Heart failure with preserved ejection fraction (HFpEF) accounts for nearly half of all heart failure cases and is associated with significant morbidity and mortality (1). Unlike heart failure with reduced ejection fraction (HFrEF), therapeutic strategies for HFpEF remain limited, with most conventional treatments offering minimal impact on clinical outcomes (2). The complex pathophysiology of HFpEF, characterized by diastolic dysfunction, systemic inflammation, and comorbidities such as hypertension, diabetes, and obesity, poses challenges in identifying effective pharmacological interventions (3).

Angiotensin-converting enzyme (ACE) inhibitors have long been a cornerstone in heart failure management due to their role in modulating the renin-angiotensin-aldosterone system (RAAS). While ACE inhibitors demonstrate clear benefits in HFrEF, their efficacy in reducing cardiovascular events in HFpEF patients has been inconsistent, with several trials failing to show significant reductions in mortality or hospitalizations (4,5).

Recently, sodium-glucose co-transporter 2 (SGLT2) inhibitors, initially developed for glycemic control in type 2 diabetes mellitus, have shown promising cardiovascular benefits independent of glucose-lowering effects (6). Large-scale clinical trials have highlighted the role of SGLT2 inhibitors in reducing heart failure hospitalizations and improving cardiovascular outcomes in patients with both HFrEF and HFpEF (7,8). The EMPEROR-Preserved trial notably demonstrated a reduction in composite cardiovascular endpoints with SGLT2 inhibitor use in HFpEF patients (9).

Given the emerging evidence supporting SGLT2 inhibitors and the traditional use of ACE inhibitors, a direct comparison of their effectiveness in HFpEF is essential to guide clinical decision-making. This study aims to evaluate and compare the impact of SGLT2 inhibitors versus ACE inhibitors on cardiovascular event reduction in patients diagnosed with HFpEF.

This retrospective cohort study was conducted to compare the effectiveness of sodium-glucose co-transporter 2 (SGLT2) inhibitors and angiotensin-converting enzyme (ACE) inhibitors in reducing cardiovascular events among patients diagnosed with heart failure with preserved ejection fraction (HFpEF).

Study Population:

A total of 300 patients aged ≥50 years with a confirmed diagnosis of HFpEF (Left Ventricular Ejection Fraction ≥50% as measured by echocardiography) were included. Patients were required to have New York Heart Association (NYHA) class II–III symptoms. Exclusion criteria were: patients with heart failure with reduced ejection fraction (HFrEF), severe renal impairment (eGFR <30 mL/min/1.73m²), history of recent myocardial infarction (within 3 months), or those on combination therapy of SGLT2 and ACE inhibitors.

Study Design and Groups:

Patients were divided into two equal groups based on the primary pharmacological therapy initiated:

Group A (n=150): Patients receiving SGLT2 inhibitors (either empagliflozin 10 mg/day or dapagliflozin 10 mg/day).

Group B (n=150): Patients receiving ACE inhibitors (either enalapril 10–20 mg/day or ramipril 5–10 mg/day).

Both groups received standard care for heart failure management, including diuretics and beta-blockers where indicated.

Outcome Measures:

The primary endpoint was the occurrence of major adverse cardiovascular events (MACE), defined as a composite of cardiovascular death, hospitalization due to heart failure, and non-fatal myocardial infarction over a follow-up period of 12 months. Secondary outcomes included individual components of MACE and all-cause mortality.

Data Collection:

Patient demographics, clinical history, comorbidities, medication adherence, echocardiographic parameters, and laboratory findings were recorded at baseline. Follow-up data were obtained through medical records and scheduled clinic visits every three months.

Statistical Analysis:

Descriptive statistics were used to summarize baseline characteristics. Kaplan-Meier survival curves were plotted to compare event-free survival between groups, and differences were assessed using the log-rank test. Cox proportional hazards regression was employed to calculate hazard ratios (HR) with 95% confidence intervals (CI) for the primary outcome, adjusting for potential confounders such as age, gender, diabetes, hypertension, and baseline NYHA class. A p-value of <0.05 was considered statistically significant. Statistical analysis was performed using SPSS software version 25.0 (IBM Corp., Armonk, NY, USA).

A total of 300 patients with HFpEF were included in the study, with 150 patients in each treatment group. Baseline characteristics such as age, gender distribution, comorbidities, and NYHA class were comparable between the two groups (Table 1). The mean age was 68.4 ± 9.2 years in the SGLT2 inhibitor group and 69.1 ± 8.7 years in the ACE inhibitor group. The prevalence of diabetes mellitus and hypertension was similar across both groups.

During the 12-month follow-up period, the incidence of major adverse cardiovascular events (MACE) was significantly lower in the SGLT2 inhibitor group compared to the ACE inhibitor group (Table 2). MACE occurred in 27 patients (18%) in Group A, whereas 45 patients (30%) in Group B experienced such events (p=0.012).

Hospitalization due to heart failure was reported in 15 patients (10%) in the SGLT2 group versus 30 patients (20%) in the ACE inhibitor group. Cardiovascular mortality was also reduced in Group A (5%) compared to Group B (9%). The rate of non-fatal myocardial infarction was 3% in the SGLT2 group and 6% in the ACE group.

Kaplan-Meier survival analysis demonstrated a significantly higher event-free survival in the SGLT2 inhibitor group (p=0.008, log-rank test). The Cox proportional hazards model revealed that treatment with SGLT2 inhibitors was associated with a 35% reduction in the risk of MACE (HR 0.65; 95% CI: 0.45–0.90).

These findings indicate that patients treated with SGLT2 inhibitors had better cardiovascular outcomes compared to those receiving ACE inhibitors (Table 2).

Table 1: Baseline Characteristics of Study Population

Table 1 shows no significant differences in baseline characteristics between the two groups.

Table 2: Incidence of Cardiovascular Events During 12-Month Follow-Up

Table 2 highlights the significant reduction in MACE and heart failure hospitalizations among patients receiving SGLT2 inhibitors compared to ACE inhibitors.

As shown in Table 2, the SGLT2 inhibitor group consistently demonstrated better outcomes across most cardiovascular endpoints, with a statistically significant difference observed in the overall MACE rate and heart failure-related hospitalizations.

This study demonstrates that sodium-glucose co-transporter 2 (SGLT2) inhibitors are more effective than angiotensin-converting enzyme (ACE) inhibitors in reducing major adverse cardiovascular events (MACE) in patients with heart failure with preserved ejection fraction (HFpEF). The findings align with emerging evidence suggesting that SGLT2 inhibitors offer significant cardioprotective benefits beyond glycemic control (1,2).

HFpEF represents a complex clinical syndrome characterized by diastolic dysfunction, systemic inflammation, endothelial dysfunction, and a high burden of comorbidities such as diabetes mellitus, obesity, and hypertension (3,4). Traditional therapies, including ACE inhibitors, have shown limited success in improving outcomes in HFpEF, despite their well-established role in heart failure with reduced ejection fraction (HFrEF) (5). Large trials such as PEP-CHF and CHARM-Preserved failed to demonstrate significant reductions in mortality or hospitalization with ACE inhibitor therapy in HFpEF patients (6,7).

The superior outcomes observed with SGLT2 inhibitors in this study are consistent with recent clinical trials, including the EMPEROR-Preserved and DELIVER trials, which highlighted the efficacy of SGLT2 inhibitors in reducing heart failure hospitalizations and composite cardiovascular outcomes in HFpEF populations (8,9). The mechanisms underlying these benefits are believed to involve natriuresis, reduction in preload and afterload, improvement in vascular function, modulation of cardiac metabolism, and anti-inflammatory effects (10,11).

In contrast, ACE inhibitors primarily target the renin-angiotensin-aldosterone system (RAAS), which, while beneficial in certain heart failure phenotypes, may not adequately address the multifactorial pathophysiology of HFpEF (12). Moreover, ACE inhibitors have been associated with side effects such as cough and hyperkalemia, potentially limiting adherence and therapeutic efficacy in some patients (13).

Our study showed a 35% relative risk reduction in MACE with SGLT2 inhibitors compared to ACE inhibitors, reinforcing their emerging role as a cornerstone in HFpEF management. Similar trends were observed in the reduction of heart failure hospitalizations, which is a critical outcome given the high rates of rehospitalization associated with HFpEF (14).

While cardiovascular mortality was lower in the SGLT2 group, the difference was not statistically significant, likely due to the limited follow-up period and sample size. However, prior meta-analyses suggest that longer-term use of SGLT2 inhibitors may confer survival benefits (15).

Limitations of this study include its retrospective design, potential for selection bias, and reliance on medical records for data collection. Additionally, variations in the choice of specific agents within each drug class and differences in patient adherence could have influenced outcomes. Future large-scale randomized controlled trials (RCTs) with extended follow-up are necessary to validate these findings and explore the long-term impact on mortality.

In conclusion, this study supports the preferential use of SGLT2 inhibitors over ACE inhibitors in reducing cardiovascular events in patients with HFpEF. Given the limited treatment options available for this patient population, SGLT2 inhibitors represent a promising therapeutic advancement. Integration of these agents into standard HFpEF management protocols could potentially improve patient outcomes and reduce healthcare burdens associated with recurrent hospitalizations.

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