Julio Rosenstock1, Leonard Chuck2, Manuel González-Ortiz3, Kate Merton4, Jagriti Craig4, George Capuano4, Rong Qiu4. 1. Dallas Diabetes and Endocrine Center at Medical City, Dallas, TX juliorosenstock@dallasdiabetes.com. 2. Diablo Clinical Research, Walnut Creek, CA. 3. Institute of Experimental and Clinical Therapeutics, Physiology Department, Health Science University Center, University of Guadalajara, Guadalajara, Mexico. 4. Janssen Research & Development, LLC, Raritan, NJ.
Abstract
OBJECTIVE: This study assessed the efficacy/safety of canagliflozin (CANA), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, plus metformin extended-release (MET) initial therapy in drug-naïve type 2 diabetes. RESEARCH DESIGN AND METHODS: This 26-week, double-blind, phase 3 study randomized 1,186 patients to CANA 100 mg (CANA100)/MET, CANA 300 mg (CANA300)/MET, CANA100, CANA300, or MET. Primary end point was change in HbA(1c) at week 26 for combinations versus monotherapies. Secondary end points included noninferiority in HbA(1c) lowering with CANA monotherapy versus MET; changes in fasting plasma glucose, body weight, and blood pressure; and proportion of patients achieving HbA(1c) <7.0% (<53 mmol/mol). RESULTS: From mean baseline HbA(1c) of 8.8% (73 mmol/mol), CANA100/MET and CANA300/MET significantly lowered HbA(1c) versus MET (median dose, 2,000 mg/day) by -1.77%, -1.78%, and -1.30% (-19.3, -19.5, and -14.2 mmol/mol; differences of -0.46% and -0.48% [-5.0 and -5.2 mmol/mol]; P = 0.001) and versus CANA100 and CANA300 by -1.37% and -1.42% (-15.0 and -15.5 mmol/mol; differences of -0.40% and -0.36% [-4.4 and -3.9 mmol/mol]; P = 0.001). CANA100 and CANA300 monotherapy met noninferiority for HbA(1c) lowering and had significantly more weight loss versus MET (-2.8, -3.7, and -1.9 kg [-3.0%, -3.9%, and -2.1%]; P = 0.016 and P = 0.002). Greater attainment of HbA(1c) <7.0% (50%, 57%, and 43%) and significantly more weight loss (-3.2, -3.9, and -1.9 kg [-3.5%, -4.2%, and -2.1%]; P = 0.001) occurred with CANA100/MET and CANA300/MET versus MET. The incidence of adverse events (AEs) related to SGLT2 inhibition (genital mycotic infections, osmotic diuresis- and volume depletion-related AEs) was higher in the CANA arms (0.4-4.4%) versus MET (0-0.8%). AE-related discontinuation rates were 1.3-3.0% across groups. The incidence of hypoglycemia was 3.0-5.5% in the CANA arms and 4.6% with MET. CONCLUSIONS: Initial therapy with CANA plus MET was more effective and generally well tolerated versus each monotherapy in drug-naïve type 2 diabetes. CANA monotherapy demonstrated noninferior HbA1c lowering versus MET.
RCT Entities:
OBJECTIVE: This study assessed the efficacy/safety of canagliflozin (CANA), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, plus metformin extended-release (MET) initial therapy in drug-naïve type 2 diabetes. RESEARCH DESIGN AND METHODS: This 26-week, double-blind, phase 3 study randomized 1,186 patients to CANA 100 mg (CANA100)/MET, CANA 300 mg (CANA300)/MET, CANA100, CANA300, or MET. Primary end point was change in HbA(1c) at week 26 for combinations versus monotherapies. Secondary end points included noninferiority in HbA(1c) lowering with CANA monotherapy versus MET; changes in fasting plasma glucose, body weight, and blood pressure; and proportion of patients achieving HbA(1c) <7.0% (<53 mmol/mol). RESULTS: From mean baseline HbA(1c) of 8.8% (73 mmol/mol), CANA100/MET and CANA300/MET significantly lowered HbA(1c) versus MET (median dose, 2,000 mg/day) by -1.77%, -1.78%, and -1.30% (-19.3, -19.5, and -14.2 mmol/mol; differences of -0.46% and -0.48% [-5.0 and -5.2 mmol/mol]; P = 0.001) and versus CANA100 and CANA300 by -1.37% and -1.42% (-15.0 and -15.5 mmol/mol; differences of -0.40% and -0.36% [-4.4 and -3.9 mmol/mol]; P = 0.001). CANA100 and CANA300 monotherapy met noninferiority for HbA(1c) lowering and had significantly more weight loss versus MET (-2.8, -3.7, and -1.9 kg [-3.0%, -3.9%, and -2.1%]; P = 0.016 and P = 0.002). Greater attainment of HbA(1c) <7.0% (50%, 57%, and 43%) and significantly more weight loss (-3.2, -3.9, and -1.9 kg [-3.5%, -4.2%, and -2.1%]; P = 0.001) occurred with CANA100/MET and CANA300/MET versus MET. The incidence of adverse events (AEs) related to SGLT2 inhibition (genital mycotic infections, osmotic diuresis- and volume depletion-related AEs) was higher in the CANA arms (0.4-4.4%) versus MET (0-0.8%). AE-related discontinuation rates were 1.3-3.0% across groups. The incidence of hypoglycemia was 3.0-5.5% in the CANA arms and 4.6% with MET. CONCLUSIONS: Initial therapy with CANA plus MET was more effective and generally well tolerated versus each monotherapy in drug-naïve type 2 diabetes. CANA monotherapy demonstrated noninferior HbA1c lowering versus MET.
Authors: Simon A Hawley; Rebecca J Ford; Brennan K Smith; Graeme J Gowans; Sarah J Mancini; Ryan D Pitt; Emily A Day; Ian P Salt; Gregory R Steinberg; D Grahame Hardie Journal: Diabetes Date: 2016-07-05 Impact factor: 9.461