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Canagliflozin: A Review of Its Use in Patients with Type 2 Diabetes Mellitus

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Abstract

Canagliflozin (Invokana™) is an orally administered sodium-glucose co-transporter-2 (SGLT2) inhibitor used in the treatment of patients with type 2 diabetes. By inhibiting the transporter protein SGLT2 in the kidneys, canagliflozin reduces renal glucose reabsorption, thereby increasing urinary glucose excretion and reducing blood glucose levels. Several randomized placebo- or active comparator-controlled trials of 26–52 weeks’ duration (plus extension phases) have shown that canagliflozin improves glycaemic control when used as monotherapy or as add-on therapy to metformin and/or other antihyperglycaemic agents, including insulin, in patients with type 2 diabetes. In addition to achieving reductions from baseline in glycosylated haemoglobin, canagliflozin also showed beneficial effects for other endpoints including reductions from baseline in fasting plasma glucose levels and bodyweight. Canagliflozin has a low risk of hypoglycaemia and was generally well tolerated in clinical trials. The most frequently reported adverse events with canagliflozin are female genital mycotic infections, urinary tract infections and increased urination. The pharmacodynamic response to canagliflozin declines with increasing severity of renal impairment, and prescribing information should be consulted regarding dosage adjustments or restrictions in moderate to severe renal dysfunction. Canagliflozin has modest effects on the serum lipid profile, some beneficial (increased high-density lipoprotein cholesterol and decreased triglycerides) and others not (increased low-density lipoprotein cholesterol). Most patients treated with canagliflozin also have a modest reduction in blood pressure. The overall effect of canagliflozin on the risk of cardiovascular disease is unknown and will be evaluated in the ongoing CANVAS trial; preliminary cardiovascular safety data suggest no increased risk. Thus, with its unique mechanism of action that is independent of insulin secretion and action, canagliflozin is a useful addition to the therapeutic options available for the management of type 2 diabetes, particularly by providing complementary treatment when used as add-on therapy.

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References

  1. Inzucchi SE, Bergenstal RM, Buse JB, et al. 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. 2012;35(6):1364–79.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2014;37(suppl 1):S81–90.

    Article  Google Scholar 

  3. American Diabetes Association. Standards of medical care in diabetes—2014. Diabetes Care. 2014;37(suppl 1):S14–80.

    Article  Google Scholar 

  4. International Diabetes Federation. IDF diabetes atlas, 2013. (2013). http://www.idf.org/diabetesatlas. Accessed 24 January 2014.

  5. International Diabetes Federation. Global diabetes plan 2011–2021. (2011). http://www.idf.org/sites/default/files/Global_Diabetes_Plan_Final.pdf. Accessed 24 January 2014.

  6. Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321(7258):405–12.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Turner RC, Cull CA, Frighi V, et al. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). UK Prospective Diabetes Study (UKPDS) Group. JAMA. 1999;281(21):2005–12.

    Article  CAS  PubMed  Google Scholar 

  8. Invokana (canagliflozin) tablets for oral use: US prescribing information. (2013). http://www.janssenmd.com/pdf/invokana/PI-INVOKANA.pdf. Accessed 14 April 2014.

  9. European Medicines Agency. Invokana 100 and 300 mg film-coated tablets: summary of product characteristics. (2013). http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002649/WC500156456.pdf. Accessed 14 April 2014.

  10. Nomura S, Sakamaki S, Hongu M, et al. Discovery of canagliflozin, a novel C-glucoside with thiophene ring, as sodium-dependent glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes mellitus. J Med Chem. 2010;53(17):6355–60.

    Article  CAS  PubMed  Google Scholar 

  11. Neumiller JJ, White JR, Campbell RK. Sodium-glucose co-transport inhibitors: progress and therapeutic potential in type 2 diabetes mellitus. Drugs. 2010;70(4):377–85.

    Article  CAS  PubMed  Google Scholar 

  12. Nair S, Wilding JP. Sodium glucose cotransporter 2 inhibitors as a new treatment for diabetes mellitus. J Clin Endocrinol Metab. 2010;95(1):34–42.

    Article  CAS  PubMed  Google Scholar 

  13. Bakris GL, Fonseca VA, Sharma K, et al. Renal sodium-glucose transport: role in diabetes mellitus and potential clinical implications. Kidney Int. 2009;75(12):1272–7.

    Article  CAS  PubMed  Google Scholar 

  14. Liang Y, Arakawa K, Ueta K, et al. Effect of canagliflozin on renal threshold for glucose, glycemia, and body weight in normal and diabetic animal models. PLoS One (electronic resource). 2012;7(2):e30555.

    Article  CAS  Google Scholar 

  15. Janssen Research & Development LLC. Canagliflozin as an adjunctive treatment to diet and exercise alone or co-administered with other antihyperglycemic agents to improve glycemic control in adults with type 2 diabetes mellitus (Endocrinologic and Metabolic Drugs Advisory Committee briefing materials). (2013). http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM334551.pdf. Accessed 9 April 2014.

  16. Stenlöf K, Cefalu WT, Kim KA, et al. Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes Metab. 2013;15(4):372–82.

    Article  PubMed Central  PubMed  Google Scholar 

  17. Lavalle-González FJ, Januszewicz A, Davidson J, et al. Efficacy and safety of canagliflozin compared with placebo and sitagliptin in patients with type 2 diabetes on background metformin monotherapy: a randomised trial. Diabetologia. 2013;56(12):2582–92.

    Article  PubMed Central  PubMed  Google Scholar 

  18. Polidori D, Sha S, Mudaliar S, et al. Canagliflozin lowers postprandial glucose and insulin by delaying intestinal glucose absorption in addition to increasing urinary glucose excretion: results of a randomized, placebo-controlled study. Diabetes Care. 2013;36(8):2154–61.

    Article  CAS  PubMed  Google Scholar 

  19. Devineni D, Curtin CR, Polidori D, et al. Pharmacokinetics and pharmacodynamics of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in subjects with type 2 diabetes mellitus. J Clin Pharmacol. 2013;53(6):601–10.

    Article  PubMed  Google Scholar 

  20. Sha S, Devineni D, Ghosh A, et al. Canagliflozin, a novel inhibitor of sodium glucose co-transporter 2, dose dependently reduces calculated renal threshold for glucose excretion and increases urinary glucose excretion in healthy subjects. Diabetes Obes Metab. 2011;13(7):669–72.

    Article  CAS  PubMed  Google Scholar 

  21. Rosenstock J, Aggarwal N, Polidori D, et al. Dose-ranging effects of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, as add-on to metformin in subjects with type 2 diabetes. Diabetes Care. 2012;35(6):1232–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Schernthaner G, Gross JL, Rosenstock J, et al. 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. 2013;36(9):2508–15.

    Article  PubMed  Google Scholar 

  23. Wilding JP, Charpentier G, Hollander P, et al. 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. 2013;67(12):1267–82.

    Article  CAS  PubMed  Google Scholar 

  24. Polidori D, Mari A, Ferrannini E. Canagliflozin, a sodium glucose co-transporter 2 inhibitor, improves model-based indices of beta cell function in patients with type 2 diabetes. Diabetologia. 2014;57(5):891–901.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Weir GC, Marselli L, Marchetti P, et al. Towards better understanding of the contributions of overwork and glucotoxicity to the beta-cell inadequacy of type 2 diabetes. Diabetes Obes Metab. 2009;11(Suppl 4):82–90.

    Article  CAS  PubMed  Google Scholar 

  26. Kim JW, You YH, Jung S, et al. miRNA-30a-5p-mediated silencing of Beta2/NeuroD expression is an important initial event of glucotoxicity-induced beta cell dysfunction in rodent models. Diabetologia. 2013;56(4):847–55.

    Article  CAS  PubMed  Google Scholar 

  27. Mamidi RN, Cuyckens F, Chen J, et al. Metabolism and excretion of canagliflozin in mice, rats, dogs, and humans. Drug Metab Dispos. 2014;42(5):903–16.

    Article  PubMed  Google Scholar 

  28. Scheen AJ. Drug-drug interactions with sodium-glucose cotransporters type 2 (SGLT2) inhibitors, new oral glucose-lowering agents for the management of type 2 diabetes mellitus. Clin Pharmacokinet. 2014;53(4):295–304.

    Article  CAS  PubMed  Google Scholar 

  29. Stenlöf K, Cefalu WT, Kim KA, et al. Long-term efficacy and safety of canagliflozin monotherapy in patients with type 2 diabetes inadequately controlled with diet and exercise: findings from the 52-week CANTATA-M study. Curr Med Res Opin. 2014;30(2):163–75.

    Article  PubMed  Google Scholar 

  30. Cefalu WT, Leiter LA, Yoon K-H, 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.

    Article  CAS  PubMed  Google Scholar 

  31. Langslet G, Cefalu WT, Leiter LA, et al. Canagliflozin demonstrates durable glycaemic improvements over 104 weeks compared with glimepiride in subjects with type 2 diabetes mellitus on metformin (abstract no. 182). In: 49th annual meeting of the European Association for the Study of Diabetes, Barcelona, 23–27 September 2013.

  32. Forst T, Guthrie R, Goldenberg R, et al. Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes on background metformin and pioglitazone. Diabetes Obes Metab. 2014;16(5):467–77.

    Article  CAS  PubMed  Google Scholar 

  33. Neal B, Perkovic V, de Zeeuw D, et al. Rationale, design, and baseline characteristics of the canagliflozin cardiovascular assessment study (CANVAS)—a randomized placebo-controlled trial. Am Heart J. 2013;166(2):217.e11–223.e11.

    Article  Google Scholar 

  34. Matthews DR, Fulcher G, Perkovic V, et al. Efficacy and safety of canagliflozin (CANA), an inhibitor of sodium glucose co-transporter 2 (SGLT2), added-on to insulin therapy +/− oral agents in type 2 diabetes (abstract no. 764). In: 48th annual meeting of the European Association for the Study of Diabetes, Berlin, 1–5 October 2012.

  35. Fulcher G, Matthews DR, Perkovic V, et al. Canagliflozin (CANA) in subjects with type 2 diabetes mellitus (T2DM) inadequately controlled on sulfonylurea (SU) monotherapy: a CANVAS substudy (abstract no. 1124-P). In: 73rd annual scientific sessions of the American Diabetes Association, Chicago, 21–25 June 2013.

  36. Wysham C, Woo VC, Mathieu C, et al. Canagliflozin (CANA) added on to dipeptidyl peptidase-4 inhibitors (DPP-4i) or glucagon-like peptide-1 (GLP-1) agonists with or without other antihyperglycemic agents (AHAs) in type 2 diabetes mellitus (T2DM) (abstract no. 1080-P). In: 73rd annual scientific sessions of the American Diabetes Association, Chicago, 21–25 June 2013.

  37. Bode B, Stenlöf K, Sullivan D, et al. Efficacy and safety of canagliflozin treatment in older subjects with type 2 diabetes mellitus: a randomized trial. Hosp Pract (Minneap). 2013;41(2):72–84.

    Article  Google Scholar 

  38. Sinclair A, Bode B, Harris S, et al. Efficacy and safety of canagliflozin compared with placebo in older patients with type 2 diabetes mellitus: a pooled analysis of clinical studies. BMC Endocr Disord. 2014;14(1):37.

    Article  PubMed Central  PubMed  Google Scholar 

  39. Yale JF, Bakris G, Cariou B, et al. Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease. Diabetes Obes Metab. 2013;15(5):463–73.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Yale JF, Bakris G, Cariou B, et al. Efficacy and safety of canagliflozin (CANA) in subjects with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) over 52 weeks (abstract no. 71). Can J Diabetes. 2013;37(suppl):S27.

    Google Scholar 

  41. Woo V, Davies M, De Zeeuw D, et al. Canagliflozin (CANA) is effective and generally well tolerated in subjects with type 2 diabetes mellitus (T2DM) and stage 3 chronic kidney disease (CKD) (abstract no. 73-LB). In: 73rd annual scientific sessions of the American Diabetes Association, Chicago, 21–25 June 2013.

  42. Inagaki N, Kondo K, Yoshinari T, et al. Efficacy and safety of canagliflozin in Japanese patients with type 2 diabetes: a randomized, double-blind, placebo-controlled, 12-week study. Diabetes Obes Metab. 2013;15(12):1136–45.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Janssen Research & Development LLC. A study of the effects of canagliflozin (JNJ-28431754) on renal endpoints in adult participants with type 2 diabetes mellitus (CANVAS-R) (ClinicalTrials.gov identifier NCT01989754). US National Institutes of Health, ClinicalTrials.gov. (2014). http://clinicaltrials.gov/ct2/show/study/NCT01989754. Accessed 27 March 2014.

  44. Janssen Research & Development LLC. Evaluation of the effects of canagliflozin on renal and cardiovascular outcomes in participants with diabetic nephropathy (CREDENCE) (ClinicalTrials.gov identifier NCT02065791). US National Institutes of Health, ClinicalTrials.gov. (2014). http://clinicaltrials.gov/ct2/show/study/NCT02065791. Accessed 10 April 2014.

  45. Scheen AJ, Van Gaal LF. Combating the dual burden: therapeutic targeting of common pathways in obesity and type 2 diabetes. Lancet Diabetes Endocrinol. 2014. doi:10.1016/S2213-8587(14)70004-X.

    Google Scholar 

  46. Barnett AH. Impact of sodium glucose cotransporter 2 inhibitors on weight in patients with type 2 diabetes mellitus. Postgrad Med. 2013;125(5):92–100.

    Article  PubMed  Google Scholar 

  47. Bays HE, Weinstein R, Law G, et al. Canagliflozin: effects in overweight and obese subjects without diabetes mellitus. Obesity. 2014;22(4):1042–9.

    Article  CAS  PubMed  Google Scholar 

  48. Toubro S, Cefalu WT, Xie J, et al. Canagliflozin, a sodium glucose co-transporter 2 inhibitor, reduces body weight mainly through loss of fat mass in subjects with type 2 diabetes (abstract no. 762). Diabetologia. 2012;55:S313–4.

    Google Scholar 

  49. Devenny JJ, Godonis HE, Harvey SJ, et al. Weight loss induced by chronic dapagliflozin treatment is attenuated by compensatory hyperphagia in diet-induced obese (DIO) rats. Obesity. 2012;20(8):1645–52.

    Article  CAS  PubMed  Google Scholar 

  50. Ferrannini E, Muscelli E, Frascerra S, et al. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest. 2014;124:499–508.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. Merovci A, Solis-Herrera C, Daniele G, et al. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J Clin Invest. 2014;124:509–14.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  52. Plosker GL. Dapagliflozin: a review of its use in type 2 diabetes mellitus. Drugs. 2012;72(17):2289–312.

    Article  CAS  PubMed  Google Scholar 

  53. Farxiga (dapagliflozin) tablets for oral use: US prescribing information. (2014). http://packageinserts.bms.com/pi/pi_farxiga.pdf. Accessed 10 February 2014.

  54. Nyirjesy P, Zhao Y, Ways K, et al. Evaluation of vulvovaginal symptoms and Candida colonization in women with type 2 diabetes mellitus treated with canagliflozin, a sodium glucose co-transporter 2 inhibitor. Curr Med Res Opin. 2012;28(7):1173–8.

    Article  CAS  PubMed  Google Scholar 

  55. Nyirjesy P, Sobel JD, Fung A, et al. Genital mycotic infections with canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus: a pooled analysis of clinical studies. Curr Med Res Opin. 2014. doi:10.1185/03007995.2014.890925.

    PubMed  Google Scholar 

  56. Nicolle LE, Capuano G, Fung A, et al. Urinary tract infection in randomized phase III studies of canagliflozin, a sodium glucose co-transporter 2 inhibitor. Postgrad Med. 2014;126(1):7–17.

    Article  PubMed  Google Scholar 

  57. Gilbert RE. Sodium-glucose linked transporter-2 inhibitors: potential for renoprotection beyond blood glucose lowering. Kidney Int. 2013. doi:10.1038/ki.2013.451.

    PubMed  Google Scholar 

  58. Baker WL, Smyth LR, Riche DM, et al. Effects of sodium-glucose co-transporter 2 inhibitors on blood pressure: a systematic review and meta-analysis. J Am Soc Hypertens. 2014. doi:10.1016/j.jash.2014.01.007.

    PubMed  Google Scholar 

  59. Wexler D, Vandebosch A, Usiskin K. Study of electrocardiogram intervals in healthy adults receiving single oral doses of canagliflozin (abstract no. 2177-PO). In: 70th annual scientific sessions of the American Diabetes Association, Orlando, 21–25 June 2010.

  60. EU OKs diabetes drug empagliflozin, to be known as Jardiance. (2014). http://www.medscape.com/viewarticle/822355. Accessed 3 April 2014.

  61. Europe approves J&J diabetes combo Vokanamet. (2014). http://www.pharmatimes.com/article/14-04-27/Europe_approves_J_J_diabetes_combo_Vokanamet.aspx. Accessed 1 May 2014.

  62. NICE consults on draft guidance recommending new drug for type 2 diabetes. (2014). http://www.nice.org.uk/newsroom/pressreleases/CanagliflozinForType2DiabetesConsultation.jsp. Accessed 14 April 2014.

  63. Burgmaier M, Heinrich C, Marx N. Cardiovascular effects of GLP-1 and GLP-1-based therapies: implications for the cardiovascular continuum in diabetes? Diabet Med. 2013;30(3):289–99.

    Article  CAS  PubMed  Google Scholar 

  64. Peters AL. Patient and treatment perspectives: revisiting the link between type 2 diabetes, weight gain, and cardiovascular risk. Cleve Clin J Med. 2009;76(suppl 5):S20–7.

    Article  PubMed  Google Scholar 

  65. Tahrani AA, Bailey CJ, Del Prato S, et al. Management of type 2 diabetes: new and future developments in treatment. Lancet. 2011;378(9786):182–97.

    Article  CAS  PubMed  Google Scholar 

  66. Plosker GL. Sitagliptin: a review of its use in patients with type 2 diabetes mellitus. Drugs. 2014;74(2):223–42.

    Article  CAS  PubMed  Google Scholar 

  67. Neslusan C, Johansen P, Willis M, et al. A health economic analysis of the long-term benefits and associated cost offsets of canagliflozin monotherapy in the United States (abstract no. 1232-P). In: 73rd annual scientific session of the American Diabetes Association, Chicago, 21–25 June 2013.

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Disclosure

The preparation of this review was not supported by any external funding. During the peer review process, the manufacturer of the agent under review was offered an opportunity to comment on the article. Changes based on any comments received were made by the author on the basis of scientific and editorial merit. Greg Plosker is a salaried employee of Adis/Springer.

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Correspondence to Greg L. Plosker.

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The manuscript was reviewed by: D.S.H. Bell, Southside Endocrinology, University of Alabama, Birmingham, AL, USA; G. Dimitriadis, 2nd Department of Internal Medicine, Research Institute & Diabetes Center, Athens University Medical School and Attikon University Hospital, Athens, Greece; J.G. Eriksson, Department of General Practice & Primary Health Care, Finland and Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland; D.T. Eurich, School of Public Health, University of Alberta, Edmonton, AB, Canada; A.J. Scheen, Division of Diabetes, Nutrition and Metabolic Disorders and Division of Clinical Pharmacology, Department of Medicine, CHU, University of Liège, Liège, Belgium.

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Plosker, G.L. Canagliflozin: A Review of Its Use in Patients with Type 2 Diabetes Mellitus. Drugs 74, 807–824 (2014). https://doi.org/10.1007/s40265-014-0225-5

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