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Meta-Analysis
. 2020 Jun 5;6(6):CD012906.
doi: 10.1002/14651858.CD012906.pub2.

Metformin monotherapy for adults with type 2 diabetes mellitus

Filip Gnesin  1 , Anne Cathrine Baun Thuesen  2   3 , Lise Katrine Aronsen Kähler  4 , Sten Madsbad  5 , Bianca Hemmingsen  6
Affiliations
Meta-Analysis

Metformin monotherapy for adults with type 2 diabetes mellitus

Filip Gnesin et al. Cochrane Database Syst Rev. .

Abstract

Background: Worldwide, there is an increasing incidence of type 2 diabetes mellitus (T2DM). Metformin is still the recommended first-line glucose-lowering drug for people with T2DM. Despite this, the effects of metformin on patient-important outcomes are still not clarified.

Objectives: To assess the effects of metformin monotherapy in adults with T2DM.

Search methods: We based our search on a systematic report from the Agency for Healthcare Research and Quality, and topped-up the search in CENTRAL, MEDLINE, Embase, WHO ICTRP, and ClinicalTrials.gov. Additionally, we searched the reference lists of included trials and systematic reviews, as well as health technology assessment reports and medical agencies. The date of the last search for all databases was 2 December 2019, except Embase (searched up 28 April 2017).

Selection criteria: We included randomised controlled trials (RCTs) with at least one year's duration comparing metformin monotherapy with no intervention, behaviour changing interventions or other glucose-lowering drugs in adults with T2DM.

Data collection and analysis: Two review authors read all abstracts and full-text articles/records, assessed risk of bias, and extracted outcome data independently. We resolved discrepancies by involvement of a third review author. For meta-analyses we used a random-effects model with investigation of risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, using 95% confidence intervals (CIs) for effect estimates. We assessed the overall certainty of the evidence by using the GRADE instrument.

Main results: We included 18 RCTs with multiple study arms (N = 10,680). The percentage of participants finishing the trials was approximately 58% in all groups. Treatment duration ranged from one to 10.7 years. We judged no trials to be at low risk of bias on all 'Risk of bias' domains. The main outcomes of interest were all-cause mortality, serious adverse events (SAEs), health-related quality of life (HRQoL), cardiovascular mortality (CVM), non-fatal myocardial infarction (NFMI), non-fatal stroke (NFS), and end-stage renal disease (ESRD). Two trials compared metformin (N = 370) with insulin (N = 454). Neither trial reported on all-cause mortality, SAE, CVM, NFMI, NFS or ESRD. One trial provided information on HRQoL but did not show a substantial difference between the interventions. Seven trials compared metformin with sulphonylureas. Four trials reported on all-cause mortality: in three trials no participant died, and in the remaining trial 31/1454 participants (2.1%) in the metformin group died compared with 31/1441 participants (2.2%) in the sulphonylurea group (very low-certainty evidence). Three trials reported on SAE: in two trials no SAE occurred (186 participants); in the other trial 331/1454 participants (22.8%) in the metformin group experienced a SAE compared with 308/1441 participants (21.4%) in the sulphonylurea group (very low-certainty evidence). Two trials reported on CVM: in one trial no CVM was observed and in the other trial 4/1441 participants (0.3%) in the metformin group died of cardiovascular reasons compared with 8/1447 participants (0.6%) in the sulphonylurea group (very low-certainty evidence). Three trials reported on NFMI: in two trials no NFMI occurred, and in the other trial 21/1454 participants (1.4%) in the metformin group experienced a NFMI compared with 15/1441 participants (1.0%) in the sulphonylurea group (very low-certainty evidence). One trial reported no NFS occurred (very low-certainty evidence). No trial reported on HRQoL or ESRD. Seven trials compared metformin with thiazolidinediones (very low-certainty evidence for all outcomes). Five trials reported on all-cause mortality: in two trials no participant died; the overall RR was 0.88, 95% CI 0.55 to 1.39; P = 0.57; 5 trials; 4402 participants). Four trials reported on SAE, the RR was 0,95, 95% CI 0.84 to 1.09; P = 0.49; 3208 participants. Four trials reported on CVM, the RR was 0.71, 95% CI 0.21 to 2.39; P = 0.58; 3211 participants. Three trial reported on NFMI: in two trials no NFMI occurred and in one trial 21/1454 participants (1.4%) in the metformin group experienced a NFMI compared with 25/1456 participants (1.7%) in the thiazolidinedione group. One trial reported no NFS occurred. No trial reported on HRQoL or ESRD. Three trials compared metformin with dipeptidyl peptidase-4 inhibitors (one trial each with saxagliptin, sitagliptin, vildagliptin with altogether 1977 participants). There was no substantial difference between the interventions for all-cause mortality, SAE, CVM, NFMI and NFS (very low-certainty evidence for all outcomes). One trial compared metformin with a glucagon-like peptide-1 analogue (very low-certainty evidence for all reported outcomes). There was no substantial difference between the interventions for all-cause mortality, CVM, NFMI and NFS. One or more SAEs were reported in 16/268 (6.0%) of the participants allocated to metformin compared with 35/539 (6.5%) of the participants allocated to a glucagon-like peptide-1 analogue. HRQoL or ESRD were not reported. One trial compared metformin with meglitinide and two trials compared metformin with no intervention. No deaths or SAEs occurred (very low-certainty evidence) no other patient-important outcomes were reported. No trial compared metformin with placebo or a behaviour changing interventions. Four ongoing trials with 5824 participants are likely to report one or more of our outcomes of interest and are estimated to be completed between 2018 and 2024. Furthermore, 24 trials with 2369 participants are awaiting assessment.

Authors' conclusions: There is no clear evidence whether metformin monotherapy compared with no intervention, behaviour changing interventions or other glucose-lowering drugs influences patient-important outcomes.

Trial registration: ClinicalTrials.gov NCT00679939 NCT00279045 NCT00327015 NCT00099866 NCT00138567 NCT01126580 NCT00103857 NCT00035568 NCT03010683 NCT00373178 NCT00396851 NCT01001962 NCT01779362 NCT02853630 NCT03982381.

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Conflict of interest statement

Filip Gnesin (FG): none known.

Lise Katrine Aronsen Kähler (LK): none known.

Anne Cathrine Thuesen (AT): has previously been employed by a subsidiary company of Novo Nordisk.

Sten Madsbad (SM): Advisory Boards: Novartis Pharma, Novo Nordisk, Merck Sharp & Dome, Sanofi‐Aventis, AstraZeneca, Johnson & Johnson, Astra‐Zeneca, Boehringer‐Ingelheim, E. Lilly, Intarcia Therapeutics, Bristol‐Meyer Squibb. Fee for lectures: Novo Nordisk, Merck, Sharp & Dome, Astra‐Zeneca, Sanofi‐Aventis, Novartis Pharma, E. Lilly, Bristol‐Meyer Squibb, Boeringer‐Ingelheim, E.Lilly. Grants for research: Novo Nordisk.

Bianca Hemmingsen (BH): none known.

Figures

1
1
Trial flow diagram.
2
2
'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included trials (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 trial ((blank cells indicate that the particular outcome was not measured in some trials)
1.1
1.1. Analysis
Comparison 1: Metformin vs no intervention, Outcome 1: Glycaemic control: HbA1c
1.2
1.2. Analysis
Comparison 1: Metformin vs no intervention, Outcome 2: Glycaemic control: HbA1c (subgroup duration of the intervention)
2.1
2.1. Analysis
Comparison 2: Metformin vs sulphonylurea, Outcome 1: Severe hypoglycaemia
2.2
2.2. Analysis
Comparison 2: Metformin vs sulphonylurea, Outcome 2: Severe hypoglycaemia (Subgroup: duration of intervention
2.3
2.3. Analysis
Comparison 2: Metformin vs sulphonylurea, Outcome 3: Anthropometric measures: BMI
2.4
2.4. Analysis
Comparison 2: Metformin vs sulphonylurea, Outcome 4: Anthropometric measures: body weight
2.5
2.5. Analysis
Comparison 2: Metformin vs sulphonylurea, Outcome 5: Anthropometric measures: body weight (duration of intervention)
2.6
2.6. Analysis
Comparison 2: Metformin vs sulphonylurea, Outcome 6: Glycaemic control: FPG
2.7
2.7. Analysis
Comparison 2: Metformin vs sulphonylurea, Outcome 7: Glycaemic control: FPG (Subgroup: duration of the intervention)
2.8
2.8. Analysis
Comparison 2: Metformin vs sulphonylurea, Outcome 8: Glycaemic control: HbA1c
2.9
2.9. Analysis
Comparison 2: Metformin vs sulphonylurea, Outcome 9: Glycaemic control: HbA1c (Subgroup: duration of the intervention)
2.10
2.10. Analysis
Comparison 2: Metformin vs sulphonylurea, Outcome 10: Intervention failure
2.11
2.11. Analysis
Comparison 2: Metformin vs sulphonylurea, Outcome 11: Intervention failure (Subgroup: duration of the intervention
3.1
3.1. Analysis
Comparison 3: Metformin vs thiazolidinedione, Outcome 1: All‐cause mortality
3.2
3.2. Analysis
Comparison 3: Metformin vs thiazolidinedione, Outcome 2: All‐cause mortality (Subgroup: duration of the intervention)
3.3
3.3. Analysis
Comparison 3: Metformin vs thiazolidinedione, Outcome 3: Serious adverse events
3.4
3.4. Analysis
Comparison 3: Metformin vs thiazolidinedione, Outcome 4: Serious adverse event (Subgroup: duration of the intervention)s
3.5
3.5. Analysis
Comparison 3: Metformin vs thiazolidinedione, Outcome 5: Cardiovascular mortality
3.6
3.6. Analysis
Comparison 3: Metformin vs thiazolidinedione, Outcome 6: Cardiovascular mortality Subgroup: duration of the intervention)
3.7
3.7. Analysis
Comparison 3: Metformin vs thiazolidinedione, Outcome 7: Anthropometric measures: BMI
3.8
3.8. Analysis
Comparison 3: Metformin vs thiazolidinedione, Outcome 8: Anthropometric measures: body weight
3.9
3.9. Analysis
Comparison 3: Metformin vs thiazolidinedione, Outcome 9: Glycaemic control: FPG
3.10
3.10. Analysis
Comparison 3: Metformin vs thiazolidinedione, Outcome 10: Glycaemic control: FPG (Subgroup: duration of the intervention)
3.11
3.11. Analysis
Comparison 3: Metformin vs thiazolidinedione, Outcome 11: Glycaemic control: FPG (Subgroup: selection bias)
3.12
3.12. Analysis
Comparison 3: Metformin vs thiazolidinedione, Outcome 12: Glycaemic control: HbA1c
3.13
3.13. Analysis
Comparison 3: Metformin vs thiazolidinedione, Outcome 13: Glycaemic control: HbA1c (Subgroup: duration of the intervention)
3.14
3.14. Analysis
Comparison 3: Metformin vs thiazolidinedione, Outcome 14: Glycaemic control: HbA1c (Subgroup: selection bias)
3.15
3.15. Analysis
Comparison 3: Metformin vs thiazolidinedione, Outcome 15: Intervention failure
3.16
3.16. Analysis
Comparison 3: Metformin vs thiazolidinedione, Outcome 16: Intervention failure (Subgroup: duration of the intervention
3.17
3.17. Analysis
Comparison 3: Metformin vs thiazolidinedione, Outcome 17: Intervention failure (Subgroup: selection bias)
4.1
4.1. Analysis
Comparison 4: Metformin vs dipeptidyl peptidase‐4 inhibitor, Outcome 1: All‐cause mortality
4.2
4.2. Analysis
Comparison 4: Metformin vs dipeptidyl peptidase‐4 inhibitor, Outcome 2: Serious adverse events
4.3
4.3. Analysis
Comparison 4: Metformin vs dipeptidyl peptidase‐4 inhibitor, Outcome 3: Anthropometric measures: body weight
4.4
4.4. Analysis
Comparison 4: Metformin vs dipeptidyl peptidase‐4 inhibitor, Outcome 4: Glycaemic control: FPG
4.5
4.5. Analysis
Comparison 4: Metformin vs dipeptidyl peptidase‐4 inhibitor, Outcome 5: Glycaemic control: HbA1c
See this image and copyright information in PMC

Update of

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Ceriello 2005 {published data only}
    1. Ceriello A, Johns D, Widel M, Eckland DJ, Gilmore KJ, Tan MH. Comparison of effect of pioglitazone with metformin or sulfonylurea (monotherapy and combination therapy) on postload glycemia and composite insulin sensitivity index during an oral glucose tolerance test in patients with type 2 diabetes. Diabetes Care 2005;28(2):266-72. - PubMed
Chanson 2014 {published data only}
    1. Chanson P, Cordier JF, Pariente A. Initial treatment of type 2 diabetes: metformin also for the Chinese! Revue du Praticien 2014;64(4):470. - PubMed
Chen 2016 {published data only}
    1. Chen W, Liu X, Ye S. Effects of metformin on blood and urine pro-inflammatory mediators in patients with type 2 diabetes. Journal of Inflammation 2016;13:34. - PMC - PubMed
Cheng 2017 {published data only}
    1. Cheng JW, Badreldin HA, Patel DK, Bhatt SH. Antidiabetic agents and cardiovascular outcomes in patients with heart diseases. Current Medical Research and Opinion 2017;33(6):985-92. - PubMed
ChiCTR‐IOR‐16009296 {published data only}
    1. ChiCTR-IOR-16009296. The effect of Jinlida granule on glycemic excursion and metabonomics in type 2 diabetic patients. www.chictr.org.cn/showprojen.aspx?proj=15637 (first registered 29 September 2016).
ChiCTR‐IPR‐16008578 {published data only}
    1. ChiCTR-IPR-16008578. Analysis of curative effect of liraglutide monotherapy, metformin monotherapy and liraglutide plus metformin dual therapy in patients with type 2 diabetes mellitus complicated with coronary artery disease. www.chictr.org.cn/showprojen.aspx?proj=14453 (first registered 1 January 2016).
ChiCTR‐IPR‐17010825 {published data only}
    1. ChiCTR-IPR-17010825. GLP-1 receptor agonists improvement of constitution in overweight and obese patients with T2DM. www.chictr.org.cn/showprojen.aspx?proj=17806 (first registered 9 March 2017).
ChiCTR‐IPR‐17011120 {published data only}
    1. ChiCTR-IPR-17011120. Evaluation of the clinical effect of saxagliptin on type 2 diabetes mellitus by diabetes simulation technology. www.chictr.org.cn/showprojen.aspx?proj=16990 (first registered 12 April 2017).
ChiCTR‐TRC‐08000231 {published data only}
    1. ChiCTR-TRC-08000231. Study on the mechanism of glucobay in chinese newly diagnosed type 2 diabetic patient. www.chictr.org.cn/showprojen.aspx?proj=9296 (first registered 10 December 2008).
ChiCTR‐TRC‐11001613 {published data only}
    1. ChiCTR-TRC-11001613. The efficacy of metformin in patients with diabetes and chronic heart failure. http://www.chictr.org.cn/hvshowproject.aspx?id=1427 (date of first registration not reported).
ChiCTR‐TRC‐11001808 {published data only}
    1. ChiCTR-TRC-11001808. The effect of metformin and glycosidase inhibitors on islet beta and alpha cells function in obese or overweight subjects with type 2 diabetes. www.chictr.org.cn/hvshowproject.aspx?id=1906 (date of first registration not reported).
ChiCTR‐TRC‐12002320 {published data only}
    1. ChiCTR-TRC-12002320. Fructus mume pill in the treatment of type 2 diabetes: a randomised controlled pilot trial. www.chictr.org.cn/hvshowproject.aspx?id=3049 (date of first registration not reported).
ChiCTR‐TRC‐12002505 {published data only}
    1. ChiCTR-TRC-12002505. Study of the relationship between blood glucose fluctuation and metformin: a random-controlled study. www.chictr.org.cn/hvshowproject.aspx?id=3572 (date of first registration not reported).
ChiCTR‐TRC‐13003368 {published data only}
    1. ChiCTR-TRC-13003368. Multi-center, randomized and controlled trial of sancai powder for the treatment of type 2 diabetes mellitus. www.chictr.org.cn/hvshowproject.aspx?id=6206 (date of first registration not reported).
ChiCTR‐TRC‐14004660 {published data only}
    1. ChiCTR-TRC-14004660. Comparison of efficacy of liraglutide, metformin and gliclazide MR on hepatic lipid content in patients with type 2 diabetes (T2DM) and non-alcoholic fatty liver (NAFLD). www.chictr.org.cn/showprojen.aspx?proj=4913 (first registered 21 September 2014).
Clarke 1968 {published data only}
    1. Clarke BF, Duncan LJ. Comparison of chlorpropamide and metformin treatment on weight and blood-glucose response of uncontrolled obese diabetics. Lancet 1968;291(7534):123-6. - PubMed
Clarke 1977 {published data only}
    1. Clarke BF, Campbell IW. Comparison of metformin and chlorpropamide in non-obese, maturity-onset diabetics uncontrolled by diet. BMJ 1977;2(6102):1576-8. - PMC - PubMed
Clarke 2001 {published data only}
    1. Clarke P, Gray A, Adler A, Stevens R, Raikou M, Cull C, et al, on behalf of the UKPDS group. Cost-effectiveness analysis of intensive blood-glucose control with metformin in overweight patients with type II diabetes (UKPDS No. 51). Diabetologia 2001;44(3):298-304. - PubMed
Coleman 2015 {published data only}
    1. Coleman RL, Holman RR. Reductions in hemoglobin and packed cell volume over 3 years in ukpds patients with newly diagnosed type 2 diabetes. Diabetes 2015;64:A440.
Cooper 2015 {published data only}
    1. Cooper CL, Hind D, Duncan R, Walters S, Lartey A, Lee E, et al. A rapid review indicated higher recruitment rates in treatment trials than in prevention trials. Journal of Clinical Epidemiology 2015;68(3):347-54. - PubMed
Cryer 2005 {published data only}
    1. Cryer DR, Nicholas SP, Henry DH, Mills DJ, Stadel BV. Comparative outcomes study of metformin intervention versus conventional approach: The COSMIC approach study. Diabetes Care 2005;28(3):539-43. - PubMed
Dalzell 1986 {published data only}
    1. Dalzell GW, Hadden DR, Atkinson AB, Kennedy L, Weaver JA. A randomized trial of tolbutamide and metformin for persistent severe hypoglycaemia in non insulin dependent diabetes mellitus (NIDDM). In: Irish Endocrine Society. Vol. 155. 1986:341-2.
EUCTR2005‐001027‐11‐GB {published data only}
    1. EUCTR2005-001027-11-GB. Diabetes in the very elderly trial - DIVET. www.clinicaltrialsregister.eu/ctr-search/trial/2005-001027-11/GB (first registered 9 May 2005).
EUCTR2007‐006665‐33‐DK {published data only}
    1. EUCTR2007-006665-33-DK. [Effekten af metformin versus placebo samt tre insulinanalog regimer med variende postprandial glukose regulation på carotis intima media tykkelse hos patienter med type 2 diabetes – et randomiseret multicenter forsøg ‘CIMT’ - Forsøget - CIMT]. www.clinicaltrialsregister.eu/ctr-search/trial/2007-006665-33/DK (first registered 3 January 2008).
EUCTR2012‐001390‐88‐CZ {published data only}
    1. EUCTR2012-001390-88-CZ. Cardioprotective and metabolic effects of metformin in patients with heart failure and diabetes. www.clinicaltrialsregister.eu/ctr-search/trial/2012-001390-88/CZ (first registered 28 March 2012).
Ferrannini 2013 {published data only}
    1. EUCTR2008-007938-21-FI. A 78 week open label extension to trials assessing the safety and efficacy of BI 10773 as monotherapy or in combination with metformin in type 2 diabetic patients. www.clinicaltrialsregister.eu/ctr-search/trial/2008-007938-21/EE (first registered 7 March 2009).
    1. Ferrannini E, Berk A, Hantel S, Pinnetti S, Hach T, Woerle HJ, et al. Long-term safety and efficacy of empagliflozin, sitagliptin, and metformin: an active-controlled, parallel-group, randomized, 78-week open-label extension study in patients with type 2 diabetes. Diabetes Care 2013;36(12):4015-21. - PMC - PubMed
    1. NCT00881530. Empagliflozin (BI 10773) in type two diabetes (T2D) patients, open label extension. clinicaltrials.gov/ct2/show/NCT00881530 (first posted 15 April 2009).
Gallo 2014 {published data only}
    1. Gallo M, Candido R, De Micheli A, Esposito K, Gentile S, Ceriello A, Associazione Medici Diabetologi. Acarbose vs metformin for new-onset type 2 diabetes. Lancet Diabetes & Endocrinology 2014;2(2):104. - PubMed
Garcia 2014 {published data only}
    1. Garcia De La Torre N, Duran A, Del Valle L, Fuentes M, Barca I, Martin P, et al. Early management of type 2 diabetes based on an SMBG strategy: the way to diabetes regression-the St. Carlos study: a 3-year, prospective, randomized, clinic-based, interventional study with parallel groups. Acta Diabetologica 2013;50(4):607-14. - PubMed
Gu 2014 {published data only}
    1. Gu S, Shi J, Tang Z, Sawhney M, Hu H, Shi L, et al. Comparison of glucose lowering effect of metformin and acarbose in type 2 diabetes mellitus: a meta-analysis. PLOS One 2015;10(5):e0126704. - PMC - PubMed
    1. Gu S, Xu X, Shi L, Sawhney M, Hu H, Dong H. Cost minimization analysis of clinical option scenarios for metformin and acarbose in treatment of type 2 diabetes: based on direct and indirect treatment comparison results. Value in Health 2014;17(7):A745. - PubMed
Haak 2013 {published data only}
    1. Haak T, Meinicke T, Jones R, Weber S, Eynatten M, Woerle HJ. Initial combination of linagliptin and metformin in patients with type 2 diabetes: efficacy and safety in a randomised, double-blind 1-year extension study. International Journal of Clinical Practice 2013;67(12):1283-93. - PMC - PubMed
Heitmann 2016 {published data only}
    1. Heitmann E, Jung H, Schloot N, Pavo I, Forst T, Trautmann M, et al. Dulaglutide: a GLP-1 receptor agonist for once weekly treatment of type 2 diabetes [Dulaglutid: GLP-1-rezeptoragonist zur einmal wöchentlichen Therapie des typ-2-diabetes]. Diabetologie und Stoffwechsel 2016;11(6):398-417.
Hirst 2012 {published data only}
    1. Hirst JA, Farmer AJ, Roberts NW, Pluddemann A, Harrison S, Ali R, et al. A systematic review of the effect of metformin treatment on glycaemic control in diabetes patients. Diabetic Medicine 2012;28:202.
Holden 2014 {published data only}
    1. Holden SE, Currie CJ. Mortality risk with sulphonylureas compared to metformin. Diabetes, Obesity & Metabolism 2014;16(10):885-90. - PubMed
Hong 2013 {published data only}
    1. Hong J, Zhang Y, Lai S, Lv A, Su Q, Dong Y, et al. Effects of metformin versus glipizide on cardiovascular outcomes in patients with type 2 diabetes and coronary artery disease. Diabetes Care May 2013;36(5):1304-11. - PMC - PubMed
Hou 2017 {published data only}
    1. Hou YC, Hu Q, Huang J, Fang JY, Xiong H. Metformin therapy and the risk of colorectal adenoma in patients with type 2 diabetes: a meta-analysis. Oncotarget 2017;8(5):8843-53. - PMC - PubMed
Hwang 2015 {published data only}
    1. Hwang IC, Park SM, Shin D, Ahn HY, Rieken M, Shariat SF. Metformin association with lower prostate cancer recurrence in type 2 diabetes: a systematic review and meta-analysis. Asian Pacific Journal of Cancer Prevention 2015;16(2):595-600. - PubMed
Ida 2017 {published data only}
    1. Ida S, Murata K, Kaneko R. Effects of metformin treatment on blood leptin and ghrelin levels in patients with type 2 diabetes mellitus. Journal of Diabetes 2017;9(5):526-35. - PubMed
ISRCTN75451837 {published data only}
    1. ISRCTN75451837. UK Prospective Diabetes Study - post study monitoring (PSM) and cohort follow-up (CFU). www.isrctn.com/ISRCTN75451837 (first registered 17 October 2000).
JPRN‐UMIN000004367 {published data only}
    1. JPRN-UMIN000004367. The efficacy of pioglitazone in reduction of urinary albumin excretion in type 2 diabetic patients with microalbuminuria. upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000005219 (first registered 12 October 2010).
JPRN‐UMIN000005327 {published data only}
    1. JPRN-UMIN000005327. Comparisons of oral agents to standardize treatment for diabetes in Japan. upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000006064 (first registered 28 March 2011).
JPRN‐UMIN000011063 {published data only}
    1. JPRN-UMIN000011063. Study for the effects of vildagriptin in combination with metformin on vascular endothelial function and systemic metabolism in patients with type 2 diabetes -multicenter, prospective, randomized, open-label, parallel group comparison. upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000012865 (first registered 28 June 2013).
Kakorin 2016 {published data only}
    1. Kakorin SV, Iskandaryan RA, Mkrtumyan AM. Glycemia control and glucose-lowering therapy in patients with type 2 diabetes mellitus and cardiovascular disease (review of multicenter randomized trials). [Russian]. Diabetes Mellitus 2016;19(3):221-8.
Kanazawa 2009 {published data only}
    1. JPRN-UMIN000001997. Effects of pioglitazone or metformin on bone markers and bone mineral density as well as parameters of atherosclerosis in patients with type 2 diabetes. upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000002434 (first registered 22 May 2009).
    1. Kanazawa I, Yamaguchi T, Yano S, Yamamoto M, Yamauchi M, Kurioka S, et al. Baseline atherosclerosis parameter could assess the risk of bone loss during pioglitazone treatment in type 2 diabetes mellitus. Osteoporos Int 2010;21:2013-8. - PubMed
Lambadiari 2018 {published data only}
    1. Lambadiari V, Pavlidis G, Kousathana F, Varoudi M, Vlastos D, Maratou E, et al. Effects of 6-month treatment with the glucagon like peptide-1 analogue liraglutide on arterial stiffness, left ventricular myocardial deformation and oxidative stress in subjects with newly diagnosed type 2 diabetes. Cardiovascular Diabetology 2018;17(1):8. - PMC - PubMed
    1. NCT03010683. Effects of agonists of glucagon like peptide - 1 receptors (GLP-1R) on arterial stiffness, endothelial glycocalyx and coronary flow reserve in patients with coronary artery disease and patients with diabetes mellitus. clinicaltrials.gov/ct2/show/NCT03010683 (first posted 5 January 2017).
Lester 2005 {published data only}
    1. Lester JW, Fernandes AW. Pioglitazone in a subgroup of patients with type 2 diabetes meeting the criteria for metabolic syndrome. International Journal of Clinical Practice 2005;59(2):134-42. - PubMed
Liakos 2014 {published data only}
    1. Liakos A, Karagiannis T, Athanasiadou E, Sarigianni M, Mainou M, Papatheodorou K, et al. Efficacy and safety of empagliflozin for type 2 diabetes: a systematic review and meta-analysis. Diabetes, Obesity & Metabolism 2014;16(10):984-93. - PubMed
Liu 2014 {published data only}
    1. Liu Q, Li S, Quan H, Li J. Vitamin B12 status in metformin treated patients: systematic review. PLOS One 2014;9(6):e100379. - PMC - PubMed
Liu 2014a {published data only}
    1. Liu X, Xiao Q, Zhang L, Yang Q, Liu X, Xu L, et al. The long-term efficacy and safety of DPP-IV inhibitors monotherapy and in combination with metformin in 18,980 patients with type-2 diabetes mellitus--a meta-analysis. Pharmacoepidemiology and Drug Safety 2014;23(7):687-98. - PubMed
Liu 2017 {published data only}
    1. Liu F, Yan L, Wang Z, Lu Y, Chu Y, Li X, et al. Metformin therapy and risk of colorectal adenomas and colorectal cancer in type 2 diabetes mellitus patients: a systematic review and meta-analysis. Oncotarget 2017;8(9):16017-26. - PMC - PubMed
MacConell 2015 {published data only}
    1. MacConell L, Gurney K, Malloy J, Zhou M, Kolterman O. Safety and tolerability of exenatide once weekly in patients with type 2 diabetes: an integrated analysis of 4,328 patients. Diabetes, Metabolic Syndrome and Obesity 2015;8:241-53. - PMC - PubMed
Mei 2014 {published data only}
    1. Mei ZB, Zhang ZJ, Liu CY, Liu Y, Cui A, Liang ZL, et al. Survival benefits of metformin for colorectal cancer patients with diabetes: a systematic review and meta-analysis. PLOS One 2014;9(3):e91818. - PMC - PubMed
MET/D/86/BERGI 1994 {unpublished data only}
    1. FDA. Submission for metformin. www.accessdata.fda.gov/drugsatfda_docs/nda/pre96/020357Orig1s000rev.pdf (last accessed 25 September 2019).
Mo 2019 {published data only}
    1. Mo D, Liu S, Ma H, Tian H, Yu H, Zhang X, et al. Effects of acarbose and metformin on the inflammatory state in newly diagnosed type 2 diabetes patients: a one-year randomized clinical study. Drug Design, Development and Therapy 2019;13:2769-76. - PMC - PubMed
Monami 2014 {published data only}
    1. Monami M, Dicembrini I, Kundisova L, Zannoni S, Nreu B, Mannucci E. A meta-analysis of the hypoglycaemic risk in randomized controlled trials with sulphonylureas in patients with type 2 diabetes. Diabetes, Obesity & Metabolism 2014;16(9):833-40. - PubMed
NCT00214591 {published data only}
    1. NCT00214591. GALLANT 5 tesaglitazar versus metformin. clinicaltrials.gov/ct2/show/NCT00214591 (first posted 22 September 2005).
NCT00282945 {published data only}
    1. NCT00282945. Beta cell function tests over time in patients with T2DM randomized to metformin or rosiglitazone. clinicaltrials.gov/ct2/show/NCT00282945 (first posted 27 January 2008).
NCT00308373 {published data only}
    1. NCT00308373. Effects of fats on blood glucose in people with and without type 2 diabetes mellitus. clinicaltrials.gov/ct2/show/NCT00308373 (first posted 29 March 2006).
NCT00373178 {published data only}
    1. NCT00373178. Metabolic effects of treatment in patients with recently diagnosed type 2 diabetes. clinicaltrials.gov/ct2/show/NCT00373178 (first posted 7 September 2006).
NCT00396851 {published data only}
    1. NCT00396851. Double blind randomized trial to compare gurmar (Gymnema Sylvestre) with metformin in type 2 diabetes. clinicaltrials.gov/ct2/show/NCT00396851 (first posted 8 November 2006).
NCT00399204 {published data only}
    1. NCT00399204. Comparison of cardiovascular outcomes of pioglitazone and metformin in type 2 diabetes patients. clinicaltrials.gov/ct2/show/NCT00399204 (first posted 14 November 2006).
NCT00481663 {published data only}
    1. NCT00481663. A study of different doses of sitagliptin (MK-0431) in participants with type 2 diabetes mellitus (MK-0431-014). clinicaltrials.gov/ct2/show/NCT00481663 (first posted 15 October 2017).
NCT00543361 {published data only}
    1. NCT00543361. Study MK0767 and metformin in type 2 diabetic patients (0767-020). clinicaltrials.gov/ct2/show/NCT00543361 (first posted 15 October 2007).
NCT00754689 {published data only}
    1. NCT00754689. Study of rimonabant/metformin combinations to investigate diabetes (blood sugar) control in patients with type 2 diabetes. clinicaltrials.gov/ct2/show/NCT00754689 (first posted 4 October 2012).
NCT01087567 {published data only}
    1. NCT01087567. INSPIRE Diabetes Study: basal bolus insulin as primary treatment of type 2 diabetes. clinicaltrials.gov/ct2/show/NCT01087567 (first posted 16 March 2010).
NCT01099618 {published data only}
    1. NCT01099618. Ketosis-prone diabetes mellitus (KPDM): metformin versus sitagliptin treatment. clinicaltrials.gov/ct2/show/NCT01099618 (first posted 7 April 2010).
NCT01217073 {published data only}
    1. NCT01217073. A dose-range finding study in participants with type 2 diabetes (MK-3102-006). clinicaltrials.gov/ct2/show/NCT01217073 (first posted 8 October 2010).
NCT01700075 {published data only}
    1. NCT01700075. Physical and chemical study of atherosclerosis mechanisms. clinicaltrials.gov/ct2/show/NCT01700075 (first posted 4 October 2012).
NCT01958671 {published data only}
    1. NCT01958671. A study of the efficacy and safety of ertugliflozin monotherapy in the treatment of participants with type 2 diabetes mellitus and inadequate glycemic control despite diet and exercise (MK-8835-003, VERTIS MONO). clinicaltrials.gov/ct2/show/NCT01958671 (first posted 9 October 2013).
NCT02234440 {published data only}
    1. NCT02234440. Effect of metformin on disease progression in patients with cryptogenic cirrhosis (NASH-related cirrhosis) with diabetes or impaired glucose tolerance or insulin resistance. clinicaltrials.gov/ct2/show/NCT02234440 (first posted 9 September 2014).
NCT02409238 {published data only}
    1. NCT02409238. Insulin resistance and mild cognitive impairment (IRMCI) study. clinicaltrials.gov/ct2/show/NCT02409238 (first posted 6 April 2015).
NCT02587741 {published data only}
    1. NCT02587741. Comparison of diabetes retinopathy among type 2 diabetic patients treated with different regimens. clinicaltrials.gov/ct2/show/NCT02587741 (first posted 27 October 2015).
NCT02694289 {published data only}
    1. NCT02694289. Effects of metformin in heart failure patients. clinicaltrials.gov/ct2/show/NCT02694289 (first posted 29 February 2016).
Palmer 2016 {published data only}
    1. Palmer SC, Mavridis D, Nicolucci A, Johnson DW, Tonelli M, Craig JC, et al. Comparison of clinical outcomes and adverse events associated with glucose-lowering drugs in patients with type 2 diabetes: a meta-analysis. JAMA 2016;316(3):313-24. - PubMed
Polzer 2015 {published data only}
    1. Polzer PK, Ni X, Dos Reis F. Prevalence and characteristics of low serum testosterone levels in men with type 2 diabetes mellitus naive to injectable therapy. Journal of Sexual Medicine 2015;12:13.
Prescrire International 2014 {published data only}
    1. Anonymous. Type 2 diabetes and metformin. First choice for monotherapy: weak evidence of efficacy but well-known and acceptable adverse effects. Prescrire International 2014;23(154):269-72. - PubMed
Prescrire International 2015 {published data only}
    1. Anonymous. Type 2 diabetes: which glucose-lowering drug, if any, after metformin? Prescrire International 2015;24(160):135. - PubMed
Rokkas 2016 {published data only}
    1. Rokkas T, Portincasa P. Colon neoplasia in patients with type 2 diabetes on metformin: a meta-analysis. European Journal of Internal Medicine 2016;33(-):60-6. - PubMed
Rosenstock 2013 {published data only}
    1. Rosenstock J, Gross J L, Aguilar-Salinas C, Hissa M, Berglind N, Ravichandran S, et al. Long-term 4-year safety of saxagliptin in drug-naive and metformin-treated patients with type 2 diabetes. Diabetic Medicine 2013;30(12):1472-6. - PubMed
Rutter 2010 {published data only}
    1. Rutter MK, Nesto RW. The BARI 2D study: a randomised trial of therapies for type 2 diabetes and coronary artery disease. Diabetes & Vascular Disease Research 2010;7(1):69-72. - PubMed
Salpeter 2003 {published data only}
    1. Salpeter S, Greyber E, Pasternak G, Salpeter E. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database of Systematic Reviews 2003, Issue 2. Art. No: CD002967. [DOI: 10.1002/14651858.CD002967.pub3] - DOI - PubMed
Sazia 2015 {published data only}
    1. Sazia S, Singh S, Shankar P, Nath R, Sachan AK, Dixit RK. Effect of metformin Vs. Eclipta alba on blood glucose level in diabetic patients. International Journal of Pharmacognosy and Phytochemical Research 2015;7(2):215-8.
Scheen 2016 {published data only}
    1. Scheen AJ. Dulaglutide (Trulicity), a new once-weekly agonist of glucagon-like peptide-1 receptors for type 2 diabetes. Revue Medicale de Liege 2016;71(3):154-60. - PubMed
Scheen 2017 {published data only}
    1. Scheen AJ. Dulaglutide for the treatment of type 2 diabetes. Expert Opinion on Biological Therapy 2017;17(4):485-96. - PubMed
The Medical Letter 2015 {published data only}
    1. Anonymous. Empagliflozin/metformin (Synjardy) for type 2 diabetes. Medical Letter on Drugs and Therapeutics 2015;57(1484):172-4. - PubMed
UKPDS 24 {published data only}
    1. UK Prospective Diabetes Study Group. United Kingdom Prospective Diabetes Study 24: a 6-year, randomized, controlled trial comparing sulfonylurea, insulin, and metformin therapy in patients with newly diagnosed type 2 diabetes that could not be controlled with diet therapy. United Kingdom Prospective Diabetes Study Group. Annals of Internal Medicine 1998;128(3):165-75. [PMID: ] - PubMed
UKPDS 72 {published data only}
    1. Clarke PM, Gray AM, Briggs A, Stevens RJ, Matthews SR, Holman RR, on behalf of the UP Prospective Diabetes Study (UKPDS). Cost-utility analyses of intensive blood glucose and tight blood pressure control in type 2 diabetes (UKPDS 72). Diabetologia 2005;48(5):868-77. - PubMed
Unnikrishnan 2016 {published data only}
    1. Unnikrishnan R, Mohan V. Metformin revisited. Diabetes Technology & Therapeutics 2016;18(3):113-4. - PubMed
Yang 2014 {published data only}
    1. Yang W, Liu J, Shan Z, Tian H, Zhou Z, Ji Q, et al. Acarbose compared with metformin as initial therapy in patients with newly diagnosed type 2 diabetes: an open-label, non-inferiority randomised trial. Lancet Diabetes & Endocrinology 2014;2(1):46-55. [DOI: 10.1016/S2213-8587(13)70021-4] - DOI - PubMed
    1. Yang W, Liu J, Shan Z, Tian H, Zhou Z, Ji Q, et al. Corrections. Lancet Diabetes and Endocrinology 2014;2(2):e4. [DOI: 10.1016/S2213-8587(13)70169-4] - DOI - PubMed
Zhang 2015 {published data only}
    1. Zhang J W, Sun Q. Metformin may improve the prognosis of patients with pancreatic cancer. Asian Pacific Journal of Cancer Prevention 2015;16(9):3937-40. - PubMed
Zhang 2016 {published data only}
    1. Zhang L, Zhang M, Zhang Y, Tong N. Efficacy and safety of dulaglutide in patients with type 2 diabetes: a meta-analysis and systematic review. Scientific Reports 2016;6:18904. - PMC - PubMed
Zhou 2017 {published data only}
    1. Zhou PT, Li B, Liu FR, Zhang MC, Wang Q, Li YY, et al. Metformin is associated with survival benefit in pancreatic cancer patients with diabetes: a systematic review and meta-analysis. Oncotarget 2017;8(15):25242-50. - PMC - PubMed
Zintzaras 2014 {published data only}
    1. Zintzaras E, Miligkos M, Ziakas P, Balk E M, Mademtzoglou D, Doxani C, et al. Assessment of the relative effectiveness and tolerability of treatments of type 2 diabetes mellitus: a network meta-analysis. Clinical Therapeutics 2014;36(10):1443-53.e9. - PubMed

References to studies awaiting assessment

ChiCTR1800018825 {unpublished data only}
    1. ChiCTR1800018825. Clinical efficacy and mechanism of Empagliflozin in the treatment of patients with new-onset type 2 diabetes and risk factor for atherosclerotic cardiovascular disease. http://www.chictr.org.cn/showproj.aspx?proj=30989 (first registered 11 October 2018).
ChiCTR1900021632 {unpublished data only}
    1. ChiCTR1900021632. Comparison of acarbose and metformin therapy on the efficacy of HbA1C, islet function and body weight in newly diagnosed elderly type 2 diabetic patients. http://www.chictr.org.cn/showproj.aspx?proj=35291 (first registered 2 March 2019).
ChiCTR‐IOR‐16007720 {unpublished data only}
    1. ChiCTR-IOR-16007720. Effects of oral hypoglycemic drugs on gut microbiota in patients with type 2 diabetes. www.chictr.org.cn/showprojen.aspx?proj=13034 (first registered 5 January 2016).
ChiCTR‐IOR‐17011477 {unpublished data only}
    1. ChiCTR-IOR-17011477. Effect of saxagliptin and Metformin on bone metabolism in patients with newly diagnosed type 2 diabetes. www.chictr.org.cn/showproj.aspx?proj=18373 (first registered 24 May 2017).
ChiCTR‐IPR‐16009666 {unpublished data only}
    1. ChiCTR-IPR-16009666. Effects of liraglutide on inducing long-term clinical remission in newly diagnosed type 2 diabetes after intensive treatment. www.chictr.org.cn/showprojen.aspx?proj=15885 (first registered 27 October 2016).
ChiCTR‐IPR‐17010811 {unpublished data only}
    1. ChiCTR-IPR-17010811. Determination for efficacy of aspirin with metformin in the treatment of type 2 diabetic patients with hyperglucagonemia. www.chictr.org.cn/hvshowproject.aspx?id=11165 (date of first registration not reported).
ChiCTR‐TCH‐10001013 {published data only}
    1. ChiCTR-TCH-10001013. Pioglitazone and/or metformin as treatment for cognitive impairments and risk of stroke in patients with type 2 diabetes. www.chictr.org.cn/showproj.aspx?proj=8525 (first registered 9 September 2010).
ChiCTR‐TRC‐11001331 {published data only}
    1. ChiCTR-TRC-11001331. Effects of DPP-4 inhibitor and /or metformin combination on type 2 diabetes. www.chictr.org.cn/hvshowproject.aspx?id=759 (date of first registration not reported).
EUCTR2005‐000461‐18‐GB {published data only}
    1. EUCTR2005-000461-18-GB. Study to determine if the cardiovascular risk indices in type 2 diabetes are similar for polycystic ovarian syndrome, and whether they may be modified by therapy - cardiovascular risk in PCOS as compared to type 2 diabetes. www.clinicaltrialsregister.eu/ctr-search/trial/2005-000461-18/GB#B (first registered 24 February 2005).
JPRN‐UMIN000000689 {published data only}
    1. JPRN-UMIN000000689. Effect of pioglitazone on renal function amelioration by measurement of cystatine C levels in the type 2 diabetic patients. upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000000828 (first registered 31 March 2008).
JPRN‐UMIN000000771 {published data only}
    1. JPRN-UMIN000000771. Multifactorial effects of insulin sensitizers. upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000000926 (first registered 16 July 2007).
JPRN‐UMIN000001085 {published data only}
    1. JPRN-UMIN000001085. Effect of insulin sensitizer treatment on carotid arterial elasticity. upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000000874 (first registered 20 March 2008).
JPRN‐UMIN000001891 {published data only}
    1. JPRN-UMIN000001891. Comparative efficacy of pioglitazone and metformin in glucose variability in type 2 diabetes. upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000002278 (first registered 15 April 2009).
JPRN‐UMIN000002099 {published data only}
    1. JPRN-UMIN000002099. Effects of metformin and pioglitazone on serum pentosidine levels in type 2 diabetes mellitus. upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000002561 (first registered 21 June 2009).
JPRN‐UMIN000003563 {published data only}
    1. JPRN-UMIN000003563. Intervention of type 2 DM with sitagliptin or high dose metformin trial in Kobe:INSIGHT-KOBE. upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000004321 (first registered 6 May 2010).
JPRN‐UMIN000006504 {published data only}
    1. JPRN-UMIN000006504. Assessment of beneficial effects on left ventricular hypertrophy and diastolic function by metformin in hypertensive patients with type2 DM. upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000007716 (first registered 7 October 2011).
JPRN‐UMIN000010624 {published data only}
    1. JPRN-UMIN000010624. Vildagliptin and biguanide on postprandial blood glucose and vascular endothelial function in type 2 diabetic patients with coronary artery disease. upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000012423 (first registered 1 May 2013).
JPRN‐UMIN000014775 {published data only}
    1. JPRN-UMIN000014775. Effect of Ipragliflozin, a new oral hypoglycemic agent, on body composition in patients with diabetes. upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000017180 (first registered 15 August 2014).
Ma 2015 {published data only}
    1. Ma L, Li J, Zhang L, Yang R, Zhao W, Li R. The effect of metformin and pioglitazone on glucagon of patients with diabetes and metabolic syndrome. [Chinese]. Chinese Journal of Clinical Nutrition 2015;23(2):65-72.
NCT01303055 {unpublished data only}
    1. NCT01303055. Effects of alogliptin on pancreatic beta cell function. clinicaltrials.gov/ct2/show/NCT01303055 (first posted 24 February 2011).
NCT01935804 {unpublished data only}
    1. NCT01935804. Effect of pioglitazone versus metformin on bone health in postmenopausal women with type 2 diabetes. clinicaltrials.gov/ct2/show/NCT01935804 (first posted 5 September 2013).
Wang 2005 {published data only}
    1. Wang HB, Deng XC, Feng YT. Clinical observation of diabetes II treatment with acarbose and metformin. Modern Hospital 2005;5(12):42–3.
Wu 2014 {published data only}
    1. Wu S, Li X, Zhang H. Effects of metformin on endothelial function in type 2 diabetes. Experimental and Therapeutic Medicine 2014;7(5):1349-53. - PMC - PubMed
Zhang 2009 {published data only}
    1. Zhang XY, Du J, Jia Y, Bai R, Yang Y, Ba Y, et al. Primary preventive effect of metformin upon atherosclerosis in patients with type 2 diabetes mellitus. National Medical Journal of China 2009;89(30):2134-7. - PubMed

References to ongoing studies

NCT01001962 {unpublished data only}
    1. NCT01001962. Double blind placebo study of JARDIANCE® (Empagliflozin) in prehypertensives type II diabetics. clinicaltrials.gov/ct2/show/NCT01001962 (first posted 27 October 2009).
NCT01779362 {published data only}
    1. Hannon TS, Kahn SE, Utzschneider KM, Buchanan TA, Nadeau KJ, Zeitler PS, et al. Review of methods for measuring β-cell function: design considerations from the restoring insulin secretion (RISE) Consortium. Diabetes, Obesity & Metabolism January 2018;20(1):14-24. [DOI: 10.1111/dom.13005] - DOI - PMC - PubMed
    1. NCT01779362. RISE adult medication study. clinicaltrials.gov/ct2/show/NCT01779362 (first posted 30 January 2013).
    1. RISE Consortium. Metabolic contrasts between youth and adults with impaired glucose tolerance or recently diagnosed type 2 diabetes: I. Observations using the hyperglycemic clamp. Diabetes Care August 2018;41(8):1696-706. [DOI: 10.2337/dc18-0244] - DOI - PMC - PubMed
    1. RISE Consortium. Metabolic contrasts between youth and adults with impaired glucose tolerance or recently diagnosed type 2 diabetes: II. Observations using the oral glucose tolerance test. Diabetes Care August 2018;41(8):1707-16. [DOI: 10.2337/dc18-0243] - DOI - PMC - PubMed
    1. RISE Consortium. Restoring Insulin Secretion (RISE): design of studies of β-cell preservation in prediabetes and early type 2 diabetes across the life span. Diabetes Care 2014;37(3):780-8. [DOI: 10.2337/dc13-1879] - DOI - PMC - PubMed
NCT02853630 {unpublished data only}
    1. CTRI/2014/01/004301. A clinical trial to study the effects of two drugs, vildagliptin and metformin in patients with type 2 diabetes mellitus. www.ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=7817 (first registered 9 January 2014).
    1. NCT02853630. A clinical trial to study the effects of two drugs, vildagliptin and metformin in patients with type 2 diabetes mellitus. clinicaltrials.gov/ct2/show/NCT02853630 (first posted 3 August 2016).
NCT03982381 {unpublished data only}
    1. NCT03982381. A multicenter, register-based, randomized, controlled trial comparing dapagliflozin with metformin treatment in early stage type 2 diabetes patients by assessing mortality and macro- and microvascular complications. https://clinicaltrials.gov/ct2/show/NCT03982381 (first posted 11 June 2019).

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References to other published versions of this review

Gnesin 2018
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