Dainius Balis

Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial

BACKGROUND Sodium-glucose cotransporter 2 (SGLT2) inhibitors improve glycaemia in patients with type 2 diabetes by enhancing urinary glucose excretion. We compared the efficacy and safety of canagliflozin, an SGLT2 inhibitor, with glimepiride in patients with type 2 diabetes inadequately controlled with metformin. METHODS We undertook this 52 week, randomised, double-blind, active-controlled, phase 3 non-inferiority trial at 157 centres in 19 countries between Aug 28, 2009, and Dec 21, 2011. Patients aged 18-80 years with type 2 diabetes and glycated haemoglobin A1c (HbA1c) of 7·0-9·5% on stable metformin were randomly assigned (1:1:1) by computer-generated random sequence via an interactive voice or web response system to receive canagliflozin 100 mg or 300 mg, or glimepiride (up-titrated to 6 mg or 8 mg per day) orally once daily. Patients, study investigators, and local sponsor personnel were masked to treatment. The primary endpoint was change in HbA1c from baseline to week 52, with a non-inferiority margin of 0·3% for the comparison of each canagliflozin dose with glimepiride. If non-inferiority was shown, we assessed superiority on the basis of an upper bound of the 95% CI for the difference of each canagliflozin dose versus glimepiride of less than 0·0%. Analysis was done in a modified intention-to-treat population, including all randomised patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00968812. FINDINGS 1450 of 1452 randomised patients received at least one dose of glimepiride (n=482), canagliflozin 100 mg (n=483), or canagliflozin 300 mg (n=485). For lowering of HbA1c at 52 weeks, canagliflozin 100 mg was non-inferior to glimepiride (least-squares mean difference -0·01% [95% CI -0·11 to 0·09]), and canagliflozin 300 mg was superior to glimepiride (-0·12% [-0·22 to -0·02]). 39 (8%) patients had serious adverse events in the glimepiride group versus 24 (5%) in the canagliflozin 100 mg group and 26 (5%) in the 300 mg group. In the canagliflozin 100 mg and 300 mg groups versus the glimepiride group, we recorded a greater number of genital mycotic infections (women: 26 [11%] and 34 [14%] vs five [2%]; men: 17 [7%] and 20 [8%] vs three [1%]), urinary tract infections (31 [6%] for both canagliflozin doses vs 22 [5%]), and osmotic diuresis-related events (pollakiuria: 12 [3%] for both doses vs one [<1%]; polyuria: four [<1%] for both doses vs two [<1%]). INTERPRETATION Canagliflozin provides greater HbA1c reduction than does glimepiride, and is well tolerated in patients with type 2 diabetes receiving metformin. These findings support the use of canagliflozin as a viable treatment option for patients who do not achieve sufficient glycaemic control with metformin therapy. FUNDING Janssen Research & Development, LLC.

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

OBJECTIVE To 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 METHODS In 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. RESULTS At week 104, reductions from baseline in A1C were −0.65%, −0.74%, and −0.55% (−7.1, −8.1, and −6.0 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 (−4.1%, −4.2%, and 0.9%, respectively) and systolic blood pressure (−2.0, −3.1, 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. CONCLUSIONS Canagliflozin 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.

Canagliflozin Slows Progression of Renal Function Decline Independently of Glycemic Effects

Sodium-glucose cotransporter 2 inhibition with canagliflozin decreases HbA1c, body weight, BP, and albuminuria, implying that canagliflozin confers renoprotection. We determined whether canagliflozin decreases albuminuria and reduces renal function decline independently of its glycemic effects in a secondary analysis of a clinical trial in 1450 patients with type 2 diabetes receiving metformin and randomly assigned to either once-daily canagliflozin 100 mg, canagliflozin 300 mg, or glimepiride uptitrated to 6-8 mg. End points were annual change in eGFR and albuminuria over 2 years of follow-up. Glimepiride, canagliflozin 100 mg, and canagliflozin 300 mg groups had eGFR declines of 3.3 ml/min per 1.73 m2 per year (95% confidence interval [95% CI], 2.8 to 3.8), 0.5 ml/min per 1.73 m2 per year (95% CI, 0.0 to 1.0), and 0.9 ml/min per 1.73 m2 per year (95% CI, 0.4 to 1.4), respectively (P<0.01 for each canagliflozin group versus glimepiride). In the subgroup of patients with baseline urinary albumin-to-creatinine ratio ≥30 mg/g, urinary albumin-to-creatinine ratio decreased more with canagliflozin 100 mg (31.7%; 95% CI, 8.6% to 48.9%; P=0.01) or canagliflozin 300 mg (49.3%; 95% CI, 31.9% to 62.2%; P<0.001) than with glimepiride. Patients receiving glimepiride, canagliflozin 100 mg, or canagliflozin 300 mg had reductions in HbA1c of 0.81%, 0.82%, and 0.93%, respectively, at 1 year and 0.55%, 0.65%, and 0.74%, respectively, at 2 years. In conclusion, canagliflozin 100 or 300 mg/d, compared with glimepiride, slowed the progression of renal disease over 2 years in patients with type 2 diabetes, and canagliflozin may confer renoprotective effects independently of its glycemic effects.

Canagliflozin: a sodium glucose co‐transporter 2 inhibitor for the treatment of type 2 diabetes mellitus

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 (RTG) 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.

Effect of canagliflozin on liver function tests in patients with type 2 diabetes

AIMS To report changes in liver function tests observed with canagliflozin, a sodium glucose co-transporter 2 inhibitor, across phase 3 studies in patients with type 2 diabetes, and to examine the relationship between changes in liver function tests and the weight loss and glycaemic improvements observed with canagliflozin. METHODS Data were pooled from four 26-week, placebo-controlled studies of canagliflozin 100 and 300mg (n=2313) and two 52-week, active-controlled studies of canagliflozin 300mg versus sitagliptin 100mg (n=1488). Analysis of covariance was performed to determine the contribution of changes in body weight and HbA1c to the changes in liver function tests. RESULTS Reductions in alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and gamma-glutamyl transferase, and increases in bilirubin were seen with canagliflozin 100 and 300mg versus placebo (nominal P<0.001 for alanine aminotransferase, aspartate aminotransferase and gamma-glutamyl transferase [both doses]; P<0.001 for alkaline phosphatase and P=0.015 for bilirubin [canagliflozin 300mg only]) at week 26 and with canagliflozin 300mg versus sitagliptin 100mg (nominal P<0.001 for alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase and bilirubin, and P<0.01 for alkaline phosphatase) at week 52. Few patients met predefined limits of change criteria for liver function tests, and none met Hys law criteria. In both populations, alanine aminotransferase, aspartate aminotransferase and gamma-glutamyl transferase reductions were fully explained by HbA1c and body weight reductions. CONCLUSIONS Canagliflozin provided improvements in liver function tests versus either placebo or sitagliptin treatments that were fully explained by the combined effects of HbA1c and body weight reductions with canagliflozin.

Longer-term safety and tolerability of canagliflozin in patients with type 2 diabetes: a pooled analysis

Abstract Objective: To evaluate the longer-term safety of canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes mellitus (T2DM). Methods: The safety/tolerability of canagliflozin 100 and 300 mg were assessed using data pooled from seven placebo- and active-controlled studies of 52–104 weeks in duration that enrolled a broad range of patients with T2DM (N = 5598). Canagliflozin 100 and 300 mg as monotherapy or in combination with various background antihyperglycemic agents (AHAs) were compared with pooled non-canagliflozin treatments (i.e. placebo, sitagliptin, glimepiride). Safety was assessed based on adverse event (AE) reports, including the incidence of AEs related to the mechanism of SGLT2 inhibition. Results: Overall AE incidence was similar with canagliflozin 100 and 300 mg and non-canagliflozin (73.7%, 74.5%, and 73.7%). The incidence of AE-related discontinuations and serious AEs was low and balanced across groups. The incidence of male and female genital mycotic infections, urinary tract infections, and AEs related to osmotic diuresis or volume depletion was higher with canagliflozin versus non-canagliflozin; these AEs generally occurred early with decreased incidence over time and incidence was similar across baseline HbA1c subgroups. The incidence of fractures and diabetic ketoacidosis was low and similar across groups. Canagliflozin was associated with a low incidence of hypoglycemia when used with background AHAs that are not associated with hypoglycemia; the incidence was higher among patients on background AHAs associated with hypoglycemia (i.e. insulin, sulfonylurea, glinide). Limitations: Limitations of this analysis include its post hoc nature. While this analysis included a broad population of patients, including those with a history or risk of cardiovascular disease or chronic kidney disease, the longer-term safety in these patient populations was not specifically evaluated. Ongoing outcome studies will provide data on the long-term safety of canagliflozin in these populations. Conclusions: Longer-term exposure to canagliflozin as monotherapy or in combination with other agents was generally well tolerated in patients with T2DM. Trial registration: ClinicalTrials.gov identifiers: NCT01106625, NCT01081834, NCT01106677, NCT00968812, NCT01106651, NCT01106690, NCT01137812.

Renal safety of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus

The incidence of renal‐related adverse events (AEs) with canagliflozin in patients with type 2 diabetes mellitus from a pooled population of patients in 7 active‐ and placebo‐controlled trials (N = 5598) and in a 104‐week study vs glimepiride (N = 1450) was low and similar in canagliflozin and non‐canagliflozin groups. In the study vs glimepiride, canagliflozin was associated with an initial acute decrease in estimated glomerular filtration rate (eGFR) that attenuated over time, while eGFR declined progressively over 104 weeks with glimepiride. The incidence of renal‐related AEs with canagliflozin was generally stable over time, while the incidence with glimepiride increased over 104 weeks. In the present analysis, based on postmarketing reports from the US Food and Drug Administration Adverse Event Reporting System, a potential signal was identified for acute kidney injury with all approved sodium glucose co‐transporter 2 (SGLT2) inhibitors (ie, canagliflozin, dapagliflozin and empagliflozin). The early onset of acute kidney injury events with SGLT2 inhibitors in postmarketing reports probably reflects the acute changes in eGFR attibutable to the known renal haemodynamic effects of SGLT2 inhibition.

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

Canagliflozin improves risk factors of metabolic syndrome in patients with type 2 diabetes mellitus and metabolic syndrome

Objective Metabolic syndrome refers to a collection of risk factors associated with the development of cardiovascular disease and type 2 diabetes mellitus (T2DM). Canagliflozin, a sodium glucose co-transporter 2 inhibitor, improves glycemic control and reduces body weight and blood pressure (BP) in a broad range of patients with T2DM. This post hoc analysis assessed the effects of canagliflozin on the components of metabolic syndrome in patients with T2DM and metabolic syndrome. Methods This analysis was based on data from 2 head-to-head studies of canagliflozin in patients with T2DM on background metformin versus glimepiride (study 1) and background metformin plus sulfonylurea versus sitagliptin 100 mg (study 2). Changes from baseline in glycemic efficacy, anthropometric measures, BP, and lipids were evaluated with canagliflozin versus glimepiride and sitagliptin at week 52 in patients who met ≥2 of the criteria for metabolic syndrome (in addition to T2DM): triglycerides ≥1.7 mmol/L; high-density lipoprotein cholesterol (HDL-C) <1.0 mmol/L (men) or <1.3 mmol/L (women); waist circumference ≥102 cm (non-Asian men), ≥88 cm (non-Asian women), >90 cm (Asian men), or >80 cm (Asian women); diagnosis of hypertension or meeting BP-related criteria (systolic BP ≥130 mmHg or diastolic BP ≥85 mmHg). Safety was assessed based on adverse event reports. Results In study 1, canagliflozin 100 and 300 mg provided similar and greater HbA1c reductions versus glimepiride, respectively. In study 2, canagliflozin 300 mg provided greater HbA1c lowering versus sitagliptin 100 mg. Canagliflozin also reduced fasting plasma glucose, body weight, body mass index, waist circumference, BP, and triglycerides, and increased HDL-C and low-density lipoprotein cholesterol versus glimepiride and sitagliptin. Canagliflozin was generally well tolerated in each study. Conclusion Canagliflozin was associated with improvements in all components of metabolic syndrome in patients with T2DM and metabolic syndrome, whereas glimepiride and sitagliptin only improved glycemic components over 52 weeks.