The SGLT2 Inhibitor Empagliflozin Ameliorates the Inflammatory Profile in Type 2 Diabetic Patients and Promotes an Antioxidant Response in Leukocytes

Abstract

Sodium–glucose co-transporter 2 inhibitors (iSGLT2) have been linked to a considerable reduction in cardiovascular risk in patients with type 2 diabetes (T2D), but the precise molecular mechanisms are still elusive. We aimed to evaluate the effects of the iSGLT2 empagliflozin on systemic inflammation and its potential antioxidant properties. This is an observational, prospective follow-up study of a cohort of fifteen patients with T2D who received 10 mg/day of empagliflozin according to standard clinical care. Measures at baseline, 12 and 24 weeks were taken. Metabolic and anthropometric parameters were evaluated. Production of mitochondrial superoxide, glutathione content, and glutathione s-reductase and catalase mRNA levels were measured in leukocytes. Serum levels of myeloperoxidase, hs-CRP and IL-10 were determined. In addition to decreased body weight and reduced glucose and HbA1c levels, we observed a reduction in superoxide production in leukocytes of diabetic patients and increased glutathione content, prominently after 24 weeks of empagliflozin treatment. Leukocyte expression of glutathione s-reductase and catalase, and serum levels of IL-10 were enhanced at 24 weeks of empagliflozin treatment. Concomitantly, reduced hs-CRP and myeloperoxidase levels were seen. This study provides evidence of the antioxidant and anti-inflammatory properties of empagliflozin treatment in humans, which may contribute to its beneficial cardiovascular effects.

Empagliflozin Ameliorates Leukocyte – Endothelium Cell Interactions and Inflammation in Type 2 Diabetic Patients

“…In this sense, the present results show a reduction in the expression of the adhesion molecule ICAM-1 and the in ammatory marker hs-CRP after 24-weeks of empagli ozin treatment. These results are in accordance with those previously reported by our group showing that empagli ozin treatment reduced levels of the in ammatory enzyme myeloperoxidase -actively involved in the development of microvascular alterations [26] -and increased release of the anti-in ammatory interleukin-10 (IL-10) [15]. Considered as a whole, these data suggest that empagli ozin ameliorates the in ammatory state and reduces the risk of CVDs.…”

“…Considered as a whole, these data suggest that empagli ozin ameliorates the in ammatory state and reduces the risk of CVDs. In support of this, empagli ozin has been shown to reverse obesity and insulin resistance through fat browning and alternative macrophage activation in mice fed a high-fat diet [27], and to reduce in ammation and boost the antioxidant response in leukocytes from type 2 diabetic patients [15].…”

“…These actions result in a decrease in leukocyteendothelium interactions, suggesting that this drug exerts a bene cial effect by protecting against the early stages of atherosclerotic process. Hyperglycaemia and increased levels of HbA 1C are key factors in the atherosclerosis process, and are related to enhanced leukocyte-endothelium interactions, mitochondrial impairment, and oxidative stress [15,19]. Enhanced leukocyte-endothelium interactions have also been linked to insulin resistance [20][21][22].…”

“…To exclude alterations due to other current medication, patients were also excluded if their hypoglycaemic, lipid-lowering, or antihypertensive treatment had been/was altered (changes in dose or type of drug) in the previous year or during the study. Empagli ozin was administered orally at doses of 10 mg/day according to normal clinical practice [14,15]. Measurements were assessed at baseline and at 12 and 24-weeks of empagli ozin treatment.…”

Prognostic value of arterial stiffness measurements in cardiovascular disease, diabetes, and its complications: The potential role of sodium‐glucose co‐transporter‐2 inhibitors

“…In short, major pathophysiologic mechanisms underlying increased arterial stiffness in diabetes mellitus include the formation of advanced glycation end products (AGEs) on the arterial wall, inducing cross‐linking of collagen molecules and subsequent loss of collagen elasticity, increased activity of renin‐angiotensin‐aldosterone system (RAAS), chronic inflammation, enhanced oxidative stress, and endothelial dysfunction (Figure ) . It has been therefore shown (mainly in experimental models) that SGLT‐2 inhibition decreases the expression of AGEs and their receptor (RAGE), while it also suppresses oxidative stress and inflammatory response . It has been also demonstrated that SGLT‐2 inhibition might provide a significant, beneficial effect on endothelial dysfunction in T2DM, although results are contradictory in shorter duration studies .…”