10-year estimate of cardiovascular risk in type 2 diabetes.

To develop and validate a recalibrated prediction model (SCORE2-Diabetes) to estimate the 10-year risk of cardiovascular disease in individuals aged over 40 years with type 2 diabetes in four different European risk regions.

Cardiovascular disease (CVD) remains a major cause of morbidity and mortality in Europe. Nearly 13 million new cases were registered in 2019 alone [2]. Type 2 diabetes mellitus is an important risk factor for CVD. Persons with diabetes from high-income countries have, on average, a 2-fold higher risk of developing CVD than persons without diabetes [3]. Therefore, the European Society of Cardiology (ESC) provides guidelines and advocates CVD risk assessment in individuals with type 2 diabetes to inform treatment decisions [4].

Risk prediction models used in the primary prevention of CVD in the general population typically estimate individual risk over a 10-year period by integrating information on measured levels of conventional CVD risk factors (ie, age, smoking status, systolic blood pressure, and total and HDL cholesterol) and information on diabetes status [5–7]. However, to account for the substantial variation in risk among persons with diabetes, additional diabetes-related information (eg, age at diabetes diagnosis, glycated hemoglobin (_HbA1c), and markers of renal function) has been included in several published risk models [8–11]. Nevertheless, the available diabetes-specific models have important potential limitations. In particular, they may not be optimally suited for use in Europe’s diverse populations because they were developed based on a limited number of observational studies and/or intervention trials and have not been systematically “recalibrated” (i.e., statistically adjusted) to reflect the substantial differences in CVD rates across European countries [2,11,12].

To address these limitations, the ESC has launched an initiative to expand the regionally recalibrated European SCORE2 10-year risk models [13] to allow use in individuals with type 2 diabetes. Described is the development, validation, and presentation of SCORE2-Diabetes for estimating the 10-year risk of nonfatal myocardial infarction, stroke, or CVD mortality in individuals with diabetes, but without prior CVD, aged over 40 years in four different European risk regions [1].

The SCORE2 diabetes project includes several components and data

For model derivation, the original SCORE2 risk prediction models for fatal and nonfatal CVD were adapted for use in individuals with type 2 diabetes, using individual data from patients with type 2 diabetes, without previous CVD, aged over 40 years, from the Scottish Care Information-Diabetes (SCID), Clinical Practice Research Datalink (CPRD), UK Biobank (UKB) and seven cohorts from the Emerging Risk Factors Collaboration (ERFC) with available information on diabetes-related variables were used. The derived risk models for each European risk region were recalibrated using the methods previously used in the development of SCORE2. External validation was performed in individuals with type 2 diabetes in four countries (Sweden, Spain, Croatia, and Malta) using data from the Swedish National Diabetes Registry (SNDR), the Information System for Primary Care Research (SIDIAP, Sistema d’Informació per al Desenvolupament de la Investigació en Atenció Primària). and two contributing registries from the European Best Information through Regional Outcome in Diabetes (EUBIROD) were used. In addition, the variation in CVD risk among individuals with type 2 diabetes across European regions was illustrated by applying the recalibrated models to data from contemporary populations in each risk region.

The primary end point was cardiovascular events, defined as a composite of cardiovascular mortality, nonfatal myocardial infarction, and nonfatal stroke. Follow-up was until the first nonfatal myocardial infarction, nonfatal stroke, death, or end of the study or registration period. Deaths that were not attributable to cardiovascular disease were treated as concurrent events.

Derivation of the SCORE2 diabetes risk model.

The model derivation included a total of 229,460 participants with diabetes and no history of CVD at baseline from SCID, CPRD, and ERFC/UKB. The mean (SD) age at baseline was 65 (± 11) years for SCID, 64 (± 11) years for CPRD, and 60 (± 8) years for ERFC/UKB. Overall, 122,609 (53.4%) of participants in all data sources were male. The median (5th, 95th percentile) follow-up in years was 10.9 in SCID, 6.0 in CPRD, and 11.3 in ERFC/UKB, in which a total of 43,706 CVD events and 28,226 non-CVD-related deaths were recorded. The association of diabetes-related variables decreased with increasing age of the participants. Associations were similar when ERFC/UKB data were excluded and when an expanded CVD end point including nonfatal HF and pAVD was used.

The C indices in the derivation datasets were 0.704 (95% CI 0.701, 0.706), 0.733, and 0.666 in SCID, CPRD, and ERFC/UKB, respectively (Fig. 1) [1]. At external validation, the C-index for SCORE2 diabetes was 0.670 using data from 168 585 persons with diabetes (34 944 CVD events) from SNDR and 0.658 using data from 21 698 persons with diabetes (2464 CVD events) from SIDIAP. Using the EUBIROD datasets of 3876 individuals from Malta and 22,821 individuals from Croatia with complete information on all risk predictors, the C-index was 0.661 and 0.688, respectively.

Internal and external validation of the SCORE2 diabetes models

Compared with SCORE2, SCORE2-Diabetes showed improved risk discrimination in individuals with diabetes, with increases in C indices (95% CI) of 0.021, 0.023, and 0.026 in SCID, CPRD, and ERFC/UKB, respectively. Slightly smaller improvements were seen in SNDR and SIDIAP with an increase in C-index of 0.009 and 0.009, respectively (Fig. 1) [1]. In the EUBIROD datasets from Malta and Croatia, the increase in C indices was 0.031 and 0.013, respectively. The C indices were similar when eGFR was calculated with different equations but were slightly attenuated when individuals with an eGFR <45 mL/min/1.73^m2 were excluded. The improvement in risk discrimination by the additional diabetes-related variables included in SCORE2-Diabetes (ie, age of diabetes diagnosis, _HbA1c, and eGFR) was greater than the improvement by total and HDL cholesterol concentration in the same model. SCORE2 diabetes also showed slightly improved discrimination against the ADVANCE risk score.

Using SCORE2 diabetes instead of SCORE2 improved risk classification and resulted in a continuous NRI of 25.2 (95% CI, 22.4, 28.0) in CPRD and 28.7 in SNDR. Using SCORE2 diabetes instead of SCORE2 resulted in a categorical NRI of 24.6 in the CPRD and 13.7 in the SNDR, with a net proportion of 44.8% and 31.9% of cases correctly reclassified, respectively.

Concordance of risks estimated with SCORE2 and SCORE2 diabetes.

After recalibration, the SCORE2 diabetes-predicted risks showed good agreement with the expected 10-year CVD incidence in each risk region and, on average, were similar to the SCORE2-derived risks within each age group. SCORE2-diabetes-predicted risks were also consistent with observed risks in persons with diabetes from nationally representative datasets with 10-year follow-up and showed better calibration than SCORE2. Use of an expanded CVD end point including nonfatal HF and pAVD resulted in an absolute 10-year risk that was approximately 1.15 times higher than that estimated with the SCORE2 diabetes CVD end point, with results varying slightly by age.

Separate risk scores for men and women with type 2 diabetes

The estimated absolute risk for a given age and combination of conventional CVD risk factors differed substantially according to the level of diabetes-related variables (Fig. 2) [1]. For example, using the SCORE2 diabetes version for an intermediate-risk region, the estimated 10-year CVD risk for a 60-year-old nonsmoker with a history of diabetes, average values of conventional risk factors (ie, systolic blood pressure of 140 mmHg, total cholesterol of 5.5 mmol/L, and HDL cholesterol of 1.3 mmol/L), HbA_1c of 50 mmol/mol, eGFR of 90 mL/min/1.73 m² and an age at diabetes diagnosis of 60 years 11.0%. For a similar man with less favorable diabetes-related risk factors (ie, _HbA1c of 70 mmol/mol, eGFR of 60 mL/min/1.73^m2, and age at diagnosis of 50 years), the estimated risk was 17.2%. For a woman with the same characteristics, the risks were 7.9% and 12.7%, respectively. Risk estimates also varied between European risk regions because of recalibration, with a man or woman with the latter risk factor values having an estimated risk of 12.9% and 9.8%, respectively, in the low-risk region and 31.2% and 34.0%, respectively, in the high-risk region (Fig. 2) [1].

The recalibrated SCORE2 diabetes models applied to simulated data representing populations from each risk region showed substantial variation in individuals aged 40 to 79 years with an estimated risk of more than 10% by region; from 61% in the low-risk region, to 96% in the very-high-risk region in men and from 51% to 94% in women, respectively, with proportions increasing with age, as expected (Fig. 3) [1].

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