Glycemic control with empagliflozin, a novel selective SGLT2 inhibitor, ameliorates cardiovascular injury and cognitive dysfunction in obese and type 2 diabetic mice

Abstract

BackgroundThere has been uncertainty regarding the benefit of glycemic control with antidiabetic agents in prevention of diabetic macrovascular disease. Further development of novel antidiabetic agents is essential for overcoming the burden of diabetic macrovascular disease. The renal sodium glucose co-transporter 2 (SGLT2) inhibitor is a novel antihyperglycemic agent for treatment of type 2 diabetes. This work was performed to determine whether empagliflozin, a novel SGLT2 inhibitor, can ameliorate cardiovascular injury and cognitive decline in db/db mouse, a model of obesity and type 2 diabetes.Methods(1) Short-term experiment: The first experiment was performed to examine the effect of 7 days of empagliflozin treatment on urinary glucose excretion and urinary electrolyte excretion in db/db mice. (2) Long-term experiment: The second experiment was undertaken to examine the effect of 10 weeks of empagliflozin treatment on cardiovascular injury, vascular dysfunction, cognitive decline, and renal injury in db/db mice.Results(1) Short-term experiment: Empagliflozin administration significantly increased urinary glucose excretion, urine volume, and urinary sodium excretion in db/db mice on day 1, but did not increase these parameters from day 2. However, blood glucose levels in db/db mice were continuously decreased by empagliflozin throughout 7 days of the treatment. (2) Long-term experiment: Empagliflozin treatment caused sustained decrease in blood glucose in db/db mice throughout 10 weeks of the treatment and significantly slowed the progression of type 2 diabetes. Empagliflozin significantly ameliorated cardiac interstitial fibrosis, pericoronary arterial fibrosis, coronary arterial thickening, cardiac macrophage infiltration, and the impairment of vascular dilating function in db/db mice, and these beneficial effects of empagliflozin were associated with attenuation of oxidative stress in cardiovascular tissue of db/db mice. Furthermore, empagliflozin significantly prevented the impairment of cognitive function in db/db mice, which was associated with the attenuation of cerebral oxidative stress and the increase in cerebral brain-derived neurotrophic factor. Empagliflozin ameliorated albuminuria, and glomerular injury in db/db mice.ConclusionsGlycemic control with empagliflozin significantly ameliorated cardiovascular injury and remodeling, vascular dysfunction, and cognitive decline in obese and type 2 diabetic mice. Thus, empagliflozin seems to be potentially a promising therapeutic agent for diabetic macrovascular disease and cognitive decline.

Effects of empagliflozin on blood pressure and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes

“…In addition, in a B Cohort 2 Figure 3. Continued mouse model of obesity and T2DM, empagliflozin ameliorated pericoronary arterial fibrosis, coronary arterial thickening and cardiac macrophage infiltration, effects that are associated with attenuation of oxidative stress in CV tissue [38]. In this analysis, events consistent with volume depletion were rare and no such events were reported in patients aged ≥75 years; however, the potential for volume depletion in vulnerable patients such as the elderly, those with renal impairment, those with low SBP and those receiving diuretics is acknowledged in the prescribing information for SGLT2 inhibitors [39][40][41] and appropriate caution should be exercised in the use of empagliflozin in such patients in clinical practice.…”

The SGLT2 Inhibitor Empagliflozin Improves the Primary Diabetic Complications in ZDF Rats

“…Interestingly, despite being a specific SGLT2 inhibitor and causing a dramatic increase in urine volume and glucose excretion in non-diabetic mice, previous studies showed that urine volume and glucose excretion in db/db mice were not changed by chronic empagliflozin treatment [49]. Ojima et al found that HbA1c and fasting blood glucose Fig.…”

Use of SGLT-2 inhibitors in the treatment of type 2 diabetes mellitus

“…These benefits were associated with significant attenuation of oxidative stress in cardiovascular and brain tissues. 28 Uric acid is the end product of purine metabolism. Hyperuricemia, in addition to causing gout, is associated with chronic kidney disease, DM and metabolic syndrome, and is considered a marker of cardiovascular (CV) risk.…”