Empagliflozin and Metformin Combination Therapy Attenuates Oxidative Stress and Inflammation in Experimental Cardio–Kidney–Metabolic Syndrome
8 affiliations
- 1Doctorado en Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana-Xochimilco, Mexico City 04960, Mexico
- 2Departamento de Fisiopatología Cardio-Renal, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City 14080, Mexico
- 3Departamento de Ciencias Naturales, Universidad Autónoma Metropolitana, Unidad Cuajimalpa, Mexico City 05348, Mexico
- 4Departamento de Sistemas Biológicos, Universidad Autónoma Metropolitana, Unidad Xochimilco, Mexico City 04960, Mexico
- 5Cardiovascular Critical Care Unit, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City 14080, Mexico
- 6Outpatient Department, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City 14080, Mexico
- 7Pharmacology Department, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City 14080, Mexico
- 8Experimental Pathology Department, Instituto Nacional de Ciencia Médicas y Nutrición “Salvador Zubirán”, Mexico City 14080, Mexico
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.
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BibTeX
@article{cortescamacho2026empagliflozin,
title = {{Empagliflozin and Metformin Combination Therapy Attenuates Oxidative Stress and Inflammation in Experimental Cardio–Kidney–Metabolic Syndrome}},
author = {Fernando Cortes-Camacho and Oscar R. Zambrano-Vásquez and Fernando E. García-Arroyo and Elena Aréchaga-Ocampo and Jorge I. Castañeda-Sánchez and Daniel Manzur-Sandoval and Francisco Javier Roldan-Gómez and Leonardo Del Valle-Mondragón and O. Emiliano Aparicio-Trejo and Constanza E. Martínez-Olivares and Rogelio Hernández-Pando and José G. Gonzaga-Sánchez and Laura G. Sánchez-Lozada and Horacio Osorio-Alonso},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27208988},
url = {https://www.mdpi.com/1422-0067/27/20/8988},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Empagliflozin and Metformin Combination Therapy Attenuates Oxidative Stress and Inflammation in Experimental Cardio–Kidney–Metabolic Syndrome
AU - Fernando Cortes-Camacho
AU - Oscar R. Zambrano-Vásquez
AU - Fernando E. García-Arroyo
AU - Elena Aréchaga-Ocampo
AU - Jorge I. Castañeda-Sánchez
AU - Daniel Manzur-Sandoval
AU - Francisco Javier Roldan-Gómez
AU - Leonardo Del Valle-Mondragón
AU - O. Emiliano Aparicio-Trejo
AU - Constanza E. Martínez-Olivares
AU - Rogelio Hernández-Pando
AU - José G. Gonzaga-Sánchez
AU - Laura G. Sánchez-Lozada
AU - Horacio Osorio-Alonso
PY - 2026
DA - 2026/10/10
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27208988
UR - https://www.mdpi.com/1422-0067/27/20/8988
AB - 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.
SN - 1422-0067
ER -