Building a healthier future to prevent aortic stenosis

This editorial refers to ‘Diabetes and elevated plasma glucose in heart valve calcification and disease: the Copenhagen General Population Study’, by M. Kaltoft et al., https://doi.org/10.1093/eurjpc/zwaf106. Aortic stenosis (AS) is the most common valvular heart disease in high-income countries, and its prevalence is rising with the ageing of the population. Characterized by progressive calcification and narrowing of the aortic valve, AS leads to increased cardiac afterload, heart failure, and death if left untreated. Once symptoms appear, the prognosis is poor in the absence of aortic valve replacement, the only available treatment to date. Despite major advances in interventional cardiology, no pharmacological therapies are currently approved to delay or prevent the onset of AS. This unmet clinical need highlights the importance of identifying modifiable and ideally causal risk factors for AS, which could guide the development of preventive and therapeutic strategies. Over the past decade, several observational and genetic studies have provided key insights into the pathogenesis of AS. Classical cardiovascular risk factors such as hypertension, dyslipidaemia, smoking, obesity, and inflammation have all been associated with the development and progression of valvular calcification. Among these, lipoprotein(a) has emerged as a particularly strong and likely causal factor,1,2 supported by both large-scale prospective cohorts and Mendelian randomization studies. More recently, attention has turned to the possible role of metabolic traits, particularly those related to insulin resistance and type 2 diabetes, in driving AS. In this issue of the Journal, Kaltoft et al.3 presents new results from the Copenhagen General Population Study (CGPS), encompassing over 110 000 individuals, providing important new evidence for the role of diabetes in predicting AS risk (TBC). The authors evaluated the associations between diabetes, elevated plasma glucose, and the risk of valvular calcification and AS. In a subset of more than 12 000 participants who underwent cardiac computed tomography, 25% had aortic valve calcification and 13% had mitral valve calcification. Compared with individuals without diabetes, those with diabetes had 67% higher odds of aortic valve calcification and 89% higher odds of mitral valve calcification. Long-term risk of incident AS was 71% higher in individuals with vs. without diabetes. Elevated plasma glucose was also independently associated with valvular calcification and AS risk. Those with fasting glucose ≥ 6.6 mmol/L (≥118 mg/dL) had a 33% higher risk of AS than individuals with levels ≤ 5.1 mmol/L (≤92 mg/dL), even after adjustment for potential confounders. Of particular interest, the study also explored potential mediators of the relationship between diabetes and AS. Approximately 27% of the association was explained by elevated body mass index, 19% by hypertension, and 4.8% by plasma triglycerides.3 These findings suggest that metabolic abnormalities, and not only hyperglycaemia per se, may play a central role in valvular degeneration and calcification. Taken together, this study offers robust epidemiological evidence supporting a link between cardiometabolic disease and AS risk and provides new and valuable insights about pathophysiology and prevention of AS. The results of the CGPS study3 are in line with emerging genetic evidence supporting a causal role for metabolic traits in the development of AS. Recent Mendelian randomization studies using genetic instruments for adiposity-related traits such as body mass index and waist-to-hip ratio, as well as circulating triglyceride-rich lipoproteins and inflammation, have also been associated with higher AS risk.4–7 These findings strengthen the biological plausibility of a causal relationship between metabolic dysfunction and valvular calcification and suggest overlapping pathophysiological mechanisms between atherosclerosis and AS. This convergence of observational, imaging, and genetic data underscores the possibility that AS may, at least in part, be preventable. While AS has long been viewed as a degenerative disease of aging, this paradigm is increasingly challenged by evidence showing that modifiable lifestyle and clinical risk factors may influence its development. In our own previous work, using data from the EPIC-Norfolk cohort, we demonstrated that in apparently healthy individuals, several modifiable clinical and lifestyle-related risk factors were strongly associated with the risk of calcific AS.8 Previous studies from our team also revealed that individuals with metabolic syndrome show faster progression of AS compared with those without metabolic syndrome.9,10 These findings suggest that the same factors that drive atherosclerotic cardiovascular disease may also promote valvular calcification, reinforcing the notion that prevention strategies targeting cardiometabolic health could be extended to AS. From a clinical perspective, these findings3 carry significant implications. Risk factor modification, particularly in individuals with diabetes, obesity, or features of metabolic syndrome, should be a priority not only to reduce the burden of coronary artery disease, but also potentially to prevent the onset or progression of AS. This includes tight glycaemic control, careful management of blood pressure and lipid levels, and adiposity. While some of these interventions are already part of the standard of care for cardiovascular risk management, they have not yet been systematically studied in the context of AS prevention. Prospective studies and randomized controlled trials are needed to confirm whether such interventions can alter the natural history of valvular calcification. Beyond lifestyle and traditional pharmacological therapies, new classes of anti-diabetic drugs may hold particular promise. Incretin-based therapies such as glucagon-like pepetide-1 (GLP-1) receptor agonists and other anti-diabetic therapies including sodium-glucose co-transporter 2 (SGLT2) inhibitors and dipeptidyl peptidase 4 (DPP-4 inhibitors) have shown substantial cardiometabolic benefits in individuals with type 2 diabetes, including weight loss, improvement in glycaemic control, and reduction in plasma triglyceride levels. Given the central role of adiposity, glucose metabolism, and triglyceride-rich lipoproteins in the pathogenesis of AS suggested by the CGPS study and others, these agents could represent an attractive therapeutic option to prevent or slow the progression of early valvular disease, but dedicated studies in AS are lacking. The randomized trial ‘A Study to Evaluate the Efficacy and Safety of DA-1229 (Evogliptin) in Patient’s Calcific Aortic Valve Disease with Mild to Moderate Aortic Stenosis (EVOID-AS)’ is currently investigating whether the DPP4 inhibitor evogliptin is able to slow the progression of AS.11 Randomized trials of incretin-based therapies in patients with AS, or in those at high risk, are urgently needed to assess their potential role in altering disease progression. Ultimately, AS prevention cannot rely solely on medical therapy. A broader societal approach is required—one that supports and promotes healthy lifestyles across the life course. A heart-healthy diet, regular physical activity, and environments that facilitate healthy behaviours should be foundational elements in our prevention strategy. As with other chronic cardiovascular conditions, early intervention and sustained lifestyle changes may hold the key to reducing the future burden of AS. The study from the CGPS3 is a timely and important reminder that AS is not merely a mechanical problem of the valve, but a complex, multifactorial disease influenced by systemic metabolic and inflammatory processes. By identifying modifiable contributors such as diabetes, obesity, and hypertriglyceridaemia, we are beginning to uncover potential levers for prevention. The path forward will require bold investments in research, innovative clinical trials, and a renewed commitment to prevention, both at the individual and population level. As we await new therapies that can slow or halt the progression of AS, we must act now to address the upstream risk factors that are already within our reach.

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