Cardiovascular and metabolic effects of metformin in patients with type 1 diabetes (REMOVAL) : a double-blind, randomised, placebo-controlled trial

Background Metformin might reduce insulin requirement and improve glycaemia in patients with type 1 diabetes, but whether it has cardiovascular benefits is unknown. We aimed to investigate whether metformin treatment (added to titrated insulin therapy) reduced atherosclerosis, as measured by progression of common carotid artery intima-media thickness (cIMT), in adults with type 1 diabetes at increased risk for cardiovascular disease. Methods REMOVAL was a double-blind, placebo-controlled trial undertaken at 23 hospital diabetes clinics in five countries (Australia, Canada, Denmark, the Netherlands, and the UK). Adults aged 40 years and older with type 1 diabetes of at least 5 years' duration and at least three of ten specific cardiovascular risk factors were randomly assigned (via an interactive voice response system) to oral metformin 1000 mg twice daily or placebo. Participants and site staff were masked to treatment allocation. The primary outcome was averaged mean far-wall cIMT, quantified annually for 3 years, analysed in a modified intention-to-treat population (all randomly assigned participants with post-randomisation data available for the outcome of interest at any given timepoint, irrespective of subsequent adherence or study participation), using repeated measures regression. Secondary outcomes were HbA1c, LDL cholesterol, estimated glomerular filtration rate (eGFR), incident microalbuminuria (not reported), incident retinopathy, bodyweight, insulin dose, and endothelial function, also analysed in all participants with post-randomisation data available for the outcome of interest at any given timepoint. This trial is registered with ClinicalTrials.gov, number NCT01483560. Findings Between Dec 14, 2011, and June 24, 2014, 493 participants entered a 3 month run-in to optimise risk factor and glycaemic control (single-blind placebo in the final month). Of 428 randomly assigned patients, 219 were allocated to metformin and 209 to placebo. Progression of mean cIMT was not significantly reduced with metformin (−0·005 mm per year, 95% CI −0·012 to 0·002; p=0·1664), although maximal cIMT (a prespecified tertiary outcome) was significantly reduced (−0·013 mm per year, −0·024 to −0·003; p=0·0093). HbA1c (mean 8·1% [SD 0·9] for metformin and 8·0% [0·8] for placebo at baseline) was reduced on average over 3 years by metformin (−0·13%, 95% CI −0·22 to −0·037; p=0·0060), but this was accounted for by a reduction at the 3-month timepoint (−0·24%, −0·34 to −0·13; p<0·0001) that was not sustained thereafter (p=0·0163 for visit-by-treatment interaction). Bodyweight (−1·17 kg, 95% CI −1·66 to −0·69; p<0·0001) and LDL cholesterol (−0·13 mmol/L, −0·24 to −0·03; p=0·0117) were reduced with metformin over 3 years of treatment, and eGFR was increased (4·0 mL/min per 1·73m2, 2·19 to 5·82; p