European Journal of Clinical Pharmacology

, Volume 72, Issue 6, pp 655–663 | Cite as

Efficacy and safety of empagliflozin as add-on to metformin for type 2 diabetes: a systematic review and meta-analysis

  • Xiaoyan Zhong
  • Dan Lai
  • Yun Ye
  • Xuping Yang
  • Bin Yu
  • Yilan Huang
Review

Abstract

Purpose

To assess the efficacy and safety of empagliflozin (EMPA) as add-on to metformin (MET) in patients with type 2 diabetes mellitus (T2DM).

Methods

We searched PubMed, Embase, Medline, OVID, Cochrane Library and Web of Science. Randomized controlled trials of EMPA as add-on to MET for T2DM were included. Two investigators independently selected studies, extracted data and assessed the risk of bias. A meta-analysis was conducted by using RevMan 5.3 software and Stata 12 software.

Results

Seven trials including 4256 patients were analysed. Compared with placebo, two different doses of EMPA significantly reduced glycated haemoglobin (HbA1c) [10 mg: weighted mean difference (WMD) −0.57 %; 95 % confidence interval (CI) −0.65 to −0.49 %, P < 0.00001; 25 mg: WMD −0.65 %; 95 % CI −0.72 to −0.57 %, P < 0.00001]. Compared with active comparators (two sitagliptin, one linagliptin and one glimepiride), 10 mg of EMPA provided a similar reduction in HbA1c [WMD −0.10 %; 95 % CI −0.23 to 0.03 %, P = 0.13], while 25 mg of EMPA provided a significantly greater reduction in HbA1c [WMD −0.13 %; 95 % CI −0.20 to −0.06 %, P = 0.0005]. In addition, EMPA as add-on to MET also had a favourable effect on body weight and blood pressure. The risk of hypoglycaemia in the EMPA group was similar to the placebo group or active comparator group.

Conclusions

EMPA as add-on to MET was well tolerated and provided additional benefits beyond glucose lowering, such as weight loss and blood pressure reduction. However, high-quality trials with large samples are still needed in order to confirm their long-term safety.

Keywords

Empagliflozin Metformin Type 2 diabetes Systematic review Meta-analysis 

Supplementary material

228_2016_2010_MOESM1_ESM.doc (94 kb)
ESM 1(DOC 94 kb)

References

  1. 1.
    Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, Peters AL, Tsapas A, Wender R, Matthews DR (2015) Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 38(1):140–149CrossRefPubMedGoogle Scholar
  2. 2.
    Action to control cardiovascular risk in Diabetes Study Group, Gerstein HC, Miller ME, Byington RP, Goff DC Jr, Bigger JT, Buse JB, Cushman WC, Genuth S, Ismail-Beigi F, Grimm RH Jr, Probstfield JL, Simons-Morton DG, Friedewald WT (2008) Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 358(24):2545–2559CrossRefGoogle Scholar
  3. 3.
    European Medicines Agency (EMA). EMEA/H/C/002677. Jardiance. EPAR. Product information. Available online at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002677/WC500168592.pdf. Accessed 18 June 2014
  4. 4.
    U.S. Food and Drug Administration. Jardiance® (empagliflozin) tablets, for oral use. Initial U.S. Approval: 2014 [prescribing information]. Ingelheim, Germany: Boehringer Ingelheim; 2014. Available online at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/204629s000lbl.pdf. Accessed 8 August 2014
  5. 5.
    DeFronzo RA, Davidson JA, Del Prato S (2012) The role of the kidneys in glucose homeostasis: a new path towards normalizing glycaemia. Diabetes Obes Metab 14(1):5–14CrossRefPubMedGoogle Scholar
  6. 6.
    Brunton SA (2015) The potential role of sodium glucose co-transporter 2 inhibitors in the early treatment of type 2 diabetes mellitus. Int J Clin Pract 69(10):1071–1087. doi:10.1111/ijcp.12675 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Macha S, Mattheus M, Pinnetti S, Woerle HJ, Broedl UC (2013) Effect of empagliflozin on the steady-state pharmacokinetics of ethinylestradiol and levonorgestrel in healthy female volunteers. Clin Drug Investig 33(5):351–357CrossRefPubMedGoogle Scholar
  8. 8.
    Macha S, Mattheus M, Pinnetti S, Seman L, Woerle HJ (2012) Pharmacokinetics of empagliflozin, a sodium glucose cotransporter 2 inhibitor, and glimepiride following co-administration in healthy volunteers: a randomised, open-label, crossover study. J Diabetes Res Clin Metab. Available online at: http://www.hoajonline.com/journals/pdf/2050-0866-1-14.pdf. Accessed 4 February 2015
  9. 9.
    Merovci A, Solis-Herrera C, Daniele G, Eldor R, Fiorentino TV, Tripathy D, Xiong J, Perez Z, Norton L, Abdul-Ghani MA, DeFronzo RA (2014) Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J Clin Invest 124(2):509–514CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Ferrannini E, Muscelli E, Frascerra S, Baldi S, Mari A, Heise T, Broedl UC, Woerle HJ (2014) Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest 124(2):499–508CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Neschen S, Scheerer M, Seelig A, Huypens P, Schultheiss J, Wu M, Wurst W, Rathkolb B, Suhre K, Wolf E, Beckers J, Hrabé de Angelis M (2015) Metformin supports the antidiabetic effect of a sodium glucose cotransporter 2 inhibitor by suppressing endogenous glucose production in diabetic mice. Diabetes 64(1):284–290CrossRefPubMedGoogle Scholar
  12. 12.
    Clar C, Gill JA, Court R, Waugh N (2012) Systematic review of SGLT2 receptor inhibitors in dual or triple therapy in type 2 diabetes. BMJ Open 2(5):1–12CrossRefGoogle Scholar
  13. 13.
    Vasilakou D, Karagiannis T, Athanasiadou E, Mainou M, Liakos A, Bekiari E, Sarigianni M, Matthews DR, Tsapas A (2013) Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med 159(4):262–274CrossRefPubMedGoogle Scholar
  14. 14.
    Monami M, Nardini C, Mannucci E (2014) Efficacy and safety of sodium glucose co-transport-2 inhibitors in type 2 diabetes: a meta-analysis of randomized clinical trials. Diabetes Obes Metab 16(5):457–466CrossRefPubMedGoogle Scholar
  15. 15.
    Zhang Q, Dou J, Lu J (2014) Combinational therapy with metformin and sodium-glucose cotransporter inhibitors in management of type 2 diabetes: systematic review and meta-analyses. Diabetes Res Clin Pract 105(3):313–321CrossRefPubMedGoogle Scholar
  16. 16.
    Liakos A, Karagiannis T, Athanasiadou E, Sarigianni M, Mainou M, Papatheodorou K, Bekiari E, Tsapas A (2014) Efficacy and safety of empagliflozin for type 2 diabetes: a systematic review and meta-analysis. Diabetes Obes Metab 16(10):984–993CrossRefPubMedGoogle Scholar
  17. 17.
    Knobloch K, Yoon U, Vogt PM (2011) Preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement and publication bias. J Craniomaxillofac Surg 39(2):91–92CrossRefPubMedGoogle Scholar
  18. 18.
    Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, Savovic J, Schulz KF, Weeks L, Sterne JA; Cochrane Bias Methods Group; Cochrane Statistical Methods Group (2011) The Cochrane collaboration’s tool for assessing risk of bias in randomised trials. BMJ 343:d5928CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Guyatt GH, Oxman AD, Kunz R, Woodcock J, Brozek J, Helfand M, Alonso-Coello P, Glasziou P, Jaeschke R, Akl EA, Norris S, Vist G, Dahm P, Shukla VK, Higgins J, Falck-Ytter Y, Schünemann HJ; GRADE Working Group (2011) GRADE guidelines: 7. Rating the quality of evidence-inconsistency. J Clin Epidemiol 64(12):1294–1302CrossRefPubMedGoogle Scholar
  20. 20.
    Rosenstock J, Seman LJ, Jelaska A, Hantel S, Pinnetti S, Hach T, Woerle HJ (2013) Efficacy and safety of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, as add-on to metformin in type 2 diabetes with mild hyperglycaemia. Diabetes Obes Metab 15(12):1154–1160CrossRefPubMedGoogle Scholar
  21. 21.
    Häring HU, Merker L, Seewaldt-Becker E, Weimer M, Meinicke T, Broedl UC, Woerle HJ; EMPA-REG MET Trial Investigators (2014) Empagliflozin as add-on to metformin in patients with type 2 diabetes: a 24-week, randomized, double-blind, placebo-controlled trial. Diabetes Care 37(6):1650–1659CrossRefPubMedGoogle Scholar
  22. 22.
    Merker L, Häring HU, Christiansen AV, Roux F, Salsali A, Kim G, Meinicke T, Woerle HJ, Broedl UC; EMPA-REG EXTEND™ MET investigators (2015) Empagliflozin as add-on to metformin in people with Type 2 diabetes. Diabet Med 32(12):1555–1567. doi:10.1111/dme.12814
  23. 23.
    Ross S, Thamer C, Cescutti J, Meinicke T, Woerle HJ, Broedl UC (2015) Efficacy and safety of empagliflozin twice daily versus once daily in patients with type 2 diabetes inadequately controlled on metformin: a 16-week, randomized, placebo-controlled trial. Diabetes Obes Metab 17(7):699–702CrossRefPubMedGoogle Scholar
  24. 24.
    DeFronzo RA, Lewin A, Patel S, Liu D, Kaste R, Woerle HJ, Broedl UC (2015) Combination of empagliflozin and linagliptin as second-line therapy in subjects with type 2 diabetes inadequately controlled on metformin. Diabetes Care 38(3):384–393CrossRefPubMedGoogle Scholar
  25. 25.
    Ridderstråle M, Andersen KR, Zeller C, Kim G, Woerle HJ, Broedl UC; EMPA-REG H2H-SU trial investigators (2014) Comparison of empagliflozin and glimepiride as add-on to metformin in patients with type 2 diabetes: a 104-week randomised, active-controlled, double-blind, phase 3 trial. Lancet Diabetes Endocrinol 2(9):691–700CrossRefPubMedGoogle Scholar
  26. 26.
    Ferrannini E, Berk A, Hantel S, Pinnetti S, Hach T, Woerle HJ, Broedl UC (2013) 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 36(12):4015–4021CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Fox CS, Pencina MJ, Wilson PW, Paynter NP, Vasan RS, D’Agostino RB Sr (2008) Lifetime risk of cardiovascular disease among individuals with and without diabetes stratified by obesity status in the Framingham heart study. Diabetes Care 31(8):1582–1584CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Båvenholm PN, Kuhl J, Pigon J, Saha AK, Ruderman NB, Efendic S (2003) Insulin resistance in type 2 diabetes: association with truncal obesity, impaired fitness, and atypical malonyl coenzyme A regulation. J Clin Endocrinol Metab 88(1):82–87CrossRefPubMedGoogle Scholar
  29. 29.
    Baker WL, Smyth LR, Riche DM, Bourret EM, Chamberlin KW, White WB (2014) Effects of sodium-glucose co-transporter 2 inhibitors on blood pressure: a systematic review and meta-analysis. J Am Soc Hypertens 8(4):262–275.e9CrossRefPubMedGoogle Scholar
  30. 30.
    Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE (2015) Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 373(22):2117–2128Google Scholar
  31. 31.
    European Medicines Agency (EMA) (2014) Jardiance®. EPAR. Public assessment report (EAM). Available online at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002677/WC500168594.pdf. Accessed 24 September 2014
  32. 32.
    FDA warns that SGLT2 inhibitors for diabetes may result in a serious condition of too much acid in the blood. Available online at: http://www.fda.gov/drugs/drugsafety/ucm446845.htm
  33. 33.
    Peters AL, Buschur EO, Buse JB, Cohan P, Diner JC, Hirsch IB (2015) Euglycemic diabetic ketoacidosis: a potential complication of treatment with sodium-glucose cotransporter 2 inhibition. Diabetes Care 38(9):1687–1693CrossRefPubMedGoogle Scholar
  34. 34.
    Shubrook JH, Bokaie BB, Adkins SE (2015) Empagliflozin in the treatment of type 2 diabetes: evidence to date. Drug Des Devel Ther 9:5793–5803CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Jardiance®. Summary of product characteristics. Available online at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002677/WC500168592.pdf. Accessed 29 September 2014
  36. 36.
    Scott LJ (2014) Empagliflozin: a review of its use in patients with type 2 diabetes mellitus. Drugs 74(15):1769–1784CrossRefPubMedGoogle Scholar
  37. 37.
    Mearns ES, Sobieraj DM, White CM, Saulsberry WJ, Kohn CG, Doleh Y, Zaccaro E, Coleman CI (2015) Comparative efficacy and safety of antidiabetic drug regimens added to metformin monotherapy in patients with type 2 diabetes: a network meta-analysis. PLoS One 10(4):e0125879. doi:10.1371/journal.pone.0125879 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Xiaoyan Zhong
    • 1
  • Dan Lai
    • 2
  • Yun Ye
    • 1
  • Xuping Yang
    • 1
  • Bin Yu
    • 3
  • Yilan Huang
    • 1
  1. 1.Department of PharmacyThe Affiliated Hospital of Luzhou Medical CollegeLuzhouPeople’s Republic of China
  2. 2.Department of ENTThe Affiliated Hospital of Luzhou Medical CollegeLuzhouPeople’s Republic of China
  3. 3.College of PharmacySichuan Medical UniversityLuzhouPeople’s Republic of China

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