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. MI events were adjudicated as ST-elevation myocardial infarction (STEMI), non-STEMI, and type 1 MI or type 2 MI. A total of 421 first MI events in the CANVAS Programme and 178 first MI events in the CREDENCE trial were recorded (83 fatal, 128 STEMI, 431 non-STEMI, and 40 unknown). No benefit of canagliflozin compared with placebo on time to first MI event was observed [hazard ratio (HR) 0.89; 95% confidence interval (CI) 0.75, 1.05]. Canagliflozin was associated with lower risk for non-STEMI (HR 0.78; 95% CI 0.65, 0.95) but suggested a possible increase in STEMI (HR 1.55; 95% CI 1.06, 2.27), with no difference in risk of type 1 or type 2 MI. There was no change in fatal MI (HR 1.22, 95% CI 0.78, 1.93). CONCLUSION: Canagliflozin was not associated with a reduction in overall MI in the pooled CANVAS Programme and CREDENCE trial population. The possible differential effect on STEMI and Non-STEMI observed in the CANVAS cohort warrants further investigation. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT01032629, NCT01989754, and NCT02065791.

Effects of canagliflozin compared with placebo on major adverse cardiovascular and kidney events in patient groups with different baseline levels of HbA1c, disease duration and treatment intensity: results from the CANVAS Program.

AIMS/HYPOTHESIS: Type 2 diabetes mellitus can manifest over a broad clinical range, although there is no clear consensus on the categorisation of disease complexity. We assessed the effects of canagliflozin, compared with placebo, on cardiovascular and kidney outcomes in the CANagliflozin cardioVascular Assessment Study (CANVAS) Program over a range of type 2 diabetes mellitus complexity, defined separately by baseline intensity of treatment, duration of diabetes and glycaemic control. METHODS: We performed a post hoc analysis of the effects of canagliflozin on major adverse cardiovascular events (MACE) according to baseline glucose-lowering treatments (0 or 1, 2 or 3+ non-insulin glucose-lowering treatments, or insulin-based treatment), duration of diabetes (<10, 10 to 16, >16 years) and HbA1c (≤53.0 mmol/mol [<7.0%], >53.0 to 58.5 mmol/mol [>7.0% to 7.5%], >58.5 to 63.9 mmol/mol [>7.5 to 8.0%], >63.9 to 69.4 mmol/mol [8.0% to 8.5%], >69.4 to 74.9 mmol/mol [>8.5 to 9.0%] or >74.9 mmol/mol [>9.0%]). We analysed additional secondary endpoints for cardiovascular and kidney outcomes, including a combined kidney outcome of sustained 40% decline in eGFR, end-stage kidney disease or death due to kidney disease. We used Cox regression analyses and compared the constancy of HRs across subgroups by fitting an interaction term (p value for significance <0.05). RESULTS: At study initiation, 5095 (50%) CANVAS Program participants were treated with insulin, 2100 (21%) had an HbA1c > 74.9 mmol/mol (9.0%) and the median duration of diabetes was 12.6 years (interquartile interval 8.0-18 years). Canagliflozin reduced MACE (HR 0.86 [95% CI 0.75, 0.97]) with no evidence that the benefit differed between subgroups defined by the number of glucose-lowering treatments, the duration of diabetes or baseline HbA1c (all p-heterogeneity >0.17). Canagliflozin reduced MACE in participants receiving insulin with no evidence that the benefit differed from other participants in the trial (HR 0.85 [95% CI 0.72, 1.00]). Similar results were observed for other cardiovascular outcomes and for the combined kidney outcome (HR for combined kidney outcome 0.60 [95% CI 0.47, 0.77]), with all p-heterogeneity >0.37. CONCLUSIONS/INTERPRETATION: In people with type 2 diabetes mellitus at high cardiovascular risk, there was no evidence that cardiovascular and renal protection with canagliflozin differed across subgroups defined by baseline treatment intensity, duration of diabetes or HbA1c.

Reasons for hospitalizations in patients with type 2 diabetes in the CANVAS programme: A secondary analysis.

AIM: To determine the reasons for hospitalizations in the CANagliflozin cardioVascular Assessment Study (CANVAS) programme and the effects of the sodium-glucose co-transporter-2 inhibitor canagliflozin on hospitalization. MATERIALS AND METHODS: A secondary analysis was performed on the CANVAS programme that included 10 142 participants with type 2 diabetes randomized to canagliflozin or placebo. The primary outcome was the rate of total (first plus all recurrent) all-cause hospitalizations (ACH). Secondary outcomes were total hospitalizations categorized by the Medical Dictionary for Regulatory Activities hierarchy at the system organ class level, reported by investigators at each centre. Outcomes were assessed using negative binomial models. RESULTS: Of the 7115 hospitalizations reported, the most common reasons were cardiac disorders (23.7%), infections and infestations (15.0%), and nervous system disorders (9.0%). The rate of total ACH was lower in the canagliflozin group (n = 5795) compared with the placebo group (n = 4347): 197.9 versus 215.8 participants per 1000 patient-years, respectively (rate ratio [RR] 0.92; 95% confidence interval [CI] 0.86, 0.98). Canagliflozin reduced the rate of total hospitalizations because of cardiac disorders (RR 0.81; 95% CI 0.75, 0.88). There was no significant difference between the canagliflozin and placebo groups in the rates of total hospitalizations because of infections and infestations (RR 0.96; 95% CI 0.86, 1.02) or nervous system disorders (RR 0.96; 95% CI 0.88, 1.05). CONCLUSIONS: In the CANVAS programme, the most common reasons for hospitalization were cardiac disorders, infections and infestations, and nervous system disorders. Canagliflozin, compared with placebo, reduced the rate of total ACH.

Canagliflozin, serum magnesium and cardiovascular outcomes-Analysis from the CANVAS Program.

BACKGROUND: Patients with type 2 diabetes (T2D) are predisposed to derangements in serum Magnesium (Mg), which may have implications for cardiometabolic events and outcomes. In clinical trials, participants with T2D randomized to sodium-glucose co-transporter 2 (SGLT2) inhibitors have shown mild to moderate increases in serum Mg from baseline levels. This post hoc analysis assesses the relation between serum Mg with cardiovascular outcomes in 10,140 participants of the Canagliflozin Cardiovascular Assessment Study (CANVAS) Program. METHODS: We evaluated the association of baseline serum Mg with the primary composite end point of death from cardiovascular causes, non-fatal myocardial infarction, and non-fatal stroke, and tested whether this association is modified by baseline serum Mg. Using mediation analysis, we determined whether change in serum Mg post-randomization mediates the beneficial effect of canagliflozin on cardiovascular outcomes. RESULTS: Mean serum Mg levels at baseline were 0.77 ± 0.09 mmol/L in both canagliflozin group and placebo groups. The canagliflozin group experienced an average increase in serum Mg by 0.07 mmol/L (95% CI, 0.065-0.072 mmol/L; p < .001) for the duration of the trial. We found no association between baseline serum Mg levels and the primary composite end point, and no evidence of effect modification by baseline Mg levels. Change in serum Mg post-randomization was not a mediator of the effects of canagliflozin on cardiovascular outcomes. CONCLUSIONS: In participants of the CANVAS Program, baseline and post-randomization serum Mg levels are not associated with cardiovascular outcomes.

Sodium-glucose co-transporter-2 inhibitors with and without metformin: A meta-analysis of cardiovascular, kidney and mortality outcomes.

AIM: To assess whether the effects of sodium-glucose co-transporter-2 (SGLT2) inhibitors on cardiovascular, kidney and mortality outcomes are consistent with and without concomitant metformin use. MATERIAL AND METHODS: We conducted a meta-analysis of event-driven, randomized, placebo-controlled SGLT2 inhibitor trials that reported cardiovascular, kidney or mortality outcomes by baseline metformin use. Treatment effects, reported as hazards ratios (HRs) and 95% confidence intervals (CIs), were pooled using random-effects meta-analysis. The main outcomes in this analysis were (i) major adverse cardiovascular events (MACE) and (ii) hospitalization for heart failure (HHF) or cardiovascular death. RESULTS: We included six trials of four SGLT2 inhibitors that enrolled a total of 51 743 participants. Baseline metformin use varied from 21% in DAPA-HF to 82% in DECLARE-TIMI 58. SGLT2 inhibitors reduced the risk of MACE, with and without concomitant metformin use (HR 0.93, 95% CI 0.87-1.00 and HR 0.82, 95% CI 0.71-0.86, respectively; P-heterogeneity = 0.14). There were also clear and separate reductions in HHF or cardiovascular death with SGLT2 inhibitors, irrespective of metformin use (HR 0.79, 95% CI 0.73-0.86 and HR 0.74, 95% CI 0.63-0.87, respectively; P-heterogeneity = 0.48), as well as for major kidney outcomes and all-cause mortality (all P-heterogeneity > 0.40). CONCLUSION: Treatment with SGLT2 inhibitors results in clear and consistent reductions in cardiovascular, kidney and mortality outcomes regardless of whether patients are receiving or not receiving metformin.

Relative and Absolute Risk Reductions in Cardiovascular and Kidney Outcomes With Canagliflozin Across KDIGO Risk Categories: Findings From the CANVAS Program.

RATIONALE & OBJECTIVE: Canagliflozin reduces the risk for cardiovascular and kidney outcomes in type 2 diabetes. This study aimed to assess the relative and absolute effects of canagliflozin on clinical outcomes across different KDIGO (Kidney Disease: Improving Global Outcomes) risk categories based on estimated glomerular filtration rate (eGFR) and urinary albumin-creatinine ratio. STUDY DESIGN: Post hoc analysis of the CANagliflozin cardioVascular Assessment Study (CANVAS) Program. SETTINGS & PARTICIPANTS: The CANVAS Program randomly assigned 10,142 participants with type 2 diabetes at high cardiovascular risk and with eGFR≥30mL/min/1.73m2 to treatment with canagliflozin or placebo. INTERVENTION(S): Canagliflozin or matching placebo. OUTCOMES: The primary outcome was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, with a set of other cardiovascular and kidney prespecified outcomes. RESULTS: Of 10,142 participants, 10,031 (98.9%) had available baseline eGFR and urinary albumin-creatinine ratio data. The proportion of participants in low-, moderate-, high-, and very high-risk KDIGO categories was 58.6%, 25.8%, 10.6%, and 5.0%, respectively. The relative effect of canagliflozin on the primary outcome (HR, 0.86; 95% CI, 0.75-0.97) was consistent across KDIGO risk categories (P trend=0.2), with similar results for other cardiovascular and kidney outcomes. Absolute reductions in the primary outcome were greater within higher KDIGO risk categories (P trend=0.03) with a similar pattern of effect for the composite of cardiovascular death or hospitalization for heart failure (P trend=0.06) and for chronic eGFR slope (P trend = 0.04). LIMITATIONS: Predominantly a low kidney risk population, relatively few participants in higher KDIGO risk categories, and exclusion of individuals with eGFR<30mL/min/1.73m2. CONCLUSIONS: Although the relative effects of canagliflozin are similar across KDIGO risk categories, absolute risk reductions are likely greater for individuals at higher KDIGO risk. The KDIGO classification system may be able to identify individuals who might derive greater benefits for end-organ protection from treatment with canagliflozin. FUNDING: This post hoc analysis was not specifically funded. The original CANVAS Program trials were funded by Janssen Research & Development, LLC and were conducted as a collaboration between the funder, an academic steering committee, and an academic research organization, George Clinical. TRIAL REGISTRATION: The original trials of the CANVAS Program were registered at ClinicalTrials.gov with study numbers NCT01032629 and NCT01989754.

The Clinical Role of Insulin Degludec/Insulin Aspart in Type 2 Diabetes: An Empirical Perspective from Experience in Australia.

Treatment intensification in people with type 2 diabetes following failure of basal insulin commonly involves the addition of a rapid-acting insulin analogue (basal plus one or more prandial doses; multiple daily injections) or by a switch to premixed insulin. Insulin degludec/insulin aspart (IDegAsp), comprising rapid-acting insulin aspart and ultra-long-acting insulin degludec in solution, enables both fasting and post-prandial glucose control, with some advantages over other treatment intensification options. These include straightforward dose titration, flexibility in dose timing, low injection burden, simplicity of switching and a lower risk of hypoglycaemia. In Australia, where insulin degludec on its own is not available, IDegAsp enables patients to still benefit from its ultra-long-acting properties. This review aims to provide guidance on where and how to use IDegAsp. Specifically, guidance is included on the initiation of IDegAsp in insulin-naïve patients, treatment intensification from basal insulin, switching from premixed or basal-bolus insulin to IDegAsp, up-titration from once- to twice-daily IDegAsp and the use of IDegAsp in special populations or situations.

Health-related quality of life among patients with comorbid diabetes and kidney disease attending a codesigned integrated model of care: a longitudinal study.

OBJECTIVE: To evaluate the impact of an integrated diabetes and kidney disease model of care on health-related quality of life (HRQOL) of patients with comorbid diabetes and chronic kidney disease (CKD). RESEARCH DESIGN AND METHODS: A longitudinal study of adult patients (over 18 years) with comorbid diabetes and CKD (stage 3a or worse) who attended a new diabetes kidney disease service was conducted at a tertiary hospital. A questionnaire consisting of demographics, clinical data, and the Kidney Disease Quality of Life (KDQOL-36) was administered at baseline and after 12 months. Paired t-tests were used to compare baseline and 12-month scores. A subgroup analysis examined the effects by patient gender. Multiple regression analysis examined the factors associated with changes in scores. RESULTS: 179 patients, 36% of whom were female, with baseline mean±SD age of 65.9±11.3 years, were studied. Across all subscales, HRQOL did not significantly change over time (p value for all mean differences >0.05). However, on subgroup analysis, symptom problem list and physical composite summary scores increased among women (MD=9.0, 95% CI 1.25 to 16.67; p=0.02 and MD=4.5, 95% CI 0.57 to 8.42; p=0.03 respectively) and physical composite scores decreased among men (MD=-3.35, 95% CI -6.26 to -0.44; p=0.03). CONCLUSION: The HRQOL of patients with comorbid diabetes and CKD attending a new codesigned, integrated diabetes and kidney disease model of care was maintained over 12 months. Given that HRQOL is known to deteriorate over time in this high-risk population, the impact of these findings on clinical outcomes warrants further investigation.

A physician-initiated double-blind, randomised, placebo-controlled, phase 2 study evaluating the efficacy and safety of inhibition of NADPH oxidase with the first-in-class Nox-1/4 inhibitor, GKT137831, in adults with type 1 diabetes and persistently elevated urinary albumin excretion: Protocol and statistical considerations.

PURPOSE: Kidney disease caused by type 1 diabetes can progress to end stage renal disease and can increase mortality risk. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) plays a major role in producing oxidative stress in the kidney in diabetes, and its activity is attenuated by GKT137831, an oral Nox inhibitor with predominant inhibitory action on Nox-1 and Nox - 4. Previous studies have demonstrated renoprotective effects with GKT137831 in various experimental models of type 1 diabetes-related kidney disease. This study will evaluate the effect of GKT137831 in treating clinical diabetic kidney disease. DESIGN: This is a multi-center, randomized, placebo-controlled trial, parallel arm study evaluating the effect on albuminuria of treatment with GKT137831 400 mg BID for 48 weeks. The study will randomize 142 participants who have persistent albuminuria and estimated glomerular filtration rate (eGFR) at baseline of at least 40 ml/min/1.73m2. PRIMARY OUTCOME MEASURES: Difference between arms in urine albumin to creatinine ratio. Secondary outcome measures include eGFR. CONCLUSION: This study is important because it may identify a new way of slowing renal disease progression in people with type 1 diabetes and albuminuria already receiving standard of care treatment.

Effect of Canagliflozin on Renal and Cardiovascular Outcomes across Different Levels of Albuminuria: Data from the CANVAS Program.

BACKGROUND: If SGLT2 inhibitors protect the kidneys by reducing albuminuria as hypothesized, people with type 2 diabetes mellitus (T2DM) with higher albuminuria should benefit more. METHODS: We conducted a post-hoc analysis of data from the CANagliflozin cardioVascular Assessment Study (CANVAS) Program, which randomized 10,142 participants with T2DM and high cardiovascular risk to canagliflozin or placebo. We assessed effects of canagliflozin on renal, cardiovascular, and safety outcomes by baseline albuminuria. The trial included 2266 participants (22.3%) with moderately increased albuminuria (urinary albumin/creatinine ratio [UACR] 30-300 mg/g) and 760 (7.5%) with severely increased albuminuria (UACR >300 mg/g) at baseline. RESULTS: Canagliflozin lowered albuminuria with greater proportional reductions in those with moderately and severely increased albuminuria (P heterogeneity<0.001). After week 13, canagliflozin slowed the annual loss of kidney function across albuminuria subgroups, with greater absolute reductions in participants with severely increased albuminuria (placebo-subtracted difference 3.01 ml/min per 1.73 m2 per year; P heterogeneity<0.001). Heterogeneity for the renal composite outcome of 40% reduction in eGFR, ESKD, or renal-related death was driven by lesser effects in participants with moderately increased albuminuria (P heterogeneity=0.03), but no effect modification was observed when albuminuria was fitted as a continuous variable (P heterogeneity=0.94). Cardiovascular and safety outcomes were mostly consistent across albuminuria levels including increased risks for amputation across albuminuria subgroups (P heterogeneity=0.66). Greater absolute risk reductions in the renal composite outcome were observed in participants with severely increased albuminuria (P heterogeneity=0.004). CONCLUSIONS: The proportional effects of canagliflozin on renal and cardiovascular outcomes are mostly consistent across patients with different levels of albuminuria, but absolute benefits are greatest among those with severely increased albuminuria.

Canagliflozin and fracture risk in individuals with type 2 diabetes: results from the CANVAS Program.

AIMS/HYPOTHESIS: An increased risk of fracture with canagliflozin vs placebo was reported from the CANagliflozin cardioVascular Assessment Study (CANVAS) Program, with heterogeneity of findings identified between the two trials that comprise the CANVAS Program, CANVAS and CANVAS-R. The objective of these analyses was to identify reasons for the possibly different effects on fracture observed between CANVAS and CANVAS-R. METHODS: This study was an analysis of two highly similar trials, CANVAS and CANVAS-R, conducted in 10,142 individuals with type 2 diabetes and history or high risk of cardiovascular disease who received canagliflozin (pooled 100/300 mg once daily) or placebo. Outcomes assessed in this analysis were effects on adjudicated fractures overall and by type, location, association with a fall, dose and follow-up time. RESULTS: A total of 496 participants recorded ≥1 fracture event during follow-up (15.40 vs 11.93 per 1000 patient-years with canagliflozin vs placebo; HR 1.26 [95% CI 1.04, 1.52]). There was significant heterogeneity in the effects on fracture (p = 0.005) between CANVAS (n = 4330: HR 1.55 [95% CI 1.21, 1.97]) and CANVAS-R (n = 5812: HR 0.86 [95% CI 0.62, 1.19]). The between-study heterogeneity in fracture risk was not clearly explained by differences in baseline characteristics, interactions of randomised treatment with participant characteristics, dose effects, duration of follow-up, metabolic effects, adverse events related to falls or adverse events possibly causing falls. CONCLUSIONS/INTERPRETATION: There was no evidence to explain clearly the fracture risk observed in the CANVAS Program or the heterogeneity in fracture risk between the two studies. The recently reported null result for fracture in the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial suggests that the observed association in CANVAS is likely to be a chance finding, although an unidentified fall-related mechanism remains a possibility. TRIAL REGISTRATION: ClinicalTrials.gov NCT01032629, NCT01989754.

Effects of canagliflozin on amputation risk in type 2 diabetes: the CANVAS Program.

AIMS/HYPOTHESIS: The primary analysis of the Canagliflozin cardioVascular Assessment Study (CANVAS) Program showed canagliflozin to have a beneficial effect on cardiovascular and renal outcomes in people with type 2 diabetes at high cardiovascular risk, but also an unexpected increased risk of major or minor lower extremity amputation. These secondary analyses explore this finding in more detail. METHODS: The effect of canagliflozin on amputation risk in the CANVAS Program was calculated for amputations of different types and proximate aetiologies and different canagliflozin doses. Univariate and multivariate associations of baseline characteristics with amputation risk were determined and proportional and absolute effects of canagliflozin were compared across subgroups. RESULTS: There were 187 (1.8%) participants with atraumatic lower extremity amputations (minor 71%, major 29%); as previously published, rates were 6.30 vs 3.37 per 1000 participant-years with canagliflozin vs placebo (HR 1.97 [95% CI 1.41, 2.75]). Risk was similar for ischaemic and infective aetiologies and for 100 mg and 300 mg doses. Overall amputation risk was strongly associated with baseline history of prior amputation (major or minor) (HR 21.31 [95% CI 15.40, 29.49]) and other established risk factors. No interactions between randomised treatment and participant characteristics explained the effect of canagliflozin on amputation risk. For every clinical subgroup studied, numbers of amputation events projected were smaller than numbers of major adverse cardiovascular events averted. CONCLUSIONS/INTERPRETATION: The CANVAS Program demonstrated that canagliflozin increased the risk of amputation (mainly minor) in this study population. Anticipated risk factors for amputation were identified, such as prior history of amputation, peripheral vascular disease and neuropathy, but no specific aetiological mechanism or at-risk subgroup for canagliflozin was identified.

Efficacy and Safety of IDegAsp Versus BIAsp 30, Both Twice Daily, in Elderly Patients with Type 2 Diabetes: Post Hoc Analysis of Two Phase 3 Randomized Controlled BOOST Trials.

INTRODUCTION: The majority of elderly patients (≥ 65 years of age) with type 2 diabetes mellitus (T2DM) will eventually require insulin therapy, but they are particularly vulnerable to hypoglycemia and challenging to treat. Insulin degludec/insulin aspart (IDegAsp) is a novel co-formulation of 70% insulin degludec and 30% insulin aspart administered in a single injection, either once or twice daily with main meals. METHODS: A combined analysis of the phase 3 BOOST INTENSIFY PREMIX I (NCT01009580) and BOOST INTENSIFY ALL (NCT01059812) trials has previously reported lower rates of hypoglycemia during the maintenance period in patients with T2DM treated with IDegAsp twice daily (BID) versus biphasic insulin aspart 30 (BIAsp 30) BID. This post hoc analysis examined the safety and efficacy of IDegAsp versus BIAsp 30 in elderly patients from the global population of these two trials, and also from the Japanese cohort of BOOST INTENSIFY ALL. RESULTS: Change in HbA1c was similar for IDegAsp versus BIAsp 30 (p > 0.5). Compared with BIAsp 30, IDegAsp resulted in significant reductions in fasting plasma glucose (p < 0.0001), numerically lower rates of overall and nocturnal hypoglycemia (global estimated rate ratios: 0.92 [0.67; 1.26]95% confidence interval [CI], p = 0.5980 and 0.67 [0.39; 1.18]95% CI, p = 0.1676, respectively), and a significantly lower total daily insulin dose at end of trial (global estimated treatment difference 0.79 [0.73; 0.87]95% CI, p < 0.0001) in elderly patients. CONCLUSION: The results described here are consistent with those of the overall trial populations, demonstrating that IDegAsp BID is efficacious in elderly patients and suggesting that there is no need for special safety precautions. FUNDING: Novo Nordisk. TRIAL REGISTRATION: ClinicalTrials.gov identifiers, NCT01009580 and NCT01059812. Plain language summary available for this article.

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. The main outcome of interest for this report was fatal or nonfatal stroke. Additional exploratory outcomes were stroke subtypes and other vascular outcomes defined according to standard criteria. Results- There were 1 958 (19%) participants with prior stroke or transient ischemic attack at baseline. These individuals were older, more frequently women, and had higher rates of heart failure, atrial fibrillation, and microvascular disease (all P<0.001) compared with those without such a history. There were 309 participants with stroke events during follow-up (123 had prior stroke or transient ischemic attack at baseline and 186 did not), at a rate of 7.93/1000 patient-years among those assigned canagliflozin and 9.62/1000 patient-years among placebo (hazard ratio, 0.87; 95% CI, 0.69-1.09). Analysis of stroke subtypes found no effect on ischemic stroke (n=253, hazard ratio, 0.95; 95% CI, 0.74-1.22), a significant reduction for hemorrhagic stroke (n=30, hazard ratio, 0.43; 95% CI, 0.20-0.89) and no effect on undetermined stroke (n=29, hazard ratio, 1.04; 95% CI, 0.48-2.22). Effects on other cardiovascular outcomes were comparable among participants with and without stroke or transient ischemic attack at baseline. Conclusions- There were too few events in the CANVAS Program to separately define the effects of canagliflozin on stroke, but benefit is more likely than harm. The observed possible protective effect for hemorrhagic stroke was based on small numbers but warrants further investigation. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifiers: NCT01032629 and NCT01989754.

The effects of canagliflozin on gout in type 2 diabetes: a post-hoc analysis of the CANVAS Program.

BACKGROUND: Sodium glucose co-transporter 2 inhibitors have been shown to reduce serum urate concentration. The Canagliflozin Cardiovascular Assessment Study (CANVAS) Program integrated data from two similarly designed, randomised, double-blind, placebo-controlled trials (CANVAS and CANVAS-Renal) assessing the cardiovascular and renal safety of canagliflozin compared with placebo in patients with type 2 diabetes. In this post-hoc analysis, we aimed to investigate the effect of canagliflozin compared with placebo on gout in the CANVAS Program. METHODS: In the CANVAS Program, individuals with type 2 diabetes and an elevated risk of cardiovascular disease were randomly assigned to receive either canagliflozin (100 or 300 mg) or placebo. In this post-hoc analysis, we assessed the effects of canagliflozin versus placebo on serum urate concentration using mixed linear models and the occurrence of either an adverse event attributed to gout flare or the commencement of a drug for gout using Kaplan-Meier analysis with Cox proportional hazards models to determine a hazard ratio (HR) and 95% CIs. All analyses were done according to the principle of intention to treat, and there was no imputation for missing data. FINDINGS: 10 142 participants were included in analyses. At baseline, mean age was 63 years (SD 8), 3633 (36%) participants were female, mean serum urate concentration was 348·9 µmol/L (95·5), and 471 (5%) of participants had a history of gout. Mean follow-up was 3·6 years (SD 2·0) and mean serum urate concentration was -23·3 µmol/L (95% CI -25·4 to -21·3) lower in participants treated with canagliflozin than in those who received placebo, equating to a 6·7% reduction in serum urate (percentage difference -6·7%, 95% CI -7·3 to -6·1). During follow-up, 80 individuals reported an episode of gout flare and 147 commenced a drug for gout. The occurrence of gout flare or the need for treatment for gout was lower in participants treated with canagliflozin than in those who received placebo (HR 0·53, 95% CI 0·40-0·71; p<0·0001). The proportional reduction for gout flare adverse events (2·0 patients with an event per 1000 patient-years in the canagliflozin group vs 2·6 patients with an event per 1000 patient-years in the placebo group; 0·64, 95% CI 0·41-0·99; p=0·046) was similar in size to that for commencement of a drug for gout (3·3 vs 5·4 patients with an event per 1000 patient-years; 0·52, 0·38-0·72; p<0·0001) and hyperuricaemia (1·8 vs 2·5 patients with an event per 1000 patient-years; 0·59, 0·37-0·93; p=0·023). INTERPRETATION: In this post-hoc analysis, compared with placebo, canagliflozin reduced serum urate concentration and also reduced events related to gout flare among patients with type 2 diabetes. A trial explicitly designed to test the effects of sodium glucose co-transporter 2 inhibition on gout is required to confirm these observations. FUNDING: Janssen Research & Development.

Cardiovascular and Renal Outcomes With Canagliflozin According to Baseline Kidney Function.

BACKGROUND: Canagliflozin is approved for glucose lowering in type 2 diabetes and confers cardiovascular and renal benefits. We sought to assess whether it had benefits in people with chronic kidney disease, including those with an estimated glomerular filtration rate (eGFR) between 30 and 45 mL/min/1.73 m2 in whom the drug is not currently approved for use. METHODS: The CANVAS Program randomized 10 142 participants with type 2 diabetes and eGFR >30 mL/min/1.73 m2 to canagliflozin or placebo. The primary outcome was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, with other cardiovascular, renal, and safety outcomes. This secondary analysis describes outcomes in participants with and without chronic kidney disease, defined as eGFR <60 and ≥60 mL/min/1.73 m2, and according to baseline kidney function (eGFR <45, 45 to <60, 60 to <90, and ≥90 mL/min/1.73 m2). RESULTS: At baseline, 2039 (20.1%) participants had an eGFR <60 mL/min/1.73 m2, 71.6% of whom had a history of cardiovascular disease. The effect of canagliflozin on the primary outcome was similar in people with chronic kidney disease (hazard ratio, 0.70; 95% CI, 0.55-0.90) and those with preserved kidney function (hazard ratio, 0.92; 95% CI, 0.79-1.07; P heterogeneity = 0.08). Relative effects on most cardiovascular and renal outcomes were similar across eGFR subgroups, with possible heterogeneity suggested only for the outcome of fatal/nonfatal stroke ( P heterogeneity = 0.01), as were results for almost all safety outcomes. CONCLUSIONS: The effects of canagliflozin on cardiovascular and renal outcomes were not modified by baseline level of kidney function in people with type 2 diabetes and a history or high risk of cardiovascular disease down to eGFR levels of 30 mL/min/1.73 m2. Reassessing current limitations on the use of canagliflozin in chronic kidney disease may allow additional individuals to benefit from this therapy. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifiers: NCT01032629, NCT01989754.

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. People with type 2 diabetes and an HbA1c of 7·0-10·5% (53-91 mmol/mol) who were aged at least 30 years and had a history of symptomatic atherosclerotic vascular disease, or who were aged at least 50 years and had at least two cardiovascular risk factors were eligible to participate. Participants in CANVAS were randomly assigned (1:1:1) to receive 300 mg canagliflozin, 100 mg canagliflozin, or matching placebo once daily. Participants in CANVAS-R were randomly assigned (1:1) to receive canagliflozin or matching placebo, at an initial dose of 100 mg daily, with optional uptitration to 300 mg from week 13 or matching placebo. Participants and all study staff were masked to treatment allocations until study completion. Prespecified outcomes reported here include a composite of sustained and adjudicated doubling in serum creatinine, end-stage kidney disease, or death from renal causes; the individual components of this composite outcome; annual reductions in estimated glomerular filtration rate (eGFR); and changes in urinary albumin-to-creatinine ratio (UACR). The trials are registered with ClinicalTrials.gov, numbers NCT01032629 (CANVAS) and NCT01989754 (CANVAS-R). FINDINGS: Between Nov 17, 2009, and March 7, 2011 (CANVAS), and Jan 17, 2014, and May 29, 2015 (CANVAS-R), 15 494 people were screened, of whom 10 142 participants (with a baseline mean eGFR 76·5 mL/min per 1·73 m2, median UACR 12·3 mg/g, and 80% of whom were receiving renin-angiotensin system blockade) were randomly allocated to receive either canagliflozin or placebo. The composite outcome of sustained doubling of serum creatinine, end-stage kidney disease, and death from renal causes occurred less frequently in the canagliflozin group compared with the placebo group (1·5 per 1000 patient-years in the canagliflozin group vs 2·8 per 1000 patient-years in the placebo group; hazard ratio 0·53, 95% CI 0·33-0·84), with consistent findings across prespecified patient subgroups. Annual eGFR decline was slower (slope difference between groups 1·2 mL/min per 1·73 m2 per year, 95% CI 1·0-1·4) and mean UACR was 18% lower (95% CI 16-20) in participants treated with canagliflozin than in those treated with placebo. Total serious renal-related adverse events were similar between the canagliflozin and placebo groups (2·5 vs 3·3 per 1000 patient-years; HR 0·76, 95% CI 0·49-1·19). INTERPRETATION: In a prespecified exploratory analysis, canagliflozin treatment was associated with a reduced risk of sustained loss of kidney function, attenuated eGFR decline, and a reduction in albuminuria, which supports a possible renoprotective effect of this drug in people with type 2 diabetes. FUNDING: Janssen Research & Development.

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. Participants were randomly assigned to canagliflozin or placebo and followed for a mean of 188 weeks. The primary end point for these analyses was adjudicated cardiovascular death or hospitalized HF. RESULTS: Participants with a history of HF at baseline (14.4%) were more frequently women, white, and hypertensive and had a history of prior cardiovascular disease (all P<0.001). Greater proportions of these patients were using therapies such as blockers of the renin angiotensin aldosterone system, diuretics, and ß-blockers at baseline (all P<0.001). Overall, cardiovascular death or hospitalized HF was reduced in those treated with canagliflozin compared with placebo (16.3 versus 20.8 per 1000 patient-years; hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.67-0.91), as was fatal or hospitalized HF (HR, 0.70; 95% CI, 0.55-0.89) and hospitalized HF alone (HR, 0.67; 95% CI, 0.52-0.87). The benefit on cardiovascular death or hospitalized HF may be greater in patients with a prior history of HF (HR, 0.61; 95% CI, 0.46-0.80) compared with those without HF at baseline (HR, 0.87; 95% CI, 0.72-1.06; P interaction =0.021). The effects of canagliflozin compared with placebo on other cardiovascular outcomes and key safety outcomes were similar in participants with and without HF at baseline (all interaction P values >0.130), except for a possibly reduced absolute rate of events attributable to osmotic diuresis among those with a prior history of HF ( P=0.03). CONCLUSIONS: In patients with type 2 diabetes mellitus and an elevated risk of cardiovascular disease, canagliflozin reduced the risk of cardiovascular death or hospitalized HF across a broad range of different patient subgroups. Benefits may be greater in those with a history of HF at baseline. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifiers: NCT01032629 and NCT01989754.

Models of care for co-morbid diabetes and chronic kidney disease.

Diabetes and chronic kidney disease (CKD) are two of the most prevalent co-morbid chronic diseases in Australia. The increasing complexity of multi-morbidity, and current gaps in health-care delivery for people with co-morbid diabetes and CKD, emphasize the need for better models of care for this population. Previously, proposed published models of care for co-morbid diabetes and CKD have not been co-designed with stake-holders or formally evaluated. Particular components of health-care shown to be effective in this population are interventions that: are structured, intensive and multifaceted (treating diabetes and multiple cardiovascular risk factors); involve multiple medical disciplines; improve self-management by the patient; and upskill primary health-care. Here we present an integrated patient-centred model of health-care delivery incorporating these components and co-designed with key stake-holders including specialist health professionals, general practitioners and Diabetes and Kidney Health Australia. The development of the model of care was informed by focus groups of patients and health-professionals; and semi-structured interviews of care-givers and health professionals. Other distinctives of this model of care are routine screening for psychological morbidity; patient-support through a phone advice line; and focused primary health-care support in the management of diabetes and CKD. Additionally, the model of care integrates with the patient-centred health-care home currently being rolled out by the Australian Department of Health. This model of care will be evaluated after implementation across two tertiary health services and their primary care catchment areas.