SGLT2 Inhibition Reduces Vascular Dysfunction in Aged Mice

SGLT2 inhibitors are used to treat type 2 diabetes. As is the case for a number of such medications, there is some evidence for them to be beneficial for aged people without this condition. In this example, researchers demonstrate improvements vascular function in aged mice that are treated with one of the approved SGLT2 inhibitors. They also note a range of other evidence for cardiovascular benefits to result from this class of intervention. It remains a question as to which of the possible underlying mechanisms are the important ones, but treatment does seem to reduce blood pressure and arterial stiffness, both of which are significant contributors to late life mortality in our species.

Therapeutic strategies such as lifestyle modifications (weight loss and increased physical activity), antihypertensive therapy, and lipid-lowering medications have shown variable effectiveness at improving endothelial function and ameliorating arterial stiffening and remodeling in older adults. Thus, additional therapeutic approaches aimed at improving vascular health in older individuals are needed. In this regard, evidence from different clinical trials demonstrates that inhibition of SGLT2 results in decreased cardiovascular events and cardiovascular disease related mortality in both patients with and without diabetes. SGLT2 co-transporters are predominantly located in the proximal renal tubules and are responsible for reabsorption of 90% of the glucose in the glomerular filtrate. Indeed, while SGLT2 inhibitors were originally designed as glucose lowering agents, growing evidence supports their beneficial, non-glucose lowering dependent, renal, and cardiovascular effects. In particular, the SGLT2 inhibitor empagliflozin (Empa) has been shown to reduce cardiovascular mortality and nonfatal myocardial infarction, stroke, and cardiovascular death regardless of the presence of type 2 diabetes.

Mechanisms postulated to explain the beneficial cardiovascular properties of SGLT2 inhibition include weight loss and antihypertensive effect, diuresis-induced blood volume reduction, increased red blood cell mass, improved myocardial bioenergetics, decreased arterial stiffness, and improved endothelial function. However, the extent to which the favorable cardiovascular effects of SGLT2 inhibitors are translatable to aging remains unknown. Given the above, the potential impact of SGLT2 inhibition on aging-related endothelial dysfunction, arterial stiffening, and remodeling warrants investigation.

Herein, we first confirmed in a cohort of adult human subjects that aging is associated with impaired endothelial function and increased arterial stiffness and that these two variables are inversely correlated. Next, we investigated whether treatment with the SGLT2 inhibitor, Empa, for 6 weeks ameliorates endothelial dysfunction and reduces arterial stiffness in aged mice with confirmed vascular dysfunction. We report that Empa-treated mice exhibited improved mesenteric endothelial function compared with control, in parallel with reduced mesenteric artery and aortic stiffness. Our findings demonstrate that Empa improves endothelial function and reduces arterial stiffness in a preclinical model of aging, making SGLT2 inhibition a potential therapeutic alternative to reduce the progression of cardiovascular disease in older individuals.


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