Efficacy and Safety of Canagliflozin, an Inhibitor of Sodium–Glucose Cotransporter 2, When Used in Conjunction With Insulin Therapy in Patients With Type 2 Diabetes

Abstract

OBJECTIVEThere are limited data about the effects of sodium-glucose cotransporter 2 inhibitors when used with insulin. We report the efficacy and safety of canagliflozin in patients with type 2 diabetes using insulin. RESEARCH DESIGN AND METHODSThe CANagliflozin CardioVascular Assessment Study is a double-blind, placebocontrolled study that randomized participants to placebo, canagliflozin 100 mg, or canagliflozin 300 mg once daily, added to a range of therapies. The primary end point of this substudy was the change in HbA 1c from baseline at 18 weeks among patients using insulin; 52-week effects were also examined. RESULTSIndividuals receiving insulin at baseline were randomized to receive placebo (n 5 690), canagliflozin 100 mg (n 5 692), or canagliflozin 300 mg (n 5 690). These individuals were 66% male and had a median age of 63 years, mean HbA 1c of 8.3% (67 mmol/mol), BMI of 33.1 kg/m 2 , estimated glomerular filtration rate of 75 mL/min/1.73 m 2 , fasting plasma glucose of 9.2 mmol/L, and a median daily insulin dose of 60 IU. Most individuals were using basal/bolus insulin. Reductions in HbA 1c with canagliflozin 100 and 300 mg versus placebo were 20. 62% (95% CI 20.69, 20.54; 26.8 mmol/mol [95% CI 27.5,25.9]; P < 0.001) and 20. 73% (95% CI 20.81, 20.65; 28.0 mmol/mol [95% CI 28.9,27.1]; P < 0.001) at 18 weeks and 20. 58% (95% CI 20.68, 20.48; 26.3 mmol/mol [95% CI 27.4, 25.2]) and 20.73% (95% CI 20. 83, 20.63; 28.0 mmol/mol [95% CI 29.1,26.9]) at 52 weeks. There were significant falls in fasting plasma glucose, body weight, and blood pressure at both time points and there was a greater incidence of hypoglycemia, genital mycotic infections, and hypovolemia with both canagliflozin doses. CONCLUSIONSCanagliflozin added to insulin therapy improved glycemic control and decreased body weight. There was a greater frequency of several anticipated side effects, although few led to discontinuation of treatment.

Effect of Sodium‐Glucose Cotransport‐2 Inhibitors on Blood Pressure in People With Type 2 Diabetes Mellitus: A Systematic Review and Meta‐Analysis of 43 Randomized Control Trials With 22 528 Patients

“…These studies were published between 2008 and 2015 from 14 countries including the United States of America (8 studies), United Kingdom (8 studies), Japan (5 studies), Germany (5 studies), Canada (4 studies), Italy (3 studies), Sweden (3 studies), and 1 study from each of Mexico, Austria, Netherlands, Finland, Poland, China, and Australia. The number of participants included in studies ranged from 2720 to 2072 47. All of these studies were randomized clinical trials with durations of 4 weeks (1 trial), 12 weeks (12 trials), 24 weeks (11 trials), 26 weeks (4 trials), 48 weeks (2 trials), 52 weeks (7 trials), 102 weeks (2 trials), 104 weeks (2 trials), and 208 weeks (1 trial).…”

“…Data were sorted by first author, year of publication, country of the study, design, age range of the participants, total sample size, SGLT2 inhibitor, comparator, number of patients, dosage, and follow‐up duration (Table 1). 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55 …”

Tolerability of canagliflozin in patients with type 2 diabetes mellitus fasting during Ramadan: Results of the Canagliflozin in Ramadan Tolerance Observational Study (CRATOS)

“…While the insulin‐independent mechanism of canagliflozin leads to a low inherent risk of hypoglycaemia, the mild osmotic diuresis it causes may be associated with an increased risk of volume–depletion events, including dehydration. Across Phase 3 studies in a broad range of patients, canagliflozin provided reductions in HbA1c, body weight, and systolic blood pressure (BP) and was generally well tolerated, with a low risk of hypoglycaemia when not used in conjunction with insulin or sulphonylureas 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22. An analysis of T2DM patients living in hot climates found that canagliflozin treatment was generally well tolerated, with a low incidence of volume depletion–related AEs 23…”

Initial Combination Therapy With Canagliflozin Plus Metformin Versus Each Component as Monotherapy for Drug-Naïve Type 2 Diabetes

“…Canagliflozin (CANA) is an SGLT2 inhibitor developed for the treatment of adults with type 2 diabetes (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23). CANA lowers the renal threshold for glucose, thereby increasing urinary glucose excretion (UGE); increased UGE results in insulinindependent glucose-lowering effects, as well as a mild osmotic diuresis and net caloric loss that can lead to weight loss and blood pressure (BP) reductions (24,25).…”