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

Abstract

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

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

“…This concern was initially raised about off‐label use of SGLT2 inhibitors in patients with type 1 DM 51, 52. Later in 2015, based on first‐year postmarketing surveillance reporting of 20 DKA cases, the FDA issued a statement warning that SGLT2 inhibitors might increase the risk of DKA 53.…”

Diabetic Ketoacidosis in a Patient with Type 1 Diabetes on Sodium-glucose Co-transporter-2 Inhibitors—a Case Report

“…[5][6][7][8][9][10] Use of SGLT2 inhibitors was associated with improvements in average glucose control, reduced postprandial hyperglycemia and glycemic variability, reduced body weight, and reduced insulin dose requirements. [11][12][13] Dual SGLT1/2 inhibitor, sotagliflozin, has also demonstrated significant reductions in HbA1c, postprandial glucose, weight, and insulin doses.…”

Sodium-glucose Co-transporter-2 Inhibitors in Type 1 Diabetes—a Dangerous Ally

“…18 In an 18-week, phase 2 study including 351 patients on multiple daily injections or CSII, canagliflozin was associated with decreases in HbA1c, insulin dose and body weight. 19 Eighty-nine of these participants underwent CGM and canagliflozin use was associated with improved indices of glycemic variability. 20 In another CGM study, significant reductions in mean blood glucose, CGM standard deviation, time spent in hyperglycemia, HbA1c, weight, systolic blood pressure (SBP), and total daily insulin dose were reported in 27 patients with canagliflozin as add-on to insulin.…”

“…The prevalence of overweight and obesity among newly diagnosed T1D subjects was 21-22% in the [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] year age group in the Pediatric Diabetes Consortium and the SEARCH for Diabetes in Youth study. 1,2 This has been attributed to a general worldwide increase in prevalence of obesity and similar risk factors such as family history, ethnicity, and sedentary lifestyle may be contributory.…”