Effects of SGLT2 inhibitors on systemic and tissue low-grade inflammation: The potential contribution to diabetes complications and cardiovascular disease.

Chronic low-grade inflammation is a recognized key feature associated with type 2 diabetes mellitus (T2DM) and its complications. In prospective randomized trials, sodium-glucose cotransporter type 2 (SGLT2) inhibitors have demonstrated benefits related to several cardiovascular and renal risk factors, including HbA1c , blood pressure, body weight, renal hyperfiltration, and improvement of cardiorenal outcomes. SGLT2 inhibitors may improve adipose tissue function and induce decreases in serum leptin, TNF-α and IL-6 while increasing adiponectin. While data on high-sensitivity C-reactive protein and other inflammatory markers are relatively scarce in humans, in animals, a number of reports have shown reductions in cytokine and chemokine concentrations in parallel with protective effects against progression of atherosclerotic lesions. Experimental findings also suggest that part of the renoprotective effects of SGLT2 inhibition may be related to anti-inflammatory actions at the kidney level. Underlying mechanisms to explain this anti-inflammatory effect are multiple, but may involve weight loss, and reduction in adipose tissue inflammation, slight increase in ketone bodies and diminution of uric acid levels or attenuation of oxidative stress. However, further studies in diabetes patients with specific assessment of inflammatory markers are still necessary to determine the specific contribution of the anti-inflammatory action of SGLT2 inhibitors to the reduction of cardiovascular and renal complications and mortality observed with this class of antidiabetic drugs.