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

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      The Lancet Diabetes & Endocrinology
      Elsevier BV

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          Abstract

          <div class="section"> <a class="named-anchor" id="S1"> <!-- named anchor --> </a> <h5 class="section-title" id="d4224158e326">Background</h5> <p id="P1">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. </p> </div><div class="section"> <a class="named-anchor" id="S2"> <!-- named anchor --> </a> <h5 class="section-title" id="d4224158e331">Methods</h5> <p id="P2">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 <sub>1c</sub>, 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. </p> </div><div class="section"> <a class="named-anchor" id="S3"> <!-- named anchor --> </a> <h5 class="section-title" id="d4224158e339">Findings</h5> <p id="P3">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 <sub>1c</sub> (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&lt;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&lt;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 1·73m <sup>2</sup>, 2·19 to 5·82; p&lt;0·0001). Insulin requirement was not reduced on average over 3 years (−0·005 units per kg, 95% CI −0·022 to 0·012; p=0·545), but there was a significant visit-by-treatment interaction (p=0·0018). There was no effect on endothelial function as measured by reactive hyperaemia index, or on retinopathy. Discontinuation of treatment in 59 (27%) participants on metformin versus 26 (12%) on placebo (p=0·0002) was mainly due to an excess of gastrointestinal adverse effects, and there was no increase in hypoglycaemia with metformin. Five deaths occurred among patients allocated to metformin and two occurred among those allocated to placebo; none were judged by site principal investigators to be related to study medication. </p> </div><div class="section"> <a class="named-anchor" id="S4"> <!-- named anchor --> </a> <h5 class="section-title" id="d4224158e350">Interpretation</h5> <p id="P4">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. </p> </div><div class="section"> <a class="named-anchor" id="S5"> <!-- named anchor --> </a> <h5 class="section-title" id="d4224158e355">Funding</h5> <p id="P5">JDRF.</p> </div>

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          Most cited references31

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          Mannheim Carotid Intima-Media Thickness and Plaque Consensus (2004–2006–2011)

          Intima-media thickness (IMT) provides a surrogate end point of cardiovascular outcomes in clinical trials evaluating the efficacy of cardiovascular risk factor modification. Carotid artery plaque further adds to the cardiovascular risk assessment. It is defined as a focal structure that encroaches into the arterial lumen of at least 0.5 mm or 50% of the surrounding IMT value or demonstrates a thickness >1.5 mm as measured from the media-adventitia interface to the intima-lumen interface. The scientific basis for use of IMT in clinical trials and practice includes ultrasound physics, technical and disease-related principles as well as best practice on the performance, interpretation and documentation of study results. Comparison of IMT results obtained from epidemiological and interventional studies around the world relies on harmonization on approaches to carotid image acquisition and analysis. This updated consensus document delineates further criteria to distinguish early atherosclerotic plaque formation from thickening of IMT. Standardized methods will foster homogenous data collection and analysis, improve the power of randomized clinical trials incorporating IMT and plaque measurements and facilitate the merging of large databases for meta-analyses. IMT results are applied to individual patients as an integrated assessment of cardiovascular risk factors. However, this document recommends against serial monitoring in individual patients.
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            Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34)

            (1998)
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              Glycaemic control of Type 1 diabetes in clinical practice early in the 21st century: an international comparison.

              Improving glycaemic control in people with Type 1 diabetes is known to reduce complications. Our aim was to compare glycaemic control among people with Type 1 diabetes using data gathered in regional or national registries.
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                Author and article information

                Journal
                The Lancet Diabetes & Endocrinology
                The Lancet Diabetes & Endocrinology
                Elsevier BV
                22138587
                August 2017
                August 2017
                : 5
                : 8
                : 597-609
                Article
                10.1016/S2213-8587(17)30194-8
                5641446
                28615149
                35d8a975-7753-49b9-b4b9-849487e1c434
                © 2017

                https://www.elsevier.com/tdm/userlicense/1.0/

                http://www.elsevier.com/open-access/userlicense/1.0/

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