Cardioprotective Effects of Sodium-Glucose Cotransporter 2 Inhibitors and Their Possible Association With Normalization of the Circadian Index of Heart Rhythm

Abstract

Background: Updated recommendations for the treatment of heart failure with reduced ejection fraction (HFrEF) include sodium-glucose cotransporter 2 (SGLT2) inhibitors and other long-established HFrEF therapies. These drugs' mechanisms of action have yet to be fully clarified.

Objective: This study evaluated the effects of SGLT2 inhibitors on the modulation of autonomic function at 1 month beyond conventional HF therapy.

Methods: This single-center, observational, prospective study was conducted from January 2020 to December 2022. Patients with type 2 diabetes who had ischemic HFrEF and met the study criteria were considered for SGLT2 inhibitor treatment with empagliflozin or dapagliflozin. Changes in the circadian index were used as the primary outcome to assess the early effects of SGLT2 inhibitors on autonomic function. Changes in functional effort capacity and laboratory findings were also evaluated. Participants' circadian index was measured by a 24-hour rhythm Holter monitoring recorder (BTL-08 Holter H100). A symptom-limited treadmill test assessed patients' effort capacities. Tests were repeated after 1 month of therapy.

Results: The mean (SD) age of the 151 participants was 56.95 (7.29) years; their mean (SD) left ventricular EF was 35.69% (7.10%), and 95 participants were men (62.9%). From baseline to 1 month, mean (SD) daytime heart rate (80.63 [9.17] vs 77.67 [8.04] beats per minute; P = .004) and nighttime heart rate (76.83 [11.34] vs 73.81 [10.25] beats per minute; P = .03) decreased significantly. Variation in the circadian indexes (mean [SD], 1.04 [0.02] vs 1.10 [0.04]; P < .001) was statistically significant, favoring increased modulation of autonomic function. The increases in exercise duration (mean [SD], 8.88 [3.69] minutes and median [IQR], 8.81 [5.76-12.13] minutes vs 9.72 [3.14] and 9.59 [7.24-12.22] minutes; P = .04) and exercise capacity (mean [SD], 203.38 [65.18] m and median [IQR], 119.22 [149.43-259.15] m vs 335.61 [51.39] and 325.79 [293.59-376.91] m; P < .001] were also significant.

Conclusion: The use of SGLT2 inhibitors during early treatment can favorably affect both autonomic dysfunction and functional effort capacity of patients with type 2 diabetes with ischemic HFrEF.

Keywords: Heart failure; heart rate; physical exertion; reduced ejection fraction; sodium-glucose transporter 2 inhibitors.