Effect of Dapagliflozin on Left Ventricular Diastolic Function in Diabetics - A Prospective Interventional Study

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INTRODUCTION

Sodium-glucose cotransporter-2 (SGLT2) inhibitors witness to alleviate adverse cardiovascular outcomes in patients with Type 2 diabetes mellitus (T2DM) and the risk for cardiovascular disease.^[1,2] In patients with established heart failure, the SGLT2 inhibitor dapagliflozin found to alleviate the risk of worsening heart failure or cardiovascular mortality regardless of the presence of diabetes mellitus (DM).^[3] In patients with DM, the left ventricular (LV) diastolic dysfunction is associated with subsequent heart failure and mortality. This study aims to evaluate the effect of dapagliflozin on the LV diastolic function in patients with T2DM and to study the baseline diastolic dysfunction in patients with T2DM and to study the diastolic function at rest and after exercise in patients with T2DM 24 weeks after taking dapagliflozin.

MATERIALS AND METHODS

The study was done in a tertiary care center from June 2021 to November 2021 for a total duration of six months. It is a prospective interventional pilot study. The study population consists of T2DM patients presenting to the cardiology outpatient department. Patients who are 18 years and older with T2DM and glycated hemoglobin (HbA1c) of 7.0–10% with LV diastolic dysfunction of at least Grade 1 on resting echocardiography were included in the study. Patients with Type 1 DM, with a history of diabetic ketoacidosis, with a history of recurrent urinary tract infection, with renal dysfunction, patients using loop diuretics or with acute coronary syndrome, with a history of stroke within six months or with LV ejection fraction of <50% and with BMI ≥30 kg/m², and with obstructive sleep apnea syndrome were excluded from the study. Patients satisfying the inclusion and exclusion criteria were enrolled in the study after taking a duly informed consent. Baseline diastolic function was measured in all patients enrolled in the study. Dapagliflozin 10 mg once daily was given to all patients enrolled in the study for 24 weeks and then the LV diastolic function was measured by e’, E/A ratio, and E/e’ at 24 weeks from baseline as assessed by stress echo.^[4]

All the patients who qualify the inclusion and exclusion criteria were taken up for the study. Taking into consideration from the previous hospital records, around 50–60 T2DM patients visit outpatient department every day. Thirty patients were eligible for the study and these patients were followed up after 24 weeks for reassessment of diastolic function.

RESULTS

Total study sample consists of 30 out of which 47% are between 51 and 60 years, 33% between 41 and 50 years, and 20% <40 years of age [Figure 1 and Table 1]. Total 70% of the study population are males and 30% are females [Figure 2 and Table 2]. The mean HBA1c value is 8.2 ± 0.7 [Table 3]. [Table 4] shows the comparison of grading of diastolic dysfunction between baseline and post 24 weeks treatment with dapagliflozin, using marginal homogeneity test with P < 0.001 which is highly statistically significant. Paired Student’s t-test was used to compare mean values of diastolic function parameters between baseline and post 24 weeks of treatment with dapagliflozin. The e’ at rest for baseline and post 24 weeks [Figure 3] of treatment with dapagliflozin shows P < 0.001 which is highly significant [Table 5]. The e’ after exercise for baseline and 24 weeks [Figure 4] of treatment with dapagliflozin shows P < 0.01 which is statistically significant [Table 5]. The E/e’ at rest for baseline and post 24 weeks [Figure 5] of treatment with dapagliflozin shows P = 0.02, which is significant [Table 5]. The E/e’ after exercise for baseline and post 24 weeks [Figure 6] of treatment with dapagliflozin shows P = 0.01, which is significant [Table 5]. The mean values of diastolic function parameters between age groups at baseline period using independent Student’s t-test show no statistical significance [Table 6]. The mean values of diastolic function parameters between age groups post 24 weeks of treatment with dapagliflozin using independent Student’s t-tests show no statistical significance [Table 7]. The mean values of diastolic function parameters between genders at baseline period using independent Student’s t-test show no statistical significance [Table 8]. The mean values of diastolic function parameters between genders at post Rx 24 weeks period using independent Student’s t-test show no statistical significance [Table 9].

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Figure 1:

Age-wise distribution of study patients.

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Figure 2:

Gender distribution of study patients.

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Figure 3:

Mean e’ at rest between baseline and post 24-week treatment with dapagliflozin.

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Figure 4:

Mean e’ after exercise between baseline and post 24-week treatment with dapagliflozin.

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Figure 5:

Mean E/e' at rest between baseline and post 24-week treatment with dapagliflozin.

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Figure 6:

Mean E/e’ after exercise between baseline and post 24-week treatment with dapagliflozin.

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DISCUSSION

The LV diastolic function as assessed by E/e’ for T2DM patients was significantly improved after six months of dapagliflozin intake. SGLT2 inhibitors are associated with weight loss, blood pressure, and an HbA1c level reduction, making an impact on LV function. Hence, in patients with T2DM, SGLT2 inhibitors may have a potential beneficial effect on LV diastolic function. Recently, it had been reported that SGLT2 inhibitors have a multiple effects on cardiac function including improvement in endothelial dysfunction and aortic stiffness,^[5] reduction in accumulation of epicardial fat^[4] as well as in visceral adipocyte hypertrophy.^[6] These mechanisms may lead to LV diastolic function improvement. Verma et al. observed in 10 patients, the effects of empagliflozin (10 mg/day), an SGLT2 inhibitor, post three months of its usage in patients with cardiovascular disease and T2DM, in relation to objective measurements of cardiac structure and function. This short duration treatment with empagliflozin was associated with a significant LVMI reduction and improvement of LV diastolic function.^[7] Matsutani et al. reported the effects of canagliflozin on LV diastolic function in 37 T2DM patients with preserved LVEF in a prospective single-center pilot study.^[8] The LV diastolic function post three months after the initiation of canagliflozin has shown significant improvement.^[8] Although the exact mechanism of the effects of SGLT2 inhibitors on LV diastolic function is uncertain, the increased diuresis with reduced pre-load may play a major role. In patients with HFrEF, HFmrEF, as well as HFpEF, LV diastolic function plays an important role in the development of cardiovascular events and outcomes. Large outcome trials demonstrated the efficacy of neurohumoral inhibition in HFrEF but not in the case of HFpEF, because the neurohumoral inhibition consistently failed to attain a positive primary outcome.^[9-11] This study shows the effectiveness of dapagliflozin on diastolic function in patients with T2DM.

CONCLUSION

The diastolic function of the heart has been significantly improved after 24 weeks of using dapagliflozin. The diastolic function parameters between age and sex groups at baseline and post 24 weeks of treatment with dapagliflozin do not correlate. The diastolic dysfunction is independent of age and sex.