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

Abstract

ObjectiveTo 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 settingInvestigator-initiated, randomised, placebo-controlled trial with a 2×3 factorial design conducted at eight hospitals in Denmark.Participants and interventions412 participants with type 2 diabetes (glycated haemoglobin (HbA1c) ≥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 HbA1c ≤7.0% (≤53 mmol/mol).OutcomesThe primary outcome was change in the mean carotid IMT (a marker of subclinical cardiovascular disease). HbA1c, insulin dose, weight and hypoglycaemic and serious adverse events were other prespecified outcomes.ResultsChange 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). HbA1c was more reduced in the metformin group (between-group difference −0.42% (95% CI −0.62% to −0.23%), p<0.001)), 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), p<0.001). The metformin group gained less weight (between-group difference −2.6 kg (95% CI −3.3 to −1.8), p<0.001). 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, p<0.001).ConclusionsMetformin in combination with insulin did not reduce carotid IMT despite larger reduction in HbA1c, 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 numberNCT00657943; Results.

Effect of metformin on plasma metabolite profile in the Copenhagen Insulin and Metformin Therapy (CIMT) trial

“…Our study adds to this research by showing a significant increase in leucine/isoleucine in participants with Type 2 diabetes mellitus, in both cross‐sectional observational and longitudinal randomized data analyses. This increase occurred despite the metformin‐treated group achieving better glucose control, showing less weight gain and needing a lower dose of insulin than the placebo‐treated participants . This is in line with Walford et al .…”

“…Changes in clinical and laboratory variables from baseline to follow-up and differences between the randomized groups have been described previously [15]. Briefly, systolic and diastolic BP decreased in both groups, and a significant decrease in heart rate was observed in the placebo group compared with the metformin group.…”

Mechanisms of action of metformin with special reference to cardiovascular protection

“…These mechanisms have been studied in experimental systems, and their clinical relevance remains to be determined. To date, some but not all studies have demonstrated evidence of reduced atherosclerotic burden in type 2 diabetes patients receiving metformin . One of these, the REducing With MetfOrmin Vascular Adverse Lesions in Type 1 Diabetes (REMOVAL) study, demonstrated a minor and transient reduction for metformin vs placebo of one measure of carotid atherosclerosis in people with type 1 diabetes with cardiovascular risk factors during 3 years of randomized treatment …”

Updates on obesity pharmacotherapy

“…Data from a large placebo-controlled clinical trial indicated that patients with obesity and uncontrolled T2DM treated with insulin plus metformin versus insulin plus placebo required significantly less insulin therapy and gained less weight. 60 If metformin is not tolerated and/or is contraindicated in the particular patient, another option is to use basal insulin therapy plus a GLP-1 agonist or SGLT-2 inhibitor to help offset insulin-induced weight gain.…”