The weight-loss revolution is in full swing, and the latest medication breakthroughs are more accessible than ever. In January, Wegovy (a brand name for semaglutide) became available in the United States in pill form. Late last year, the manufacturers of both Wegovy and Zepbound (a brand name for tirzepatide) announced a new plan to lower prices.
Now, a new type of weight-loss drug known as a “triple agonist” is being touted as the latest game changer. These meds, which are still in development, act on three different hormone receptors in your body to influence eating and metabolism. (Present-day weight-loss drugs work on just one or two hunger-related hormones.)
One particular triple agonist, called retatrutide, has recently been shown in clinical trials to help people with severe obesity shed almost 30 percent of their body weight after about 48 weeks. (Compare that to semaglutide and tirzepatide, which result in 13.7 percent and about 20 percent body weight reductions after 72 weeks, respectively.)
“We’ve never seen weight loss at this level before,” says Ania Jastreboff, MD, PhD, the director of the Yale Obesity Research Center at the Yale School of Medicine, who has been involved in research on the drug. But for that very reason, triple agonists are not for everyone, she cautions. (Put more bluntly, don’t even think about using it to shed a few pounds before your college reunion next year.)
We asked obesity medicine experts for everything you need to know about retatrutide, also known as “Triple G”: how it works, how safe and effective it is, when it will be available, and who it’s designed to treat.
How Do Triple Agonists Work?
Triple agonists are a new class of weight-loss medications that work by activating three different hormone receptors linked to weight and metabolism: GLP-1, GIP, and glucagon. “The first GLP-1 receptor agonist that became available was semaglutide,” explains Louis Aronne, MD, the Sanford I. Weill Professor of Metabolic Research at Weill Cornell Medicine. Semaglutide is available under the brand names Ozempic and Wegovy. Next came tirzepatide (Zepbound and Mounjaro), which acts on GLP-1 as well as GIP (glucose-dependent insulinotropic polypeptide), a second gut hormone. Think of GIP as a power-up that can boost GLP-1’s weight-loss effects.
Triple agonists, as the name suggests, add a third ingredient to the mix. There are several types of triple agonists currently being studied, but the one closest to FDA approval is retatrutide. In addition to GLP-1 and GIP, it targets glucagon, a hormone your pancreas makes to help regulate your blood sugar level.
By activating your body’s glucagon receptors in addition to its GLP-1 and GIP receptors, retatrutide ultimately helps raise your resting metabolic rate, which means your body burns more calories. The drug also helps trigger your liver to break down stored fat. “We think this will be important for people who are obese who also have MASH, a form of fatty liver disease,” says Mehmet Furkan Burak, MD, an endocrinologist at Harvard Medical School who has done research on weight-loss medications.
So far, retatrutide seems to induce more weight loss than what’s currently available on the market. People lose on average about 14 percent of their body weight on semaglutide, about 20 percent on tirzepatide, and about 28 percent on retatrutide.
Who Is Retatrutide Meant For?
Retatrutide is still in clinical trials and isn’t expected to become available for at least another six months. But even then, “it won’t be first-line treatment” for weight issues, says Dr. Jastreboff. Since it can cause people to lose almost 30 percent of their body weight, it will most likely be reserved for patients with severe obesity, currently defined as those with a body mass index (BMI) of over 40.
“We want to use it in people who will still be considered obese even if they lose 15 to 20 percent of their body weight or have obesity with another serious condition, like heart failure or liver disease,” adds Dr. Burak. “If you have a BMI of 28, retatrutide isn’t for you.”
This is particularly important given some of its side effects, says Dr. Jastreboff. The most common ones are nausea, diarrhea, constipation, vomiting, and decreased appetite—which can occur with semaglutide and tirzepatide, too. But retatrutide can also cause a temporary increase in heart rate that needs to be carefully monitored, since it can lead to more serious complications, such as heart arrhythmia, says Dr. Burak. “What we’ve seen in the clinical trials is that the heart rate goes up in the first six months and then comes back down,” he explains. A 2023 study published in The New England Journal of Medicine reported 19 cases of cardiac arrhythmia in patients, mainly at the highest doses, but 17 continued on with treatment.
Using Retatrutide Safely
Recent retatrutide studies report that up to 18 percent of people stop taking the drug because of side effects. But it’s possible to minimize them by increasing your dose slowly. “During the clinical trials, we had to follow a protocol where we increased the dose every month until we got to the desired level,” explains Dr. Jastreboff. “But what we’ve seen since then is that if you go up on your dose more slowly and let patients’ bodies adjust to the drug until side effects diminish or even disappear, then people do much better.”
One concern is that a patient may lose too much weight—reportedly one reason why people dropped out of a recent clinical trial. And given how much weight loss the drug can induce, it’s a valid concern. “One way to minimize that is to really restrict who can go on the drug,” says Dr. Burak—again, only allowing people above a certain BMI threshold to take it. And as with other weight-loss medications, “everyone on triple agonists should be getting counseling with specific diet and exercise recommendations,” says Dr. Aronne.
Retatrutide is also available in some U.S. cities on the black market, which alarms researchers like Dr. Burak. “We worry that people will try to use this drug to lose weight before the summer or an event like a wedding and get seriously ill as a result,” he says. “These drugs can be lifesavers for certain people. But if you don’t need them, or don’t use them correctly, they can sabotage your health.”
Ultimately, when it comes to any weight-loss drug, keep things in perspective. “Losing more weight doesn’t necessarily mean you’re healthier,” says Dr. Aronne. It’s important to keep in mind the improvements you make with your blood pressure, blood sugar, and other health factors, too. “We see health benefits when people lose even just 5 percent of their body weight,” he says, “and that’s what matters.”
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