Canagliflozin Provides Durable Glycemic Improvements and Body Weight Reduction Over 104 Weeks Versus Glimepiride in Patients With Type 2 Diabetes on Metformin: A Randomized, Double-Blind, Phase 3 Study

Abstract

OBJECTIVETo assess the efficacy/safety of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, compared with glimepiride over 104 weeks in patients with type 2 diabetes inadequately controlled with metformin. RESEARCH DESIGN AND METHODSIn this randomized, double-blind study, patients (N = 1,450) received canagliflozin 100 or 300 mg or glimepiride (titrated up to 6 or 8 mg/day) during a 52-week core period followed by a 52-week extension. RESULTSAt week 104, reductions from baseline in A1C were 20.65%, 20.74%, and 20.55% (27.1, 28.1, and 26.0 mmol/mol) with canagliflozin 100 and 300 mg and glimepiride, respectively. Durability analyses showed sustained A1C lowering with both canagliflozin doses versus glimepiride. Reductions in body weight (24.1%, 24.2%, and 0.9%, respectively) and systolic blood pressure (22.0, 23.1, and 1.7 mmHg, respectively) were seen with canagliflozin 100 and 300 mg compared with glimepiride at week 104. The overall adverse event (AE) incidence was 73.3%, 77.9%, and 78.4% with canagliflozin 100 and 300 mg and glimepiride; the incidence of AE-related discontinuations was low across groups (6.2%, 9.5%, and 7.3%, respectively). Incidences of genital mycotic infections, urinary tract infections, and osmotic diuresis-related AEs were higher with canagliflozin than glimepiride; these were generally mild to moderate in intensity and led to few discontinuations. Fewer patients had hypoglycemia episodes with canagliflozin 100 and 300 mg than glimepiride (6.8%, 8.2%, and 40.9%). Mild decreases in estimated glomerular filtration rate occurred initially with canagliflozin; these attenuated over 104 weeks. CONCLUSIONSCanagliflozin provided durable glycemic improvements compared with glimepiride and was generally well tolerated in patients with type 2 diabetes receiving background treatment with metformin over 104 weeks.

Cardiovascular Safety, Long‐Term Noncardiovascular Safety, and Efficacy of Sodium–Glucose Cotransporter 2 Inhibitors in Patients With Type 2 Diabetes Mellitus: A Systemic Review and Meta‐Analysis With Trial Sequential Analysis

“…11, 12, 22, 23, 24, 25, 26, 27, 28, 29, 30 For cardiovascular outcomes analysis, 3 RCTs11, 12, 22 and 2 observational studies23, 24 were included with 351 476 patients and median follow‐up of 3.1 years. Nine RCTs contributed to the analysis of long‐term noncardiovascular safety and efficacy of SGLT2 inhibitors, with a medium follow‐up of 2 years 11, 12, 22, 25, 26, 27, 28, 29, 30. All trials were carried out with patients who had type 2 DM.…”

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

“…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…”