Weight loss drugs fail some patients

Weight-loss drugs like Ozempic and Wegovy have shown dramatic results, with users losing up to 15% of their body weight on average. These medications, including semaglutide, mimic a natural gut hormone that regulates appetite and blood sugar. The hormone, GLP-1, triggers physiological responses such as insulin release to control blood sugar, slows stomach emptying to prolong fullness and signals the brain’s hunger centers to suppress appetite. But they don’t work for everyone.

About 10% to 30% of patients are considered non-responders, losing less than 5% of their body weight after six months on the highest dose. Some simply stop taking the drug too soon. Others take doses below the recommended amount. Widespread use of suboptimal dosing further reduces effectiveness, as the medication may not reach the threshold needed to produce significant metabolic changes.

Obesity itself is complex, driven by four distinct types of hunger that GLP-1 drugs may not all address. Metabolic hunger reflects the body’s baseline caloric needs, while gut-driven hunger arises from physiological hunger signals. Brain-driven hunger involves habitual or stress-related eating, and emotional hunger stems from anxiety or depression. GLP-1 drugs don’t address emotional eating, which stems from psychological rather than physiological triggers. A Japanese study found emotional eaters saw little change on these medications, as the underlying emotional drivers remained untreated. Cognitive behavioral therapy may help, while high-protein, high-fiber diets could enhance the drug’s effectiveness for gut-driven hunger by promoting satiety and stabilizing blood sugar.

For brain-driven hunger, drugs like tirzepatide (Mounjaro), which target both GLP-1 and GIP, might work better by addressing multiple hormonal pathways. Resistance training can help those with slow metabolic rates by increasing resting energy expenditure, making it easier to maintain a caloric deficit. For patients with a hungry brain, switching to dual agonists may provide a more full approach to appetite suppression.

The takeaway is that one-size-fits-all weight loss treatments often fail. The push for precision obesity medicine—tailoring drugs to a patient’s genes and lifestyle—could be the next step. While genetic testing for variants linked to non-response is not yet widespread, it represents a potential advancement in matching patients with therapies that align with their biological and behavioral profiles.