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Meta-Analysis
. 2019 Dec 3;12(12):CD008558.
doi: 10.1002/14651858.CD008558.pub2.

Metformin for prevention or delay of type 2 diabetes mellitus and its associated complications in persons at increased risk for the development of type 2 diabetes mellitus

Kasper S Madsen  1 , Yuan Chi  2 , Maria-Inti Metzendorf  3 , Bernd Richter  3 , Bianca Hemmingsen  3
Affiliations
Meta-Analysis

Metformin for prevention or delay of type 2 diabetes mellitus and its associated complications in persons at increased risk for the development of type 2 diabetes mellitus

Kasper S Madsen et al. Cochrane Database Syst Rev. .

Abstract

Background: The projected rise in the incidence of type 2 diabetes mellitus (T2DM) could develop into a substantial health problem worldwide. Whether metformin can prevent or delay T2DM and its complications in people with increased risk of developing T2DM is unknown.

Objectives: To assess the effects of metformin for the prevention or delay of T2DM and its associated complications in persons at increased risk for the T2DM.

Search methods: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Scopus, ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry Platform and the reference lists of systematic reviews, articles and health technology assessment reports. We asked investigators of the included trials for information about additional trials. The date of the last search of all databases was March 2019.

Selection criteria: We included randomised controlled trials (RCTs) with a duration of one year or more comparing metformin with any pharmacological glucose-lowering intervention, behaviour-changing intervention, placebo or standard care in people with impaired glucose tolerance, impaired fasting glucose, moderately elevated glycosylated haemoglobin A1c (HbA1c) or combinations of these.

Data collection and analysis: Two review authors read all abstracts and full-text articles and records, assessed risk of bias and extracted outcome data independently. We used a random-effects model to perform meta-analysis and calculated risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, using 95% confidence intervals (CIs) for effect estimates. We assessed the certainty of the evidence using GRADE.

Main results: We included 20 RCTs randomising 6774 participants. One trial contributed 48% of all participants. The duration of intervention in the trials varied from one to five years. We judged none of the trials to be at low risk of bias in all 'Risk of bias' domains. Our main outcome measures were all-cause mortality, incidence of T2DM, serious adverse events (SAEs), cardiovascular mortality, non-fatal myocardial infarction or stroke, health-related quality of life and socioeconomic effects.The following comparisons mostly reported only a fraction of our main outcome set. Fifteen RCTs compared metformin with diet and exercise with or without placebo: all-cause mortality was 7/1353 versus 7/1480 (RR 1.11, 95% CI 0.41 to 3.01; P = 0.83; 2833 participants, 5 trials; very low-quality evidence); incidence of T2DM was 324/1751 versus 529/1881 participants (RR 0.50, 95% CI 0.38 to 0.65; P < 0.001; 3632 participants, 12 trials; moderate-quality evidence); the reporting of SAEs was insufficient and diverse and meta-analysis could not be performed (reported numbers were 4/118 versus 2/191; 309 participants; 4 trials; very low-quality evidence); cardiovascular mortality was 1/1073 versus 4/1082 (2416 participants; 2 trials; very low-quality evidence). One trial reported no clear difference in health-related quality of life after 3.2 years of follow-up (very low-quality evidence). Two trials estimated the direct medical costs (DMC) per participant for metformin varying from $220 to $1177 versus $61 to $184 in the comparator group (2416 participants; 2 trials; low-quality evidence). Eight RCTs compared metformin with intensive diet and exercise: all-cause mortality was 7/1278 versus 4/1272 (RR 1.61, 95% CI 0.50 to 5.23; P = 0.43; 2550 participants, 4 trials; very low-quality evidence); incidence of T2DM was 304/1455 versus 251/1505 (RR 0.80, 95% CI 0.47 to 1.37; P = 0.42; 2960 participants, 7 trials; moderate-quality evidence); the reporting of SAEs was sparse and meta-analysis could not be performed (one trial reported 1/44 in the metformin group versus 0/36 in the intensive exercise and diet group with SAEs). One trial reported that 1/1073 participants in the metformin group compared with 2/1079 participants in the comparator group died from cardiovascular causes. One trial reported that no participant died due to cardiovascular causes (very low-quality evidence). Two trials estimated the DMC per participant for metformin varying from $220 to $1177 versus $225 to $3628 in the comparator group (2400 participants; 2 trials; very low-quality evidence). Three RCTs compared metformin with acarbose: all-cause mortality was 1/44 versus 0/45 (89 participants; 1 trial; very low-quality evidence); incidence of T2DM was 12/147 versus 7/148 (RR 1.72, 95% CI 0.72 to 4.14; P = 0.22; 295 participants; 3 trials; low-quality evidence); SAEs were 1/51 versus 2/50 (101 participants; 1 trial; very low-quality evidence). Three RCTs compared metformin with thiazolidinediones: incidence of T2DM was 9/161 versus 9/159 (RR 0.99, 95% CI 0.41 to 2.40; P = 0.98; 320 participants; 3 trials; low-quality evidence). SAEs were 3/45 versus 0/41 (86 participants; 1 trial; very low-quality evidence). Three RCTs compared metformin plus intensive diet and exercise with identical intensive diet and exercise: all-cause mortality was 1/121 versus 1/120 participants (450 participants; 2 trials; very low-quality evidence); incidence of T2DM was 48/166 versus 53/166 (RR 0.55, 95% CI 0.10 to 2.92; P = 0.49; 332 participants; 2 trials; very low-quality evidence). One trial estimated the DMC of metformin plus intensive diet and exercise to be $270 per participant compared with $225 in the comparator group (94 participants; 1 trial; very-low quality evidence). One trial in 45 participants compared metformin with a sulphonylurea. The trial reported no patient-important outcomes. For all comparisons there were no data on non-fatal myocardial infarction, non-fatal stroke or microvascular complications. We identified 11 ongoing trials which potentially could provide data of interest for this review. These trials will add a total of 17,853 participants in future updates of this review.

Authors' conclusions: Metformin compared with placebo or diet and exercise reduced or delayed the risk of T2DM in people at increased risk for the development of T2DM (moderate-quality evidence). However, metformin compared to intensive diet and exercise did not reduce or delay the risk of T2DM (moderate-quality evidence). Likewise, the combination of metformin and intensive diet and exercise compared to intensive diet and exercise only neither showed an advantage or disadvantage regarding the development of T2DM (very low-quality evidence). Data on patient-important outcomes such as mortality, macrovascular and microvascular diabetic complications and health-related quality of life were sparse or missing.

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Conflict of interest statement

Kasper S Madsen (KM): none known

Yuan Chi (YC): none known

Maria‐Inti Metzendorf (MM): none known

Bernd Richter (BR): none known

Bianca Hemmingsen (BH): none known

Figures

1
1
Trial flow diagram (as of 29.05.2017, Mim)
2
2
'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies (blank cells indicate that the particular outcome was not measured in some trials).
3
3
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study (blank cells indicate that the trial did not measure that particular outcome).
1.1
1.1. Analysis
Comparison 1 Metformin versus placebo or diet and exercsie, Outcome 1 All‐cause mortality.
1.2
1.2. Analysis
Comparison 1 Metformin versus placebo or diet and exercsie, Outcome 2 Incidence of type 2 diabetes.
1.3
1.3. Analysis
Comparison 1 Metformin versus placebo or diet and exercsie, Outcome 3 Incidence of type 2 diabetes (blinded vs open‐label).
1.4
1.4. Analysis
Comparison 1 Metformin versus placebo or diet and exercsie, Outcome 4 Incidence of type 2 diabetes (duration of the intervention).
1.5
1.5. Analysis
Comparison 1 Metformin versus placebo or diet and exercsie, Outcome 5 Incidence of type 2 diabetes (ethnicity).
1.6
1.6. Analysis
Comparison 1 Metformin versus placebo or diet and exercsie, Outcome 6 Non‐serious adverse events.
1.7
1.7. Analysis
Comparison 1 Metformin versus placebo or diet and exercsie, Outcome 7 2‐hr glucose values.
1.8
1.8. Analysis
Comparison 1 Metformin versus placebo or diet and exercsie, Outcome 8 2‐hr glucose values (blinded vs open‐label).
1.9
1.9. Analysis
Comparison 1 Metformin versus placebo or diet and exercsie, Outcome 9 2‐hr glucose values (duration of intervention).
1.10
1.10. Analysis
Comparison 1 Metformin versus placebo or diet and exercsie, Outcome 10 2‐r glucose values (ethnicity).
1.11
1.11. Analysis
Comparison 1 Metformin versus placebo or diet and exercsie, Outcome 11 HbA1c (blinded vs open‐label).
1.12
1.12. Analysis
Comparison 1 Metformin versus placebo or diet and exercsie, Outcome 12 HbA1c (duration of intervention).
1.13
1.13. Analysis
Comparison 1 Metformin versus placebo or diet and exercsie, Outcome 13 HbA1c (ethnicity).
1.14
1.14. Analysis
Comparison 1 Metformin versus placebo or diet and exercsie, Outcome 14 Fasting plasma glucose.
1.15
1.15. Analysis
Comparison 1 Metformin versus placebo or diet and exercsie, Outcome 15 Fasting plasma glucose (blinded vs open‐label).
1.16
1.16. Analysis
Comparison 1 Metformin versus placebo or diet and exercsie, Outcome 16 Fasting plasma glucose (duration of the intervention).
1.17
1.17. Analysis
Comparison 1 Metformin versus placebo or diet and exercsie, Outcome 17 Fasting plasma glucose (ethnicity).
2.1
2.1. Analysis
Comparison 2 Metformin versus intensive diet plus exercise, Outcome 1 All‐cause mortality.
2.2
2.2. Analysis
Comparison 2 Metformin versus intensive diet plus exercise, Outcome 2 Incidence of type 2 diabetes.
2.3
2.3. Analysis
Comparison 2 Metformin versus intensive diet plus exercise, Outcome 3 Incidence of type 2 diabetes (duration of intervention).
2.4
2.4. Analysis
Comparison 2 Metformin versus intensive diet plus exercise, Outcome 4 Incidence of type 2 diabetes (ethnicity).
2.5
2.5. Analysis
Comparison 2 Metformin versus intensive diet plus exercise, Outcome 5 2‐hr plasma glucose.
2.6
2.6. Analysis
Comparison 2 Metformin versus intensive diet plus exercise, Outcome 6 2‐hr plasma glucose (ethnicity).
2.7
2.7. Analysis
Comparison 2 Metformin versus intensive diet plus exercise, Outcome 7 HbA1c.
2.8
2.8. Analysis
Comparison 2 Metformin versus intensive diet plus exercise, Outcome 8 HbA1c (duration of intervention).
2.9
2.9. Analysis
Comparison 2 Metformin versus intensive diet plus exercise, Outcome 9 HbA1c (ethnicity).
2.10
2.10. Analysis
Comparison 2 Metformin versus intensive diet plus exercise, Outcome 10 Fasting plasma glucose.
2.11
2.11. Analysis
Comparison 2 Metformin versus intensive diet plus exercise, Outcome 11 Fasting plasma glucose (duration of intervention).
2.12
2.12. Analysis
Comparison 2 Metformin versus intensive diet plus exercise, Outcome 12 Fasting plasma glucose (ethnicity).
3.1
3.1. Analysis
Comparison 3 Metformin versus sulphonylurea, Outcome 1 2‐hr plasma glucose.
3.2
3.2. Analysis
Comparison 3 Metformin versus sulphonylurea, Outcome 2 Fasting plasma glucose.
4.1
4.1. Analysis
Comparison 4 Metformin versus acarbose, Outcome 1 All‐cause mortality.
4.2
4.2. Analysis
Comparison 4 Metformin versus acarbose, Outcome 2 Incidence of type 2 diabetes.
4.3
4.3. Analysis
Comparison 4 Metformin versus acarbose, Outcome 3 2‐hr plasma glucose.
4.4
4.4. Analysis
Comparison 4 Metformin versus acarbose, Outcome 4 Fasting plasma glucose.
5.1
5.1. Analysis
Comparison 5 Metformin versus thiazolidinediones, Outcome 1 Incidence of type 2 diabetes.
5.2
5.2. Analysis
Comparison 5 Metformin versus thiazolidinediones, Outcome 2 2‐hr plasma glucose.
5.3
5.3. Analysis
Comparison 5 Metformin versus thiazolidinediones, Outcome 3 Fasting plasma glucose.
6.1
6.1. Analysis
Comparison 6 Metformin + intensive diet and exercise versus intensive diet and exercise, Outcome 1 All‐cause mortality.
6.2
6.2. Analysis
Comparison 6 Metformin + intensive diet and exercise versus intensive diet and exercise, Outcome 2 Incidence of type 2 diabetes.
6.3
6.3. Analysis
Comparison 6 Metformin + intensive diet and exercise versus intensive diet and exercise, Outcome 3 Incidence of type 2 diabetes (blinded vs open‐label).
6.4
6.4. Analysis
Comparison 6 Metformin + intensive diet and exercise versus intensive diet and exercise, Outcome 4 Incidence of type 2 diabetes (duration of the intervention).
6.5
6.5. Analysis
Comparison 6 Metformin + intensive diet and exercise versus intensive diet and exercise, Outcome 5 Incidence of type 2 diabetes (ethnicity).
6.6
6.6. Analysis
Comparison 6 Metformin + intensive diet and exercise versus intensive diet and exercise, Outcome 6 2‐hr glucose values.
6.7
6.7. Analysis
Comparison 6 Metformin + intensive diet and exercise versus intensive diet and exercise, Outcome 7 Fasting plasma glucose.
6.8
6.8. Analysis
Comparison 6 Metformin + intensive diet and exercise versus intensive diet and exercise, Outcome 8 Fasting plasma glucose (blinded vs open‐label).
6.9
6.9. Analysis
Comparison 6 Metformin + intensive diet and exercise versus intensive diet and exercise, Outcome 9 Fasting plasma glucose (duration of the intervention).
See this image and copyright information in PMC

Update of

  • doi: 10.1002/14651858.CD008558

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ChiCTR‐TRC‐09000548 {published data only}
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    1. EUCTR2008‐004497‐40‐GB. The effect of metformin on weight and cardiovascular risk markers in abdomenally obese subjects with impaired fasting glucose previously treated for 12 months with either rimonabant or placebo ‐ use of metformin following weight loss and improvement in CV risk. apps.who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2008‐004497‐40‐GB (accessed 20 March 2019).
Fleming 2002 {published data only}
    1. Fleming R, Hopkinson ZE, Michael Wallace A, Greer IA, Sattar N. Ovarian function and metabolic factors in women with oligomenorrhoea treated with metformin in a randomised double blind placebo‐controlled trial. Journal of Clinical Endocrinology and Metabolism 2002;87(2):569‐74. - PubMed
Flores‐Saenz 2003 {published data only}
    1. Flores‐Saenz JL, Trujillo‐Arriaga HM, Rivas‐Vilchis JF, Mendez‐Francisco JD, Alarcon‐Aguilar FJ, Roman‐Ramos R. Crossover and double blind study with metformin and rosiglitazone in impaired glucose tolerance subjects. Proceedings of the Western Pharmacology Society 2003;46:143‐7. - PubMed
Gómez‐Díaz 2012 {published data only}
    1. Gómez‐Díaz RA, Talavera JO, Pool EC, Ortiz‐Navarrete FV, Solórzano‐Santos F, Mondragón‐González R, et al. Metformin decreases plasma resistin concentrations in pediatric patients with impaired glucose tolerance: a placebo‐controlled randomised clinical trial. Metabolism 2012;61(9):1247‐55. - PubMed
Gore 2005 {published data only}
    1. Gore DC, Wolf SE, Sanford A, Herndon DN, Wolfe RR. Influence of metformin on glucose intolerance and muscle catabolism following severe burn injury. Annals of Surgery 2005;241(2):334‐42. - PMC - PubMed
Gram 2011 {published data only}
    1. Gram J, Henriksen JE, Grodum E, Juhl H, Hansen TB, Christiansen C, et al. Pharmacological treatment of the pathogenetic defects in type 2 diabetes: The randomised multicenter South Danish diabetes study. Diabetes Care 2011;34(1):27‐33. - PMC - PubMed
Guardado‐Mendoza R 2018 {published data only}
    1. Guardado‐Mendoza R, Jimenez‐Ceja L, Farfan D, Alvarez‐Canales M, Salazar‐Lopez S, Montes De Oca M, et al. Diabetes prevention with lifestyle, linagliptin and metformin in patients with prediabetes: The PRELLIM project. Diabetologia 2018;61:S22‐3.
Haukeland 2008 {published data only}
    1. Haukeland JW, Konopski Z, Loeberg EM, Haaland TK, Volkmann HL, Raschpichler G. A randomised, placebo controlled trial with metformin in patients with NAFLD. Hepatology 2008;48(4):334‐9.
Ishida 2005 {published data only}
    1. Ishida W, Satoh J. Characteristic of metformin for treatment of impaired glucose tolerance. Nihon Rinsho 2005;63 Suppl 2:433‐7. - PubMed
Kato 2009 {published data only}
    1. Kato T, Sawai Y, Kanayama H, Taguchi H, Terabayashi T, Taki F, et al. Comparative study of low‐dose pioglitazone or metformin treatment in Japanese diabetic patients with metabolic syndrome. Experimental and Clinical Endocrinology & Diabetes 2009;117(10):593‐603. - PubMed
Kelly 2012 {published data only}
    1. Kelly AS, Bergenstal RM, Gonzalez‐Campoy JM, Katz H, Bank AJ. Effects of exenatide vs. metformin on endothelial function in obese patients with pre‐diabetes: a randomised trial. Cardiovascular Diabetology 2012;11(64):1327‐35. - PMC - PubMed
Kendall 2013 {published data only}
    1. Kendall D, Vail A, Amin R, Barrett T, Dimitri P, Ivison F, et al. Metformin in obese children and adolescents: the MOCA trial. Journal of Clinical Endocrinology and Metabolism 2013;98(1):322‐9. - PubMed
Kilic 2011 {published data only}
    1. Kilic S, Yilmaz N, Zulfikaroglu E, Erdogan G, Aydin M, Batioglu S. Inflammatory‐metabolic parameters in obese and non‐obese normoandrogenemic polycystic ovary syndrome during metformin and oral contraceptive treatment. Gynecological Endocrinology 2011;27(9):622‐9. - PubMed
Koev 2004 {published data only}
    1. Koev D, Koeva L. Treatment of subjects with obesity and impaired fasting glucose with metformin. Endokrinologya 2004;9(4):207‐13.
Krysiak 2012 {published data only}
    1. Krysiak R, Okopien B. Lymphocyte‐suppressing and systemic anti‐inflammatory effects of high‐dose metformin in simvastatin‐treated patients with impaired fasting glucose. Atherosclerosis 2012;225(2):403‐7. - PubMed
Lehtovirta 2001 {published data only}
    1. Lehtovirta M, Forsén B, Gullström M, Häggblom M, Eriksson JG, Taskinen MR, et al. Metabolic effects of metformin in patients with impaired glucose tolerance. Diabetic Medicine 2001;18(7):578‐83. - PubMed
Li 2009b {published data only}
    1. Li AM, Zhao J. Effect of renshen jianxin capsule for alleviating insulin resistance in patients with coronary heart disease and glucose tolerance impairment. Chinese Journal of Integrated Traditional & Western Medicine 2009;29(9):830‐3. - PubMed
LIMIT‐1 {published data only}
    1. Hertog HM, Vermeer SE, Achterberg S, Algra A, Kappelle LJ, Dippel DWJ, et al. Safety and feasibility of treatment with metformin in patients with TIA or minor ischaemic stroke and impaired glucose tolerance: a randomised open‐label phase II trial. Cerebrovascular Diseases 2009;17(Suppl 6):151.
Lu 2011 {published data only}
    1. Lu YH, Lu JM, Wang SY, Li CL, Zheng RP, Tian H, et al. Outcome of intensive integrated intervention in participants with impaired glucose regulation in China. Advances in Therapy 2011;28(6):511‐9. - PubMed
Malin 2013 {published data only}
    1. Malin SK, Braun B. Effect of metformin on substrate utilization after exercise training in adults with impaired glucose tolerance. Applied Physiology, Nutrition, & Metabolism 2013;38(4):427‐30. - PubMed
Medical letter {published data only}
    1. Anonymous. Metformin for prediabetes. JAMA 2017;317(11):1171. - PubMed
Morel 1999 {published data only}
    1. Morel Y, Golay A, Perneger T, Lehmann T, Vadas L, Pasik C, et al. Metformin treatment leads to an increase in basal, but not insulin‐stimulated, glucose disposal in obese patients with impaired glucose tolerance. Diabetic Medicine 1999;16(8):650‐5. - PubMed
    1. Morel Y, Lehmann T, Vadas L, Golay A. Effect of metformin on insulin‐resistance in obese patients with glucose‐intolerance. Schweizerische medizinische Wochenschrift 1996;126(Suppl 74/I):12.
NCT00108615 {published data only}
    1. NCT00108615. Effects of insulin sensitizers in subjects with impaired glucose tolerance. clinicaltrials.gov/ct2/show/NCT00108615 (first posted 5 March 2016).
NCT02338193 {published data only}
    1. NCT02338193. Dapagliflozin and metformin, alone and in combination, in overweight/obese prior GDM women (DAPA‐GDM). clinicaltrials.gov/ct2/show/NCT02338193 (first posted 14 January 2015).
NCT03258723 {published data only}
    1. NCT03258723. Diabetes prevention with lifestyle intervention and metformin escalation (LIME). clinicaltrials.gov/ct2/show/NCT03258723 (first posted 23 August 2017).
Pre‐DICTED {published data only}
    1. NCT03503942. The pre‐diabetes interventions and continued tracking to ease‐out diabetes (Pre‐DICTED) program. https://clinicaltrials.gov/ct2/show/NCT03503942 Accessed 16th. - PMC - PubMed
RESIST {published data only}
    1. Garnett SP, Gow M, Ho M, Baur LA, Noakes M, Woodhead HJ, et al. Optimal macronutrient content of the diet for adolescents with prediabetes; RESIST a randomised control trial. Journal of Clinical Endocrinology & Metabolism 2013;98(5):2116‐25. - PubMed
Retnakaran 2012 {published data only}
    1. Retnakaran R, Ye C, Hanley AJ, Harris SB, Zinman B. Discordant effects on central obesity, hepatic insulin resistance, and alanine aminotransferase of low‐dose metformin and thiazolidinedione combination therapy in patients with impaired glucose tolerance. Diabetes, Obesity & Metabolism 2012;14(1):91‐3. - PubMed
Rodríguez‐Moctezuma 2005 {published data only}
    1. Rodríguez‐Moctezuma JR, Robles‐López G, López‐Carmona JM, Gutiérrez‐Rosas MJ. Effects of metformin on the body composition in subjects with risk factors for type 2 diabetes. Diabetes, Obesity & Metabolism 2005;7(2):189‐92. - PubMed
Scheen 2009 {published data only}
    1. Scheen AJ, Tan MH, Betteridge DJ, Birkeland K, Schmitz O, Charbonnel B. Long‐term glycaemic effects of pioglitazone compared with placebo as add‐on treatment to metformin or sulphonylurea monotherapy in PROactive (PROactive 18). Diabetic Medicine 2009;26(12):1242‐9. - PubMed
Schuster 2004 {published data only}
    1. Schuster D, Gaillard T, Rhinesmith S, Habash D, Osei K. Impact of metformin on glucose metabolism in nondiabetic, obese African Americans: A placebo‐controlled, 24‐month randomised study. Diabetes Care 2004;27(11):2768‐9. - PubMed
SLCTR/2016/026 {unpublished data only}
    1. SLCTR/2016/026. Effects of metformin and lifestyle modifications on the progression of the atherosclerosis among individuals with impaired glucose tolerance. slctr.lk/trials/slctr‐2016‐026 (accessed 16 September 2019).
STOP‐NIDDM {published data only}
    1. Chiasson JL, Gomis R, Hanefeld M, Josse RG, Karasik A, Laakso M. The STOP‐NIDDM trial: An international study on the efficacy of an alpha‐ glucosidase inhibitor to prevent type 2 diabetes in a population with impaired glucose tolerance: Rationale, design, and preliminary screening data. Diabetes Care 1998;21(10):1720‐5. - PubMed
Stroup 2013 {published data only}
    1. Stroup S. Effect of metformin on weight in patients with schizophrenia with impaired fasting glucose. Neuropsychopharmacology. 2013; Vol. 38:S41.
Sultana 2012 {published data only}
    1. Sultana SS, Amin F, Rahman A, Afsana F. A comparative study with metformin and pioglitazone versus metformin alone in nonalcoholic fatty liver disease in newly detected glucose intolerant patients. Diabetologia 2012;55:S500.
UKPDS {published data only}
    1. Turner R, Rachman J, Holman R. UK Prospective Diabetes Study. Diabetes und Stoffwechsel 1996;5(3):78‐80.
Vitolins 2017 {published data only}
    1. Vitolins MZ, Isom SP, Blackwell CS, Kernodle D, Sydell JM, Pedley CF, et al. The healthy living partnerships to prevent diabetes and the diabetes prevention program: a comparison of year 1 and 2 intervention results. Translational Behavioral Medicine June 2017;7(2):371‐8. - PMC - PubMed
Wan 2010 {published data only}
    1. Wan Q, Wang F, Wang F, Guan Q, Liu Y, Wang C, et al. Regression to normoglycaemia by fenofibrate in pre‐diabetic subjects complicated with hypertriglyceridaemia: a prospective randomised controlled trial. Diabetic Medicine 2010;27(11):1312‐7. - PubMed
Zinman 2010 {published data only}
    1. Zinman B, Harris SB, Neuman J, Gerstein HC, Retnakaran RR, Raboud J, et al. Low‐dose combination therapy with rosiglitazone and metformin to prevent type 2 diabetes mellitus (CANOE trial): a double‐blind randomised controlled study. Lancet 2010;376(9735):103‐11. - PubMed

References to studies awaiting assessment

ChiCTR‐IPR‐17012309 {published data only}
    1. ChiCTR‐IPR‐17012309. The effect of metformin on the number and function of the circulating endothelial progenitor cells in prediabetic patients. www.chictr.org.cn/showproj.aspx?proj=21001 (accessed 5 April 2019).
EDIT 1997 {published data only}
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    1. Holman RR, Blackwell L, Manley SE, Tucker L, Frighi V, Stratton IM. Results from the early diabetes intervention trial. Diabetes 2003;52(Suppl. 1):A16.
    1. Holman RR, Blackwell L, Stratton IM, Manley SE, Tucker L, Frighi V. Six‐years results from the Early Diabetes Intervention Trial. Diabetic Medicine 2003;20(Suppl. 2):15.
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NCT02409238 {published data only}
    1. NCT02409238. Insulin resistance and mild cognitive impairment (IRMCI) study. clinicaltrials.gov/ct2/show/NCT02409238 (first posted 6 April 2015);‐:‐.
Polanco 2015 {published data only}
    1. Polanco MA, Barrientos R, Godinez SA, Sanchez S, Leanos R, Plascencia S. Preventing the development of type 2 diabetes in subjects at high risk in western Mexico, using metformin and changes in lifestyle, followed 10 years. Diabetes 2015;64:A687.

References to ongoing studies

CTRI/2017/09/009635 {published data only}
    1. CTRI/2017/09/009635. A study of life style modification with and without metformin in prediabetic subjects. www.ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=16184 (accessed 5 April 2019).
ePRECIDE 2017 {published and unpublished data}
    1. Unpublished protocol. Provided by the investigators.
    1. EUCTR2013‐000418‐39‐AT. Early prevention of diabetes complications in people with hyperglycaemia in Europe ‐ e‐PREDICE. apps.who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2013‐000418‐39‐AT (accessed 8 April 2016).
    1. EudraCT 2013‐000418‐39. Early prevention of diabetes complications in people with hyperglycaemia in Europe. www.clinicaltrialsregister.eu/ctr‐search/search?query=2013‐000418‐39 (accessed 17 March 2016).
    1. NCT03222765. Prevention of microvascular complications in prediabetes e‐PREDICE Study (ePREDICE). clinicaltrials.gov/ct2/show/NCT03222765 (first posted 19 July 2017).
    1. ePRECIDE. The project. www.epredice.eu/en/the‐project (accessed 17 March 2016).
Espinoza 2019 {published data only}
    1. Espinoza SE, Musi N, Wang CP, Michalek J, Orsak B, Romo T, et al. Rationale and study design of a randomized clinical trial of metformin to prevent frailty in older adults with pre‐diabetes. Journals of Gerontology Biological Sciences and Medical Sciences March 2019; Vol. pii: glz078. - PMC - PubMed
    1. NCT02570672. Metformin for preventing frailty in high‐risk older adults. clinicaltrials.gov/ct2/show/NCT02570672 (first posted 7 October 2015).
Ji 2019 {published data only}
    1. Ji L, Sun N, Zhang Y, Zhang L, Shen S, Wang X, et al. Efficacy of metformin in preventing progression to diabetes in Chinese subjects with impaired glucose regulation: protocol for a multicenter, open‐label, randomized, controlled clinical study. Diabetes Obesity Metabolism September 2019;Epub ahead of print:No page numbers. - PubMed
    1. NCT03441750. Efficacy of metformin in preventing diabetes in China (ChinaDPP). clinicaltrials.gov/ct2/show/NCT03441750 (first posted 21 February 2018).
JPRN‐UMIN000018995 {published and unpublished data}
    1. JPRN‐UMIN000018995. Metformin therapy for East Asian women with recent gestational diabetes mellitus and glucose abnormalities: a multicenter, randomised, open‐label trial. upload.umin.ac.jp/cgi‐open‐bin/icdr_e/ctr_view.cgi?recptno=R000021900 (accessed 16 September 2019).
Nadeau 2014 {published and unpublished data}
    1. NCT01779362. RISE adult medication study (RISE Adult). clinicaltrials.gov/ct2/show/NCT01779362 (first posted 30 January 2013).
    1. Nadeau KJ, Mather KJ, Arslanian SA, Buchanan TA, Caprio S, Edelstein SL, et al. RISE Consortium. Restoring Insulin Secretion (RISE): design of studies of beta‐cell preservation in prediabetes and early type 2 diabetes across the life span. Diabetes Care 2014;37(3):780‐8. - PMC - PubMed
NCT01804049 {published data only}
    1. NCT01804049. Metformin and muscle in insulin‐resistant older veterans (M&M). clinicaltrials.gov/ct2/show/NCT01804049 (first posted 5 March 2013).
NCT02915198 {published and unpublished data}
    1. NCT02915198. Investigation of metformin in pre‐diabetes on atherosclerotic cardiovascular outcomes (VA‐IMPACT). clinicaltrials.gov/ct2/show/NCT02915198 (first posted 26 September 2016).
NCT02969798 {published data only}
    1. NCT02969798. Pre‐diabetes in subject with impaired fasting glucose (IFG) and impaired glucose tolerance (IGT). clinicaltrials.gov/show/NCT02969798 (first received 16 March 2016).
NCT03194009 {published data only}
    1. NCT03194009. Prudente; diabetes prevention via exercise, nutrition and treatment (PRuDENTE). clinicaltrials.gov/ct2/show/NCT03194009 (first posted 21 June 2017).
Rhee 2019 {published and unpublished data}
    1. NCT02981121. Hospital‐based diabetes prevention study in Korea. clinicaltrials.gov/ct2/show/NCT02981121 (first posted 2 December 2016).
    1. Rhee SY, Chon S, Ahn KJ, Woo JT, Korean Diabetes Prevention Study Investigators. Hospital‐based Korean diabetes prevention study: a prospective, multi‐center, randomized, open‐label controlled study. Diabetes and Metabolism Journal 2019;43(1):49‐58. - PMC - PubMed

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