Metformin versus placebo in combination with insulin analogues in patients with type 2 diabetes mellitus—the randomised, blinded Copenhagen Insulin and Metformin Therapy (CIMT) trial

摘要

Objective To assess the effect of metformin versus placebo both in combination with insulin analogue treatment on changes in carotid intima-media thickness (IMT) in patients with type 2 diabetes. Design and setting Investigator-initiated, randomised, placebo-controlled trial with a 2×3 factorial design conducted at eight hospitals in Denmark. Participants and interventions 412 participants with type 2 diabetes (glycated haemoglobin (HbA_1c) ≥7.5% (≥58?mmol/mol); body mass index 25?kg/m2) were in addition to open-labelled insulin treatment randomly assigned 1:1 to 18?months blinded metformin (1?g twice daily) versus placebo, aiming at an HbA_1c ≤7.0% (≤53?mmol/mol). Outcomes The primary outcome was change in the mean carotid IMT (a marker of subclinical cardiovascular disease). HbA_1c, insulin dose, weight and hypoglycaemic and serious adverse events were other prespecified outcomes. Results Change in the mean carotid IMT did not differ significantly between the groups (between-group difference 0.012?mm (95% CI ?0.003 to 0.026), p=0.11). HbA_1c was more reduced in the metformin group (between-group difference ?0.42% (95% CI ?0.62% to ?0.23%), p0.001)), despite the significantly lower insulin dose at end of trial in the metformin group (1.04?IU/kg (95% CI 0.94 to 1.15)) compared with placebo (1.36?IU/kg (95% CI 1.23 to 1.51), p0.001). The metformin group gained less weight (between-group difference ?2.6?kg (95% CI ?3.3 to ?1.8), p0.001). The groups did not differ with regard to number of patients with severe or non-severe hypoglycaemic or other serious adverse events, but the metformin group had more non-severe hypoglycaemic episodes (4347 vs 3161, p0.001). Conclusions Metformin in combination with insulin did not reduce carotid IMT despite larger reduction in HbA_1c, less weight gain, and smaller insulin dose compared with placebo plus insulin. However, the trial only reached 46% of the planned sample size and lack of power may therefore have affected our results. Trial registration number NCT00657943; Results.