This analysis of patients with type 2 diabetes from the RIACE cohort showed that very few of these individuals fell in the moderate-risk category according to both ESC classifications. Moreover, the proportion of participants in the very high-risk risk category was approximately twice higher than that of participants in the high-risk category according to the 2019 classification. These findings are consistent with previous reports assessing the distribution of patients from diabetes outpatient clinics according to the 2019 ESC classification [19, 20], in which the proportion of individuals at moderate risk was similar and that of those at very high risk was even higher than in the RIACE cohort. However, using the 2021 classification, the proportion of participants in the very high-risk category became about half of that of participants in the high-risk category, due to the reallocation of patients with at least three additional ASCVD risk factors to the high-risk category. The finding that these patients showed a much lower mortality risk than those with TOD and/or previous ASCVD event(s) and closer to those in the high-risk category as in the 2019 classification is consistent with the revised risk stratification system proposed in the 2021 guidelines. Finally, within the very high-risk category, the mortality risk of individuals with TOD only was almost similar to that of patients with previous ASCVD event(s), with and without TOD, according to the 2019 classification, and higher than that of patients with previous ASCVD event(s) only, according to the 2021 classification. These findings might reflect the strong, independent association of microangiopathy, especially DKD, with measures of macroangiopathy such as left ventricular hypertrophy  and coronary calcification . It is in fact plausible that, in individuals with TOD due to DKD and/or DR but without established ASCVD, the overall risk of death results from both overt microvascular and subclinical macrovascular diseases, thus indicating the need for noninvasive assessment of subclinical ASCVD and treatment with drugs providing protection from both ASCVD and DKD .
Taken together, the results of this analysis provide important insights into the risk stratification of patients with type 2 diabetes, though comparison between the ESC classification system and the existing prediction tools is not feasible as the former allows only a broad categorization of patients according to the risk of death from ASCVD, instead of quantifying the predicted risk. As stated above, prediction algorithms have several pitfalls that limit their performance in these individuals . One limitation is that many of them have been derived from general population samples and not established (or validated) in people with type 2 diabetes. The ESC guidelines do in fact discourage to apply those from the general population to patients with diabetes [11, 12], though comparisons with diabetes-specific algorithms have not univocally shown that the latter ones perform better [8, 24]. Another limitation is the time-period when they were developed, as some of them date back to several years ago and, hence, do not consider the impact of recent therapeutic advances on ASCVD risk. Moreover, they estimate risk of different outcomes, including all-cause or ASCVD mortality and ASCVD events, with most of them being specific for myocardial infarction and stroke without considering other events, such as heart failure and peripheral artery disease. More importantly, they are mainly based on ASCVD risk factors, as only few of them consider previous ASCVD events [25, 26], thus being applicable also to patients with established ASCVD, and/or the presence of TOD, which was found to be associated with an extremely elevated mortality risk among the RIACE participants. In fact, many of the most used algorithms, either derived from the general population [9, 27,28,29,30] or people with type 2 diabetes [31, 32], do not include measures of TOD. In addition, the remaining algorithms consider only measure(s) of kidney damage, i.e., serum creatinine or eGFR [26, 33], albuminuria , or both [25, 35]. Therefore, it is not surprising that the Risk Equations for Complications of Type 2 Diabetes (RECODe), a tool for predicting complications and death that includes previous ASCVD events, serum creatinine, and albumin:creatinine ratio, was found to perform better than six of the above algorithms .
In this regard, the ESC classification system appears to be superior as it considers also TODs other than DKD, such as retinopathy and neuropathy. However, other complications are not taken into account, such as non-alcoholic fatty liver disease, which has been shown to independently predict fatal and non-fatal ASCVD events , and particularly measures of subclinical atherosclerosis. These measures include (a) coronary, carotid, or lower limb artery stenosis, as assessed by computed tomography angiography or ultrasound, which the American Diabetes Association guidelines consider an index of high risk if higher than 50% ; (b) functional imaging; (c) ankle–brachial index; and (d) coronary artery calcium scoring. All these are considered as risk modifiers, particularly the latter , which is recommended for coronary risk assessment in asymptomatic adults at intermediate 10-year risk (10% to 20%) or low-to-intermediate 10-year risk (6% to 10%), with calcium score driving reclassification of these individuals to the low-risk or high-risk category .
However, the ESC stratification systems do not appear to reflect the wide range of ASCVD risk observed in people with type 2 diabetes , as attested by the negligible number of patients in the moderate-risk category with both ESC classifications and the assignment of the majority of participants to the very high-risk category with the 2019 classification. This is likely because they do not take into account the degree of ASCVD risk factor control, at variance with all the existing risk prediction tools. In fact, optimal treatment of ASCVD risk factors in individuals with type 2 diabetes was found to significantly reduce or even eliminate the excess risk of death and ASCVD events compared to non-diabetic controls [40, 41]. As a consequence, the ESC stratification systems might overestimate mortality risk in a great number of people with type 2 diabetes and, as acknowledged by the ESC Scientific Document Group , may not be appropriate to accurately quantify risk differences. This interpretation is in keeping with a systematic review and network meta-analysis of randomized controlled trials  and a clinical practice guideline based on it , which stratified adults with type 2 diabetes into five risk categories using the RECODe prediction model  and assigned those with ≤ 3 and > 3 additional ASCVD risk factors to the very low- and low-risk category, respectively.
Strength of our study includes the large sample size, the assessment of a wide range of clinical parameters, and the completeness of baseline and follow-up data. However, there are several limitations. First, the lack of information on the causes of death did not allow detecting ASCVD deaths, to which the ESC classification systems specifically refer. Second, results may have been affected by the lack of information on left ventricular hypertrophy and diabetic neuropathy, which were considered for defining TOD in the 2019 and 2021 classification, respectively [11, 12]. Third, the study findings may not be applicable to the general ambulatory population, as only part of the individuals with type 2 diabetes attend Diabetes Clinics in Italy. Finally, the observational design makes causal interpretation impossible.
In conclusion, risk stratification of patients with type 2 diabetes from the RIACE cohort showed that only a few of them fell in the moderate-risk category according to both ESC classifications and that the majority of participants were assigned to the very high-risk category according to 2019 classification, due to the inclusion of those with at least three additional ASCVD risk factors. This suggests that the ESC stratification systems might overestimate mortality risk in patients with type 2 diabetes without TOD and ASCVD because they do not take into account the degree of ASCVD risk factor control. Reallocating individuals with at least three additional ASCVD risk factors to the high-risk category as in the 2021 classification was consistent with the observed all-cause mortality data. Mortality risk increased across categories according to both classifications, but differences among categories were more evident using the 2021 stratification criteria. Within the very high-risk category, risk of death was found to be particularly high in the presence TOD (namely microangiopathy), irrespective of established ASCVD, possibly due to the association with subclinical vascular disease.