CagriSema

Overview

CagriSema is Novo Nordisk's investigational, once-weekly fixed-dose combination of cagrilintide and semaglutide. Cagrilintide is a long-acting amylin analogue; semaglutide is a GLP-1 receptor agonist. The programme studies whether complementary appetite and metabolic signals can produce greater effects than either component alone.

The combination has substantial randomized human evidence, including phase 3 trials in obesity and type 2 diabetes. It nevertheless remains investigational. Novo Nordisk submitted a US New Drug Application in December 2025, and its May 2026 investor presentation listed a US decision as expected in Q4 2026. As of 3 August 2026, submission is not approval.

Verified identity: a combination, not one molecule

CagriSema is two active peptide medicines in one fixed-dose product. It is not a new covalently linked molecule, so it has no single amino-acid sequence, molecular formula, CAS number or molecular weight. Assigning one combined identity value would be chemically misleading.

FDA GSRS records cagrilintide active moiety as UNII AO43BIF1U8, CAS 1415456-99-3, a 37-residue peptide sequence KCNTATCATQRLAEFLRHSSNNFGPILPPTNVGSNTP, estimated formula C194H312N54O58S2 and average molecular weight 4409 Da. PubChem CID 164618153 is explicitly cagrilintide acetate, with formula C194H312N54O59S2; that extra oxygen belongs to the separately represented acetate form and must not be silently substituted for the active moiety.

PubChem records semaglutide as CID 56843331, CAS 910463-68-2, UNII 53AXN4NNHX, formula C187H291N45O59 and molecular weight 4114 g/mol. These component identities stay separate even when the medicines are supplied together.

PeptideGuide's only citation lead, PMID 33567185, is the STEP 1 semaglutide trial and does not test CagriSema. Its dose, half-life and colour-coded safety claims were rejected rather than promoted.

Mechanistic rationale

Cagrilintide activates amylin/calcitonin-family receptors involved in satiety and food-intake signalling. Semaglutide activates GLP-1 receptors, reducing food intake and affecting glucose-dependent insulin and glucagon responses. The combination is intended to engage complementary pathways; that rationale does not itself prove additive benefit, safety or a long-term clinical outcome.

The components also retain their own pharmacology and adverse-effect boundaries. “CagriSema” should therefore not be treated as a novel single receptor agonist or as evidence that every effect of either component is automatically larger in combination.

Current regulatory status

Novo Nordisk filed a US NDA on 18 December 2025 for a once-weekly subcutaneous product containing cagrilintide 2.4 mg plus semaglutide 2.4 mg for weight management in specified adults. The company's Q1 2026 investor presentation placed the expected US decision in Q4 2026. FDA's public drug approval data did not contain a CagriSema or cagrilintide approval when checked on 3 August 2026.

EMA decision P/0307/2023 grants a product-specific paediatric waiver for cagrilintide/semaglutide. A waiver or paediatric plan is a development decision, not a marketing authorisation. A case-insensitive search of the current EU Union Register dataset found 0 matches for CagriSema or cagrilintide. No Russian marketing authorisation was found in the indexed regulator and medicine-register surfaces reviewed. These are bounded current searches, not a claim about every national database or future decision.

Early combination evidence

The phase 1b study (PMID 33894838, NCT 03600480) exposed 95 adults to multiple-dose combinations with semaglutide 2.4 mg. Reported elimination half-lives were 159-195 hours for cagrilintide and 145-165 hours for semaglutide. Those are component values under a trial protocol, not one “CagriSema half-life.” Gastrointestinal events were common and mostly mild or moderate; the investigators called for larger and longer trials.

In the 32-week phase 2 diabetes trial (PMID 37364590, NCT 04982575), 92 participants received CagriSema, semaglutide or cagrilintide. Mean HbA1c change was -2.2, -1.8 and -0.9 percentage points, respectively; the comparison with semaglutide did not reach conventional statistical significance (p=0.075). Mean weight change was -15.6%, -5.1% and -8.1%. Gastrointestinal events were frequent, and no level 2 or 3 hypoglycaemia was reported.

Pivotal obesity evidence

REDEFINE 1: without type 2 diabetes

REDEFINE 1 (PMID 40544433, NCT 05567796) randomized 3,417 adults with obesity or overweight plus a complication, without type 2 diabetes, for 68 weeks. Under the treatment-policy estimand—regardless of adherence or treatment changes—mean weight change was -20.4% with CagriSema and -3.0% with placebo.

The sponsor also highlighted -22.7% versus -2.3% under a trial-product estimand that models continued treatment. Both are legitimate prespecified questions, but they are not interchangeable. Reporting 22.7% without the estimand boundary overstates what was observed across all randomized participants regardless of adherence.

REDEFINE 2: with type 2 diabetes

REDEFINE 2 (PMID 40544432, NCT 05394519) randomized 1,206 adults with type 2 diabetes and overweight or obesity. At 68 weeks, mean weight change was -13.7% with CagriSema versus -3.4% with placebo. Gastrointestinal events occurred in 72.5% versus 34.4%; 73.5% versus 15.9% reached HbA1c at or below 6.5%. The population and endpoint context differ from REDEFINE 1, so the percentages should not be pooled as one expected result.

Active-comparator and East Asian evidence

REDEFINE 4 was an open-label 84-week phase 3 comparison with tirzepatide 15 mg in 809 adults. Novo Nordisk reported roughly 23% mean weight loss with CagriSema, but the trial failed its primary non-inferiority endpoint versus tirzepatide. A large weight change does not convert a failed comparative endpoint into a positive head-to-head result. The result was company-reported; no peer-reviewed primary publication was located in this review.

Peer-reviewed REDEFINE 5 (PMID 42009015, NCT 05813925) randomized 331 East Asian adults. At 68 weeks mean weight change was -18.4% with CagriSema and -11.9% with semaglutide; treatment discontinuation was 10% versus 6%, and gastrointestinal events were reported by 53% versus 51%. This supplies regional evidence, not proof of identical effects in every population.

Type 2 diabetes evidence

REIMAGINE 1 (PMID 42251860, NCT 06323174) enrolled 189 adults with early type 2 diabetes managed with diet and exercise. At 40 weeks the 2.4/2.4 mg arm changed HbA1c by -1.8 percentage points versus -0.1 with placebo, and weight by -13.8% versus -1.4%. Adverse events occurred in 79% versus 66%, predominantly gastrointestinal.

REIMAGINE 3 (PMID 42251856, NCT 06323161) randomized 274 adults using basal insulin. At 40 weeks the two CagriSema arms reduced HbA1c by -2.33 percentage points versus -0.66 with placebo and weight by about 10-12%. No severe hypoglycaemia occurred; adverse events were reported in 80%, 71% and 71% of the two active arms and placebo.

REIMAGINE 2 company results in June 2026 described statistical superiority to semaglutide 2.4 mg for HbA1c by 0.16 percentage points among 2,713 participants. Until a full peer-reviewed primary report is available, that headline should remain provisional and should not be mixed with the published REIMAGINE trials.

Safety and product-quality boundaries

Across large trials, gastrointestinal events—especially nausea, vomiting, diarrhoea and constipation—were the dominant reported harms. Event frequency, discontinuation and estimand handling must accompany efficacy numbers. The programme is not yet equivalent to a regulator-reviewed final label, and rare, delayed or product-specific risks may remain unresolved.

The two components have different identities, targets and pharmacokinetics; their trial half-lives do not justify a vendor-style “seven-day CagriSema half-life.” There is also no approved dose, manufacturing specification or finished product against which an online “CagriSema” vial can be assumed equivalent. FDA specifically says cagrilintide cannot be used in compounding.

Current research programme

An exact ClinicalTrials.gov intervention query for CagriSema on 3 August 2026 returned 30 records: 17 completed, 5 active, not recruiting, 5 recruiting, 1 not yet recruiting and 2 withdrawn. The query captures studies that name the combination and related presentations; registry status is not a positive outcome or an approval.

Active questions include the roughly 7,000-participant REDEFINE 3 cardiovascular-outcomes trial (NCT 05669755), long-term maintenance, adolescent obesity, muscle and bone outcomes, neuropathy and alternative product presentations. Outcomes remain unknown until reported and independently reviewed.

Russian literature and research review

A 2025 Russian-origin review by Berkovskaya and colleagues at Sechenov University summarizes the early CagriSema programme, including the 92-person phase 2 diabetes trial. It predates the decisive phase 3 and regulatory record and therefore cannot validate later outcomes or approval.

A second Russian-origin review by Shestakova and Bashlykova discusses incretin and combination development, but contains naming/transliteration errors and conflates unrelated development products. Those passages were not used for identity. Russian-language medical news also summarizes REDEFINE and REIMAGINE results, but remains secondary reporting.

No Russian-origin primary CagriSema human trial or Russian marketing authorisation was located in the accessible indexed review. Russian literature broadens the search and helps detect regional terminology; it does not raise the evidence level beyond the underlying primary trials.

Sport, WADA and evidence conclusion

The indexed official 2026 WADA Prohibited List was searched for CagriSema, cagrilintide, semaglutide, GLP-1 and amylin; no specific named match was found. No S0 or other WADA class is inferred, and absence of a named match is not permission. Product composition, route, athlete-specific rules and future list updates still require an official check. WADA status is separate from medicine approval and legality.

CagriSema now has a serious phase 3 evidence base, but the honest conclusion is narrower than the headlines: it is a promising investigational two-drug combination, not one peptide, not approved, not supported by its imported PMID, and not proven superior to tirzepatide by REDEFINE 4. The FDA decision, completed cardiovascular outcomes and peer-reviewed active-comparator results are the next evidence-changing events.