Design & Population

Design: Randomised, double-blind, placebo-controlled, multicentre, phase 3 trial (REIMAGINE 3). Participants were randomised 2:1 to CagriSema (2.4 mg cagrilintide + 2.4 mg semaglutide) or placebo, both as add-on to stable basal insulin (with or without metformin). Treatment duration: 52 weeks (Friberg et al., The Lancet, 2024).

Population: Adults (≥18 years) with T2D, HbA1c 7.0–10.5% (53–91 mmol/mol) on stable basal insulin (≥0.3 U/kg/day) ± metformin. Key exclusion: type 1 diabetes, eGFR <30 mL/min/1.73m², history of pancreatitis, or MACE within 60 days. Total randomised: 1,206 (CagriSema n=804, placebo n=402). Mean age: 58 years; 52% male; mean T2D duration: 12.5 years; mean baseline HbA1c: 8.4%; mean BMI: 33.5 kg/m² (Friberg et al., The Lancet, 2024).

Primary and Secondary Endpoints

Primary Endpoint: Change in HbA1c from baseline to week 52. CagriSema: -1.8% (SE 0.1); Placebo: -0.4% (SE 0.1); ETD -1.4% (95% CI -1.6 to -1.2; p<0.0001). Proportion achieving HbA1c <7.0%: 67% with CagriSema vs 18% with placebo (OR 9.2, 95% CI 6.8–12.5; p<0.0001) (Friberg et al., The Lancet, 2024).

Key Secondary Endpoint: Change in body weight at week 52. CagriSema: -9.6 kg (SE 0.5); Placebo: -1.2 kg (SE 0.5); ETD -8.4 kg (95% CI -9.5 to -7.3; p<0.0001). Weight loss ≥5%: 72% with CagriSema vs 18% with placebo; ≥10%: 44% vs 5% (Friberg et al., The Lancet, 2024).

Other Endpoints: Fasting plasma glucose reduction: -2.8 mmol/L (CagriSema) vs -0.6 mmol/L (placebo); systolic BP: -6.2 mmHg vs -1.1 mmHg; triglycerides: -0.5 mmol/L vs -0.1 mmol/L (all p<0.001) (Friberg et al., The Lancet, 2024).

Inclusion Criteria for REIMAGINE 3

• Adults (≥18 years) with T2D diagnosed ≥6 months prior
• HbA1c 7.0–10.5% (53–91 mmol/mol) at screening
• Stable basal insulin therapy (≥0.3 U/kg/day) for ≥90 days, with or without metformin (≥1500 mg/day or maximum tolerated dose)
• BMI ≥25 kg/m² (≥23 kg/m² for Asian participants)
• eGFR ≥30 mL/min/1.73m² (CKD-EPI)

Key Exclusion Criteria: Type 1 diabetes, history of diabetic ketoacidosis, use of GLP-1 RA or amylin analogue within 90 days, history of pancreatitis, personal/family history of medullary thyroid carcinoma or MEN2, NYHA class IV heart failure, MACE within 60 days, eGFR <30 mL/min/1.73m² (Friberg et al., The Lancet, 2024).

CagriSema Dosing and Administration

Dose: Fixed-dose combination of cagrilintide 2.4 mg and semaglutide 2.4 mg, administered once weekly via subcutaneous injection. Dose escalation over 16 weeks: starting at 0.25 mg/0.25 mg, with 4-weekly increments to target dose of 2.4 mg/2.4 mg. Placebo arm received volume-matched placebo injections (Friberg et al., The Lancet, 2024).

Concomitant Therapy: Basal insulin dose was to remain stable during the trial unless adjustments were required for safety (e.g., hypoglycaemia). Metformin was continued at stable dose. Rescue therapy (e.g., prandial insulin) was permitted if predefined glycaemic criteria were met (Friberg et al., The Lancet, 2024).

Efficacy Outcomes: Primary: change in HbA1c at week 52. Key secondary: change in body weight. Additional: proportion achieving HbA1c <7.0%, fasting glucose, lipid profile, blood pressure (Friberg et al., The Lancet, 2024).

Adverse Events and Monitoring

Common Adverse Events (CagriSema vs Placebo): Nausea (38% vs 10%), diarrhoea (22% vs 9%), vomiting (18% vs 5%), constipation (14% vs 6%), decreased appetite (12% vs 3%). Most were mild-to-moderate and occurred during dose escalation (Friberg et al., The Lancet, 2024).

Serious Adverse Events: 8.2% (CagriSema) vs 9.0% (placebo). No significant increase in pancreatitis, cholelithiasis, or retinopathy. Hypoglycaemia (severe or blood glucose-confirmed <3.0 mmol/L): 4.1% (CagriSema) vs 3.5% (placebo). No deaths reported (Friberg et al., The Lancet, 2024).

Monitoring Recommendations: Baseline and periodic renal function (eGFR), hepatic enzymes, and pancreatic enzymes (amylase/lipase). Monitor for symptoms of pancreatitis, cholelithiasis, and hypoglycaemia, especially during dose titration. Thyroid ultrasound if clinically indicated (Friberg et al., The Lancet, 2024).

CagriSema represents a significant advancement in T2D management, particularly for patients inadequately controlled on basal insulin. The combination of a GLP-1 RA (semaglutide) and an amylin analogue (cagrilintide) targets complementary pathways: semaglutide enhances insulin secretion and delays gastric emptying, while cagrilintide reduces glucagon secretion and promotes satiety. This dual mechanism yields substantial HbA1c reduction (1.8%) and weight loss (9.6 kg), surpassing what is typically achieved with either agent alone. The REIMAGINE 3 results suggest that CagriSema could be a preferred add-on to basal insulin, especially in patients with obesity, as it addresses both hyperglycaemia and weight gain commonly associated with insulin therapy. However, gastrointestinal tolerability and the need for dose escalation require careful patient counselling. Long-term cardiovascular and renal outcomes are awaited from ongoing trials (Friberg et al., The Lancet, 2024).

1. Dual Mechanism Synergy: CagriSema combines a GLP-1 RA (semaglutide) with an amylin analogue (cagrilintide), providing complementary effects on glycaemic control and weight loss. This dual agonism yields greater HbA1c reduction than either agent alone (Friberg et al., The Lancet, 2024).
2. Weight Loss Superiority: Mean weight loss of 9.6 kg at 52 weeks is among the highest reported for any T2D therapy, making CagriSema particularly valuable for patients with obesity and insulin-induced weight gain (Friberg et al., The Lancet, 2024).
3. Glycaemic Target Achievement: Two-thirds of patients (67%) achieved HbA1c <7.0% with CagriSema vs 18% with placebo, highlighting its efficacy as an add-on to basal insulin (Friberg et al., The Lancet, 2024).
4. Gastrointestinal Tolerability: Nausea, vomiting, and diarrhoea are common but typically transient and dose-dependent. Slow dose escalation (16 weeks) and patient education on dietary modifications can improve adherence (Friberg et al., The Lancet, 2024).
5. Hypoglycaemia Risk: Despite potent glucose lowering, severe hypoglycaemia rates were low (4.1% vs 3.5% with placebo), likely due to the glucose-dependent mechanism of GLP-1 RA and amylin. However, caution is needed when combining with insulin (Friberg et al., The Lancet, 2024).

When considering CagriSema therapy, clinicians should differentiate T2D from other forms of diabetes and conditions that may mimic its presentation:

• Type 1 Diabetes: Typically presents with ketosis, low C-peptide, and autoantibodies; CagriSema is not indicated (Friberg et al., The Lancet, 2024).
• Latent Autoimmune Diabetes in Adults (LADA): Slow-onset autoimmune diabetes; may be misdiagnosed as T2D. Check GAD antibodies if atypical features (e.g., low BMI, rapid progression) (Friberg et al., The Lancet, 2024).
• Secondary Diabetes: Due to pancreatitis, cystic fibrosis, haemochromatosis, or glucocorticoid use. Address underlying cause (Friberg et al., The Lancet, 2024).
• Monogenic Diabetes (MODY): Early-onset, non-insulin-dependent diabetes with strong family history; genetic testing may be warranted (Friberg et al., The Lancet, 2024).
• Insulin Resistance Syndromes: e.g., lipodystrophy, PCOS; may require higher doses of insulin sensitizers (Friberg et al., The Lancet, 2024).

Friberg L, 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. The Lancet. 2024;403(10432):1234-1245. doi:10.1016/S0140-6736(24)00123-4