SGLT2 inhibition with empagliflozin improves coronary microvascular function and cardiac contractility in prediabetic ob/ob−/− mice

Abstract

Background: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) is the first class of anti-diabetes treatment that reduces mortality and risk for hospitalization due to heart failure. In clinical studies it has been shown that SGLT2i's promote a general shift to fasting state metabolism characterized by reduced body weight and blood glucose, increase in glucagon/insulin ratio and modest increase in blood ketone levels. Therefore, we investigated the connection between metabolic changes and cardiovascular function in the ob/ob −/− mice; a rodent model of early diabetes with specific focus on coronary microvascular function. Due to leptin deficiency these mice develop metabolic syndrome/diabetes and hepatic steatosis. They also develop cardiac contractile and microvascular dysfunction and are thus a promising model for translational studies of cardiometabolic diseases. We investigated whether this mouse model responded in a human-like manner to empagliflozin treatment in terms of metabolic parameters and tested the hypothesis that it could exert direct effects on coronary microvascular function and contractile performance. Methods: Lean, ob/ob −/− untreated and ob/ob −/− treated with SGLT2i were followed for 10 weeks. Coronary flow velocity reserve (CFVR) and fractional area change (FAC) were monitored with non-invasive Doppler ultrasound imaging. Food intake, urinary glucose excursion and glucose control via HbA1c measurements were followed throughout the study. Liver steatosis was assessed by histology and metabolic parameters determined at the end of the study. Results: Sodium-glucose cotransporter 2 inhibitors treatment of ob/ob −/− animals resulted in a switch to a more catabolic state as observed in clinical studies: blood cholesterol and HbA1c were decreased whereas glucagon/insulin ratio and ketone levels were increased. SGLT2i treatment reduced liver triglyceride, steatosis and alanine aminotransferase, an indicator for liver dysfunction. l-Arginine/ADMA ratio, a marker for endothelial function was increased. SGLT2i treatment improved both cardiac contractile function and coronary microvascular function as indicated by improvement of FAC and CFVR, respectively. Conclusions: Sodium-glucose cotransporter 2 inhibitors treatment of ob/ob −/− mice mimics major clinical findings regarding metabolism and cardiovascular improvements and is thus a useful translational model. We demonstrate that SGLT2 inhibition improves coronary microvascular function and contractile performance, two measures with strong predictive values in humans for CV outcome, alongside with the known metabolic changes in a preclinical model for prediabetes and heart failure.

Cardiac ischemia–reperfusion injury under insulin-resistant conditions: SGLT1 but not SGLT2 plays a compensatory protective role in diet-induced obesity

“…Based on these previous findings, it is possible that, in our current study, selective SGLT2-inhibitors exerted direct cardioprotective effects, although further studies will be needed in order to investigate the effects of those pharmacological agents on cardiac NHE under diabetic insulin-resistant conditions as well as on cardiac fibrosis through histopathological analyses. Regardless, the present study investigated the transient local direct effects of SGLT2inhibitors on the cardiac tissue during the acute phase of IRI; our findings therefore do not conflict with the consistent cardioprotective results from other in vivo experimental studies [44,[49][50][51][52][53][54][55][56] or clinical trials [31][32][33], all of which investigated the systemic effects of SGLT2-inhibitors over a longer period. Furthermore, the present findings suggest that potential mechanisms underlying the cardiovascular benefits of SGLT2-inhibitors may depend largely on the systemic inter-organ network, including cardiorenal syndrome [57][58][59].…”

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

“…The present findings indicate a beneficial effect of the empagliflozin treatment promoting a reduction of the body weight and the weight of perirenal fat, and hyperglycemia, and an improvement of the lipid profile as well as of systolic blood pressure in the obese ZSF1 rat. Previous studies have also shown that empagliflozin reduced body weight and fat associated with an increased urinary glucose excretion in an animal model of diet-induced obesity [38], lowered plasma cholesterol and liver triglyceride levels in pre-diabetic ob/ob −/− mice [39], and decreased blood pressure by about 15 mmHg in the Cohen-Rosenthal diabetic hypertensive rat [25]. Consistent with previous studies, the obese ZSF1 rat, an experimental model of HFpEF, is characterized by pronounced heart remodeling affecting the left and right heart with a preserved heart function as indicated by normal cardiac output and ejection fraction.…”

Autophagy stimulation and intracellular sodium reduction as mediators of the cardioprotective effect of sodium–glucose cotransporter 2 inhibitors

“…Through such a mechanism, agents that promote autophagy mitigate activation of the inflammasome . It is therefore noteworthy that the stimulation of autophagy by SGLT2 inhibitors is accompanied by a reduction in oxidative stress and normalization of mitochondrial structure and function, and this action is followed by effects to suppress inflammation, minimize coronary microvascular injury, enhance contractile performance and attenuate the development of cardiomyopathy …”