Efficacy and safety of co-administered once-weekly cagrilintide 2.4 mg with once-weekly semaglutide 2.4 mg in type 2 diabetes: a multicentre, randomised, double-blind, active-controlled, phase 2 trial

Background Combining the GLP-1 receptor agonist semaglutide with the long-acting amylin analogue cagrilintide has weight-loss benefits; the impact on glycated haemoglobin (HbA(1c)) is unknown. This trial assessed the efficacy and safety of co-administered semaglutide with cagrilintide (CagriSema) in participants with type 2 diabetes. Methods This 32-week, multicentre, double-blind, phase 2 trial was conducted across 17 sites in the USA. Adults with type 2 diabetes and a BMI of 27 kg/m(2) or higher on metformin with or without an SGLT2 inhibitor were randomly assigned (1:1:1) to once-weekly subcutaneous CagriSema, semaglutide, or cagrilintide (all escalated to 2 center dot 4 mg). Randomisation was done centrally using an interactive web response system and was stratified according to use of SGLT2 inhibitor treatment (yes vs no). The trial participants, investigators, and trial sponsor staff were masked to treatment assignment throughout the trial. The primary endpoint was change from baseline in HbA(1c); secondary endpoints were bodyweight, fasting plasma glucose, continuous glucose monitoring (CGM) parameters, and safety. Efficacy analyses were performed in all participants who had undergone randomisation, and safety analyses in all participants who had undergone randomisation and received at least one dose of the trial medication. This trial is registered on ClinicalTrials.gov (NCT04982575) and is complete. Findings Between Aug 2 and Oct 18, 2021, 92 participants were randomly assigned to CagriSema (n=31), semaglutide (n=31), or cagrilintide (n=30). 59 (64%) participants were male; the mean age of participants was 58 years (SD 9). The mean change in HbA(1c) from baseline to week 32 (CagriSema: -2 center dot 2 percentage points [SE 0 center dot 15]; semaglutide: -1 center dot 8 percentage points [0 center dot 16]; cagrilintide: -0 center dot 9 percentage points [0 center dot 15]) was greater with CagriSema versus cagrilintide (estimated treatment difference -1 center dot 3 percentage points [95% CI -1 center dot 7 to -0 center dot 8]; p<0 center dot 0001), but not versus semaglutide (-0 center dot 4 percentage points [-0 center dot 8 to 0 center dot 0]; p=0 center dot 075). The mean change in bodyweight from baseline to week 32 (CagriSema: -15 center dot 6% [SE 1 center dot 26]; semaglutide: -5 center dot 1% [1 center dot 26]; cagrilintide: -8 center dot 1% [1 center dot 23]) was greater with CagriSema versus both semaglutide (p<0 center dot 0001) and cagrilintide (p<0 center dot 0001). The mean change in fasting plasma glucose from baseline to week 32 (CagriSema: -3 center dot 3 mmol/L [SE 0 center dot 3]; semaglutide: -2 center dot 5 mmol/L [0 center dot 4]; cagrilintide: -1 center dot 7 mmol/L [0 center dot 3]) was greater with CagriSema versus cagrilintide (p=0 center dot 0010) but not versus semaglutide (p=0 center dot 10). Time in range (3 center dot 9-10 center dot 0 mmol/L) was 45 center dot 9%, 32 center dot 6%, and 56 center dot 9% at baseline and 88 center dot 9%, 76 center dot 2%, and 71 center dot 7% at week 32 with CagriSema, semaglutide, and cagrilintide, respectively. Adverse events were reported by 21 (68%) participants in the CagriSema group, 22 (71%) in the semaglutide group, and 24 (80%) in the cagrilintide group. Mild or moderate gastrointestinal adverse events were most common; no level 2 or 3 hypoglycaemia was reported. No fatal adverse events were reported. Interpretation In people with type 2 diabetes, treatment with CagriSema resulted in clinically relevant improvements in glycaemic control (including CGM parameters). The mean change in HbA(1c) with CagriSema was greater versus cagrilintide, but not versus semaglutide. Treatment with CagriSema resulted in significantly greater weight loss versus semaglutide and cagrilintide and was well tolerated. These data support further investigation of CagriSema in this population in longer and larger phase 3 studies. Copyright (c) 2023 Elsevier Ltd. All rights reserved.

Automated summary

This study assessed the efficacy and safety of co-administered semaglutide with cagrilintide in participants with type 2 diabetes. The results showed that the combination treatment resulted in clinically relevant improvements in glycemic control and weight loss compared to cagrilintide alone, and it was well tolerated.