegovy.

That uncertainty matters because clinicians say biology is only part of the explanation. Yale Medicine noted that genetics does not come close to accounting for the full spread of responses seen in day-to-day practice. Fatima Cody Stanford told AP: “It’s all about explaining that different people have different responses,” and added: “The dysfunction may not be the same” from one patient to another. In other words, a flat response on the scales may reflect differences in hormones, appetite signalling and energy regulation, but it may also reflect problems that have little to do with a patient’s effort or discipline.

Real-world prescribing adds another layer. Healthline reported that many people labelled as non-responders have never reached a full tolerated dose, have stopped early because of gastrointestinal side effects, or have not been on treatment long enough for a fair test. Clinicians also pointed to severe insulin resistance, sleep disruption, sarcopenia and medication-related weight gain as reasons results can stall. AP added that sleep apnoea, antidepressants, steroids and contraceptives may also obstruct progress. For older adults, tolerability may be a bigger issue still: the AAMC report cited a 2018 analysis showing that people over 65 were more likely than younger adults to discontinue GLP-1 treatment because of gastrointestinal side effects.

The practical implication is that poor response should trigger reassessment rather than resignation. Yale Medicine said some patients who lose too much weight can simply have their dose reduced rather than stopping treatment altogether. At the other end of the spectrum, surgery remains a live option. Healthline quoted bariatric surgeon Mir Ali saying that, for eligible patients, surgical weight loss remains the most effective long-term treatment. The same report said sleeve gastrectomy and Roux-en-Y gastric bypass typically deliver average weight reductions of 25% to 35%, and Yale Medicine noted that combining surgery with a GLP-1 drug may be especially effective for some patients.

For older men, in particular, the bigger question may not be whether the scales move dramatically, but whether treatment improves health without eroding strength and independence. Batsis told the AAMC that his patients care about “getting out of a chair, playing with their grandchildren, not being admitted into a nursing home”. That is a very different goal from the glossy before-and-after narrative that has powered the obesity-drug boom. The evidence now emerging suggests Wegovy can be transformative for many people, less potent for some, and plainly disappointing for others. What it still cannot do is tell doctors in advance exactly which patient will fall into which group.