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Cited by 357Diabetes Treatment and ManagementDiabetes, Cardiovascular Risks, and LipoproteinsDiabetes Management and Research

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

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Petrie, John R, Chaturvedi, Nishi, Ford, Ian, Brouwers, Martijn C G J, Greenlaw, Nicola, Tillin, Therese, Hramiak, Irene, Hughes, Alun D +161 more·2017·The Lancet Diabetes & Endocrinology
DOI 10.1016/s2213-8587(17)30194-8PMC PMC5641446
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Abstract

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 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; 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 1·73m 2, 2·19 to 5·82; p<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. Interpretation 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. Funding JDRF.

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  • The study found no difference in the primary end point, minimal and nonsustained effects on HbA1c, minimal effects on weight (1 kg reduction), and no change in total daily insulin dose.

    “The study ultimately found no difference in the primary end point, minimal and nonsustained effects on HbA 1c , minimal effects on weight (1 kg reduction), and no change in total daily insulin dose (246).”

    From The management of type 1 diabetes in adults. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) (2021) · cites this paper as [246]

    The Discussion reports no significant difference in the primary cIMT outcome. The Results report a small HbA1c reduction that was not sustained and a 1.17 kg reduction in bodyweight. However, the claim that total daily insulin dose did not change is too absolute: the Results found no average reduction in weight-adjusted insulin dose over three years, but did find a small, sustained reduction after six months. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • The addition of metformin in adults with type 1 diabetes was associated with small reductions in body weight, insulin dose, and lipid levels but did not sustainably improve A1C.

    “The addition of metformin in adults with type 1 diabetes was associated with small reductions in body weight, insulin dose, and lipid levels but did not sustainably improve A1C (69,70).”

    From 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes—2025 (2025) · cites this paper as [70]

  • The largest study to date assessed metformin 1 g twice daily in 428 people with type 1 diabetes for 3 years, with a primary end point of changes in mean carotid intima-media thickness.

    “The largest study to date assessed the use of metformin 1 g, twice daily, in 428 people with type 1 diabetes who were treated for 3 years, with a primary end point of changes in mean carotid intima-media thickness, a marker of cardiovascular disease risk.”

    From The management of type 1 diabetes in adults. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) (2021) · cites this paper as [246]

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Research works printed but not linked: 21

  1. [1]Livingstone SJ Looker HC Hothersall EJ Risk of cardiovascular disease and total mortality in adults with type 1 diabetes: Scottish registry linkage study PLoS Med 2012 9 e1001321 23055834 PMC3462745
  2. [5]Conway B Miller RG Costacou T Adiposity and mortality in type 1 diabetes Int J Obes (Lond) 2009 33 796 805 19451912 PMC2755198
  3. [7]American Diabetes Association Standards of medical care in diabetes—2017 Diabetes Care 2017 40 suppl 1 S1 S135 28637892
  4. [9]UK Prospective Diabetes Study Group Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34) Lancet 1998 352 854 865 9742977
  5. [11]Peters SA den Ruijter HM Grobbee DE Bots ML Results from a carotid intima-media thickness trial as a decision tool for launching a large-scale morbidity and mortality trial Circ Cardiovasc Imaging 2013 6 20 25 23204038
  6. [12]Bots ML Evans Gregory W Riley WA Grobbee DE Carotid intima-media thickness measurements in intervention studies design options, progression rates, and sample size considerations Stroke 2003 34 2985 2994 14615619
  7. [13]Lorenz MW Polak JF Kavousi M PROG-IMT Study Group Carotid intima-media thickness progression to predict cardiovascular events in the general population (the PROG-IMT collaborative project): a meta-analysis of individual participant data Lancet 2012 379 2053 2062 22541275 PMC3918517
  8. [15]Petrie JR Chaturvedi N Ford I on behalf of the REMOVAL Trial Team Metformin in adults with type 1 diabetes: design and methods of REducing with MetfOrmin Vascular Adverse Lesions (REMOVAL): an international multicentre trial Diabetes Obes Metab 2017 19 509 516 27935183 PMC5357575
  9. [16]Touboul PJ Hennerici MG Meairs S Mannheim carotid intima-media thickness and plaque consensus (2004–2006–2011). An update on behalf of the advisory board of the 3rd, 4th and 5th Watching the Risk Symposia, at the 13th, 15th and 20th European Stroke Conferences, Mannheim, Germany, 2004, Brussels, Belgium, 2006, and Hamburg, Germany, 2011 Cerebrovasc Dis 2012 34 290 296 23128470 PMC3760791
  10. [17]Meijer R Grobee DE Bots ML Mannheim consensus on carotid intima-media thickness: opposite and complementary points of view Cerebrovasc Dis 2006 21 415 416 16549909
  11. [18]Polak JF Backlund JY Cleary PA DCCT/EDIC Research Group Progression of carotid artery intima-media thickness during 12 years in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study Diabetes 2011 60 607 613 21270271 PMC3028362
  12. [19]Lund SS Tarnow L Astrup AS Effect of adjunct metformin treatment in patients with type-1 diabetes and persistent inadequate glycaemic control. A randomized study PLoS One 2008 3 e3363 18852875 PMC2566605
  13. [20]Libman IM Miller KM DiMeglio LA T1D Exchange Clinic Network Metformin RCT Study Group Effect of metformin added to insulin on glycemic control among overweight/obese adolescents with type 1 diabetes: a randomized clinical trial JAMA 2015 314 2241 2250 26624824
  14. [21]Lund SS Tarnow L Astrup AS Effect of adjunct metformin treatment on levels of plasma lipids in patients with type 1 diabetes Diabetes Obes Metab 2009 11 966 977 19558610
  15. [22]Vasamsetti SB Karnewar S Kanugula AK Thatipalli AR Kumar JM Kotamraju S Metformin inhibits monocyte-to-macrophage differentiation via AMPK-mediated inhibition of STAT3 activation: potential role in atherosclerosis Diabetes 2015 64 2028 2041 25552600
  16. [24]Beisswenger PJ Methylglyoxal in diabetes: link to treatment, glycaemic control and biomarkers of complications Biochem Soc Trans 2014 42 450 456 24646259
  17. [25]Preiss D Lloyd SM Ford I Metformin for non-diabetic patients with coronary heart disease (the CAMERA study): a randomised controlled trial Lancet Diabetes Endocrinol 2014 2 116 124 24622715
  18. [26]Polak JF Szklo M Kronmal RA The value of carotid artery plaque and intima-media thickness for incident cardiovascular disease: the multi-ethnic study of atherosclerosis J Am Heart Assoc 2013 2 e000087 23568342 PMC3647272
  19. [27]Pitocco D Zaccardi F Tarzia P Metformin improves endothelial function in type 1 diabetic subjects: a pilot, placebo-controlled randomized study Diabetes Obes Metab 2013 15 427 431 23167274
  20. [28]Nigam SK Wu W Bush KT Hoenig MP Blantz RC Bhatnagar V Handling of drugs, metabolites, and uremic toxins by kidney proximal tubule drug transporters Clin J Am Soc Nephrol 2015 10 2039 2049 26490509 PMC4633783
  21. [29]Bell S Farran B McGurnaghan S Risk of acute kidney injury and survival in patients treated with metformin: an observational cohort study BMC Nephrol 2017 18 163 28526011 PMC5437411

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Authors
Petrie, J. R., Chaturvedi, N., Ford, I., Brouwers, M. C. G. J., Greenlaw, N., Tillin, T., Hramiak, I., Hughes, A. D., Jenkins, A. J., Klein, B. E. K., Klein, R., Ooi, T. C., Rossing, P., Stehouwer, C. D. A., Sattar, N., Colhoun, H. M., Nickerson, H., Lou, O., Dutta, S., Haw, J., Anderson, C., Kean, S., Thomson, E., Gillespie, L., Gibb, J., Greenlaw, N., Keech, A., Jenkins, A., March, K., Williams, S., Coady, E., Bots, M., Dreyer, J., Jan, T., Sheffy, K., Lusky, R., Peleg, S., Shore, A., Carty, D., Donnan, P., Witham, M., Adler, A., Lonn, E., Rauchhaus, P., Lindsay, R., Brouwers, M., Van-Melckebeke, J., Gillespie, L., Hamill, T., Cuthbertson, L., Murray, A., Jolly, L., Miller, E., Hair, J., Bell, A., Carmichael, S., Douglas, E., Surtees, P., Dinnett, E., Allan, J., Watson, C., McLaughlin, M., Brindley, G., Smillie, E., Motherwell, D., MacDonald, S., Ellis, P., Stuart, D., Travers, M., Brearley, S., Greig, L., Colman, P., Nankervis, A., Forulanos, S., West, D., Vaughan, S., Bjorasen, M., Donlan, J., Vrazas, J., O'Neal, D., Horsburgh, J., Pater, H., Kent, S., Twigg, S., Fulcher, G., Denner, R., Piotrowicz, A., Januszewski, A., Coy, A., Paul, T., McDonald, C., Tereschyn, S., Schmidt, N., Weingert, M., Heard, H., Burke, S., Ooi, T., Lochnan, H., Sorisky, A., Keely, E., Malcolm, J., Maranger, J., Favreau, C., Petherick, S., Boles, K., Rossing, P., Hansen, T., Lund, S., Hemmingsen, B., Thorogood, N., Green, K., Robinson, T., Abouglilia, K., Nayman, D., Miller, C., Warren, R., Aizawa, K., Balasubramani, M., Toth, S., Harvey, K., Birch, G., Atkin, S., Sathyapalan, T., James, A., Javed, Z., Wilding, J., Martin, B., Birch, S., Wilcox, A., Watson, N., Oliver, N., Jugnee, N., Rutter, M., Turgut, T., Shaju, A., Yau, S., Subin, S., Walker, M., Wake, D., Miller, C., Millward, A., Chong, P., Hibbert, M., George, J., Schaper, N., Pinxt, J., op het Roodt, J., Phillips, S., Murray, L., Sleigh, L., Collier, A., Sit, L., Allan, K., Cook, J., Campbell, K., Hodge, L., Leese, G., Reekie, G., Jaap, A., Sudworth, A., White, A., McKnight, J., Steven, L., McKay, G., Llano, A., Currie, G., Lennon, E., Johnstone, J., & Shields, K.
Affiliations
  • University of Glasgow (GB)
  • University College London (GB)
  • St Joseph's Health Care (CA)
  • University of Wisconsin–Madison (US)
  • Ottawa Hospital (CA)
  • Maastricht University Medical Centre (NL)
  • Institute of Genetics and Cancer (GB)
  • The University of Sydney (AU)
  • University of Copenhagen (DK)
Corresponding author
Petrie, John R
ORCID
Venue
The Lancet Diabetes & Endocrinology
Publisher
Elsevier BV
Published
2017-08
Volume
5
Issue
8
Pages
597-609
ISSN
2213-8587 (ISSN-L)
DOI
10.1016/s2213-8587(17)30194-8
PMC
PMC5641446
OpenAlex
W2624031057
Cited by
357
References
10
Citations by year
2026: 22 · 2025: 37 · 2024: 41 · 2023: 26 · 2022: 40 · 2021: 41 · 2020: 47 · 2019: 48 · 2018: 33 · 2017: 21
FWCI
32.23
Type
journal article
Language
en
Open access
Licence
Locations
  • The Lancet Diabetes & Endocrinology (acceptedVersion)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
  • PubMed Central (acceptedVersion)
  • ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion)
  • Research Publications (Maastricht University) (submittedVersion, other-oa)
  • Discovery Research Portal (University of Dundee) (submittedVersion)
  • Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
  • UCL Discovery (University College London) (submittedVersion)
  • Royal Devon and Exeter Research Repository (Royal Devon and Exeter) (submittedVersion)
  • Utrecht University Repository (Utrecht University) (submittedVersion)
Funders
  • Steno Diabetes Center Copenhagen (SDCC 3.A Complications)
  • British Heart Foundation (CS/13/1/30327)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
Keywords
metformin, type 1 diabetes, cardiovascular risk, atherosclerosis, carotid intima-media thickness, insulin therapy, glycemic control, LDL cholesterol, endothelial function, microalbuminuria, retinopathy, estimated glomerular filtration rate, body weight, cardiovascular disease prevention, older adults, HbA1c
MeSH terms
Diabetes Mellitus, Type 1, Double-Blind Method, Female, Glomerular Filtration Rate, Humans, Hypoglycemic Agents, Male, Metformin, Middle Aged, Risk Factors, Treatment Outcome, Atherosclerosis, Carotid Intima-Media Thickness

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