「最强减重药」瑞他鲁肽走到三期临床了：还没获批，先别碰灰色市场

Ever since it was discovered that GLP-1s can lead to such significant weight loss, the industry has been booming. From injectable semaglutide and tirzepatide to a pill GLP-1, drug companies have been innovating nonstop in recent years. At the same time, supplements claiming to offer similar effects have been popping up, as well as robust telehealth and gray market routes for getting the drugs.

Basically, the GLP-1 industry is booming—to varying degrees of success and safety. The latest GLP-1 innovation that you may have seen making headlines is retatrutide. Just like semaglutide and tirzepatide, this medication is being developed by drug companies as the newest iteration in the GLP-1 space, and it’s purportedly the strongest one yet.

But is that super strength a good thing? And is it as safe as its peers? Here’s everything you need to know about retatrutide, according to doctors.

Meet the experts: Holly Lofton, MD, is director of the medical weight management program at NYU Langone Health. Jennifer Manne-Goehler, MD, is an assistant professor of medicine at Harvard Medical School and a technical consultant on GLP-1s to the World Health Organization.

What is retatrutide?

First, a quick refresher on GLP-1s: These medications mimic a hormone (called glucagon-like peptide-1, or GLP-1, for short) that is responsible for a bunch of things that have to do with regulating blood sugar and fullness, like triggering insulin secretion and signaling satiety to the brain.

Semaglutide (the generic name for meds like Ozempic and Wegovy) mimics just the GLP-1 hormone, while tirzepatide (the generic name for Mounjaro and Zepbound) targets an additional one called glucose-dependent insulinotropic polypeptide (GIP). It’s thought that combining the two offers a more comprehensive approach to managing diabetes and obesity, but in terms of weight loss their effects seem to be about the same, with tirzepatide having a slight edge.

Retatrutide adds a third hormone receptor agonist, glucagon, for an even more powerful approach to diabetes and obesity care. “We call this the triple G agonist,” says Holly Lofton, MD, director of the medical weight management program at NYU Langone Health and a principal investigator in a retatrutide clinical trial at the hospital. “The additional benefit of glucagon agonism, beyond tirzepatide’s GLP-1/GIP agonism, is greater delay in gastric emptying and improved fat-cell metabolism.” Basically, it’s a stronger, faster-acting drug than its predecessors.

Well, that’s the case when it comes to weight loss, says Jennifer Manne-Goehler, MD, an assistant professor of medicine at Harvard Medical School and a technical consultant on GLP-1s to the World Health Organization. Despite being a triple G agonist, “reta,” as it’s called for short, seems to have the same effect on lowering glucose levels in people with type 2 diabetes as other GLP-1 medications. Where it really shines is weight loss, making it a potentially game-changing drug for those with clinical obesity, she says.

Is retatrutide safe?

Both Dr. Lofton and Dr. Manne-Goehler say that retatrutide appears to be similarly safe as other GLP-1 medicines thus far. “In the leading clinical trials to date, gastrointestinal symptoms were the most common form of adverse events, as they are for other GLP-1 therapies,” says Dr. Manne-Goehler.

However, retatrutide is still in the clinical testing phase and hasn’t yet been approved by the FDA. (It’s pretty far along in that process, though. Eli Lilly, the maker of retatrutide, is nearing the end of phase 3 of testing. Phase 3 testing, which compares retatrutide to existing medications like semaglutide and tirzepatide, is the final step before sending it to the FDA for regulatory approval.)

Unfortunately, in the meantime, versions of the drug have been showing up on the gray market, just as they did for semaglutide and tirzepatide. Both experts stress that this is definitely not the way to go if you think you may want to try retatrutide—for a few reasons.

First, you may not be getting the real thing, so it may not even work. “I have had reports of patients taking reta from gray market vendors who have had no weight loss,” says Dr. Lofton. “This is due to the fact that these compounds often don’t contain any active ingredient, but may also contain [additives] that could be harmful.”

Which brings us to the second, more important problem: The drug may be outright unsafe. You never know what might be in a medication you get on the gray market because it’s unregulated. There’s no quality control, no cleanliness and safety assurances, or even any consistent recipe to make the drug—and it’s much harder to get accountability if something goes wrong.

What We Know About the Biggest Risks of Retatrutide So Far

A lot of the discussion around GLP-1 medications in recent years has highlighted the dangers of rapid weight loss. Changes in bone density, loss of muscle mass, higher risk of gallstones, pancreatitis—these concerns and more can make the prospect of starting a weight loss drug a little nerve-racking. But both our experts agree that retatrutide doesn’t currently appear to come with any additional major risks compared to the semaglutide and tirzepatide options already on the market.

“I think the most important point is that, so far, we haven't seen a completely unexpected safety signal with retatrutide,” says Dr. Lofton. The potential negative side effects have looked pretty similar to the existing weight loss drugs, particularly when it comes to those gastrointestinal issues, she explains. That said, there are a few things she says she is paying particularly close attention to with the retatrutide clinical trials she’s currently leading.

Muscle loss, bone density, and gallbladder health should all be watched closely.

The weight loss achieved with retatrutide is comparable to bariatric surgeries, per Dr. Lofton, which means patients can lose about 28 percent of their body weight over the course of two years, compared to 10 percent with GLP-1s. “Because the degree of weight loss is so impressive, we must keep in mind that this drug is not for cosmetic weight loss but for those with clinical obesity, which is a chronic medical condition,” she says.

One major thing providers should keep their eyes on is what exactly is behind the decreasing number on the scale. “I think we have to pay attention not just to the percentage of weight lost, but to what that weight consists of,” Dr. Lofton says. The risk for muscle loss or decreases in bone density exists with any rapid weight loss, but potentially especially so when it happens as quickly as it does for folks on retatrutide, she says.

Relatedly, doctors should pay close attention to gallbladder health. “Rapid weight loss itself increases gallstone risk, so I don't think we should automatically attribute those events to reta use, but with the degree of weight loss we're seeing, the gallbladder deserves particular attention,” Dr. Lofton says.

There are some questions emerging about heart health.

Phase 2 studies showed some risk for an increase in heart rate while on retatrutide, Dr. Lofton says, which is not the case for other GLP-1s. The effects were minor and peaked at around 24 weeks after starting the drug, but then subsided on their own. That said, any patients with cardiovascular disease or arrhythmia risk will want to pay close attention to any changes in heart rate or opt for other GLP-1 medications, Dr. Lofton says.

Retatrutide may also affect the skin in new ways.

Unlike with other GLP-1s, dysesthesia, or altered skin sensation, has been popping up as a side effect across early trials, Dr. Lofton says. Some patients in phase 3 trials reported mild to moderate dysesthesia that typically resolved itself during treatment, but “that's something that I would want to understand better with longer follow-up,” she says.

Overall, for folks with clinical obesity, retatrutide is emerging as an option that will lead to more weight loss, and faster. That speed and magnitude come with some extra questions, but as the trial and approval process continues on, researchers are feeling hopeful about this newest option to treat obesity.