Cagrilintide vs Mazdutide.

Cagrilintide (development code AM833) is a long-acting, once-weekly synthetic analogue of the pancreatic hormone amylin, developed by Novo Nordisk. It is a "dual amylin and calcitonin receptor agonist" (DACRA)-class peptide engineered with a lipidation (fatty-acid acylation) that prolongs its half-life, and is being investigated for chronic weight management in adults with overweight or obesity, both as a monotherapy and as the amylin component of the fixed-dose combination CagriSema (with semaglutide).

Mazdutide (IBI362, originally LY3305677) is an investigational once-weekly injectable dual agonist of the GLP-1 and glucagon receptors, based on a mammalian oxyntomodulin analog. It is being developed by Innovent Biologics under a license from Eli Lilly, primarily for obesity and type 2 diabetes and with additional metabolic indications under study. It is furthest advanced in China, where it has progressed through Phase 3 trials, but it is not an approved medicine in the United States or Europe. Like other dual agonists, it is designed to pair appetite and glucose control with added energy expenditure.

Native amylin is co-secreted with insulin from pancreatic beta cells and reduces food intake by promoting meal-ending satiety, slowing gastric emptying, and suppressing glucagon. Cagrilintide mimics this by activating amylin and calcitonin receptors, which are heterodimers of the calcitonin receptor with receptor-activity-modifying proteins (RAMPs). Preclinical work in RAMP1/RAMP3 knockout mice (eBioMedicine, 2025) indicates cagrilintide's weight-lowering effect is mediated largely through brain amylin receptors 1 and 3 in hindbrain and hypothalamic circuits that govern appetite. Because amylin signaling is mechanistically distinct from GLP-1, combining the two (as in CagriSema) is intended to engage complementary satiety pathways and produce additive weight loss.

Mazdutide derives from oxyntomodulin, a natural gut hormone that engages both the GLP-1 and glucagon receptors. GLP-1 activation drives appetite suppression, delayed gastric emptying, and glucose-dependent insulin release, while glucagon-receptor activation is thought to increase energy expenditure and reduce hepatic fat. The combined signaling is intended to produce weight loss alongside improvements in lipids, blood pressure, liver enzymes and other metabolic markers. Structural modifications extend its half-life to allow weekly subcutaneous administration.

Human data are now substantial for the combination and growing for monotherapy. The pivotal phase 3 REDEFINE 1 trial in over 3,400 adults with overweight/obesity without diabetes (NEJM 2025, PMID 40544433) reported mean weight loss of roughly 20.4% with CagriSema, 11.8% with cagrilintide monotherapy, 14.9% with semaglutide, and about 3% with placebo at 68 weeks; cagrilintide thus produced clinically meaningful weight loss on its own, though less than the combination. REDEFINE 2 studied CagriSema in type 2 diabetes, and additional REDEFINE/REIMAGINE program trials (e.g., REIMAGINE 2 in The Lancet Diabetes & Endocrinology, 2026) extend the dataset. The brain-receptor mechanism evidence (eBioMedicine, PMID 40609154) is preclinical (mouse), so the molecular target attribution should not be read as proven in humans; most large efficacy data describe the semaglutide combination rather than cagrilintide alone.

A randomised, double-blind, placebo-controlled Phase 2 trial in 248 Chinese adults with overweight or obesity, published in Nature Communications (2023), tested mazdutide 3 mg, 4.5 mg and 6 mg over 24 weeks. Mean body-weight reductions reached roughly 11% at the 6 mg dose versus about 3% with placebo, with dose-dependent effects. Participants also showed improvements in waist circumference, blood pressure, blood lipids, liver transaminases and serum uric acid. Earlier Phase 1b studies in Chinese adults with overweight/obesity and with type 2 diabetes supported tolerability and metabolic benefit at higher doses. Phase 3 obesity and diabetes programs (the GLORY series) have since been conducted in China, and GLORY-1, a randomised placebo-controlled Phase 3 trial of once-weekly mazdutide in Chinese adults with obesity or overweight, was published in the New England Journal of Medicine in 2025. A further Phase 2 randomised controlled trial in Chinese adults with a body mass index of at least 30 and without diabetes was reported in Med, and mazdutide has been included in network meta-analyses of glucagon receptor agonists that pool metabolic outcomes across compounds. Evidence outside Chinese populations and long-term outcome data remain limited. The trials are sponsor-run, of moderate size, and almost entirely single-country, so generalisability to other ancestries, body-composition distributions and background diets is untested. There is no cardiovascular outcome trial for mazdutide, no published head-to-head randomised comparison with semaglutide or tirzepatide, and no multi-year durability or weight-regain dataset. By contrast, semaglutide and tirzepatide each have global multi-thousand-participant Phase 3 programs and regulatory approval in the United States and Europe, and semaglutide additionally has dedicated cardiovascular outcome data, which places mazdutide an evidence tier behind them despite broadly similar reported weight reductions. Regulatory acceptance in one country also does not substitute for the outcome evidence that has not yet been generated.

In the REDEFINE program the safety profile of cagrilintide and CagriSema was reported as broadly consistent with incretin/amylin-based therapies, with predominantly mild-to-moderate gastrointestinal effects (nausea, vomiting, diarrhea, constipation) as the most common adverse events, generally most pronounced during dose escalation. Long-term safety, cardiovascular outcomes, and the safety of cagrilintide as a standalone therapy are not yet fully characterized in published phase 3 data, and head-to-head long-term comparisons remain limited. As an investigational agent, cagrilintide has no established safety profile for use outside of controlled clinical trials; material sold as research-only "cagrilintide" is not a regulated medicine and carries unknown identity, purity, and contamination risks.

Across trials, the most common adverse events were gastrointestinal, including nausea, diarrhoea and decreased appetite, typical of GLP-1-based agents and generally most pronounced during dose escalation. Overall tolerability was described as favorable in the Phase 2 study, but as an investigational drug its full safety profile, including uncommon and long-term risks, is not yet established. Glucagon-receptor activation warrants monitoring of parameters such as heart rate and hepatic markers in ongoing studies. Documented class considerations for incretin-based agents include gallbladder and biliary events, reported pancreatitis, delayed gastric emptying with implications for sedation and anaesthesia, loss of lean mass in parallel with fat loss, and rodent thyroid C-cell findings that shaped labelling for several approved GLP-1 drugs. A trial adequate to characterise these requires scheduled laboratory chemistry, vital-sign monitoring, pregnancy prevention requirements, protocol-defined dose-reduction and stopping rules, and independent adjudication of serious events, none of which exists outside a regulated study. Mazdutide is not approved or commercially supplied in the United States or Europe, so material sold there as mazdutide comes from unregulated research-chemical or compounding channels with no verified identity, potency, purity or sterility, no stability data, and no route for reporting harm. Peptide products from such channels have been associated with mislabelling and contamination, which makes any observed effect, benign or adverse, difficult to attribute to the intended molecule.

Cagrilintide is investigational and not approved by the FDA as a standalone drug. Novo Nordisk submitted an NDA for the CagriSema combination (cagrilintide plus semaglutide) for weight management on December 18, 2025; as of mid-2026 it remains under FDA review and is not yet approved.

Mazdutide is investigational and not approved by the FDA or EMA. Its development is most advanced in China, where a regulatory filing for obesity/overweight has been pursued following Phase 3 results. Any use outside an authorized clinical trial is unapproved.