What's new?

This study highlights the potential of vascular age (VA) and arterial stiffness (AS) as new tools for improving cardiovascular risk (CVR) assessment in individuals with type 1 diabetes mellitus. Traditionally, CVR is calculated using models that may underestimate the risk, especially in younger people or individuals without hypertension. Integrating VA, derived from carotid artery measurements, and AS, assessed via pulse wave velocity, into existing CVR tools can enhance the accuracy of risk assessment. This approach can help clinicians identify high‑risk individuals earlier, potentially guiding more timely interventions for preventing cardiovascular complications. Future research could focus on validating these findings across broader populations and exploring how these tools might influence treatment decisions.

Introduction

Among people with type 1 diabetes mellitus (T1DM), cardiovascular disease (CVD) stands as the leading cause of mortality.¹ Nonobstructive coronary artery disease is the most common coronary complication among individuals with long‑lasting T1DM.² Steno type 1 risk engine (ST1RE) is a prediction model based on an analysis of 4306 adults with T1DM for estimating the risk of the first fatal or nonfatal CVD event using some of the variables specific for T1DM, such as diabetes duration, albuminuria, and glycated hemoglobin (HbA_1c).³ ST1RE calculator was recommended to assess cardiovascular risk (CVR) in people with T1DM according to the 2023 European Society of Cardiology (ESC) Guidelines for the management of cardiovascular disease.⁴

Arterial stiffness (AS), that is progressing rigidity of the arterial walls, is an early predictor of cardiovascular complications and cardiovascular mortality among people with T1DM.^5-7 These individuals have higher pulse wave velocity (PWV) than healthy controls of the same age.⁷ The gold standard parameter of AS assessment is PWV.⁸

Another parameter used in CVR evaluation is carotid artery intima‑media thickness (cIMT) measured using ultrasonography.⁹ Based on the Diabetes Control and Complications Trial (DCCT) / Epidemiology of Diabetes Interventions and Complications (EDIC) cohort, cIMT was weakly related to subsequent coronary artery events, but the association did not remain significant after adjusting for coexistent traditional CVR factors.¹⁰ However, using cIMT, we can calculate vascular age (VA) based on the results obtained by Engelen et al.¹¹ The use of VA may contribute to the identification of high CVD risk in T1DM.¹²

We aimed to investigate the association between VA, AS, and ST1RE categories in people with T1DM. To our knowledge, this is the first study to use VA in combination with the ST1RE model to assess CVR in individuals with T1DM.

Patients and methods

Results

We initially invited 140 participants to take part in our study. However, 12 of them were excluded due to insufficient data from the questionnaires, 3 due to hypothyroidism, 2 due to CRP levels exceeding 5 ng/ml, 10 due to insufficient hemodynamic measurement data, and 4 for not meeting our quality control criteria. Finally, we investigated a total of 109 adults at a median (IQR) age of 32.4 (25.5–38.6) years and diabetes duration of 14 (10–20) years (Table 1).

VA was higher than the chronological age among 92 participants (84.4%), while the median (IQR) difference was 13.4 (4.1–23.5) years. Most of them had elevated HbA_1c level and only 11 participants (10.9%) met the criteria for diabetes control (HbA_1c ≤6.5%). All individuals were treated with intensive insulin therapy. Thirty‑one participants (28.4%) used insulin pumps, and the others used insulin pens. The patients with overt hypertension were excluded, but 56 oarticipants (51.4%) had elevated peripheral BP on the 24‑hour measurement.

Based on the standard ST1RE score, 90 individuals (82.6%) were at a low risk od CDV (<⁠10%), and only 19 individuals (17.4%) were at a moderate risk (10%–20%). No participant was at a high risk. We also calculated the modified ST1RE with VA instead of the chronological age, which yielded 55 participants (50.5%) with low risk, 26 (23.9%) with moderate risk, and 28 (25.7%) with high risk (Table 2). It means that using VA instead of the  chronological age moved 35 individuals (32.1%) to a higher‑risk category (Figure 1). The median (IQR) 10‑year CV event risk was 9.68% (4.61%–20.08%), almost 2‑fold higher than the standard ST1RE value of 4.74% (3.24%–8.12%).

The participants were stratified into 3 categories using the modified ST1RE score (Table 2). Higher risk was associated with male sex, older age, and longer T1DM duration. Diabetic complications, including retinopathy, were more prevalent in the high‑risk group than in the moderate- and low‑risk groups. Cardiovascular parameters, such as aortic PWV, cIMT, and VA, progressively worsened across the risk categories, with marked differences observed (P <⁠0.001). Additionally, the ACR was elevated in the high‑risk group (P = 0.02).

The correlation results are shown in Table 3. PWV was positively related to cIMT, VA, chronological age, diabetes duration, standard ST1RE score, and modified ST1RE score. The standard and modified ST1RE scores were positively associated with cIMT, VA, and PWV.

The univariable logistic regression analysis demonstrated 11 variables associated with the high‑risk category according to the modified ST1RE. The final multivariable logistic regression model showed that PWV was positively associated with high CVR based on the modified ST1RE score (OR, 2.37; 95% CI, 1.46–3.84; P = 0.004). The association was independent of sex, BMI, and at least one diabetic complication (Table 4).

Discussion

We found that VA was significantly higher than the chronological age in T1DM adults without overt hypertension and CVD. Implementing VA to the ST1RE score moved 32.1% of the participants to a higher‑risk category. Modified ST1RE was positively related to PWV, independently of the presence of diabetic complications, current smoking, BMI, and sex.

VA provides an estimation of the physiological age of the vasculature.^11,21 Our study demonstrated a positive association between VA based on the cIMT and ST1RE scores, indicating that higher VA was associated with a higher CVR, which corresponds to earlier studies.²² Viñals et al²³ demonstrated that both cIMT and plaque presence increased in tandem with rising ST1RE scores. Early vascular aging develops even in normotensive children with T1DM.^24,25 Our findings are in line with previous studies that have shown significantly elevated cIMT in individuals with T1DM, as compared with healthy controls.⁹ In past studies, VA was calculated using CVR models including the Framingham Risk Score and the Systematic Coronary Risk Evaluation (SCORE) which skip risk factors specific to T1DM.^26,27 While cIMT may not significantly improve the prediction of CVR when used alone, calculating VA based on cIMT results can enhance the accuracy of CVR assessment.^10,28 VA calculated on the basis of cIMT was used instead of chronological age to calculate CVR using the Framingham Risk Score by Jamthikar et al²⁹ but never before using ST1RE.²⁷

While in the T2DM population physicians can assess CVR using the SCORE 2 diabetes calculator, there is still no validated tool to asssess CVR in the Polish T1DM population. Estimated CVR is crucial to making right therapeutic decisions, as in the case of hyperlipidemia treatment and in people without hypertension but with elevated BP.³⁰ McGurnaghan et al³¹ created a model predicting the 10‑year risk of CVD in T1DM individuals based on the national register in Scotland, externally validated with the Swedish National Diabetes Register. This detailed model includes factors such as diabetic complications, HbA_1c, level and diabetes duration, but also social deprivation and average HbA_1c level from the last 5 years. The last 2 factors are rarely accessible in Polish T1DM individuals. The second model proposed in the 2023 ESC Guidelines for the management of CVD is ST1RE.⁴ It was created based on 4306 T1DM adults from Steno Diabetes Center in Gentofte, Denmark. Later, it was validated for the 5‑year risk in Italy, but not for the 10‑year risk.^3,4,32 However, Denmark and Scotland are in the low‑risk group, Italy and Sweden are in the moderate‑risk group, and Poland is in the high‑risk group.³³ Compared with the 2019 ESC risk classification, ST1RE performs better in predicting cardiovascular events in all risk groups, but it leads to significantly less aggressive statin treatment.^34,35

Helmink et al³⁶ introduced the LIFE‑T1D model to estimate both 10‑year and lifetime CVD risk in individuals with T1DM. This new approach, derived from the Swedish National Diabetes Register and externally validated in Danish and United Kingdom cohorts, highlights the importance of longer‑term risk estimates beyond the traditional 10‑year horizon. However, as the authors note, further validations, particularly in high‑risk regions, are necessary before clinical implementation can be widely recommended.³⁶

Therefore, we assume that ST1RE could underestimate CVR in high‑risk countries such as Poland. In our study, based on the standard ST1RE score, the majority of participants were at a low risk despite poor glycemic and lipid control and common diabetic complications, so standard ST1RE did not help to differentiate therapy according to CVR in this group. On the other hand, cIMT in 84.4% of the participants was higher than the mean value for their age, suggesting increased CVR. Implementation of VA calculated based on cIMT in the ST1RE was associated with a higher score and reclassified 32.1% of individuals to a higher‑risk category. Modified ST1RE was positively associated with AS, an established CVR indicator. We need a validated model to adequately assess CVR in people with T1DM in Poland and other high‑risk countries. In the meantime, however, using VA and AS could help make clinical decisions in doubtful situations.

The study group comprised patients with T1DM lasting for but without CVD, with atherosclerosis in CCAs, a family history of early CVD, and previously diagnosed hypertension. Most of them did not meet the target criteria for HbA_1c and LDL‑C levels.^16,37 However, Kim et al³⁸ found that 32.7% of adolescents with T1DM at the age of 15.4 (2.8) years did not meet the LDL‑Clevel criteria according to the Pediatric and Adolescent Diabetes and American Diabetes Association. According to Szadkowska et al,³⁹ only 25.5% of Polish young adults (aged 18–30 years) achieved the goal of HbA_1c  level below 6.5%. In the Poznań Prospective Study, only 10% of adults with T1DM achieved an HbA_1c level below or equal to 6.5%, and just 6% met their LDL‑C target.⁴⁰ Lipid target achievement in the Polish general population without T1DM is also poor.^41-43

Helleputte et al⁴⁴ investigated AS and its association with standard ST1RE and ESC/European Association for the Study of Diabetes (EASD) 2019 criteria in a group of 54 participants aged 46 (9.5) years with a mean (SD) T1DM duration of 27 (8.8) years without cardiovascular diseases, but including patients with hypertension and dyslipidemia. Compared with our study group, the participants recruited by Helleputte et al⁴⁴ were older, with longer diabetes duration, more frequent retinopathy, and diabetic kidney disease, but had similar HbA_1c and LDL‑C levels, despite 46.3% of them using statins or other lipid‑lowering drugs. In our group, more participants met the 2019 ESC/EASD criteria for LDL‑C level.⁴⁴

Interestingly, HbA_1c and lipid parameters did not differ significantly across the risk categories, possibly reflecting comparable short‑term metabolic control in all groups. In contrast, vascular changes (as measured by cIMT and VA) may capture the cumulative impact of long‑term exposure.⁹ Individuals in high and moderate‑risk categories also have lower lipid targets and probably undergo more intensive (nonpharmacological) treatments to meet these goals. LDL‑C target achievement seems to be more relevant than absolute LDL‑C values.⁴⁵ Although LDL‑C and HbA1_c levels were similar across the categories, age (or VA), T1DM duration, smoking status, SBP, and albuminuria varied significantly, suggesting that these factors may more strongly determine ST1RE category in this relatively young T1DM population.

The pathophysiology of AS development in T1DM is multifactorial.⁷ Chronic hyperglycemia results in the buildup of advanced glycation end products, low‑grade inflammation, endothelial dysfunction, arterial media calcification, and preterm atherosclerosis. The result of this multifactorial process is the thickening of vascular walls, which causes AS.^1,7,46 Moreover, it affects other classic CVR factors. The occurrence of hypertension, dyslipidemia, and obesity is significantly higher in people with T1DM than the general population.^1,47-49

Our findings demonstrated that AS, as measured by aortic PWV, and VA was positively associated with both ST1RE scores. Llauradó et al⁵⁰ showed that PWV was positively associated with the standard ST1RE score (R_s = 0.777; P <⁠0.001) and increased with each subsequent ST1RE group. Similar results were obtained by Helleputte et al.⁴⁴ In our study, the association between PWV and the standard ST1RE score was weaker (R_s = 0.59; P <⁠0.001). This could be due to different methods of PWV measurement, and the low heterogeneity of the study group.⁴⁴

We excluded individuals with overt hypertension, but more than half of the study group had elevated BP during the 24‑hour measurement. This is in line with the study by Lithovius et al⁵¹ who diagnosed masked hypertension in 23% of adolescents with T1DM.