Amylin: A Novel Diabetes and Obesity Therapy

For several years now, SGLT2 inhibitors and incretin therapies have dominated the diabetes therapeutic landscape because of their glucose-lowering potency, low associated risk for hypoglycemia, weight-loss properties, and other cardio-renal-metabolic benefits. Incretin therapies are also well established as an obesity treatment in patients without diabetes.

Kevin J. Fernando, MBChB

I was therefore pleased to attend a symposium entitled “Amylin as a Novel Diabetes and Obesity Therapy” at the American Diabetes Association (ADA) 86th Scientific Sessions in New Orleans. Long-acting amylin analogs are emerging as a promising new class of injectable therapy for diabetes and obesity and potentially a future first-choice therapy for most patients with obesity or diabetes without comorbidities.

Amylin is not new; the FDA approved pramlintide in 2005 for treating patients with type 1 and type 2 diabetes (T2D) who use insulin. But pramlintide is a short-acting analog of amylin that requires multiple daily injections before major meals. Additionally, pramlintide causes severe hypoglycemia in some patients. Pramlintide never received marketing authorization in the United Kingdom because of clinical and regulatory factors.

What Is Amylin?

Thomas A. Lutz, PhD, professor of veterinary physiology at the University of Zurich, opened the symposium by describing the neuropharmacology and biological actions of amylin.

Amylin is a pancreatic peptide hormone that is co-secreted with insulin from the pancreatic beta cells. It promotes satiety, slows gastric emptying, and reduces postprandial glucagon secretion. Notably, amylin prevents the decrease in energy expenditure that typically results from decreased eating and loss in body weight. By counteracting this physiological slowdown, amylin promotes a higher total rate of energy expenditure and fat oxidation. This same phenomenon is seen with the newer, long-acting amylin analogs such as cagrilintide.

Why might long-acting amylin analogs provide advantages over current pharmacotherapy for diabetes and obesity?

Better Tolerability

While current incretin therapies such as semaglutide and tirzepatide can achieve marked reductions in blood glucose and body weight, not everyone can tolerate their gastrointestinal (GI) adverse effects. Studies have demonstrated that long-acting amylins induce milder GI side effects than GLP-1 receptor agonists. They may thus serve as alternatives to incretin therapies or be combined with incretin therapies to enhance their weight-loss and glucose-lowering efficacy.

In practice, long-acting amylin analogs may prove useful in accentuating and sustaining weight loss when incretin therapies do not achieve or maintain desired weight loss or are not tolerated.

Positive Effects on Bone Health

The effect of GLP-1 receptor agonists on bone health is unclear; evidence suggests that GLP-1 receptor agonists cause a modest reduction in bone mineral density and enhance bone remodeling (specifically, bone resorption), much like calorie restriction does. But no association between GLP-1 receptor agonists and an increased risk for fractures in patients with obesity has been established.

Amylin is part of the calcitonin peptide family and has complex receptor biology. Amylin and calcitonin receptors (CTRs) are intimately linked. The CTR serves as a core binding component for functional amylin receptors in the body. Calcitonin is a key hormone involved in bone regulation. Activation of the CTR by amylin promotes bone formation and inhibits bone resorption by stimulating osteoblast activity and inhibiting osteoclast activity.

Better Preservation of Skeletal Muscle Mass and Function?

Incretin therapies still raise concerns about reduced skeletal muscle mass and function (see my commentary from Obesity Week 2025). In fact, other symposia at ADA 2026 discussed combining myostatin inhibitors (such as bimagrumab) with GLP-1 receptor agonists to facilitate ongoing weight loss while preserving muscle mass.

In contrast, Lutz suggested that amylin analogs may result in better preservation of skeletal muscle and function, compared with GLP-1 receptor analogs. Satellite cells are the primary stem cells in adult skeletal muscle and are essential for muscle repair, regeneration, and growth. Satellite cells specifically express the CTR, and it is postulated that amylin agonist binding to these satellite cell CTRs may help preserve skeletal muscle. Lutz acknowledged that preclinical data for the long-acting amylin analogs cagrilintide and eloralintide were not conclusive, however.

Increase in Leptin Responsiveness and Sensitivity

Leptin is a hormone produced by adipocytes that helps regulate food intake and energy expenditure. Leptin stimulates the hypothalamus to increase satiety, reduce hunger, and increase energy expenditure. In many patients with obesity, the brain can become leptin-resistant, meaning that even high levels of leptin do not suppress appetite or impact energy expenditure.

It is well established that amylin and leptin work synergistically to promote weight loss. Amylin sensitizes the brain to leptin, thus resulting in a more pronounced reduction in food intake and body weight than either hormone working alone. Notably, GLP-1 receptor agonists such as semaglutide do not synergize with leptin.

Clinical Trial Data for Long-Acting Amylin Analogs

Carel le Roux, MBChB, PhD, professor of chemical pathology at University College Dublin, outlined clinical trial data for long-acting amylin analogs (as monotherapy and in combination therapy) and discussed their efficacy, safety, and tolerability with the aim of predicting how these molecules might be used in clinical practice.

He discussed phase 2 data for cagrilintide in patients with overweight and obesity but without T2D first. Weight-loss data showed a classical dose-response effect: Cagrilintide (4.5 mg weekly) was associated with a 10.8% reduction in body weight from baseline, vs a 3% reduction with placebo, after 26 weeks. Additionally, improvements were seen in dyslipidemia. But cagrilintide was associated with smaller A1c reductions, compared with the active comparator liraglutide (3 mg daily). What was most striking, though, was that cagrilintide had substantially better GI tolerability, compared with liraglutide.

Le Roux then discussed phase 2 data for eloralintide in patients with overweight and obesity but without T2D. Again, a dose-response effect was demonstrated, with eloralintide (9 mg weekly) demonstrating an impressive -20% mean change in body weight from baseline, compared with -0.4% with placebo, after 48 weeks. GI tolerability was also reassuring even in patients who were immediately started on 9 mg rather than being titrated in a stepwise manner from 3 mg to 9 mg. Vomiting rates were 11% in those started on 9 mg and much lower (2%) in those titrated from 3 mg to 9 mg.

Phase 2 data for petrelintide in patients with obesity but without T2D from the ZUPREME-1 study was also outlined. Yet again, a dose-response effect was observed with double-digit (10.7%) mean body weight reduction achieved after 42 weeks. However, what was most impressive was GI tolerability, with most GI adverse effects with petrelintide being mild (77%).

Le Roux continued with data from combination approaches containing long-acting amylin analogs. CagriSema is a once-weekly fixed combination injection of cagrilintide (2.4 mg) and semaglutide (2.4 mg). CagriSema is dosed from two separate compartments on the same pen device.

The REDEFINE-1 study demonstrated an impressive -22.7% change in body weight from baseline after 68 weeks with CagriSema (Novo Nordisk), compared with -16.1% with semaglutide 2.4 mg, -11.8% with cagrilintide 2.4 mg, and -2.3% with placebo. Notably, the weight loss associated with CagriSema over 68 weeks was less than the sum of the weight loss seen with cagrilintide alone over 68 weeks and semaglutide alone over 68 weeks. Le Roux postulated that this result might be related in part to patients’ differing neuronal responses in the hindbrain. Some may have been stimulated by amylin, some by semaglutide, and some by both hormones.

Le Roux also reviewed categorical weight-loss data from REDEFINE-1. About 23% of individuals on CagriSema lost more than 30% of their body weight. Interestingly, participants who didn’t tolerate the highest dose of CagriSema lost the same amount of weight as those that did. There was no clear linear relationship between mean CagriSema dose and mean percent weight loss after 68 weeks. Le Roux suggested that these data may shift future obesity treatment strategies away from pushing for the maximum tolerated dose to using the minimally effective dose.

Reassuringly it appears that there is no significant worsening of side effects with CagriSema, compared with its individual components. The most reported adverse events were GI effects, and onset occurred mainly during dose escalation, which is consistent with the GLP-1 receptor agonist class.

REDEFINE-2 investigated the effects of CagriSema in patients with T2D and found up to 15.7% body weight reduction. It is well established that patients with T2D consistently lose less weight than patients without T2D. A1c reduction with CagriSema was up to 2.1%. A1c reductions were observed early in the trial (after around 20 weeks) and maintained for the duration of the study. The adverse event profile was like that of REDEFINE-1.

Finally, zenagamtide (previously known as amycretin) was discussed. It is a novel, unimolecular GLP-1 and amylin receptor agonist. Subcutaneous zenagamtide is dosed from a pen device with a single compartment. In a multiple ascending dose study, zenagamtide was associated with > 20% weight loss at 36 weeks and an adverse effect profile like that in early phase studies for GLP-1 and amylin receptor agonists.

In patients with T2D, once-weekly subcutaneous zenagamtide was associated with -14.5% mean change in body weight from baseline and 1.8% reduction in A1c. Once-daily oral zenagamtide was associated with a -10.1% mean change in body weight from baseline and 1.5% reduction in A1c. Notably, no weight loss plateau was observed after 36 weeks for the higher doses of zenagamtide, irrespective of administration method.

Amylin-based therapies will have future roles as monotherapies and as combination therapies for new patients who already are close to their treatment targets, said Le Roux. These therapies also could help patients who have undergone bariatric surgery or those who are taking other obesity medications that are not yet at their treatment target.

W. Timothy Garvey, MD, symposium chair and professor of medicine in the Department of Nutrition Sciences at the University of Alabama in Birmingham, suggested that long-acting amylins could become first-line therapies for most patients with obesity or adiposity-based long-term conditions. But if a patient has complications such as metabolic dysfunction-associated steatotic liver disease or metabolic dysfunction-associated steatohepatitis, which are ameliorated by GLP-1-based medications, then the latter class should be used instead. For patients with high BMI and biomechanical complications who need > 20% weight loss, potent dual or triple agonists such as tirzepatide or retatrutide (“triple-G,” an investigational GLP-1, GIP, and glucagon agonist) can be considered.

In conclusion, from a primary care perspective, long-acting amylin therapies will be a useful addition to our toolbox because they offer clinically meaningful weight loss, potent glucose-lowering, and good GI tolerability. Long-acting amylin therapies will play a key role for patients who do not reach targets with current incretin-based therapies or who cannot tolerate them well. In clinical practice, this means that primary care will need to think beyond glycemia and use these agents earlier as part of a more flexible, obesity-focused treatment pathway.

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