Effects of different sodium–glucose cotransporter 2 inhibitors in heart failure with reduced or preserved ejection fraction: a network meta-analysis

Heart failure (HF) results from either contraction or relaxation dysfunction of the heart, leading to multisystem symptoms and signs. Despite a decrease in the age-standardized prevalence of HF from 1990 to 2019, the reduction is not significant, and HF remains a significant cause of disability and death worldwide (1). Currently, in developed countries (2–4), such as Britain, France, and the United States, the prevalence of HF ranges from 1.5% to 2.0%, while in developing countries (5) and regions, such as Asia and Africa, it spans from 1.3% to 6.7%. According to the latest definitions by the European and American Heart Association, HF is categorized into three main types, namely, HF with mildly reduced ejection fraction (HFrEF) (LVEF, <40%), HF with moderately reduced ejection fraction (LVEF, 40%–50%), and HF with preserved ejection fraction (HFpEF) (EF, ≥50%). However, many previous meta-analyses defined HFpEF as EF ≥ 45%, which contrasts with the current HF classification. Hence, our study adopts the definition of HFpEF ≥ 50%.

SGLT2i is a new class of antidiabetic medications originally developed for managing diabetes. Recent research demonstrated their efficacy in improving outcomes for patients with HF, such as reduction in hospitalizations, cardiovascular mortality, adverse cardiac remodeling, and other associated factors, irrespective of the presence of diabetes. In addition, adverse cardiac remodeling is a critical mechanism in the progression of HF and serves as an independent risk factor for mortality and morbidity in patients with cardiovascular disease (5). Nevertheless, the comprehensive evaluation of SGLT2i effects on adverse cardiac remodeling in HF patients remains limited, with existing studies yielding divergent results. Despite the generally favorable effects of SGLT2i on HF patients, there is a lack of consensus on the most effective SGLT2i variation for HF treatment. Therefore, we conducted a systematic review and meta-analysis of randomized controlled trials (RCT), including a subgroup analysis based on varying ejection fractions to assess the effectiveness and safety profile of six SGLT2i for HF. This study aims to offer valuable evidence to aid clinical decision-making in HF management.

The statistical analysis was conducted using Stata 15.1 software for network meta-analysis. Relative risks or odds ratios were determined for dichotomous variables, while continuous variables were analyzed using the frequentist methodology in network meta-analysis. Heterogeneity was set as I² < 50% and p > 0.01 for the fixed effect model. Otherwise, the random effects model was applied. Pooled results for continuous variables were expressed as the mean difference (MD). The surface under the cumulative ranking (SUCRA) was employed to indicate the preferred ranking of each treatment. Small sample effects were investigated through a network funnel plot. P < 0.05 was considered statistically significant.

This review analyzed 77 RCT involving 43,561 patients using Bayesian network meta-analysis for a comprehensive evaluation. The study encompassed more than 10 outcome indicators, including a composite of hospitalization for HF and CV death, hospitalization for HF and CV death, a composite of urinary and reproductive effects, and an assessment of the cardiac structure. Subgroup analysis was performed based on the ejection fraction of HF. Although the efficacy of SGLT2i varies slightly with different LVEF baselines of patients, it may be beneficial in patients with HF regardless of LVEF baseline. Compared with the placebo, SGLT2i demonstrated a significant advantage in reducing a composite of hospitalization for HF and CV death, hospitalization for HF and CV death, and KCQQ scores while showing no significant impact on reducing all-cause mortality. Indirect comparisons between different SGLT2i suggest improvements in a composite of hospitalization for HF and CV death, hospitalization for HF, and CV death. Sotagliflozin outperformed empagliflozin and dapagliflozin in reducing hospitalization for HF and CV death. However, there is no difference between empagliflozin and dapagliflozin. Nevertheless, given the limited research on sotagliflozin, further investigation is warranted.

Regarding the safety profile in total HF patients, SGLT2i are associated with an increased risk of urinary and reproductive system infections, with dapagliflozin showing the highest risk among them. However, there is no distinction between various types of SGLT2i. A previous meta-analysis (83) showed that, except for dapagliflozin, SGLT2i did not increase incidences of urinary and reproductive system infections, which is consistent with our findings. Moreover, the US Food and Drug Administration has included this potential side effect in its list of adverse reactions. HCT was utilized as a reference indicator to assess low blood volume. The meta-analysis demonstrated that SGLT2i resulted in a rise in HCT relative to placebo, implying an elevated hypotension hazard for SGLT2i. The primary mechanism of action of SGLT2i involves the inhibition of the SGLT2 transporter, predominantly located in the S1 segment of the proximal tubules (84), increasing the excretion of glucose in the urine. Nevertheless, inhibiting SGLT2i also diminishes sodium reabsorption in the proximal tubules, potentially increasing sodium excretion. Previous studies (85, 86) reported a correlation between the administration of SGLT2i and a reduction of body weight and blood pressure.

The network meta-analysis results indicated that dapagliflozin and empagliflozin significantly improved NT-proBNP and 6MWT. However, no statistically significant difference was observed among different SGLT2i. While SGLT2i have shown promise in treating HF, it is crucial to determine whether they directly influence the heart's structural function. Therefore, we collected relevant indicators, such as LAVi, E/e', LVMi, and LVEDV, to systematically evaluate the changes in cardiac structure in HF patients treated with SGLT2i. The results showed that SGLT2i significantly reduced LVMi, LVEDV, LAVi, and LVESV and increased LVEF, reflecting significant benefits in improving cardiac systolic and diastolic function. Cardiac anatomy and functional parameters are vital in predicting the prognosis and quality of life in HF patients. Animal studies conducted on T2DM models revealed the positive effects of SGLT2i on left ventricular hypertrophy and dilation (87, 88), as well as cardiac systolic and diastolic function. LAVi and E/e' are predictive factors (89) used to evaluate cardiac diastolic function. Our research revealed that SGLT2i did not reduce E/e' in HFrEF patients. Nonetheless, subgroup analysis indicated SGLT2i could enhance the E/e' and LAVi of patients with HFpEF, potentially due to differing mechanisms between HFpEF and HFrEF.

According to the grading of HFpEF by the European and American Heart Association, this study conducted subgroup analysis based on ejection fraction. The HFpEF (EF ≥ 50%) group did not show significant differences in reducing a composite of hospitalization for HF and CV death, hospitalization for HF, CV death, and all-cause death. No significant differences were observed between different SGLT2i. However, some meta-analyses have shown that (90–92) SGLT2i can reduce a composite of HF and CV death hospitalizations. However, the previous study defined HFpEF as EF greater than 40%, which differs from our study. Therefore, our study should be more convincing. Regarding the safety of HFpEF patients, SGLT2i also present risks of urinary and reproductive infections, with empagliflozin and sotagliflozin being notable culprits. Canagliflozin has demonstrated higher safety compared to sotagliflozin in this aspect. In terms of improving ventricular remodeling, compared to placebo, SGLT2i have shown improvement in LAVi, E/e', LVEF, and LVMi. However, no significant differences were observed in LVESV and LVEDV, and there was no difference between different SGLT2i. The mechanism of HFpEF remains unclear, and left ventricular diastolic dysfunction is considered the main pathophysiological mechanism underlying the occurrence of HFpEF (93). Our research also confirmed that SGLT2i can improve the diastolic function of HFpEF patients. Typically, remodeling the structure of the patient's heart can significantly enhance their prognosis and quality of life. Unfortunately, there has been limited research on the quality of life scores of HFpEF patients; thus, this outcome measure was not included in our analysis.

In the subgroup analysis of HFrEF (EF <50%), the network meta-analysis results revealed significant effects of SGLT2i in reducing hospitalization for HF, CV death, all-cause death, NT-ProBNP, and 6MWT. Interestingly, this finding contrasts with the statistical results obtained before conducting the subgroup analysis, indicating the importance of evaluating the contribution of SGLT2i to HF based on ejection fraction. Furthermore, SGLT2i showed significant advantages in improving all-cause death. The indirect comparison revealed no statistical difference between different SGLT2i. Regarding the safety of HFrEF, dapagliflozin significantly increased the risk of a composite of urinary and reproductive infections compared to placebo. Additionally, our analysis revealed that SGLT2i could enhance KCCQ scores in HFrEF patients. Regarding ventricular remodeling, our study revealed that SGLT2i reduced LVMi, LVESV, and LVEDV and increased LVEF. These findings suggest that SGLT2i can enhance diastolic and systolic function in patients with HFrEF, thereby potentially augmenting the prognostic outcomes for these patients. The therapeutic effect of SGLT2i on cardiac structural remodeling was found to be significantly better in HFrEF patients compared to HFpEF patients, with SGLT2i demonstrating superiority in improving cardiac diastolic function in HFpEF patients. Consistent with our findings, a previous meta-analysis (94) showed that empagliflozin had a more significant effect in improving cardiac structure.

This study presents several limitations. ① This study mainly focuses on empagliflozin and dapagliflozin, with relatively little research available on canagliflozin, sotagliflozin, ipragliflozin, and ertugliflozin. Future research should explore these alternative SGLT2i to provide a more comprehensive understanding of their efficacy and safety profiles. ② Currently, there is only one direct comparison between dapagliflozin and empagliflozin available in current literature, leading to an indirect evaluation of the efficacy and safety of canagliflozin, sotagliflozin, ipragliflozin, and ertugliflozin in treating HF patients. Consequently, a potential bias exists between the reported results and the actual drug performances, underscoring the need for further direct-controlled trials to validate their efficacy and safety profiles. ③ There are variations in baseline characteristics such as gender, age, race, and chronic medical conditions among the included studies, potentially resulting in clinical heterogeneity. ④ Variations in follow-up durations between the six SGLT2i drug studies and within individual studies for each drug could introduce bias into the study results. ⑤ The limited number of studies on HF with HFpEF (EF ≥ 50%) underscores the necessity for more research to substantiate the relevant findings.

In summary, SGLT2i can significantly improve the prognosis of all patients with HF despite the associated increased risk of urinary and reproductive infections. Overall, HF patients benefit from enhanced cardiac remodeling, with those with HFrEF experiencing the most substantial benefits. Indirect comparisons between different SGLT2i revealed no significant differences in HFrEF. Among the six types of SGLT2i, sotagliflozin demonstrated superiority over empagliflozin and dapagliflozin in reducing hospitalization for HF and cardiovascular death in total HF. Canagliflozin exhibited higher safety than sotagliflozin regarding urinary and reproductive infections in patients with HFpEF. Overall, SGLT2i showed better efficacy in patients with HFrEF than those with HFpEF.

The author(s) declare financial support was received for the research, authorship, and/or publication of this article.

Funded by Military Logistical Special Project for Health Care (23KYBJ06).

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

XL: Formal Analysis, Methodology, Software, Writing – original draft, Writing – review & editing. HZ: Methodology, Project administration, Writing – review & editing. YC: Conceptualization, Formal Analysis, Investigation, Methodology, Supervision, Writing – review & editing. YH: Investigation, Resources, Software, Writing – original draft. XF: Data curation, Investigation, Methodology, Writing – original draft. KZ: Investigation, Methodology, Writing – review & editing. MW: Resources, Validation, Writing – original draft.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fcvm.2024.1379765/full#supplementary-material↗