The Impact of SGLT2 Inhibitors on Inflammation: A Systematic Review and Meta-analysis of Studies in Rodents

Background: Inhibition of sodium-glucose cotransporter-2 (SGLT2) has received remarkable attention due to the beneficial effects observed in diabetes mellitus, heart failure, and kidney disease. Several mechanisms have been proposed for these pleiotropic effects, including anti-inflammatory ones. Our systematic review and meta-analysis aimed to assess the effect of SGLT2 inhibition on inflammatory markers in experimental models.

Methods: A literature search was conducted to detect studies examining the effect of SGLT2 inhibitors on inflammatory markers [interleukin-6 (IL-6), C reactive protein (CRP), tumor necrosis factor-α (TNF-α), and monocyte chemoattractant protein-1 (MCP-1)]. Consequently, a meta-analysis of the included studies was performed, assessing the differences in the levels of the inflammatory markers between the treatment groups as its primary outcome. Moreover, risk of bias, sensitivity analysis and publication bias were evaluated.

Results: The systematic literature review yielded 30 studies whose meta-analysis suggested that treatment with an SGLT2 inhibitor resulted in decreases of IL-6 [standardized mean difference (SMD): -1.56, 95% CI -2.06 to -1.05), CRP (SMD: -2.17, 95% CI -2.80 to -1.53), TNF-α (SMD: -1.75, 95% CI -2.14 to -1.37), and MCP-1 (SMD: -2.04, 95% CI -2.91 to -1.17). The effect on CRP and TNF-α was of lesser magnitude in cases of empagliflozin use. Moderate-to-substantial heterogeneity and possible publication bias were noted. The findings remained largely unaffected after the sensitivity analyses, the exclusion of outlying studies, and trim-and-fill analyses.

Conclusion: The present meta-analysis suggests that SGLT2 inhibition results in reduction of inflammatory markers in animal models, further validating the suggested anti-inflammatory mechanism of action.