The pharmacological logic is elegant. Amylin naturally suppresses postprandial glucose excursions and curbs appetite through actions in brainstem regions such as the area postrema and the nucleus tractus solitarius, while also slowing gastric emptying. Amylin agonism first entered the clinic with pramlintide, a synthetic amylin analogue approved for both type 1 and type 2 diabetes, but its modest effects on glycated haemoglobin (HbA1c) and body weight, together with demanding dosing schedules, limited its impact. The new agents overcome these barriers through long-acting engineering. Cagrilintide is a long-lasting amylin analogue paired in CagriSema with semaglutide, a GLP-1 receptor agonist. Zenagamtide goes further, folding both the amylin and GLP-1 receptor pharmacophores into a single unimolecular co-agonist that can be given by injection or, with the aid of the absorption enhancer SNAC, as an oral tablet. Eloralintide, by contrast, is a long-acting dual amylin and calcitonin receptor agonist acting predominantly at the amylin type 1 receptor, with albumin binding allowing weekly dosing and a pharmacokinetic half-life of roughly 15 days.

Zenagamtide’s oral data read like a teaser for what injection can achieve. In a phase 1 randomised, double-blind, placebo-controlled trial, oral zenagamtide over 85 days produced weight loss of up to 13.1 percent at the 250 mg dose, corresponding to 11.9 kg, alongside reductions in BMI of about 4.1 kg/m2, waist circumference decreases of up to 9.5 cm, systolic blood pressure falls of 3 to 9 mmHg, and small favourable shifts in glucose and lipids. The drug was absorbed rapidly, reaching maximum levels within roughly 42 minutes, and had a terminal half-life between 92 and 100 hours, explaining the durable effect. Adverse events were predominantly mild-to-moderate gastrointestinal complaints concentrated at higher doses, and doses above 25 mg were judged intolerable. One serious event, a case of diabetic ketoacidosis, was subsequently traced to newly diagnosed type 1 diabetes in the participant rather than to the drug itself.

The subcutaneous formulation is where zenagamtide becomes genuinely startling. In a phase 1b/2a study lasting 36 weeks, the highest dose of 60 mg achieved a mean body weight reduction of 24.3 percent, an estimated treatment difference of 23.2 percent against placebo, with HbA1c falling by 0.6 percent and fasting plasma glucose by 0.8 mmol/L at the top dose. Dose escalation to 60 mg proved safe and tolerable, with nausea, vomiting, diarrhoea and reduced appetite as the main complaints, no clinically meaningful drops in ionised calcium, and no QT prolongation exceeding 60 ms. That magnitude of weight loss, approaching the results of bariatric surgery, places an injectable co-agonist among the most effective pharmacological anti-obesity therapies ever tested.

Eloralintide tells a different story, one of pure amylin agonism. In a 48-week phase 2, double-blind, randomised, placebo-controlled trial, the 9 mg dose produced a mean weight reduction of 20.1 percent, or 21.3 kg, with all active doses from 1 mg upward significantly outperforming placebo. BMI fell by up to 7.8 kg/m2 and waist circumference by up to 17.1 cm. Notably, body composition analysis revealed a 3:1 fat-to-lean mass loss ratio, a favourable profile for a class often criticised for stripping muscle along with fat. The adverse event pattern was also distinctive: rather than the nausea and vomiting typical of GLP-1 drugs, fatigue, headache and appetite loss dominated, injection-site reactions were reported in a dose-dependent minority, and no cases of pancreatitis or cholecystitis occurred. Pulse rate actually fell by up to 14.4 beats per minute in early studies, the opposite of the heart rate increase seen with GLP-1 receptor agonists, and gastric emptying effects were negligible.

CagriSema, the furthest along in development, has now delivered phase 3 data in both obesity and diabetes. In a 68-week trial in people with overweight or obesity, 32.1 percent of whom had prediabetes, the combination reduced body weight by 20.4 percent under the treatment-policy estimand and by 22.7 percent, an absolute loss of 26.6 kg, under the trial-product estimand, decisively outperforming either semaglutide alone (14.9 percent) or cagrilintide alone (11.5 percent). Nearly one in five participants lost 30 percent or more of their body weight. Fat mass fell by 17.0 kg against 8.4 kg of lean mass, waist circumference shrank by 13.4 cm more than placebo, systolic blood pressure dropped by 9.9 mmHg, and 87.7 percent of participants with prediabetes reverted to normoglycaemia. Quality-of-life instruments measuring the impact of weight on daily living improved significantly.

In type 2 diabetes, CagriSema is currently the best-characterised amylin-based agent, and its results are remarkable across the disease spectrum. In people with overweight or obesity and T2DM, 68 weeks of treatment cut HbA1c by 1.4 percent and weight by up to 15.7 percent, with time in glycaemic range nearly doubling from 43.6 to 86.8 percent on continuous glucose monitoring. In the REIMAGINE 1 trial of treatment-naïve patients, HbA1c fell by 1.8 percent with the 2.4 mg dose, and strikingly, roughly one in two participants achieved formal T2DM remission, defined as HbA1c below 6.5 percent without any antidiabetic medication after a 12-week off-treatment period. In REIMAGINE 3, patients already on basal insulin achieved HbA1c reductions of up to 2.33 percent while actually reducing their daily insulin requirement by about 20 units, and in REIMAGINE 2 the combination beat both semaglutide and cagrilintide head-to-head on glycaemic control while producing 14.2 percent weight loss. A composite outcome of HbA1c at or below 6.5 percent plus at least 10 percent weight loss was achieved by 57.3 percent of patients on the high dose versus zero on semaglutide alone.

Safety across the class appears broadly acceptable and largely consistent with established incretin therapy for the GLP-1-containing agents. Mild-to-moderate gastrointestinal events, chiefly nausea, vomiting, diarrhoea and constipation, peak during dose escalation and remain the leading cause of discontinuation, affecting roughly 72 to 80 percent of CagriSema users in some trials against 34 to 40 percent on placebo. Hypoglycaemia was uncommon and mostly attributable to concomitant sulfonylurea use. A handful of acute pancreatitis cases and injection-site reactions were recorded in the large diabetes trials, and malignancy rates were similar to placebo. Transient, subclinical dips in ionised calcium were seen with zenagamtide, a pharmacological echo of its calcitonin-family receptor activity. Eloralintide’s cleaner gastrointestinal profile, combined with its heart-rate-lowering effect, raises the prospect of an option for patients who cannot tolerate GLP-1-based regimens, although its fatigue and appetite-loss signals, and rare mood-related events that resolved within days of discontinuation, warrant continued scrutiny.

The pipeline behind these three drugs is now extraordinarily dense. Zenagamtide is being tested across the AMAZE programme in T2DM, weight maintenance, knee osteoarthritis, obstructive sleep apnoea, heart failure with preserved and mildly reduced ejection fraction, and in hepatic and renal impairment, alongside an oral formulation being evaluated in Japanese and Chinese populations. Eloralintide’s ENLIGHTEN trials span obesity with and without diabetes, sleep apnoea, osteoarthritis and combinations with tirzepatide and other incretins. CagriSema faces head-to-head comparisons with semaglutide and tirzepatide, renal and cardiovascular outcome studies, paediatric programmes, and even a trial in painful diabetic peripheral neuropathy. The authors of the review caution that no data yet exist on hard vascular complications, metabolic liver disease or sleep apnoea outcomes, and that evidence in type 1 diabetes remains minimal. Still, the convergence is unmistakable: three chemically distinct approaches to amylin signalling, each delivering double-digit weight loss, profound glycaemic benefits, blood pressure reductions of up to 10 mmHg, and in the case of CagriSema, the tantalising possibility of putting early type 2 diabetes into remission with a weekly injection. If the ongoing phase 3 programmes validate these findings, the amylin era of metabolic medicine may have only just begun.

Subject of Research: Amylin-based receptor agonists for the treatment of obesity and type 2 diabetes mellitus

Article Title: New Amylin-Based Agonists for the Treatment of Obesity and Type 2 Diabetes Mellitus

Article References: New Amylin-Based Agonists for the Treatment of Obesity and Type 2 Diabetes Mellitus. (n.d.). https://doi.org/10.1007/s13300-026-01921-0

Image Credits: AI Generated

DOI: 10.1007/s13300-026-01921-0

Keywords: amylin, zenagamtide, amycretin, eloralintide, CagriSema, cagrilintide, semaglutide, obesity, type 2 diabetes, GLP-1 receptor agonists, weight loss, diabetes remission