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

Tanaka, Atsushi; Hisauchi, Itaru; Tanaka, Isao; Sezai, Akira; Toyoda, Shigeru; Tomiyama, Hirofumi; Sata, Masataka; Ueda, Shinichiro; Oyama, Jun‐ichi; Kitakaze, Masafumi; Murohara, Toyoaki; Node, Koichi; Investigators, Candle Trial

doi:10.1002/ehf2.12707

Cited by 55 publications

(81 citation statements)

References 25 publications

(42 reference statements)

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“…Those studies suggested that improved vascular function was likely to be associated with empagliflozin-mediated glycemic and non-glycemic actions, such as weight loss and volume contraction. This empagliflozin-induced reduction in ePV was comparable to that reported by previous studies of SGLT2 inhibitors 13,35 . However, a direct effect of the agent on vascular function remains to be fully elucidated.…”

Section: And Other Physiologicalsupporting

confidence: 90%

Secondary analyses to assess the profound effects of empagliflozin on endothelial function in patients with type 2 diabetes and established cardiovascular diseases: The placebo‐controlled double‐blind randomized effect of empagliflozin on endothelial function in cardiovascular high risk diabetes mellitus: Multi‐center placebo‐controlled double‐blind randomized trial

Tanaka

Shimabukuro

Machii

et al. 2020

J of Diabetes Invest

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Aims/Introduction Recent clinical trials on sodium–glucose cotransporter 2 inhibitors showed improved outcomes in patients with type 2 diabetes at a high risk of cardiovascular events. However, the underlying effects on endothelial function remain unclear. Materials and Methods The effect of empagliflozin on endothelial function in cardiovascular high risk diabetes mellitus: Multi‐center placebo‐controlled double‐blind randomized (EMBLEM) trial in patients with type 2 diabetes and cardiovascular disease showed empagliflozin treatment for 24 weeks had no effect on peripheral endothelial function measured by reactive hyperemia peripheral arterial tonometry. This post‐hoc analysis of the EMBLEM trial included a detailed evaluation of the effects of empagliflozin on peripheral endothelial function in order to elucidate the clinical characteristics of responders or non‐responders to treatment. Results Of the 47 patients randomized into the empagliflozin group, 21 (44.7%) showed an increase in the reactive hyperemia index (RHI) after 24 weeks of intervention, with no apparent difference in the clinical characteristics between patients whose RHI either increased (at least >0) or did not increase. There was also no obvious difference between the treatment groups in the proportion of patients who had a clinically meaningful change (≥15%) in log‐transformed RHI. No correlation was found between changes in RHI and clinical variables, such as vital signs and laboratory parameters. Conclusions Treatment with empagliflozin for 24 weeks in patients with type 2 diabetes and cardiovascular disease did not affect peripheral endothelial function, and was not related to changes in clinical variables, including glycemic parameters. These findings suggest that the actions of sodium–glucose cotransporter 2 inhibitors other than direct improvement in peripheral endothelial function were responsible, at least in the early phase, for the clinical benefits found in recent cardiovascular outcome trials.

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Section: And Other Physiologicalsupporting

confidence: 90%

Secondary analyses to assess the profound effects of empagliflozin on endothelial function in patients with type 2 diabetes and established cardiovascular diseases: The placebo‐controlled double‐blind randomized effect of empagliflozin on endothelial function in cardiovascular high risk diabetes mellitus: Multi‐center placebo‐controlled double‐blind randomized trial

Tanaka

Shimabukuro

Machii

et al. 2020

J of Diabetes Invest

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“…At baseline, the median trial mean glycated haemoglobin A1c was 8.1% and BMI was 30.1. Eligibility criteria included coronary artery disease or macrovascular disease in 35 trials, 3 6 7 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 atrial fibrillation in 1 trial, 65 heart failure in 9 trials, 66 67 68 69 70 71 72 73 74 chronic kidney disease and/or albuminuria in 37 trials, 8 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 …”

Section: Resultsmentioning

confidence: 99%

Sodium-glucose cotransporter protein-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials

Palmer

Tendal

Mustafa

et al. 2021

BMJ

416

310

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Objective To evaluate sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists in patients with type 2 diabetes at varying cardiovascular and renal risk. Design Network meta-analysis. Data sources Medline, Embase, and Cochrane CENTRAL up to 11 August 2020. Eligibility criteria for selecting studies Randomised controlled trials comparing SGLT-2 inhibitors or GLP-1 receptor agonists with placebo, standard care, or other glucose lowering treatment in adults with type 2 diabetes with follow up of 24 weeks or longer. Studies were screened independently by two reviewers for eligibility, extracted data, and assessed risk of bias. Main outcome measures Frequentist random effects network meta-analysis was carried out and GRADE (grading of recommendations assessment, development, and evaluation) used to assess evidence certainty. Results included estimated absolute effects of treatment per 1000 patients treated for five years for patients at very low risk (no cardiovascular risk factors), low risk (three or more cardiovascular risk factors), moderate risk (cardiovascular disease), high risk (chronic kidney disease), and very high risk (cardiovascular disease and kidney disease). A guideline panel provided oversight of the systematic review. Results 764 trials including 421 346 patients proved eligible. All results refer to the addition of SGLT-2 inhibitors and GLP-1 receptor agonists to existing diabetes treatment. Both classes of drugs lowered all cause mortality, cardiovascular mortality, non-fatal myocardial infarction, and kidney failure (high certainty evidence). Notable differences were found between the two agents: SGLT-2 inhibitors reduced mortality and admission to hospital for heart failure more than GLP-1 receptor agonists, and GLP-1 receptor agonists reduced non-fatal stroke more than SGLT-2 inhibitors (which appeared to have no effect). SGLT-2 inhibitors caused genital infection (high certainty), whereas GLP-1 receptor agonists might cause severe gastrointestinal events (low certainty). Low certainty evidence suggested that SGLT-2 inhibitors and GLP-1 receptor agonists might lower body weight. Little or no evidence was found for the effect of SGLT-2 inhibitors or GLP-1 receptor agonists on limb amputation, blindness, eye disease, neuropathic pain, or health related quality of life. The absolute benefits of these drugs vary substantially across patients from low to very high risk of cardiovascular and renal outcomes (eg, SGLT-2 inhibitors resulted in 5 to 48 fewer deaths in 1000 patients over five years; see interactive decision support tool ( https://magicevidence.org/match-it/200820dist/#!/ ) for all outcomes. Conclusions In patients with type 2 diabetes, SGLT-2 inhibitors and GLP-1 receptor agonists reduced cardiovascular and renal outcomes, with notable differences in benefits and harms. Absolute benefits are determined by individual risk profiles of patients, with clear implications for clinical practice, as reflected in the BMJ Rapid Recommendations directly informed by this systematic review. Systematic review registration PROSPERO CRD42019153180.

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“…A total of 21 RCTs [ 10 , 24 , 25 , 29 – 31 , 33 , 39 – 52 ] were recognized eligible in this meta-analysis, including 3 in crossover design [ 41 , 44 , 50 ]. A total of 10,978 participants were enrolled, including 6236 in the SGLT2i group and 4821 in the control group.…”

Section: Resultsmentioning

confidence: 99%

“…The mean follow-up period ranged from 14 days to one year, including three studies [ 41 , 50 , 51 ] less than 3 months. Participants with T2DM that were mostly in stage A–B HF were enrolled in 10 studies [ 24 , 25 , 39 , 40 , 44 , 46 , 48 , 49 , 51 , 52 ], and patients with T2DM and stage C HF were enrolled in 11 studies [ 10 , 29 – 31 , 33 , 41 – 43 , 45 , 47 , 50 ]. LVMI, LVEDVI, LVESVI, LAVI, LVEF, GLS, the E/e’ ratio, plasma NT-proBNP level, and the KCCQ score were reported in 6 [ 24 , 25 , 29 , 44 , 45 , 52 ], 3 [ 25 , 29 , 30 ], 3 [ 25 , 29 , 30 ], 4 [ 25 , 29 , 45 , 52 ], 9 [ 24 , 25 , 29 – 31 , 39 , 40 , 44 , 45 ], 4 [ 24 , 39 , 44 , 51 ], 8 [ 24 , 25 , 30 , 31 , 44 , 45 , 49 , 52 ], 11 [ 10 , 24 , 25 , 31 , 41 , 44 – 46 , 48 – 50 ] and 3 [ 10 ...…”

Section: Resultsmentioning

confidence: 99%

“…The impacts on LVEF [ 25 , 26 ], global longitudinal strain (GLS) [ 24 , 27 ], and diastolic function [ 25 , 28 ] were also inconsistent in different studies. Similarly, in patients with T2DM and HF, the effects of SGLT2i on left ventricular hypertrophy [ 27 , 29 ], cardiac function [ 27 , 30 , 31 ], and neurohormonal parameters [ 32 , 33 ] were inconsistent. Whether such diversity was due to insufficient sample size or heterogeneity among studies remains to be explored.…”

Section: Introductionmentioning

confidence: 99%

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Effect of sodium–glucose cotransporter 2 inhibitors on cardiac structure and function in type 2 diabetes mellitus patients with or without chronic heart failure: a meta-analysis

Zhao

Wang

et al. 2021

Cardiovasc Diabetol

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Background Although the benefits of sodium–glucose cotransporter 2 inhibitors (SGLT2i) on cardiovascular events have been reported in patients with type 2 diabetes mellitus (T2DM) with or without heart failure (HF), the impact of SGLT2i on cardiac remodelling remains to be established. Methods We searched the PubMed, Embase, Cochrane Library and Web of Science databases up to November 16th, 2020, for randomized controlled trials reporting the effects of SGLT2i on parameters of cardiac structure, cardiac function, plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) level or the Kansas City Cardiomyopathy Questionnaire (KCCQ) score in T2DM patients with or without chronic HF. The effect size was expressed as the mean difference (MD) or standardized mean difference (SMD) and its 95% confidence interval (CI). Subgroup analyses were performed based on the stage A–B or stage C HF population and HF types. Results Compared to placebo or other antidiabetic drugs, SGLT2i showed no significant effects on left ventricular mass index, left ventricular end diastolic volume index, left ventricular end systolic volume index, or left atrial volume index. SGLT2i improved left ventricular ejection fraction only in the subgroup of HF patients with reduced ejection fraction (MD 3.16%, 95% CI 0.11 to 6.22, p = 0.04; I2 = 0%), and did not affect the global longitudinal strain in the overall analysis including stage A–B HF patients. SGLT2i showed benefits in the E/e’ ratio (MD − 0.45, 95% CI − 0.88 to − 0.03, p = 0.04; I2 = 0%), plasma NT-proBNP level (SMD − 0.09, 95% CI − 0.16 to − 0.03, p = 0.004; I2 = 0%), and the KCCQ score (SMD 3.12, 95% CI 0.76 to 5.47, p = 0.01; I2 = 0%) in the overall population. Conclusion The use of SGLT2i was associated with significant improvements in cardiac diastolic function, plasma NT-proBNP level, and the KCCQ score in T2DM patients with or without chronic HF, but did not significantly affect cardiac structural parameters indexed by body surface area. The LVEF level was improved only in HF patients with reduced ejection fraction.

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

Cited by 55 publications

References 25 publications

Sodium-glucose cotransporter protein-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials

Effect of sodium–glucose cotransporter 2 inhibitors on cardiac structure and function in type 2 diabetes mellitus patients with or without chronic heart failure: a meta-analysis

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