Abstract 12826: Genetic Variation in SLC5A2 Mimicking SGLT2-Inhibition Lowers Risk of Cardiovascular Disease and All-Cause Mortality

Abstract

Background: Treatment with sodium-glucose co-transporter 2 (SGLT2)-inhibitors reduces risk of hospitalization for heart failure and all-cause mortality, but the mechanisms are unclear. Hypothesis: We hypothesized that a functional genetic variant in SLC5A2 , encoding SGLT2, mimics pharmacological SGLT2-inhibition on risk of cardiovascular disease and all-cause mortality. Methods: 112,745 individuals from two similar studies of the Danish general population were included and genotyped for a common variant causing familial renal glucosuria, rs61742739 (c.1961A>G; p.Asn654Ser) in SLC5A2 . This variant was examined for association with risk of heart failure (N=6,260), myocardial infarction (N=5,778), ischemic heart disease (N=12,504), and all-cause mortality (N=16,410) during a median of 42 years of follow-up, and for potential mediators of these associations related to glycemic control, body mass, blood pressure, circulating blood volume, and lipids. Results: The rs61742739 variant lowered risk of heart failure by 31%, myocardial infarction by 21%, ischemic heart disease by 16%, and all-cause mortality by 22%, and was associated with lower plasma glucose and lipoprotein(a). Lower plasma glucose mediated 4.2% (95%CI:1.3-10.2%; p=0.01) of the effect of genotype on risk of heart failure, 5.3% (1.5-21.2; p=0.02) on risk of myocardial infarction, 7.5% (2.2-25.1; p=0.01) on risk of ischemic heart disease, and 10.5% (3.0-26.8; p<0.01) of the effect on risk of all-cause mortality. Similar estimates for lipoprotein(a) lacked statistical significance. Conclusion: A functional genetic variant in SLC5A2 , encoding SGLT2, is causally associated with a 31% lower risk of heart failure, a 21% lower risk of myocardial infarction, a 16% lower risk of ischemic heart disease, and a 22% lower risk of all-cause mortality. These effects were partly mediated through lower plasma glucose.