Reversibility of adverse cardiac remodeling in type 2 diabetes mellitus patients: focus on sodium-glucose cotransporter-2 inhibitors

Abstract

Sodium-glucose cotransporter-2 (SGLT2) inhibitors have been recently approved by world-reputed medical associations as a milestone of class A management of heart failure (HF) with reduced ejection fraction (HFrEF) after pooling strong evidence (mainly for dapagliflozin or empagliflozin) regarding their beneficial impact on total occurrences of cardiovascular deaths and hospitalizations for HF in patients with and without type 2 diabetes mellitus (T2DM). Having a wide range of profile of favorable pleiotropic effects on heart, vessels, and kidney, SGLT2 inhibitors probably have a class-specific tissue protective ability, while its exact molecular mechanism has not been clearly understood yet. However, whether these agents retain their potency to reverse adverse cardiac remodeling remains unclear. The review elucidates the role of SGLT2 inhibitors in the potential reversibility of cardiac remodeling in connection with the improvement of clinical outcomes among T2DM patients having HF. Herein, we discussed the effects of SGLT2 inhibitors on cardiac structure and hemodynamics in T2DM patients. We revealed that empagliflozin had sufficient benefits in alleviating the adverse cardiac remodeling in HFrEF individuals than other SGLT2 inhibitors. These findings can open a new vision for the optimization of HF therapy in the near future.

Keywords

Heart failure (HF) / sodium-glucose cotransporter-2 inhibitors (SGLT2) / adverse cardiac remodeling / type 2 diabetes mellitus (T2DM)

References

[1] Legallois D,Alexandre J.Definition of left ventricular remodelling following ST-elevation myocardial infarction: a systematic review of cardiac magnetic resonance studies in the past decade.Heart Fail Rev2022;27:37-48

[2] Yang D,Liu FY.The Roles of noncardiomyocytes in cardiac remodeling.Int J Biol Sci2020;16:2414-29 PMCID:PMC7378633

[3] Berezin AE.Adverse cardiac remodelling after acute myocardial infarction: old and new biomarkers.Dis Markers2020;2020:1215802 PMCID:PMC7306098

[4] Bhatt AS,Velazquez EJ.Adverse remodeling and reverse remodeling after myocardial infarction.Curr Cardiol Rep2017;19:71

[5] Tham YK,Ooi JY,McMullen JR.Pathophysiology of cardiac hypertrophy and heart failure: signaling pathways and novel therapeutic targets.Arch Toxicol2015;89:1401-38

[6] Bertero E.Metabolic remodelling in heart failure.Nat Rev Cardiol2018;15:457-70

[7] Schirone L,Palmerio S.A review of the molecular mechanisms underlying the development and progression of cardiac remodeling.Oxid Med Cell Longev2017;2017:3920195 PMCID:PMC5511646

[8] Wu QQ,Yuan Y.Mechanisms contributing to cardiac remodelling.Clin Sci (Lond)2017;131:2319-45

[9] Cohn JN,Sharpe N.Cardiac remodeling-concepts and clinical implications: a consensus paper from an international forum on cardiac remodeling.Journal of the American College of Cardiology2000;35:569-82

[10] Reindl M,Tiller C.Prognosis-based definition of left ventricular remodeling after ST-elevation myocardial infarction.Eur Radiol2019;29:2330-9 PMCID:PMC6443916

[11] Maddox TM,Allen LA.Writing Committee2021 update to the 2017 ACC expert consensus decision pathway for optimization of heart failure treatment: answers to 10 pivotal issues about heart failure with reduced ejection fraction: a report of the American college of cardiology solution set oversight committee.J Am Coll Cardiol2021;77:772-810

[12] Patoulias D,Katsimardou A,Doumas M.Meta-analysis Assessing the effect of sodium-glucose co-transporter-2 inhibitors on left ventricular mass in patients with type 2 diabetes mellitus.Am J Cardiol2020;134:149-52

[13] Food and Drug Administration. FDA approves treatment for wider range of patients with heart failure. Available from: https://www.fda.gov/news-events/press-announcements/fda-approves-treatment-wider-range-patients-heart-failure [Last accessed on 19 Apr 2022]

[14] European Commission. Union register of medicinal products for human use. Available from: https://ec.europa.eu/health/documents/community-register/html/h930.htm [Last accessed on 19 Apr 2022]

[15] Berezin AE.Shift of conventional paradigm of heart failure treatment: from angiotensin receptor neprilysin inhibitor to sodium-glucose co-transporter 2 inhibitors?.Future Cardiol2021;17:497-506

[16] Cowie MR.SGLT2 inhibitors: mechanisms of cardiovascular benefit beyond glycaemic control.Nat Rev Cardiol2020;17:761-72

[17] Briasoulis A,Bakris GL.SGLT2 inhibitors and mechanisms of hypertension.Curr Cardiol Rep2018;20:1

[18] Hallow KM,Greasley PJ,Boulton DW.Why do SGLT2 inhibitors reduce heart failure hospitalization?.Diabetes Obes Metab2018;20:479-87

[19] Verma S.SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review.Diabetologia2018;61:2108-17

[20] Nespoux J.Renal effects of SGLT2 inhibitors: an update.Curr Opin Nephrol Hypertens2020;29:190-8 PMCID:PMC7224333

[21] Liu B,Zhang Y.Mechanisms of protective effects of SGLT2 inhibitors in cardiovascular disease and renal dysfunction.Curr Top Med Chem2019;19:1818-49

[22] Kolijn D,Tian Y.Empagliflozin improves endothelial and cardiomyocyte function in human heart failure with preserved ejection fraction via reduced pro-inflammatory-oxidative pathways and protein kinase Gα oxidation.Cardiovasc Res2021;117:495-507

[23] Tentolouris A,Tzeravini E,Tentolouris N.SGLT2 inhibitors: a review of their antidiabetic and cardioprotective effects.Int J Environ Res Public Health2019;16:2965 PMCID:PMC6720282

[24] Kelly MS,Huntsberry AM,Portillo I.Efficacy and renal outcomes of SGLT2 inhibitors in patients with type 2 diabetes and chronic kidney disease.Postgrad Med2019;131:31-42

[25] Neuen BL,Heerspink HJL.SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and meta-analysis.2019;7:845-54

[26] Toyama T,Jun M.Effect of SGLT2 inhibitors on cardiovascular, renal and safety outcomes in patients with type 2 diabetes mellitus and chronic kidney disease: A systematic review and meta-analysis.Diabetes Obes Metab2019;21:1237-50

[27] Zou CY,Sang YQ,Liang J.Effects of SGLT2 inhibitors on cardiovascular outcomes and mortality in type 2 diabetes: a meta-analysis.Medicine (Baltimore)2019;98:e18245 PMCID:PMC6919451

[28] Zannad F,Pocock SJ.SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials.Lancet2020;396:819-29

[29] Petrie MC,Docherty KF.Effect of Dapagliflozin on Worsening Heart Failure and Cardiovascular Death in Patients With Heart Failure With and Without Diabetes.JAMA2020;323:1353-68 PMCID:PMC7157181

[30] Packer M,Filippatos GS.EMPEROR-Reduced Trial Committees and InvestigatorsEvaluation of the effect of sodium-glucose co-transporter 2 inhibition with empagliflozin on morbidity and mortality of patients with chronic heart failure and a reduced ejection fraction: rationale for and design of the EMPEROR-Reduced trial.Eur J Heart Fail2019;21:1270-8

[31] Szarek M,Steg PG.SOLOIST-WHF committees and investigatorseffect of sotagliflozin on total hospitalizations in patients with type 2 diabetes and worsening heart failure: a randomized trial.Ann Intern Med2021;174:1065-72

[32] Anker SD,Filippatos G.EMPEROR-preserved trial investigatorsempagliflozin in heart failure with a preserved ejection fraction.N Engl J Med2021;385:1451-61

[33] Yu YW,Wang YH.Effect of sodium-glucose cotransporter 2 inhibitors on cardiac structure and function in type 2 diabetes mellitus patients with or without chronic heart failure: a meta-analysis.Cardiovasc Diabetol2021;20:25 PMCID:PMC7836497

[34] Dhingra NK,Puar P.SGLT2 inhibitors and cardiac remodelling: a systematic review and meta-analysis of randomized cardiac magnetic resonance imaging trials.ESC Heart Fail2021;8:4693-700 PMCID:PMC8712921

[35] Zhang N,Tse G.Effect of sodium-glucose cotransporter-2 inhibitors on cardiac remodelling: a systematic review and meta-analysis.Eur J Prev Cardiol2022;28:1961-73

[36] Santos-Gallego CG,Requena-Ibanez JA.EMPA-TROPISM (ATRU-4) InvestigatorsRandomized trial of empagliflozin in nondiabetic patients with heart failure and reduced ejection fraction.J Am Coll Cardiol2021;77:243-55

[37] Lee MMY,Wetherall K.Effect of empagliflozin on left ventricular volumes in patients with type 2 diabetes, or prediabetes, and heart failure with reduced ejection fraction (SUGAR-DM-HF).Circulation2021;143:516-25 PMCID:PMC7864599

[38] Oldgren J,Åkerblom A.Effects of 6 weeks of treatment with dapagliflozin, a sodium-glucose co-transporter-2 inhibitor, on myocardial function and metabolism in patients with type 2 diabetes: A randomized, placebo-controlled, exploratory study.Diabetes Obes Metab2021;23:1505-17

[39] Singh JSS,Vickneson K.Dapagliflozin versus placebo on left ventricular remodeling in patients with diabetes and heart failure: the REFORM trial.Diabetes Care2020;43:1356-9 PMCID:PMC7245350

[40] McDonagh TA,Adamo M. ESC Scientific Document Group 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2021;42:3599-726.[PMID:35373785 DOI:10.1714/3777.37630] Caution!

[41] Kim GH,Burkhoff D.Reverse remodelling and myocardial recovery in heart failure.Eur Heart J2021;42:3599-726