Empagliflozin and Metformin Combination Therapy Attenuates Oxidative Stress and Inflammation in Experimental Cardio–Kidney–Metabolic Syndrome

Abstract

This study evaluated the therapeutic effects of the empagliflozin+metformin (E+M) combination on cardio–kidney–metabolic syndrome (CKMS) using an experimental model. Animals were fed a Paigen-type (high-fat) diet supplemented with sugar-sweetened beverages to induce the CKMS phenotype. After confirming metabolic, cardiovascular, and renal alterations, animals were randomized into untreated and E+M-treated groups for 30 days while continuing the diet. Cardiovascular risk factors, vasoactive substances in the heart and kidney, oxidative stress, and the expression of inflammatory markers and the lipogenic transcription factors ChREBP and SREBP1 were analyzed. The E+M combination reduced body weight, hyperglycemia, fasting glucose, and hypertension, while restoring the lipid profile and improving oral glucose tolerance and renal function (p < 0.05). It also reduced posterior wall and interventricular septal thickening, as well as the elevated septum/posterior wall (PP/PS) ratio observed in the CKMS group (p < 0.05). Likewise, the increases in angiotensin II and nitric oxide concentrations in the hearts and kidneys were attenuated (p < 0.05). The CKMS group exhibited glomerular hypertrophy and reduced total antioxidant capacity mitochondrial complex I and II activities, glutathione peroxidase, glutathione reductase, and superoxide dismutase activities, and Nrf2 and IL-10 expression, all of which were restored by combination therapy (p < 0.05). In contrast, the upregulation of IGF-1, aldose reductase, sorbitol dehydrogenase, ChREBP, IL-6, TNFα, and NF-κB observed in the CKMS group was reduced following E+M treatment (p < 0.05). Overall, the E+M combination attenuated metabolic alterations and suppressed renal oxidative stress and inflammation, providing cardiac and renal protection at both functional and structural levels. These effects appear to be mediated by the modulation of key proteins involved in vascular tone, uric acid metabolism, oxidative stress, inflammation, and regulation of transcription factors involved in carbohydrate and lipid metabolism.