GLP-1: the hormone that got out of control

This article grew out of routine work—weekly curation of scientific news for the “Capital of the Country” portal column. Over the past few months, the topic of GLP‑1 drugs, obesity, and related metabolic research has come up far too often to remain a set of scattered notes. At some point it became clear: a more coherent picture was needed. Additional interest in the subject is also fueled by personal experience—I’m currently going through this journey myself.

In the early 1980s, scientists discovered that after a meal the intestine releases a short peptide—glucagon-like peptide‑1. It prompts the pancreas to secrete insulin, slows gastric emptying, and quietly tells the brain: “enough.” Natural GLP‑1 survives in the bloodstream for only a few minutes, so it had little practical use. Until someone noticed that the venom of the Gila monster lizard contains a very similar but much longer-lived molecule. That’s how exenatide was born—the first drug in a new class. More advanced versions followed, and in 2017–2021 semaglutide and tirzepatide turned a niche medicine for diabetics into a cultural phenomenon, the subject of waiting lists, and one of the fastest-growing markets in the history of pharmaceuticals.

Today these drugs truly do what once seemed almost impossible. A large international review of more than 90,000 patients showed that GLP‑1 agonists reduce the risk of heart attacks, strokes, heart failure, and premature death by about 13%. The effect lasted on average nearly three years and was observed even in people without diabetes. An observational study of 111,000 women added another surprise: among those taking semaglutide or tirzepatide, the odds of developing breast cancer were about 30% lower.

And then it turned out that a hormone once considered mainly a regulator of blood sugar and appetite interferes with many more processes. In early studies, the drugs reduced alcohol consumption, cravings for nicotine, and even opioids. A large observational study recorded a 30–40% lower risk of aggressive behavior among users. What began as a diabetes treatment is gradually ceasing to look like only a diabetes treatment.

But there are side effects, and they are quite noticeable. Classic nausea, vomiting, and constipation are familiar to almost everyone. An analysis of hundreds of thousands of Reddit posts using neural networks added menstrual-cycle disruptions, chills, hot flashes, and unexplained fatigue to the list. Fitness-tracker data showed that after starting therapy people begin moving less. The drugs “eat up” not only fat but also part of muscle mass. When a person stops the injections, about seven out of ten regain the weight. There’s also a social layer: someone who lost weight on Ozempic often looks worse in others’ eyes than someone who lost weight through diet and exercise. Plus there’s huge variability in outcomes—genetics partly explains why some people lose twenty percent of their body weight while others barely lose five.

These drugs have already noticeably changed the approach to treating obesity and diabetes. And the science doesn’t stop there. Tablets have appeared—orforglipron and similar small molecules—that can be taken at any time without regard to meals. In head-to-head comparisons they outperform oral semaglutide both in glucose control and in weight loss. New oral drugs, judging by the data, not only dampen hunger but also mute the “pleasure center” response to food. Other groups are learning to “lock” peptides into rings so they last longer. Some are creating “Trojan horses”—attaching to an incretin a molecule that, inside the cell, additionally triggers metabolic switches. Swedish researchers developed a pill that doesn’t affect appetite at all, but activates metabolism directly in skeletal muscle. In parallel, they found a natural short peptide, BRP, which in animals reduces weight with almost none of the typical side effects. For those tired of lifelong injections, there is an endoscopic “resurfacing” of the duodenal mucosa.

One of the main drawbacks of current drugs is precisely that they mostly make the body eat less, but hardly make it expend more. That’s why attempts to find a workaround look especially interesting. The protein MTCH2 (sometimes called Mitch) functions in mitochondria as a mode switch. When it is active, the cell produces energy efficiently and everything extra goes into fat. If MTCH2 activity is reduced, mitochondria start burning more fuel to get the same energy, and at the same time they become less effective at turning into mature fat cells. Mice without this protein did not gain weight even on a high-fat diet, had more muscle, and a healthier heart. Against the backdrop of GLP‑1s, which work mainly “from above”—through the brain and gut—this approach looks like an attempt to act “from below,” at the level of cellular energetics.

The quality of dietary fat also matters. Palmitic acid triggers inflammation and insulin resistance, while oleic acid from olive oil has the opposite effect. Even the old metformin turned out to be more complex than people thought: part of its effect goes through the brain. And misfolding of the insulin precursor quietly damages beta cells.

GLP‑1 drugs remain one of the most impressive breakthroughs of the past decades. They truly reduce weight, blood sugar, and cardiovascular risk. But the hormone that got out of control continues to spring surprises—both good and not so good. Research is moving on: new forms, new targets, and a more precise understanding of mechanisms are emerging.

And here the scientific overview unexpectedly runs into very practical questions. What dose to stay on if the effect is already good. How not to lose muscle during rapid weight loss. Whether it’s worth trying to take breaks or whether it’s better to look for the minimally effective maintenance dose. The answers are not yet universal—they strongly depend on the individual, the pace of weight loss, strength training, and how carefully one manages to keep protein intake up. Ultimately, it is these everyday decisions that determine how sustainable the result will be.