Mendelian Randomisation reveals SGLT-1 Inhibition's Potential in Reducing NAFLD Risk.

NAFLD has no approved pharmacological treatments. SGLT-1 is a glucose transporter which mediates small intestinal glucose absorption. We evaluated the impact of genetically proxied SGLT-1 inhibition (SGLT-1i) on serum liver transaminases and NAFLD risk. We used a missense variant, rs17683430, in the SLC5A1 gene (encoding SGLT1) associated with HbA1c in a genome-wide association study (n = 344182) to proxy SGLT-1i. Outcome genetic data comprised 1,483 NAFLD cases and 17,781 controls. Genetically proxied SGLT-1i was associated with reduced NAFLD risk (OR 0.36; 95%CI 0.15, 0.87; p = 0.023) per 1 mmol/mol HbA1c reduction, and with reductions in liver enzymes (ALT, AST, GGT). Genetically proxied HbA1c, not specifically via SGLT-1i, was not associated with NAFLD risk. Colocalisation did not demonstrate genetic confounding. Overall, genetically proxied SGLT-1i is associated with improved liver health, this may be underpinned by SGLT-1 specific mechanisms. Clinical trials should evaluate the impact of SGLT-1/2 inhibitors on the prevention and treatment of NAFLD.