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. 2019 Apr 18;4(4):CD012368.
doi: 10.1002/14651858.CD012368.pub2.

Metformin and second- or third-generation sulphonylurea combination therapy for adults with type 2 diabetes mellitus

Kasper S Madsen  1 , Pernille Kähler, Lise Katrine Aronsen Kähler, Sten Madsbad, Filip Gnesin, Maria-Inti Metzendorf, Bernd Richter, Bianca Hemmingsen
Affiliations

Metformin and second- or third-generation sulphonylurea combination therapy for adults with type 2 diabetes mellitus

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

Abstract

Background: The number of people with type 2 diabetes mellitus (T2DM) is increasing worldwide. The combination of metformin and sulphonylurea (M+S) is a widely used treatment. Whether M+S shows better or worse effects in comparison with other antidiabetic medications for people with T2DM is still controversial.

Objectives: To assess the effects of metformin and sulphonylurea (second- or third-generation) combination therapy for adults with type 2 diabetes mellitus.

Search methods: We updated the search of a recent systematic review from the Agency for Healthcare Research and Quality (AHRQ). The updated search included CENTRAL, MEDLINE, Embase, ClinicalTrials.gov and WHO ICTRP. The date of the last search was March 2018. We searched manufacturers' websites and reference lists of included trials, systematic reviews, meta-analyses and health technology assessment reports. We asked investigators of the included trials for information about additional trials.

Selection criteria: We included randomised controlled trials (RCTs) randomising participants 18 years old or more with T2DM to M+S compared with metformin plus another glucose-lowering intervention or metformin monotherapy with a treatment duration of 52 weeks or more.

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 the GRADE instrument.

Main results: We included 32 RCTs randomising 28,746 people. Treatment duration ranged between one to four years. We judged none of these trials as low risk of bias for all 'Risk of bias' domains. Most important events per person were all-cause and cardiovascular mortality, serious adverse events (SAE), non-fatal stroke (NFS), non-fatal myocardial infarction (MI) and microvascular complications. Most important comparisons were as follows:Five trials compared M+S (N = 1194) with metformin plus a glucagon-like peptide 1 analogue (N = 1675): all-cause mortality was 11/1057 (1%) versus 11/1537 (0.7%), risk ratio (RR) 1.15 (95% confidence interval (CI) 0.49 to 2.67); 3 trials; 2594 participants; low-certainty evidence; cardiovascular mortality 1/307 (0.3%) versus 1/302 (0.3%), low-certainty evidence; serious adverse events (SAE) 128/1057 (12.1%) versus 194/1537 (12.6%), RR 0.90 (95% CI 0.73 to 1.11); 3 trials; 2594 participants; very low-certainty evidence; non-fatal myocardial infarction (MI) 2/549 (0.4%) versus 6/1026 (0.6%), RR 0.57 (95% CI 0.12 to 2.82); 2 trials; 1575 participants; very low-certainty evidence.Nine trials compared M+S (N = 5414) with metformin plus a dipeptidyl-peptidase 4 inhibitor (N = 6346): all-cause mortality was 33/5387 (0.6%) versus 26/6307 (0.4%), RR 1.32 (95% CI 0.76 to 2.28); 9 trials; 11,694 participants; low-certainty evidence; cardiovascular mortality 11/2989 (0.4%) versus 9/3885 (0.2%), RR 1.54 (95% CI 0.63 to 3.79); 6 trials; 6874 participants; low-certainty evidence; SAE 735/5387 (13.6%) versus 779/6307 (12.4%), RR 1.07 (95% CI 0.97 to 1.18); 9 trials; 11,694 participants; very low-certainty evidence; NFS 14/2098 (0.7%) versus 8/2995 (0.3%), RR 2.21 (95% CI 0.74 to 6.58); 4 trials; 5093 participants; very low-certainty evidence; non-fatal MI 15/2989 (0.5%) versus 13/3885 (0.3%), RR 1.45 (95% CI 0.69 to 3.07); 6 trials; 6874 participants; very low-certainty evidence; one trial in 64 participants reported no microvascular complications were observed (very low-certainty evidence).Eleven trials compared M+S (N = 3626) with metformin plus a thiazolidinedione (N = 3685): all-cause mortality was 123/3300 (3.7%) versus 114/3354 (3.4%), RR 1.09 (95% CI 0.85 to 1.40); 6 trials; 6654 participants; low-certainty evidence; cardiovascular mortality 37/2946 (1.3%) versus 41/2994 (1.4%), RR 0.78 (95% CI 0.36 to 1.67); 4 trials; 5940 participants; low-certainty evidence; SAE 666/3300 (20.2%) versus 671/3354 (20%), RR 1.01 (95% CI 0.93 to 1.11); 6 trials; 6654 participants; very low-certainty evidence; NFS 20/1540 (1.3%) versus 16/1583 (1%), RR 1.29 (95% CI 0.67 to 2.47); P = 0.45; 2 trials; 3123 participants; very low-certainty evidence; non-fatal MI 25/1841 (1.4%) versus 21/1877 (1.1%), RR 1.21 (95% CI 0.68 to 2.14); P = 0.51; 3 trials; 3718 participants; very low-certainty evidence; three trials (3123 participants) reported no microvascular complications (very low-certainty evidence).Three trials compared M+S (N = 462) with metformin plus a glinide (N = 476): one person died in each intervention group (3 trials; 874 participants; low-certainty evidence); no cardiovascular mortality (2 trials; 446 participants; low-certainty evidence); SAE 34/424 (8%) versus 27/450 (6%), RR 1.68 (95% CI 0.54 to 5.21); P = 0.37; 3 trials; 874 participants; low-certainty evidence; no NFS (1 trial; 233 participants; very low-certainty evidence); non-fatal MI 2/215 (0.9%) participants in the M+S group; 2 trials; 446 participants; low-certainty evidence; no microvascular complications (1 trial; 233 participants; low-certainty evidence).Four trials compared M+S (N = 2109) with metformin plus a sodium-glucose co-transporter 2 inhibitor (N = 3032): all-cause mortality was 13/2107 (0.6%) versus 19/3027 (0.6%), RR 0.96 (95% CI 0.44 to 2.09); 4 trials; 5134 participants; very low-certainty evidence; cardiovascular mortality 4/1327 (0.3%) versus 6/2262 (0.3%), RR 1.22 (95% CI 0.33 to 4.41); 3 trials; 3589 participants; very low-certainty evidence; SAE 315/2107 (15.5%) versus 375/3027 (12.4%), RR 1.02 (95% CI 0.76 to 1.37); 4 trials; 5134 participants; very low-certainty evidence; NFS 3/919 (0.3%) versus 7/1856 (0.4%), RR 0.87 (95% CI 0.22 to 3.34); 2 trials; 2775 participants; very low-certainty evidence; non-fatal MI 7/890 (0.8%) versus 8/1374 (0.6%), RR 1.43 (95% CI 0.49 to 4.18; 2 trials); 2264 participants; very low-certainty evidence; amputation of lower extremity 1/437 (0.2%) versus 1/888 (0.1%); very low-certainty evidence.Trials reported more hypoglycaemic episodes with M+S combination compared to all other metformin-antidiabetic agent combinations. Results for M+S versus metformin monotherapy were inconclusive. There were no RCTs comparing M+S with metformin plus insulin. We identified nine ongoing trials and two trials are awaiting assessment. Together these trials will include approximately 16,631 participants.

Authors' conclusions: There is inconclusive evidence whether M+S combination therapy compared with metformin plus another glucose-lowering intervention results in benefit or harm for most patient-important outcomes (mortality, SAEs, macrovascular and microvascular complications) with the exception of hypoglycaemia (more harm for M+S combination). No RCT reported on health-related quality of life.

PubMed Disclaimer

Conflict of interest statement

KM: had an inadvertent conflict of interest because he had owned a small number of shares with Novo Nordisk A/S before registering the title. Without prompting KM amended the situation by selling the shares, so he no longer has a direct financial benefit as first author. Cochrane Metabolic and Endocrine Disorders contacted the Cochrane Funding Arbiter for guidance, who agreed to allow the review to proceed with KM as a first author, providing that this issue was clearly explained in the declarations of interest. KM received a scholarship from Michaelsen Fonden.

PK: equities in Novo Nordisk A/S.

LK: none known.

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

FG: none known.

MIM: none known.

BR: none known.

BH: none known.

Figures

1
1
Trial flow diagram
 AHRQ: Agency for Healthcare Research and Quality; DPP4‐I: dipeptidyl‐peptidase 4 inhibitor; GLP1‐A: glucagon‐like peptide 1 analogue; M+S: metformin + sulphonylurea; SGLT2‐I: sodium‐glucose co‐transporter 2 inhibitor
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)
See this image and copyright information in PMC

Update of

  • doi: 10.1002/14651858.CD012368

References

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    1. GSK Study ID BRL‐049653/231. BRL‐049653/231‐RECORD: rosiglitazone evaluated for cardiac outcomes and regulation of glycaemia in diabetes. gsk‐studyregister.com/study/7631 (accessed 1 April 2017).
    1. Home PD, Jones NP, Pocock SJ, Beck‐Nielsen H, Gomis R, Hanefeld M, et al. Rosiglitazone RECORD study: glucose control outcomes at 18 months. Diabetic Medicine 2007;24(6):626‐34. - PMC - PubMed
    1. Home PD, Kahn SE, Jones NP, Noronha D, Beck‐Nielsen H, Viberti G. Experience of malignancies with oral glucose‐lowering drugs in the randomised controlled ADOPT (A Diabetes Outcome Progression Trial) and RECORD (Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycaemia in Diabetes) clinical trials. Diabetologia 2010;53(9):1838‐45. - PMC - PubMed
    1. Home PD, Pocock SJ, Beck‐Nielsen H, Curtis PS, Gomis R, Hanefeld M, et al. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open‐label trial. Lancet 2009;373(9681):2125‐35. - PubMed
    1. Home PD, Pocock SJ, Beck‐Nielsen H, Gomis R, Hanefeld M, Dargie H, et al. Rosiglitazone evaluated for cardiac outcomes and regulation of glycaemia in diabetes (RECORD): study design and protocol. Diabetologia 2005;48(9):1726‐35. - PubMed
Leiter 2015 {published data only}
    1. Blonde L, Stenlof K, Fung A, Xie J, Canovatchel W, Meininger G. Effects of canagliflozin on body weight and body composition in patients with type 2 diabetes over 104 weeks. Postgraduate Medicine 2016;128(4):371‐80. - PubMed
    1. Cefalu WT, Leiter LA, Yoon K‐H, Arias P, Niskanen L, Xie J, et al. Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA‐SU): 52 week results from a randomised, double‐blind, phase 3 non‐inferiority trial. Lancet 2013;382(9896):941‐50. - PubMed
    1. Desai M, Merton K, Davies MJ, Vijapurkar U, Balis D. Canagliflozin provides greater improvement in risk factors of metabolic syndrome (MetS) versus glimepiride in patients with type 2 diabetes and MetS on background metformin. Diabetologia 2016;59:S340‐1.
    1. Heerspink HJ, Desai M, Jardine M, Balis D, Meininger G, Perkovic V. Canagliflozin slows progression of renal function decline independently of glycemic effects. Journal of the American Society of Nephrology : JASN 2017;28(1):368‐75. - PMC - PubMed
    1. John M, Cerdas S, Violante R, Deerochanawong C, Hassanein M, Slee A, et al. Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus living in hot climates. International Journal of Clinical Practice 2016;70(9):775‐85. - PMC - PubMed
Maffioli 2013 {published data only}
    1. Maffioli P, Fogari E, D’Angelo A, Perrone T, Derosa G. Ultrasonography modifications of visceral and subcutaneous adipose tissue after pioglitazone or glibenclamide therapy combined with rosuvastatin in type 2 diabetic patients not well controlled by metformin. European Journal of Gastroenterology & Hepatology 2013;25(9):1113‐22. - PubMed
Matthews 2010 {published data only}
    1. Ahren B, Foley JE, Dejager S, Akacha M, Shao Q, Heimann G, et al. Higher risk of hypoglycemia with glimepiride versus vildagliptin in patients with type 2 diabetes is not driven by high doses of glimepiride: divergent patient susceptibilities?. Diabetes Therapy 2014;5(2):459‐69. - PMC - PubMed
    1. Ahren B, Foley JE, Ferrannini E, Matthews DR, Zinman B, Dejager S, et al. Changes in prandial glucagon levels after a 2‐year treatment with vildagliptin or glimepiride in patients with type 2 diabetes inadequately controlled with metformin monotherapy. Diabetes Care 2010;33(4):730‐2. - PMC - PubMed
    1. Ahren B, Mathieu C, Bader G, Schweizer A, Foley JE. Efficacy of vildagliptin versus sulfonylureas as add‐on therapy to metformin: comparison of results from randomised controlled and observational studies. Diabetologia 2014;57(7):1304‐7. - PubMed
    1. Bader G, Geransar P, Schweizer A. Vildagliptin more effectively achieves a composite endpoint of HbA1c < 7 % without hypoglycaemia and weight gain compared with glimepiride after 2 years of treatment. Diabetes Research and Clinical Practice 2013;100(3):e78‐81. - PubMed
    1. EudraCT 2004‐004559‐21. A multicenter, randomized, double‐blind, active controlled study to compare the long‐term effect (up to 5 years) of treatment with LAF237 50 mg bid to glimepiride up to 6 mg daily as add‐on therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy. www.clinicaltrialsregister.eu/ctr‐search/trial/2004‐004559‐21/IT (accessed 11 March 2017).
Nauck 2013 {published data only}
    1. Blonde L, Russell‐Jones D. The safety and efficacy of liraglutide with or without oral antidiabetic drug therapy in type 2 diabetes: an overview of the LEAD 1‐5 studies. Diabetes, Obesity & Metabolism 2009;11 Suppl 3:26‐34. - PubMed
    1. Bode BW, Brett J, Falahati A, Pratley RE. Comparison of the efficacy and tolerability profile of liraglutide, a once‐daily human GLP‐1 analog, in patients with type 2 diabetes ≥65 and <65 years of age: a pooled analysis from phase III studies. American Journal of Geriatric Pharmacotherapy 2011;9(6):423‐33. - PubMed
    1. Buse JB, Garber A, Rosenstock J, Schmidt WE, Brett JH, Videbaek N, et al. Liraglutide treatment is associated with a low frequency and magnitude of antibody formation with no apparent impact on glycemic response or increased frequency of adverse events: results from the Liraglutide Effect and Action in Diabetes (LEAD) trials. Journal of Clinical Endocrinology and Metabolism 2011;96(6):1695‐702. - PubMed
    1. Davies MJ, Chubb BD, Smith IC, Valentine WJ. Cost‐utility analysis of liraglutide compared with sulphonylurea or sitagliptin, all as add‐on to metformin monotherapy in type 2 diabetes mellitus. Diabetic Medicine 2012;29(3):313‐20. - PMC - PubMed
    1. Fonseca VA, Devries JH, Henry RR, Donsmark M, Thomsen HF, Plutzky J. Reductions in systolic blood pressure with liraglutide in patients with type 2 diabetes: insights from a patient‐level pooled analysis of six randomized clinical trials. Journal of Diabetes and its Complications 2014;28(3):399‐405. - PMC - PubMed
NCT00367055 {published data only}
    1. GSK Study ID 101765. Rosiglitazone‐metformin combination versus metformin‐sulfonylurea combination on beta‐cell function in type 2 diabetes. gsk‐studyregister.com/study/2645 (accessed 28 June 2017).
    1. NCT00367055. Rosiglitazone‐metformin combination versus metformin‐sulfonylurea combination on beta‐cell function in type 2 diabetes. clinicaltrials.gov/ct2/show/study/NCT00367055 (accessed 28 June 2017).
Petrica 2009 {published data only}
    1. Petrica L, Petrica M, Vlad A, Jianu CD, Gluhovschi G, Ianculescu C, et al. Nephro‐ and neuroprotective effects of rosiglitazone versus glimepiride in normoalbuminuric patients with type 2 diabetes mellitus: a randomized controlled trial. Wiener Klinische Wochenschrift 2009;121(23‐24):765‐75. - PubMed
Petrica 2011 {published data only}
    1. Petrica L, Vlad A, Petrica M, Jianu CD, Gluhovschi G, Gadalean F, et al. Pioglitazone delays proximal tubule dysfunction and improves cerebral vessel endothelial dysfunction in normoalbuminuric people with type 2 diabetes mellitus. Diabetes Research and Clinical Practice 2011;94(1):22‐32. - PubMed
Ridderstråle 2014 {published data only}
    1. Brice R, Spencer W, Asaro‐Harris A, Zeller C, Hach T, Salsali A, et al. Analysis of empagliflozin vs glimepiride by Quality and Outcomes Framework targets: post hoc analysis of a head‐to‐head study. Diabetic Medicine 2015;32:95‐6.
    1. Chirila C, Zheng Q, Davenport E, Kaschinski D, Pfarr E, Hach T, et al. Treatment satisfaction in type 2 diabetes patients taking empagliflozin compared with patients taking glimepiride. Quality of Life Research 2016;25(5):1199‐207. - PMC - PubMed
    1. Khunti K, Bingham‐Gardiner P, Hassan SW, Zeller C, Naderali E, Salsali A, et al. Efficacy and safety of empagliflozin compared with glimepiride in South Asian patients with type 2 diabetes in a head‐to‐head study. Diabetic Medicine 2015;32:96.
    1. Kohler S, Kaspers S, Salsali A, Zeller C, Woerle HJ. Effect of empagliflozin (EMPA) on bone fractures in patients with type 2 diabetes (T2DM). Diabetologia 2016;59:S26.
    1. NCT01167881. Efficacy and safety of empagliflozin (BI 10773) with metformin in patients with type 2 diabetes. clinicaltrials.gov/ct2/show/NCT01167881 (accessed 18 July 2017).
Ristic 2007 {published data only}
    1. CDJN608A2308. A multicenter, double‐blind, randomized, parallel‐group study to evaluate the efficacy and safety of nateglinide and gliclazide in combination with metformin, in type 2 diabetes patients inadequately controlled on maximally tolerated doses of metformin alone. www.novctrd.com/CtrdWeb/displaypdf.nov?trialresultid=1852 (accessed 17 July 2017).
    1. CDJN608A2308. Six month extension to a multicenter, double‐blind, randomized, parallel‐group study to evaluate the efficacy and safety of nateglinide and gliclazide in combination with metformin, in type 2 diabetes patients inadequately controlled on maximally tolerated doses of metformin alone. www.novctrd.com/CtrdWeb/displaypdf.nov?trialresultid=1850 (accessed 17 July 2017).
    1. Ristic S, Collober‐Maugeais C, Cressier F, Tang P, Pecher E. Nateglinide or gliclazide in combination with metformin for treatment of patients with type 2 diabetes mellitus inadequately controlled on maximum doses of metformin alone: 1‐year trial results. Diabetes, Obesity & Metabolism 2007;9(4):506‐11. - PubMed
    1. Ristic S, Collober‐Maugeais C, Pecher E, Cressier F. Comparison of nateglinide and gliclazide in combination with metformin, for treatment of patients with type 2 diabetes mellitus inadequately controlled on maximum doses of metformin alone. Diabetic Medicine 2006;23(7):757‐62. - PMC - PubMed
Schernthaner 2015 {published data only}
    1. NCT01006603. Saxagliptin compared to glimepiride in elderly type 2 diabetes patients, with inadequate glycemic control on metformin (GENERATION). clinicaltrials.gov/ct2/show/NCT01006603 (accessed 2 August 2017).
    1. Perl S, Cook W, Wei C, Ohman P, Hirshberg B. Effects of glimepiride versus saxagliptin on beta‐cell function and hypoglycemia: a post hoc analysis in older patients with type 2 diabetes inadequately controlled with metformin. Clinical Therapeutics 2016;38(12):2578‐88. - PubMed
    1. Perl S, Cook W, Wei C, Ohman P, Hirshberg B. Low beta‐cell function at baseline is associated with higher rates of hypoglycemia in response to treatment with glimepiride in elderly patients with type 2 diabetes inadequately controlled with metformin. Diabetes 2015;64:A319.
    1. Schernthaner G, Durán‐Garcia S, Hanefeld M, Langslet G, Niskanen L, Östgren CJ, et al. Efficacy and tolerability of saxagliptin compared with glimepiride in elderly patients with type 2 diabetes: a randomized, controlled study (GENERATION). Diabetes, Obesity & Metabolism 2015;17(7):630‐8. - PubMed
Seck 2010 {published data only}
    1. Krobot KJ, Ferrante SA, Davies MJ, Seck T, Meininger GE, Williams‐Herman D, et al. Lower risk of hypoglycemia with sitagliptin compared to glipizide when either is added to metformin therapy: a pre‐specified analysis adjusting for the most recently measured HbA(1c) value. Current Medical Research and Opinion 2012;28(8):1281‐7. - PubMed
    1. NCT00094770. An investigational drug study in patients with type 2 diabetes mellitus (0431‐024). clinicaltrials.gov/ct2/show/study/NCT00094770 (accessed 14 July 2017).
    1. Nauck MA, Meininger G, Sheng D, Terranella L, Stein PP. Efficacy and safety of the dipeptidyl peptidase‐4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double‐blind, non‐inferiority trial. Diabetes, Obesity & Metabolism 2007;9(2):194‐205. - PubMed
    1. Ommen ES, Xu L, O'Neill EA, Goldstein BJ, Kaufman KD, Engel SS. Comparison of treatment with sitagliptin or sulfonylurea in patients with type 2 diabetes mellitus and mild renal impairment: a post hoc analysis of clinical trials. Diabetes Therapy 2015;6(1):29‐40. - PMC - PubMed
    1. Seck T, Nauck M, Sheng D, Sunga S, Davies MJ, Stein PP, et al. Safety and efficacy of treatment with sitagliptin or glipizide in patients with type 2 diabetes inadequately controlled on metformin: a 2‐year study. International Journal of Clinical Practice 2010;64(5):562‐76. - PubMed
Vaccaro 2017 {published data only}
    1. Chilelli. Long‐term effect of pioglitazone vs glimepiride on lipoprotein oxidation in patients with type 2 diabetes: a prospective randomized study. Manuscript draft (accessed 19 March 2018). - PubMed
    1. NCT00700856. Thiazolidinediones or sulphonylureas and cardiovascular accidents intervention trial (TOSCA IT). clinicaltrials.gov/ct2/show/NCT00700856 (accessed 9 October 2017).
    1. Vaccaro O, Masulli M, Bonora E, Prato S, Giorda CB, Maggioni AP, et al. Addition of either pioglitazone or a sulfonylurea in type 2 diabetic patients inadequately controlled with metformin alone: impact on cardiovascular events. A randomized controlled trial. Nutrition, Metabolism, and Cardiovascular Diseases 2012;22(11):997‐1006. - PubMed
    1. Vaccaro O, Masulli M, Bonora E, Prato S, Nicolucci A, Rivellese AA, et al. The TOSCA.IT trial: a study designed to evaluate the effect of pioglitazone versus sulfonylureas on cardiovascular disease in type 2 diabetes. Diabetes Care 2012; Vol. 35, issue 12:e82. [PUBMED: 23173143] - PMC - PubMed
    1. Vaccaro O, Masulli M, Nicolucci A, Bonora E, Prato S, Maggioni AP, et al. Effects on the incidence of cardiovascular events of the addition of pioglitazone versus sulfonylureas in patients with type 2 diabetes inadequately controlled with metformin (TOSCA.IT): a randomised, multicentre trial. Lancet Diabetes Endocrinology 2017;5(11):887‐97. - PubMed

References to studies excluded from this review

ACCORD 2007 {published data only}
    1. Buse JB, Bigger JT, Byington RP, Cooper LS, Cushman WC, Friedewald WT, et al. Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial: design and methods. American Journal of Cardiology 2007;99(12a):21i‐33i. - PubMed
    1. NCT00000620. Action to control cardiovascular risk in diabetes (ACCORD). clinicaltrials.gov/ct2/show/NCT00000620 (accessed 3 March 2018).
Alsharidah 2018 {published data only}
    1. Alsharidah M, Algeffari M, Abdel‐Moneim AH, Lutfi MF, Alshelowi H. Effect of combined gliclazide/metformin treatment on oxidative stress, lipid profile, and hepatorenal functions in type 2 diabetic patients. Saudi Pharmaceutical Journal 2018;26(1):1‐6. - PMC - PubMed
Araki 2015 {published data only}
    1. Araki E, Tanizawa Y, Tanaka Y, Taniguchi A, Koiwai K, Kim G, et al. Long‐term treatment with empagliflozin as add‐on to oral antidiabetes therapy in Japanese patients with type 2 diabetes mellitus. Diabetes, Obesity & Metabolism 2015;17(7):665‐74. - PubMed
    1. NCT01368081. Empagliflozin (BI 10773) comprehensive add‐on study in Japanese subjects with type 2 diabetes mellitus. clinicaltrials.gov/ct2/show/NCT01368081 (accessed 3 March 2018).
Bermudez‐Pirela 2007 {published data only}
    1. Bermudez‐Pirela VJ, Cano C, Medina MT, Souki A, Lemus MA, Leal EM, et al. Metformin plus low‐dose glimeperide significantly improves Homeostasis Model Assessment for insulin resistance (HOMA(IR)) and beta‐cell function (HOMA(beta‐cell)) without hyperinsulinemia in patients with type 2 diabetes mellitus. American Journal of Therapeutics 2007;14(2):194‐202. - PubMed
Berndt‐Zipfel 2013 {published data only}
    1. Berndt‐Zipfel C, Michelson G, Dworak M, Mitry M, Loffler A, Pfutzner A, et al. Vildagliptin in addition to metformin improves retinal blood flow and erythrocyte deformability in patients with type 2 diabetes mellitus ‐ results from an exploratory study. Cardiovascular Diabetology 2013;12:59. - PMC - PubMed
    1. NCT01565096. Effect of adding vildagliptin on beta cell function and cardiovascular risk markers in patients with moderate metabolic control during metformin monotherapy. clinicaltrials.gov/ct2/show/NCT01565096 (accessed 3 March 2018).
Bode 2013 {published data only}
    1. Bode B, Stenlof K, Sullivan D, Fung A, Usiskin K. Efficacy and safety of canagliflozin treatment in older subjects with type 2 diabetes mellitus: a randomized trial. Hospital Practice (1995) 2013;41(2):72‐84. - PubMed
    1. NCT01106651. A safety and efficacy study of canagliflozin in older patients (55 to 80 years of age) with type 2 diabetes mellitus. clinicaltrials.gov/ct2/show/NCT01106651 (accessed 3 March 2018).
Bruce 2006 {published data only}
    1. Bruce S, Park JS, Fiedorek FT, Howlett HC. Beta‐cell response to metformin‐glibenclamide combination tablets (Glucovance) in patients with type 2 diabetes. International Journal of Clinical Practice 2006;60(7):783‐90. - PubMed
    1. NCT00035568. A research study to assess the mechanism by which glucovance, metformin, and glyburide work to control glucose levels In patients with type 2 diabetes. clinicaltrials.gov/ct2/show/NCT00035568 (accessed 3 March 2018).
Charbonnel 2006 {published data only}
    1. Charbonnel B, Karasik A, Liu J, Wu M, Meininger G. Efficacy and safety of the dipeptidyl peptidase‐4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care 2006;29(12):2638‐43. - PubMed
    1. NCT00086515. Metformin add‐on study in patients with type 2 diabetes mellitus (0431‐020)(COMPLETED). clinicaltrials.gov/ct2/show/NCT00086515 (accessed 3 March 2018).
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
CTRI/2013/02/003417 {published data only}
    1. CTRI/2013/02/003417. Restudy of the PURSE HIS Population for the prevalence of risk factors causing blood vessel damage to heart muscle, brain tissue or peripheral tissue and to give advice on diet, exercise and if necessary small dose of drug to prevent conversion of pre‐diabetes to diabetes. www.ctri.nic.in/Clinicaltrials/pdf_generate.php?trialid=6005&EncHid=... (accessed 9 March 2018).
Derosa 2015 {published data only}
    1. Derosa G, D'Angelo A, Maffioli P. Sitagliptin in type 2 diabetes mellitus: efficacy after five years of therapy. Pharmacological Research 2015;100:127‐34. - PubMed
EUCTR2004‐002549‐11‐FI {published data only}
    1. Eudract: 2004‐002549‐11. An open, multi‐centre and long‐term extension study to evaluate the safety and tolerability of oral tesaglitazar therapy in patients with type 2 diabetes ‐ GALLEX 1. www.clinicaltrialsregister.eu/ctr‐search/search?query=eudract_number:200... (accessed 3 March 2018).
EUCTR2006‐001240‐30‐BE {published data only}
    1. Eudract: 2006‐001240‐30. Long term double blind comparison of gliclazide MR (30 to 120 mg daily per os) and rosiglitazone (4 to 8 mg daily per os) given in combination with metformin in type 2 diabetic patients. A 2‐year international, multicentre, randomised, double‐blind, parallel‐group study followed by a 2‐year double blind extension ‐ ENDORSE. www.clinicaltrialsregister.eu/ctr‐search/search?query=eudract_number:200... (accessed 3 March 2018).
EUCTR2009‐014727‐23‐IT {published data only}
    1. Eudract: 2009‐014727‐23. Multi‐center, randomized, open‐label, two‐parallel arm, intervention trial comparing DPP‐IV inhibitor vildagliptin with glibenclamide (glyburide) in achieving and maintaining good blood glucose control in type 2 diabetic patients in treatment failure with metformin alone ‐ Long‐term clinical effectiveness of DPP‐IV inhibitors. www.clinicaltrialsregister.eu/ctr‐search/search?query=eudract_number:200... (accessed 3 March 2018).
EUCTR2009‐017524‐36‐HU {published data only}
    1. Eudract: 2009‐017524‐36. A phase III, multicenter, double‐blind, active‐controlled, 52‐week extension study to evaluate the safety and efficacy of dutogliptin in patients with type 2 diabetes mellitus receiving background treatment with glimepiride alone or in combination with metformin or with pioglitazone alone. www.clinicaltrialsregister.eu/ctr‐search/search?query=eudract_number:200... (accessed 3 March 2018).
Gregorio 1989 {published data only}
    1. Gregorio F, Ambrosi F, Angelici F, Cristallini S, Dini FL, Vespasiani G, et al. Body mass index, blood lactate and therapeutic effectiveness of metformin in type II diabetes mellitus. Medicina (Florence, Italy) 1989;9(2):200‐4. - PubMed
Haering 2015 {published data only}
    1. Haering HU, Merker L, Christiansen AV, Roux F, Salsali A, Kim G, et al. Empagliflozin as add‐on to metformin plus sulphonylurea in patients with type 2 diabetes. Diabetes Research and Clinical Practice 2015;110(1):82‐90. - PubMed
    1. NCT01289990. Safety and efficacy of empagliflozin (BI 10773) and sitagliptin versus placebo over 76 weeks in patients with type 2 diabetes. clinicaltrials.gov/ct2/show/NCT01289990 (accessed 3 March 2018).
    1. Roden M, Merker L, Christiansen AV, Roux F, Salsali A, Kim G, et al. Safety, tolerability and effects on cardiometabolic risk factors of empagliflozin monotherapy in drug‐naive patients with type 2 diabetes: a double‐blind extension of a phase III randomized controlled trial. Cardiovascular Diabetology 2015;14:154. - PMC - PubMed
Hassanein 2014 {published data only}
    1. Hassanein M, Abdallah K, Schweizer A. A double‐blind, randomized trial, including frequent patient‐physician contacts and Ramadan‐focused advice, assessing vildagliptin and gliclazide in patients with type 2 diabetes fasting during Ramadan: the STEADFAST study. Vascular Health and Risk Management 2014;10:319‐26. - PMC - PubMed
Heller 2018 {published data only}
    1. Heller SR, Pratley RE, Sinclair A, Festa A, Kiljanski J, Brusko CS, et al. Glycaemic outcomes of an individualized treatment approach for older vulnerable patients: a randomized, controlled study in type 2 diabetes mellitus (IMPERIUM). Diabetes, Obesity & Metabolism 2018;20(1):148‐56. - PMC - PubMed
    1. NCT02072096. A comparison of two treatment strategies in older participants with type 2 diabetes mellitus (T2DM) (IMPERIUM). clinicaltrials.gov/ct2/show/NCT02072096 (accessed 3 March 2018).
Hermann 2001 {published data only}
    1. Hermann LS, Kalen J, Katzman P, Lager I, Nilsson A, Norrhamn O, et al. Long‐term glycaemic improvement after addition of metformin to insulin in insulin‐treated obese type 2 diabetes patients. Diabetes, Obesity & Metabolism 2001;3(6):428‐34. - PubMed
Inagaki 2013 {published data only}
    1. Inagaki N, Watada H, Murai M, Kagimura T, Gong Y, Patel S, et al. Linagliptin provides effective, well‐tolerated add‐on therapy to pre‐existing oral antidiabetic therapy over 1 year in Japanese patients with type 2 diabetes. Diabetes, Obesity & Metabolism 2013;15(9):833‐43. - PubMed
    1. NCT01204294. Comprehensive add on study in Japan. clinicaltrials.gov/ct2/show/NCT01204294 (accessed 3 March 2018).
Iqbal 2014 {published data only}
    1. Iqbal N, Allen E, Ohman P. Long‐term safety and tolerability of saxagliptin add‐on therapy in older patients (aged >/= 65 years) with type 2 diabetes. Clinical Interventions in Aging 2014;9:1479‐87. - PMC - PubMed
ISRCTN19750520 {published data only}
    1. ISRCTN19750520. Reduced urine albumin excretion in community based collaborative care in elderly Chinese with type 2 diabetes. www.isrctn.com/ISRCTN19750520 (accessed 9 March 2018).
ISRCTN41840459 {published data only}
    1. ISRCTN41840459. A study to assess the release profiles from fixed combination tablets (gliclazide MR/metformin). www.isrctn.com/ISRCTN41840459 (accessed 3 March 2018).
Jackson 1987 {published data only}
    1. Jackson RA, Hawa MI, Jaspan JB, Sim BM, Disilvio L, Featherbe D, et al. Mechanism of metformin action in non‐insulin‐dependent diabetes. Diabetes 1987;36(5):632‐40. - PubMed
Javaid 2007 {published data only}
    1. Javaid A, Hasan R, Zaib A, Mansoor S. A comparative study of the effects of hypoglycemic agents on serum electrolytes in the diabetic patients. Pakistan Journal of Pharmaceutical Sciences 2007;20(1):67‐71. - PubMed
Johansen 2007 {published data only}
    1. Johansen OE, Gullestad L, Blaasaas KG, Orvik E, Birkeland KI. Effects of structured hospital‐based care compared with standard care for type 2 diabetes‐The Asker and Baerum Cardiovascular Diabetes Study, a randomized trial. Diabetic Medicine 2007;24(9):1019‐27. - PubMed
    1. NCT00133718. A 2 year trial of patients with type 2 diabetes focusing on cardiovascular diagnostics and metabolic control. clinicaltrials.gov/ct2/show/NCT00133718?term=NCT00133718&rank=1 (accessed 3 March 2018).
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 (accessed 3 March 2018).
Kala 2017 {published data only}
    1. Kala 2017. A comparative study of efficacy and safety among metformin with sitagliptin, metformin with voglibose, and metformin with glimepiride in patients with type 2 diabetes mellitus. Asian Journal of Pharmaceutical and Clinical Research 2017;Vol 10(Issue 12):313‐16.
Malha 2014 {published data only}
    1. Malha LP, Taan G, Zantout MS, Azar ST. Glycemic effects of vildagliptin in patients with type 2 diabetes before, during and after the period of fasting in Ramadan. Therapeutic Advances in Endocrinology and Metabolism 2014;5(1):3‐9. - PMC - PubMed
Marre 2002 {published data only}
    1. Marre M, Howlett H, Lehert P, Allavoine T. Improved glycaemic control with metformin‐glibenclamide combined tablet therapy (Glucovance) in type 2 diabetic patients inadequately controlled on metformin. Diabetic Medicine 2002;19(8):673‐80. - PubMed
Meneghini 2010 {published data only}
    1. Meneghini LF, Traylor L, Schwartz SL. Improved glycemic control with insulin glargine versus pioglitazone as add‐on therapy to sulfonylurea or metformin in patients with uncontrolled type 2 diabetes mellitus. Endocrine Practice 2010;16(4):588‐99. - PubMed
Moon 2014 {published data only}
    1. Moon JS, Ha KS, Yoon JS, Lee HW, Lee HC, Won KC. The effect of glargine versus glimepiride on pancreatic beta‐cell function in patients with type 2 diabetes uncontrolled on metformin monotherapy: open‐label, randomized, controlled study. Acta Diabetologica 2014;51(2):277‐85. - PubMed
    1. NCT00562172. Insulin glargine (lantus) vs sulfonylurea (SU) for BETA cell function (BETA study). clinicaltrials.gov/ct2/show/NCT00562172 (accessed 3 March 2018).
Morikawa 2011 {published data only}
    1. Morikawa A, Ishizeki K, Iwashima Y, Yokoyama H, Muto E, Oshima E, et al. Pioglitazone reduces urinary albumin excretion in renin‐angiotensin system inhibitor‐treated type 2 diabetic patients with hypertension and microalbuminuria: the APRIME study. Clinical and Experimental Nephrology 2011;15(6):848‐53. - PubMed
Nauck 2006 {published data only}
    1. NCT01511172. Effect of liraglutide as add‐on to metformin compared to either liraglutide or metformin alone, or to a combination of metformin and a SU (sulphonylurea) agent in subjects with type 2 diabetes. clinicaltrials.gov/ct2/show/NCT01511172 (accessed 3 March 2018).
    1. Nauck MA, Hompesch M, Filipczak R, Le TD, Zdravkovic M, Gumprecht J. Five weeks of treatment with the GLP‐1 analogue liraglutide improves glycaemic control and lowers body weight in subjects with type 2 diabetes. Experimental and Clinical Endocrinology & Diabetes 2006;114(8):417‐23. - PubMed
NCT00269061 {published data only}
    1. NCT00269061. An exploratory MRI study in type 2 diabetic subjects: a randomized, double‐blinded, placebo‐controlled trial to evaluate the measurement of fluid volumes by MRI in the lower extremities of subjects receiving pioglitazone. clinicaltrials.gov/ct2/show/NCT00269061 (accessed 3 March 2018).
NCT00449605 {published data only}
    1. NCT00449605. A glycemic control evaluation of glimepiride versus rimonabant on top of metformin in type 2 diabetes (ALLEGRO). clinicaltrials.gov/ct2/show/NCT00449605?term=NCT00449605&rank=1 (accessed 3 March 2018).
NCT00518882 {published data only}
    1. NCT00518882. Effect of liraglutide or exenatide added to an ongoing treatment on blood glucose control in subjects with type 2 diabetes (LEAD‐6). clinicaltrials.gov/ct2/show/NCT00518882 (accessed 9 March 2018).
NCT00543751 {published data only}
    1. NCT00543751. Placebo controlled metformin and sulfonylurea combination study in patients with type 2 diabetes (0767‐025). clinicaltrials.gov/ct2/show/NCT00543751 (accessed 9 March 2018).
NCT00839527 {published data only}
    1. NCT00839527. A randomized, double‐blind, placebo and active‐controlled, parallel‐group, multicenter study to determine the efficacy and safety of albiglutide administered in combination with metformin and glimepiride compared with metformin plus glimepiride and placebo and with metformin plus glimepiride and pioglitazone in subjects with type 2 diabetes mellitus. clinicaltrials.gov/ct2/show/NCT00839527 (accessed 3 March 2018).
NCT00909597 {published data only}
    1. NCT00909597. A study of taspoglutide versus pioglitazone in patients with type 2 diabetes. clinicaltrials.gov/ct2/show/NCT00909597 (accessed 3 March 2018).
NCT00947557 {published data only}
    1. NCT00947557. A phase III, randomized, double‐blind, placebo‐controlled, multicenter study to evaluate the safety and efficacy of dutogliptin in patients with type 2 diabetes mellitus on background treatment with glimepiride with or without metformin. clinicaltrials.gov/ct2/show/NCT00947557 (accessed 9 March 2018).
NCT01087567 {published data only}
    1. NCT01087567. INSPIRE diabetes study: basal bolus insulin as primary treatment of type 2 diabetes. clinicaltrials.gov/ct2/show/NCT01087567 (accessed 9 March 2018).
NCT01106625 {published data only}
    1. NCT01106625. The CANTATA‐MSU Trial (canagliflozin treatment and trial analysis ‐ metformin and sulphonylurea). clinicaltrials.gov/ct2/show/NCT01106625 (accessed 3 March 2018).
NCT01426737 {published data only}
    1. NCT01426737. The Swiss glucose variability study. clinicaltrials.gov/ct2/show/NCT01426737 (accessed 26 June 2017).
NCT01455883 {published data only}
    1. NCT01455883. A study to evaluate ITCA 650 compared to glimepiride for the treatment of type 2 diabetes. clinicaltrials.gov/ct2/show/NCT01455883 (accessed 3 March 2018).
NCT01481116 {published data only}
    1. NCT01481116. Efficacy and safety of TAK‐875 compared to glimepiride when used with metformin in participants with type 2 diabetes. clinicaltrials.gov/ct2/show/results/NCT01481116 (accessed 26 June 2017).
NCT01593137 {published data only}
    1. NCT01593137. A long‐term, randomized, open‐labeled, parallel‐group trial to compare the effects of liraglutide and sulphonylurea (glimepiride) both in combination with metformin on clinical, endothelial and image markers of cardiovascular risk in patients with type 2 diabetes. clinicaltrials.gov/ct2/show/NCT01593137 (accessed 3 March 2018).
NCT02244164 {published data only}
    1. NCT02244164. Pathophysiological study of the increase in pancreatic volume in type 2 diabetes treatments. clinicaltrials.gov/ct2/show/NCT02244164 (accessed 3 March 2018).
NCT02462369 {published data only}
    1. NCT02462369. Saxagliptin's effects on microalbuminuria improvement in type 2 diabetic patients. clinicaltrials.gov/ct2/show/NCT02462369 (accessed 28 February 2018).
NCT02587741 {published data only}
    1. NCT02587741. Comparison of diabetes retinopathy among type 2 diabetic patients treated with different regimens (CORRECT). clinicaltrials.gov/ct2/show/NCT02587741 (accessed 3 March 2018).
NCT02616666 {published data only}
    1. NCT02616666. A pragmatic trial to evaluate the comparative effectiveness between dapagliflozin and standard of care in type 2 diabetes patients (DECIDE Study). clinicaltrials.gov/ct2/show/NCT02616666 (accessed 9 March 2018).
NCT03060980 {published data only}
    1. NCT03060980. Comparison of efficacy, safety, and tolerability of ITCA 650 to empagliflozin and glimepiride as add‐on metformin. clinicaltrials.gov/ct2/show/NCT03060980 (accessed 9 March 2018).
Onuchin 2010 {published data only}
    1. Onuchin SG, Elsukova OS, Solov'ev OV, Onuchina EL. Capabilities of hypoglycemic therapy in women with decompensated type 2 diabetes mellitus. Terapevticheskii Arkhiv 2010;82(8):34‐41. - PubMed
Rosenstock 2006 {published data only}
    1. Rosenstock J, Sugimoto D, Strange P, Stewart JA, Soltes‐Rak E, Dailey G. Triple therapy in type 2 diabetes: insulin glargine or rosiglitazone added to combination therapy of sulfonylurea plus metformin in insulin‐naive patients. Diabetes Care 2006;29(3):554‐9. - PubMed
Rosenstock 2018 {published data only}
    1. NCT02033889. A study to evaluate the efficacy and safety of ertugliflozin in participants with type 2 diabetes mellitus and inadequate glycemic control on metformin monotherapy (MK‐8835‐007). clinicaltrials.gov/ct2/show/NCT02033889 (accessed 28 February 2018).
    1. Rosenstock J, Frias J, Pall D, Charbonnel B, Pascu R, Saur D, et al. Effect of ertugliflozin on glucose control, body weight, blood pressure and bone density in type 2 diabetes mellitus inadequately controlled on metformin monotherapy (VERTIS MET). Diabetes, Obesity & Metabolism 2018;20(3):520‐9. - PubMed
Rubin 2008 {published data only}
    1. NCT00095030. Study comparing muraglitazar with glimepiride in type 2 diabetics who are not controlled with metformin alone. clinicaltrials.gov/ct2/show/NCT00095030 (accessed 26 June 2017).
    1. Rubin CJ, Ledeine JM, Fiedorek FT. Improvement of glycaemic and lipid profiles with muraglitazar plus metformin in patients with type 2 diabetes: an active‐control trial with glimepiride. Diabetes & Vascular Disease Research 2008;5(3):168‐76. - PubMed
Shankar 2017 {published data only}
    1. NCT01755156. A study to evaluate the safety, tolerability, and efficacy of the addition of omarigliptin (MK‐3102) to participants with type 2 diabetes mellitus who have inadequate glycemic control on metformin therapy (MK‐3102‐024). clinicaltrials.gov/ct2/show/NCT01755156 (accessed 28 February 2018).
    1. Shankar RR, Inzucchi SE, Scarabello V, Gantz I, Kaufman KD, Lai E, et al. A randomized clinical trial evaluating the efficacy and safety of the once‐weekly dipeptidyl peptidase‐4 inhibitor omarigliptin in patients with type 2 diabetes inadequately controlled on metformin monotherapy. Current Medical Research and Opinion 2017;33(10):1853‐60. - PubMed
Tolman 2009 {published data only}
    1. NCT00494312. Safety study of pioglitazone compared to glyburide on liver function. clinicaltrials.gov/ct2/show/NCT00494312?term=NCT00494312&rank=1 (accessed 3 March 2018).
    1. Tolman KG, Freston JW, Kupfer S, Perez A. Liver safety in patients with type 2 diabetes treated with pioglitazone: results from a 3‐year, randomized, comparator‐controlled study in the US. Drug Safety 2009;32(9):787‐800. - PubMed
UKPDS 1998 {published data only}
    1. ISRCTN75451837. UK prospective diabetes study ‐ post study monitoring (PSM) and cohort follow‐up (CFU). www.isrctn.com/ISRCTN75451837 (accessed 9 March 2018).
    1. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood‐glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352(9131):837‐53. - PubMed
Weissman 2014 {published data only}
    1. Weissman PN, Carr MC, Ye J, Cirkel DT, Stewart M, Perry C, et al. HARMONY 4: randomised clinical trial comparing once‐weekly albiglutide and insulin glargine in patients with type 2 diabetes inadequately controlled with metformin with or without sulfonylurea. Diabetologia 2014;57(12):2475‐84. - PubMed
Yki‐Järvinen 1999 {published data only}
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References to studies awaiting assessment

Müller‐Wieland 2018 {published data only}
    1. Müller‐Wieland D, Kellerer M, Cypryk K, Skripova D, Rohwedder K, Johnsson E, et al. Efficacy and safety of dapagliflozin or dapagliflozin plus saxagliptin versus glimepiride as add‐on to metformin in patients with type 2 diabetes. Diabetes, Obesity & Metabolism 2018;20(11):2598‐607. - PMC - PubMed
    1. NCT02471404. Efficacy and safety of dapagliflozin and dapagliflozin plus saxagliptin in combination with metformin in type 2 diabetes patients compared with sulphonylurea. clinicaltrials.gov/ct2/show/NCT02471404 (accessed 28 February 2018).
NCT02564926 {published data only}
    1. NCT02564926. Foxiga Korea local phase 4 study (BEYOND). clinicaltrials.gov/ct2/show/NCT02564926 (accessed 28 February 2018).

References to ongoing studies

EUCTR2011‐003335‐63‐IT {published data only}
    1. EUCTR2011‐003335‐63‐IT. Effects of liraglutide on ß‐cell function in type 2 diabetic patients with secondary failure to oral hypoglycemic agents. A randomized, controlled, parallel groups, open‐label, phase II study. apps.who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2011‐003335‐63‐IT (accessed 28 February 2018).
EUCTR2012‐000152‐34‐IT {published data only}
    1. EUCTR2012‐000152‐34‐IT. Evaluation of the effect of treatment with DPP‐4 inhibitor on endothelial function versus sulphonylurea on markers of oxidative stress and inflammation and platelet function in patients with diabetes mellitus type 2 in primary failure with metformin and with HbA1c values below 8, 5%. apps.who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2012‐000152‐34‐IT (accessed 28 February 2018).
JPRN‐UMIN000008815 {published data only}
    1. JPRN‐UMIN000008815. The effect of DPP‐4 inhibitor on pancreatic beta cell function and renal function in type 2 diabetic patients. upload.umin.ac.jp/cgi‐open‐bin/ctr_e/ctr_view.cgi?recptno=R000010271 (accessed 28 February 2018).
NCT01243424 {published data only}
    1. Marx N, Rosenstock J, Kahn SE, Zinman B, Kastelein JJ, Lachin JM, et al. Design and baseline characteristics of the cardiovascular outcome trial of linagliptin versus glimepiride in type 2 diabetes (CAROLINA(R)). Diabetes & Vascular Disease Research 2015;12(3):164‐74. - PMC - PubMed
    1. NCT01243424. CAROLINA: Cardiovascular outcome study of linagliptin versus glimepiride in patients with type 2 diabetes. clinicaltrials.gov/ct2/show/NCT01243424 (accessed 28 February 2018).
NCT01794143 {published data only}
    1. NCT01794143. A comparative effectiveness study of major glycemia‐lowering medications for treatment of type 2 diabetes (GRADE). clinicaltrials.gov/ct2/show/NCT01794143 (accessed 28 February 2018).
    1. Nathan DM, Buse JB, Kahn SE, Krause‐Steinrauf H, Larkin ME, Staten M, et al. Rationale and design of the glycemia reduction approaches in diabetes: a comparative effectiveness study (GRADE). Diabetes Care 2013;36(8):2254‐61. - PMC - PubMed
NCT02142309 {published data only}
    1. NCT02142309. Glycemic durability after metformin failure (AMAZING). clinicaltrials.gov/ct2/show/NCT02142309 (accessed 28 February 2018).
NCT02730377 {published data only}
    1. NCT02730377. Efficacy in controlling glycaemia with Victoza® (liraglutide) as add‐on to metformin vs. OAD's as add‐on to metformin after up to 104 weeks of treatment in subjects with type 2 diabetes (LIRA‐PRIME). clinicaltrials.gov/ct2/show/NCT02730377 (accessed 28 February 2018).
NCT02769481 {published data only}
    1. NCT02769481. Safety and efficacy of bexagliflozin compared to glimepiride as add‐on therapy to metformin in type 2 diabetes subjects. clinicaltrials.gov/ct2/show/NCT02769481 (accessed 28 February 2018).
NCT03332771 {published data only}
    1. NCT03332771. Efficacy and safety of sotagliflozin versus glimepiride and placebo in subjects with type 2 diabetes mellitus that are taking metformin monotherapy (SOTA‐GLIM). clinicaltrials.gov/ct2/show/NCT03332771 (accessed 9 March 2018).

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