CagriSema Tops Tirzepatide 5 mg for Weight Loss in REIMAGINE 5

Once-weekly cagrilintide and semaglutide (CagriSema; Novo Nordisk) at its 1.0 mg/1.0 mg dose produced greater weight loss than tirzepatide (Mounjaro; Eli Lilly) 5 mg, with comparable glycated hemoglobin A_1C (HbA_1C) lowering, in adults with type 2 diabetes (T2D), according to topline phase 3 results announced September 21, 2026. For pharmacists, the data speak to patients who do not reach or remain on the highest available doses of current therapies, a group Novo cited directly in framing the results.¹

CagriSema is a fixed-dose combination of cagrilintide, a long-acting amylin receptor agonist, and semaglutide (Ozempic, Wegovy; Novo Nordisk), a glucagon-like peptide-1 (GLP-1) receptor agonist. The REIMAGINE 5 (NCT06534411) and REDEFINE 9 (NCT06388187) findings were reported as topline results.¹

Head-to-Head Against Tirzepatide

REIMAGINE 5 enrolled adults with T2D inadequately controlled on metformin, a sodium-glucose cotransporter 2 inhibitor, or both. Participants received CagriSema 1.0 mg/1.0 mg or tirzepatide 5 mg, with dual primary end points of change in HbA_1C and relative change in body weight from baseline to week 60.¹

At week 60, CagriSema produced an estimated average weight loss of approximately 12.4% versus 9.1% with tirzepatide, meeting the superiority threshold. HbA_1C reductions were 1.71% with CagriSema and 1.67% with tirzepatide, confirming noninferiority. Novo reported both results using the efficacy estimand. The release did not include enrollment, statistical values, or adverse event (AE) rates; however, the company described CagriSema as well tolerated, with a safety profile consistent with previous studies.¹

The comparator dose matters when interpreting the result. Under the tirzepatide label, patients start at 2.5 mg once weekly and increase to 5 mg after 4 weeks, with further 2.5 mg increases permitted after at least 4 weeks on the current dose, up to a maximum of 15 mg weekly in adults.^1,3

“The result is encouraging, but the dose is important to note. In adults with T2D, CagriSema produced greater weight loss than tirzepatide 5 mg. That tells us how these specific doses compare; it does not tell us whether CagriSema would outperform tirzepatide at 10 or 15 mg,” Jennifer Goldman, PharmD, CDCES, BC-ADM, FCCP, a professor of pharmacy practice at the Massachusetts College of Pharmacy and the director of cardiometabolic services at Well Life Medical in Peabody, Massachusetts, told Pharmacy Times.

“The 5 mg comparison is still clinically relevant. Some patients do well at that dose, while others cannot tolerate or do not need further escalation. Pharmacists should see this as evidence for another potentially useful option, not as a ranking of the drugs across all doses,” Goldman continued.

REDEFINE 9 in Adults With Overweight or Obesity

REDEFINE 9 evaluated CagriSema as an adjunct to a reduced-calorie diet and increased physical activity in adults with overweight or obesity. The 1.0 mg/1.0 mg dose produced a 21.0% weight reduction at week 68 versus 2.0% with placebo, meeting the primary superiority end point. CagriSema also outperformed placebo on prespecified supportive end points, including systolic blood pressure, waist-to-height ratio, and fasting lipid profile. The trial also tested a 1.7 mg/1.7 mg dose, but the release did not report results for that treatment group.¹

Context From REIMAGINE 3

The topline data follow REIMAGINE 3, a randomized, double-blind, placebo-controlled phase 3 trial published in The Lancet. The study enrolled 274 adults with T2D receiving stable once-daily basal insulin, with or without metformin, at 46 centers in 6 countries. Mean baseline HbA_1C was approximately 8.8%.²

At week 40, HbA_1C fell 2.33% with CagriSema 2.4 mg/2.4 mg and 2.10% with 1.0 mg/1.0 mg, compared with 0.66% with placebo. Estimated treatment differences vs placebo were −1.68 and −1.44 percentage points, respectively (P < .0001 for both). CagriSema also produced body weight reductions of 10% to 12%.²

AEs occurred in approximately 80% of participants receiving the higher dose, 71% receiving the lower dose, and 71% receiving placebo, and were mostly mild or moderate gastrointestinal events. No severe hypoglycemia was reported. There was one death in the 1.0 mg/1.0 mg group, but this was deemed due to malignancy and unrelated to treatment. For pharmacists supporting patients on basal insulin, the absence of severe hypoglycemia alongside weight reduction addresses 2 limitations the investigators identified with basal insulin therapy: weight gain and hypoglycemia risk.²

Regulatory Status

CagriSema remains investigational. Novo filed a new drug application with the FDA in December 2025 for weight management, with a decision expected in the fourth quarter of 2026. The release does not describe a regulatory filing for T2D.¹

“Before this changes a treatment conversation, I want to see the full trial data, especially AEs, discontinuations, and outcomes under the different analyses,” Goldman said. “The best treatment is one a patient can tolerate, access, and continue long enough to benefit from.”

REFERENCES

1. Novo's CagriSema delivers superior weight loss versus tirzepatide in REIMAGINE 5 trial. News release. Novo Nordisk. September 21, 2026. Accessed September 23, 2026. https://www.novonordisk.com/content/nncorp/global/en/news-and-media/news-and-ir-materials/news-details.html?id=916774

2. Rosenstock J, Billings LK, Gajria R, et al. Cagrilintide–semaglutide (CagriSema) as an add-on to basal insulin in adults with type 2 diabetes (REIMAGINE 3): a randomised, double-blind, placebo-controlled, multicentre, phase 3 study. Lancet. 2026;408(10549):38-51. doi:10.1016/S0140-6736(26)01022-6

3. Mounjaro (tirzepatide). Prescribing information. Eli Lilly and Company. Accessed September 23, 2026. https://www.guidelinecentral.com/drug/d2d7da5d-ad07-4228-955f-cf7e355c8cc0/mounjaro