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Impact of SGLT2 inhibitors on cardiovascular outcomes and metabolic events in Chinese han patients with chronic heart failure

Diabetology & Metabolic Syndrome volume 16, Article number: 299 (2024) Cite this article

Abstract

Objective

This study aimed to evaluate the real-world impact of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on the efficacy, safety, and metabolic profiles of patients with chronic heart failure (CHF), both with and without type 2 diabetes mellitus (T2DM).

Methods

A cohort of 1,130 patients with reduced ejection fraction chronic heart failure (HFrEF) was recruited from Zhongnan Hospital of Wuhan University, spanning January 2021 to August 2023. Among these, 154 patients received SGLT2i therapy, while 131 patients were assigned to a non-SGLT2i group, following specified inclusion and exclusion criteria. The association between SGLT2i therapy and the risk of primary and secondary endpoints was analyzed, alongside the effect of guideline-recommended heart failure medications at varying dosages on Major Adverse Cardiovascular Events (MACE).

Results

SGLT2i treatment led to reductions in blood pressure, uric acid, NT-proBNP, and pulmonary artery pressure, while increasing body mass index (BMI) and left ventricular ejection fraction (LVEF) in CHF patients. Multivariate Cox regression analysis revealed that SGLT2i therapy reduced the primary endpoint risk by 40.3% (HR 0.597, 95% CI 0.356–0.973, p = 0.047). Univariate Cox regression indicated that SGLT2i might also reduce the incidence of new diagnoses of atrial fibrillation, non-fatal acute myocardial infarction, and MACE in CHF patients. Moreover, the use of a four-drug combination for heart failure management was associated with a lower risk of MACE compared to monotherapy.

Conclusion

SGLT2i therapy not only enhances LVEF but also significantly reduces ambulatory blood pressure, uric acid, fasting blood glucose, pulmonary artery pressure, and NT-proBNP levels in CHF patients. Additionally, SGLT2i improves prognosis by lowering the risk of both primary and secondary endpoints. Compared to monotherapy, a four-drug regimen for CHF substantially reduces the risk of MACE, supporting the effectiveness of comprehensive treatment strategies.

Introduction

Heart failure (HF) is a complex clinical condition characterized by structural and/or functional abnormalities of the heart, leading to impaired ventricular filling or contraction, which manifests as associated symptoms and signs. HF is marked by high morbidity and mortality rates, compromised cardiac function, reduced quality of life, and increased healthcare costs [1]. Advances in treatment have prolonged the life expectancy of patients with ischemic cardiomyopathy; however, the prevalence of HF continues to rise globally, exacerbated by population aging, placing a significant strain on healthcare systems. Recent estimates indicate that the annual prevalence of HF ranges from 1 to 20 cases per 1,000 individuals worldwide [2], with evidence suggesting an increasing incidence across Asia [3]. Consequently, HF has emerged as a critical global public health issue, emphasizing the need for ongoing treatment research to reduce its social and economic burden.

Sodium-glucose cotransporter 2 (SGLT2), a high-capacity, low-affinity transporter located in the kidney’s proximal tubule [4], mediates over 90% of glucose reabsorption. SGLT2 inhibitors (SGLT2i) reduce plasma glucose levels by increasing urinary excretion of glucose and sodium, producing natriuretic and diuretic effects independent of insulin [5]. Initially developed for managing type 2 diabetes mellitus (T2DM) due to their glucose-lowering properties, SGLT2i have been shown to confer significant cardiovascular benefits in HF patients. Since 2015, a series of large, randomized controlled trials have demonstrated that SGLT2i can effectively reduce cardiovascular death, HF rehospitalization, and major adverse cardiovascular events (MACE). The EMPA-REG OUTCOME trial was the first to indicate that empagliflozin improved cardiovascular outcomes, reducing cardiac mortality and HF relapse compared to placebo5. This was followed by trials such as EMPEROR-Reduced and DAPA-HF [6, 7], which confirmed that SGLT2i benefit HF patients with reduced ejection fraction (HFrEF), regardless of diabetes status.

Reflecting these findings, the 2021 ESC Heart Failure Guidelines introduced the "Four Pillars" approach to HF treatment, which includes SGLT2i alongside renin-angiotensin system (RAS) inhibitors, β-blockers, and mineralocorticoid receptor antagonists (MRA). This marked a paradigm shift in HF management. Subsequent trials, EMPEROR-Preserved and DELIVER, further established that SGLT2i could reduce cardiovascular death and HF hospitalization in patients with HF with mid-range (HFmrEF) and preserved (HFpEF) ejection fraction, leading to their inclusion in the 2023 ESC Guidelines for these HF phenotypes [8,9,10]. Currently, four SGLT2i—empagliflozin, canagliflozin, dapagliflozin, and ertugliflozin—are FDA-approved. Additional studies have shown SGLT2i benefits beyond glycemic control, including blood pressure reduction, renal protection, arrhythmia prevention, and acute myocardial infarction risk reduction.

Despite the accumulating evidence, further studies are required to validate these benefits in HF patients in different populations. Few studies have been conducted in China, primarily limited to meta-analyses, and there remains debate regarding the clinical efficacy and incidence of adverse cardiovascular events associated with SGLT2i in HF patients. This retrospective study aims to evaluate the effects of SGLT2i on blood pressure, serum uric acid (UA), and other metabolic indicators, as well as on cardiac structure, function, and cardiovascular prognosis in patients with chronic HF (CHF). Additionally, we examine the effects of the "new quadruple" drug regimen on MACE risk among CHF patients.

Methods

Data sources and study population

We retrospectively collected data on 1,130 patients with heart failure with reduced ejection fraction (HFrEF) who visited Zhongnan Hospital of Wuhan University between January 2021 and August 2023. This single-center cohort study included patients who met the following criteria: (a) diagnosed with HFrEF according to international diagnostic criteria, (b) admitted to Zhongnan Hospital during the specified period, and (c) with complete medical records. Exclusion criteria were: (a) previous SGLT2 inhibitor (SGLT2i) treatment or intolerance, (b) symptomatic hypotension or systolic blood pressure < 90 mmHg in two or more of the three blood pressure measurements during treatment, (c) recent (within 12 weeks prior to inclusion) acute heart failure, acute myocardial infarction, unstable angina, stroke, or transient ischemic event, (d) concurrent acute cerebrovascular accident, malignancy, liver damage, psychiatric illness, multiple organ failure, severe valvular disease, restrictive cardiomyopathy, active myocarditis, constrictive pericarditis, hypertrophic cardiomyopathy, symptomatic bradycardia, second- or third-degree atrioventricular block, consciousness disorders, severe infection, or anemia, and (e) incomplete clinical data, poor treatment compliance, resistance to therapy, or loss to follow-up.

After applying the inclusion and exclusion criteria, 845 patients were excluded, leaving a final cohort of 285 HFrEF patients was shown in Fig. 1. These patients were divided into two groups based on their use of SGLT2i: the SGLT2i group (n = 131), consisting of patients who took dapagliflozin, and the non-SGLT2i group (n = 154), consisting of patients who did not. All participants received standard guideline-recommended medications for chronic heart failure (CHF).

Fig. 1
figure 1

Study flow

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Measurement of outcome

Initially, baseline, follow-up, data were compared between the two groups to assess the impact of SGLT2 inhibitors (SGLT2i) on various clinical indicators in heart failure patients. Subsequently, Cox regression analysis and Kaplan–Meier (K-M) survival curves were utilized to evaluate the effects of SGLT2i on both primary and secondary endpoints in chronic heart failure (CHF) patients. Finally, the impact of the number of orally administered CHF medications on the risk of major adverse cardiovascular events (MACEs) was analyzed using Cox regression and K-M survival curves.

The primary endpoint was defined as a composite event comprising emergency visits (including an emergency visit, access to a hospital emergency service, and outpatient visits scheduled as urgent) for heart failure and/or cardiovascular death. Secondary endpoints included all-cause mortality, incidence of new diagnoses of coronary heart disease, new diagnoses of atrial fibrillation, new diagnoses of arrhythmia, new diagnoses of type 2 diabetes, non-fatal acute myocardial infarction, non-fatal cerebral infarction, cardiovascular death, and MACEs (a composite of non-fatal acute myocardial infarction, non-fatal cerebral infarction, or cardiovascular death).

Data collection

Using the electronic medical record system of Zhongnan Hospital of Wuhan University, we collected comprehensive baseline and follow-up data, including demographic information, physical examination findings, medical history, comorbidities, laboratory test results, imaging findings, therapeutic interventions, and clinical outcomes. Data were extracted from the hospital’s management system and included both baseline assessments and follow-up data for each treatment group. Blood pressure measurements were taken by a trained nurse to ensure accuracy. To sum up, Venous blood samples were obtained from patients who were required to fast overnight (more than 10 h). Subsequently, laboratory parameters including N-terminal pro-brain natriuretic peptide (NT) (proBNP), blood urea nitrogen (BUN), UA, serum creatinine (SCR) and procedures namely echocardiography, electrocardiogram(ECG), blood pressure and heart rate were measured in the Department of Clinical Laboratory of our hospital.

All data were meticulously reviewed by two independent researchers to maintain data integrity. Any discrepancies between reviewers were resolved through discussion or by consulting a third investigator. Key outcome events for follow-up included heart failure readmissions, heart failure-related emergency visits, cardiovascular death, all-cause mortality, incidence of new diagnoses of coronary heart disease, major adverse cardiovascular events (MACEs), non-fatal acute myocardial infarction, fatal cerebral infarction, new diagnoses of atrial fibrillation, new diagnoses of arrhythmia, and new diagnoses of type 2 diabetes.

Statistical analysis

Statistical analyses were conducted using R software (version 4.2.3; Foundation for Statistical Computing, Vienna, Austria) and SPSS software (version 26.0; IBM, Armonk, New York, USA). To determine the distribution characteristics of all variables, we prioritized the Kolmogorov–Smirnov test. Count data are reported as absolute frequency and percentage. Measurement data with a skewed distribution are presented as median and interquartile range (IQR), while normally distributed measurement data are expressed as mean ± standard deviation (x̄ ± s).

For comparisons between the two groups, the independent sample t-test was used if the data followed a normal distribution; otherwise, the Mann–Whitney U test was applied. Categorical data were analyzed using the chi-square test. Paired sample comparisons were conducted using the Wilcoxon signed-rank test.

Survival analysis was performed using the Cox proportional hazards model and Kaplan–Meier survival curves. The association between SGLT2 inhibitor (SGLT2i) use and the risk of primary and secondary endpoints was initially assessed using Cox regression and Kaplan–Meier survival curve analyses. Subsequently, the effect of various dosages of heart failure medications on major adverse cardiovascular events (MACEs) was evaluated. In this study, a two-tailed p-value of < 0.05 was considered statistically significant.

Results

Characteristics of participants

As illustrated in Fig. 1, between January 1, 2021, and August 1, 2023, a total of 1,130 patients with chronic heart failure with reduced ejection fraction (HFrEF) who visited the Department of Cardiovascular Medicine at Zhongnan Hospital of Wuhan University were initially assessed. Based on predefined inclusion criteria, 610 patients were deemed eligible, while 325 patients were excluded due to exclusion criteria, resulting in a final study cohort of 285 patients with chronic heart failure (CHF). The cohort was stratified according to dapagliflozin use: 131 patients were assigned to the SGLT2 inhibitor (SGLT2i) group, while 154 patients comprised the non-SGLT2i group.

Comparison of baseline characteristics between SGLT2i group and non-SGLT2i group

Table 1 presents a comparison of the baseline clinical characteristics between the SGLT2i and non-SGLT2i groups. In the SGLT2i group, 31 patients (23.7%) were female and 100 (76.3%) were male, with a median age of 66 years and a median follow-up duration of 65 days. In the non-SGLT2i group, there were 39 females (25.3%) and 115 males (74.7%), with a median age of 67 years and a median follow-up time of 58 days. Compared to the non-SGLT2i group, the SGLT2i group had a significantly higher proportion of patients with type 2 diabetes and elevated fasting blood glucose levels (p < 0.05). No significant differences were observed between the two groups in other baseline parameters (p > 0.05).

Table 1 Baseline characteristics of the study population
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Clinical characteristics after follow-up between the SGLT2i group and the non-SGLT2i group

A comparison of clinical characteristics between the SGLT2i group and the non-SGLT2i group after follow-up is shown in Table 2. The ambulatory systolic blood pressure, the ambulatory diastolic blood pressure, right atrium diameter (RAD) and pulmonary hypertension (PH) proportions were all reduced in the SGLT2i group compared to the non-SGLT2i group, while the LVEF and BMI were higher (p < 0.05). The incidence rates of cardiovascular outcomes in the study cohort were computed during the follow-up period. The SGLT2i group had lower incidence rates of emergency visits for heart failure, HF, all-cause death, new diagnoses of non-fatal acute myocardial infarction, MACEs and new diagnoses of atrial fibrillation (p < 0.05) than the non-SGLT2i group.

Table 2 Characteristics between the SGLT2i group and the non-SGLT2i group after follow-up
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Clinical characteristics baseline and follow-up between the SGLT2i group and the non-SGLT2i group

The comparison of clinical characteristics baseline and follow-up between the SGLT2i and non-SGLT2i groups was shown in Tables 3 and 4. In the non-SGLT2i group, ambulatory systolic blood pressure, ambulatory diastolic blood pressure, heart rate and N-terminal B-type natriuretic peptide (NT-proBNP) were lower than in the baseline data, although LVEF was higher (p < 0.05). UA, ambulatory diastolic and systolic blood pressure, heart rate, fasting blood glucose and NT-proBNP all declined in the SGLT2i group as compared to baseline data, while LVEF rose (p < 0.05). When the clinical data from both the baseline and follow-up periods were combined, it was found that while the ambulatory systolic and diastolic blood pressures of the two groups decreased after the follow-up, the SGLT2i group's ambulatory systolic and diastolic blood pressures were lower than those of the non-SGLT2i group (p < 0.05). Additionally, the changes in uric acid (UA), left ventricular ejection fraction (LVEF), and NT-proBNP baseline and follow-up were assessed in both groups. The SGLT2i group exhibited a greater mean increase in LVEF and a more significant mean decrease in UA and NT-proBNP compared to the non-SGLT2i group (p < 0.05). This suggests that the SGLT2i group may experience more substantial improvements in uric acid levels, left ventricular ejection function, and overall cardiac function than the non-SGLT2i group.

Table 3 The comparison of clinical characteristics between the SGLT2i and non-SGLT2i groups
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Table 4 The comparison of clinical characteristics (follow-up to baseline) between the SGLT2i and non-SGLT2i groups
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Impact of SGLT2i on primary endpoint events in patients with chronic heart failure

Without history of cerebral infarction, without history of alcohol abuse, use of angiotensin-converting enzyme inhibitors (ACEIs), use of angiotensin receptor blockers (ARB), use of angiotensin-neprilysin receptor inhibitors (ARNI), use of SGLT2i, reduced serum creatinine (SCR).), reduced blood urea nitrogen (BUN) and decreased NT-proBNP were associated with lower primary endpoint events (composite endpoint: heart failure/cardiovascular death) in regression analysis compared with univariate Cox. Then, the Cox proportional risk model was adjusted with the patients' oral chronic heart failure medications, including ACEI/ARB/ARNI, beta-blockers, MRA, and diuretics, and We found oral SGLT2i can reduce the primary endpoint event risk by 45% (HR 0.550, 95%CI 0.318 ~ 0.952, p = 0.033). Furthermore, components with p < 0.05 in the single-factor Cox regression analysis were used as confounding factors in the multivariate Cox regression analysis, we found oral SGLT2i can reduce the probability of the primary endpoint event by 40.3% (HR 0.597, 95%CI 0.356 ~ 0.973, p = 0.047). The complete data are shown in Tables 5 and 6. According to the K-M survival curve and a Log-Rank test, we found that SGLT2i might decrease the risk of the primary endpoint event (p = 0.015) (Fig. 2).

Table 5 Univariate and multivariate Cox proportional hazard analyses for the primary endpoint events according to SGLT2i patients
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Table 6 Log-Rank analyses for the primary endpoint events according to SGLT2i patients
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Fig. 2
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Kaplan–Meier curves for the primary endpoint events in the CHF patients

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Effect of SGLT2i on the risk of secondary endpoints in patients with chronic heart failure

To assess the correlation between SGLT2i use and the risk of secondary endpoint events in patients with chronic heart failure (CHF), a univariate Cox regression analysis was performed. The results indicated that oral SGLT2i significantly reduced the risk of major adverse cardiovascular events (MACEs), new diagnoses of non-fatal acute myocardial infarction, and new diagnoses of atrial fibrillation by 73.3%, 67.6%, and 88.4%, respectively (HR 0.267, 95% CI 0.090–0.795, p = 0.018; HR 0.324, 95% CI 0.107–0.986, p = 0.047; HR 0.116, 95% CI 0.015–0.903, p = 0.040). Complete data are presented in Table 7.

Table 7 Log-Rank analyses for the primary endpoint events according to SGLT2i patients
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The effects of SGLT2i on MACEs, new diagnoses of non-fatal acute myocardial infarction, and new diagnoses of atrial fibrillation in CHF patients were further evaluated using Kaplan–Meier (K-M) survival curves and Log-Rank tests. The findings demonstrated that SGLT2i use was associated with a significant reduction in the risk of these secondary endpoints in CHF patients (p < 0.05), as shown in Figs. 3, 4, and 5.

Fig. 3
figure 3

Kaplan–Meier curves for the MACEs in the CHF patients

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Fig. 4
figure 4

Kaplan–Meier curves for the event of the new diagnoses of non-fatal acute myocardial infarction in the CHF patients

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Fig. 5
figure 5

Kaplan–Meier curves for the event of new diagnoses of atrial fibrillation in the CHF patients

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Effect of chronic heart failure medication combinations on the risk of MACEs

Cox regression analysis showed that using a four-drug combination for chronic heart failure (CHF) reduced the risk of major adverse cardiovascular events (MACEs) by 50.6% compared to a single-drug regimen (HR 0.494, 95% CI 0.247–0.989, p = 0.046). No significant differences were found between other drug combination groups. Full data are provided in Tables 8 and 9.

Table 8 Univariate Cox proportional hazard analyses for the MACEs according to the different number of CHF drugs
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Table 9 Univariate Cox proportional hazard analyses for the MACEs according to the different number of CHF drugs
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Kaplan–Meier (K-M) survival curves and Log-Rank analyses were performed to evaluate the impact of varying numbers of CHF medications on MACEs risk. The results indicated that taking four medications significantly reduced the risk of MACEs compared to single-drug use (p < 0.05), as shown in Figs. 6 and 7.

Fig. 6
figure 6

Kaplan–Meier curves for the different numbers of CHF drugs

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Fig. 7
figure 7

Kaplan–Meier curves for the comparison of the single-drug group and the quadruple-drug in CHF patients

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Discussion

The "new quadruple" therapy, incorporating dapagliflozin, has replaced the "Golden Triangle" as the recommended standard treatment for chronic heart failure (CHF) in both national and international guidelines. However, limited clinical studies have been conducted on SGLT2 inhibitors, and their effects on parameters such as uric acid and body mass index (BMI) remain subjects of debate. Currently, limited research has explored how different combinations of anti-heart failure (HF) medications impact the prognosis of CHF patients, highlighting the need for further investigation.

It is well-established that hypertension is a major risk factor for HF and other cardiovascular diseases. Evidence suggests that SGLT2 inhibitors effectively reduce blood pressure [4, 11,12,13,14,15]. This study observed that ambulatory systolic and diastolic blood pressures in both the SGLT2i and non-SGLT2i groups were lower than baseline after a median follow-up of 2 months. Notably, the SGLT2i group showed significantly greater reductions in blood pressure compared to the non-SGLT2i group (p < 0.05), indicating a potential antihypertensive effect of SGLT2i. While the precise mechanisms remain under investigation, several pathways may be involved. First, SGLT2 inhibitors promote urinary glucose and sodium excretion by inhibiting renal tubular reabsorption, resulting in osmotic diuresis [16]. Additionally, this excretion may modulate the renin–angiotensin–aldosterone system (RAAS), ultimately reducing blood pressure. Some studies suggest that SGLT2i may decrease sympathetic nervous system sensitivity, potentially benefiting hypertension and HF [4].

We also found a significant reduction in uric acid (UA) levels in the SGLT2i group after follow-up, with a larger average decrease compared to the non-SGLT2i group (p < 0.05). According to a study by McCormick et al., SGLT2i may benefit the cardiovascular system and reduce hospitalizations and emergency visits for individuals with primary gout and recurrent attacks [17]. Randomized controlled trials also show that SGLT2i can reduce serum UA levels in both diabetic and non-diabetic populations [18,19,20,21]. Potential mechanisms for UA reduction include inhibition of renal UA reabsorption transporters such as URAT1 and modulation of the NLRP3 inflammasome. Additionally, SGLT2i may influence UA metabolism by reducing intracellular glucose influx into proximal tubular cells, increasing sirtuin-1 production, and inhibiting xanthine oxidase activity. Further research is required to clarify these mechanisms [22, 23].

Cardiac structural and functional changes contribute to HF development and are independent risk factors for cardiovascular morbidity and mortality. In preclinical studies, empagliflozin delayed cardiac function decline and improved systolic performance in HF models [23, 24]. Data from the Scottish REFORM study indicate that dapagliflozin improved left ventricular volumes in HF patients with type 2 diabetes, though there was no significant impact on left ventricular mass index (LVMI) or end-diastolic volume [25, 26]. In this study, SGLT2i significantly increased left ventricular ejection fraction in CHF patients, though it had no marked effect on cardiac structure. The shorter follow-up period may account for differences from other studies [27, 28]. Importantly, we also found a lower prevalence of pulmonary hypertension in the SGLT2i group after follow-up (p < 0.05), suggesting that SGLT2i may reduce pulmonary artery pressure in CHF patients, with a potential greater efficacy in patients with HFpEF and HFmrEF. While the GLISCAR trial also observed improvements in pulmonary artery pressure with SGLT2i, echocardiography was the primary measurement tool in this study. Right heart catheterization may provide more accurate measurements in future studies [29].

Our study further revealed that SGLT2i significantly reduced the risk of primary endpoint events (composite outcome: emergency medical consultation due to HF or cardiovascular death). In multi-factor Cox regression analysis, SGLT2i use was associated with a 40.3% reduction in the risk of primary events (HR 0.597, 95% CI 0.356–0.973, p = 0.047). This is consistent with findings from the DAPA-HF and DELIVER trials, which demonstrated a reduction in major composite events of cardiovascular death or HF exacerbation [30,31,32]. Several other large studies, such as CANVAS, DECLARE TIMI-58, EMPA-REG OUTCOME, and DELIVER [33,34,35,36], have reported similar outcomes. A meta-analysis by He et al. showed that SGLT2i use in patients with type 2 diabetes and acute myocardial infarction (AMI) was associated with fewer in-stent restenosis events and reduced infarct size and inflammation [37]. These findings may be attributed to the anti-inflammatory effects of SGLT2i, as well as attenuation of neurohormonal activation, cardiomyocyte necrosis, and reperfusion injury, though further basic research is warranted [38,39,40,41].

Studies have shown that after 6 months of follow-up using SGLT2i, serum oxidative stress markers such as Nox-2, 8-isoprostane and inflammatory indicators such as the platelet activity biomarker sP-selectin, high sensitivity C-reactive protein, and insulin resistance such as insulin resistance Index (HOMA-IR) were significantly improved [42, 43]. The potential mechanisms explaining these effects could be found in the anti-oxidant action by SGLT2i. The cellular reduction–oxidation (redox) imbalance leads to Oxidative stress by regulating certain signaling pathways (such as p38 MAPK, Nrf2, and NF-kB) involved in β-cell dysfunction and insulin resistance [44]. Studies have reported that SGLT2 inhibitor suppressed oxidative stress and fibrosis through activation of Nrf2/ARE signaling [45]. In addition, other studies have shown that SGLT2 inhibitors also reduce markers of oxidative stress and reactive oxygen species including hydrogen peroxide and the attenuation of oxidative stress and inflammation associated with SGLT2 inhibitors is likely multifactorial, and a number of mechanisms including decreased uric acid, reduced epicardial fat, alterations in adipokine levels and up-regulation of autophagy all may play a role [46].

Researchers have investigated the impact of SGLT2 inhibitors (SGLT2i) on the risk of atrial fibrillation or atrial flutter in patients with heart failure with reduced ejection fraction (HFrEF). Our findings indicate that treatment with SGLT2i can significantly reduce the risk of atrial fibrillation in this population, particularly when the duration of treatment is less than 1.5 years. Furthermore, SGLT2i treatment is associated with a lower incidence of atrial fibrillation [47]. This study also suggests that SGLT2i may decrease the occurrence of new episodes of atrial fibrillation. Preliminary hypotheses propose that SGLT2i may improve the dysregulation of sodium ions (Na +) and calcium ions (Ca2 +) in cardiomyocytes, which is related to atrial fibrillation. Additionally, SGLT2i may enhance mitochondrial function, influence cardiac energy metabolism, reduce inflammation and oxidative stress, and inhibit sympathetic nervous system activity [48,49,50,51,52,53]. However, these mechanisms require further validation through subsequent basic research. Moreover, we observed that SGLT2i could reduce the risk of new diagnoses of non-fatal acute myocardial infarction in patients with chronic heart failure (CHF). Nevertheless, the mechanisms underlying the benefits of SGLT2i on non-cardiovascular mortality remain unclear and warrant further investigation.

Despite the efficacy of these agents in HF as demonstrated by major randomized controlled trials, real-world application may be limited by patient variability, heart rate reduction, renal insufficiency, or noncompliance. Additionally, few studies have assessed the impact of different combinations of these four agents on CHF outcomes. A 2020 analysis suggested that a four-drug regimen could extend life expectancy by 4.4 years compared to conventional treatment [54]. A 2022 systematic review reported that quadruple therapy reduced the hazard ratio for HF to 0.39, extending survival by approximately 5 years [55]. This study’s Cox regression and Kaplan–Meier survival analysis further support that quadruple therapy reduces MACE incidence in CHF patients, underscoring its potential as an initial HF treatment strategy [55].

Limitations of the study

This study has limitations. First, as a single-center observational study with a relatively short follow-up period, confounding factors may have influenced the results, and larger cohort studies are needed for confirmation. Second, the small sample size, primarily comprising hospitalized CHF patients, may limit generalizability. Third, this study focused exclusively on HFrEF patients. Given that SGLT2i is the first HF medication effective across the ejection fraction spectrum, further research is needed across different HF types. Fourth, the completeness of data collection and recording posed constraints. Future multi-center studies with extended follow-up periods are essential to validate these findings. Lastly, this study did not include patients with severe renal insufficiency, dialysis, or rapidly progressive kidney disease; thus, additional follow-up studies are needed to address these populations.

Conclusion

In conclusion, SGLT2 inhibitors show promise in reducing ambulatory blood pressure, improving metabolic parameters, decreasing pulmonary artery pressure, and enhancing cardiac function in patients with chronic heart failure (CHF). Additionally, SGLT2i therapy significantly lowers the risk of both primary and secondary adverse endpoints, contributing to improved patient outcomes. Moreover, a quadruple-drug regimen for CHF management substantially reduces the risk of major adverse cardiovascular events (MACE) compared to monotherapy. These findings provide a valuable foundation for future research directions and offer critical insights for advancing clinical management strategies in CHF.

Availability of data and materials

No datasets were generated or analysed during the current study.

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Acknowledgements

We would like to gratefully acknowledge the support from Zhongnan Hospital of Wuhan University, the study participants who participated in this work.

Funding

This study was supported by Zhongnan Hospital of Wuhan University Key Projects Fund (Grant Numbers PTXM2023006), Zhongnan Hospital of Hubei Provincial Administration of Traditional Chinese Medicine Scientific Research Project (Grant Numbers ZY023F047) and Wuhan Municipal Health Commission (Grant Numbers WJ2023M074).

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  1. Fei Li, Rewaan Baheti, and Mengying Jin have contributed equally to this work and share first authorship.

Authors and Affiliations

  1. Department of Cardiovascular Medicine, Zhongnan Hospital of Wuhan University, No 169 Donghu Road, Wuchang District, Wuhan, 430071, Hubei Province, China

    Fei Li, Rewaan Baheti, Mengying Jin, Wei Xiong & Jing Wan

  2. Department of Cardiology and Thirsty Diseases, Jiangxia District Traditional Chinese Medicine Hospital, Wuhan, 430200, China

    Jiawei Duan

  3. Department of Cardiovascular Medicine, The Fifth Hospital of Huangshi, Huangshi, 435000, China

    Peng Fang

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  1. Fei Li
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Contributions

Fei Li, Rewaan Baheti and Mengying Jin have contributed equally to this work and share first authorship. FL, RB and MYJ: concept and design, acquisition, analysis, and interpretation of data; drafting the manuscript; WX, JWD and PF data collection, concept and design; JW: supervision, revising the manuscript. All authors gave final approval of the version to be published. All authors have agreed on the journal to which the article has been submitted and agreed to be accountable for all aspects of the work.

Corresponding author

Correspondence to Jing Wan.

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The ethics committee of Zhongnan Hospital of Wuhan University approved this study, and informed consent was obtained from all patients or their relatives or legally accepted representatives. All experiments were performed by the relevant guidelines and regulations according to the principles expressed in the Declaration of Helsinki.

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Li, F., Baheti, R., Jin, M. et al. Impact of SGLT2 inhibitors on cardiovascular outcomes and metabolic events in Chinese han patients with chronic heart failure. Diabetol Metab Syndr 16, 299 (2024). https://doi.org/10.1186/s13098-024-01553-z

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Keywords

Diabetology & Metabolic Syndrome

ISSN: 1758-5996

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