CagriSema Outperforms Semaglutide in Lowering HbA1C, Reducing Weight Across REIMAGINE Trials

New phase 3 data presented at the 2026 American Diabetes Association (ADA) Scientific Sessions in New Orleans demonstrate that cagrilintide/semaglutide (CagriSema; Novo Nordisk), an investigational once-weekly fixed-dose combination of a long-acting amylin analog and a glucagon-like peptide-1 receptor agonist (GLP-1 RA), produced significant reductions in hemoglobin A_1C (HbA_1C) and body weight across a diverse spectrum of adults with type 2 diabetes (T2D).

Results from the REIMAGINE 1 (NCT06323174), 2 (NCT06065540), and 3 (NCT06323161) trials were simultaneously published in The Lancet Diabetes & Endocrinology (REIMAGINE 1 and 2) and The Lancet (REIMAGINE 3).^1-6

“What we can definitively [see] is, in this average population with a spectrum of patients, that CagriSema is better than semaglutide for weight and A_1C, but the difference is bigger and more important for people that [have greater overweight] and with higher A_1C,” John B. Buse, MD, PhD, the Verne S. Caviness distinguished professor of medicine at the University of North Carolina Department of Medicine’s Division of Endocrinology and Metabolism and lead author of REIMAGINE-2, said in an interview with Pharmacy Times.

REIMAGINE 1: Earlier-Stage Disease

REIMAGINE 1 enrolled 189 adults with T2D who had inadequate glycemic control and had not previously received injectable diabetes therapy. In this 40-week, randomized, double-blind, placebo-controlled trial, participants receiving CagriSema 2.4 mg/2.4 mg once weekly achieved a mean HbA_1C reduction of 1.8% from a baseline of 7.8% and a 13.8% relative reduction in body weight from a baseline of 101.3 kg, both statistically significant versus placebo (P < .0001).^1,7

The lower dose (1 mg/1 mg) produced reductions of approximately 1.5% in HbA_1C and 11.8% in body weight, also significantly superior to placebo. Adverse events (AEs) were primarily gastrointestinal (GI) in nature, occurring in 53% of participants in the 2.4 mg/2.4 mg group; AE-related discontinuations were low at 3% across all active arms.^1,7

REIMAGINE 2: Head-to-Head Against Components

The largest of the three trials, REIMAGINE 2, enrolled 2713 adults with T2D inadequately controlled on metformin with or without a sodium-glucose cotransporter-2 (SGLT2) inhibitor and compared CagriSema directly against semaglutide (Ozempic, Wegovy; Novo Nordisk) alone, cagrilintide alone, and placebo over 68 weeks. CagriSema 2.4 mg/2.4 mg produced a mean HbA_1C reduction of 1.91% from a baseline of 8.2%, significantly greater than the 1.75% reduction achieved with semaglutide 2.4 mg alone (P = .0035).^2,7

The study showed that the fixed-dose combination lowered blood glucose more effectively than semaglutide alone, and patients taking CagriSema lost more weight than those on existing therapies. GI AEs occurred in 67.2% of patients in the highest CagriSema dose group, with a discontinuation rate of 8.5%, compared to 6.6% for semaglutide 2.4 mg.^2,7

“I think it is generally true that the GI [AEs] kind of go along with the power to promote weight loss,” Buse explained. “The ‘tolerability’ issue for CagriSema is really more about its tremendous power to enhance satiety and reduce food intake and the fine line between feeling full and feeling nauseated.”

REIMAGINE 3: Add-On to Basal Insulin

REIMAGINE 3 addressed one of the most clinically challenging populations in T2D management: adults inadequately controlled on once-daily basal insulin, with or without metformin. In this 40-week, placebo-controlled trial enrolling 274 participants, CagriSema 2.4 mg/2.4 mg reduced HbA_1C by 2.33% from a mean baseline of 8.8%, effectively bringing mean HbA_1C to approximately 6.5%, alongside a 12.0% relative weight reduction; no severe hypoglycemia occurred despite the addition of CagriSema to ongoing basal insulin therapy.³

A Novel Dual Mechanism: Implications for Pharmacist-Led Diabetes Care

Amylin is a hormone produced in the pancreas alongside insulin that helps balance blood glucose levels and promotes satiety after eating. Amylin agonists—synthetic compounds that mimic the effects of the natural hormone—represent a newer therapeutic class. CagriSema pairs cagrilintide, a long-acting amylin receptor agonist, with semaglutide, a well-established GLP-1 RA.⁷

With Novo Nordisk having filed a new drug application with the FDA for CagriSema for weight management in December 2025—with a regulatory decision expected in Q4 2026—pharmacists should begin familiarizing themselves with this emerging class of dual-mechanism therapies. If approved for T2D indications, CagriSema would introduce a new injectable option pharmacists will counsel patients on, covering a wide clinical spectrum from those not yet on pharmacotherapy to those already requiring basal insulin.⁷

The GI tolerability profile, consistent with the established GLP-1 RA class, means that pharmacist counseling on GI management strategies and dose titration adherence will be essential at the point of dispensing and in ongoing medication therapy management. Across REIMAGINE 1 through 3, CagriSema consistently outperformed semaglutide monotherapy for both HbA_1C reduction and weight loss, supporting the rationale for dual amylin–GLP-1 receptor agonism in T2D.^1-3,7

REFERENCES

1. Aroda VR, Buzzetti R, Dalskov M, et al. Efficacy and safety of once-weekly CagriSema in adults with type 2 diabetes inadequately controlled on diet and exercise: a randomised, double-blind, placebo-controlled, phase 3 study (REIMAGINE 1). Lancet Diabetes Endocrinol. Online first: June 7, 2026. Accessed June 10, 2026. doi:10.1016/S2213-8587(26)00126-9

2. Buse J, Bajaj H, Dalskov S, et al. CagriSema versus semaglutide or cagrilintide in people with type 2 diabetes (REIMAGINE 2): a randomised, controlled, phase 3 study. Lancet Diabetes Endocrinol. Online first: June 7, 2026. Accessed June 10, 2026. doi:10.1016/S2213-8587(26)00125-7

3. 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. Online first: June 7, 2026. Accessed June 10, 2026. doi:10.1016/S0140-6736(26)01022-6

4. A Research Study to See How Much CagriSema Lowers Blood Sugar and Body Weight Compared to Placebo in People With Type 2 Diabetes Treated With Diet and Exercise (REIMAGINE 1). ClinicalTrials.gov Identifier: NCT06323174. Last Updated April 2, 2026. Accessed June 10, 2026. https://clinicaltrials.gov/study/NCT06323174

5. A Research Study to See How Well CagriSema Compared to Semaglutide, Cagrilintide and Placebo Lowers Blood Sugar and Body Weight in People With Type 2 Diabetes Treated With Metformin With or Without an SGLT2 Inhibitor (REIMAGINE 2). ClinicalTrials.gov Identifier: NCT06065540. Last Updated January 22, 2026. Accessed June 10, 2026. https://clinicaltrials.gov/study/NCT06065540

6. A Research Study to See How Much CagriSema Lowers Blood Sugar and Body Weight Compared to Placebo in People With Type 2 Diabetes Treated With Once-daily Basal Insulin With or Without Metformin (REIMAGINE 3). ClinicalTrials.gov Identifier: NCT06323161. Last Updated November 28, 2025. Accessed June 10, 2026. https://clinicaltrials.gov/study/NCT06323161

7. CagriSema 2.4 mg/2.4 mg demonstrated significant reduction in HbA1c and weight across multiple studies in the REIMAGINE program presented at ADA 2026. News Release. Novo Nordisk. Released June 7, 2026. Accessed June 10, 2026. https://www.novonordisk.com/content/nncorp/global/en/news-and-media/news-and-ir-materials/news-details.html?id=916567