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. Methods The percentages of mediating effects of 19 biomarkers were determined by comparing the hazard ratios for the effect of randomized treatment from an unadjusted model and from a model adjusting for the biomarker of interest. Multivariable analyses were used to assess the joint effects of biomarkers that mediated most strongly in univariable analyses. Results Early changes after randomization in levels of 3 biomarkers (urinary albumin:creatinine ratio, serum bicarbonate, and serum urate) were identified as mediating the effect of canagliflozin on heart failure. Average post-randomization levels of 14 biomarkers (systolic blood pressure, low-density lipoprotein and high-density lipoprotein cholesterol, total cholesterol, urinary albumin:creatinine ratio, weight, body mass index, gamma glutamyltransferase, hematocrit, hemoglobin concentration, serum albumin, erythrocyte concentration, serum bicarbonate, and serum urate) were identified as significant mediators. Individually, the 3 biomarkers with the largest mediating effect were erythrocyte concentration (45%), hemoglobin concentration (43%), and serum urate (40%). In a parsimonious multivariable model, erythrocyte concentration, serum urate, and urinary albumin:creatinine ratio were the 3 biomarkers that maximized cumulative mediation (102%). Conclusions A diverse set of potential mediators of the effect of canagliflozin on heart failure were identified. Some mediating effects were anticipated, whereas others were not. The mediators that were identified support existing and novel hypothesized mechanisms for the prevention of heart failure with sodium glucose cotransporter 2 inhibitors

Self-organized criticality in the hysteresis of the Sherrington - Kirkpatrick model

We study hysteretic phenomena in random ferromagnets. We argue that the angle dependent magnetostatic (dipolar) terms introduce frustration and long range interactions in these systems. This makes it plausible that the Sherrington - Kirkpatrick model may be able to capture some of the relevant physics of these systems. We use scaling arguments, replica calculations and large scale numerical simulations to characterize the hysteresis of the zero temperature SK model. By constructing the distribution functions of the avalanche sizes, magnetization jumps and local fields, we conclude that the system exhibits self-organized criticality everywhere on the hysteresis loop.Comment: 4 pages, 4 eps figure

Initiation of the SGLT2 inhibitor canagliflozin to prevent kidney and heart failure outcomes guided by HbA1c, albuminuria, and predicted risk of kidney failure

Background: Sodium glucose co-transporter-2 (SGLT2) inhibitors reduce the risk of kidney and heart failure events independent of glycemic effects. We assessed whether initiation of the SGLT2 inhibitor canagliflozin guided by multivariable predicted risk based on clinical characteristics and novel biomarkers is more efficient to prevent clinical outcomes compared to a strategy guided by HbA1c or urinary-albumin-creatinine ratio (UACR) alone. Methods: We performed a post-hoc analysis of the CANVAS trial including 3713 patients with available biomarker measurements. We compared the number of composite kidney (defined as a sustained 40% decline in eGFR, chronic dialysis, kidney transplantation, or kidney death) and composite heart failure outcomes (defined as heart failure hospitalization or cardiovascular (CV) death) prevented per 1000 patients treated for 5 years when canagliflozin was initiated in patients according to HbA1c ≥ 7.5%, UACR, or multivariable risk models consisting of: (1) clinical characteristics, or (2) clinical characteristics and novel biomarkers. Differences in the rates of events prevented between strategies were tested by Chi2-statistic. Results: After a median follow-up of 6.1 years, 144 kidney events were recorded. The final clinical model included age, previous history of CV disease, systolic blood pressure, UACR, hemoglobin, body weight, albumin, estimated glomerular filtration rate, and randomized treatment assignment. The combined biomarkers model included all clinical characteristics, tumor necrosis factor receptor-1, kidney injury molecule-1, matrix metallopeptidase-7 and interleukin-6. Treating all patients with HbA1c ≥ 7.5% (n = 2809) would prevent 33.0 (95% CI 18.8 to 43.3) kidney events at a rate of 9.6 (95% CI 5.5 to 12.6) events prevented per 1000 patients treated for 5 years. The corresponding rates were 5.8 (95% CI 3.4 to 7.9), 16.6 (95% CI 9.5 to 22.0) (P < 0.001 versus HbA1c or UACR approach), and 17.5 (95% CI 10.0 to 23.0) (P < 0.001 versus HbA1c or UACR approach; P = 0.54 versus clinical model). Findings were similar for the heart failure outcome. Conclusion: Initiation of canagliflozin based on an estimated risk-based approach prevented more kidney and heart failure outcomes compared to a strategy based on HbA1c or UACR alone. There was no apparent gain from adding novel biomarkers to the clinical risk model. These findings support the use of risk-based assessment using clinical markers to guide initiation of SGLT2 inhibitors in patients with type 2 diabetes

Effects of canagliflozin on heart failure outcomes associated with preserved and reduced ejection fraction in type 2 diabetes: results from the CANVAS Program

Patients with type 2 diabetes mellitus are at high risk of developing heart failure (HF).1 Sodium glucose co-transporter 2 (SGLT2) inhibitors have been demonstrated, in large scale trials, to reduce the risk of HF events in patients with type 2 diabetes deemed to be at high risk based on established cardiovascular disease or multiple risk factors.2-4 However, it is unclear whether benefits are experienced across the broad spectrum of HF patients that includes those with preserved (HFpEF) as well as reduced ejection fraction (HFrEF)

High sensitivity cardiac troponin T and N-terminal pro-BNP predict cardiovascular events and death in patients with type 2 diabetes mellitus

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Effects of ischaemic conditioning on major clinical outcomes in people undergoing invasive procedures: systematic review and meta-analysis.

OBJECTIVE:  To summarise the benefits and harms of ischaemic conditioning on major clinical outcomes in various settings. DESIGN:  Systematic review and meta-analysis. DATA SOURCES:  Medline, Embase, Cochrane databases, and International Clinical Trials Registry platform from inception through October 2015. STUDY SELECTION:  All randomised controlled comparisons of the effect of ischaemic conditioning on clinical outcomes were included. DATA EXTRACTION:  Two authors independently extracted data from individual reports. Reports of multiple intervention arms were treated as separate trials. Random effects models were used to calculate summary estimates for all cause mortality and other pre-specified clinical outcomes. All cause mortality and secondary outcomes with P<0.1 were examined for study quality by using the GRADE assessment tool, the effect of pre-specified characteristics by using meta-regression and Cochran C test, and trial sequential analysis by using the Copenhagen Trial Unit method. RESULTS:  85 reports of 89 randomised comparisons were identified, with a median 80 (interquartile range 60-149) participants and median 1 (range 1 day-72 months) month intended duration. Ischaemic conditioning had no effect on all cause mortality (68 comparisons; 424 events; 11 619 participants; risk ratio 0.96, 95% confidence interval 0.80 to 1.16; P=0.68; moderate quality evidence) regardless of the clinical setting in which it was used or the particular intervention related characteristics. Ischaemic conditioning may reduce the rates of some secondary outcomes including stroke (18 trials; 5995 participants; 149 events; risk ratio 0.72, 0.52 to 1.00; P=0.048; very low quality evidence) and acute kidney injury (36 trials; 8493 participants; 1443 events; risk ratio 0.83, 0.71 to 0.97; P=0.02; low quality evidence), although the benefits seem to be confined to non-surgical settings and to mild episodes of acute kidney injury only. CONCLUSIONS:  Ischaemic conditioning has no overall effect on the risk of death. Possible effects on stroke and acute kidney injury are uncertain given methodological concerns and low event rates. Adoption of ischaemic conditioning cannot be recommended for routine use unless further high quality and well powered evidence shows benefit

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 cana-gliflozin or placebo. The association between baseline GDF-15 and cardiovascular (non-fatal myocardial infarction, non-fatal stroke, cardiovascular death), HF, and kidney (40% estimated glomerular filtration rate decline, end-stage kidney disease, renal death) outcomes was assessed using multivariable adjusted Cox regression models. During median follow-up of 6.1 years (N=3549 participants with available samples), 555 cardiovascular, 129 HF, and 137 kidney outcomes occurred. Each doubling in baseline GDF-15 was significantly associated with a higher risk of cardiovascular (hazard ratio [HR], 1.2; 95% CI, 1.0‒1.3), HF (HR, 1.5; 95% CI, 1.2‒2.0) and kidney (HR, 1.5; 95% CI, 1.2‒2.0) outcomes. Baseline GDF-15 did not modify canagliflozin’s effect on cardiovascular, HF, and kidney outcomes. Canaglifozin treatment modestly lowered GDF-15 compared with placebo; however, GDF-15 did not mediate the protective effect of canagliflozin on cardiovascular, HF, or kidney outcomes. CONCLUSIONS: In patients with type 2 diabetes at high cardiovascular risk, higher GDF-15 levels were associated with a higher risk of cardiovascular, HF, and kidney outcomes. Canagliflozin modestly lowered GDF-15, but GDF-15 reduction did not mediate the protective effect of canagliflozin

Cardiovascular and renal outcomes with canagliflozin in patients with peripheral arterial disease: Data from the CANVAS Program and CREDENCE trial

Aim: To define the proportional and absolute benefits of the sodium-glucose co-transporter-2 inhibitor canagliflozin in patients with type 2 diabetes (T2D) with and without peripheral arterial disease (PAD). Materials and Methods: We pooled individual participant data from the CANVAS Program (n = 10 142) and CREDENCE trial (n = 4401). In this post hoc analysis, the main outcomes of interest were major adverse cardiovascular events (MACE: non-fatal myocardial infarction, non-fatal stroke or cardiovascular death), kidney outcomes, and extended major adverse limb events (MALE). Cox proportional hazards models were used to assess canagliflozin treatment effects in those with and without PAD. Absolute risk reductions per 1000 patients treated for 2.5 years were estimated using Poisson regression. Results: Of 14 543 participants, 3159 (21.7%) had PAD at baseline. In patients with PAD, canagliflozin reduced MACE (hazard ratio, 0.76; 95% confidence interval, 0.62-0.92), with similar relative benefits for other cardiovascular and kidney outcomes in participants with or without PAD at baseline (all Pinteraction >.268). There was no increase in the relative risk of extended MALE with canagliflozin, irrespective of baseline PAD history (Pinteraction >.864). The absolute benefits of canagliflozin were greater in those with PAD. Conclusions: Patients with T2D and PAD derived similar relative cardiorenal benefits from canagliflozin treatment but higher absolute benefits compared with those without PAD, with no increase in extended MALE