Why does a medication work wonders for one person but barely affects another? Two individuals can start on the same GLP-1 prescription—at the same dosage—and end up in vastly different circumstances by year’s end. Research from the 23andMe Research Institute has highlighted this striking variability: some may lose less than 5 percent of their body weight, or even gain weight, while others shed over 20 percent. This puzzling disparity is central to understanding the Ozempic phenomenon, revealing that what once seemed straightforward now appears to necessitate a more tailored approach.
So, what explains this difference? I had a chat with Dr. Anthony Puopolo, who’s been closely following the research. Dr. Puopolo, a board-certified physician and chief medical officer at LifeMD with 25 years in the field, offered some insights.
How we overeat might be key to understanding Ozempic’s effectiveness. Some folks indulge in food because it looks irresistible or smells divine, while others eat for comfort in response to stress and low moods. This distinction could impact how well a GLP-1 drug works; research from Japan suggests that those who overeat due to cravings tend to lose more weight compared to emotional eaters, who may see less impressive results.
Dr. Puopolo emphasized that emotional eating isn’t a reason to withhold the drug. Instead, he views it as an indicator that additional support might be beneficial. Options include cognitive behavioral therapy, stress management techniques, or other medications like naltrexone or bupropion. Identifying these behaviors doesn’t require expensive tests; simple questionnaires can quickly categorize individuals as external, emotional, or restrictive eaters.
There’s also the question of genetics. Researchers at Stanford have found certain genetic variants—in about 10 percent of the population—that seem to dampen the medication’s effects, even when these individuals produce more of the hormone naturally. The hope is to eventually have a genetic test that reveals upfront whether the treatment is likely to be effective.
However, Dr. Puopolo cautions that such a test isn’t on the horizon yet. While the genetic variants are real, he notes their impact is quite minor. Interestingly, he points out that a more reliable indicator of success might be early weight loss; losing at least 5 pounds in the first three months could be a more accurate predictor than any genetic profile.
As for who tends to lose the most weight on Ozempic, gender appears to be a significant predictor, with women generally losing more than men. People with Type 2 diabetes often experience slightly less weight loss compared to those without it, and, again, emotional eaters find themselves at the lower end of the spectrum. Rapid early weight reduction appears to indicate a greater total loss over time.
A recent study from Duke University suggests that our pancreas produces a significant amount of GLP-1 naturally, which raises an intriguing possibility: those who respond well to small doses may just have higher natural levels of the hormone. While Dr. Puopolo acknowledges the importance of this finding, he remains skeptical about its predictive value for medication response. He attributes variations to receptor genetics and individual eating habits rather than baseline hormone levels.
The gut microbiome also plays a role in this equation, impacting how the medication works and vice versa. Some early research even suggests a connection between bacteria in the gut and blood-sugar responses. However, Dr. Puopolo advises against pre-treating the gut to improve outcomes, stating there’s no solid evidence to support this idea for weight loss.
A study from the University of Virginia adds a note of caution on weight loss with these drugs. While they do lead to weight reduction, this doesn’t always translate to improved fitness or muscle retention; a considerable portion of the weight lost can be muscle rather than fat. Dr. Puopolo confirms that a third of lost weight might not be fat, particularly affecting older adults, men, and those losing weight rapidly. He suggests that increased protein intake and resistance training can help mitigate muscle loss.
With the introduction of an oral version of Wegovy expected in 2026, patients now have to decide between a daily pill that must be taken on an empty stomach or an injection that bypasses digestion. Dr. Puopolo frames the choice more in terms of adherence than chemistry. Both forms are pharmacologically similar when taken correctly, but the pill comes with a potential adherence challenge. For those who might struggle with that, the injection may yield more consistent results.
Interestingly, many GLP-1 users report changes beyond appetite suppression. Some note diminished cravings for alcohol, shopping, or smoking. Dr. Puopolo describes this as evidence that these medications affect the brain’s reward system, particularly noted with alcohol, and possibly with nicotine and certain compulsive behaviors. The mechanism at play appears nuanced; these drugs don’t eliminate pleasure but rather reduce the compulsion to seek out rewards, leading to a new understanding of how they function.
These medications are increasingly being recognized not just as weight-loss solutions but as tools for improving heart health and metabolic function. Dr. Puopolo argues that many patients may be missing out on benefits due to outdated perceptions. He points to trial data supporting cardiovascular advantages that extend beyond initial weight, yet prescribers still categorize these as diabetes medications, influenced by insurance protocols and public perceptions focused on weight alone.
A common concern about stopping GLP-1 medications is weight regain, which is well-documented. Dr. Puopolo stresses that these drugs generally don’t provide a permanent solution, with around 75 percent of individuals regaining lost weight within a year of discontinuation. However, there are exceptions, especially among those who adopt sustainable lifestyle changes or who begin treatment at lower weights. Overall, he represents obesity as a chronic condition needing ongoing management.
Looking forward, the idea of a comprehensive test that evaluates genes, gut health, hormones, and psychological factors to predict response to Ozempic seems to be a few years away. Dr. Puopolo places it at about 5 to 10 years from practical application. However, he believes the urgency isn’t as pressing compared to other medical areas. For now, the focus should be on pairing the right drug with a patient’s eating habits and health status, then tracking responses in the first few months—an approach already advocated by the American Diabetes Association.
In the end, the most straightforward predictor of how Ozempic will work for an individual might just hinge on its initial effects within the first ninety days.
