Natriuretic Peptides and Prognosis in Patients With Type 2 Diabetes Mellitus and High Risk for Cardiovascular Events.

Background: The prognosis of individuals with and without an established heart failure (HF) diagnosis and similarly elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels is not well-known.

Methods And Results: CANVAS (Canagliflozin Cardiovascular Assessment Study) trial participants were stratified according to baseline NT-proBNP quartiles and history of HF at baseline. Adjusted event rates per 1000 patient-years of follow-up for hospitalizations for HF, cardiovascular mortality, and kidney events were assessed, and hazard ratios (HR) were calculated using Cox proportional hazard models.

Fasting Substrate Concentrations Predict Cardiovascular Outcomes in the CANagliflozin cardioVascular Assessment Study (CANVAS).

Objective: To examine whether the circulating substrate mix may be related to the incidence of heart failure (HF) and cardiovascular (CV) mortality and how it is altered by canagliflozin treatment.

Research Design And Methods: We measured fasting glucose, free fatty acids (FFA), glycerol, β-hydroxybutyrate, acetoacetate, lactate, and pyruvate concentrations in 3,581 samples from the CANagliflozin cardioVascular Assessment Study (CANVAS) trial at baseline and at 1 and 2 years after randomization. Results were analyzed by univariate and multivariate Cox proportional hazards models.

Stress Cardiac Biomarkers, Cardiovascular and Renal Outcomes, and Response to Canagliflozin.

Background: Circulating biomarkers reflecting different mechanistic pathways may identify at-risk individuals with diabetes who may benefit from sodium-glucose cotransporter-2 (SGLT2) inhibitors.

Objectives: The purpose of this study was to determine if high-sensitivity cardiac troponin T (hs-cTnT), soluble suppression of tumorigenesis-2 (sST2), and insulin-like growth factor binding protein 7 (IGFBP7) levels, either alone or in combination, may modify the treatment benefits of canagliflozin.

Methods: In the CANVAS (CANagliflozin cardioVascular Assessment Study) biomarker substudy, we evaluated the prognostic significance of baseline biomarker measurements, the long-term trajectory of each, and response to canagliflozin on key cardiovascular and kidney outcomes.

Association Between Circulating GDF-15 and Cardio-Renal Outcomes and Effect of Canagliflozin: Results From the CANVAS Trial.

Background Studies have suggested that sodium glucose co-transporter 2 inhibitors exert anti-inflammatory effects. We examined the association of baseline growth differentiation factor-15 (GDF-15), a marker of inflammation and cellular injury, with cardiovascular events, hospitalization for heart failure (HF), and kidney outcomes in patients with type 2 diabetes in the CANVAS (Canagliflozin Cardiovascular Assessment Study) and determined the effect of the sodium glucose co-transporter 2 inhibitor canagliflozin on circulating GDF-15. Methods and Results The CANVAS trial randomized 4330 people with type 2 diabetes at high cardiovascular risk to canagliflozin or placebo.

Effects of canagliflozin on myocardial infarction: a post hoc analysis of the CANVAS programme and CREDENCE trial.

Aims: Given the benefits of sodium glucose co-transporter 2 inhibition (SGLT2i) in protecting against heart failure in diabetic patients, we sought to explore the potential impact of SGLT2i on the clinical features of patients presenting with myocardial infarction (MI) through a post hoc analysis of CANVAS Programme and CREDENCE trial.

Methods And Results: Individuals with type 2 diabetes and history or high risk of cardiovascular disease (CANVAS Programme) or type 2 diabetes and chronic kidney disease (CREDENCE) were included. The intervention was canagliflozin 100 or 300 mg (combined in the analysis) or placebo.

Insulin-Like Growth Factor Binding Protein 7 Predicts Renal and Cardiovascular Outcomes in the Canagliflozin Cardiovascular Assessment Study.

Objective: To analyze the association between concentrations of plasma insulin-like growth factor binding protein 7 (IGFBP7) with renal and cardiac outcomes among participants with type 2 diabetes and high cardiovascular risk.

Research Design And Methods: Associations between IGFBP7 levels and clinical outcomes were assessed among participants in the Canagliflozin Cardiovascular Assessment Study (CANVAS) with type 2 diabetes and high cardiovascular risk.

Results: Among CANVAS participants, 3,577 and 2,898 had IGFBP7 measured at baseline and 1 year, respectively.

Effects of Canagliflozin on Amino-Terminal Pro-B-Type Natriuretic Peptide: Implications for Cardiovascular Risk Reduction.

Background: Canagliflozin reduces cardiovascular events including hospitalization for heart failure (HHF) in patients with type 2 diabetes and cardiovascular risk. Elevated amino-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations are associated with HF diagnosis and predict cardiovascular risk.

Objectives: The purpose of this study was to measure NT-proBNP in CANVAS (Canagliflozin Cardiovascular Assessment Study) participants.

The effects of combination canagliflozin and glucagon-like peptide-1 receptor agonist therapy on intermediate markers of cardiovascular risk in the CANVAS program.

Background: Sodium glucose co-transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP1-RA) reduce cardiovascular events, and improve intermediate markers of cardiometabolic health, in those with type 2 diabetes. We investigated these effects in the CANVAS Program.

Methods And Results: The CANVAS Program comprised 2 double-blind, randomized, placebo-controlled trials (CANVAS and CANVAS-R) done in patients with type 2 diabetes and elevated cardiovascular risk.

Clinical outcomes with canagliflozin according to baseline body mass index: results from post hoc analyses of the CANVAS Program.

Aims: Sodium glucose co-transporter 2 (SGLT2) inhibitors reduce several cardiovascular risk factors, including plasma glucose, blood pressure, albuminuria and body weight. Long-term treatment lowers risks of cardiovascular and renal events. The objective of this post hoc analysis was to determine the effects of canagliflozin treatment versus placebo on clinical outcomes in relation to body mass index (BMI).

Mediators of the Effects of Canagliflozin on Heart Failure in Patients With Type 2 Diabetes.

Objectives: The purpose of this study was to explore potential mediators of the effects of canagliflozin on heart failure in the CANVAS Program (CANagliflozin cardioVascular Assessment Study; NCT01032629 and CANagliflozin cardioVascular Assessment Study-Renal; NCT01989754).

Background: Canagliflozin reduced the risk of heart failure among patients with type 2 diabetes in the CANVAS Program. The mechanism of protection is uncertain.

Canagliflozin and Stroke in Type 2 Diabetes Mellitus.

Background and Purpose- This study reports the detailed effects of canagliflozin on stroke, stroke subtypes, and vascular outcomes in participants with and without cerebrovascular disease (stroke or transient ischemic attack) at baseline from the CANVAS (Canagliflozin Cardiovascular Assessment Study) Program. Methods- The CANVAS Program, comprising 2 similarly designed and conducted clinical trials, randomly assigned 10 142 participants with type 2 diabetes mellitus and high cardiovascular risk to canagliflozin or placebo. Its primary outcome was a composite of major adverse cardiovascular events.

Canagliflozin and renal outcomes in type 2 diabetes: results from the CANVAS Program randomised clinical trials.

Background: In the Canagliflozin Cardiovascular Assessment Study (CANVAS) Program, canagliflozin reduced the rates of major adverse cardiovascular events and the results suggested a renal benefit in patients with type 2 diabetes who were at high risk for cardiovascular events, compared with those treated with placebo. Here we report the results of a prespecified exploratory analysis of the long-term effects of canagliflozin on a range of sustained and adjudicated renal outcomes.

Methods: The CANVAS Program consists of two double-blind, randomised trials that assessed canagliflozin versus placebo in participants with type 2 diabetes who were at high risk of cardiovascular events, done at 667 centres in 30 countries.

Canagliflozin and Heart Failure in Type 2 Diabetes Mellitus: Results From the CANVAS Program.

Background: Canagliflozin is a sodium glucose cotransporter 2 inhibitor that reduces the risk of cardiovascular events. We report the effects on heart failure (HF) and cardiovascular death overall, in those with and without a baseline history of HF, and in other participant subgroups.

Methods: The CANVAS Program (Canagliflozin Cardiovascular Assessment Study) enrolled 10 142 participants with type 2 diabetes mellitus and high cardiovascular risk.

Canagliflozin for Primary and Secondary Prevention of Cardiovascular Events: Results From the CANVAS Program (Canagliflozin Cardiovascular Assessment Study).

Background: Canagliflozin is a sodium glucose cotransporter 2 inhibitor that significantly reduces the composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke in patients with type 2 diabetes mellitus and elevated cardiovascular risk. The comparative effects among participants with and without a history of cardiovascular disease (secondary versus primary prevention) were prespecified for evaluation.

Methods: The CANVAS Program (Canagliflozin Cardiovascular Assessment Study) randomly assigned 10 142 participants with type 2 diabetes mellitus to canagliflozin or placebo.

Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes.

Background Canagliflozin is a sodium-glucose cotransporter 2 inhibitor that reduces glycemia as well as blood pressure, body weight, and albuminuria in people with diabetes. We report the effects of treatment with canagliflozin on cardiovascular, renal, and safety outcomes. Methods The CANVAS Program integrated data from two trials involving a total of 10,142 participants with type 2 diabetes and high cardiovascular risk.

Optimizing the analysis strategy for the CANVAS Program: A prespecified plan for the integrated analyses of the CANVAS and CANVAS-R trials.

Two large cardiovascular outcome trials of canagliflozin, comprising the CANVAS Program, will complete in early 2017: the CANagliflozin cardioVascular Assessment Study (CANVAS) and the CANagliflozin cardioVascular Assessment Study-Renal (CANVAS-R). Accruing data for the sodium glucose co-transporter 2 (SGLT2) inhibitor class has identified questions and opportunities that were not apparent when the trials were designed. Accordingly, a series of modifications have been made to the planned analyses.

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.

Impact of Age and Estimated Glomerular Filtration Rate on the Glycemic Efficacy and Safety of Canagliflozin: A Pooled Analysis of Clinical Studies.

Objective: Reduced efficacy has been reported in the elderly; it may be a consequence of an age-dependent decline in estimated glomerular filtration rate (eGFR) rather than ageing per se. We sought to determine the impact of these 2 parameters, as well as sex and baseline body mass index (BMI), on the efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in people with type 2 diabetes.

Methods: Data were pooled from 6 randomized, double-blind, placebo-controlled studies (18 or 26 weeks; N=4053).

Efficacy and Safety of Canagliflozin in Individuals Aged 75 and Older with Type 2 Diabetes Mellitus: A Pooled Analysis.

Objectives: To compare the efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 inhibitor developed to treat type 2 diabetes mellitus (T2DM), in individuals younger than 75 and those aged 75 and older.

Design: Randomized Phase 3 studies.

Setting: International study centers.

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).

Efficacy and Safety of Canagliflozin Used in Conjunction with Sulfonylurea in Patients with Type 2 Diabetes Mellitus: A Randomized, Controlled Trial.

Introduction: The efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, was evaluated in patients with type 2 diabetes mellitus (T2DM) inadequately controlled on sulfonylurea monotherapy.

Methods: The CANagliflozin cardioVascular Assessment Study (CANVAS) is a double-blind, placebo-controlled cardiovascular outcomes study that randomized participants to placebo or canagliflozin 100 or 300 mg once daily in addition to routine therapy. Participants in the CANVAS trial are men and women aged ≥30 years with T2DM and a history or high risk of cardiovascular disease, and inadequate glycemic control (glycated hemoglobin [HbA1c] ≥7.

Efficacy and safety of canagliflozin, an inhibitor of sodium-glucose cotransporter 2, when used in conjunction with insulin therapy in patients with type 2 diabetes.

Objective: There are limited data about the effects of sodium-glucose cotransporter 2 inhibitors when used with insulin. We report the efficacy and safety of canagliflozin in patients with type 2 diabetes using insulin.

Research Design And Methods: The CANagliflozin CardioVascular Assessment Study is a double-blind, placebo-controlled study that randomized participants to placebo, canagliflozin 100 mg, or canagliflozin 300 mg once daily, added to a range of therapies.

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.

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.