Cindy Tong

Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise

Canagliflozin 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.

Long-term efficacy and safety of canagliflozin monotherapy in patients with type 2 diabetes inadequately controlled with diet and exercise: findings from the 52-week CANTATA-M study

Abstract Objective: Canagliflozin is a sodium glucose co-transporter 2 inhibitor developed for treatment of type 2 diabetes mellitus (T2DM). The long-term efficacy and safety of canagliflozin monotherapy were evaluated over 52 weeks in patients with T2DM inadequately controlled with diet and exercise. Research design and methods: This randomized, double-blind, Phase 3 study included a placebo-controlled, 26-week core period (canagliflozin 100 or 300 mg vs placebo) and an active-controlled, 26-week extension (blinded switch of placebo-treated patients to sitagliptin 100 mg [placebo/sitagliptin]). Clinical trial registration: ClinicalTrials.gov identifier: NCT01081834. Main outcome measures: Efficacy endpoints assessed at 52 weeks included changes in hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), and systolic blood pressure (BP); and percentage changes in body weight and fasting plasma lipids. Adverse events (AEs) were recorded throughout the study. Efficacy data are reported for canagliflozin 100 and 300 mg (placebo/sitagliptin group was used to maintain the double-blind and to serve as a control group for safety purposes; not as an efficacy comparator); safety data are reported for canagliflozin 100 and 300 mg and placebo/sitagliptin. Results: Efficacy analyses included 451 patients who were randomized and dosed, entered the extension, and did not receive rescue therapy during the core period. Safety analyses included 584 patients who were randomized and dosed. At Week 52, canagliflozin 100 and 300 mg provided dose-related decreases from baseline in HbA1c of −0.81% and −1.11%. Canagliflozin 100 and 300 mg decreased FPG (−1.5 and −2.2 mmol/L [−27.4 and −39.1 mg/dL]), body weight (−3.3% and −4.4%), and systolic BP (−1.4 and −3.9 mmHg); decreased triglycerides and increased HDL-C and LDL-C were also seen. Over 52 weeks, overall AE rates were 67.2%, 66.0%, and 64.1% with canagliflozin 100 and 300 mg and placebo/sitagliptin; rates of serious AEs and AE-related discontinuations were low across groups. Compared with placebo/sitagliptin, canagliflozin was associated with higher rates of genital mycotic infections and AEs related to osmotic diuresis; these led to few discontinuations. Rates of volume depletion AEs and documented hypoglycemia were low across groups. Conclusions: Canagliflozin monotherapy provided sustained improvement in glycemic control and body weight reduction, and was generally well tolerated in patients with T2DM over 52 weeks.

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

OBJECTIVE This 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 METHODS This 18-week, double-blind, phase 2 study randomized 351 patients (HbA1c 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 HbA1c reduction from baseline of ≥0.4% (≥4.4 mmol/mol) and no increase in body weight. Other end points included changes in HbA1c, body weight, and insulin dose, as well as hypoglycemia incidence. Safety was assessed by adverse event (AE) reports. RESULTS More patients had both HbA1c 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 HbA1c, 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. CONCLUSIONS Canagliflozin provided reductions in HbA1c, 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.

Diabetic Ketoacidosis With Canagliflozin, a Sodium–Glucose Cotransporter 2 Inhibitor, in Patients With Type 1 Diabetes

OBJECTIVE To assess the incidence of serious adverse events (AEs) of diabetic ketoacidosis (DKA) with canagliflozin, a sodium–glucose cotransporter 2 inhibitor, as an add-on to insulin in adults with type 1 diabetes. RESEARCH DESIGN AND METHODS In this 18-week, randomized, double-blind, phase 2 study, patients (N = 351; HbA1c 7.0–9.0% [53–75 mmol/mol]) on multiple daily insulin injections or continuous subcutaneous insulin infusion received canagliflozin 100 or 300 mg or placebo once daily. The incidence of ketone-related AEs, defined as any event from a prespecified list of preferred terms (i.e., acidosis, blood ketone body increased, blood ketone body present, DKA, diabetic ketoacidotic hyperglycemic coma, ketoacidosis, ketonemia, ketonuria, ketosis, metabolic acidosis, urine ketone body present), including serious AEs of DKA, was assessed based on AE reports. RESULTS At week 18, the incidence of any ketone-related AE with canagliflozin 100 and 300 mg was 5.1% (n = 6 of 117) and 9.4% (n = 11 of 117), respectively; no patients in the placebo group experienced a ketone-related AE. The incidence of serious AEs of DKA was 4.3% (n = 5 of 117) with canagliflozin 100 mg and 6.0% (n = 7 of 117) with canagliflozin 300 mg; all serious events occurred in the presence of circumstances that are known to potentially precipitate DKA (e.g., infection, insulin pump failure). Among the 12 patients with a serious AE of DKA, blood glucose levels ranged from 9.4 to >44.4 mmol/L (170 to >800 mg/dL). Baseline characteristics were generally similar in patients with and without a ketone-related AE. CONCLUSIONS Canagliflozin was associated with an increased incidence of serious AEs of DKA in patients with type 1 diabetes inadequately controlled with insulin. Mitigation strategies are needed for use in future clinical trials to reduce the risk of DKA with canagliflozin treatment in patients with type 1 diabetes.

Efficacy and safety of canagliflozin by baseline HbA1c and known duration of type 2 diabetes mellitus.

AIMS Canagliflozin, a sodium glucose co-transporter 2 inhibitor, has demonstrated glycemic improvements across studies of patients with type 2 diabetes mellitus (T2DM). The impact of canagliflozin on HbA1c lowering was assessed by baseline HbA1c and known duration of T2DM. METHODS This post hoc analysis pooled data from patients with T2DM enrolled in four 26-week, placebo-controlled, Phase 3 studies of canagliflozin (N=2313). Change in HbA1c from baseline to Week 26 was assessed in the overall population and in subgroups by baseline HbA1c (<8.0%, 8.0%-<9.0%, and ≥9.0%) and known duration of T2DM (<5 years, 5-<10 years, and ≥10 years). RESULTS Relative to placebo, canagliflozin 100 and 300 mg provided greater HbA1c reductions in the overall population. Progressively larger placebo-subtracted reductions in HbA1c with canagliflozin 100 and 300 mg were seen with increasing baseline HbA1c. HbA1c reductions were similar across subgroups based on known duration of T2DM. Both canagliflozin doses were generally well tolerated across subgroups, with a safety and tolerability profile consistent with that seen in Phase 3 studies. CONCLUSIONS Canagliflozin provided glycemic improvements in patients with T2DM across a range of baseline HbA1c and known duration of T2DM.

Effect of canagliflozin, a sodium–glucose cotransporter 2 inhibitor, on measurement of serum 1,5‐anhydroglucitol (坎格列净，一种钠‐葡萄糖共转运体2抑制剂，对血清1,5‐脱水葡萄糖醇测定的影响)

Serum levels of 1,5-anhydroglucitol (1,5-AG) can be used as a measure of glycemic control in patients with diabetes. 1,5-anhydroglucitol is a non-metabolizable glucose analog that competes with glucose for renal reabsorption. In individuals with hyperglycemia, excess plasma glucose that enters the urine prevents renal reabsorption of 1,5-AG, leading to decreased serum 1,5-AG levels. Serum levels of 1,5-AG are determined using an enzymatic assay (GlycoMark; GlycoMark Inc., New York, NY, USA). This test provides a measure of glycemic control on a shorter time scale than measurement of HbA1c levels (1,5-AG reflects changes in plasma glucose over ∼2 weeks vs 8–10 weeks for HbA1c). Measurement of 1,5-AG levels has been used to evaluate the metabolic effects of several antihyperglycemic agents (AHAs); specifically, levels of serum 1,5-AG have been shown to increase when patients with type 2 diabetes mellitus (T2DM) are treated with metformin, glimepiride, or pioglitazone. Potential interference with the results of the 1,5-AG assay (GlycoMark®) has been reported for sodium– glucose cotransporter (SGLT) 2 inhibitors, a new class of AHAs developed for the treatment of patients with T2DM. The SGLT2 inhibitors decrease plasma glucose in patients with hyperglycemia by inhibiting renal glucose reabsorption via SGLT2 (the primary renal transporter responsible for reabsorption of glucose from the urine), thereby increasing urinary glucose excretion. 1,5-anhydroglucitol is transported by SGLT4, but there are no known interactions between 1,5-AG and SGLT2. Interference with the 1,5-AG assay by SGLT2 inhibitors may lead to falsely low serum 1,5-AG measurements in patients with improved glycemic control who are treated with this class of agent. Canagliflozin is an SGLT2 inhibitor approved in the US and by the European Union for the treatment of patients with T2DM. The efficacy of canagliflozin in improving glycemic control, as measured by reductions in HbA1c and fasting and postprandial plasma glucose (FPG and PPG, respectively), and the overall safety and tolerability profile of canagliflozin in patients with T2DM have been reported previously. Herein we report findings from a post hoc analysis of 1,5-AG levels using archived samples from a subset of patients who participated in a randomized, double-blind, placebocontrolled, Phase 3 study of canagliflozin monotherapy in patients with T2DM. Detailed methods from the Phase 3 study of canagliflozin monotherapy have been reported elsewhere. Archived samples (which met manufacturer specifications for storage, namely <3 years at –70°C) from 20 patients each from the canagliflozin 300 mg and placebo treatment groups of that study were included in the present post hoc analysis; this sample size was determined based on an estimate of absolute changes in serum 1,5-AG levels. Archived samples were randomly selected from a pool of samples stored in a central laboratory (Covance, Geneva, Switzerland), from patients with matching baseline and post-baseline (Week 26) samples. In patients included in the present analysis, baseline HbA1c ranged from 6.6% to 9.1%. All patients in the present study provided written informed consent prior to participation. The study was conducted in accordance with guidelines of Good Clinical Practices and the Declaration of Helsinki, and the protocol and amendments were approved by review boards at participating institutions. The GlycoMark® 1,5-AG assay was performed according to manufacturer specifications. Change from Correspondence Dainius A. Balis, Janssen Research & Development, LLC, 920 Route 202 South, Raritan, NJ 08869, USA. Tel.: +1 908 704 5173 Fax: +1 908 927 7977 Email: dbalis@its.jnj.com

Glycaemic efficacy of canagliflozin is largely independent of baseline β-cell function or insulin sensitivity.

Canagliflozin is a sodium-glucose co-transporter 2 inhibitor approved for the treatment of adults with Type 2 diabetes. In phase III studies, canagliflozin reduced HbA1c, body weight and blood pressure, and was generally well tolerated [1–6]. Canagliflozin lowers plasma glucose by lowering the renal threshold for glucose and increasing urinary glucose excretion [7,8]. This article is protected by copyright. All rights reserved.

Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus from Latin America

Abstract Objective: This post hoc analysis evaluated the efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus (T2DM) from Latin America. Research design and methods: Analyses were performed in subgroups of patients from Latin America based on data from three individual, 26-week, placebo-controlled studies of canagliflozin (monotherapy [n = 116/584], add-on to metformin [n = 199/918], and add-on to metformin plus sulfonylurea [n = 76/469]) and three individual, 52-week, active-controlled studies of canagliflozin (add-on to metformin versus sitagliptin [n = 240/1101], add-on to metformin versus glimepiride [n = 155/1450], and add-on to metformin plus sulfonylurea versus sitagliptin [n = 156/755]). Main outcome measures: Changes from baseline in HbA1c, body weight, and systolic blood pressure (BP) with canagliflozin 100 and 300 mg versus placebo or active comparator (i.e., sitagliptin or glimepiride) were evaluated in the overall study populations and Latin American subgroups. Safety was assessed based on adverse event (AE) reports. Results: Canagliflozin 100 and 300 mg provided reductions in HbA1c, body weight, and systolic BP across studies in patients from Latin America that were generally similar to those seen in the overall populations of patients with T2DM. The AE profile in patients from Latin America was equivalent to that in the overall populations; higher rates of genital mycotic infections and osmotic diuresis–related AEs were seen with canagliflozin versus comparators. Limitations of this study include the post hoc analysis of data and the small sample size of patients from Latin America. Conclusion: Canagliflozin improved glycemic control, reduced body weight and systolic BP, and was generally well tolerated in patients with T2DM from Latin America. Clinical trial registration: NCT01081834; NCT01106677; NCT01106625; NCT00968812; NCT01137812.

Prevalence and Determinants of Engagement with Obesity Care in the United States: Engagement with Obesity Care in the United States

Medical management of obesity can result in significant weight loss and reduce the burden of obesity‐related complications. This report employs a new conceptual model to quantify engagement with obesity care and associated determinants in the US adult population.