Advertisement

European Journal of Clinical Pharmacology

, Volume 70, Issue 10, pp 1149–1158 | Cite as

Efficacy and safety of canagliflozin in subjects with type 2 diabetes: systematic review and meta-analysis

  • Xu-Ping Yang
  • Dan Lai
  • Xiao-Yan Zhong
  • Hong-Ping Shen
  • Yi-Lan HuangEmail author
Review Article

Abstract

Purpose

To assess the efficacy and safety of the novel sodium glucose co-transporter 2 (SGLT2) inhibitor—canagliflozin for type 2 diabetes (T2DM).

Methods

A search of Medline (1946–January 2014), Embase (1950–January 2014), and The Cochrane Library for randomized controlled trials of canagliflozin compared to placebo or active comparator in T2DM was performed. Clinical Trials website and unpublished U.S. Food and Drug Administration data were also searched.

Results

Ten trials including 6,701 patients were analyzed. Compared with placebo, canagliflozin produced absolute reductions in glycated hemoglobin A1c levels when used as monotherapy (weighted mean difference (WMD) −1.08 %, 95 % confidence interval (CI) [−1.25 to −0.90], p < 0.00001) or add-on treatment (WMD −0.73 %, 95 %CI [−0.84 to −0.61], p < 0.00001). When compared with other active comparators, canagliflozin significantly reduced HbA1c by −0.21 % (WMD, 95 %CI [−0.33 to −0.08], p = 0.001). Canagliflozin led to greater body weight loss (vs. placebo, WMD −2.81 kg, 95 %CI [−3.26 to −2.37]; vs. active comparators, WMD −3.49 kg, 95 %CI [−4.86 to −2.12]). Hypoglycemia with canagliflozin was similar to placebo or sitagliptin, and was lower than glimepiride (risk ratio (RR) 0.15, 95 %CI [0.10 to 0.22]). Genital tract infections were more common with canagliflozin (vs. placebo, RR 3.76, 95 %CI [2.23 to 6.35]; vs. active comparators, RR 4.95, 95 %CI [3.25 to 7.52]). Similar incidences of urinary tract infections were noted with canagliflozin compared with control groups.

Conclusion

Canagliflozin led to improvements in reducing glycated hemoglobin A1c levels and body weight with low risk of hypoglycemia in patients with T2DM. Common adverse effects including genital tract infections and osmotic diuresis-related AEs were identified and reviewed. Risks of cardiovascular events are even less certain, and more data on long-term effects are needed.

Keywords

Canagliflozin Sodium glucose co-transporter 2 inhibitor Type 2 diabetes Systematic review 

Notes

Conflict of interest

The authors have nothing to disclose

Supplementary material

228_2014_1730_MOESM1_ESM.doc (36 kb)
ESM 1 (DOC 36 kb)
228_2014_1730_MOESM2_ESM.doc (50 kb)
ESM 2 (DOC 50 kb)
228_2014_1730_MOESM3_ESM.doc (55 kb)
ESM 3 (DOC 55 kb)
228_2014_1730_MOESM4_ESM.doc (42 kb)
ESM 4 (DOC 41 kb)
228_2014_1730_MOESM5_ESM.doc (42 kb)
ESM 5 (DOC 41 kb)
228_2014_1730_MOESM6_ESM.doc (40 kb)
ESM 6 (DOC 40 kb)
228_2014_1730_MOESM7_ESM.doc (40 kb)
ESM 7 (DOC 40 kb)
228_2014_1730_MOESM8_ESM.doc (40 kb)
ESM 8 (DOC 40 kb)
228_2014_1730_MOESM9_ESM.doc (40 kb)
ESM 9 (DOC 40 kb)
228_2014_1730_MOESM10_ESM.doc (40 kb)
ESM 10 (DOC 40 kb)
228_2014_1730_MOESM11_ESM.doc (39 kb)
ESM 11 (DOC 39 kb)
228_2014_1730_MOESM12_ESM.doc (40 kb)
ESM 12 (DOC 39 kb)
228_2014_1730_MOESM13_ESM.doc (38 kb)
ESM 13 (DOC 38 kb)
228_2014_1730_MOESM14_ESM.doc (40 kb)
ESM 14 (DOC 40 kb)

References

  1. 1.
    Danaei G, Finucane MM, Lu Y et al (2011) National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2.7 million participants. Lancet 378(9785):31–40CrossRefPubMedGoogle Scholar
  2. 2.
    Inzucchi SE, Bergenstal RM, Buse JB et al (2012) Management of hyperglycemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 35(6):1364–1379PubMedCentralCrossRefPubMedGoogle Scholar
  3. 3.
    Tahrani AA, Bailey CJ, Del Prato S et al (2011) Management of type 2 diabetes: new and future developments in treatment. Lancet 378(9786):182–197CrossRefPubMedGoogle Scholar
  4. 4.
    Cook MN, Girman CJ, Stein PP et al (2007) Initial monotherapy with either metformin or sulphonylureas often fails to achieve or maintain current glycaemic goals in patients with type 2 diabetes in UK primary care. Diabet Med 24(4):350–358CrossRefPubMedGoogle Scholar
  5. 5.
    Neumiller JJ, White JR Jr, Campbell RK (2010) Sodium-glucose co-transport inhibitors: progress and therapeutic potential in type 2 diabetes mellitus. Drugs 70(4):377–385CrossRefPubMedGoogle Scholar
  6. 6.
    Nair S, Wilding JP (2010) Sodium glucose co-transporter 2 inhibitors as a new treatment for diabetes mellitus. J Clin Endocrinol Metab 95(1):34–42CrossRefPubMedGoogle Scholar
  7. 7.
    Rahmoune H, Thompson PW, Ward JM et al (2005) Glucose transporters in human renal proximal tubular cells isolated from the urine of patients with non-insulin-dependent diabetes. Diabetes 54(12):3427–3434CrossRefPubMedGoogle Scholar
  8. 8.
    Gerich JE (2010) Role of the kidney in normal glucose homeostasis and in the hyperglycaemia of diabetes mellitus: therapeutic implications. Diabet Med 27(2):136–142CrossRefPubMedGoogle Scholar
  9. 9.
    FDA advisory committee recommends approval of canagliflozin for treatment of adults with type 2 diabetes. 2013.Available from: http://www.fda.gov/ newsevents/newsroom/pressannouncements/ ucm345848. htm [Last accessed 28 October 2013]
  10. 10.
    Lamos EM, Younk LM, Davis SN (2013) Canagliflozin, an inhibitor of sodium-glucose cotransporter 2, for the treatment of type 2 diabetes mellitus. Expert Opin Drug Metab Toxicol 9(6):763–775CrossRefPubMedGoogle Scholar
  11. 11.
    Riser Taylor S, Harris KB (2013) The clinical efficacy and safety of sodium glucose co-transporter 2 inhibitors in adults with type 2 diabetes mellitus. Pharmacotherapy 33(9):984–999CrossRefPubMedGoogle Scholar
  12. 12.
    Musso G, Gambino R, Cassader M et al (2012) A novel approach to control hyperglycemia in type 2 diabetes: sodium glucose co-transport (SGLT) inhibitors: systematic review and meta-analysis of randomized trials. Ann Med 44(4):375–393CrossRefPubMedGoogle Scholar
  13. 13.
    Clar C, Gill JA, Court R et al (2012) Systematic review of SGLT2 receptor inhibitors in dual or triple therapy in type 2 diabetes. BMJ Open 2(5). [PMC3488745]Google Scholar
  14. 14.
    Vasilakou D, Karagiannis T, Athanasiadou E et al (2013) Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med 159(4):262–274CrossRefPubMedGoogle Scholar
  15. 15.
    Higgins JPT, Green S (2011) Cochrane handbook for systematic reviews of interventions. The Cochrane CollaborationGoogle Scholar
  16. 16.
    Review Manager (RevMan) [Computer program] (2012) Version 5.2. Copenhagen: The Nordic Cochrane Centre, The Cochrane CollaborationGoogle Scholar
  17. 17.
    Stenlof K, Cefalu WT, Kim KA et al (2013) Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes Metab 15(4):372–382PubMedCentralCrossRefPubMedGoogle Scholar
  18. 18.
    Rosenstock J, Aggarwal N, Polidori D et al (2012) Dose-ranging effects of canagliflozin, a sodium-glucose co-transporter 2 inhibitor, as add-on to metformin in subjects with type 2 diabetes. Diabetes Care 35(6):1232–1238PubMedCentralCrossRefPubMedGoogle Scholar
  19. 19.
    Bode B, Stenlof K, Sullivan D et al (2013) Efficacy and safety of canagliflozin treatment in older patients with type 2 diabetes mellitus: a randomized trial. Hosp Pract 41(2):72–84CrossRefGoogle Scholar
  20. 20.
    Inagaki N, Kondo K, Iwasaki T et al (2013) Efficacy and safety of canagliflozin in Japanese patients with type 2 diabetes: a randomized, double-blind, placebo-controlled, 12-week study†. Diabetes Obes Metab 15(12):1136–1145PubMedCentralCrossRefPubMedGoogle Scholar
  21. 21.
    Wilding JP, Charpentier G, Hollander P et al (2013) Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sulphonylurea: a randomised trial. Int J Clin Pract 67(12):1267–1282CrossRefPubMedGoogle Scholar
  22. 22.
    Janssen Research & Development LLC. The CANTATA-MP Trial (CANagliflozin Treatment and Trial Analysis - Metformin and Pioglitazone). (NCT01106690). ClinicalTrials.gov Web site. [Last accessed 28 October 2013]Google Scholar
  23. 23.
    Yale JF, Bakris G, Cariou B et al (2013) Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease. Diabetes Obes Metab 15(5):463–473PubMedCentralCrossRefPubMedGoogle Scholar
  24. 24.
    Lavalle-González FJ, Januszewicz A, Davidson J et al (2013) Efficacy and safety of canagliflozin compared with placebo and sitagliptin in patients with type 2 diabetes on background metformin monotherapy: a randomised trial. Diabetologia 56(12):2582–2592PubMedCentralCrossRefPubMedGoogle Scholar
  25. 25.
    Schernthaner G, Gross JL, Rosenstock J et al (2013) Canagliflozin compared with sitagliptin for patients with type 2 diabetes who do not have adequate glycemic control with metformin plus sulfonylurea: a 52-week randomized trial. Diabetes Care 36(9):2508–2515PubMedCentralCrossRefPubMedGoogle Scholar
  26. 26.
    Cefalu WT, Leiter LA, Yoon KH et al (2013) Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 weeks results from a randomised, double-blind, phase 3 non-inferiority trial. Lancet 382(9896):941–950CrossRefPubMedGoogle Scholar
  27. 27.
    American Diabetes Association (2013) Standard of medical care in diabetes—2013. Diabetes Care 36(suppl 1):S11–S66PubMedCentralCrossRefGoogle Scholar
  28. 28.
    Fowler MJ (2007) Diabetes treatment, part 2: oral agents for glycemic management. Clin Diabetes 25:131–134CrossRefGoogle Scholar
  29. 29.
    Guh DP, Zhang W, Bansback N et al (2009) The incidence of comorbidities related to obesity and overweight: a systematic review and meta-analysis. BMC Public Health 9:88PubMedCentralCrossRefPubMedGoogle Scholar
  30. 30.
    Sha S, Devineni D, Ghosh A et al (2011) Canagliflozin, a novel inhibitor of sodium glucose co-transporter 2, dose dependently reduces calculated renal threshold for glu-cose excretion and increases urinary glu-cose excretion in healthy subjects. Diabetes Obes Metab 13:669–672CrossRefPubMedGoogle Scholar
  31. 31.
    Kahleova H, Mari A, Nofrate V et al (2012) Improvement in β-cell function after diet-induced weight loss is associated with decrease in pancreatic polypeptide in subjects with type 2 diabetes. J Diabetes Complicat 26(5):442–449CrossRefPubMedGoogle Scholar
  32. 32.
    Calado J (2009) Dapagliflozin, an oral sodium glucose cotransporter type 2 inhibitor for the treatment of type 2 diabetes mellitus. IDrugs 12(12):785–798PubMedGoogle Scholar
  33. 33.
    Weidmann P, De Court M, Ferrari P (1992) Effect of diuretics on the plasma lipid profile. Eur Heart J 13(suppl G):61–67CrossRefPubMedGoogle Scholar
  34. 34.
    Devineni D, Morrow L, Hompesch M et al (2012) Canagliflozin improves glycaemic control over 28 days in subjects with type 2 diabetes not optimally controlled on insulin. Diabetes Obes Metab 14(6):539–545CrossRefPubMedGoogle Scholar
  35. 35.
    Davis SN, Shavers C, Mosqueda-Garcia R, Costa F (1997) Effects of differing antecedent hypoglycemia on subsequent counter-regulation in normal humans. Diabetes 46:1328–1335CrossRefPubMedGoogle Scholar
  36. 36.
    U.S. Food and Drug Administration. FDA Briefing Document. NDA204042. Invokana (Canagliflozin) Tablets. Rockville, MD: U.S. Food and Drug Administration; 2013. Accessed at www.fda.gov/downloads/Advisory Committees/ Committees Meeting Materials/Drugs/Endo-crinologic and Metabolic Drugs Advisory Committee /UCM334550.pdf on 24 January 2013
  37. 37.
    Cardiovascular disease risk factors. World Heart Federation 2014; http:// www.world-heart-federation.org/cardiovascular-health/cardiovascular-disease- risk- factors/ (Last accessed on 12 January 2014)
  38. 38.
    Janssen Research & Development, LLC. A Randomized, Multicenter, Double-Blind, Parallel, Placebo-Controlled Study of the Effects of JNJ-28431754 on Cardiovascular Outcomes in Adult Subjects With Type 2 Diabetes Mellitus ClinicalTrials.gov Web site. (Last accessed on 12 January 2014)Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Xu-Ping Yang
    • 1
  • Dan Lai
    • 2
  • Xiao-Yan Zhong
    • 4
  • Hong-Ping Shen
    • 1
  • Yi-Lan Huang
    • 3
    Email author
  1. 1.Department of PharmacyThe TCM Hospital Affiliated to Luzhou Medical CollegeLuzhouPeople’s Republic of China
  2. 2.Department of ENTThe Affiliated Hospital of Luzhou Medical CollegeLuzhouPeople’s Republic of China
  3. 3.Department of PharmacyThe Affiliated Hospital of Luzhou Medical CollegeLuzhouPeople’s Republic of China
  4. 4.College of PharmacyLuzhou Medical CollegeLuzhouPeople’s Republic of China

Personalised recommendations