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Effects of canagliflozin in patients with type 2 diabetes and chronic heart failure: a randomized trial (CANDLE).

ABSTRACT: AIMS:Little is known about the impact of sodium glucose co-transporter 2 (SGLT2) inhibitors on cardiac biomarkers, such as natriuretic peptides, in type 2 diabetes (T2D) patients with concomitant chronic heart failure (CHF). We compared the effect of canagliflozin with glimepiride, based on changes in N-terminal pro-brain natriuretic peptide (NT-proBNP), in that patient population. METHODS AND RESULTS:Patients with T2D and stable CHF, randomized to receive canagliflozin 100 mg or glimepiride (starting-dose: 0.5 mg), were examined using the primary endpoint of non-inferiority of canagliflozin vs. glimepiride, defined as a margin of 1.1 in the upper limit of the two-sided 95% confidence interval (CI) for the group ratio of percentage change in NT-proBNP at 24 weeks. Data analysis of 233 patients showed mean left ventricular ejection fraction (LVEF) at randomization was 57.6 ± 14.6%, with 71% of patients having a preserved LVEF (?50%). Ratio of NT-proBNP percentage change was 0.48 (95% CI, -0.13 to 1.59, P = 0.226) and therefore did not meet the prespecified non-inferiority margin. However, NT-proBNP levels did show a non-significant trend lower in the canagliflozin group [adjusted group difference; -74.7 pg/mL (95% CI, -159.3 to 10.9), P = 0.087] and also in the subgroup with preserved LVEF [-58.3 (95% CI, -127.6 to 11.0, P = 0.098]). CONCLUSIONS:This study did not meet the predefined primary endpoint of changes in NT-proBNP levels, with 24 weeks of treatment with canagliflozin vs. glimepiride. Further research is warranted to determine whether patients with heart failure with preserved ejection fraction, regardless of diabetes status, could potentially benefit from treatment with SGLT2 inhibitors.

SUBMITTER: Tanaka A

PROVIDER: S-EPMC7373938 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Effects of canagliflozin in patients with type 2 diabetes and chronic heart failure: a randomized trial (CANDLE).

Tanaka Atsushi A Hisauchi Itaru I Taguchi Isao I Sezai Akira A Toyoda Shigeru S Tomiyama Hirofumi H Sata Masataka M Ueda Shinichiro S Oyama Jun-Ichi JI Kitakaze Masafumi M Murohara Toyoaki T Node Koichi K

ESC heart failure 20200429 4

<h4>Aims</h4>Little is known about the impact of sodium glucose co-transporter 2 (SGLT2) inhibitors on cardiac biomarkers, such as natriuretic peptides, in type 2 diabetes (T2D) patients with concomitant chronic heart failure (CHF). We compared the effect of canagliflozin with glimepiride, based on changes in N-terminal pro-brain natriuretic peptide (NT-proBNP), in that patient population.<h4>Methods and results</h4>Patients with T2D and stable CHF, randomized to receive canagliflozin 100 mg or ...[more]

PMID: 32349193

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Project description:BackgroundThe successful management of heart failure (HF) involves guideline-based medical therapy as well as self-management behavior. As a result, the management of HF is moving toward a proactive real-time technological model of assisting patients with monitoring and self-management.ObjectiveThe aim of this paper was to evaluate the efficacy of enhanced self-management via a mobile app intervention on health-related quality of life, self-management, and HF readmissions.MethodsA single-center randomized controlled trial was performed. Participants older than 45 years and admitted for acute decompensated HF or recently discharged in the past 4 weeks were included. The intervention group ("app group") used a mobile app, and the intervention prompted daily self-monitoring and promoted self-management. The control group ("no-app group") received usual care. The primary outcome was the change in Minnesota Living with Heart Failure Questionnaire (MLHFQ) score from baseline to 6 and 12 weeks. Secondary outcomes were the Self-Care Heart Failure Index (SCHFI) questionnaire score and recurrent HF admissions.ResultsA total of 83 participants were enrolled and completed all baseline assessments. Baseline characteristics were similar between the groups except for the prevalence of ischemic HF. The app group had a reduced MLHFQ at 6 weeks (mean 37.5, SD 3.5 vs mean 48.2, SD 3.7; P=.04) but not at 12 weeks (mean 44.2, SD 4 vs mean 45.9, SD 4; P=.78), compared to the no-app group. There was no effect of the app on the SCHFI at 6 or 12 weeks. The time to first HF readmission was not statistically different between the app group and the no-app group (app group 11/42, 26% vs no-app group 12/41, 29%; hazard ratio 0.89, 95% CI 0.39-2.02; P=.78) over 12 weeks.ConclusionsThe adaptive mobile app intervention, which focused on promoting self-monitoring and self-management, improved the MLHFQ at 6 weeks but did not sustain its effects at 12 weeks. No effect was seen on HF self-management measured by self-report. Further research is needed to enhance engagement in the app for a longer period and to determine if the app can reduce HF readmissions in a larger study.Trial registrationClinicalTrials.gov NCT03149510; https://clinicaltrials.gov/ct2/show/NCT03149510.

Project description:BackgroundSodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of a deterioration in heart failure (HF) and mortality in patients with a broad range of cardiovascular risks. Recent guidelines recommend considering the use of SGLT2 inhibitors in patients with type 2 diabetes (T2D) and HF, irrespective of their glycemic control status and background use of other glucose-lowering agents including metformin. However, only a small number of studies have investigated whether the effects of SGLT2 inhibitor in these patients differ by the concomitant use of other glucose-lowering agents.MethodsThis was a post-hoc analysis of the CANDLE trial (UMIN000017669), an investigator-initiated, multicenter, open-label, randomized, controlled trial. The primary aim of the analysis was to assess the effect of 24 weeks of treatment with canagliflozin, relative to glimepiride, on N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration in patients with T2D and clinically stable chronic HF. In the present analysis, the effect of canagliflozin on NT-proBNP concentration was assessed in the patients according to their baseline use of other glucose-lowering agents.ResultsAlmost all patients in the CANDLE trial presented as clinically stable (New York Heart Association class I to II), with about 70% of participants having HF with a preserved ejection fraction phenotype (defined as a left ventricular ejection fraction ≥ 50%) at baseline. Of the 233 patients randomized to either canagliflozin (100 mg daily) or glimepiride (starting dose 0.5 mg daily), 85 (36.5%) had not been taking any glucose-lowering agents at baseline (naïve). Of the 148 patients who had been taking at least one glucose-lowering agent at baseline (non-naïve), 44 (29.7%) and 127 (85.8%) had received metformin or a dipeptidyl dipeptidase-4 (DPP-4) inhibitor, respectively. The group ratio (canagliflozin vs. glimepiride) of proportional changes in the geometric means of NT-proBNP concentration was 0.95 (95% confidence interval [CI] 0.76 to 1.18, p = 0.618) for the naïve subgroup, 0.92 (95% CI 0.79 to1.07, p = 0.288) for the non-naïve subgroup, 0.90 (95% CI 0.68 to 1.20, p = 0.473) for the metformin-user subgroup, and 0.91 (95% CI 0.77 to 1.08, p = 0.271) for the DPP-4 inhibitor-user subgroup. No heterogeneity in the effect of canagliflozin, relative to glimepiride, on NT-proBNP concentration was observed in the non-naïve subgroups compared to that in the naïve subgroup.ConclusionThe impact of canagliflozin treatment on NT-proBNP concentration appears to be independent of the background use of diabetes therapy in the patient population examined. Trial registration University Medical Information Network Clinical Trial Registry, number 000017669. Registered on May 25, 2015.

Project description:Depression is common in patients with cardiac disease, especially in patients with heart failure, and is associated with increased risk of adverse health outcomes. Some evidence suggests that aerobic exercise may reduce depressive symptoms, but to our knowledge the effects of exercise on depression in patients with heart failure have not been evaluated.To determine whether exercise training will result in greater improvements in depressive symptoms compared with usual care among patients with heart failure.Multicenter, randomized controlled trial involving 2322 stable patients treated for heart failure at 82 medical clinical centers in the United States, Canada, and France. Patients who had a left ventricular ejection fraction of 35% or lower, had New York Heart Association class I to IV heart failure, and had completed the Beck Depression Inventory II (BDI-II) score were randomized (1:1) between April 2003 and February 2007. Depressive scores ranged from 0 to 59; scores of 14 or higher are considered clinically significant.Participants were randomized either to supervised aerobic exercise (goal of 90 min/wk for months 1-3 followed by home exercise with a goal of ?120 min/wk for months 4-12) or to education and usual guideline-based heart failure care.Composite of death or hospitalization due to any cause and scores on the BDI-II at months 3 and 12.Over a median follow-up period of 30 months, 789 patients (68%) died or were hospitalized in the usual care group compared with 759 (66%) in the aerobic exercise group (hazard ratio [HR], 0.89; 95% CI, 0.81 to 0.99; P = .03). The median BDI-II score at study entry was 8, with 28% of the sample having BDI-II scores of 14 or higher. Compared with usual care, aerobic exercise resulted in lower mean BDI-II scores at 3 months (aerobic exercise, 8.95; 95% CI, 8.61 to 9.29 vs usual care, 9.70; 95% CI, 9.34 to 10.06; difference, -0.76; 95% CI,-1.22 to -0.29; P = .002) and at 12 months (aerobic exercise, 8.86; 95% CI, 8.67 to 9.24 vs usual care, 9.54; 95% CI, 9.15 to 9.92; difference, -0.68; 95% CI, -1.20 to -0.16; P = .01).Compared with guideline-based usual care, exercise training resulted in a modest reduction in depressive symptoms, although the clinical significance of this improvement is unknown.clinicaltrials.gov Identifier: NCT00047437.

Project description:Findings from previous studies of the effects of exercise training on patient-reported health status have been inconsistent.To test the effects of exercise training on health status among patients with heart failure.Multicenter, randomized controlled trial among 2331 medically stable outpatients with heart failure with left ventricular ejection fraction of 35% or less. Patients were randomized from April 2003 through February 2007.Usual care plus aerobic exercise training (n = 1172), consisting of 36 supervised sessions followed by home-based training, vs usual care alone (n = 1159). Randomization was stratified by heart failure etiology, which was a covariate in all models.Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary scale and key subscales at baseline, every 3 months for 12 months, and annually thereafter for up to 4 years. The KCCQ is scored from 0 to 100 with higher scores corresponding to better health status. Treatment group effects were estimated using linear mixed models according to the intention-to-treat principle.Median follow-up was 2.5 years. At 3 months, usual care plus exercise training led to greater improvement in the KCCQ overall summary score (mean, 5.21; 95% confidence interval, 4.42 to 6.00) compared with usual care alone (3.28; 95% confidence interval, 2.48 to 4.09). The additional 1.93-point increase (95% confidence interval, 0.84 to 3.01) in the exercise training group was statistically significant (P < .001). After 3 months, there were no further significant changes in KCCQ score for either group (P = .85 for the difference between slopes), resulting in a sustained, greater improvement overall for the exercise group (P < .001). Results were similar on the KCCQ subscales, and no subgroup interactions were detected.Exercise training conferred modest but statistically significant improvements in self-reported health status compared with usual care without training. Improvements occurred early and persisted over time.clinicaltrials.gov Identifier: NCT00047437.

Dataset Information

Effects of canagliflozin in patients with type 2 diabetes and chronic heart failure: a randomized trial (CANDLE).

Publications

Effects of canagliflozin in patients with type 2 diabetes and chronic heart failure: a randomized trial (CANDLE).

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