In a mouse model of cardiovascular-kidney-metabolic (CKM) syndrome, sotagliflozin — the only SGLT inhibitor shown to reduce heart attacks and strokes in human trials — reduced atherosclerotic plaque burden, triglycerides, and TNF-α more than empagliflozin at matched levels of glucosuria and plasma cholesterol. It also tripled postprandial GLP-1, cut hepatic de novo lipogenesis, boosted β-oxidation and ketogenesis, and raised energy expenditure independent of body mass — effects not replicated by the selective SGLT2 inhibitor empagliflozin.
This is animal evidence only, and the findings must be interpreted accordingly. Still, the mechanistic story is clinically compelling: sotagliflozin's unique SGLT1 blockade in the gut appears to reshape whole-body substrate use toward fat oxidation and simultaneously stimulate GLP-1 release, creating metabolic effects that selective SGLT2 inhibitors cannot match. This could finally explain why sotagliflozin — unlike empagliflozin, dapagliflozin, or canagliflozin — reduced atherothrombotic events in the SCORED trial. The finding that benefit may extend to non-diabetic CKD is particularly notable, as this population currently lacks targeted atherosclerosis therapies. Limitations include the use of male LDL-receptor-deficient mice, a pharmacological rather than physiological model, and the absence of female or diabetic cohorts. As a preprint posted on bioRxiv and not yet peer-reviewed, these results require independent replication and human validation before they can influence clinical practice.