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

Abstract

Objective:

Canagliflozin is a sodium glucose co-transporter 2 inhibitor developed for treatment of type 2 diabetes mellitus (T2DM). The long-term efficacy and safety of canagliflozin monotherapy were evaluated over 52 weeks in patients with T2DM inadequately controlled with diet and exercise.

Research design and methods:

This randomized, double-blind, Phase 3 study included a placebo-controlled, 26-week core period (canagliflozin 100 or 300 mg vs placebo) and an active-controlled, 26-week extension (blinded switch of placebo-treated patients to sitagliptin 100 mg [placebo/sitagliptin]).

Clinical trial registration:

ClinicalTrials.gov identifier: NCT01081834.

Main outcome measures:

Efficacy endpoints assessed at 52 weeks included changes in hemoglobin A_1c (HbA_1c), fasting plasma glucose (FPG), and systolic blood pressure (BP); and percentage changes in body weight and fasting plasma lipids. Adverse events (AEs) were recorded throughout the study. Efficacy data are reported for canagliflozin 100 and 300 mg (placebo/sitagliptin group was used to maintain the double-blind and to serve as a control group for safety purposes; not as an efficacy comparator); safety data are reported for canagliflozin 100 and 300 mg and placebo/sitagliptin.

Results:

Efficacy analyses included 451 patients who were randomized and dosed, entered the extension, and did not receive rescue therapy during the core period. Safety analyses included 584 patients who were randomized and dosed. At Week 52, canagliflozin 100 and 300 mg provided dose-related decreases from baseline in HbA_1c of −0.81% and −1.11%. Canagliflozin 100 and 300 mg decreased FPG (−1.5 and −2.2 mmol/L [−27.4 and −39.1 mg/dL]), body weight (−3.3% and −4.4%), and systolic BP (−1.4 and −3.9 mmHg); decreased triglycerides and increased HDL-C and LDL-C were also seen. Over 52 weeks, overall AE rates were 67.2%, 66.0%, and 64.1% with canagliflozin 100 and 300 mg and placebo/sitagliptin; rates of serious AEs and AE-related discontinuations were low across groups. Compared with placebo/sitagliptin, canagliflozin was associated with higher rates of genital mycotic infections and AEs related to osmotic diuresis; these led to few discontinuations. Rates of volume depletion AEs and documented hypoglycemia were low across groups.

Conclusions:

Canagliflozin monotherapy provided sustained improvement in glycemic control and body weight reduction, and was generally well tolerated in patients with T2DM over 52 weeks.

Keywords::

• Body weight reduction
• Canagliflozin
• Glycemic control
• Phase 3 study
• Sodium glucose co-transporter 2 (SGLT2) inhibitor
• Type 2 diabetes mellitus

Transparency

Declaration of funding

Canagliflozin has been developed by Janssen Research & Development LLC, in collaboration with Mitsubishi Tanabe Pharma Corporation. Janssen Research & Development LLC was involved in study design and conduct, and acquisition, analysis, and interpretation of the data. The manuscript was prepared by the authors, with editorial assistance funded by the sponsor. All authors had full access to the data, were responsible for the integrity of the data and the accuracy of the data analysis, and reviewed, edited, and approved the manuscript for publication.

Declaration of financial/other relationships

K.S. and K.-A.K. have no proprietary interest in the tested product, do not have a significant equity interest in the sponsor of the covered study, and have not received significant payments of other sorts from the sponsor. W.T.C. has served as principal investigator on both basic research and clinical research grants received by his institutions from AstraZeneca, Johnson & Johnson, LLC, MannKind Corporation, GlaxoSmithKline, Sanofi, Proctor & Gamble, Nutrition 21, and Lexicon Pharmaceuticals; served as a consultant for Shire Development, LLC, Lexicon Pharmaceuticals, Halozyme Therapeutics, and Intarcia Therapeutics Inc.; and provided a lecture unrelated to product development to key opinion leaders as part of a Novo Nordisk symposium and an agreement made to his institution. E.J. has served on advisory panels for Novo Nordisk, Bristol-Myers Squibb, AstraZeneca, and Laboratorios FAES; served as a principal clinical investigator for Novo Nordisk, Eli Lilly and Company, Boehringer Ingelheim, Merck Sharpe & Dohme, and Janssen; and served on the speakers bureau of Eli Lilly and Company, Novo Nordisk, and Merck Sharpe & Dohme. M.A., R.E., C.T., W.C., and G.M. are full-time employees of Janssen Research & Development LLC, and M.A. owns stock in the company.

CMRO peer reviewers may have received honoraria for their review work. The peer reviewers on this manuscript have disclosed that they have no relevant financial relationships.

Acknowledgments

The authors thank all investigators, study teams, and patients for participating in this study. The authors acknowledge Yue Zhao PhD, who was the statistician on the study and held the position of senior manager at Janssen Research & Development LLC at the time of her death. Editorial support was provided by Kimberly Dittmar PhD of MedErgy, and was funded by Janssen Global Services LLC.

Previous presentation: This study was previously presented, in part, in abstract form at the 73rd Scientific Sessions of the American Diabetes Association, Chicago, IL, 21–25 June 2013.