Hyperglycemia and genetic susceptibility in relation to incident degenerative aortic valve stenosis

Abstract Aims While the association between diabetes and degenerative aortic valve stenosis (AS) is well established, the relationship between prediabetes and AS remains unclear, and the potential influence of genetic susceptibility on these associations has yet to be explored. We aimed to examine the association between hyperglycemia, including prediabetes and diabetes, and incident degenerative AS and to explore whether genetic susceptibility modify these associations. Methods and results This population-based cohort study analyzed data from 461,017 UK Biobank participants who were divided into three groups (normoglycemia, prediabetes, and type 2 diabetes) according to their baseline glycemic status. The primary outcome was incident degenerative AS, while the secondary outcome was AS-related events, a composite outcome of AS-related intervention or death due to AS. During a median follow-up of 14.3 years, 5,307 AS and 2,209 AS-related events were documented. Compared with normoglycemia, the adjusted HR (95% CI) for incident AS of prediabetes and diabetes were 1.21 (95% CI, 1.13-1.30) and 1.66 (95% CI, 1.52-1.80), respectively. The corresponding values for incident AS-related events were 1.26 (95% CI, 1.13-1.41) and 1.60 (95% CI, 1.40-1.83), respectively. For the joint associations, participants with prediabetes or diabetes had a higher risk of AS and AS-related events regardless of genetic risk and the highest hazard was observed in those with diabetes and high genetic risk (AS: HR, 3.25, 95% CI, 2.82-3.74; AS-related events: HR, 3.79, 95% CI, 3.05-4.72). Conclusion Prediabetes, in addition to diabetes, was associated with an increased risk of AS and AS-related events, independent of a genetic risk score for AS.