Genetic variation in SLC5A2 mimicking SGLT2-inhibition and risk of cardiovascular disease and all-cause mortality: reduced risk not explained by lower plasma glucose

• Published in: Cardiovascular research 2023-07
• Main Authors: Bechmann, Louise E, Emanuelsson, Frida, Nordestgaard, Børge G, Benn, Marianne
• Format: Article
• Language: English
• ISSN: 1755-3245

Treatment with sodium-glucose co-transporter 2(SGLT2)-inhibitors reduces risk of cardiovascular disease and mortality, but the mechanism is unclear. We hypothesized that a functional genetic variant in SLC5A2, known to be associated with familial renal glucosuria, would mimic pharmacological SGLT2-inhibition, and thus provide an opportunity to examine potential mediators of the effects on lower risk of cardiovascular disease and mortality. We examined 112,712 individuals from the Copenhagen City Heart Study and Copenhagen General Population Study (CCHS+CGPS), 488,687 from the UK Biobank, and 342,499 from FinnGen, genotyped for SLC5A2 rs61742739, c.1961A>G; p.(Asn654Ser). The 2.0% heterozygotes and 0.01% homozygotes were pooled as carriers and compared with the 98% non-carriers. First, we examined risk of cardiovascular disease and mortality; second, whether carrying the variant was associated with potential mediators of the effect; and third, whether identified potential mediators could explain the observed reduced risk of cardiovascular disease and mortality. In the CCHS+CGPS, carriers vs. non-carries had 31% lower risk of heart failure, 21% lower risk of myocardial infarction, 16% lower risk of ischaemic heart disease, and 22% lower risk of all-cause mortality. Corresponding values in meta-analyses of the three studies combined were lower risk by 10%, 6%, 6%, and 9%, respectively. The SLC5A2 rs61742739 variant was not associated with risk of ischaemic stroke or cardiovascular mortality. Of the lower risks observed in CCHS+CGPS, lower plasma glucose mediated 2.0%(P=0.004) on heart failure, 3.1%(P=0.09) on myocardial infarction, 4.1%(P=0.02) on ischaemic heart disease, and 6.0%(P=0.39) on all-cause mortality; corresponding values in the UK Biobank were 2.9%(P=0.70), 1.5%(P=0.77), 4.1%(P=0.23), and 3.1%(P=0.21), respectively. A functional genetic variant in SLC5A2, mimicking SGLT2-inhibition, was associated with lower risk of heart failure, myocardial infarction, ischaemic heart disease, and all-cause mortality. These effects were at most minimally mediated through lower plasma glucose. The mechanism behind the reductions in risk of cardiovascular disease and all-cause mortality seen during SGLT2-inhibitor treatment is not fully understood. We examined potential mediators of these effects using a functional genetic variant in the gene encoding SGLT2, a variant that mimics the effect of pharmacological SGLT2-inhibition regarding reductions in risk of cardiov