Effect of Empagliflozin and Liraglutide on the Nucleotide-Binding and Oligomerization Domain-Like Receptor Family Pyrin Domain-Containing 3 Inflammasome in a Rodent Model of Type 2 Diabetes Mellitus

Objectives: Chronic inflammation has been identified as an important driver of cardiovascular disease in type 2 diabetes (T2D) and can lead to a higher risk of cardiovascular events and rehospitalization. Empagliflozin or liraglutide represent 2 classes of drugs with proven efficacy in the treatment of T2D to reduce macrovascular complications; however, the exact mechanism behind their cardioprotective properties remains incompletely understood. The nucleotide-binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is implicated in the progression of cardiovascular disease and linked to the progression of cardiovascular risk factors, such as T2D.

Methods: We set out to determine whether the sodium-glucose cotransporter-2 inhibitor, empagliflozin, or the glucagon-like peptide-1 receptor antagonist, liraglutide, modified components of NLRP3 in a rodent model of T2D, which recapitulates many of the features of humans with T2D. Empagliflozin and liraglutide were used for 8 weeks in a 32-week-old rat model of T2D and compared with an age- and sex-matched control. After treatment, left ventricular tissue samples and blood plasma were obtained for immunoblotting and an interleukin-1β enzyme-linked immunossay. NLRP3, apoptosis-associated speck-like protein, pro-caspase-1 as well as the cleaved caspase-1 subunits p12 and p10 were assessed by Western blot.

Results: Goto-Kakizaki rats demonstrated increased NLRP3 inflammasome activation, but neither empagliflozin nor liraglutide demonstrated any impact across the NLRP3 inflammasome pathways or interleukin-1β levels.

Conclusions: The data suggest that the cardioprotective benefits demonstrated by sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor antagonists occur independently of the NLRP3 inflammasome.