Effects of SGLT2 Inhibitor on Left Ventricular Function: A Meta-analysis

Background: Although a variety of research have signicant protective action on the cardiovascular system when use of SGLT2 inhibitor, it is still unclear how can improve ventricular remodeling and fundamentally Reduce the mortality of cardiovascular. The purpose of this meta-analysis is to explore the ecacy of sodium glucose cotransporter type 2 (SGLT-2) inhibitors in improving left ventricular (LV) remodeling in patients with type 2 diabetes (T2DM). Methods: We searched articles published before September 30, 2020, regardless of language, in 4 electronic databases: PubMed, EMBASE, Cochrane Library and Web of Science. We included randomized controlled trials in this meta-analysis. The differences in the mean changes in left ventricular echocardiographic parameters between the treatment group and control group were evaluated. Results: Combined outcome indicators showed that SGLT2 inhibitors, LAVI (WMD (cid:0) -6.29 (cid:0) 95 (cid:0) CI (cid:0) -10 (cid:0) -2.58 (cid:0)(cid:0) P (cid:0) 0.001) , E/e' (cid:0) WMD (cid:0) -2.15 (cid:0) 95 (cid:0) CI (cid:0) -4.08 (cid:0) -0.21 (cid:0)(cid:0) P=0.003 (cid:0) , LVEF(WMD (cid:0) 3.67 (cid:0) 95 (cid:0) CI (cid:0) 0.59 (cid:0) 6.75 (cid:0)(cid:0) P=0.02) , LVEDV( WMD (cid:0) -1.99 (cid:0) 95 (cid:0) CI (cid:0) -26.49 (cid:0) -22.50 (cid:0)(cid:0) P=0.87), LVESV(WMD (cid:0) -8.36 (cid:0) 95 (cid:0) CI (cid:0) -17.36 (cid:0) -0.65 (cid:0)(cid:0)


Background
Currently, there are 382 million people with diabetes in the world, which will increase to 592 million in 2035, 90% of which are type 2 diabetes patients [1],Compared with non-diabetic patients, diabetic patients have twice the cardiovascular risk and are more prone to left ventricular dysfunction and heart failure [3][4], But intensive hypoglycemia does not reduce cardiovascular risk [5]. Until the advent of SGLT2 inhibitors, breaking this deadlock, Results from a large cardiovascular trial in patients with type 2 diabetes suggest that sodium-glucose co-transporter 2 (SGLT2) inhibitors may improve cardiovascular outcomes, particularly by reducing the risk of hospitalization for heart failure. [6][7][8][9] The current pharmacological treatments for heart failure include diuretics, angiotensin-converting enzyme inhibitors (ACEI)/angiotensin II receptor antagonists (ARBs), beta-blockers, sacubatril valsartan, aldosterone receptor antagonists, and digoxin.
[10] SGLT2 inhibitors are designed to lower blood glucose levels by speci cally inhibiting glucose reabsorption from the proximal renal tubules, and recent studies suggest cardiac bene ts. Several clinical studies have been conducted on the effects of SGLT2 inhibitors on ventricular structure and function. Although many hypotheses have been proposed, the mechanism by which it reduces hospitalization in patients with heart failure remains uncertain, and the impact on cardiac function is controversial. Left ventricular mass (LVM) is an independent predictor of cardiovascular events such as myocardial infarction, hospitalization for heart failure and mortality. [11][12] We performed a meta-analysis of randomized controlled trials of cardiac function to assess the effect of SGLT2 inhibitors on cardiac remodeling in patients with type 2 diabetes mellitus. Analyze the role of this drug in cardiac remodeling and provide data to support the drug mechanism.

Eligibility criteria
We included randomized controlled trials with parallel group or crossover designs in this meta-analysis, Study participants were type 2 diabetic patients, The outcome of the included studies must contain the following 6 cardiac function and structure measures: LVEF, LV end-diastolic diameter (LVEDD), LV endsystolic diameter (LVESD), LV end-diastolic volume (LVEDV), LV end-systolic volume (LVESV), LV mass index (LVMI) and mitral in ow E velocity to tissue Doppler e′ratio (E/e′).

Information sources and search strategy
We searched articles published before September 30, 2020, regardless of language, in 4 electronic databases: PubMed, EMBASE, Cochrane Library and Web of Science. The articles were selected by manual screening Two methodologically trained independent reviewers screened titles and abstracts to determine whether they met the eligibility criteria. The reviewers read the full text and extracted relevant data after consensus was reached. Any differences were resolved through discussion and arbitration, if necessary, by a third reviewer. The reasons for inclusion or exclusion are recorded in detail. Case reports, letters and minutes of meetings were excluded.

De nition of outcomes
The outcome of this meta-analysis was the difference in the mean change in echocardiographic parameters between the treatment group and control group. The echocardiographic parameters included LVEF, LVEDV, LVESV, LVMI and E/e′.

Statistical analysis
We calculated weighted mean differences (WMDs) with 95% con dence intervals (CIs) to assess effect size for continuous variables including LVEF, LVEDV, LVESV, LVMI and E/e′. In the meta-analysis, we used a random effects model to combine estimators. We also considered a xed effect model additionally for exploration of the discrepancy in results. The I² statistic, τ² statistic, and Cochran's Q test were used to assess statistical heterogeneity among the studies. All statistical analyses were performed using R version 3.1.0 (R Foundation for Statistical Computing, Vienna, Austria). P values of < 0.05 was regarded as statistically signi cant for treatment effects and test for heterogeneity, respectively.

Discussion
SGLT2 inhibitors reduce hospitalization rates in patients with heart failure, but do not affect atherosclerosis-related events, and the primary mechanism may be related to improved left ventricular function [13]. The current pharmacological mechanisms considered are: (1) renal sodium excretion, glucose excretion, diuresis, and lowering of glomerular capillary blood pressure [14]. (2) Increase oxygen supply to the heart, improve energy metabolism, reduce myocardial brosis, and reduce epicardial fat deposition. (3) Improved endothelial function, reduced vascular resistance, and reduced aortic wall strength. (4) Affects neurohormonal pathways in the heart and decreases activation of the sympathetic nervous system [15][16]. The above mechanisms affect cardiac remodeling by reducing cardiac pre-and postload and improving insulin resistance. [17] Some of the current non-randomized controlled trials have demonstrated that SGLT2 inhibitors reduce left ventricular mass index and diastolic function after 3 to 6 months of treatment in diabetic patients, including empagli ozin [18],canagli ozin [19], dapagli ozin [20], tofogli ozin [21]. However, these studies included limited populations and had short follow-up periods. It has also been suggested that in patients with type 2 diabetes, tofogli ozin does not signi cantly improve left ventricular systolic or diastolic function [22]. The present study suggests that empagli ozin can signi cantly improve cardiac remodeling in patients with type 2 diabetes, with signi cant reductions in E/E' and LAVI levels after treatment; however, there were no signi cant differences in LEVF levels, LVEDV and LVESV levels after treatment. This suggests that empagli ozin may provide short-term cardiac bene t to patients, whether it improves their long-term prognosis remains to be explored. This study has limitations (1) The literature is less than 25 weeks long and there are few studies of longterm drug prognosis. (2) The limited number of included studies and the small number of cases in some of the studies, which included patients with type 2 diabetes with different disease severity, disease duration, and whether they were co-morbid with other diseases, may lead to some heterogeneity in the results (3) As the literature with positive results is more likely to be published, there may be systematic errors. It can be seen that more large sample, high quality RCTs are needed to further con rm the conclusions reached in this study.
In summary, empagli ozin may improve cardiac remodeling. Current studies in animals and humans with diabetes suggest that SGLT2 inhibitors can potentially improve LV mass index and diastolic function. However, the biological effects of SGLT2 inhibitors on cardiac structure and function remain uncertain and need to be supported by additional studies in RCTs.

Conclusion
Our ndings support the role of SGLT2 inhibitors on preservation of cardiac function. However, the evidence is currently limited to T2MD patients. There is an urgent need to investigate the T2MD outcome of SGLT2 inhibitors therapy outside the T2MD setting, where the evidence is still scarce and of low quality.