Sotagliflozin Reprograms Hepatic Lipid Metabolism and Attenuates Atherosclerosis Beyond Empagliflozin in CKM Mice

Background: Sodium-glucose cotransporter-2 (SGLT2) inhibitors reduce cardiovascular mortality and chronic kidney disease (CKD) progression in cardiovascular-kidney-metabolic (CKM) syndrome, but this benefit derives primarily from reductions in heart failure and cardiovascular mortality rather than in atherothrombotic events. Sotagliflozin, which inhibits both intestinal SGLT1 and renal SGLT2, is the only drug in this class shown to lower rates of myocardial infarction and stroke in CKD. However, its mechanism remains unclear, and its effectiveness in non-diabetic CKD has not been studied. We hypothesized that dual SGLT1/2 inhibition reprograms systemic substrate utilization toward fatty acid oxidation, which may partially account for this protective effect. Methods: CKD was induced in male low-density lipoprotein receptor-deficient mice by 5/6 nephrectomy. Sham and CKD mice received a high-fat diet and drinking water containing sotagliflozin, empagliflozin, or vehicle for 16 weeks, at doses that produced equivalent fractional excretion of glucose. We quantified atherosclerosis en face and in the aortic sinus. Indirect calorimetry, echocardiography, hepatic RNA sequencing, plasma acylcarnitine profiling, and in vivo deuterium labeling of palmitate were performed. Results: At matched levels of glucosuria and plasma total cholesterol, sotagliflozin decreased body mass, atherosclerosis burden, triglycerides, and TNF- more than empagliflozin, and raised postprandial total GLP-1 approximately 3-fold, while both drugs similarly improved albuminuria and diastolic function. Sotagliflozin increased energy expenditure independent of body mass and lowered respiratory exchange ratio despite compensatory hyperphagia. Sotagliflozin reduced hepatic lipogenic genes and de novo lipogenic flux, while increasing {beta}-oxidation and ketogenesis; empagliflozin only activated the oxidative pathway. Conclusions: In experimental CKM syndrome, dual SGLT1/2 inhibition reduces atherosclerosis and metabolic syndrome more effectively than selective SGLT2 inhibition and is associated with reprogramming of hepatic lipid metabolism. These results suggest that sotagliflozin could be an attractive candidate for mitigating atherosclerotic risk in non-diabetic CKD.