1.
Empagliflozin reduces oxidative stress through inhibition of the novel inflammation/NHE/[Na+]c/ROS-pathway in human endothelial cells.
Uthman, L, Li, X, Baartscheer, A, Schumacher, CA, Baumgart, P, Hermanides, J, Preckel, B, Hollmann, MW, Coronel, R, Zuurbier, CJ, et al
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2022;:112515
Abstract
Inflammation causing oxidative stress in endothelial cells contributes to heart failure development. Sodium/glucose cotransporter 2 inhibitors (SGLT2i's) were shown to reduce heart failure hospitalization and oxidative stress. However, how inflammation causes oxidative stress in endothelial cells, and how SGLT2i's can reduce this is unknown. Here we hypothesized that 1) TNF-α activates the Na+/H+ exchanger (NHE) and raises cytoplasmatic Na+ ([Na+]c), 2) increased [Na+]c causes reactive oxygen species (ROS) production, and 3) empagliflozin (EMPA) reduces inflammation-induced ROS through NHE inhibition and lowering of [Na+]c in human endothelial cells. Human umbilical vein endothelial cells (HUVECs) and human coronary artery endothelial cells (HCAECs) were incubated with vehicle (V), 10 ng/ml TNF-α, 1 µM EMPA or the NHE inhibitor Cariporide (CARI, 10 µM) and NHE activity, intracellular [Na+]c and ROS were analyzed. TNF-α enhanced NHE activity in HCAECs and HUVECs by 92% (p < 0.01) and 51% (p < 0.05), respectively, and increased [Na+]c from 8.2 ± 1.6 to 11.2 ± 0.1 mM (p < 0.05) in HCAECs. Increasing [Na+]c by ouabain elevated ROS generation in both HCAECs and HUVECs. EMPA inhibited NHE activity in HCAECs and in HUVECs. EMPA concomitantly lowered [Na+]c in both cell types. In both cell types, TNF α-induced ROS was lowered by EMPA or CARI, with no further ROS lowering by EMPA in the presence of CARI, indicating EMPA attenuated ROS through NHE inhibition. In conclusion, inflammation induces oxidative stress in human endothelial cells through NHE activation causing elevations in [Na+]c, a process that is inhibited by EMPA through NHE inhibition.
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Risk of orthostatic hypotension associated with sodium-glucose cotransporter-2 inhibitor treatment: A meta-analysis of randomized controlled trials.
Rong, X, Li, X, Gou, Q, Liu, K, Chen, X
Diabetes & vascular disease research. 2020;(5):1479164120953625
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Abstract
OBJECTIVE The aim of this study was to assess the association between sodium-glucose cotransporter-2 (SGLT2) inhibitors and the risk of orthostatic hypotension (OH) in patients with type 2 diabetes mellitus (T2DM). METHOD A systematic literature retrieval was performed using PubMed, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) from inception up to 16 October 2019. Data for study characteristics and outcomes of interest were extracted from each eligible study. Pooled risk ratios (RRs) with 95% confidence intervals (CI) for OH were calculated using a random-effects model. RESULT A total of 16 studies (n = 12,749) were included in our meta-analysis, with a result of 44 incident OH cases (29 in the SGLT2 inhibitor group, and 15 in the control group). The pooled RR was 1.17 (95% CI: 0.65-2.09). There was no evidence that receiving SGLT2 inhibitors increased the risk of OH, when stratified by age, duration of T2DM, or placebo-control or active-control and baseline blood pressure. CONCLUSION This meta-analysis suggested that, in general, SGLPT2 inhibitors did not increase the risk of OH in patients with T2DM. The possibility of OH should be, therefore, considered on an individual basis, especially in patients with a history of OH, long duration of T2DM, or comorbidities.
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Effects of SGLT2 inhibitors on fractures and bone mineral density in type 2 diabetes: An updated meta-analysis.
Li, X, Li, T, Cheng, Y, Lu, Y, Xue, M, Xu, L, Liu, X, Yu, X, Sun, B, Chen, L
Diabetes/metabolism research and reviews. 2019;(7):e3170
Abstract
BACKGROUND The aim of the study is to update and determine the effects of sodium glucose cotransporter 2 (SGLT2) inhibitor therapy on fracture and bone mineral density (BMD) in patients with type 2 diabetes mellitus (T2DM). METHODS We identified 27 eligible randomized controlled trials (RCTs) that compared the efficacy and safety of SGLT2 inhibitors to a placebo in 20 895 T2DM participants, with an average duration of 64.22 weeks. The relative risk (RR) of bone fracture and weighted mean difference (WMD) of changes in the BMD from baseline were determined to evaluate the risk of fracture. The degree of heterogeneity was evaluated by the I2 statistic, and publication bias was estimated using a funnel plot and Egger test. RESULTS The pooled RR was 1.02 (95% CI [0.81, 1.28]) with low heterogeneity, indicating that SGLT2 inhibitor treatment was not correlated with a higher risk of fracture. Additionally, no increased risk was found for patients with different ages, sexes, and levels of HbA1c and some biochemical indicators. Three trials with 1303 patients reported a change in the BMD from baseline. SGLT2 inhibitor treatment did not decrease the BMD at four skeletal sites (lumbar spine, femoral neck, total hip, and distal forearm), and the overall WMD was 0.08 (95% CI [-0.09, 0.26]). No significant publication bias was detected. CONCLUSIONS No increased risk for bone fracture was detected in patients with T2DM treated with SGLT2 inhibitors in this meta-analysis. SGLT2 inhibitor therapy did not appear to affect bone health, but more long-term detailed data are needed to validate this conclusion.