Amylin-Based Drugs Emerge as Next-Generation Weight-Loss Treatments

The field of weight-loss drugs is moving more quickly than ever since medications that mimic GLP-1, a type of peptide hormone in the gut, hit the market to treat weight issues and diabetes. But while there has been huge interest in the drugs, their side effects—which predominantly affect the GI system—cause roughly 40% of people who start them to stop taking them within a year.

Amylins are a group of peptide hormones that work in similar ways to GLP-1s by curbing appetite signals in the brain and encouraging the stomach to empty. They target different receptors on cells, so their effect can be complementary to that of GLP-1s and other drugs in their hormone group (called incretins). But unlike incretins, amylins don’t seem to cause as many severe side effects such as nausea, vomiting, and stomach cramping.

Scientists from Novo, which makes Wegovy and Ozempic, reported this week that their experimental amylin-based compound CagriSema, taken as a weekly injection, helped people who were overweight or obese lose 22.4% of their starting body weight after a year compared to those taking a placebo. The company also reported on fMRI studies of the brain that showed CagriSema changed brain responses to food, potentially making food fixations less intense. And in people with Type 2 diabetes, the drug reduced the amount of harmful fat in the liver and pancreas, an early but encouraging sign that the medication may contribute to health benefits beyond those associated with weight loss. CagriSema is a combination of the semaglutide—the active ingredient in Wegovy and Ozempic—with cagrilintide, an amylin analogue that mimics a hormone made in the pancreas that regulates feelings of being full.

Martin Holst Lange, executive vice president and chief scientific officer at Novo, says that the company also has an earlier stage study in people with Type 2 diabetes showing that CagriSema can reduce neuropathic pain, which affects about half of people with the disease. “It’s super exciting because we are showing that beyond weight loss and glycemic control, CagriSema can do more to help people in their everyday life,” says Lange. “So we are quite enthusiastic about what we are seeing.”

Researchers from Eli Lilly, which makes Zepbound (tirzepatide), reported that EloraTZP, its experimental combination drug of the amylin analogue eloralintide and tirzepatide, helped people who were overweight or had obesity and also had Type 2 diabetes to lose 23% of their starting body weight compared to 14.8% among those using tirzepatide alone after nearly a year. The weekly injectable also helped people to lower A1C, a measure of diabetes, by more than either tirzepatide or the amylin compound alone. The company has been studying the amylin part of the combination on its own, but plans to study the combination in additional studies beginning this year.

Zealand Pharmaceuticals, a Danish biotech company, also shared results from its study published Sept. 29 in the Lancet of its amylin-based compound petrelintide, an experimental weekly injectable. It helped people who were overweight or obese—but who didn't have diabetes—lose on average 10% of their body weight. (People who took a placebo lost only 1.7% of their body weight on average.) In the study, those even on the highest doses of the experimental drug reported similar rates of side effects as those who took a placebo shot.

Because of their efficacy and favorable side-effect profile, at least in experiments, amylin-based medications may one day be an attractive first-line therapy for many people who are looking to lose a moderate amount of weight without the unpleasant side effects associated with the GLP-1 group of weight-loss drugs. “The amylins still cause some nausea, but it’s at less than half the rate of what we generally see in GLP-1 trials,” says Dr. Timothy Garvey, professor in nutrition sciences and senior scientist in the nutrition obesity research center at University of Alabama who led the petrelintide trial. Not everyone needs drastic weight loss, he says, so amylin drugs could be a welcome option for them. “As more of these tools become available, we can individualize care better,” he says. “Primary care physicians may have an easier time prescribing these since they are better tolerated. So I am personally very sanguine about amylins.”