AimsCanagliflozin is a sodium glucose co-transporter 2 inhibitor in development for type 2 diabetes mellitus (T2DM). The efficacy and safety of canagliflozin were evaluated in subjects with T2DM inadequately controlled with diet and exercise.MethodsIn this 26-week, randomized, double-blind, placebo-controlled, phase 3 trial, subjects (N = 584) received canagliflozin 100 or 300 mg or placebo once daily. Primary endpoint was the change from baseline in haemoglobin A1c (HbA1c) at week 26. Secondary endpoints included the proportion of subjects achieving HbA1c < 7.0%; change from baseline in fasting plasma glucose (FPG), 2-h postprandial glucose (PPG) and systolic blood pressure (BP); and percent change in body weight, high-density lipoprotein cholesterol (HDL-C) and triglycerides. Adverse events (AEs) were recorded throughout the study.ResultsAt week 26, HbA1c was significantly reduced from baseline with canagliflozin 100 and 300 mg compared with placebo (−0.77, −1.03 and 0.14%, respectively; p < 0.001 for both). Both canagliflozin doses significantly decreased FPG, 2-h PPG, body weight and systolic BP (p < 0.001 for all), and increased HDL-C compared with placebo (p < 0.01 for both). Overall incidences of AEs were modestly higher with canagliflozin versus placebo; rates of serious AEs and AE-related discontinuations were low and similar across groups. Incidences of genital mycotic infections, urinary tract infections and osmotic diuresis-related AEs were higher with canagliflozin; these led to few discontinuations. The incidence of hypoglycaemia was low across groups.ConclusionCanagliflozin treatment improved glycaemic control, reduced body weight and was generally well tolerated in subjects with T2DM inadequately controlled with diet and exercise.

OBJECTIVEThis study assessed the efficacy and safety of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, as add-on to insulin in adults with type 1 diabetes. RESEARCH DESIGN AND METHODSThis 18-week, double-blind, phase 2 study randomized 351 patients (HbA 1c 7.0-9.0% [53-75 mmol/mol]) on multiple daily insulin injections or continuous subcutaneous insulin infusion to canagliflozin 100 or 300 mg or placebo. The primary end point was the proportion of patients achieving at week 18 both HbA 1c reduction from baseline of ‡0.4% ( ‡4.4 mmol/mol) and no increase in body weight. Other end points included changes in HbA 1c , body weight, and insulin dose, as well as hypoglycemia incidence. Safety was assessed by adverse event (AE) reports. RESULTSMore patients had both HbA 1c reduction ‡0.4% and no increase in body weight with canagliflozin 100 and 300 mg versus placebo at week 18 (36.9%, 41.4%, 14.5%, respectively; P < 0.001). Both canagliflozin doses provided reductions in HbA 1c , body weight, and insulin dose versus placebo over 18 weeks. The incidence of hypoglycemia was similar across groups; severe hypoglycemia rates were low (1.7-6.8%). Overall incidence of AEs was 55.6%, 67.5%, and 54.7% with canagliflozin 100 and 300 mg and placebo; discontinuation rates were low (0.9-1.3%). Increased incidence of ketone-related AEs (5.1%, 9.4%, 0%), including the specific AE of diabetic ketoacidosis (DKA) (4.3%, 6.0%, 0%), was seen with canagliflozin 100 and 300 mg versus placebo. CONCLUSIONSCanagliflozin provided reductions in HbA 1c , body weight, and insulin dose with no increase in hypoglycemia, but increased rates of ketone-related AEs, including DKA, in adults with type 1 diabetes inadequately controlled with insulin.Type 1 diabetes is an autoimmune disease characterized by progressive destruction of pancreatic b-cells, resulting in loss of endogenous insulin production and hyperglycemia (1). Consequently, treatment of type 1 diabetes requires lifelong insulin therapy to maintain normal blood glucose levels. Type 1 diabetes is associated with increased morbidity and mortality related to microvascular and macrovascular

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.

OBJECTIVETo assess the efficacy and safety of MK-0941, a glucokinase activator (GKA), when added to stable-dose insulin glargine in patients with type 2 diabetes.RESEARCH DESIGN AND METHODSIn this double-blind study, 587 patients taking stable-dose insulin glargine (±metformin ≥1,500 mg/day) were randomized (1:1:1:1:1) to MK-0941 10, 20, 30, or 40 mg or matching placebo t.i.d. before meals (a.c.). This study included an initial 14-week, dose-ranging phase followed by a 40-week treatment phase during which patients were to be uptitrated as tolerated to 40 mg (or placebo) t.i.d. a.c. The primary efficacy end point was change from baseline in A1C at Week 14.RESULTSAt Week 14, A1C and 2-h postmeal glucose (PMG) improved significantly versus placebo with all MK-0941 doses. Maximal placebo-adjusted least squares mean changes from baseline in A1C (baseline A1C 9.0%) and 2-h PMG were −0.8% and −37 mg/dL (−2 mmol/L), respectively. No significant effects on fasting plasma glucose were observed at any dose versus placebo. By 30 weeks, the initial glycemic responses noted at 14 weeks were not sustained. MK-0941 at one or more doses was associated with significant increases in the incidence of hypoglycemia, triglycerides, systolic blood pressure, and proportion of patients meeting criteria for predefined limits of change for increased diastolic blood pressure.CONCLUSIONSIn patients receiving stable-dose insulin glargine, the GKA MK-0941 led to improvements in glycemic control that were not sustained. MK-0941 was associated with an increased incidence of hypoglycemia and elevations in triglycerides and blood pressure.

Canagliflozin monotherapy provided sustained improvement in glycemic control and body weight reduction, and was generally well tolerated in patients with T2DM over 52 weeks.

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The sodium glucose co-transporter 2 (SGLT2) inhibitor canagliflozin is a novel treatment option for adults with type 2 diabetes mellitus (T2DM). In patients with hyperglycemia, SGLT2 inhibition lowers plasma glucose levels by reducing the renal threshold for glucose (RT G ) and increasing urinary glucose excretion (UGE). Increased UGE is also associated with a mild osmotic diuresis and net caloric loss, which can lead to reductions in body weight and blood pressure (BP). After promising results from preclinical and phase I/II studies, the efficacy and safety of canagliflozin was evaluated in a comprehensive phase III development program in over 10,000 patients with T2DM on various background therapies. Canagliflozin improved glycemic control and provided reductions in body weight and BP versus placebo and active comparators in studies of up to 2 years' duration. Canagliflozin was generally well tolerated, with higher incidences of adverse events (AEs) related to the mechanism of action, including genital mycotic infections and AEs related to osmotic diuresis. Results from the preclinical and clinical studies led canagliflozin to be the first-in-class SGLT2 inhibitor approved in the United States, and support canagliflozin as a safe and effective therapeutic option across a broad range of patients with T2DM.

Chronic sitagliptin treatment improves glycemic control by lowering the appearance of oral glucose, postprandial endogenous glucose release, and glucagon response, and by improving insulin sensitivity and β-cell glucose sensing in response to both oral and iv glucose.