TY - JOUR
T1 - Cardiovascular and metabolic effects of metformin in patients with type 1 diabetes (REMOVAL)
T2 - a double-blind, randomised, placebo-controlled trial
AU - Petrie, John R.
AU - Chaturvedi, Nishi
AU - Ford, Ian
AU - Brouwers, Martijn C. G. J.
AU - Greenlaw, Nicola
AU - Tillin, Therese
AU - Hramiak, Irene
AU - Hughes, Alun D.
AU - Jenkins, Alicia J.
AU - Klein, Barbara E. K.
AU - Klein, Ronald
AU - Ooi, Teik C.
AU - Rossing, Peter
AU - Stehouwer, Coen D. A.
AU - Sattar, Naveed
AU - Colhoun, Helen M.
AU - REMOVAL Study Grp
PY - 2017/8
Y1 - 2017/8
N2 - 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 intimamedia 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 HbA(1c), 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). HbA(1c) (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; pInterpretation These data do not support use of metformin to improve glycaemic control in adults with long-standing type 1 diabetes as suggested by current guidelines, but suggest that it might have a wider role in cardiovascular risk management.
AB - 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 intimamedia 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 HbA(1c), 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). HbA(1c) (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; pInterpretation These data do not support use of metformin to improve glycaemic control in adults with long-standing type 1 diabetes as suggested by current guidelines, but suggest that it might have a wider role in cardiovascular risk management.
KW - INTIMA-MEDIA THICKNESS
KW - GLYCEMIC CONTROL
KW - ENDOTHELIAL FUNCTION
KW - OF-VIEW
KW - COMPLICATIONS
KW - PROGRESSION
KW - DEFICIENCY
KW - MORTALITY
KW - DISEASE
KW - DESIGN
U2 - 10.1016/S2213-8587(17)30194-8
DO - 10.1016/S2213-8587(17)30194-8
M3 - Article
SN - 2213-8587
VL - 5
SP - 597
EP - 609
JO - The Lancet Diabetes & Endocrinology
JF - The Lancet Diabetes & Endocrinology
IS - 8
ER -