Next-gen weight-loss drugs: the amylin shots to watch

Semaglutide and tirzepatide rewrote obesity treatment by imitating GLP-1, a gut hormone that tells the brain to stop eating. The catch is tolerability. Roughly four in 10 patients who begin these weekly injections stop within the first year, worn down by nausea, vomiting, and abdominal cramps. A drug that delivers double-digit weight loss in a trial does little for someone who abandons it in month four. That dropout rate, more than any ceiling on effectiveness, is the problem drugmakers are now working to fix.

Their answer is amylin, a hormone the pancreas releases after meals that blunts hunger signaling and slows the rate at which the stomach clears. Because amylin binds to a different set of cell receptors than GLP-1 does, the two can be loaded into a single weekly shot without simply stacking one set of gastrointestinal effects on another. At the European Association for the Study of Diabetes meeting in Milan, Novo Nordisk, Eli Lilly $LLY, and the Danish biotech Zealand Pharma each presented human trial data on amylin compounds, findings reported by Time.

The numbers point in two directions at once. Combination drugs that attach an amylin analogue to an existing GLP-1 medicine have produced some of the largest weight-loss figures yet recorded in obesity trials. Amylin injections given on their own have delivered more moderate results, but with side-effect rates close to those seen with a placebo shot. The practical consequence is a menu rather than a single default — physicians matching the compound to how much weight a patient needs to lose and how much discomfort they can absorb.

This list covers the specific next-generation weight-loss drugs now moving through late-stage trials and regulatory review: what each compound contains, what it achieved in testing, which company developed it, and how close it is to a pharmacy shelf. One has an FDA decision pending. The others remain in human testing with no approval date attached. Together they map where obesity medicine heads after GLP-1.

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CagriSema produced an average loss of 22.4% of starting body weight after a year of weekly injections in adults with obesity or overweight, far above the average in the placebo group. It is the amylin-based compound closest to reaching the U.S. market.

The drug pairs two active ingredients. The first is semaglutide, already sold as Wegovy and Ozempic. The second is cagrilintide, an amylin analogue that imitates the pancreatic hormone governing the sensation of fullness. Because amylin and GLP-1 bind to separate receptors, the two ingredients reinforce each other rather than duplicating the same signal.

Novo Nordisk also reported fMRI brain imaging from people taking CagriSema showing altered responses to food, a result the company has framed as evidence the drug may dull food fixation rather than only suppressing hunger. Among participants with type 2 diabetes, the company reported reductions in harmful fat stored in the liver and pancreas. That is an early signal that the benefits could extend past the number on the scale, though it has not been established in a large outcomes trial.

Martin Holst Lange, Novo's chief scientific officer, has pointed to a separate finding from an earlier-stage study in patients with type 2 diabetes: a reduction in neuropathic pain, a complication that affects about half of people living with the disease. Lange has called the result encouraging. It comes from preliminary research rather than a completed late-stage program, and it supports no clinical claim yet.

Novo has filed CagriSema with the U.S. Food and Drug Administration, seeking clearance for adults who have obesity or are overweight but do not have diabetes. A decision is expected by the end of the year. Approval would make it the first amylin-GLP-1 combination available by prescription in the U.S., giving physicians a weekly injectable that works through two hormone pathways instead of one. Until that decision lands, it remains an investigational drug, and the 22.4% figure describes trial conditions rather than everyday use.

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EloraTZP is Eli Lilly $LLY's experimental weekly injection combining eloralintide, an amylin analogue, with tirzepatide, the active ingredient in Zepbound and Mounjaro. In a trial enrolling adults who carried excess weight and also had type 2 diabetes, the pairing cut 23% of starting body weight over nearly a year, against 14.8% for tirzepatide alone.

A1C improved more on the combination than it did on tirzepatide by itself or on the amylin drug alone. A1C is the blood test that reflects average glucose control over roughly three months. In a trial group that all had type 2 diabetes, that reading carries as much weight as the scale figure, because the pairing improved both at once rather than trading one against the other.

Tirzepatide is not a pure GLP-1 drug. It acts on the GLP-1 receptor and the GIP receptor, which is part of why it has outperformed semaglutide on weight loss in head-to-head testing. Eloralintide introduces a third pathway, since amylin signals fullness through separate cell receptors. EloraTZP is an attempt to layer a distinct hunger mechanism onto an already potent dual-receptor medication.

Lilly has been developing eloralintide as a standalone candidate alongside the combination work, which leaves the company two routes. An amylin-only injection would suit patients who want appetite suppression without the digestive burden of incretin drugs. The combination aims at the other end of the spectrum, where the goal is the largest reduction a patient can tolerate.

One caveat belongs with the 23% figure. Every participant in the reported trial had type 2 diabetes, a group that typically loses less weight on these medications than people without the disease. Novo Nordisk's headline number for CagriSema came from a wider population that did not have diabetes. The two percentages are not directly comparable until EloraTZP is tested in a similar group of patients.

Lilly has said it will begin additional studies of the combination this year, which places EloraTZP well behind CagriSema in development. No regulatory filing has been made, and no approval timeline has been attached to the drug.

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Petrelintide is a weekly injectable amylin analogue from the Danish biotech Zealand Pharma, and it contains no GLP-1 component at all. Trial results published Sept. 29 in The Lancet showed adults who were overweight or had obesity, but did not have diabetes, lost an average of 10% of their body weight on the drug. Those given a placebo injection lost 1.7%.

The tolerability figures drew as much attention as the weight result. Participants taking the highest doses tested reported side effects at rates close to those seen in the placebo group. That is a departure from what incretin-based injections have shown, where nausea and vomiting are common enough to push many patients off treatment within months.

Dr. Timothy Garvey, an obesity researcher at the University of Alabama, led the petrelintide trial. He has said amylin compounds still cause some nausea, but at less than half the rate usually recorded in GLP-1 studies. His case for the drug does not rest on beating the competition on raw percentages. It rests on the argument that many patients do not need the largest possible result, and that a moderate loss someone keeps taking is worth more than a bigger one they abandon.

A 10% reduction in body weight falls well short of what the amylin-GLP-1 combinations have delivered. It still lands in the range clinicians link to improvements in blood pressure, blood sugar control, and sleep apnea. Garvey has framed a wider set of options as a route to individualizing care, rather than steering every patient toward the strongest drug available.

Petrelintide remains in human testing. Zealand has not submitted it to the U.S. Food and Drug Administration, and no regulatory timeline has been attached to it. The Lancet results come from a single trial, and obesity medicines normally need a broader program of studies, including larger and longer ones, before regulators weigh an approval. For now, what sets the drug apart is the pairing of moderate weight loss with placebo-like tolerability at the doses studied.

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Amylin and GLP-1 reach a similar outcome through different biological doors. Both hormones signal to the brain that eating can stop, and both slow the rate at which the stomach empties. They bind to separate receptors on cells, and that separation is the basis for the current wave of combination injections.

GLP-1 is a peptide hormone made in the gut, and it belongs to a class of hormones called incretins. Amylin does not. Amylin is made in the pancreas, released alongside insulin, and it regulates the feeling of fullness after a meal. Drugs built to mimic either hormone reach the same appetite circuitry. A patient on one can report the same drop in food preoccupation as a patient on the other.

The difference shows up in the digestive tract. GLP-1 medications slow gastric emptying substantially. That mechanism is tied to the nausea, vomiting, and stomach cramping that drive roughly 40% of people off the drugs within a year. Amylin analogues also act on stomach emptying. Trial results reported so far by Novo Nordisk, Eli Lilly $LLY, and Zealand Pharma point to severe gastrointestinal effects showing up less often.

Because the receptors are distinct, pairing an amylin analogue with a GLP-1 drug in one weekly shot does not double the side-effect load the way raising a GLP-1 dose would. The two mechanisms add their appetite effects together while working through different pathways.

That points to two patient groups rather than one. People who quit a GLP-1 drug because they could not tolerate it are the clearest candidates for an amylin-only injection. People who need the largest possible reduction in body weight are the candidates for a combination.

Timothy Garvey, a professor in nutrition sciences at the University of Alabama, has said better tolerability could also widen the prescribing pool. He has argued that amylin-based drugs could be simpler for primary care doctors to prescribe, since patients are less likely to abandon them.

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CagriSema sits closest to market. Novo Nordisk has asked U.S. regulators to clear the weekly injection for adults who are overweight or have obesity but do not have diabetes, and a Food and Drug Administration decision is expected by the end of the year. Clearance would make it the first prescription product in the U.S. to pair an amylin analogue with a GLP-1 medication in a single shot.

The rest of the amylin pipeline sits further back. Eli Lilly $LLY has said it will start additional studies of its eloralintide-tirzepatide combination this year, which puts the compound in an expansion phase rather than a filing phase. Zealand Pharma's petrelintide has one published trial behind it and no regulatory submission. Neither has a public approval date.

The drugs are splitting into two tiers. Adding an amylin analogue to an existing incretin drug has produced the largest percentage of starting body weight lost in trials so far, with both combinations clearing 22% over roughly a year. Amylin used on its own has produced smaller figures, in the 10% range, with side-effect rates close to those logged in placebo groups. The two profiles suit different patients rather than forming a single ranking. Someone who needs to lose 100 pounds and someone who needs to lose 25 are not candidates for the same prescription.

None of this changes the near-term picture for anyone currently taking a weight-loss injection. Semaglutide and tirzepatide remain the only approved options with established safety and efficacy records, and they will stay the default while the amylin compounds work through testing and review.

The Milan presentations signal a change in what counts as a competitive result. For several years the headline number in obesity trials was percentage of body weight lost. Dropout rates have become the second number that matters, and the companies building amylin drugs are competing on both at once. Within a year or two, physicians may be weighing tolerability against potency rather than prescribing whichever drug produces the largest figure.