The Lancet July 04, 2026

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

Julio Rosenstock, Liana K Billings, Reena Gajria, Francesco Giorgino, Nanna Borup Johansen, Klara R Klein, et al.

Bottom Line

In adults with type 2 diabetes inadequately controlled on basal insulin, the addition of the once-weekly dual agonist cagrilintide–semaglutide (CagriSema) yielded profound improvements in glycemic control and substantial weight loss compared to placebo, without increasing the risk of severe hypoglycemia.

Key Findings

1. At 40 weeks, mean HbA1c decreased by 2.33% with CagriSema 2.4 mg/2.4 mg and by 2.10% with CagriSema 1.0 mg/1.0 mg, compared to a 0.66% reduction with placebo (estimated treatment differences of -1.68 and -1.44 percentage points, respectively; p<0.0001).

2. CagriSema 2.4 mg/2.4 mg induced a relative mean body weight reduction of 12.0% versus a 1.1% gain with placebo (estimated treatment difference of -13.1 percentage points; p<0.0001).

3. A significantly higher proportion of participants on CagriSema 2.4 mg/2.4 mg achieved the rigorous HbA1c target of <7.0% compared to those receiving placebo (75% vs. 16%).

4. The incidence of severe (level 3) hypoglycemia was zero across the trial groups, demonstrating that the profound glycemic reductions did not come at the cost of dangerous hypoglycemic events.

Study Design

Design

RCT

Double-Blind

Sample

274

Patients

Duration

40 wk

Median

Setting

Multicenter, 6 countries

Population Adults with type 2 diabetes (baseline HbA1c 7.0-10.5%; mean 8.8%) inadequately controlled on a stable regimen of once-daily basal insulin, with or without metformin.

Intervention Once-weekly subcutaneous cagrilintide–semaglutide (CagriSema) at fixed doses of either 2.4 mg/2.4 mg or 1.0 mg/1.0 mg.

Comparator Dose-matched once-weekly placebo.

Outcome Mean change in HbA1c (percentage points) from baseline to week 40.

Study Limitations

• The relatively short follow-up duration of 40 weeks limits the ability to evaluate the long-term durability of glycemic improvements, weight loss, and cardiovascular/microvascular outcomes.

• The modest sample size (N=274) may limit the statistical power to detect rare but clinically important adverse events or nuanced treatment differences among patient subgroups.

• High rates of transient, mild-to-moderate gastrointestinal adverse events, characteristic of the GLP-1/amylin combination class, may impact medication adherence in real-world clinical practice.

Clinical Significance

REIMAGINE 3 presents a paradigm shift for advanced type 2 diabetes management, strongly supporting 'insulin de-intensification.' By adding dual GLP-1 and amylin receptor agonism (CagriSema), patients can avoid the escalation to complex basal-bolus insulin regimens. This combination mitigates the weight gain and high hypoglycemic risks typically associated with prandial insulin, instead driving double-digit percentage weight loss and excellent glycemic control.

Historical Context

Historically, patients with type 2 diabetes who fail to achieve their glycemic targets on basal insulin alone have required escalation to multiple daily insulin injections (prandial insulin). This approach exacerbates weight gain and heightens the risk of potentially dangerous hypoglycemic episodes. While GLP-1 receptor agonists have been successfully leveraged to counter these side effects, combining semaglutide (a GLP-1 analogue) with cagrilintide (a long-acting amylin analogue) leverages complementary mechanisms to synergistically enhance satiety, delay gastric emptying, and suppress postprandial glucagon. Following the success of this fixed-dose combination in earlier-stage obesity and diabetes, REIMAGINE 3 was designed to explicitly test CagriSema's utility in this challenging, insulin-treated, advanced disease population.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

How do the distinct mechanisms of cagrilintide and semaglutide complement each other to improve glycemic control without causing severe hypoglycemia when added to basal insulin?

Key Response

Semaglutide is a GLP-1 agonist that stimulates glucose-dependent insulin release and inhibits glucagon. Cagrilintide is an amylin analogue that delays gastric emptying and promotes satiety. Because their incretin and amylin-mimetic effects are glucose-dependent, they do not inherently provoke hypoglycemia on their own, making the combination safe alongside basal insulin if dosed correctly.

Resident

When starting a patient on CagriSema who is already taking basal insulin for inadequately controlled type 2 diabetes, how should you manage their existing basal insulin dose to mitigate hypoglycemia risk?

Key Response

Although CagriSema has a glucose-dependent mechanism, adding its profound insulin-sensitizing and secretagogue effects to exogenous basal insulin increases the risk of iatrogenic hypoglycemia. Clinical practice typically dictates preemptively reducing the basal insulin dose by 10 to 20 percent upon initiation, followed by careful titration based on fasting blood glucose monitoring.

Fellow

Given the delayed gastric emptying effects of both amylin analogues and GLP-1 agonists, what are the synergistic gastrointestinal implications of CagriSema for patients with long-standing type 2 diabetes, and how might this affect the absorption of other oral medications?

Key Response

Patients with chronic type 2 diabetes often have underlying diabetic gastroparesis. Combining two agents that profoundly slow gastric emptying can exacerbate gastrointestinal intolerance (nausea, vomiting) and significantly alter the pharmacokinetics by delaying the Tmax of co-administered oral medications. This necessitates careful medication reconciliation and monitoring for narrow-therapeutic-index drugs.

Attending

How does the efficacy profile of CagriSema as an add-on to basal insulin shift the treatment paradigm away from traditional prandial insulin (basal-bolus regimens) for patients with advanced type 2 diabetes?

Key Response

Historically, patients failing basal insulin were transitioned to complex basal-bolus regimens, which inherently drive weight gain and hypoglycemia. CagriSema offers a basal-plus alternative that simplifies the regimen, actively reverses weight gain, and provides profound A1c lowering with a safer hypoglycemia profile, reinforcing the shift to replace prandial insulin as the preferred next step in most patients.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

In evaluating the efficacy of a dual-agonist like CagriSema against a placebo add-on to insulin, how does the absence of an active comparator arm (such as semaglutide alone) limit the statistical interpretation of the synergistic contribution of cagrilintide?

Key Response

While a placebo-controlled design confirms the baseline efficacy and safety of the combination, it fails to isolate the incremental benefit of the amylin analogue over standard-of-care GLP-1 RA therapy. A multi-arm factorial or active-comparator design is required to rigorously quantify whether the combination yields synergistic rather than purely additive effects.

Journal Editor

What blinding challenges and potential unblinding biases must be scrutinized when evaluating a trial involving potent weight-loss and GI-modifying agents like CagriSema versus placebo?

Key Response

The pronounced side-effect profile of CagriSema, particularly significant weight loss and gastrointestinal symptoms like nausea, frequently leads to functional unblinding of both patients and investigators. This can bias subjective adverse event reporting, patient lifestyle behaviors, and insulin titration decisions by investigators, potentially inflating the apparent efficacy profile.

Guideline Committee

How does the REIMAGINE 3 trial data influence the ADA/EASD guideline algorithms regarding the preferred intensification strategy for patients with type 2 diabetes not achieving glycemic targets on basal insulin alone?

Key Response

Current ADA/EASD guidelines recommend adding a GLP-1 RA or GIP/GLP-1 RA before considering prandial insulin in most patients failing basal insulin. The REIMAGINE 3 data strengthens this algorithm by demonstrating that a GLP-1/amylin co-agonist offers profound weight loss and A1c benefits without increasing severe hypoglycemia, prompting guidelines to position CagriSema as a preferred, high-efficacy intensification step.

Clinical Landscape

Noteworthy Related Trials

2014

DUAL II Trial

n = 413 · Diabetes Care

Tested

Insulin degludec and liraglutide (IDegLira) fixed-ratio combination

Population

Patients with type 2 diabetes uncontrolled on basal insulin

Comparator

Insulin degludec

Endpoint

Change in HbA1c from baseline to 26 weeks

Key result: IDegLira provided superior glycemic control compared with insulin degludec alone, with weight loss and no increased hypoglycemia risk.

2017

SUSTAIN 5 Trial

n = 397 · Lancet Diabetes Endocrinol

Tested

Once-weekly subcutaneous semaglutide (0.5 mg or 1.0 mg)

Population

Adults with type 2 diabetes inadequately controlled on basal insulin

Comparator

Placebo

Endpoint

Change in HbA1c from baseline to week 30

Key result: Semaglutide significantly reduced HbA1c and body weight compared with placebo when added to basal insulin.

2023

SURPASS-6 Trial

n = 1428 · JAMA

Tested

Once-weekly tirzepatide (5 mg, 10 mg, or 15 mg)

Population

Adults with type 2 diabetes inadequately controlled on basal insulin

Comparator

Placebo

Endpoint

Change in HbA1c from baseline to week 40

Key result: Tirzepatide significantly reduced HbA1c and body weight compared with placebo when added to titrated insulin glargine.

Tailored to your role

Want this tailored to you?

Add your specialty or training stage to get role-specific takeaways and more questions.

Personalize this analysis