title: Rationale and design of a randomized trial to test the safety and non-inferiority of canagliflozin in patients with diabetes with chronic heart failure: the CANDLE trial.
abstract: BACKGROUND
  Because type 2 diabetes mellitus is associated strongly with an increased risk of cardiovascular diseases, the number of patients with diabetes with chronic heart failure is increasing steadily. However, clinical evidence of therapeutic strategies in such patients is still lacking. A recent randomized, placebo-controlled trial in patients with type 2 diabetes with high cardiovascular risk demonstrated that the SGLT2 inhibitor, empagliflozin, reduced the incidence of hospitalization for heart failure. Because SGLT2 inhibitors cause a reduction in body weight and blood pressure in addition to improving glycemic control, they have the potential to exert beneficial effects on the clinical pathophysiology of heart failure. The aim of the ongoing CANDLE trial is to test the safety and non-inferiority of canagliflozin, another SGLT2 inhibitor, compared with glimepiride, a sulfonylurea agent, in patients with type 2 diabetes mellitus and chronic heart failure.
  
  
  METHODS
  A total of 250 patients with type 2 diabetes who are drug-naïve or taking any anti-diabetic agents and suffering from chronic heart failure with a New York Heart Association classification I to III will be randomized centrally into either canagliflozin or glimepiride groups (1: 1) using the dynamic allocation method stratified by age (<65, ≥65 year), HbA1c level (<6.5, ≥6.5 %), and left ventricular ejection fraction (<40, ≥40 %). After randomization, all the participants will be given the add-on study drug for 24 weeks in addition to their background therapy. The primary endpoint is the percentage change from baseline in NT-proBNP after 24 weeks of treatment. The key secondary endpoints after 24 weeks of treatment are the change from baseline in glycemic control, blood pressure, body weight, lipid profile, quality of life score related to heart failure, and cardiac and renal function.
  
  
  CONCLUSIONS
  The CANDLE trial is the first to assess the safety and non-inferiority of canagliflozin in comparison with glimepiride in patients with type 2 diabetes with chronic heart failure. This trial has the potential to evaluate the clinical safety and efficacy of canagliflozin on heart failure. Trial registration Unique trial Number, UMIN000017669.
authors.affiliation: Department of Cardiovascular Medicine, Saga University, Saga, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tanaka
authors.affiliation: Department of Cardiovascular Medicine, Dokkyo Medical University School of Medicine, Mibu, Japan.
authors.forename: Teruo
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Department of Clinical Medicine and Development, National Cerebral and Cardiovascular Center, Suita, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kitakaze
authors.affiliation: Department of Advanced Cardiology, Saga University, Saga, Japan.
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Oyama
authors.affiliation: Department of Cardiovascular Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Sata
authors.affiliation: Department of Cardiology, Koshigaya Hospital, Dokkyo Medical University, Koshigaya, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Taguchi
authors.affiliation: Department of Cardiovascular Medicine, Nippon Medical School, Tokyo, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Shimizu
authors.affiliation: Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Watada
authors.affiliation: Department of Cardiology, Tokyo Medical University, Tokyo, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Tomiyama
authors.affiliation: Department of Cardiovascular Medicine, Kitasato University School of Medicine, Sagamihara, Japan.
authors.forename: Junya
authors.initials: J
authors.lastname: Ako
authors.affiliation: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Sakata
authors.affiliation: Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Japan.
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Anzai
authors.affiliation: Kansai Rosai Hospital Cardiovascular Center, Amagasaki, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Uematsu
authors.affiliation: Cardiology Department, Kameda Medical Center, Kamogawa, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Jichi Medical University, Shimotsuke, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Eguchi
authors.affiliation: Department of Cardiology, Tokyo Medical University, Tokyo, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Yamashina
authors.affiliation: First Department of Internal Medicine, Nara Medical University, Kashihara, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Saito
authors.affiliation: The Clinical Research Center, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Department of Clinical Pharmacology & Therapeutics, University of the Ryukyus School of Medicine, Okinawa, Japan.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Ueda
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Murohara
authors.affiliation: Department of Cardiovascular Medicine, Saga University, Saga, Japan. node@cc.saga-u.ac.jp.
authors.forename: Koichi
authors.initials: K
authors.lastname: Node
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001559:Benzhydryl Compounds / Q000627:therapeutic use; D001786:Blood Glucose / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D000068896:Canagliflozin / Q000627:therapeutic use*; D002908:Chronic Disease; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D005260:Female; D005960:Glucosides / Q000627:therapeutic use; D006333:Heart Failure / Q000188:drug therapy / Q000209:etiology*; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008297:Male; D008687:Metformin / Q000627:therapeutic use; D008875:Middle Aged; D011788:Quality of Life; D013453:Sulfonylurea Compounds / Q000627:therapeutic use*
chemical_list: D001559:Benzhydryl Compounds; D001786:Blood Glucose; D005960:Glucosides; D007004:Hypoglycemic Agents; D013453:Sulfonylurea Compounds; D000068896:Canagliflozin; C057619:glimepiride; D008687:Metformin; C570240:empagliflozin
keywords: Canagliflozin; Chronic heart failure; Glimepiride; NT-proBNP; Non-inferiority; SGLT2 inhibitor; Safety; Type 2 diabetes mellitus