Калибровка аортального клапана по типу 2 диабет: тяжелый вес коморбидов.

This editorial refers to ‘Factors associated with aortic valve calcification in type 2 diabetes—a Steno INTEN-CT substudy’, by A. Haujir et al. , https://doi.org/10.1093/ehjci/jeag139 .

Degenerative aortic stenosis (AS) is the most common valvular heart disease requiring intervention, 1 with its prevalence rising with ageing and clustering of cardiovascular risk factors. 2 To date, pharmacological attempts to prevent or slow disease progression once significant AS has developed have consistently failed, underscoring the need to understand and target earlier stages of this disease. Aortic valve calcification (AVC) is an underlying pathophysiological mechanism in AS and is commonly observed in individuals with type 2 diabetes (T2D). 3 In AVC, inflammatory cell infiltration and activation of valvular interstitial cells promote fibrosis and stiffening of the valve cusps, followed by progressive accumulation of calcific deposits that eventually cause haemodynamic obstruction. 4 Although a direct effect of dysglycaemia on this fibrocalcific process is biologically plausible, epidemiological data suggest that the association between T2D and AS may be mediated, to a substantial extent, through coexisting hypertension, dyslipidaemia, chronic kidney disease (CKD), and obesity rather than glycaemic burden per se .

Echocardiography remains the gold standard for diagnosing and grading AS, but cardiac computed tomography (CT) has emerged as an important addition in selected cases, particularly in patients with discordant AS. Importantly, cardiac CT can detect AVC before overt AS develops, opening possibilities for screening strategies, risk stratification, and design of trials aimed at preventing progression from subclinical AVC to symptomatic AS. In parallel, cardiac CT has become an important tool in assessing coronary artery calcification (CAC) with important implications for cardiovascular risk stratification and preventive measures. The STENO INTEN-CT trial is an example of CT-guided risk management in T2D. 5 This investigator-initiated, pragmatic, event-driven study enrols ∼7300 patients with T2D and no known ischaemic heart disease, all of whom undergo non-contrast cardiac CT for CAC scoring. Participants are randomized to standard care, with CAC results blinded, or CAC-guided treatment. In the CAC-guided arm, high-risk individuals (CAC ≥ 100) are targeted for intensification of multifactorial therapy, including sodium-glucose co-transporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 receptor agonists, high-intensity lipid-lowering therapy, antihypertensives, and antithrombotic treatment, whereas very low-risk individuals (CAC = 0) are managed with less intensive targets.

Haujir et al . 6 present a prespecified cross-sectional substudy from STENO INTEN-CT trial that focuses specifically on AVC in T2D. This analysis included 4570 participants with T2D and no known ischaemic heart disease, aged 55–69 years (men) or 60–74 years (women), all of whom underwent non-contrast cardiac CT with Agatston scoring of AVC severity, measured at a core laboratory. The severity of T2D was reflected through HbA1c, disease duration, and the number of glucose lowering drugs. AVC was modelled as an ordinal outcome (0, 0–300, >300 Agatston units) using logistic regression adjusted for demographic and clinical covariates. Nearly half of participants (46%) had detectable AVC, and 5% had more advanced calcification (≥300 Agatston units). With increasing AVC burden, patients were older and more often male; had a greater prevalence of hypertension, obesity, CKD, and dyslipidaemia; and were more frequently treated with statins and SGLT2 inhibitors. In multivariable models, age, body mass index (BMI), CKD, statin use, and LDL cholesterol were associated with higher AVC. LDL cholesterol showed a stronger association with AVC in men than in women ( P for interaction = 0.025). Importantly, none of the three T2D severity markers, HbA1c, diabetes duration, or treatment intensity, was associated with AVC after adjustment for comorbidities.

These findings add to a growing body of evidence suggesting that, once T2D is established and accompanied by multiple comorbidities, the degree of glycaemic control no longer independently predicts AVC burden. Similar signals have been observed in several population-based cohorts. In the Cardiovascular Health Study of 5201 participants, hypertension and lipid levels, but not T2D, predicted aortic sclerosis, 7 and in the Danish DANCAVAS cohort of 14 073 participants, age, obesity, and hypertension remained associated with AVC after adjustment for confounders including CAC, whereas diabetes and hyperlipidaemia did not. 8 By contrast, in the Multi-Ethnic Study of Atherosclerosis (MESA) of 6780 participants without known history of cardiovascular disease, diabetes, and metabolic syndrome were associated with higher AVC prevalence. 9 However, within the diabetic subgroup much of this excess risk appeared to be explained by the individual components of the metabolic syndrome, particularly hypertension and dyslipidaemia.

More contemporary data from the Swedish CArdioPulmonary bioImage Study (SCAPIS) extend these observations across the full spectrum of dysglycaemia. Among 29 331 middle-aged participants randomly selected from the general population, the prevalence of AVC increased stepwise from normoglycaemia through prediabetes, newly detected diabetes, and known diabetes. 3 After adjustment for age, sex, smoking, LDL cholesterol, and hypertension, prediabetes, newly detected diabetes, and known diabetes were each associated with AVC in a graded manner. In sensitivity analyses that additionally adjusted for BMI, the associations for prediabetes and newly detected diabetes were attenuated, suggesting that excess adiposity accounts for a substantial part of the link between early dysglycaemia and AVC. An analysis of the Swedish National Diabetes Registry reinforces the importance of risk factor control as patients with T2D and an increasing number of uncontrolled cardiovascular risk had a substantially higher risk of AS, yet even individuals with apparently optimal risk factor control remained at excess risk compared with those without diabetes. 10

CKD emerged as one of the conventional risk factors independently associated with AVC in the STENO INTEN-CT substudy, consistent with prior work from the Chronic Renal Insufficiency Cohort (CRIC) study 11 which also demonstrated a dose-dependent inverse relationship between estimated glomerular filtration rate and AVC burden, which remained after adjustment for traditional cardiovascular risk factors. In addition, the sex-specific association between LDL cholesterol and AVC that was observed is consistent with findings from the with DANCAVAS cohort, where dyslipidaemia was a more dominant correlate of AVC in men and hypertension in women. 12 In SCAPIS, the associations between conventional cardiovascular risk factors and AVC were broadly similar in men and women, with the exception of LDL cholesterol, which in unadjusted analyses was linked to AVC in women but not in men. In fully adjusted models, LDL cholesterol itself did not remain significant, whereas a diagnosis of hyperlipidaemia and higher lipoprotein(a) (Lp(a)) were independently associated with AVC in both women and men. 13 In the STENO INTEN-CT substudy, however, Lp(a) was not measured, leaving its contribution to the presence and severity of AVC in patients with T2D unknown.

The observed association between statin use and higher AVC in the STENO INTEN-CT trial may reflect, as the authors have mentioned, confounding by indication, as statins are disproportionately prescribed to patients with dyslipidaemia and high overall cardiovascular risk, who are themselves more likely to have AVC. Similar patterns have been observed in observational studies showing positive associations between statin use and CAC scores, but randomized trial data show no calcification-promoting effect. Whether statins exert any direct effect on valvular calcification, potentially involving PCSK9 upregulation, is being explored in ongoing studies. Likewise, the higher prevalence of AVC in patients on SGLT2 inhibitors in STENO INTEN-CT probably reflects treatment of individuals with higher cardiovascular or renal risk, rather than a causal effect of the drugs on valve calcification. Prospective studies are needed to determine whether SGLT2 inhibitors can slow down progression of early stage AVC to AS.

The STENO INTEN-CT substudy has several limitations. First, the study population was characterized by relatively well-controlled T2DM, with median HbA1c around 49–50 mmol/mol, which limit the generalizability of the findings to patients with more advanced or poorly controlled disease. Second, the cross-sectional design precludes any assessment of causality or of how risk factors influence the development and progression of AVC over time. Third, Lp(a), markers of insulin resistance and beta-cell function were not measured, why important aspects of T2DM could not be characterized. Finally, because patients with high CAC in the main trial receive intensified risk factor management and cardioprotective therapies, treatment changes over time may attenuate or modify some of the associations observed in this substudy.

Nonetheless, this study adds to the growing body of evidence that in people with T2DM, it is the overall burden and clustering of cardiometabolic risk factors that drives calcific valve disease, whereas hyperglycaemia on its own seems less informative once diabetes is established. For clinicians, these findings suggest that prevention strategies for calcific aortic valve disease in T2D should prioritize comprehensive management of obesity, blood pressure, lipids, and kidney function, rather than focusing narrowly on HbA1c targets. Future longitudinal imaging studies are needed to determine whether aggressive risk factor modification can change the natural history of AVC and delay or prevent its progression to symptomatic AS. As serial CT data from STENO INTEN-CT, SCAPIS, and other cohorts become available, we may finally be able to develop and test preventive strategies in the earliest stages of AVC and at the same time identify individuals at highest risk of rapid progression to symptomatic AS so that timely valvular intervention can be offered.

Contributor Information

Ayah Fayad,
Division of Cardiology, Department of Medicine, Karolinska Institutet, Solna, S1:02, Stockholm 171 76, Sweden.

Anne Wang Gottlieb,
Division of Cardiology, Department of Medicine, Karolinska Institutet, Solna, S1:02, Stockholm 171 76, Sweden.

Bahira Shahim,
Division of Cardiology, Department of Medicine, Karolinska Institutet, Solna, S1:02, Stockholm 171 76, Sweden.

Author contributions

Bahira Shahim (Conceptualization, Supervision, Writing—review & editing [lead], Writing—original draft [supporting]), Ayah Fayad (Conceptualization [supporting], Writing—original draft [lead]), and Anne Wang Gottlieb (Conceptualization, Supervision, Writing—original draft, Writing—review & editing [supporting])

Funding

A.F. and A.W.G.: none. B.S. is supported by the Stockholm County Council (FoUI-988371), the Swedish Heart-Lung Foundation (grants 20220524; 20230578; 20250207), the Swedish Research Council (grant 2022-01472), the Swedish Society for Medical Research (SSMF; SG-23-0142-B), the Swedish Society of Medicine (SLS; grant 987010), Karolinska Institute (2-116/2023), and the Swedish Foundation for Strategic Research.

Data availability

No new data were created or analysed in this editorial. Data sharing is not applicable to this article.

References

Associated Data

Data Availability Statement

No new data were created or analysed in this editorial. Data sharing is not applicable to this article.