CagriSema vs Zepbound: differences, evidence and safety

CagriSema is an investigational once-weekly injection that combines cagrilintide (an amylin analogue) with semaglutide. Novo Nordisk filed it with the FDA in December 2025 and expects a decision in Q4 2026. Zepbound (tirzepatide) is FDA approved for chronic weight management and obstructive sleep apnea. In the only obesity head-to-head trial, an open-label Human RCT with 809 participants, tirzepatide 15 mg produced more weight loss than CagriSema (25.5% vs 23.0% at 84 weeks, Novo Nordisk, 2026). None of the three head-to-head trials has been published in a peer-reviewed journal yet.

Item	CagriSema	Zepbound (tirzepatide)
US FDA status	Not approved; NDA filed 2025-12-18 (Novo)	Approved 2023-11-08 for weight management; second indication (OSA) 2024-12-20 (Drugs@FDA)
Next regulatory step	FDA decision expected Q4 2026; no public action date (Q2 report)	Already approved; label last revised 8/2026 (label)
Compounding	Cagrilintide cannot be compounded under federal law (FDA)	Shortage over 2024-12-19; 503B exclusion proposed 2026-04-30, final decision pending (FDA)
WADA 2026	Cagrilintide is unapproved, so S0 (non-approved substances) applies (USADA)	Not prohibited; monitored by WADA (USADA)
Strongest evidence	Human RCT, phase 3 (n=3,417, REDEFINE 1)	Approved label plus phase 3 RCTs (n=2,539, SURMOUNT-1)
Head-to-head trials	3, all completed: NCT06131437, NCT06221969, NCT06534411
Last checked	2026-10-04

What changed (October 2026): the three CagriSema abstracts Novo presented in September 2026 (appetite and brain imaging, organ fat, bone) are summarized, Novo’s latest statement on FDA timing is added, and the sport section covers the 2027 WADA List.

CagriSema vs Zepbound at a glance

Feature	CagriSema	Zepbound
What it is	Fixed-dose pair: cagrilintide + semaglutide	Single molecule: tirzepatide
Class	Amylin analogue + GLP-1 receptor agonist	GIP and GLP-1 receptor agonist
Sponsor	Novo Nordisk	Eli Lilly (also sold as Mounjaro for diabetes)
Main research focus	Obesity; type 2 diabetes	Obesity; sleep apnea; type 2 diabetes (as Mounjaro)
Pivotal obesity trial	REDEFINE 1: −20.4% at 68 weeks	SURMOUNT-1: −20.9% (15 mg) at 72 weeks
Head-to-head, obesity	23.0% (REDEFINE 4)	25.5%; tirzepatide led
Approval status	Investigational; under FDA review	FDA approved (2023)
WADA	S0 applies while unapproved	Not prohibited
Route studied	Once-weekly injection	Once-weekly injection
Trial lengths	60–84 weeks	52–88 weeks
Main safety concerns	GI events (79.6% vs 39.9% placebo); fatigue	Boxed warning (thyroid C-cell tumors in rats); GI events; pancreatitis; gallbladder disease

What is CagriSema?

CagriSema is Novo Nordisk’s once-weekly injection of cagrilintide 2.4 mg, a long-acting amylin analogue, and semaglutide 2.4 mg, a GLP-1 receptor agonist (Novo Nordisk, 2025). An analogue is a lab-made version of a natural hormone, here amylin. The FDA application covers adults with obesity, or overweight with at least one weight-related condition. It rests on two trials: REDEFINE 1 (3,417 adults) and REDEFINE 2 (1,206 adults with type 2 diabetes). Novo says CagriSema would be the first once-weekly combination of GLP-1 and amylin analogues for weight management. It is not approved, and outside clinical trials it cannot be obtained legally.

What is Zepbound?

Zepbound is Eli Lilly’s brand of tirzepatide for weight management. The FDA approved it on 2023-11-08 and added a new indication on 2024-12-20 (Drugs@FDA). The label covers long-term weight reduction in adults with obesity, or overweight with a weight-related condition. It also covers moderate to severe obstructive sleep apnea in adults with obesity (Zepbound label, 2026). The same molecule has been sold as Mounjaro for type 2 diabetes since its approval on 2022-05-13 (Drugs@FDA, Mounjaro).

How they work differently

• CagriSema: two separate peptides given together. Semaglutide acts on the GLP-1 receptor, and cagrilintide acts as an amylin analogue (Novo Nordisk, 2025).
  Zepbound: one peptide that activates two incretin receptors, GIP and GLP-1 (Zepbound label). Incretins are gut hormones released after eating.
• CagriSema: in the REIMAGINE 5 record, the dose is raised every 4 weeks over an 8-week period.
  Tirzepatide: in the same trial, the dose is raised over 4 weeks (NCT06534411).
• Both: both act on the GLP-1 receptor, and GI adverse events were frequent with each in their pivotal trials (Garvey 2025; Jastreboff 2022).

Both drugs pair GLP-1 with a second target, and the targets differ: amylin for CagriSema, GIP for tirzepatide. The head-to-head trials are the first direct test of which pairing produces more weight loss.

Evidence head-to-head: what the trials show

Three phase 3 trials have randomized people to CagriSema or tirzepatide. All are open-label, meaning participants knew which drug they were taking. Results are reported two ways. The “efficacy” estimand estimates the result if everyone had stayed on treatment. The “treatment-regimen” estimand counts everyone, including people who stopped.

Outcome	CagriSema	Tirzepatide
Weight, obesity, 84 wk (efficacy)	23.0% — Human RCT, n=809 (REDEFINE 4)	25.5% (15 mg) — same trial
Weight, obesity, 84 wk (regimen)	20.2% — same trial	23.6% — same trial
Weight, type 2 diabetes, 68 wk	15.2% — Human RCT, n=1,024 (REIMAGINE 4; record)	15.8% (15 mg); CagriSema non-inferior
HbA1c, type 2 diabetes, 68 wk	−1.9 points — same trial	−2.2 points; CagriSema missed non-inferiority
Weight, type 2 diabetes, lower doses, 60 wk	12.4% (1.0/1.0 mg) — Human RCT, n=1,023 (REIMAGINE 5; record)	9.1% (5 mg); CagriSema superior
HbA1c, lower doses, 60 wk	−1.71 points — same trial	−1.67 points; non-inferior
Sleep apnea	No trial reported	AHI −25.3 vs −5.3 events/h on placebo — Human RCT, n=469 (SURMOUNT-OSA; record)
Keeping weight off	No withdrawal trial reported	Stopping: 14.0% regain vs 5.5% further loss — Human RCT, n=670 (SURMOUNT-4)

In REDEFINE 4, the obesity trial with 809 participants, CagriSema “did not meet the primary endpoint of showing non-inferiority on weight loss” against tirzepatide 15 mg (Novo Nordisk 6-K, 2026). Non-inferiority means “not meaningfully worse”. REIMAGINE 4 enrolled 1,024 adults with type 2 diabetes (NCT06221969). Weight results were close (15.2% vs 15.8%), but tirzepatide lowered HbA1c more (Novo Nordisk Q2 2026). REIMAGINE 5 compared lower doses of both drugs in 1,023 adults with type 2 diabetes (NCT06534411). CagriSema 1.0/1.0 mg was superior to tirzepatide 5 mg on weight, with similar HbA1c (Novo Nordisk, 2026). That is CagriSema’s first head-to-head win, though only at lower doses. On 2026-10-04, a PubMed search found no peer-reviewed publication of any of the three trials.

Cross-trial numbers (not a direct comparison): REDEFINE 1 reported −20.4% with CagriSema vs −3.0% with placebo at 68 weeks (Human RCT, n=3,417) (Garvey 2025). SURMOUNT-1 reported −20.9% with tirzepatide 15 mg vs −3.1% with placebo at 72 weeks (Human RCT, n=2,539) (Jastreboff 2022). The trials differ in length and population, so the 0.5-point gap between them means little. A network meta-analysis pooled 262 trials with 99,791 participants. It estimated one-year weight loss vs lifestyle change alone at −14.9% for tirzepatide and −14.8% for CagriSema, with moderate to high certainty (Nong 2026, BMJ).

New CagriSema data, September 2026 (abstracts, not peer reviewed): at the EASD meeting Novo presented three abstracts. In a 52-week brain-imaging study in adults with overweight or obesity, weight fell 22.4% more with CagriSema than with placebo, and participants reported less “food noise”, fewer cravings and less hunger. In an MRI sub-study of REIMAGINE 1, in early type 2 diabetes, CagriSema reduced fat in the abdomen, around the liver and in the pancreas compared with placebo at 40 weeks. A post hoc analysis of REIMAGINE 2 gave what its authors call “preliminary reassurance regarding bone changes” at 68 weeks. The release gives no sample sizes or safety data for these analyses, and none compares CagriSema with tirzepatide [Human RCT, sponsor abstracts] (Novo Nordisk, 2026-09-30).

Which fits which goal?

• Weight loss in obesity: tirzepatide has more evidence. It won the only direct obesity comparison and has an approved label (REDEFINE 4).
• Blood sugar in type 2 diabetes: tirzepatide has more evidence at full doses. It lowered HbA1c by 2.2 points vs 1.9 for CagriSema in REIMAGINE 4, where CagriSema missed non-inferiority (Q2 2026 report).
• Weight at lower doses in type 2 diabetes: CagriSema has the stronger result (12.4% vs 9.1% in REIMAGINE 5), so far as a sponsor topline only (REIMAGINE 5).
• Obstructive sleep apnea: only tirzepatide has trial data and a label for it (Malhotra 2024).
• Keeping weight off long term: tirzepatide has a randomized withdrawal trial. None has been reported for CagriSema (Aronne 2024).

These are statements about evidence, not a choice for any person. That decision belongs to a clinician who knows the person’s health history. How we compare peptides explains the evidence levels used here.

Can CagriSema and Zepbound be combined?

No controlled human study has tested CagriSema together with tirzepatide. Three ClinicalTrials.gov records include both drugs, and all compare them head to head rather than together (NCT06131437). Both products act on the GLP-1 receptor (Zepbound label). Combining them would therefore mean taking two drugs that hit the same target, and no trial has measured that. A separate page covers what is known about pairing cagrilintide with a different incretin drug: retatrutide and cagrilintide.

Safety and regulatory status

Side effects in trials. GI events were frequent with both drugs. In REDEFINE 1, they occurred in 79.6% of people on CagriSema vs 39.9% on placebo (Human RCT, n=3,417) (Garvey 2025). In REDEFINE 2, the figures were 72.5% vs 34.4% (Human RCT, n=1,206) (Davies 2025). In SURMOUNT-1, GI events were the most common adverse events with tirzepatide. Adverse events led 4.3%, 7.1% and 6.2% of people on 5, 10 and 15 mg to stop treatment, vs 2.6% on placebo (Human RCT, n=2,539) (Jastreboff 2022). The BMJ network meta-analysis of RCTs placed CagriSema among the drugs with the highest discontinuation due to adverse events. CagriSema also raised fatigue risk, by 92 more cases per 1,000 people. Tirzepatide reduced fat mass the most (25.7%) but also lean mass the most (8.3%) (Nong 2026). In REDEFINE 4, Novo reported that most GI events were mild to moderate and “diminished over time” (Novo Nordisk, 2026).

Label warnings (Zepbound). The label carries a boxed warning: tirzepatide causes thyroid C-cell tumors in rats, and whether it does so in humans is unknown. Zepbound must not be used by anyone with a personal or family history of medullary thyroid carcinoma or MEN 2. Listed warnings also include:

• severe GI reactions
• acute kidney injury
• gallbladder disease
• pancreatitis
• hypoglycemia
• diabetic retinopathy complications in patients with type 2 diabetes (section revised 8/2026)
• aspiration under general anesthesia

(Zepbound label). CagriSema has no FDA label yet, so its official warning list does not exist.

Jurisdiction	CagriSema	Zepbound
FDA	Under review; decision expected Q4 2026	Approved: weight management, sleep apnea
US compounding	Cagrilintide barred (FDA)	Shortage resolved 2024-12-19 (FDA); 503B exclusion proposed
Sport (WADA)	S0 while unapproved	Permitted; monitored

FDA says companies have illegally sold unapproved drugs containing tirzepatide, retatrutide and other incretins “falsely labeled ‘for research purposes’”. It also states that cagrilintide cannot be used in compounding under federal law (FDA, 2026). The tirzepatide shortage ended on 2024-12-19, and the compounding grace periods ended in February and March 2025 (FDA). On 2026-04-30, FDA proposed excluding tirzepatide from the 503B bulks list. It has not made a final decision (FDA). For athletes, USADA says GLP-1 drugs are not prohibited and need no exemption, though WADA monitors them (USADA). The 2027 List, in force from 2027-01-01, names semaglutide and tirzepatide on WADA’s Monitoring Program: labs test for them, but they are not prohibited (USADA athlete advisory). Cagrilintide is not approved by any regulator, so it falls under S0, WADA’s prohibited class for non-approved substances (USADA).

How long do effects take in studies?

The head-to-head trials measured their main results at 60, 68 and 84 weeks, so they say little about the early weeks (NCT06534411). In REIMAGINE 2, Novo reported that “no weight loss plateau was observed at week 68” for CagriSema. In other words, weight was still falling when the trial ended (Novo Nordisk, 2026). For tirzepatide, SURMOUNT-4 shows what happens after stopping. After 36 weeks on the drug, people who switched to placebo regained 14.0% of body weight over the next 52 weeks. Those who stayed on it lost a further 5.5% (Human RCT, n=670) (Aronne 2024). No similar stopping trial has been reported for CagriSema. For where CagriSema sits among other late-stage drugs, see retatrutide vs CagriSema and retatrutide vs tirzepatide vs semaglutide.