Canagliflozin improves glycaemic control over 28 days in subjects with type 2 diabetes not optimally controlled on insulin

Abstract

Aim:Canagliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor that is being investigated for the treatment of type 2 diabetes mellitus (T2DM). Methods:This was a randomized, double-blind, placebo-controlled, parallel-group, 28-day study conducted at two sites, in 29 subjects with T2DM not optimally controlled on insulin and up to one oral antihyperglycaemic agent. Subjects were treated with canagliflozin 100 mg QD or 300 mg twice daily (BID) or placebo. Safety, tolerability, pharmacokinetic characteristics and pharmacodynamic effects of canagliflozin were examined. Glucose malabsorption following a 75-g oral glucose challenge was also examined.Results: Canagliflozin pharmacokinetics were dose-dependent, and the elimination half-life ranged from 12 to 15 h. After 28 days, the renal threshold for glucose excretion was reduced; urinary glucose excretion was increased; and A1C, fasting plasma glucose and body weight decreased in subjects administered canagliflozin (A1C reductions: 0.19% with placebo, 0.73% with 100 mg QD, 0.92% with 300 mg BID; body weight changes: 0.03 kg increase with placebo, 0.73 kg reduction with 100 mg QD, 1.19 kg reduction with 300 mg BID). Glucose malabsorption was not observed with canagliflozin treatment. There were no deaths, serious adverse events or severe hypoglycaemic episodes. The incidence of adverse events was similar across groups. There were no clinically meaningful changes in routine laboratory safety tests, vital signs or electrocardiograms. Conclusion:In subjects receiving insulin and oral antihyperglycaemic therapy, canagliflozin was well tolerated without evidence for glucose malabsorption, had pharmacokinetic characteristics consistent with once-daily dosing, and improved glycaemic control.

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).…”

“…It has been reported that SGLT2 inhibitors increase urinary output by between 107 and 470 mL/d 69. Therefore, the increased urinary sodium excretion may reduce plasma volume, resulting in reduced BP, particularly with increasing age 20. Moreover, Imprialos et al have also reported a potential direct natriuretic effect of SGLT2 inhibitors 67…”

“…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)

“…Canagliflozin lowers plasma glucose by promoting urinary glucose excretion, which results in a mild osmotic diuresis that may be associated with a reduction in intravascular volume 6, 7, 8, 9. 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.…”

Efficacy and Safety of Canagliflozin, a Sodium–Glucose Cotransporter 2 Inhibitor, as Add-on to Insulin in Patients With Type 1 Diabetes

“…Canagliflozin reduces blood glucose levels through an insulin-independent mechanism by lowering the renal threshold for glucose and increasing urinary glucose excretion, which results in a mild osmotic diuresis and net caloric loss (11)(12)(13). In phase 3 studies, canagliflozin improved glycemic control, reduced body weight and blood pressure, and was generally well tolerated across a broad range of patients with type 2 diabetes (10,14).…”