Once people understood Glucagon-like peptide 1 (GLP-1) medicines » weight loss potential, the race between pharmaceutical companies was on. Among current options, Wegovy can help people lose an average of 10 percent of their body weight in a year, while people taking Zepbound experienced a loss of about 15 percent on average over the same period. Soon, the most powerful GLP-1 treatment yet could hit the market: retatrutide.
Already popular on the Internet peptide gray market, the new drug, initially developed by Eli Lilly, brought participants in a recent clinical study to lose more than a quarter of their body weight in 80 weeks at the highest dose—results comparable to bariatric surgery. Approval from the U.S. Food and Drug Administration could soon follow.
But bodies don’t just lose weight without potential adverse effects. Weight loss alone can change muscles, bones, and more. While next-generation GLP-1 drugs promote higher loss ratesclinicians want to ensure that the desire to lose weight and see improvements such as better cardiovascular health is balanced with the very real risks that can accompany treatment.
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Fat, muscle or bone?
People generally lose weight when they consume fewer calories than their body expends. A common way to reduce calories is to diet, while bariatric surgery removes or modifies part of the gastrointestinal tract to reduce the absorption of food – and therefore calories.
GLP-1 is a gut hormone released in response to a meal that helps people feel full. It also increases insulin release and reduces blood sugar. Semaglutide (sold under the names Ozempic and Wegovy by Novo Nordisk) binds to the hormone’s receptor for longer periods of time, making people feel full longer and eat less. Newer versions of GLP-1 drugs, such as tirzepatide (sold as Zepbound and Mounjaro by Eli Lilly) and Novo Nordisk’s upcoming drug, CagriSema, target more than one type of gut hormone receptor, while retatrutide hits three.
In any weight loss, not everything that comes out is fat. “You can’t just burn fat,” says Caroline Apovian, an obesity medicine specialist at Harvard Medical School and Brigham and Women’s Hospital in Boston. (Apovian has previously consulted for Novo Nordisk and Eli Lilly.)
When a person takes in fewer nutrients than they need, their body begins to use fat stores. This metabolic process requires amino acids, the building blocks of proteins. If amino acids are not sufficiently replenished from dietary proteins, the body will recycle parts of the muscles instead. “Anything that’s going to produce significant weight loss,” Apovian says, “there’s going to be a percentage of muscle.”
Reports suggest that GLP-1 treatments may cause between 25 to 40 percent loss of lean mass, which includes muscle mass– although more studies are needed to understand how this affects strength.
People who lose a lot of weight very quickly will also lose bone mass, says Apovian. Losing muscle and fat puts less strain on bones, she explains, so a lighter body could lead to lighter bones.
For many people, lighter bones may not be a problem. But women, who have higher rates of GLP-1 treatment use than menmay be at increased risk of bone weakening during menopause, when bone loss naturally accelerates. Apovian has seen patients who lost weight on GLP-1 drugs develop osteopenia, or low bone mass. “If it gets worse, they fracture,” she said. “It was mainly women who told us that [using GLP-1s] It wasn’t worth the weight loss.
Eli Lilly’s recent retatrutide clinical trial did not evaluate changes in participants’ muscle or bone mass, a company spokesperson said. Scientific American; “However, Lilly continues to evaluate body composition and long-term outcomes.”
Pay attention to your gallbladder
People who lose large amounts of body fat in a short period of time may also be at greater risk of developing gallstones, says Rozalina McCoy, an endocrinologist at the University of Maryland School of Medicine. Rapid weight loss increases bile acids, which are used to break down fats during digestion. When this happens, “there’s a saturation of the bile with cholesterol, so the bile becomes much thicker and slimier,” she says.
GLP-1 medications also slow gastric emptying (the movement of food through the gastrointestinal tract), which prevents the gallbladder from distributing bile. “It just kind of sits there and forms these gallstones,” McCoy says. Obesity increases the risk of gallstones in general, but clinical trial data has shown that people on GLP-1 treatment have a 37% higher relative risk of developing gallstones. develop gallbladder diseasewhich may include the formation of gallstones.
People considering GLP-1 treatment often worry about rare side effects, such as an increased risk of thyroid cancer, “but gallstones occur in a decent subgroup of these patients,” says Armen Yerevanian, an endocrinologist at Massachusetts General Hospital.
Weight loss, fast and slow
The recent retatrutide trial found that people taking the drug lost 28.3 percent of their body weight, or about 70 pounds, in a year and a half. Although this is comparable to long-term results of bariatric surgeryMcCoy says the rate of weight loss from retatrutide is not as rapid as with surgery. “With metabolic surgery, people lose a lot of weight within the first month. You don’t see that with medications,” she says.
The results of Retatrutide also do not work as quickly as those of methods such as rapid modified protein sparinga medically monitored diet in which people consume about 800 calories per day, Yerevanian explains. (A sedentary adult typically needs to consume between 1,600 and 2,400 calories to maintain their current weight). “I don’t think the weight loss from retatrutide is rapid enough to be worried about from that point of view,” he says.
People who would otherwise resort to modified fasting or bariatric surgery may be candidates for retatrutide – and some scientists think Some people may see health benefits from greater weight reductions than the drug provides. Retatrutide and other next-generation GLP-1 drugs could also help people which do not meet the currently available GLP-1s.
Doctors need to closely monitor people taking these medications to make sure they don’t lose too much weight or suffer from nutritional deficiencies, Yerevanian says. Doses of GLP-1 drugs are “pretty easy to readjust, because if you take them off, they’ll put weight back on,” he adds.
Preliminary evidence suggests this weight regained after stopping GLP-1 treatment is more likely to return as fat than lean mass. The benefits for cardiovascular health and diabetes also appear to reverse. Experts, including McCoy, have suggested that such weight rebounds could leave people in worse health than they were before treatment.
Prevention is worth a pound of lost muscle
There are ways to reduce muscle and bone loss when taking a GLP-1 medication, says Apovian. Supplementing with calcium and vitamin D can help prevent bone loss. For the muscles, protein is the key. “It seems like most Americans are getting enough protein,” she says, but “if you’re on a GLP-1 or if you’re trying to lose weight and you’re on a low-calorie diet, that’s when you need to be aware of it.” »
This protein intake should be combined with resistance training, says Apovian. Strength training, even with light weights, can help prevent muscle loss, although she notes that most of the patients she treats probably don’t do enough resistance training.
As these medications become more effective and accessibleclinicians need better guidelines for who is eligible for which medication, Yerevanian says. People with larger bodies face challenges societal stigmawhich can lead some people to feel pressure to lose a lot of weight, quickly. But some clinicians say prescribing these drugs is about balancing risks and benefits, not about considering a person’s size. “We’ve never had the ability to lose this much weight in a healthy way before,” says McCoy. “I think as a society we need to make sure that all of these treatments remain focused on better health and not on weight on a scale.”
