Dataset Information

Efficacy and safety of sodium-glucose cotransporter-2 inhibitors for heart failure with mildly reduced or preserved ejection fraction: a systematic review and meta-analysis of randomized controlled trials.

ABSTRACT:

Aims

We sought to conduct a meta-analysis to evaluate the efficacy and safety of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in patients with heart failure (HF) with preserved ejection fraction (HFpEF) and HF with mildly reduced ejection fraction (HFmrEF).

Methods

We searched the Cochrane Library, MEDLINE (via PubMed), Embase, and ClinicalTrials.gov till March 2023 to retrieve all randomized controlled trials of SGLT2i in patients with HFpEF or HFmrEF. Risk ratios (RRs) and standardized mean differences (SMDs) with their 95% conﬁdence intervals (95% CIs) were pooled using a random-effects model.

Results

We included data from 14 RCTs. SGLT2i reduced the risk of the primary composite endpoint of first HF hospitalization or cardiovascular death (RR 0.81, 95% CI: 0.76, 0.87; I² = 0%); these results were consistent across the cohorts of HFmrEF and HFpEF patients. There was no significant decrease in the risk of cardiovascular death (RR 0.96, 95% CI: 0.82, 1.13; I² = 36%) and all-cause mortality (RR 0.97, 95% CI: 0.89, 1.05; I² = 0%). There was a significant improvement in the quality of life in the SGLT2i group (SMD 0.13, 95% CI: 0.06, 0.20; I² = 51%).

Conclusion

The use of SGLT2i is associated with a lower risk of the primary composite outcome and a higher quality of life among HFpEF/HFmrEF patients. However, further research involving more extended follow-up periods is required to draw a comprehensive conclusion.

Systematic review registration

PROSPERO (CRD42022364223).

SUBMITTER: Cheema HA

PROVIDER: S-EPMC10602781 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Publications

Efficacy and safety of sodium-glucose cotransporter-2 inhibitors for heart failure with mildly reduced or preserved ejection fraction: a systematic review and meta-analysis of randomized controlled trials.

Cheema Huzaifa Ahmad HA Shafiee Arman A Athar Mohammad Mobin Teymouri MMT Rafiei Mohammad Ali MA Mehmannavaz Atefe A Jafarabady Kyana K Shahid Abia A Ahmad Adeel A Ijaz Sardar Hassan SH Dani Sourbha S SS Minhas Abdul Mannan Khan AMK Nashwan Abdulqadir J AJ Fudim Marat M Fonarow Gregg C GC

Frontiers in cardiovascular medicine 20231012

<h4>Aims</h4>We sought to conduct a meta-analysis to evaluate the efficacy and safety of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in patients with heart failure (HF) with preserved ejection fraction (HFpEF) and HF with mildly reduced ejection fraction (HFmrEF).<h4>Methods</h4>We searched the Cochrane Library, MEDLINE (via PubMed), Embase, and ClinicalTrials.gov till March 2023 to retrieve all randomized controlled trials of SGLT2i in patients with HFpEF or HFmrEF. Risk ratios (RRs) and ...[more]

PMID: 37900570

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Project description:AimsSodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to be an effective therapy in improving heart failure outcomes. We conducted a meta-analysis of randomized controlled trials to evaluate the efficacy of SGLT2 inhibitors in heart failure patients with either a reduced or preserved ejection fraction.Methods and resultsWe searched MEDLINE and EMBASE for large (≥1000 patients) randomized controlled trials evaluating the effects of SGLT2 inhibitors compared with placebo in the setting of heart failure until September 2021. Our primary outcome was the composite of heart failure hospitalization and cardiovascular death, and secondary outcomes included all-cause mortality and total heart failure hospitalizations. We pooled hazard ratios and risk ratios and evaluated risk of bias with the Cochrane Collaboration tool. Four randomized controlled trials (DAPA HF, EMPEROR-Preserved, EMPEROR-Reduced, and SOLOIST-WHF) were included (n = 15 684); two of which evaluated patients with a reduced LVEF, one of which evaluated patients with a preserved LVEF, and one of which included both. Treatment with SGLT2 inhibitors resulted in a significant reduction in the composite of CV death and heart failure hospitalization (HR: 0.76, 95% CI: 0.70, 0.82, I2 : 0%, P < 0.00001). This was consistent in sub-groups of patients with LVEF ≤40% (n = 9199, HR: 0.74, 95% CI: 0.68, 0.81, I2 : 0%) and LVEF >40% (n = 6482, HR: 0.78, 95% CI: 0.68, 0.89, I2 : 0%, P-for-interaction: 0.57), as well as in sub-groups of patients with and without diabetes mellitus at baseline (P-for-interaction: 0.81). SGLT2 inhibitors were associated with a significant reduction in cardiovascular death (HR: 0.87, 95% CI: 0.79, 0.97, I2 : 0%, P < 0.00001) and total heart failure hospitalization (RR: 0.71, 95% CI: 0.67, 0.76, I2 : 0%, P < 0.00001); although a potential trend towards reduced all-cause mortality was noted with SGLT2 inhibitors, no statistically significant difference was observed (HR: 0.91, 95% CI: 0.83, 1.00, I2 : 14%, P = 0.05).ConclusionsSodium-glucose cotransporter 2 inhibitors reduce cardiovascular death and heart failure hospitalization among patients with heart failure, regardless of LVEF status.

Project description:BackgroundIn heart failure with reduced ejection fraction (HFrEF), sodium-glucose cotransporter-2 (SGLT2) inhibitors were demonstrated to lower cardiovascular mortality (CV death) and hospitalization for heart failure (HHF); however, the advantages of SGLT2 inhibitors in heart failure with mildly reduced (HFmrEF) or preserved ejection fraction (HFpEF) are less clear. SGLT2 inhibitors were reported to enhance quality of life (QoL) in HFmrEF or HFpEF patients; however, the findings among studies are inconsistent.ObjectiveTo conduct an updated systematic review and meta-analysis of recent data to assess the effect of SGLT2 inhibitors on cardiovascular outcomes and QoL in patients with HFmrEF or HFpEF.MethodThree databases were searched for studies that evaluated SGLT2 inhibitors and their effect on cardiovascular outcomes, including CV death, HHF, all-cause death, and the composite outcome of CV death, HHF, and urgent visit for heart failure (HF), and patient QoL (Kansas City Cardiomyopathy Questionnaire [KCCQ] score compared to baseline, and increase in KCCQ score ≥ 5 points) that were published during January 2000-August 2022. The meta-analysis was performed using the inverse variance method and random-effects model. INPLASY registration: INPLASY202290023.ResultsSixteen studies (9 recent RCTs) were included, and a total of 16,710 HFmrEF or HFpEF patients were enrolled. SGLT2 inhibitors significantly reduced composite cardiovascular outcome (CV death/HHF/urgent visit for HF; pooled hazard ratio [HR]: 0.80, 95% confidence interval [95%CI]: 0.74-0.86) and HHF alone (HR: 0.74, 95%CI: 0.67-0.82), but there was no significant reduction in CV death alone (HR: 0.93, 95%CI: 0.82-1.05). Benefit of SGLT2 inhibitors for decreasing CV death/HHF was observed across all subgroups, including left ventricular ejection fraction (LVEF) range, diabetes status, New York Heart Association functional class, and baseline renal function. For total HHF, SGLT2 inhibitors conferred benefit in both LVEF 50-60% (HR: 0.64, 95%CI: 0.54-0.76), and LVEF >60% (HR: 0.84, 95%CI: 0.71-0.98). Significant change was observed in the KCCQ-clinical summary score compared to baseline (mean difference: 1.33, 95%CI: 1.31-1.35), and meaningful improvement in QoL was shown across all 3 types of increase in KCCQ score ≥ 5 points.ConclusionThis study demonstrates the benefits of SGLT2 inhibitors for improving cardiovascular outcomes and QoL in HFmrEF or HFpEF patients.

Project description:ObjectivesHeart failure with mildly reduced ejection fraction (HFmrEF) or heart failure with preserved ejection fraction (HFpEF) are associated with significant morbidity and mortality, as well as growing health and economic burden. Sodium-glucose co-transporter 2 (SGLT2) inhibitors are very promising for the outcome improvement of patients with HFpEF or HFmrEF. The meta-analysis was performed to investigate the effects of SGLT2 inhibitors in HFpEF or HFmrEF, by pooling data from all clinically randomized controlled trials (RCTs) available to increase power to testify.MethodsStudies were searched in electronic databases from inception to November, 2022. We performed a meta-analysis to estimate the effect of SGLT2 inhibitors on clinical endpoints in patients with HFpEF or HFmrEF, using trial-level data with consistent endpoint definitions. The primary outcome was the composite of heart failure (HF) hospitalization or cardiovascular death. Hazard ratio (HR) was pooled with 95% confidence interval (CI) for dichotomous data. This study was registered with INPLASY 2022110095.ResultsSix studies involving 15,989 participants were included into the final analysis. Pooled analyses revealed that SGLT2 inhibitors significantly reduced the composite of HF hospitalization or cardiovascular death [HR: 0.79 (0.72-0.85); I2 = 0%; P < 0.00001] and HF hospitalizations [HR: 0.74 (0.67-0.82); I2 = 0%; P < 0.00001]. This finding was seen in both HFmrEF trials [HR: 0.76 (0.67-0.87); I2 = 49%; P < 0.0001] and HFpEF subgroup studies [HR: 0.70 (0.53-0.93); I2 = 0%; P = 0.01]. The incidence of any serious adverse events [OR: 0.89 (0.83-0.96); I2 = 0%; P = 0.002] was significantly lower in the SGLT2 inhibitor arm. No significant differences were observed between the two groups with regard to cardiovascular death and all-cause death.ConclusionsThis meta-analysis of patients with heart failure of left ventricular ejection fraction (LVEF) > 40% showed that SGLT2 inhibitors significantly reduce the risk of the composite of cardiovascular death and hospitalization for heart failure, but not cardiovascular death and all-cause death. Nevertheless, given that SGLT2 inhibitors may reduce the risk of hospitalization for heart failure, they should be considered the fundamental treatment for all patients with HFpEF or HFmrEF.

Project description:BackgroundHeart failure with preserved ejection fraction (HFpEF) is associated with a high risk of mortality and frequent hospitalization. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have favorable cardiovascular protective effect and could decrease the risk of mortality and hospitalization in patients with heart failure with reduced ejection fraction. However, the effect of SGLT2 inhibitors for HFpEF has not been well studied.PurposeThe aim of this meta-analysis is to systematically assess the effects of SGLT2 inhibitors in patients with HFpEF.MethodsMEDLINE, EMBASE, Ovid, Cochrane Library, Chinese National Knowledge Infrastructure Database, VIP database, Chinese Biomedical Database, and Wanfang Database were searched from inception to November 2021 for randomized controlled trials (RCTs) of SGLT2 inhibitors for HFpEF. Risk bias was assessed for included studies according to Cochrane handbook. The primary outcome was the composite of first hospitalization for heart failure (HHF) or cardiovascular mortality. First HHF, cardiovascular mortality, total HHF, all-cause mortality, exercise capacity, ventricular diastolic function, and adverse events were considered as secondary endpoints. PROSPERO registration: CRD42021291122.ResultsA total of 12 RCTs including 10,883 patients with HFpEF (SGLT2 inhibitors group: 5,621; control group: 5,262) were included. All included RCTs were at low risk of bias. Meta-analysis showed that SGLT2 inhibitors significantly reduced the composite of first HHF or cardiovascular mortality (HR:0.78, 95% CI: [0.70, 0.87], P< 0.00001, I 2 = 0%), first HHF (HR:0.71, 95% CI: [0.62, 0.83], P < 0.00001, I 2 = 0%), total HHF (RR:0.75, 95% CI: [0.67, 0.84], P<0.00001, I 2 = 0%), E/e' (MD: -1.22, 95% CI: [-2.29, -0.15], P = 0.03, I 2 = 59%) and adverse events (RR:0.92, 95% CI: [0.88, 0.97], P = 0.001, I 2 = 0%). No statistical differences were found in terms of cardiovascular mortality, all-cause mortality, NT-proBNP, BNP and 6-min walk test distance.ConclusionSGLT2 inhibitors significantly improve cardiovascular outcomes with a lower risk of serious adverse events in patients with HFpEF. However, these findings require careful recommendation due to the small number of RCTs at present. More multi-center, randomized, double-blind, placebo-controlled trials are needed.Systematic review registration[https://www.crd.york.ac.Uk/prospero/], identifier [CRD42021291122].

Project description:BackgroundMany therapies for heart failure (HF) have shown differential impact across the spectrum of left ventricular ejection fraction (LVEF).ObjectivesIn this prespecified analysis, the authors assessed the effects of semaglutide across the baseline LVEF strata in patients with the obesity phenotype of HF with preserved ejection fraction (HFpEF) in the STEP-HFpEF (Semaglutide Treatment Effect in People with obesity and HFpEF) trial.MethodsSTEP-HFpEF randomized 529 patients (263 semaglutide; 266 placebo). For this prespecified analysis, patients were categorized into 3 groups based on LVEF: 45% to 49% (n = 85), 50% to 59% (n = 215), and ≥60% (n = 229).ResultsAt 52 weeks, semaglutide improved the dual primary endpoints of Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (estimated treatment difference: EF [ejection fraction] 45%-49%: 5.0 points [95% CI: -2.7 to 12.8 points], EF 50%-59%: 9.8 points [95% CI: 5.0 to 14.6 points], and EF ≥60%: 7.4 points [95% CI: 2.8 to 12.0 points]; P interaction = 0.56) and body weight (EF: 45%-49%: -7.6 [95% CI: -10.7 to -4.4], EF 50%-59%: -10.6 [95% CI: -12.6 to -8.6] and EF ≥60%: -11.9 [95% CI: -13.8 to -9.9]; P interaction = 0.08), to a similar extent across LVEF categories. Likewise, LVEF did not influence the benefit of semaglutide on confirmatory secondary endpoints: 6-minute walk distance (P interaction = 0.19), hierarchal composite endpoint (P interaction = 0.43), and high-sensitivity C-reactive protein (P interaction = 0.26); or exploratory endpoint of N-terminal pro-brain natriuretic peptide (P interaction = 0.96). Semaglutide was well-tolerated across LVEF categories.ConclusionsIn patients with HFpEF and obesity, semaglutide 2.4 mg improved symptoms, physical limitations, and exercise function, and reduced inflammation and body weight to a similar extent across LVEF categories. These data support treatment with semaglutide in patients with the obesity phenotype of HFpEF regardless of LVEF. (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity [STEP-HFpEF]; NCT04788511).

Project description:AimsEmpagliflozin, a sodium-glucose co-transporter 2 inhibitor, was shown to be effective in patients with heart failure with preserved ejection fraction (HFpEF) in the EMPEROR-Preserved trial. The present study aims to evaluate the cost-effectiveness of empagliflozin among Japanese patients with HFpEF.Methods and resultsA Markov cohort model was developed to evaluate the cost-effectiveness of empagliflozin added to standard of care (SoC) compared with SoC alone in patients with HFpEF from the perspective of the Japanese healthcare system and with a lifetime horizon. In addition to clinical events, the progression of disease severity was modelled based on the migration of Kansas City Cardiomyopathy Questionnaire-Clinical Summary Scores (KCCQ-CSS). Model inputs, including risk of clinical events, costs, and utilities/disutilities, were derived from EMPEROR-Preserved trial data, a claims database and published literature. The generalizability of model results was investigated by applying various subgroups including age, body mass index (BMI), and region Asia, based on the subgroup analysis of EMPEROR-Preserved data. In the base-case analysis, empagliflozin yielded additional quality-adjusted life years (QALYs; 0.11) with an incremental cost of $1408 per patient for Japanese patients with HFpEF. Incremental cost, mainly derived from drug acquisition cost ($1963 per patient), was largely offset by reduced cost in hospitalization for heart failure (HHF) and cardiovascular death (-$537 per patient and -$166 per patient, respectively). Treatment of empagliflozin provided incremental 0.11 QALYs and 0.08 life years compared with SoC alone. The incremental cost-effectiveness ratio (ICER) was $12 772 (¥1 662 689)/QALY, which was below the Japanese willingness-to-pay (WTP) threshold of $38 408 (¥5 000 000)/QALY. The results were consistent across all the subgroups considered, and empagliflozin was dominant over SoC alone in the region Asia and BMI < 25 kg/m2 subgroups. ICERs for the remaining subgroups ranged from $7520/QALY (¥978 972/QALY, patients with baseline age ≥ 75 years) to $31 049/QALY (¥4 041 896/QALY, patients with baseline New York Heart Association class III/IV). Deterministic sensitivity analysis result showed that the treatment effect on HHF is the biggest driver of the cost-effectiveness analysis, while the ICER will be still under the threshold even if no effect of empagliflozin on HHF was assumed. The probabilistic sensitivity analysis result showed that 64% of simulations were cost-effective based on the Japanese WTP threshold.ConclusionsEmpagliflozin was demonstrated to be cost-effective for patients with HFpEF in Japan based on EMPEROR-Preserved trial data.

Dataset Information

Efficacy and safety of sodium-glucose cotransporter-2 inhibitors for heart failure with mildly reduced or preserved ejection fraction: a systematic review and meta-analysis of randomized controlled trials.

Aims

Methods

Results

Conclusion

Systematic review registration

Publications

Efficacy and safety of sodium-glucose cotransporter-2 inhibitors for heart failure with mildly reduced or preserved ejection fraction: a systematic review and meta-analysis of randomized controlled trials.

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