Recent Advances in Understanding the Molecular Mechanisms of SGLT2 Inhibitors in Atrial Remodeling
Abstract
:1. Introduction
2. Methods
3. Results and Discussions
3.1. Molecular Mechanisms of SGLT2is and Atrial Remodeling
3.1.1. Inflammation
3.1.2. Oxidative Stress and Mitochondrial Dysfunction
3.1.3. Autonomic Dysfunction
3.1.4. Fibrosis
3.1.5. Myocardial Energy Metabolism
3.1.6. Sodium and Calcium Metabolism
3.1.7. Other Mechanisms
Weight Loss
Hematocrit and Erythropoietin
Blood Pressure
Angio- and Thrombogenesis
Molecules
Epigenetic Effects
4. Clinical Implications
4.1. Atrial Fibrillation
4.2. Other Cardiac Conditions
4.3. Other Non-Cardiac Conditions
4.4. Cardiovascular Aging
5. Conclusions and Future Perspectives
Author Contributions
Funding
Conflicts of Interest
References
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No. | Year | Study | Ref. No. | No. of Subjects | Subject Type | Comparison | Endpoints | Conclusions |
---|---|---|---|---|---|---|---|---|
1 | 2017 | Persson F et al. | [29] | 40.980 | Human, type 2 diabetes | Dapagliflozin vs. DPP-4 inhibitors (dose not specified) | Major adverse cardiovascular events; non-fatal MI, non-fatal stroke, cardiovascular mortality, all-cause mortality, hospitalization for HF, atrial fibrillation, and severe hypoglycemia | Lower risk of major adverse cardiovascular events, hospitalization for HF and all-cause mortality |
2 | 2017 | Natali A et al. | [23] | 75 | Human, type 2 diabetes | Empagliflozin 10 mg/day vs. Satagliptin 100 mg/day | Global longitudinal strain, left ventricle ejection fraction, left atrial volume, E/E′, VO2max, cardiac autonomic function tests, and plasma biomarkers | |
3 | 2018 | David S et al. | [30] | review | v | GLP-1 agonists vs. SGLT2i vs. DPP-4 inhibitors | Structural and electrical atrial remodeling | GLP-1 agonists and SGLT2 and DPP-4 inhibitors do not accelerate or decelerate the development of new-onset AF |
4 | 2018 | David S et al. | [31] | review | Human | Several antidiabetic drugs | Reversal of cardiac remodeling | Metformin and SGLT2is can prevent or ameliorate HF |
5 | 2019 | Lee HC et al. | [20] | 13 | Spontaneous hypertensive rats | Empagliflozin 20 mg/day vs. control | Electrocardiography, echocardiography, invasive hemodynamic study, biomarkers, and tissue analyses | Beneficial effects on systemic blood pressure, renal function, ameliorated left atrial dilatation, intra-cardiac fibrosis, contraction, and relaxation dysfunction |
6 | 2019 | Iwakura K et al. | [32] | review | Human | Several antidiabetic drugs | Left ventricle hypertrophy, left atrium dilatation, systolic and diastolic function | SGLT2is decrease the incidence of hospitalization for HF, cardiovascular death, and left ventricle mass |
7 | 2019 | Ferrini M et al. | [22] | review | Human | Several antidiabetic drugs | Major adverse cardiovascular events, HF outcome, sudden cardiac death, AF | Glucose-lowering drugs may reduce the progression and avoid the onset of HF |
8 | 2019 | Shao Q et al. | [21] | 96 | Diabetic rats | Empagliflozin 10 mg/kg/day vs. empagliflozin 30 mg/kg/day vs. control | Left atrium diameter, interstitial fibrosis AF, atrial mitochondrial respiratory function, mitochondrial membrane potential, and mitochondrial biogenesis | Empagliflozin can ameliorate atrial structural and electrical remodeling and improve mitochondrial function and mitochondrial biogenesis in type 2 DM |
9 | 2020 | Kang S et al. | [33] | 11 | Cardiac fibroblasts from human atrial tissue | Empagliflozin 10/25 mg/day vs. control | Myofibroblast activity, cell morphology, and cell-mediated extracellular matrix remodeling | Empagliflozin significantly attenuated TGF-b1e-induced fibroblast activation |
10 | 2020 | Lan NSR et al. | [34] | 44 | Human, acute coronary syndrome, and type 2 diabetes | Empagliflozin 10/25 mg/day vs. control | E/e′ ratio, left ventricle mass index, and left ventricle diastolic function | Empagliflozin is associated with a reduction in left ventricle mass and favorable changes in diastolic function |
11 | 2021 | Lee TW et al. | [35] | review | Human | Several antidiabetic drugs | New-onset AF, atrial dilatation and fibrosis, mitochondrial function, and mitochondrial biogenesis | Empagliflozin and canagliflozin—no effect on the incidence of AF in patients with DM, dapagliflozin reduced AF risk and atrial flutter events |
12 | 2021 | Ibrahim NE et al. | [36] | review | Human | SGLT2is vs. control | Concentrations of atrial natriuretic peptide, B-type natriuretic peptide, and N-terminal pro-B-type natriuretic peptide, and reduction in high-sensitivity troponin | Reduction in concentrations of atrial natriuretic peptide, B-type natriuretic peptide, and N-terminal pro-B-type natriuretic peptide and high-sensitivity Troponin C in patients receiving SLGT2is |
13 | 2021 | Tanaka H et al. | [37] | 210 | Human, non-ischemic diabetic cardiomyopathy | SGLT2is vs. control | New-onset AF | SGLT2is can significantly reduce new-onset AF |
14 | 2021 | Nishinarita R et al. | [38] | 12 | Beagle dogs, induced AF | Canagliflozin (3 mg/kg/day) vs. control | Atrial effective refractory period, conduction velocity, and AF inducibility | Canagliflozin and possibly other SGLT2is might be useful for preventing AF and suppressing the promotion of atrial remodeling |
15 | 2021 | Bode D et al. | [26] | - | Obese rats | Dual SGLT-1&2 inhibitors (sotagliflozin 30 mg/day) vs. control | LA remodeling | Dual SGLT-1&2 inhibitors ameliorated left atrial remodeling and exerted an anti-arrhythmic effect on left atrial cardiomyocytes |
16 | 2021 | Lin YW et al. | [39] | 32 | Rats, induced left heart dilatation | Dapagliflozin 10 mg/kg/day vs. control | Electrocardiography and echocardiography, hemodynamic studies, and postmortem tissue analyses | Dapagliflozin suppresses cardiac fibrosis and endoplasmic reticulum stress |
17 | 2021 | Kearney A et al. | [40] | review | Human | SGLT2is | - | Reduction in left ventricle end-systolic volume, left ventricle end-diastolic volume, and N-terminal pro-B-type natriuretic peptide, suggesting reverse left ventricle remodeling |
18 | 2021 | Lee Z et al. | [24] | review | Human | SGLT2is | - | SGLT2is are beneficial for HF regardless of diabetic status |
19 | 2021 | Damy T et al. | [7] | review | Human | SGLT2is | - | SGLT2is are beneficial for HF regardless of diabetic status |
20 | 2021 | Kondo H et al. | [41] | 364 | Human | Canagliflozin 10 µmol/L (cell culture) vs control | Superoxide sources and the expression of inflammation, fibrosis, and myocardial stretch genes | Canagliflozin has global anti-inflammatory and anti-apoptotic effects in the human myocardium |
21 | 2021 | Vrachatis DA et al. | [42] | review | Human | SGLT2is | - | Pathophysiologic mechanisms involved in AF seem to be favorably affected by SGLT2 inhibition |
22 | 2021 | Tschope C et al. | [43] | review | Human | Several antidiabetic drugs | - | SGLT2is are beneficial for HF regardless of diabetic status and LVEF |
23 | 2022 | Mantovani A et al. | [44] | review | Human | Several antidiabetic drugs | - | SGLT2is reduce major adverse cardiovascular events, all-cause mortality, and hospitalization for HF regardless of the presence or absence of type 2 DM and left ventricle ejection fraction |
24 | 2022 | Von Lewinski D et al. | [2] | 402 | Human, HF, with reduced or midrange ejection fraction | Ertugliflozin 5 mg/day vs. control | Total burden of ventricular arrhythmias | Trial design |
25 | 2023 | Manolis AA et al. | [3] | review | Human | SGLT2is | - | SGLT2is can reverse atrial and ventricular remodeling and ameliorate mitochondrial dysfunction |
26 | 2022 | Savage P et al. | [45] | review | Human | SGLT2is | - | SGLT2is are associated with a greater incidence of clinical benefits (as defined by rates of death, HF events, time to first HF event) |
27 | 2022 | Theofilis P et al. | [46] | review | Human | SGLT2is | - | SGLT2ihave beneficial effects on cardiac remodeling and attenuate HF progression |
28 | 2022 | Thirumathyam R et al. | [47] | 20 | Human, type 2 diabetes, body mass index ≥ 28 kg/m2, glycated hemoglobin ≤ 9%, fasting C-peptide > 500 pmol/L | Empagliflozin 25 mg/day vs. insulin | Change in myocardial diastolic function | Study protocol |
29 | 2022 | Dong M et al. | [48] | review | Human | SGLT2is vs. GLP-1 agonists | - | GLP-1RAs and SGLT2is cross the blood–brain barrier and can be applied in the treatment of central nervous system diseases |
30 | 20222 | Subramanian M et al. | [49] | 48 | Human, nonobstructive hypertrophic cardiomyopathy | Empagliflozin 10/25 mg/day or dapagliflozin 5/10 mg/day vs. control | Improvement of at least 1.5 in the E/e ratio and a reduction of >1 NYHA functional class | SGLT2is have favorable effects on diastolic function and functional capacity |
31 | 2022 | Patoulias D et al. | [25] | review | Human | SGLT2is | Role of SGLT2i in acute HF | Insufficient data to substantiate the use of SGLT2is in acute HF |
32 | 2023 | Koizumi T et al. | [50] | 48 | Diabetic rats | Empagliflozin 30 mg/kg/day vs. control | Examine whether empagliflozin suppresses mitochondrial-ROS generation and mitigates fibrosis. | Empagliflozin reduced mitochondrial oxidative stress and prevented atrial remodeling in a murine model of type 2 DM |
33 | 2023 | Berezin AA et al. | [27] | 417 | Human, HF with preserved, midrange, and reduced ejection fraction | Dapagliflozin 10 mg/day vs. control | Modulation of adropin levels | The levels of adropin seem to be a predictor for the favorable modification of hemodynamic performances during SGLT2 inhibition |
34 | 2023 | Chen Y et al. | [28] | review | Human | SGLT2i | Molecular mechanisms of SGLT2i on ventricular remodeling | SGLT2 receptor is almost not expressed in the heart, so its target is difficult to determine at present |
35 | 2023 | Lorenzo-Almorós A et al. | [4] | review | Human | Several antidiabetic drugs | - | Structural, electrical, and autonomic remodeling may lead to AF |
36 | 2023 | Nassif ME et al. | [51] | 587 | Human, HF with preserved or reduced ejection fraction | Dapagliflozin 10 mg vs. control | Change in the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score at 12 weeks | Dapagliflozin improved Kansas City Cardiomyopathy Questionnaire Clinical Summary Score at 12 weeks by 5.0 points |
37 | 2023 | Scatularo CE et al. | [52] | 54 | Human, endomyocardial fibrosis | - | Demographic, clinical, biochemical, and imaging variables | 7.4% of patients with endomyocardiofibrosis were treated with SGLT2is |
38 | 2024 | Avula V et al. | [53] | 1280 | Human, cancer therapy-related cardiac dysfunction | SGLT2is vs. control | Acute HF exacerbation, All-cause mortality | Patients on SGLT2is had a lower risk of acute HF exacerbation |
39 | 2023 | Escobar C et al. | [54] | review | Human | Dapagliflozin 10 mg/day | - | Dapagliflozin has effects on reversing cardiac remodeling, reducing cardiac fibrosis and inflammation, and improving endothelial dysfunction |
40 | 2024 | El-Saied SB et al. | [55] | 70 | Human, HF with mildly reduced ejection fraction, and DM | Empagliflozin 10 mg/day or dapagliflozin 10 mg/day vs. control | Demographic, clinical, biochemical, and imaging variables | SGLT2is cause significant improvement of left atrium volume and functions, with further improvement of left ventricle diastolic and longitudinal functions |
41 | 2024 | Carberry J et al. | [56] | 100 | Human, left ventricular systolic dysfunction after myocardial infarction | Empagliflozin 10 mg/day vs. control | Change in left ventricle end-systolic volume indexed to body surface area over 24 weeks from randomization | Study design |
42 | 2024 | Fakih W et al. | [57] | 20 | Human and porcine model | SGLT2i | Examined whether activated factor X induces pro-remodeling and profibrotic responses in atrial endothelial cells | Sotagliflozin and empagliflozin prevented the FXa-induced eNOS-NO/ROS imbalance and the induction of endothelial senescence |
43 | 2024 | Žlahtič T et al. | [58] | case report | Human | - | - | SGLT2is are a cornerstone in the management of HF patients |
44 | 2024 | Kodur N et al. | [59] | review | Human | - | - | SGLT2is have shown promise in reducing HF-related morbidity and mortality |
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Minciună, I.-A.; Tomoaia, R.; Mihăilă, D.; Cismaru, G.; Puiu, M.; Roșu, R.; Simu, G.; Frîngu, F.; Irimie, D.A.; Caloian, B.; et al. Recent Advances in Understanding the Molecular Mechanisms of SGLT2 Inhibitors in Atrial Remodeling. Curr. Issues Mol. Biol. 2024, 46, 9607-9623. https://doi.org/10.3390/cimb46090571
Minciună I-A, Tomoaia R, Mihăilă D, Cismaru G, Puiu M, Roșu R, Simu G, Frîngu F, Irimie DA, Caloian B, et al. Recent Advances in Understanding the Molecular Mechanisms of SGLT2 Inhibitors in Atrial Remodeling. Current Issues in Molecular Biology. 2024; 46(9):9607-9623. https://doi.org/10.3390/cimb46090571
Chicago/Turabian StyleMinciună, Ioan-Alexandru, Raluca Tomoaia, Dragos Mihăilă, Gabriel Cismaru, Mihai Puiu, Radu Roșu, Gelu Simu, Florina Frîngu, Diana Andrada Irimie, Bogdan Caloian, and et al. 2024. "Recent Advances in Understanding the Molecular Mechanisms of SGLT2 Inhibitors in Atrial Remodeling" Current Issues in Molecular Biology 46, no. 9: 9607-9623. https://doi.org/10.3390/cimb46090571