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

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.


INTRODUCTION
Adverse cardiac remodeling is a general characteristic of heart structural abnormalities and impaired diastolic and systolic functions, which reflect a natural evolution of a large number of cardiovascular (CV) diseases, such as acute coronary syndrome or acute myocardial infarction, valvular heart disease, cardiomyopathies, and myocarditis [1] . The pathogenesis of adverse cardiac remodeling (ACR) is complex, and it is strongly related to heart failure (HF) development and progression [2,3] . Indeed, changes in the structure of the left ventricle (LV) at the different stages of HF development involve multiple interactions between myocardial cellular components and extracellular matrix, which are under tight auto-paracrine regulation [4] . Ischemia/reperfusion, atherosclerosis, and microvascular obstruction, along with conventional CV risk factors (e.g., hypertension, dyslipidemia, and smoking), as well as metabolic co-morbidities, such as type 2 diabetes mellitus (T2DM), insulin resistance, and overweight and obesity, are considered to be powerful triggers for adverse cardiac remodeling through activation of numerous cellular signaling pathways (e.g., calcineurin and calcium-/calmodulin-dependent protein kinases, nitric oxide-cyclic GMPcascade, protein kinase G type Iα activity, and phosphatidylinositol 3-kinase/Akt/mTOR signaling) directly and indirectly influencing viability of myocardium and modification of its architecture [5,6] . Finally, mitochondrial dysfunction, oxidative stress, autophagy, and apoptosis lead to progressive cardiac myocyte loss, cardiac hypertrophy and extensive interstitial fibrosis [7,8] . Cumulatively, these changes intervene in transitioning from adaptive cardiac remodeling into maladaptive ACR, reflecting an occurrence of diastolic and systolic myocardial dysfunction [9] . The presence of enlarged cardiac cavities, LV hypertrophy, global strain rate alteration, and reduced LV ejection fraction (LVEF) are consistently associated with the advance of HF and poor clinical outcomes [10] .
During the last decades, ACR has been regarded to be a target for point-of-care in patients with HF. However, the implementation of a four-pillar scheme [i.e., sodium-glucose cotransporter 2 (SGLT2) inhibitor, angiotensin receptor-neprilysin inhibitor along with beta-blockers, and mineralocorticoid receptor antagonist] in the management of HF led to undoubted benefits in a reversion of ACR [11] . Even though SGLT2 inhibitors have exerted a sufficient potency to improve the untoward course of T2DM decreasing all-cause and CV mortality, admission due to HF development, the underlying molecular mechanisms of reversibility of ACR, remains poorly understood. Moreover, recent studies have demonstrated that SGLT2 inhibitors exerted their additional CV effects in close dependence on concomitant medication. Indeed, Patoulias et al. (2021) [12] pooled the findings from the three most important randomized placebo-controlled clinical trials (RCTs) including DAPA-HF, EMPEROR-Reduced, and VERTIS CV, with a total of 16,720 T2DM patients. They revealed that SGLT2 inhibitors demonstrated their additional CV benefits in close relation to concomitant medications (composite of total HF admission + CV death). For instance, among HF with reduced ejection fraction (HFrEF), patients receiving mineralocorticoid antagonists or angiotensin receptor-neprilysin inhibitors, treatment with SGLT-2 inhibitors resulted in a remarkable decrease in the primary outcome, while among those not receiving loop diuretics, SGLT-2 inhibitors were not superior to placebo. Despite the fact that different phenotypes of HF [i.e., HFrEF (EF < 40%), HF with mildly reduced (HFmrEF, EF = 40%-49%), and preserved (HFpEF, EF ≥ 50%) ejection fraction] are sufficiently distinguished in etiology, age/gender predominance, and signature of co-morbidities and coexisting conditions, SGLT2 inhibitors exerted their positive impact in the improvement of CV mortality and reduction of HF readmission regardless on HF. As a result, the United States Food and Drug Association and the European Medical Agency have recently approved SGLT2 inhibitors (mainly empagliflozin) for use in HF regardless of their phenotypes [13,14] , but it remained unclear whether SGLT2 inhibitors benefit outcomes in HF patients in connection with a reversion of ACR [15] . The aim of the review is to elucidate the role of SGLT2 inhibitors in the potential reversibility of ACR through attenuation of the untoward clinical course of disease in T2DM patients.

Plausible mechanisms of actions
SGLT-2 inhibitors were originally designed as anti-diabetic agents with a unique molecular mechanism that affects the regulation of SGLT-2-related glucose reabsorption in proximal tubule of nephron resulting in glycosuria, decreasing fasting plasma glucose, reducing glycated hemoglobin (HbA1c), and resulting in weight loss. However, a wide range of the effects of SGLT2 inhibitors with serious clinical significance has been found [16] . Nevertheless, mild-to-moderate hypoglycemic effect of these agents was not closely corresponded to their dramatic favorable pleiotropic effects on CV and renal outcomes, which requires an additional explanation of their mechanism of actions. The simplest assumption is considered to be realistic; a decrease in sustained systemic blood pressure results in natriuresis and declining activity of the sympathetic nervous system, which can translate into improvement of CV prognosis and slowing kidney disease progression. Body weight reduction may also be a potential mechanism for the alleviation of CV risk [17] . Apart from this, it has been hypothesized that SGLT2 inhibitors can be involved in the regulation of Na+/H+ exchange in heart and kidney, leading to both cardiac and renal protection. Through their stimulating effect on diuresis and natriuresis, these agents can decrease the interstitial osmotic gradient, preload, and after-load, and thereby potentially improve vascular structure and function [18] . Acting as stimulators of erythropoiesis due to "mimicking" effect of systemic hypoxia in the kidney, SGLT2 inhibitors seem to be powerful triggers for non-specific tissue protection [19,20] . In addition, they may modulate the production of a wide spectrum of adipokines (e.g., leptin, visfatin, and adiponectin), myokines (e.g., apelin and irisin) and pro-inflammatory cytokines (e.g., interleukin-2, interleukin-6, interferon-gamma, and tumor necrosis factor-alpha) through the impact of the sirtuin pathway [21] . This signaling pathway is also responsible for the turnover of myocardial metabolism from aerobic glycolysis to oxidation of other substrates, such as ketone acids, free fatty acids, and branched-chain amino acids, which appear to be a powerful modulator for mitochondrial function, playing a pivotal role in preconditioning and oxidative stress [22] . Finally, the sirtuin-1 pathway seems to be a central player in SGLT2-related regulation of reducing cardiac cells necrosis as well as cardiac and kidney fibrosis [22] . Figure 1 illustrates potent molecular mechanisms underlying tissue protective ability of SGLT2 inhibitors.
Although there is much scientific evidence and assumptions about the effect of SGLT2 inhibitors on cardiac and kidney protection, the exact underlying molecular mechanisms of actions of these agents remain uncertain.

Cardiovascular and renal protective benefits of SGLT2 inhibitors in T2DM patients
Renal and myocardial benefits of SGLT2 inhibitors have been clearly documented in numerous observational and clinical studies [23] . The basic characteristics of the SGLT2 inhibitors from RCTs are reported in Table 1. A systematic review of 10 RCTs based on the data received from patients with T2DM and chronic kidney disease (CKD) with an estimated glomerular filtration rate (eGFR) > 30 mL/min/1.73 m 2 has undeniably revealed that several SGLT2 inhibitors (empagliflozin, dapagliflozin, canagliflozin, and ertugliflozin) were by far more effective than placebo in decreasing serum levels of fasting glucose and HbA1c [24] . Therefore, a reduced incidence of progressive declining eGFR slope on follow-up was noticed shortly after initiating SGLT2 inhibitors. In addition, SGLT2 inhibitors significantly reduced albuminuria and its turnover to proteinuria. Finally, another systematic review and meta-analysis of four RCTs (EMPA-REG OUTCOME, CANVAS Program, CREDENCE, and DECLARE-TIMI 58) depicted CV or renal outcome of SGLT2 inhibitors (empagliflozin, canagliflozin, and dapagliflozin); and based on the pooled data of a total of 38,723 participants, the study has shown the superiority of these agents versus placebo in a composite renal outcome (i.e., renal replacement therapy by dialysis, kidney transplantation, CKD-related death, end-stage CKD, and acute kidney injury) [25] . The meta-analysis of 27 RCTs, in which 7363 participants with T2DM and CKD were recruited, has convincingly demonstrated that SGLT2 inhibitors attenuated CV mortality risk mainly related to a decrease in non-fatal acute myocardial infarction, non-fatal stroke, or incident HF, whereas allcause mortality rate was not remarkably reduced [26] .  [27] polled the data of 61,076 patients with T2DM, who were selected in 42 clinical studies and treated with SGLT2 inhibitors or placebo. The authors have reported that the treatment with SGLT2 inhibitors was strongly associated with a significant reduction in the incidence of major adverse CV events (MACEs), acute myocardial infarctions, and CV and all-cause mortality. However, the risk of ischemic stroke was not reduced.
The meta-analysis of DAPA-HF (dapagliflozin) and EMPEROR-Reduced (empagliflozin) trials, which have been recently completed, has yielded strong evidence for the superiority of SGLT2 inhibitors versus placebo in reduction of all-cause mortality, death due to CV events, the combined risk of CV death and first HF hospitalization, the composite end point of recurrent HF admissions or CV death, and the risk of untoward renal outcomes in HFrEF patients with stable hemodynamics [28] . Yet, dapagliflozin and empagliflozin alone exhibited their favorable profile in significantly reducing the risk of HF decompensation, MACEs or death due to CV events when compared to placebo in HFrEF patients regardless of the presence of T2DM [29,30] . Principally to note, DAPA-HF and EMPEROR-Reduced have been mainly included hemodynamically stable patients with HFrEF (LVEF < 40%). Unlike the trials mentioned above, the SOLOIST-WHF trial selected patients shortly after urgent hospitalization for worsening HF who received a minimum of one dose of innovative SGLT1/2 inhibitor sotagliflozin or placebo prior to the discharge (48.8%) or within two days after discharge (51.2%). The primary combined end point in the study was referred to as CV deaths, HF hospitalizations, and urgent visits for HF manifestation [31] . The authors found that the total number of prespecified clinical outcomes occurred sufficiently lower in the sotagliflosin group than in the placebo group [31] . In addition to that, empagliflozin in the EMPEROR-Preserved trial appeared to be the first agent from the SGLT2 inhibitors that unequivocally reduced the risk of CV morbidity or admission due to HF in HFpEF patients with and without T2DM [32] . Thus, SGLT2 inhibitors (predominantly empagliflozin and dapagliflozin) have demonstrated their ability to improve survival and prevent HF hospitalization mainly in HFrEF, whereas their potency to reduce mortality did not clearly relate to attenuation of ACR. In addition, SGLT2 inhibitors (empagliflozin, dapagliflozin, canagliflozin, ertugliflozin, and luseogliflozin) improved renal outcomes and declined the risk of HF occurrence in T2DM patients.

Meta-analyses of clinical studies devoted to SGLT2 inhibitors' effect on adverse cardiac remodeling
The meta-analyses, which have been previously reported, have demonstrated controversial data regarding cardiac protection and the possibility to reverse adverse cardiac remodeling. Indeed, Yu et al. (2021) [33] did not find strong evidence that SGLT2 inhibitors influence ACR parameters, such as LV mass index, LV enddiastolic and end-systolic volume indexes, or left atrial volume index; however, the beneficial changes in the E/e' ratio, biological markers (e.g., NT-pro brain natriuretic peptide) and quality of life have been concisely determined. In addition, SGLT2 inhibitors appeared to be significantly effective in LV ejection fraction increase solely among patients with HFrEF. The authors concluded that the use of SGLT2 inhibitors in T2DM patients regardless of HF was closely associated with substantial improvement of diastolic function, but not with structural parameters of adverse cardiac remodeling. In another meta-analysis that has been recently published by Dhingra et al. (2021) [34] , five randomized clinical trials (n = 408) have been included with the aim of comparing the effects of SGLT2 inhibitors and placebo (the period of treatment > 3 months) on structural cardiac parameters reflecting ACR, which was determined by cardiac magnetic resonance imaging. Authors found that management of HF with SGLT2 inhibitors was associated with a more remarkable regression of LV mass but not LV mass index, than in the placebo group, while there was no significant difference in these parameters depending on HF phenotype.
The meta-analysis of 13 RCTs by Zhang et al. (2021) [35] has evaluated the impact of four SGLT2 inhibitors (i.e., empagliflozin, canagliflozin, dapagliflozin, and luseogliflozin) on cardiac performances that concisely characterize ACR in T2DM patients with or without known HF. Although ACR was not in the focus of assessment in most of the studies, four of them (i.e., SUGAR-DM-HF, EMPA-TROPISM, REFORM, and DAPACARD) had pre-specified magnetic resonance imaging for the main study or echocardiographic for the sub-study [36][37][38][39] . In fact, other studies that were included in the meta-analysis focused on both clinical courses of the disease and imaging features of ACR. To up-to-date knowledge, the methodological approaches of the meta-analysis did not exert an impact on its final interpretation. The overall population was composed of 1251. T2DM patients managed with SGLT2 inhibitors. The authors reported that conventional characteristics of ACR, including LVEF, LV mass, LV mass index, dimensions and volumes of left cavities, and E-wave deceleration time, were beneficially improved during the therapy. In addition to that, the assessment of cardiac images in subgroups yielded proof of the protective effects of SGLT2 inhibitors on ACR in HF patients independently from their glycemic status. In addition, the most profound reversion of ACR was confirmed in HFrEF patients mainly treated with empagliflozin than those with other SGLT2 inhibitors. The authors, thus, reported that the reversibility of ACR in HFrEF patients is considered to be a remarkable attribute of the innate capabilities of empagliflozin, which is considered to be more beneficial than other SGLT2 inhibitors regardless of glycemic status. Admittedly, these findings are regarded to be remarkably impressive for HF management because they open new dawn for HF patients. The current European Cardiology Society clinical guideline has also included new indications for SGLT2 inhibitors, which are now emphasized as: (1) reduction of the risk of HF hospitalization and death for T2DM patients at higher risk of HF; and (2) improving a clinical status along with reducing the risk of HF hospitalization and CV mortality in HFrEF patients regardless of their glycemic status [38][39][40] . However, only two SGLT2 inhibitors (dapagliflozin or empagliflozin) are seemed to be recommended for HFrEF patients, while significantly more molecules of these agents have been incorporated into the recommendations for the medical care of T2DM patients. In fact, the greatest weakness of the finding is that there is a lack of direct comparisons between different agents to prevent misunderstanding in possible class-specific effects received in RTCs. The meta-analysis provided a remarkable confirmation of the unequal efficacy of SGLT2 inhibitors on a reversion of ACR in HFrEF patients, which is related to the finding that empagliflozin appeared to be superior to other drugs from the group.
Last but not least, SGLT2 inhibitors are considered to be a quite intriguing clinical approach to speculate whether there are able to restore global cardiac function and attenuate ACR in connection with declining unfavorable outcomes in de novo acute and chronic HF in post-ST elevation myocardial infarction individuals or patients with acute myocarditis [41] .

CONCLUSION
Favorable pleiotropic effects of SGLT2 inhibitors on clinical outcomes and cardiac and kidney function have been more profoundly established in T2DM patients regardless of HF phenotype presentation and in individuals with prevalent HF, mostly with HFrEF independently from T2DM. The results of recent metaanalyses have shown that at least four SGLT2 inhibitors (empagliflozin, dapagliflozin, canagliflozin, and luseogliflozin) demonstrated their superiority over placebo on a reversion of ACR in T2DM patients with and without HF. Along with it, it remains uncertain whether these agents yield a class-related effect on cardiac structure and function, quality of life, well-being, and clinical course. Future large clinical trials need to be provided with the aim of elucidating the plausible impact of different SGLT2 inhibitors on adverse cardiac remodeling in numerous patient populations using direct face-to-face comparison.