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SGLT2 inhibitors decrease cardiovascular death and heart failure hospitalizations in patients with heart failure: A systematic review and meta-analysis.

ABSTRACT:

Background

Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the composite of heart failure (HF) hospitalizations or cardiovascular mortality among patients with HF. However, the efficacy of SGLT2 inhibitors in secondary endpoints of randomized trials and in subgroups of HF patients is not well known.

Methods

We performed a systematic review and meta-analysis of placebo-controlled, randomized trials of SGLT2 inhibitors in patients with HF. PubMed, Embase, and Cochrane databases were searched for trials published up to January 21, 2021. Data were extracted from published reports and quality assessment was performed per Cochrane recommendations. Hazard ratios (HRs) with 95% CI were pooled across trials. The primary endpoints of interest were all-cause and cardiovascular mortality.

Results

Out of 3969 database results, 15 randomized trials and 20,241 patients were included; 10,594 (52·3%) received SGLT2 inhibitors. All-cause mortality (HR 0·86; 95% CI 0·79-0·94; p = 0·0007; I²=0%) and cardiovascular mortality (HR 0·86; 95% CI 0·78-0·96; p = 0·006; I²=0%) were significantly lower in patients treated with SGLT2 inhibitors compared with placebo. The composite of cardiovascular mortality, HF hospitalizations, or urgent visits for HF was significantly reduced with SGLT2 inhibitors in all the following subgroups: male, female, age < 65, age ≥ 65, race - Black and White, estimated glomerular filtration rate (eGFR) <60, eGFR ≥60, New York Heart Association (NYHA) class II, NYHA ≥III, and HF with preserved ejection fraction.

Interpretation

In patients with HF, SGLT2 inhibitors significantly reduce all-cause and cardiovascular mortality compared with placebo. In addition, the composite of cardiovascular mortality or HF hospitalizations/urgent visits is reduced with SGLT2 inhibitors across subgroups of sex, age, race, eGFR, HF functional class, and ejection fraction.

SUBMITTER: Cardoso R

PROVIDER: S-EPMC8257984 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: Sodium-glucose co-transporter 2 (SGLT2) inhibitors are an emerging class of glucose-lowering drugs that have become increasingly relevant for the treatment and prevention of heart failure (HF). Therefore, we aimed to investigate various SGLT2 inhibitors in patients with established HF at baseline and focused on the different types of HF. Methods: An extensive search of PubMed and Web of Science until January 2021 was done. Two reviewers, independently and in duplicate, applied the selection criteria. This meta-analysis was conducted according to the PRISMA guidelines. Data were pooled using a random-effects model. Randomized controlled trials (RCTs) of SGLT2 inhibitors vs. a comparator in patients with HF reporting clinical outcomes were included. The primary efficacy outcome was the composite of hospitalization for HF (HHF) or cardiovascular (CV) mortality. All-cause mortality, CV mortality, and HHF were considered as secondary endpoints. Subgroup analyses involving the status of diabetes, type of HF, administered type of SGLT2 inhibitor, sex, age, body mass index (BMI), estimated glomerular filtration rate (eGFR), cause of HF, and concomitant medication were performed. Results: Seventeen RCTs, comprising a total of 20,749 participants, were included (n = 10,848 treated with SGLT2 inhibitors and n = 9,901 treated with a comparator). Treatment with SGLT2 inhibitors in a HF population was associated with a 27% relative risk reduction (RRR) of HHF or CV mortality [risk ratio (RR) = 0.73, 95% CI = 0.68-0.78], 32% RRR of HHF (RR = 0.68, 95% CI = 0.62-074), 18% RRR of CV mortality (RR = 0.82, 95% CI = 0.73-0.91), and 17% RRR of all-cause mortality (RR = 0.83, 95% CI = 0.75-0.91). The effect of SGLT2 inhibitors on the primary endpoint was consistent among the different gliflozines. The effect of SGLT2 inhibitors on the primary endpoint was independent of underlying diabetes mellitus, age, sex, BMI, renal function, and HF type. Conclusions: SGLT2 inhibitors are associated with improved CV outcomes in patients with HF.

Project description:AimsNo studies have comprehensively compared the efficacy of sodium-glucose cotransporter-2 (SGLT2) inhibitors, renin-angiotensin system (RAS) inhibitors, and angiotensin receptor neprilysin (ARN) inhibitors based on different type of heart failure, including heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). The aim of this network meta-analysis was to evaluate the relative efficacy of SGLT2 inhibitor (SGLT2i), RAS inhibitor (RASi) and ARN inhibitor (ARNI) in different types of heart failure.MethodsA systemic literature search was performed from inception to 19 November 2022 for randomized control trials assessing the risk of cardiovascular (CV) death or hospitalization for heart failure (HHF) of these drugs in HF. A network meta-analysis was performed. Risk ratio (RR) with 95% confidence intervals (CI) were synthesized.ResultsSeventeen studies were selected with a total of 61 489 patients. In patients with HFrEF, ARNI led to a reduced risk of a composite outcome of CV death or HHF when compared with placebo (RR = 0.83, 95% CI 0.77-0.89). Similar trends were observed when focusing on the outcome of CV death or HHF alone. In patients with HFpEF, SGLT2i showed the beneficial effects on the CV death or HHF events when compared with placebo and RASi (RR = 0.82, 95% CI 0.74-0.92; RR = 1.16, 95% CI 1.02-1.31). For CV death, all these three drugs could not show beneficial effects in HFpEF. For the incidence of HHF in HFpEF, both SGLT2i and ARNI demonstrated the beneficial effects but SGLT2i was superior to ARNI. There were no differences in the events of discontinuation under these drugs when compared with placebo or each other in either HFrEF or HFpEF patients. SGLT2i showed the least renal injury among these interventions in HFrEF and there were no differences in the incidence of renal injury of these interventions in HFpEF.ConclusionsAmong these drugs, ARNI showed the greatest ability to lower the incidence of CV death or HHF and SGLT2i exerted the least renal injury in patients with HFrEF. In patients with HFpEF, SGLT2i was associated with a reduction in the risk of CV death or HHF. There were no differences in the incidence of renal injury of these interventions in HFpEF. The intolerance of these drugs were comparable in both HFrEF and HFpEF.

Project description:Acute heart failure (AHF) is a major public health concern, affecting 26 million worldwide. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a class of glucose-lowering drugs, comprising canagliflozin, dapagliflozin, and empagliflozin that are being explored for AHF. We aim to meta-analyze the effectiveness of SGLT2 inhibitors compared to placebo for primary outcomes including all-cause and cardiovascular mortality, heart failure events, symptomatic improvement, and readmissions. Our secondary outcome is the risk of serious adverse events. This meta-analysis has been designed in accordance with the PRISMA Statement 2020. A systematic search across PubMed, Scopus, and Cochrane Library was conducted through August 13, 2022. The following keywords were utilized: sglt2, sodium-glucose transporter 2 inhibitors, sglt2 inhibitors, decompensated heart failure, de-novo heart failure, and/or acute heart failure. Only randomized controlled trials (RCTs) with adult patients (>18 years), hospitalized with de-novo AHF, acutely decompensated chronic heart failure with reduced, borderline, or preserved ejection, and receiving SGLT2 inhibitors were included. A quantitative analytical methodology was applied where the standardized mean difference (SMD) applying 95% confidence intervals (CI) for continuous outcomes and risk ratio (RR) with 95% CI was yielded. All tests were carried out on Review Manager 5.4 (Cochrane). In total, three RCTs were included pooling in a total of 1831 patients where 49.9% received SGLT2 inhibitors. The mean age was 72.9 years in the interventional group compared to 70.6 years in the placebo. Only 33.7% of the sample was female. The follow-up spanned 2−9 months. Heart failure events were reduced by 62% in the interventional group (RR = 0.66, p < 0.0001). readmissions had a reduced risk of 24% with SGLT2 inhibitors (RR = 0.76, p = 0.03). We assessed the efficacy and safety of SGLT2 inhibitors in preventing complications post-AHF. The odds of all-cause mortality, cardiovascular mortality, heart failure events, and re-admissions rates were substantially reduced within the first 1−9 months of hospitalization.

Project description:BackgroundIn patients with type 2 diabetes (T2D) and a history of heart failure (HF), sodium-glucose cotransporter-2 inhibitors (SGLT2is) have demonstrated cardiovascular (CV) benefits. However, the comparative efficacy of individual SGLT2is remains uncertain. This network meta-analysis (NMA) compared the efficacy and safety of five SGLT2is (canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, and sotagliflozin) on CV outcomes in these patients.Materials and methodsPubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched up to September 23, 2022, to identify all randomized controlled trials (RCTs) comparing SGLT2is to placebo in T2D patients with HF. The main outcomes included composite CV death/heart failure hospitalization (HFH), HFH, CV death, all-cause mortality, and adverse events. Pairwise and NMA approaches were applied.ResultsOur analysis included 11 RCTs with a total of 20,438 patients with T2D and HF. All SGLT2is significantly reduced HFH compared to standard of care (SoC) alone. "Add-on" SGLT2is, except ertugliflozin, significantly reduced composite CV death/HFH relative to SoC alone. Moreover, canagliflozin had lower composite CV death/HFH compared to dapagliflozin. Based on the surface under the cumulative ranking curve (SUCRA), the top-ranked SGLT2is for reducing HFH were canagliflozin (95.5%), sotagliflozin (66.0%), and empagliflozin (57.2%). Head-to-head comparisons found no significant differences between individual SGLT2is in reducing CV death. "Add-on" SGLT2is reduced all-cause mortality compared with SoC alone, although only dapagliflozin was statistically significant. No SGLT2is were significantly associated with serious adverse events. A sensitivity analysis focusing on HF-specific trials found that dapagliflozin, empagliflozin, and sotagliflozin significantly reduced composite CV death/HFH, consistent with the main analysis. However, no significant differences were identified from their head-to-head comparisons in the NMA. The SUCRA indicated that sotagliflozin had the highest probability of reducing composite CV death/HFH (97.6%), followed by empagliflozin (58.4%) and dapagliflozin (44.0%).ConclusionSGLT2is significantly reduce the composite CV death/HFH outcome. Among them, canagliflozin may be considered the preferred treatment for patients with diabetes and a history of heart failure, but it may also be associated with an increased risk of any adverse events compared to other SGLT2is. However, a sensitivity analysis focusing on HF-specific trials identified sotagliflozin as the most likely agent to reduce CV death/HFH, followed by empagliflozin and dapagliflozin.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42022353754.

Project description:BackgroundSodium-glucose cotransporter 2 (SGLT2) inhibitors have shown promise in improving cardiovascular outcome in patients with heart failure (HF) and diabetes mellitus (DM). Although these benefits have been confirmed by several meta-analyses, small studies have not been included into these pooled analyses.AimPublication of recent RCTs prompted us to perform this updated meta-analysis to examine the consistency of favorable cardiovascular outcomes of SGLT2 inhibitors in HF patients by inclusion of clinical trials with small sample size.MethodsWe conducted a systematic review of the literature in PubMed/Medline and ClinicalTrials.gov to identify all RCTs investigating the benefits of SGLT2 inhibitors in patients with HF. The primary endpoint of this meta-analysis was to compare the cardiovascular death (CVD) and hospitalization for HF (HHF) between patients who received an SGLT2 inhibitor and those who received a placebo or a non-SGLT2 inhibitor. We used a risk difference (RD) and log hazard ratio (HR) to pool the reported difference across the included RCTs.ResultsA total of 12 RCTs encompassing 59,825 patients at different stages of HF and DM were included, 32,448 patients in the SGLT2 inhibitor group and 27,377 patients in the control group. A pooled analysis of RCTs, regardless of HF severity or DM status, showed a significantly reduced RD for CVD (RD =-0.01, 95% CI [-0.01, 0.00], P=0.01) and HHF (RD =-0.02, 95% CI [-0.03, -0.01], P=0.0005) in patients who received a SGLT2 inhibitor compared to those who did not. A sub-group analysis showed a significantly reduced RD for CVD (RD =-0.01, 95% CI [-0.02, 0.00], P=0.03) and HHF (RD =-0.02, 95% CI [-0.03, 0.00], P=0.01) in patients with DM who received SGLT2 inhibitors regardless of the severity of HF. Also, regardless of DM status, RD for HHF favored the use of SGLT2 inhibitor than the control medication (RD =-0.05, 95% CI [-0.06, -0.03], P<0.00001).ConclusionSGLT2 inhibitors have shown a promise in reducing CVD and HHF in patients with HF, regardless of ejection fraction or diabetes status.