Myocardial infarction (MI) is a common and serious cardiovascular condition that frequently leads to decreased exercise capacity and reduced quality of life [1]. As such, exercise capacity is a crucial determinant of prognosis following an acute myocardial infarction [2]. Despite notable advancements in medical therapies and revascularization techniques, many patients recovering from MI continue to encounter significant challenges in restoring their functional capacity and overall well-being [3]. Consequently, there is a pressing need for strategies aimed at enhancing exercise capacity and improving functional outcomes in this patient population [4,5]. Recent clinical trials have demonstrated that certain glucose-lowering agents, particularly sodium-glucose co-transporter 2 (SGLT2) inhibitors such as empagliflozin and canagliflozin, can effectively reduce the incidence of cardiovascular events in diabetic and non-diabetic patients [6-8]. Moreover, these agents have been shown to enhance exercise capacity in individuals with cardiovascular conditions including heart failure syndrome [9-11].

The 6-Minute Walk Test (6-MWT) is a widely recognized and reliable measure of exercise capacity that has been extensively utilized in clinical trials addressing cardiovascular diseases. Improvements in the distance covered during the 6MWT are associated with favorable clinical outcomes, including reduced rates of hospitalization and mortality [12]. Therefore, the 6-MWT is considered a clinically relevant metric for assessing exercise capacity among patients with cardiovascular disease [13].

This study aimed to evaluate the effects of empagliflozin on exercise capacity in patients following acute myocardial infarction who are undergoing primary percutaneous coronary intervention (PCI). By investigating this relationship, we sought to contribute to the understanding of the potential benefits of SGLT2 inhibitors in facilitating rehabilitation and enhancing functional recovery in this vulnerable patient population.

This study utilized data from the ELITE-PCI trial, a prospective, single-center, randomized, triple-blind, placebo-controlled investigation. Patients diagnosed with acute myocardial infarction (AMI) who underwent primary percutaneous coronary intervention (PCI) at Afshar Hospital in Yazd, Iran, were enrolled from June 8, 2023, to May 25, 2024. Ethical approval was obtained from the Shahid Sadoughi Medical University of Yazd (IR.SSU.MEDICINE.REC.1401.211).

Inclusion and Exclusion Criteria

Inclusion criteria comprised adults aged 18 years or older presenting with AMI who were eligible for primary PCI. Exclusion criteria included prior administration of empagliflozin, significant renal impairment, contraindications to SGLT2 inhibitor therapy, and patients unable to walk due to orthopedic issues.

Patient Assessment

By the ELITE-PCI trial protocol, all participants underwent comprehensive history taking and physical examination upon admission to the emergency department. Following this, electrocardiogram (ECG) acquisition and echocardiography were performed. Various parameters assessed included ECG changes, left ventricular ejection fraction (LVEF), age, sex, body mass index (BMI), diabetes status, blood pressure, lipid profile, glomerular filtration rate (GFR), smoking history, past medical history (including previous myocardial infarction [MI], PCI, coronary artery bypass grafting [CABG], and chronic obstructive pulmonary disease [COPD]), as well as medications administered post-MI.

Following the diagnosis of ST-elevation myocardial infarction and the completion of primary PCI, eligible patients were enrolled in the trial. Participants were randomly assigned in a 1:1 ratio, with 60 patients in each group, to receive either oral empagliflozin (10 mg once daily, Gloripa, Abidi Pharmaceutical Company, Tehran, Iran) or a placebo, initiated within 48 hours post-angioplasty. Randomization was conducted using software from RANDOM.ORG. Before discharge, patients performed a 6MWT under the supervision of a cardiologist, and the distance covered was recorded.

Follow-Up

Follow-up assessments were conducted at 12 weeks post-myocardial infarction, during which patients again performed the 6MWT.

Outcome

The primary outcome of the study was the change in 6MW distance performance from randomization to week 12.

Statistical Analysis

All analyses were conducted using IBM SPSS version 26. Descriptive statistics summarized the demographic and clinical characteristics of the study population, presenting continuous variables as means and standard deviations (SD) and categorical variables as frequencies and percentages. To evaluate the efficacy of empagliflozin on 6MWT outcomes compared to placebo, independent t-tests assessed mean differences at both baseline and the 12-week follow-up. Additionally, linear regression analysis was performed to identify factors influencing 6MWT performance, with results reported using p-values and a significance level set at p ≤ 0.05.

In the ELIT-PCI trial, 120 patients were enrolled, with 107 completing the six-minute walk test (6-MWT)—54 in the empagliflozin group and 53 in the placebo group. The mean age was similar between groups (59.4 ± 10.2 years for empagliflozin vs. 57.3 ± 11.3 years for placebo, p=0.325), and sex distribution was also comparable (90.7% male in empagliflozin vs. 92.5% in placebo, p > 0.999). Both groups had similar body mass index (BMI) values (26.4 vs. 26.9 kg/m², p=0.506), glomerular filtration rates (GFR) (85.5 vs. 85.3 ml/min, p=0.948), and blood pressure readings (systolic blood pressure: 124.9 vs. 120.6 mmHg, p=0.453; diastolic blood pressure: 81.5 vs. 77.3 mmHg, p=0.059). Baseline 6-MWT distances were also comparable (193.9 vs. 205.8 meters, p=0.512), and left ventricular ejection fraction (LVEF) was similar (35.5% vs. 35.0%, p=0.421). The prevalence of comorbidities, including diabetes mellitus, hypertension, and hyperlipidemia, did not differ significantly between groups [Table 1].

Values are given as median±SD and no. (%). BMI (body mass index), GFR (glomerular filtration rate), SBP (systolic blood pressure), DBP (diastolic blood pressure), LVEF (left ventricular ejection fraction), 6MWT (6-minute walk test), DM (diabetes mellitus), HTN (hypertension), HLP (hyperlipidemia), COPD (Chronic obstructive pulmonary disease), MI (myocardial infraction), PCI (Percutaneous Coronary Intervention), CABG (coronary artery bypass grafting), CVA (cerebrovascular accident). Significant p value is ≤0.05.

Table 1: Comparison of Baseline Characteristics between Empagliflozin and Placebo Groups.

Analysis of the 6-minute walk test (6-MWT) distances showed no statistically significant differences between the empagliflozin and placebo groups at baseline, after 12 weeks, or in the change in walked distance (Δ walked distance: 12-week 6MWT distance - baseline 6MWT distance), with p-values exceeding 0.05. While mean differences suggested a trend towards improvement in both groups, these changes did not achieve statistical significance within the established confidence intervals [Table 2, Fig 1].

Table 2: Comparison of 6-Minute Walk Test Distances between Empagliflozin and Placebo Groups at Baseline and 12 Weeks.

Note: 6-MWT: 6-Minute Walk Test; SE: Standard Error; CI: Confidence Interval; Δ: Change in walked distance, Δ walked distance: 12-week 6MWT distance-baseline 6MWT distance.

 Figure 1: Comparison Of Six-Minute Walk Test (6-MWT) Distance Between Empagliflozin And Placebo Groups In Patients Post-Myocardial Infarction. Panel A: Baseline 6-MWT Distances. Panel B: 12-Week 6-MWT Distances. Panel C: Change in Walking Distance from the Baseline to 12 Weeks.   

The subgroup analysis evaluating diabetic versus non-diabetic patients demonstrated improvements in the 6-minute walk test (6-MWT) for both the Empagliflozin and Placebo groups after 12 weeks. Notably, non-diabetic patients consistently outperformed their diabetic counterparts. Statistical analyses indicated no significant differences between the diabetic and non-diabetic groups across both treatment conditions; however, the difference approached statistical significance within the Empagliflozin group (p=0.081).

Changes in 6-minute walk test (Δ 6MWT) distance were analyzed by stratifying patients into groups based on their outcomes, as follows:

- Worsened: Δ walked distance < 0 meters

- Unchanged: Δ walked distance 0 to < 20 meters

- Mildly improved: Δ walked distance 20 to < 100 meters

- Moderately improved: Δ walked distance 100 to < 200 meters

- Significantly improved: Δ walked distance ≥ 200 meters

The distribution of improvements in walked distance across these categories exhibited a similar trend in both the empagliflozin and placebo groups, with no statistically significant difference identified (p=0.217) [Fig 2].

Fig 2: Distribution of Walked Distance Change Categories in Empagliflozin and Placebo Groups.

A hierarchical multiple linear regression analysis was conducted to predict the 12-week 6-minute walk test (6-MWT) distance. The model incorporated baseline 6-MWT distance, age, left ventricular ejection fraction (LVEF), sex, diastolic blood pressure, and history of percutaneous coronary intervention (PCI).

The Normal P-P Plot of standardized residuals for the 12-week 6-MWT results exhibited an approximately normal distribution, supporting the validity of the linear regression model [Fig 3].

Fig 3: Normal P-P Plot of Standardized Residuals for the 12-Week 6-Minute Walk Test.

Additionally, the scatterplot illustrated the relationship between the standardized predicted values from the regression model and the 12-week 6-MWT results, indicating a moderate correlation and suggesting that the model adequately predicts the dependent variable within the observed range [Fig 4].

Fig 4: Scatter Plot of 12-Week 6-Minute Walk Test Distance against Standardized Predicted Values from Regression Analysis.

The final model was statistically significant [F(6,100)=18.82, p=0.001], accounting for 53% of the variance in the 12-week 6-MWT distance (adjusted R²=0.50). Significant independent predictors included baseline 6-MWT distance (p < 0.001), age (p=0.012), LVEF at 12 weeks (p=0.003), sex (p=0.001), diastolic blood pressure (p=0.013), and history of PCI (p=0.030) [Table 3].

Table 3: Linear Regression Analysis Predicting 12-Week 6-MWT Distance (Meter) After Primary PCI.

R² = 0.530, Adjusted R² = 0.502, F(6,100) = 18.82, p < 0.001Note: 6-MWT = six-minute walk test; LVEF = left ventricular ejection fraction; DBP = diastolic blood pressure; PCI_history = history of percutaneous coronary intervention. Sex is coded with a male as the reference category (coefficients represent the difference between females and males). Diagnostic checks of residuals did not reveal any significant violations of assumptions.

Diagnostic assessment of the residuals indicated no significant violations of model assumptions.

Several additional variables were considered for inclusion in the model but were ultimately excluded due to their reduction in predictive power. Notably, body mass index (BMI), empagliflozin treatment, myocardial infarction territory, and coronary artery disease (CAD) risk factors were not significant predictors of the 12-week 6-MWT distance in this analysis.

The results of the ELIT-PCI trial provide valuable insights into the efficacy of empagliflozin in enhancing exercise capacity, as measured by the 6-minute walk test (6-MWT). Although the 6-minute walk test (6MWT) is primarily used to assess exercise capacity in patients with heart failure, it is also applicable to individuals with ischemic heart disease. This test is notable for its reproducibility and safety [14]. Thus, our study employed the 6MWT as a key assessment tool.

Despite the initial hypothesis that empagliflozin would lead to significant improvements in walking distance compared to placebo, our analysis revealed no statistically significant differences between the two groups at baseline, after 12 weeks, or in the change in walking distance. These findings are critical for understanding the impact of empagliflozin on functional outcomes in patients undergoing treatment for coronary artery disease.

Functional capacity in cardiac patients is influenced by a myriad of factors, including clinical variables such as left ventricular ejection fraction (LVEF), the presence of comorbidities (e.g., diabetes and hypertension), and demographic characteristics such as age and sex. Psychosocial factors, including levels of depression, anxiety, and the availability of social support, significantly affect exercise tolerance and overall physical performance. Furthermore, lifestyle factors, particularly physical activity levels, and nutritional status, are critical for maintaining and enhancing fitness 15-17]. Participation in structured cardiac rehabilitation programs has been shown to markedly improve functional capacity.

Graphical Abstract

Additionally, pharmacological interventions and the surrounding exercise environment contribute to overall exercise performance and recovery outcomes. Addressing these interconnected factors is essential for improving the quality of life and prognostic outcomes in individuals with cardiac conditions [18,19].

The demographic and clinical characteristics of the participants were comparable across both groups, with no significant differences in age, sex distribution, BMI, GFR, or blood pressure. This homogeneity enhances the reliability of the results, ensuring that observed outcomes are more likely attributable to the intervention rather than confounding factors. The baseline 6-MWT distances were also similar, indicating that any observed changes in walking performance were not influenced by pre-existing differences in physical capacity. Although the mean differences in walking distance suggested a potential trend towards improvement in both groups, the lack of statistical significance (P values > 0.05) indicates that these changes may not be clinically meaningful. This aligns with previous studies that have shown variable effects of SGLT2 inhibitors on exercise capacity, suggesting that while these medications may confer cardiovascular benefits, their direct impact on functional capacity may be limited in certain populations [20-23].

Our study demonstrated that higher baseline functional capacity serves as a predictor of improved functional capacity following myocardial infarction (MI) during the recovery phase. This finding emphasizes the significance of pre-MI exercise levels as a critical determinant of post-MI rehabilitation outcomes. Patients exhibiting greater initial functional capacity may possess an enhanced physiological reserve, allowing them to better withstand the stresses associated with acute illness and subsequent recovery [24,25].

Moreover, individuals with higher baseline functional capacity are more likely to participate in rehabilitation programs and adhere to prescribed exercise regimens, thereby further facilitating their recovery [26]. The observed positive correlation between baseline functional capacity and recovery outcomes suggests that early interventions aimed at enhancing exercise capacity before an MI could yield substantial long-term benefits [27].

Additionally, our results underscore the necessity for tailored rehabilitation strategies that account for individual baseline fitness levels, as such approaches may optimize recovery trajectories and improve the overall quality of life for cardiac patients.

In recent years, substantial research has focused on the effects of SGLT2 inhibitors in patients with heart failure, often excluding individuals with acute infarction. Nonetheless, the recent EMMY trial has demonstrated a positive effect of these medications in patients with acute infarction [28-30]. In contrast, the present study did not find a short-term benefit of empagliflozin on functional capacity compared to placebo in patients following myocardial infarction (MI).

These results suggest that the mechanisms by which empagliflozin exerts its beneficial effects in populations with heart failure and diabetes may not be applicable to the acute post-MI recovery phase. Factors such as the timing of administration, the severity of myocardial injury, and the presence of comorbidities and advanced managments including primary percutaneous coronary intervention (pPCI) may contribute to the lack of observed efficacy [4].

Moreover, it is conceivable that the therapeutic window for achieving optimal benefits from empagliflozin may be narrower in post-MI patients compared to those with chronic heart failure or diabetes. Future research is warranted to further explore these dynamics, including the potential role of empagliflozin at different stages of cardiac rehabilitation and its effects on long-term outcomes beyond the immediate recovery phase.

Although previous studies have demonstrated an association between higher body mass index (BMI) and poorer functional capacity, our study did not find this relationship within the examined cohort [31]. This discrepancy may be attributed to various factors, including the specific characteristics of our study population, such as age, comorbidities, and the timing of assessments.

Moreover, it is plausible that the influence of BMI on functional capacity is moderated by additional variables, such as levels of physical activity or muscle mass, which were not comprehensively addressed in our analysis [32]. Furthermore, the interaction between obesity and cardiovascular function may differ among individuals, suggesting that BMI alone may not serve as a sufficient predictor of functional capacity in patients recovering from myocardial infarction [33,34].

While prior studies have established that left ventricular (LV) diastolic function is a predictor of exercise capacity following myocardial infarction (MI), our study identified LV systolic function as an independent predictor of functional capacity in this population [35,36]. This finding implies that the heart's ability to contract effectively and pump blood is a critical determinant of functional outcomes, perhaps more so than previously acknowledged.

The distinction between systolic and diastolic function is crucial, as LV systolic function directly influences cardiac output and exercise tolerance. Patients with preserved systolic function may demonstrate improved exercise capacity, even in the presence of diastolic dysfunction, highlighting the complexity of cardiac recovery after MI [37-40].

Moreover, our results suggest that interventions designed to enhance LV systolic function could be especially advantageous for improving functional capacity in post-MI patients. This underscores the need for a targeted approach in cardiac rehabilitation that prioritizes the optimization of systolic function to promote better recovery outcomes.

Limitations

This study has several limitations. First, only 107 enrolled patients completed the 6-minute walk test (6-MWT), which may affect both the statistical power and the generalizability of the findings. Furthermore, the 12-week intervention period may be insufficient for detecting significant changes in exercise capacity. Additionally, unmeasured confounding variables, such as medication adherence and lifestyle modifications, could influence the results. Finally, while the 6-MWT is a valuable measure of physical capacity, it may not capture all dimensions of physical fitness.

This sub-study of the ELIT-PCI trial did not find a significant benefit of empagliflozin on exercise capacity as assessed by the 6-minute walk test (6-MWT). However, it contributes to the broader understanding of functional outcomes in patients with coronary artery disease. Future research should investigate the mechanisms behind the lack of significant improvement in walking distance, considering factors such as patient selection, intervention duration, and concurrent therapies that may influence exercise capacity. Further studies are needed to clarify the effects of empagliflozin and similar agents on functional status across diverse populations.

Acknowledgment

We are very grateful to Abidi Pharmaceutical Company for providing empagliflozin and placebo for conducting this study.

Conflict of interest

The authors declare that there is no conflict of interest.

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