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Canagliflozin in Conjunction With Sulfonylurea Maintains Glycemic Control and Weight Loss Over 52 Weeks: A Randomized, Controlled Trial in Patients With Type 2 Diabetes Mellitus

      Abstract

      Purpose

      Our aim was to investigate the long-term efficacy and safety of canagliflozin, a sodium−glucose co-transporter 2 inhibitor, added to background sulfonylurea (SU) monotherapy for patients with type 2 diabetes mellitus.

      Methods

      The CANagliflozin cardioVascularAssessment Study (CANVAS) was a double-blind, placebo-controlled cardiovascular outcomes study that randomly assigned participants to receive placebo or canagliflozin 100 or 300 mg once daily in addition to routine therapy. CANVAS included a prespecified SU substudy of patients taking background doses of SU monotherapy; data from the primary efficacy evaluation at 18 weeks have been published previously. We performed a retrospective analysis of the SU substudy at 52 weeks to measure long-term efficacy and safety of canagliflozin used with an SU. The primary objective of the long-term extension was to assess the change from baseline to 52 weeks in glycosylated hemoglobin (HbA1c).

      Findings

      A total of 215 patients were included in the 52-week extension study. Patients receiving both 100-mg and 300-mg doses of canagliflozin achieved a sustained reduction in HbA1c relative to patients receiving placebo (−0.61% [95% CI, −0.941% to −0.282%] and −0.66% [95% CI, −0.993% to −0.332%], respectively), regardless of baseline HbA1c, duration of diabetes, SU dose, estimated glomerular filtration rate, or body mass index. A sustained reduction in fasting plasma glucose was also found in both 100-mg and 300-mg groups, relative to the placebo group (−2.04 mmol/L [95% CI, −2.778 to −1.299 mmol/L] and −1.88 mmol/L [95% CI, −2.623 to −1.146 mmol/L], respectively). Weight was reduced significantly at 52 weeks in both 100-mg and 300-mg groups, relative to placebo (−1.9% [95% CI, −3.2% to −0.7%] and −2.0% [95% CI, −3.2% to –0.7%], respectively). Reduction in systolic blood pressure was also reported for both dose groups relative to the placebo group, but there was no clear difference in HDL-C, LDL-C, or triglyceride levels. Canagliflozin was generally well tolerated. While documented hypoglycemia occurred in 14% of patients on placebo, the frequency of hypoglycemia with the addition of canagliflozin was similar. There was an increased frequency of genital mycotic infections in both men (5.1%) and women (10.4%) in both canagliflozin groups combined, relative to the placebo group (0%), and their frequency increased in the higher-dose group. There was a slightly higher rate of renal impairment in those treated with canagliflozin versus placebo (2.1% vs 0%).

      Implications

      After 52 weeks, patients receiving canagliflozin added to background SU had sustained reductions in HbA1c and fasting plasma glucose, without increasing hypoglycemia and body weight; safety findings were generally consistent with the known safety profile of the drug. ClinicalTrials.gov identifier: NCT01032629.

      Key words

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      References

        • Farag Y.M.
        • Gaballa M.R.
        Diabesity: an overview of a rising epidemic.
        Nephrol Dialysis Transplant. 2011; 26 (Accessed October 2017.): 28-35
      1. National Institute for Health and Care Excellence (NICE). Type 2 diabetes in adults: management. https://www.nice.org.uk/guidance/ng28. Accessed October 2017.

        • Sarwar N.
        • Gao P.
        • Seshasai S.R.
        • et al.
        Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies.
        Lancet. 2010; 375 (https://www.ncbi.nlm.nih.gov/pubmed/20609967. Accessed October 2017): 2215-2222
        • Liebl A.
        • Khunti K.
        • Orozco-Beltran D.
        • Yale J.F.
        Health economic evaluation of type 2 diabetes mellitus: a clinical practice focused review.
        Clin Med Insights Endocrinol Diabetes. 2015; 8 (Accessed October 2017.): 13-19
        • Inzucchi S.E.
        • Bergenstal R.M.
        • Buse J.B.
        • et al.
        Management of hyperglycaemia 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).
        Diabetologia. 2012; 55: 1577-1596
        • American Diabetes Association
        Standards of medical care in diabetes--2015: summary of revisions.
        Diabetes Care. 2015; 38 (Accessed October 2017.): S4
        • Neumiller J.J.
        • White Jr., J.R.
        • Campbell R.K.
        Sodium-glucose co-transport inhibitors: progress and therapeutic potential in type 2 diabetes mellitus.
        Drugs. 2010; 70: 377-385
        • 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: 1232-1238
        • Polidori D.
        • Sha S.
        • Ghosh A.
        • et al.
        Validation of a novel method for determining the renal threshold for glucose excretion in untreated and canagliflozin-treated subjects with type 2 diabetes mellitus.
        J Clin Endocrinol Metab. 2013; 98: E867-E871
        • AstraZeneca Canada Inc
        PRFORXIGA® [product monograph].
        AstraZeneca Canada Inc, Mississauga, ON2016
        • Janssen Inc
        PrINVOKAMET® [product monograph].
        Janssen, Inc, Raritan, NJ2017
        • Boehringer Ingelheim (Canada) Ltd
        PrJARDIANCE™ [product monograph].
        Boehringer Ingelheim (Canada) Ltd, Burlington, ONJanuary 9, 2017
      2. US Food and Drug Administration. FDA Drug Safety Communication: FDA revises labels of SGLT2 inhibitors for diabetes to include warnings about too much acid in the blood and serious urinary tract infections. https://www.fda.gov/Drugs/DrugSafety/ucm475463.htm. Accessed June 1, 2017.

      3. European Medicines Agency. EMA confirms recommendations to minimise ketoacidosis risk with SGLT2 inhibitors for diabetes. http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2016/02/WC500202388.pdf. Accessed October 2017

        • Stenlof K.
        • Cefalu W.T.
        • Kim K.A.
        • 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: 372-382
        • Cefalu W.T.
        • Leiter L.A.
        • 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: 941-950
        • Devineni D.
        • Morrow L.
        • Hompesch M.
        • et al.
        Canagliflozin improves glycaemic control over 28 days in subjects with type 2 diabetes not optimally controlled on insulin.
        Diabetes Obes Metab. 2012; 14: 539-545
        • Qiu R.
        • Balis D.
        • Capuano G.
        • et al.
        Canagliflozin: Efficacy and Safety in Combination with Metformin Alone or with Other Antihyperglycemic Agents in Type 2 Diabetes.
        Diabetes Ther. 2016; 7 (Accessed October 2017.): 659-678
        • Neal B.
        • Perkovic V.
        • Matthews D.R.
        • et al.
        Rationale, design and baseline characteristics of the CANagliflozin cardioVascular Assessment Study-Renal (CANVAS-R): A randomized, placebo-controlled trial.
        Diabetes Obes Metab. 2017; 19: 387-393
        • Fulcher G.
        • Matthews D.R.
        • Perkovic V.
        • et al.
        Efficacy and Safety of Canagliflozin Used in Conjunction with Sulfonylurea in Patients with Type 2 Diabetes Mellitus: A Randomized, Controlled Trial.
        Diabetes Ther. 2015; 6 (Accessed October 2017.): 289-302
        • Wilding J.P.
        • 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: 1267-1282
        • Strojek K.
        • Yoon K.H.
        • Hruba V.
        • et al.
        Dapagliflozin added to glimepiride in patients with type 2 diabetes mellitus sustains glycemic control and weight loss over 48 weeks: a randomized, double-blind, parallel-group, placebo-controlled trial.
        Diabetes Ther. 2014; 5 (Accessed October 2017.): 267-283
        • Neal B.
        • Perkovic V.
        • Mahaffey K.W.
        • et al.
        Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes.
        N Engl J Med. 2017; 377 (Accessed October 2017.): 644-657