Combination of a Glucagon-Like Peptide 1 Analog and a Sodium-Glucose Cotransporter 2 Inhibitor Improves Lipid Metabolism Compared to the Monotherapies in Experimental Metabolic Syndrome

Background: Obesity is a risk factor for insulin resistance, dyslipidemia, fatty liver disease, and all disorders associated with metabolic syndrome. Here we evaluated the association of the glucagon-like peptide 1 (GLP-1) analog, liraglutide, and the sodium-glucose cotransporter-2 (SGLT-2) inhibitor, canagliflozin, on the improvement of metabolic syndrome symptoms in a high-fat diet (HFD)-in- duced obesity rat model. Methods: Male Wistar rats received either a control diet or HFD ad libitum for 5 months. After 4 months of diet, HFD rats were randomly divided into four experimental groups (HFD, HFD + liraglutide, HFD + canagliflozin, and HFD + liraglutide + canagliflozin). Treatment groups received liraglutide (100 µg/kg) and/or canagliflozin (10 mg/kg) once daily for one month. Body mass and food intake were monitored throughout the experiment. An oral glucose tolerance test, biochemical parameters, epididymal and liver fat, and adipocyte morphology were assessed after the treatment period. Results: Rats on the HFD developed obesity, glucose intolerance, dyslipidemia, and fatty liver. Liraglutide reduced food intake and body weight, normalized the lipid profile, and reduced abdominal and liver fat. Canagliflozin slightly reduced body mass and improved glucose tolerance and dyslipidemia. The combination therapy was more effective than the monotherapies in normalizing the lipid profile. Conclusions: The combination of liraglutide and canagliflozin was more effective than the monotherapies in improving dyslipidemia and liver fat. These results indicate that the combination of GLP-1 receptor agonists and SGLT-2 inhibitors is a promising therapeutic strategy to treat dyslipidemia, and possibly prevent fatty liver disease in metabolic syndrome and obese patients.