Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy.

BACKGROUND: Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium-glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS: In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin-angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS: The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P = 0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P = 0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P = 0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS: In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years. (Funded by Janssen Research and Development; CREDENCE ClinicalTrials.gov number, NCT02065791.).

Factors influencing longitudinal changes of circulating liver enzyme concentrations in subjects randomized to placebo in four clinical trials.

Liver enzyme concentrations are measured as safety end points in clinical trials to detect drug-related hepatotoxicity, but little is known about the epidemiology of these biomarkers in subjects without hepatic dysfunction who are enrolled in drug trials. We studied alanine and aspartate aminotransferase (ALT and AST) in subjects randomized to placebo who completed assessments over 36 mo in a cardiovascular outcome trial [the Stabilisation of Atherosclerotic Plaque by Initiation of Darapladib Therapy ("STABILITY") trial; n = 4,264; mean age: 64.2 yr] or over 12 mo in three trials that enrolled only subjects with type 2 diabetes (T2D) [the DIA trials; n = 308; mean age: 62.4 yr] to investigate time-dependent relationships and the factors that might affect ALT and AST, including body mass index (BMI), T2D, and renal function. Multivariate linear mixed models examined time-dependent relationships between liver enzyme concentrations as response variables and BMI, baseline T2D status, hemoglobin A1c levels, and renal function, as explanatory variables. At baseline, ALT was higher in individuals who were men, <65 yr old, and obese and who had glomerular filtration rate (GFR) >60 ml·min-1·1.73 m-2. ALT was not significantly associated with T2D at baseline, although it was positively associated with HbA1c. GFR had a greater impact on ALT than T2D. ALT concentrations decreased over time in subjects who lost weight but remained stable in individuals with increasing BMI. Weight change did not alter AST concentrations. We provide new insights on the influence of time, GFR, and HbA1c on ALT and AST concentrations and confirm the effect of sex, age, T2D, BMI, and BMI change in subjects receiving placebo in clinical trials. NEW & NOTEWORTHY Clinical trials provide high-quality data on liver enzyme concentrations from subjects randomized to placebo that can be used to investigate the epidemiology of these biomarkers. The adjusted models show the influence of sex, age, time, renal function, type 2 diabetes, HbA1c, and body mass index on alanine aminotransferase and aspartate aminotransferase concentrations and their relative importance. These factors need to be considered when assessing potential signals of hepatotoxicity in trials of new drugs and in clinical trials investigating subjects with nonalcoholic fatty liver disease.

Diabetic ketoacidosis in patients with type 2 diabetes treated with sodium glucose co-transporter 2 inhibitors versus other antihyperglycemic agents: An observational study of four US administrative claims databases.

PURPOSE: To compare the incidence of diabetic ketoacidosis (DKA) among patients with type 2 diabetes mellitus (T2DM) who were new users of sodium glucose co-transporter 2 inhibitors (SGLT2i) versus other classes of antihyperglycemic agents (AHAs). METHODS: Patients were identified from four large US claims databases using broad (all T2DM patients) and narrow (intended to exclude patients with type 1 diabetes or secondary diabetes misclassified as T2DM) definitions of T2DM. New users of SGLT2i and seven groups of comparator AHAs were matched (1:1) on exposure propensity scores to adjust for imbalances in baseline covariates. Cox proportional hazards regression models, conditioned on propensity score-matched pairs, were used to estimate hazard ratios (HRs) of DKA for new users of SGLT2i versus other AHAs. When I2 <40%, a combined HR across the four databases was estimated. RESULTS: Using the broad definition of T2DM, new users of SGLT2i had an increased risk of DKA versus sulfonylureas (HR [95% CI]: 1.53 [1.31-1.79]), DPP-4i (1.28 [1.11-1.47]), GLP-1 receptor agonists (1.34 [1.12-1.60]), metformin (1.31 [1.11-1.54]), and insulinotropic AHAs (1.38 [1.15-1.66]). Using the narrow definition of T2DM, new users of SGLT2i had an increased risk of DKA versus sulfonylureas (1.43 [1.01-2.01]). New users of SGLT2i had a lower risk of DKA versus insulin and a similar risk as thiazolidinediones, regardless of T2DM definition. CONCLUSIONS: Increased risk of DKA was observed for new users of SGLT2i versus several non-SGLT2i AHAs when T2DM was defined broadly. When T2DM was defined narrowly to exclude possible misclassified patients, an increased risk of DKA with SGLT2i was observed compared with sulfonylureas.

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.

Rationale, design and baseline characteristics of the CANagliflozin cardioVascular Assessment Study-Renal (CANVAS-R): A randomized, placebo-controlled trial.

AIMS: The primary aim of the CANagliflozin cardioVascular Assessment Study-Renal (CANVAS-R) is to determine whether the favourable effects of inhibition of the sodium glucose co-transporter 2 (SGLT2) on blood glucose, blood pressure and body weight are accompanied by protection against adverse renal outcomes. MATERIALS AND METHODS: CANVAS-R is a prospective, randomized, double-blind, placebo-controlled trial in patients with type 2 diabetes with a history or high risk of cardiovascular events. Patients were randomly assigned to once-daily placebo or canagliflozin 100 mg (with optional uptitration to 300 mg) for a planned average of 2.5 years of follow-up. The primary outcome is kidney disease progression, defined by class change in albuminuria. The two secondary outcomes are the composite of hospitalized heart failure or cardiovascular death, and cardiovascular death alone. Effects on end-stage renal disease and a range of other outcomes will also be explored. RESULTS: A total of 5812 participants were recruited at 422 sites in 24 countries between January 2014 and May 2015. The mean baseline age was 64 years, mean duration of diabetes was 14 years, mean glycated haemoglobin level was 8.3% and mean body mass index was 32 kg/m2 . Of these participants, 37% were women, 71% had a history of cardiovascular disease, 22.3% had microalbuminuria and 8.7% had macroalbuminuria. The mean baseline estimated glomerular filtration rate was 76 mL/min/1.73 m2 . The study will have at least 90% power ( P = .05) to detect a 22% or greater reduction in the risk of progression of albuminuria. CONCLUSIONS: The trial should define the potential renoprotective effect of canagliflozin and will provide additional important new data about its effects on vascular outcomes, death and kidney failure.

A post-hoc analysis of the comparative efficacy of canagliflozin and glimepiride in the attainment of type 2 diabetes-related quality measures.

BACKGROUND: The randomized, double-blind CANTATA-SU (CANagliflozin Treatment And Trial Analysis Sulfonyl Urea) clinical trial compared the use of canagliflozin (100 mg or 300 mg) and maximally tolerated glimepiride (6-8 mg) over 104 weeks as add-on therapy for patients with type 2 diabetes mellitus (T2DM) inadequately controlled with metformin. Compared with glimepiride, canagliflozin use was associated with durable reductions in glycated hemoglobin (A1C), blood pressure (BP), and body weight. The aim of this post-hoc analysis of the CANTATA-SU trial was to assess the comparative efficacy of canagliflozin and glimepiride in the attainment of recently updated diabetes-related quality measures (QMs) for up to 104 weeks of treatment. METHODS: This post-hoc analysis evaluated the proportions of patients achieving individual diabetes-related QMs using data from the randomized, double-blind, Phase 3 CANTATA-SU trial. Change in A1C from baseline, and proportions of the study population achieving QMs: A1C <7.0 %, <8.0 %, and >9.0 % were assessed. Secondary endpoints included change in BP from baseline, and the proportions of the study population achieving QMs related to BP and body weight. RESULTS: The proportions of patients in the canagliflozin 100 mg, canagliflozin 300 mg, and glimepiride groups meeting criteria for all QMs were similar at baseline. At 52 and 104 weeks of treatment, canagliflozin 100 mg and canagliflozin 300 mg provided better or similar reductions in A1C from baseline and achievement of glycemic control QMs compared with glimepiride. At 52 and 104 weeks of treatment, the attainment of QMs related to reductions in body weight and BP all favored canagliflozin compared with glimepiride. Canagliflozin was associated with lower incidence of documented hypoglycemia and severe hypoglycemia compared with glimepiride. CONCLUSIONS: Using the recently adjusted and currently accepted diabetes-related QMs, this analysis observed superior glycemic control with canagliflozin compared with maximally tolerated glimepiride in patients with T2DM who were previously poorly controlled on metformin monotherapy. Compared with maximally tolerated glimepiride, canagliflozin resulted in better achievement of diabetes-related QMs related to weight loss and BP, and was associated with lower incidences of hypoglycemic events. TRIAL REGISTRATION: Clinical trial registry name: CANagliflozin Treatment And Trial Analysis-Sulfonylurea (CANTATA-SU) SGLT2 Add-on to Metformin Versus Glimepiride. CLINICAL TRIAL REGISTRATION NUMBER: NCT00968812 , registered August 28, 2009.

Efficacy and Safety of Canagliflozin in Type 2 Diabetes Patients of Different Ethnicity.

OBJECTIVE: To assess the efficacy and safety of the sodium glucose co-transporter 2 (SGLT2) inhibitor canagliflozin in patients of different ethnicities. DESIGN SETTING AND PATIENTS: Post hoc analysis of data pooled from four randomized, placebo-controlled, phase 3 studies of adults with inadequately controlled type 2 diabetes mellitus (T2DM). INTERVENTIONS: Once daily oral canagliflozin 100 mg or 300 mg, or placebo. MAIN OUTCOME MEASURES: Efficacy endpoints included change from baseline in HbA1c, body weight (BW), systolic blood pressure (SBP), and lipids at week 26; safety and tolerability were assessed by adverse event reports. RESULTS: Of the 2,313 patients included in this pooled analysis, 609 self-identified as Hispanic/Latino. Hispanic/Latino patients had a mean age of 54 years, mean duration of T2DM of 7 years, mean HbA1c of 8.1%, mean body mass index of 31.2 kg/m(2), and mean SBP of 126.1 mm Hg. There were more women in the non-Hispanic/Latino cohort (63%) compared with the Hispanic/Latino cohort. Placebo-subtracted changes in HbA1c were -.82% with canagliflozin 100 mg and -.94% with canagliflozin 300 mg in the Hispanic/Latino cohort, which were similar to reductions observed in the non-Hispanic/Latino cohort. Significantly greater dose-related reductions in HbA1c, BW, and SBP were observed with both canagliflozin doses compared with placebo. Canagliflozin was generally well-tolerated. Genital mycotic infections were less frequent in Hispanic/Latino women than in non-Hispanic/Latino women. CONCLUSIONS: The SGLT2 inhibitor canagliflozin was generally well-tolerated and was associated with clinically meaningful reductions in HbA1c, BW, and SBP in both Hispanic/Latino and non-Hispanic/Latino patients with T2DM.

Effects of canagliflozin on body weight and relationship to HbA1c and blood pressure changes in patients with type 2 diabetes.

AIMS/HYPOTHESIS: Canagliflozin, a sodium glucose co-transporter 2 inhibitor, reduces HbA1c, body weight and systolic BP (SBP) in patients with type 2 diabetes. As weight loss is known to reduce both HbA1c and SBP, these analyses were performed to evaluate the contribution of weight loss resulting from treatment with canagliflozin to HbA1c and SBP reductions in patients with type 2 diabetes. METHODS: Pooled data from four placebo-controlled Phase 3 studies (N = 2,250) in patients with type 2 diabetes were used in the analyses. In each study, patients were treated with placebo, canagliflozin 100 mg or canagliflozin 300 mg, once daily for 26 weeks. Changes from baseline in body weight, HbA1c and SBP were measured at week 26, and the contribution of weight loss to the lowering of HbA1c and SBP was obtained using ANCOVA. RESULTS: Canagliflozin 100 and 300 mg reduced mean body weight, HbA1c and SBP compared with placebo (p < 0.001 for each), and more patients had body-weight reductions >0%, ≥5% and ≥10% with canagliflozin treatment than with placebo. Weight-loss-independent and weight-loss-associated mechanisms contributed to HbA1c and SBP lowering with canagliflozin: ~85% of HbA1c lowering and ~60% of SBP lowering was independent of weight loss. CONCLUSIONS/INTERPRETATION: In patients with type 2 diabetes, canagliflozin provided clinically meaningful body-weight reductions, and the weight loss contributed to reductions in HbA1c and SBP.

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.

Efficacy and safety of canagliflozin in patients with type 2 diabetes and stage 3 nephropathy.

BACKGROUND/AIMS: Some sodium glucose co-transporter 2 (SGLT2) inhibitors are approved for the treatment of patients with type 2 diabetes mellitus (T2DM) with an estimated glomerular filtration rate (eGFR) of ≥45 ml/min/1.73 m(2). The efficacy and safety of canagliflozin, an approved SGLT2 inhibitor, was evaluated in patients with stage 3 chronic kidney disease (CKD; eGFR ≥30 to <60 ml/min/1.73 m(2)). METHODS: This analysis used integrated data from four randomized, placebo-controlled, phase 3 studies that enrolled patients with T2DM and stage 3 CKD. RESULTS are presented for the overall population as well as subgroups with stage 3a CKD (eGFR ≥45 and <60 ml/min/1.73 m(2)) and stage 3b CKD (eGFR ≥30 and <45 ml/min/1.73 m(2)). RESULTS: Among all subjects studied with stage 3 CKD, placebo-subtracted reductions in HbA1c (-0.38 and -0.47%; p < 0.001), body weight (-1.6 and -1.9%; p < 0.001), and systolic blood pressure (-2.8 and -4.4 mm Hg; p < 0.01) were seen with canagliflozin 100 and 300 mg, respectively. Decreases in HbA1c, body weight, and systolic blood pressure were examined in the stage 3a and 3b CKD subgroups, with greater decreases in HbA1c, -0.47% (-0.61, -0.32) and body weight in subjects in stage 3a CKD, -1.8% (-2.3, -1.2) with canagliflozin 100 mg. Initial declines in eGFR were seen early following treatment initiation with canagliflozin, but trended towards baseline over time. The most common adverse events with canagliflozin included genital mycotic infections and adverse events related to reduced intravascular volume likely secondary to osmotic diuresis. CONCLUSION: In subjects with T2DM and stage 3 CKD, canagliflozin reduced HbA1c, body weight, and blood pressure, and was generally well tolerated.

Efficacy and safety of canagliflozin compared with placebo in older patients with type 2 diabetes mellitus: a pooled analysis of clinical studies.

BACKGROUND: Canagliflozin is a sodium glucose co-transporter 2 inhibitor developed for the treatment of patients with type 2 diabetes mellitus (T2DM). The efficacy and safety of canagliflozin were evaluated in patients with T2DM <65 and ≥65 years of age. METHODS: Pooled data from 4 randomised, placebo-controlled, 26-week, Phase 3 studies (N = 2,313) evaluating canagliflozin 100 and 300 mg were analysed by age: <65 years (n = 1,868; mean age, 52.8 years) or ≥65 years (n = 445; mean age, 69.3 years). Efficacy evaluations included change from baseline in glycaemic parameters and systolic blood pressure (BP), and percent change from baseline in body weight. Assessment of safety/tolerability included adverse event (AE) reports, incidence of documented hypoglycaemia, and percent change from baseline in fasting plasma lipids. RESULTS: Canagliflozin 100 and 300 mg reduced HbA1c and fasting plasma glucose relative to placebo in patients <65 and ≥65 years of age. Both canagliflozin doses reduced body weight and systolic BP relative to placebo in patients <65 and ≥65 years of age. Incidence of overall AEs was similar across all treatment groups in patients <65 and ≥65 years of age. Incidences of serious AEs and AE-related discontinuations were similar across all treatment groups in patients <65 years of age and higher with canagliflozin 100 mg than other groups in patients ≥65 years of age. As in patients <65 years of age, incidences of genital mycotic infections and osmotic diuresis-related AEs were higher with canagliflozin relative to placebo in those ≥65 years of age. Incidences of urinary tract infections (UTIs), renal-related AEs, AEs related to volume depletion, and documented hypoglycaemia episodes were similar across all treatment groups in patients ≥65 years of age; no notable trends were observed with canagliflozin 100 and 300 mg relative to placebo in these AEs among patients <65 years of age. Changes in lipid parameters with canagliflozin were similar in both age subsets. CONCLUSIONS: Canagliflozin improved glycaemic control, body weight, and systolic BP, and was generally well tolerated in older patients with T2DM. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01081834; NCT01106677; NCT01106625; NCT01106690.

Rationale, design, and baseline characteristics of the Canagliflozin Cardiovascular Assessment Study (CANVAS)--a randomized placebo-controlled trial.

Sodium glucose co-transporter 2 inhibition is a novel mode of treatment for type 2 diabetes mellitus (T2DM). The sodium glucose co-transporter 2 inhibitor canagliflozin lowered blood glucose, blood pressure, and body weight, with increased risk of urogenital infections in Phase 2 studies. Effects on macrovascular complications of diabetes remain to be determined. CANVAS is a double-blind, placebo-controlled trial designed to evaluate the effects of canagliflozin on the risk of cardiovascular disease and to assess safety and tolerability in patients with inadequately controlled T2DM and increased cardiovascular risk. The first of 2 planned phases randomized 4,330 individuals to placebo, canagliflozin 100 or 300 mg (1:1:1) with planned follow-up of about 2 years to substantiate potential cardiovascular protection by assessing key biomarkers and to achieve initial safety objectives. By the end of mid-September 2012, a total of 7174 patient-years of follow-up were accrued. Mean baseline age was 62 years, duration of diabetes 13 years; hemoglobin A1c 8.2%, fasting plasma glucose 9.3 mmol/L, and body mass index 32 kg/m(2). Of the participants, 34% are female and 57% had a history of atherosclerotic vascular disease. Participants will be followed up to achieve primary safety and tolerability objectives and to investigate secondary outcomes. The planned second phase will not be undertaken. CANVAS will define the effects of canagliflozin on biomarkers and provide data on cardiovascular safety against established regulatory parameters.

Acute pancreatitis risk in type 2 diabetes patients treated with canagliflozin versus other antihyperglycemic agents: an observational claims database study.

Objective: Observational evidence suggests that patients with type 2 diabetes mellitus (T2DM) are at increased risk for acute pancreatitis (AP) versus those without T2DM. A small number of AP events were reported in clinical trials of the sodium glucose co-transporter 2 inhibitor canagliflozin, though no imbalances were observed between treatment groups. This observational study evaluated risk of AP among new users of canagliflozin compared with new users of six classes of other antihyperglycemic agents (AHAs).Methods: Three US claims databases were analyzed based on a prespecified protocol approved by the European Medicines Agency. Propensity score adjustment controlled for imbalances in baseline covariates. Cox regression models estimated the hazard ratio of AP with canagliflozin compared with other AHAs using on-treatment (primary) and intent-to-treat approaches. Sensitivity analyses assessed robustness of findings.Results: Across the three databases, there were between 12,023-80,986 new users of canagliflozin; the unadjusted incidence rates of AP (per 1000 person-years) were between 1.5-2.2 for canagliflozin and 1.1-6.6 for other AHAs. The risk of AP was generally similar for new users of canagliflozin compared with new users of glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, sulfonylureas, thiazolidinediones, insulin, and other AHAs, with no consistent between-treatment differences observed across databases. Intent-to-treat and sensitivity analysis findings were qualitatively consistent with on-treatment findings.Conclusions: In this large observational study, incidence rates of AP in patients with T2DM treated with canagliflozin or other AHAs were generally similar, with no evidence suggesting that canagliflozin is associated with increased risk of AP compared with other AHAs.

Reliability and feasibility of methods to quantitatively assess peripheral edema.

OBJECTIVE: To evaluate methods to assess peripheral edema for reliability, feasibility and correlation with the classic clinical assessment of pitting edema. DESIGN: Cross-sectional observational study. SETTING: Large primary care clinic in Marshfield, Wisconsin, USA. PARTICIPANTS: Convenience sample of 20 patients with type 2 diabetes and a range of edema severity, including patients without edema. METHODS: Eight methods of edema assessment were evaluated: (1) clinical assessment of pit depth and recovery at three locations, (2) patient questionnaire, (3) ankle circumference, (4) figure-of-eight (ankle circumference using eight ankle/foot landmarks), (5) edema tester (plastic card with holes of varying size pressed to the ankle with a blood pressure cuff), (6) modified edema tester (edema tester with bumps), (7) indirect leg volume (by series of ankle/leg circumferences), and (8) foot/ankle volumetry by water displacement. Patients were evaluated independently by three nurse examiners. RESULTS: Water displacement and ankle circumference had high inter-examiner agreement (intraclass correlation coefficient 0.93, 0.96 right; 0.97, 0.97 left). Agreement was inconsistent for figure-of-eight (0.64, 0.86), moderate for indirect leg volume (0.53, 0.66), and low for clinical assessments at all locations. Agreement was low for the edema testers but varied by the pressure administered. Correlation with the classic, subjective clinical assessment was good for the nurse-performed assessments and patient questionnaire. Ankle circumference and patient questionnaires each took 1 minute to complete. Other tools took >5 minutes to complete. CONCLUSIONS: Water displacement and ankle circumference showed excellent reliability; however, water displacement is a time-consuming measure and may pose implementation challenges in the clinical and clinical trial environments. Patient-reported level and frequency of edema, based on an unvalidated questionnaire, was generally well correlated with the physician assessment of edema severity and may prove to be another reliable and accurate method of assessing edema. Additional study is needed to evaluate the validity and responsiveness of these methods.

Achieving the composite endpoint of HbA1c, body weight, and systolic blood pressure reduction with canagliflozin in patients with type 2 diabetes.

OBJECTIVE: In addition to achieving glycemic control, weight loss and blood pressure (BP) reduction are important components of type 2 diabetes mellitus (T2DM) management, as many patients with T2DM are overweight/obese and/or have hypertension. Canagliflozin, an SGLT2 inhibitor, has demonstrated improvements in HbA1c, body weight (BW), and systolic BP across a broad range of patients with T2DM. This analysis evaluated achievement of composite endpoints of HbA1c, BW, and systolic BP targets with canagliflozin versus placebo. METHODS: This post hoc analysis evaluated the proportion of T2DM patients achieving the composite endpoint of HbA1c reduction ≥0.5%, BW reduction ≥3%, and systolic BP reduction ≥4mmHg with canagliflozin 100 and 300mg compared with placebo using pooled data from four 26-week, phase 3 studies (N = 2313; NCT01081834, NCT01106677, NCT01106625, NCT01106690). The proportion of patients achieving the composite endpoint of HbA1c <7.0%, BW reduction ≥3%, and BP <130/80 mmHg was also evaluated. RESULTS: At week 26, greater proportions of patients met individual HbA1c, BW, and systolic BP targets with canagliflozin versus placebo. A greater proportion of patients treated with canagliflozin 100 or 300 mg versus placebo also achieved the composite endpoint of HbA1c reduction ≥0.5%, BW reduction ≥3%, and systolic BP reduction ≥4 mmHg at week 26 (21.1%, 25.3%, and 5.7%, respectively; odds ratios [95% CI] of 4.5 [3.1, 6.5] and 5.6 [3.8, 8.2]). A greater proportion of patients also achieved the composite endpoint of HbA1c <7.0%, BW reduction ≥3%, and BP <130/80 mmHg with canagliflozin 100 and 300 mg versus placebo (14.7%, 20.9%, and 3.3%, respectively; odds ratios [95% CI] of 5.2 [3.2, 8.4] and 8.4 [5.2, 13.5]). Canagliflozin was generally well tolerated, with a safety profile similar to that seen in other phase 3 studies. CONCLUSIONS: Patients with T2DM were more likely to achieve clinically important reductions in HbA1c, BW, and systolic BP with canagliflozin versus placebo.

Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone.

OBJECTIVE: The efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, added to ongoing metformin therapy, were assessed in patients with type 2 diabetes who had inadequate glycemic control (HbA(1c) [A1C] >or=7 and or=1,500 mg/day) were randomly assigned to receive the addition of placebo or sitagliptin 100 mg once-daily in a 1:2 ratio for 24 weeks. Patients exceeding specific glycemic limits were provided rescue therapy (pioglitazone) until the end of the study. The efficacy analyses were based on an all-patients-treated population using an ANCOVA and excluded data obtained after glycemic rescue. RESULTS: At week 24, sitagliptin treatment led to significant reductions compared with placebo in A1C (-0.65%), fasting plasma glucose, and 2-h postmeal glucose. Fasting insulin, fasting C-peptide, fasting proinsulin-to-insulin ratio, postmeal insulin and C-peptide areas under the curve (AUCs), postmeal insulin AUC-to-glucose AUC ratio, homeostasis model assessment of beta-cell function, and quantitative insulin sensitivity check index were significantly improved with sitagliptin relative to placebo. A significantly greater proportion of patients achieved an A1C <7% with sitagliptin (47.0%) than with placebo (18.3%). There was no increased risk of hypoglycemia or gastrointestinal adverse experiences with sitagliptin compared with placebo. Body weight decreased similarly with sitagliptin and placebo. CONCLUSIONS: Sitagliptin 100 mg once-daily added to ongoing metformin therapy was efficacious and well tolerated in patients with type 2 diabetes who had inadequate glycemic control with metformin alone.

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

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.

Effects of canagliflozin on body weight and body composition in patients with type 2 diabetes over 104 weeks.

OBJECTIVES: Canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, has been associated with weight loss in a broad range of patients with type 2 diabetes mellitus (T2DM). This analysis further evaluated changes in body weight and composition with canagliflozin in two 104-week, Phase 3 studies. METHODS: In Study 1, patients aged 18-80 years (N = 1,450) received canagliflozin 100 or 300 mg or glimepiride as add-on to metformin for a 52-week core treatment period, followed by a 52-week extension period. In Study 2, patients aged 55-80 years (N = 714) received canagliflozin 100 or 300 mg or placebo added to stable background antihyperglycemic agents for a 26-week core treatment period, followed by a 78-week extension period. Percent change from baseline in body weight; proportion of patients with any weight loss, ≥5% weight loss, and ≥10% weight loss; change in body mass index (BMI) and waist circumference; change in body weight across weight-loss quartiles; and changes in body composition were evaluated in both studies. RESULTS: Canagliflozin 100 and 300 mg provided sustained weight loss versus either glimepiride or placebo over 104 weeks. More patients experienced any weight loss and ≥5% weight loss with canagliflozin versus comparator. Across the 3 highest weight-loss quartiles, canagliflozin provided greater weight loss versus glimepiride or placebo. BMI and waist circumference reductions were observed with canagliflozin 100 and 300 mg versus either glimepiride or placebo over 104 weeks; more patients had BMI or waist circumference reductions with canagliflozin versus comparator. Body composition analysis indicated that the majority of weight loss was due to loss of fat mass. Canagliflozin was generally well tolerated, with increased incidence of adverse events related to the SGLT2 inhibition mechanism. CONCLUSIONS: Canagliflozin 100 and 300 mg provided sustained reductions in body weight, BMI, and waist circumference in a greater proportion of patients with T2DM versus glimepiride or placebo over 104 weeks. TRIAL REGISTRATION: ClinicalTrials.gov NCT00968812, NCT01106651.

Canagliflozin: Efficacy and Safety in Combination with Metformin Alone or with Other Antihyperglycemic Agents in Type 2 Diabetes.

Metformin is typically the first pharmacologic treatment recommended for type 2 diabetes mellitus (T2DM), but many patients do not achieve glycemic control with metformin alone and eventually require combination therapy with other agents. Canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, was assessed in a comprehensive Phase 3 clinical development program consisting of ~10,000 participants, of which ~80% were on background therapy that consisted of metformin alone or in combination with other antihyperglycemic agents (AHAs; e.g., pioglitazone, sulfonylurea, and insulin). In addition, the efficacy and safety of canagliflozin and metformin as the initial combination therapy and canagliflozin monotherapy were assessed versus metformin in treatment-naïve patients with T2DM. Across studies in patients with T2DM who were on metformin alone or in combination with other AHAs, canagliflozin 100 and 300 mg provided improvements in glycated hemoglobin for up to 104 weeks. Canagliflozin was also associated with reductions in body weight and systolic blood pressure when added to background therapy consisting of metformin alone or with other AHAs. Canagliflozin was generally well tolerated, with increased incidence of adverse events (AEs) related to the mechanism of SGLT2 inhibition (i.e., genital mycotic infections, urinary tract infections, and osmotic diuresis-related AEs). Consistent with its insulin-independent mechanism of action, canagliflozin was associated with low rates of hypoglycemia when background therapy did not include sulfonylurea or insulin. Due to its favorable efficacy and safety profile, these results suggest that adding canagliflozin to a background regimen consisting of metformin or implementing treatment with a fixed-dose regimen of canagliflozin and metformin would provide an effective and safe treatment regimen for T2DM management. FUNDING: Janssen Global Services, LLC.

Effects of Canagliflozin on Fracture Risk in Patients With Type 2 Diabetes Mellitus.

CONTEXT: Canagliflozin is a sodium glucose cotransporter 2 inhibitor developed to treat type 2 diabetes mellitus (T2DM). OBJECTIVE: The purpose of this study was to describe the effects of canagliflozin on bone fracture risk. DESIGN AND SETTING: This was a randomized phase 3 study in patients with T2DM. PATIENTS AND INTERVENTIONS: Canagliflozin doses of 100 and 300 mg were evaluated in the overall population of patients from 9 placebo- and active-controlled studies (N = 10 194), as well as in separate analyses of a single trial enriched with patients with a prior history/risk of cardiovascular disease (ie, the CANagliflozin cardioVascular Assessment Study [CANVAS]; N = 4327) and a pooled population of 8 non-CANVAS studies (N = 5867). OUTCOME MEASURES: The incidence of adjudicated fracture adverse events (AEs), fall-related AEs, and volume depletion-related AEs was assessed. RESULTS: The incidence of fractures was similar with canagliflozin (1.7%) and noncanagliflozin (1.5%) in the pooled non-CANVAS studies. In CANVAS, a significant increase in fractures was seen with canagliflozin (4.0%) vs placebo (2.6%) that was balanced between the upper and lower limbs. The incidence of fractures was higher with canagliflozin (2.7%) vs noncanagliflozin (1.9%) in the overall population, which was driven by the increase of fractures in CANVAS. The incidence of reported fall-related AEs was low, but significantly higher with canagliflozin in CANVAS, potentially related to volume depletion-related AEs, but not significantly different in the pooled non-CANVAS studies and the overall population. CONCLUSIONS: Fracture risk was increased with canagliflozin treatment, driven by CANVAS patients, who were older, with a prior history/risk of cardiovascular disease, and with lower baseline estimated glomerular filtration rate and higher baseline diuretic use. The increase in fractures may be mediated by falls; however, the cause of increased fracture risk with canagliflozin is unknown.