Canagliflozin reduces inflammation and fibrosis biomarkers: a potential mechanism of action for beneficial effects of SGLT2 inhibitors in diabetic kidney disease

Abstract

Aims/hypothesis The sodium–glucose cotransporter 2 (SGLT2) inhibitor canagliflozin slows progression of kidney function decline in type 2 diabetes. The aim of this study was to assess the effect of the SGLT2 inhibitor canagliflozin on biomarkers for progression of diabetic kidney disease (DKD). Methods A canagliflozin mechanism of action (MoA) network model was constructed based on an in vitro transcriptomics experiment in human proximal tubular cells and molecular features linked to SGLT2 inhibitors from scientific literature. This model was mapped onto an established DKD network model that describes molecular processes associated with DKD. Overlapping areas in both networks were subsequently used to select candidate biomarkers that change with canagliflozin therapy. These biomarkers were measured in 296 stored plasma samples from a previously reported 2 year clinical trial comparing canagliflozin with glimepiride. Results Forty-four proteins present in the canagliflozin MoA molecular model overlapped with proteins in the DKD network model. These proteins were considered candidates for monitoring impact of canagliflozin on DKD pathophysiology. For ten of these proteins, scientific evidence was available suggesting that they are involved in DKD progression. Of these, compared with glimepiride, canagliflozin 300 mg/day decreased plasma levels of TNF receptor 1 (TNFR1; 9.2%; p < 0.001), IL-6 (26.6%; p = 0.010), matrix metalloproteinase 7 (MMP7; 24.9%; p = 0.011) and fibronectin 1 (FN1; 14.9%; p = 0.055) during 2 years of follow-up. Conclusions/interpretation The observed reduction in TNFR1, IL-6, MMP7 and FN1 suggests that canagliflozin contributes to reversing molecular processes related to inflammation, extracellular matrix turnover and fibrosis. Trial registration ClinicalTrials.gov NCT00968812 Electronic supplementary material The online version of this article (10.1007/s00125-019-4859-4) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Empagliflozin Inhibits Basal and IL-1β-Mediated MCP-1/CCL2 and Endothelin-1 Expression in Human Proximal Tubular Cells

“…Despite large-scale clinical trials showing nephroprotection promptly after initiating SGLT2i, data regarding the anti-inflammatory potential of SGLT2i in humans are rather scarce. For example, canagliflozin treatment decreased the plasma levels of biomarkers related to inflammation and fibrosis, such as tumor necrosis factor receptor 1, IL-6, matrix metalloproteinase 7 and fibronectin 1, during a two-year follow-up when analyzing samples from a clinical phase II study [42]. Dapagliflozin reduced urinary IL-6 concentrations in a post hoc analysis of a cross-over clinical trial [43].…”

Covid-19 and Diabetes: A Complex Bidirectional Relationship

“…An additional class of anti-diabetic medications associated with lowering inflammation are the glifozins, or SGLT2 (sodium-glucose cotransporter-2/SLC5A2) inhibitors, which attenuate reabsorption of glucose in the kidney to lower blood sugar. So far, this reported anti-inflammatory effect focuses on the kidney, cardiovascular system and pancreas, rather than lungs ( 96 , 97 ), though it has been shown to indirectly reduce pulmonary infection in diabetic mice ( 98 ). Although SGLT2 inhibitors are associated with dehydration and anorexia and therefore may pose a risk for critically ill patients, a new study focusing on hospitalized adult patients with Covid-19 commenced in April 2020, with the aim of understanding the substantial cardio- and nephroprotective effects of SLGT2 inhibitors in reducing disease progression, complications, and all-cause mortality ( 99 ).…”

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“…The basic mechanism to explain the effects on oxidative stress may involve anti-inflammatory actions of SGLT2 inhibitors [59]. Diabetic patients treated with canagliflozin showed lower plasma levels of TNF receptor and interleukin 6 in comparison to glimepiride group [66]. Animal studies also suggested anti-inflammatory actions of SGLT2 inhibitors.…”