Why GLP-1 – New weight-loss drugs like Ozempic and Wegovy can produce striking results for many users, but a meaningful share—often labeled “non-responders”—lose little weight even after months on the highest tolerated dose. Research points to behavior, biology, genetics,
It can be disorienting when the scale doesn’t budge—especially when the promise seems so direct. Weight-loss jabs such as Ozempic and Wegovy (semaglutide) have become a modern reference point for dramatic change, with users losing up to 15 percent of their body fat on average.
Semaglutide is a glucagon-like peptide 1 (GLP-1 receptor agonist) drug. It mimics a natural gut hormone released after we eat. That hormone sets off multiple physiological responses that help regulate body weight: it releases insulin to help control blood sugar levels. slows stomach emptying so people feel fuller for longer. and signals the brain’s hunger centres to suppress appetite.
Yet even with that tightly mapped biology, not everyone who takes GLP-1 drugs will shed a significant amount of weight. People are often called “non-responders” when they lose less than 5 percent of their body weight after roughly six months of treatment on the highest tolerated dose. Research suggests that between 10 percent and 30 percent of patients fall into this group.
Some of the reasons are painfully practical. Many people labelled as non-responders to GLP-1 receptor agonists such as semaglutide do not take the medication correctly or stop before an adequate therapeutic effect can be achieved. Studies show up to 20-60 percent of people stop treatment within the first year. and widespread use of the drug in doses below the recommended amounts can also reduce the effect.
But there’s more than adherence at play. Certain metabolic issues may interfere with semaglutide’s actions. Insulin resistance—when the body’s cells stop responding properly to insulin—could blunt how the drug works. Sleep disruption is another potential barrier: poor sleep is shown to delay the release of the body’s natural GLP-1 hormone.
Then there are the medications that come with trade-offs. People taking other drugs, such as corticosteroids and psychotropic drugs (including antidepressants) that can cause weight gain, may find GLP-1 drugs don’t work very well for them.
Even the label “non-responder” doesn’t always mean the same underlying problem. Sex may influence how people respond to semaglutide. with research showing women taking semaglutide consistently lose more weight compared to men. A review of 47 randomised controlled trials involving over 23. 000 patients found the greatest weight-loss effect from GLP-1 drugs appeared in participants who were young. female. and not diagnosed with diabetes—conditions associated with better insulin sensitivity.
One reason proposed for women’s stronger response involves higher oestrogen levels. Oestrogen improves insulin sensitivity and stimulates GLP-1 secretion.
Genetics adds another layer, and it complicates the idea of a one-size-fits-all breakthrough. Scientists have identified variants in the gene coding for the enzyme PAM (peptidyl-glycine alpha-amidating monooxygenase) that appears to cause GLP-1 resistance. This genetic change is carried by approximately 10 percent of the population. People with the mutation have higher circulating levels of GLP-1 but without the expected biological effect—meaning more GLP-1 hormone may be needed to achieve the same response as in people without the mutation. The result is a form of clear resistance to the hormone.
Research looking at the genetics of nearly 28. 000 people taking a GLP-1 drug also identified genetic issues in another set of receptor genes called GLP-1R and GIPR. Those genetic differences affected both weight loss and side effects. People with these issues had higher body mass index (BMI) and body mass on average. and were more likely to have type 1 diabetes and other metabolic issues. In other words. some genetic profiles may help explain why some people fail to lose any weight when taking a GLP-1 drug.
There’s also a mismatch problem—when medication targets one pathway but obesity is being driven by another. The body operates based on four distinct types of hunger. If a medication targets something that is not the primary cause of a person’s obesity, the response can be small.
The first type is baseline slow-burn hunger. the minimum number of calories the body must consume to function. also known as metabolic rate. The second is hungry gut, a genuine physiological need to eat. Hunger can also be driven by the brain as “hungry brain. ” where people eat from habit or stress. or by emotions as “emotional hunger. ” where people eat to cope with how they feel.
For patients with emotional hunger, GLP-1 drugs don’t address the root causes of anxiety and depression driving overeating. An observational study carried out in Japan found emotional eaters were less likely to see significant weight changes when using GLP-1 drug treatment.
That points toward an approach beyond medication alone. Integrating cognitive behavioural therapy may be important for people who struggle with emotional hunger and are using a GLP-1 drug. For hungry gut patients, a high-protein, high-fibre diet can enhance the drug’s effectiveness.
For hungry brain patients, switching to dual agonists such as tirzepatide (commercially known as Mounjaro)—which targets two digestive hormones, GLP-1 and glucose-dependent insulinotropic peptide (GIP)—may be useful. For slow-burn hunger, resistance training can increase resting metabolic rate.
In the middle of all these variations. one truth stands out: weight-loss drugs have proven effective for many people. but their uneven results show how urgently the medical system needs a more individualized way to match treatment to the person in front of it. Moving toward developing precision obesity medicine would mean analyzing a patient’s unique genes and lifestyle patterns to match them with the correct medication.
Genetic testing for variants linked to non response is not common today, but it represents the next step in helping ensure patients are given therapies that work better for them—rather than hoping the same strategy will work for every body, every background, and every kind of hunger.
GLP-1 semaglutide Ozempic Wegovy non-responders precision medicine obesity insulin resistance sleep disruption cognitive behavioural therapy tirzepatide Mounjaro genetics