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

The rationale for the experiment rests on how differently the two drug classes act. Incretin-based therapies such as semaglutide and tirzepatide mimic gut-derived hormones that slow gastric emptying, enhance insulin secretion and signal to brainstem and hypothalamic circuits that suppress appetite. Amylin-based agents such as cagrilintide act on a distinct receptor complex, the amylin receptor formed by AM-LNR in combination with the calcitonin receptor CALCR, and appear to reduce food intake through partly separable neural pathways. Retatrutide, the most advanced triple agonist in clinical development, adds glucagon receptor activity, which in preclinical models is associated with increased energy expenditure and favorable effects on lipid metabolism. The Copenhagen group reasoned that engaging all five receptors at once might capture complementary benefits that no single molecule, however sophisticated, could deliver.

To test this, the researchers used diet-induced obese male rats, a standard preclinical model in which animals become obese after prolonged exposure to a high-fat diet. Animals received daily subcutaneous injections of cagrilintide, retatrutide, the two drugs co-administered, or comparator regimens built around semaglutide and tirzepatide at matched doses. The results were striking: co-administration of cagrilintide and retatrutide produced dose-dependent reductions in body weight and food intake that surpassed both equimolar monotherapies and matched-dose combinations incorporating the established incretin drugs. Across multiple studies, the combination also reduced fat-pad masses and improved circulating markers of metabolic health, including total cholesterol, triglycerides and insulin, without evidence of the liver enzyme elevations that can signal hepatic stress.

A central question in obesity pharmacology is whether a drug simply makes animals eat less or whether it does something more. The team addressed this with pair-feeding and weight-matching experiments, designs in which control animals are given either the same amount of food as treated animals or are calorie-restricted until their body weight matches that of drug-treated animals. These experiments revealed that the enhanced weight loss seen with the combination could not be explained by reduced food intake alone. In other words, even when caloric intake was held constant, the cagrilintide-retatrutide pairing drove greater reductions in body weight than calorie restriction by itself, pointing to additional mechanisms, potentially involving energy expenditure, nutrient partitioning or the glucagon receptor’s effects on lipid handling.

The study went beyond physiology into molecular territory. Using advanced mass spectrometry workflows, including enrichment of extracellular vesicles from plasma, the researchers profiled the circulating proteome of treated animals. Plasma proteomic analysis showed that the combination therapy was associated with enrichment of proteins involved in bioenergetic processes, a signature consistent with altered fuel metabolism rather than mere caloric deprivation. By comparing drug-treated animals with weight-matched calorie-restricted controls, the team could separate molecular changes that simply track weight loss from those that are drug-specific, an analytical distinction they argue is essential for interpreting the biology of next-generation anti-obesity therapies.

The brain was the other major focus. Obesity drugs act centrally, and the specific neuronal programs they engage determine both their efficacy and their side-effect profile. The researchers performed bulk RNA sequencing of two key brain regions: the hypothalamus, the master hub of energy homeostasis, and the dorsal vagal complex in the brainstem, a critical relay for visceral sensory information and a major site of action for GLP-1-based drugs. Brain transcriptomic profiling revealed convergent central neuronal programs linked to energy balance regulation, and importantly, the combination therapy elicited stronger responses in hypothalamic and dorsal vagal complex gene modules than either monotherapy. The team used co-expression network analysis and cell-type enrichment mapping to connect these transcriptional signatures to specific neuronal populations, and found that modules activated by the combination were enriched for genes previously associated with human body mass index in genome-wide association studies.

These molecular findings carry practical implications for drug design. The field is currently racing to develop unimolecular multi-receptor agonists, single peptides engineered to bind several receptors at once, exemplified by retatrutide itself and by amycretin, a GLP-1 and amylin receptor co-agonist that has shown promising results in early clinical trials. The Copenhagen study suggests a blueprint for such molecules: a next-generation single agent that combines GLP-1, GIP, glucagon and amylin receptor activity in one backbone could, in principle, reproduce the pharmacology of the cagrilintide-retatrutide pair without requiring two separate injections. The authors frame their preclinical data as direct guidance for the design of these next-generation unimolecular agonists, identifying which receptor combinations and dose ratios appear most productive.

The clinical context makes the findings timely. Retatrutide has delivered powerful weight loss in a pivotal phase 3 obesity trial, and co-administered cagrilintide and semaglutide, marketed as a fixed-dose combination, has already demonstrated substantial efficacy in adults with overweight or obesity. Yet a persistent challenge remains in achieving maximal weight loss and metabolic control, particularly for patients living with both obesity and type 2 diabetes. The Copenhagen study suggests that adding amylin receptor agonism on top of a triple incretin agonist may push efficacy further than simply optimizing incretin pharmacology alone. The researchers also probed tolerability signals, including conditioned taste aversion tests in lean rats, which are used as a proxy for nausea-like aversive effects, and found dose-dependent responses that will inform how such combinations might be titrated in future studies.

Important caveats apply. All of the efficacy data come from male rats, and sex differences in response to obesity pharmacotherapy are well documented, so replication in female animals and eventually in humans will be essential. The doses used in rodents also cannot be translated directly to the clinic, and combination therapy raises questions about tolerability, cost and dosing complexity that only human trials can resolve. Nonetheless, the study provides one of the most comprehensive preclinical characterizations to date of what happens when the incretin and amylin systems are engaged simultaneously, integrating behavioral, metabolic, proteomic and transcriptomic readouts within a single experimental framework. The underlying data, including proteomic datasets deposited in the PRIDE repository and gene expression data in ArrayExpress, along with all analysis code released on GitHub, have been made openly available to the research community.

As obesity medicines evolve from single-hormone mimics toward rationally designed polypharmacology, the Copenhagen results make a compelling case that the amylin system is the most promising partner for the incretin drugs that have already transformed the field. If the five-receptor strategy translates from rats to humans, the ceiling on pharmacologically achievable weight loss, long constrained by the limits of GLP-1 receptor agonism, may be considerably higher than anyone dared to project just a few years ago.

Subject of Research: Combination therapy with cagrilintide and retatrutide for enhanced weight loss and metabolic outcomes in obese rats

Article Title: Cagrilintide and retatrutide combination therapy enhances weight loss and metabolic outcomes in obese male rats

Article References: Petersen, J., Merrild, C., Holm, S. K., Kurgan, N., Hassan, S., Mathiesen, C. V., Börchers, S., Svendsen, C., D’Anna, S., Andersen, N. R., Klein, A. B., Fritzen, A. M., Deshmukh, A. S., Pers, T. H., & Clemmensen, C. (2026). Cagrilintide and retatrutide combination therapy enhances weight loss and metabolic outcomes in obese male rats. Nature Metabolism. https://doi.org/10.1038/s42255-026-01603-y

Image Credits: AI Generated

DOI: 10.1038/s42255-026-01603-y

Keywords: cagrilintide, retatrutide, obesity, GLP-1 receptor agonist, amylin, glucagon receptor, GIP, weight loss pharmacotherapy, Nature Metabolism, multi-receptor agonist, metabolic health, preclinical study