Empagliflozin improved systolic blood pressure, endothelial dysfunction and heart remodeling in the metabolic syndrome ZSF1 rat

Abstract

Background: Empagliflozin (empa), a selective sodium-glucose cotransporter (SGLT)2 inhibitor, reduced cardiovascular mortality and hospitalization for heart failure in patients with type 2 diabetes at high cardiovascular risk independent of glycemic control. The cardiovascular protective effect of empa was evaluated in an experimental model of metabolic syndrome, the obese ZSF1 rat, and its' lean control. Methods: Lean and obese ZSF1 rats were either non-treated or treated with empa (30 mg/kg/day) for 6 weeks. Vascular reactivity was assessed using mesenteric artery rings, systolic blood pressure by tail-cuff sphygmomanometry, heart function and structural changes by echocardiography, and protein expression levels by Western blot analysis. Results: Empa treatment reduced blood glucose levels from 275 to 196 mg/dl in obese ZSF1 rats whereas normoglycemia (134 mg/dl) was present in control lean ZSF1 rats and was unaffected by empa. Obese ZSF1 rats showed increased systolic blood pressure, and blunted endothelium-dependent relaxations associated with the appearance of endothelium-dependent contractile responses (EDCFs) compared to control lean rats. These effects were prevented by the empa treatment. Obese ZSF1 rats showed increased weight of the heart and of the left ventricle volume without the presence of diastolic or systolic dysfunction, which were improved by the empa treatment. An increased expression level of senescence markers (p53, p21, p16), tissue factor, VCAM-1, SGLT1 and SGLT2 and a down-regulation of eNOS were observed in the aortic inner curvature compared to the outer one in the control lean rats, which were prevented by the empa treatment. In the obese ZSF1 rats, no such effects were observed. The empa treatment reduced the increased body weight and weight of lungs, spleen, liver and perirenal fat, hyperglycemia and the increased levels of total cholesterol and triglycerides in obese ZSF1 rats, and increased blood ketone levels and urinary glucose excretion in control lean and obese ZSF1 rats. Conclusion: Empa reduced glucose levels by 28% and improved both endothelial function and cardiac remodeling in the obese ZSF1 rat. Empa also reduced the increased expression level of senescence, and atherothrombotic markers at arterial sites at risk in the control lean, but not obese, ZSF1 rat.

The Novel Phosphate and Bile Acid Sequestrant Polymer SAR442357 Delays Disease Progression in a Rat Model of Diabetic Nephropathy

“…These effects can result in overall improvements in kidney disease and pathology, which is evident from lower hypertrophy and the histopathological analysis. Furthermore, it should be noted that polypharmacological characteristics of SAR442357 are similar to those of SGLT2 inhibitor empagliflozin reported in ZSF1 rats (Park et al, 2020). The latter has been approved as a treatment option for CKD/DKD patients.…”

Metabolic Syndrome in patients with type 2 diabetes and atherosclerotic cardiovascular disease: A post hoc analyses of the EMPA-REG OUTCOME trial

“…The consistent treatment effect of empagli ozin on mortality and cardiorenal and HF outcomes regardless of the MetS status expands previous ndings demonstrating consistent CV bene t across various subgroups. For example, it has been shown that empagli ozin reduced the risk of cardiorenal and mortality outcomes across subgroups based on the TIMI secondary prevention risk score as well as in those with or without HF and presumed resistant hypertension, and heart failure with reduced ejection fraction irrespective of diabetes and chronic kidney disease 5,[20][21][22][23] . Findings, that may be generalized to a large proportion of "real-world" patients 24 .…”

Bibliometric Study of Sodium Glucose Cotransporter 2 Inhibitors in Cardiovascular Research

“…Although an increasing number of studies on HFpEF have been conducted (Anker et al, 2019), more in-depth research on SGLT2 inhibitors in HFpEF is expected to be conducted in the future. In addition, SGLT2 inhibitors have significant therapeutic effects on hypertension (Park et al, 2020) and atherosclerotic disease (Nasiri-Ansari et al, 2018). Furthermore, recent studies have indicated that SGLT2 inhibitors enhance cardiac systolic function by improving myocardial energy production by directing myocardial fuel metabolism away from glucose synthesis toward ketone body (KB) formation (Ferrannini et al, 2016;Santos-Gallego et al, 2019).…”

“…By inhibiting the protein SGLT2, which is expressed in the proximal convoluted tubule, SGLT2 inhibitors lower glucose levels independent of insulin action. Currently, SGLT2 inhibitors are recognized to possess a considerably broader scope of benefits in addition to simply hypoglycemic effects, including the induction of modest weight loss, natriuresis, and diuresis and reducing blood pressure (Zelniker and Braunwald, 2018;Park et al, 2020). Traditional antidiabetic drugs do not always reduce the cardiovascular (CV) complications of diabetes; however, the potential applications of SGLT2 inhibitors in CV disease (Docherty et al, 2020;Heerspink et al, 2020;Slomski, 2020) have attracted increasing intense research interest.…”