Why GLP-1 Drugs Work Better for Some Than Others
Disclosure: I wrote this article and used AI as a “professional editor” to refine and shorten overly long or complicated sentences.
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By now, almost everyone has heard of GLP-1.
GLP-1 stands for glucagon-like peptide-1. It is a hormone our own body releases after we eat. This hormone binds to the GLP-1 receptor and can trigger several functions, depending on the cell expressing the receptor. In general, GLP-1 prompts the release of insulin to help control blood sugar; it slows down how quickly the stomach empties while signaling to the “appetite centers” in the brain to reduce hunger. In other words, we feel full for longer.
Besides GLP-1, there is also another hormone released in our gut that regulates insulin and, more generally, appetite. This hormone is GIP (which stands for glucose-dependent insulinotropic polypeptide, formerly called gastric inhibitory polypeptide), and it binds to the GIP receptor. So, in other words, GIP also helps regulate appetite.
This is why medications that mimic GLP-1 (or activate both the GLP-1 and GIP receptors) have changed how obesity is treated, and for some people they work remarkably well. But they do not work the same for everyone: a meaningful minority of people lose very little weight, or none at all.
So, why do GLP-1 (and GIP) drugs work extremely well for some, but not at all for others?
As always in this series, the explanation is intentionally simplified. The underlying science is considerably more complex, but the core ideas can be grasped without all of the details.
Just for the interested reader, GLP-1/GIP drugs are GLP-1 (and GIP) receptor agonists. An agonist is any molecule that binds and activates the receptor. Semaglutide (the active ingredient in Ozempic and Wegovy) is a lab-made molecule that mimics the natural hormone GLP-1, but it has been modified to be more stable and remain active longer in the body. This is why it is called a GLP-1 receptor agonist. Tirzepatide (the active ingredient in Mounjaro and Zepbound) is a lab-made molecule designed to activate both the GIP and GLP-1 receptors.
Reasons Why Some Lose and Others Don’t
Let’s start with some definitions. In obesity medicine, “success” is often defined as losing at least 5% of your starting body weight, because that is roughly the point where health markers start to improve. A “non-responder” is often defined as someone who fails to reach that 5% after an adequate dose and duration (typically after several months at the highest tolerated dose).
Various clinical trials have shown that GLP-1/GIP drugs are indeed a breakthrough for obesity treatment. For semaglutide (a GLP-1 receptor agonist), mean weight loss was 16.9% versus 2.4% with placebo (68 weeks, obesity without diabetes: the STEP 1 trial). For tirzepatide (a dual GLP-1/GIP agonist), the mean loss climbed with dose, and the highest dose (15 mg) reached 22.5% versus 2.4% for placebo (72 weeks, obesity without diabetes: the SURMOUNT-1 trial). At that dose, 39.7% achieved ≥25% weight loss. These are impressive numbers. But even at that top dose, about 4% still failed to reach even 5% weight loss.
The 4% figure is especially interesting because it comes from an analysis that accounts for many of the obvious explanations. It estimates what happens while people stay on the drug, so it isn’t mainly about stopping early, and the trial excluded people with type 2 diabetes. In everyday use, non-response is more common because those factors do come into play: people stop early, often due to side effects, may not reach or remain on an effective dose, have diabetes, or take other medications that promote weight gain (including corticosteroids and certain antidepressants). But even after accounting for many of these factors, some people still respond poorly.
Poor response is only one part of a broader pattern: people differ widely in how strongly they respond. In the trial, nearly 40% lost at least 25% of their body weight. Researchers are beginning to identify biological factors that may help explain this variation. One recent clue came from genetics.
In a recent study (published in April 2026 in Nature), researchers performed a genome-wide analysis of nearly 28,000 people who had taken these drugs. Comparing weight loss with genetic variation, the study identified a variant in the GLP-1 receptor gene that correlated with increased weight loss. It also found a variant in the GIP receptor gene linked to more nausea and vomiting; across the study, these side effects tended to go hand in hand with more weight loss (this GIP receptor variant was only associated with side effects in patients taking tirzepatide, which targets both the GLP-1 and GIP receptors).
This weight-loss finding was then confirmed in an independent group: the US government’s All of Us Research Program, which links volunteers’ DNA to their actual medical records. There, the same gene variant showed an effect in the same direction.
While the study linked a GLP-1 receptor variant to greater weight loss (and a GIP receptor variant to side effects), some limitations remain.
First, the genome-wide search for variants was done in people of European ancestry, so we know much less about how genetic variants shape the response in everyone else.
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Second, genetics is only part of the answer. It explains some of the differences in how people respond, but not most of it.
Not All Obesity Is the Same
Obesity is not a single condition, and different underlying drivers may respond differently to GLP-1/GIP treatments. This is a very complex topic, so let’s use an example that can be easily pictured:
Researchers at the Mayo Clinic have described people with a “hungry brain,” who need an unusually large amount of food before they feel satisfied. Others have a “hungry gut”: they feel full quickly after a meal but get hungry again soon afterward.
How does this connect to GLP-1/GIP drugs?
GLP-1 drugs act on both the gut and the brain, but they’re especially good at the gut side, keeping you full for longer, which is exactly what the “hungry gut” type is missing. Those with a “hungry brain” tend to respond less and may do better on a drug aimed more squarely at the brain’s appetite signals.
This example is a simplified way to state that obesity is a complex condition, and treatment needs to align with the underlying drivers. GLP-1/GIP drugs certainly hit the spot for a lot of people, but not for everyone.
What Are the Risks?
Whether or not one loses weight, taking GLP-1/GIP drugs is not risk-free.
Rapid weight loss is not all fat; some is lean mass, including muscle. In analyses of the major trials, up to around 40% of the weight lost on semaglutide, and roughly 25% on tirzepatide, came from lean mass rather than fat. That matters because muscle helps regulate blood sugar and supports bone health. However, some of this is an expected response to carrying less weight, and adequate protein plus resistance training appear to meaningfully preserve muscle during treatment.
This also has a sting in the tail if treatment stops. Much of the lost weight often returns, while rebuilding lost muscle may be more difficult. This is a reason the muscle question matters even for people who don’t stay on the drug forever.
In Summary
Semaglutide and tirzepatide produce meaningful weight loss for a lot of people. But they are not without trade-offs, such as muscle loss alongside fat. And they treat obesity without curing it: stop the drug, and much of the weight often returns.
The interesting questions now are not whether these drugs work, but for whom, how well, and for how long. We already know that they do not work equally for everyone: a minority lose little or nothing. Some of that gap comes down to familiar factors such as stopping early, underdosing, type 2 diabetes, or taking other medications that promote weight gain. But there is more to it, and we are only starting to understand the underlying biology, from different obesity phenotypes to genetic differences affecting the drugs’ effectiveness.
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