Efficacy and safety of Canagliflozin (CANA), an inhibitor of Sodium Glucose Co-Transporter 2 (SGLT2), added on to insulin therapy with or without oral agents in type 2 diabetes (T2D)
Question: SGLT2 inhibition is a novel treatment modality for T2D. We report here a pre-specified substudy of the CANagliflozin cardioVascular Assessment Study (CANVAS) defining the efficacy and safety of CANA in subjects with T2D on insulin.
Methodology: CANVAS is a double-blind, placebo (PBO)-controlled study that randomized 4,330 individuals at elevated cardiovascular risk to the addition of CANA 100 or 300 mg or PBO once daily to stable ongoing diabetes therapy. The subgroup using insulin (≥30 IU/d) included 565, 566, and 587 subjects, respectively. Primary endpoint for this substudy was change from baseline in HbA1c at 18 weeks while insulin doses were to be kept unchanged per protocol. Major vascular outcomes remained blinded.
Results: Baseline demographics showed no imbalances; 67% of subjects were male and 59% had a history of a prior vascular event. Mean baseline characteristics were age 63 y, HbA1c 8.3%, BMI 33.8 kg/m2, body weight 97.0 kg, fasting plasma glucose (FPG) 9.4 mmol/L, total cholesterol 4.3 mmol/L, and blood pressure (BP) 138/76 mmHg. Mean insulin dose at baseline was 83 IU/d (most using basal/bolus regimens); median duration of diabetes was 15 y. CANA 100 and 300 mg improved measures of glycaemia compared with PBO, with PBO-subtracted reductions in HbA1c (-0.65% and -0.73%) and FPG (-1.3 and -1.6 mmol/L), and a greater proportion of subjects reaching HbA1c < 7.0% than PBO (19.8%, 24.7%, and 7.7%, respectively) (P< 0.001 for all). Relative to PBO, CANA 100 and 300 mg reduced body weight (-1.9% and -2.4%) and systolic BP (-2.6 and -4.4 mmHg) (P< 0.001 for all), with increases in HDL-C (0.8% and 4.7%; P< 0.001 for CANA 300 mg; P= NS for CANA 100 mg), LDL-C (6.3% and 6.6%), total cholesterol (1.0% and 3.3%), and LDL-C/HDL-C ratio (4.9% and 1.9%); small changes in triglycerides were seen (0.2% and -2.0%; P= NS).
AEs were reported for CANA 100 and 300 mg and PBO in 63%, 65%, and 59% of subjects and serious AEs in 5.5%, 4.9%, and 6.4%, respectively. Rate of AEs leading to discontinuation was higher with CANA 300 mg (5.3%) than CANA 100 mg or PBO (both 1.9%). Genital mycotic infections were more common with CANA 100 and 300 mg than PBO (female: 11.8%, 9.9%, and 2.2%; male: 4.0%, 8.3%, and 0.5%, respectively), as were AEs of pollakiuria (3.7%, 5.6%, and 0.5%, respectively) and hypotension (1.2%, 2.6%, and 0%, respectively). Higher incidence of UTI was seen with CANA 300 mg (3.4%) than CANA 100 mg or PBO (2.3% and 2.1%, respectively) although rates for all groups were low. Incidence of hypoglycaemia was higher with CANA 100 and 300 mg (both 49%) than PBO (37%).
Conclusions: CANA added to stable insulin therapy improved glycaemic control and produced significant improvements in a number of efficacy parameters important in the management of T2D with effects of the 300 mg dose numerically greater than the 100 mg dose. CANA was generally well tolerated but was associated with a greater frequency of genital mycotic infections and hypoglycaemia.