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 the 2019 and 2021 ESC classification. 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, whereas the opposite was found using the 2021 classification, due to the reallocation of patients with at least three additional ASCVD risk factors to the high-risk category. 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 in the 2019 classification, and higher than that of patients with previous ASCVD event(s) only, according to the 2021 classification.
The distribution of patients with type 2 diabetes according to the 2019 ESC risk categories is consistent with previous reports from diabetes outpatient clinics [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. The reallocation of individuals with at least three additional ASCVD risk factors without TOD or previous ASCVD event(s) to the high-risk category as in the 2021 classification is consistent with our 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. The negligible number of patients in the moderate-risk category in both classifications and the assignment of the majority of participants to the very high-risk category in the 2019 classification do not reflect the wide range of ASCVD risk observed in people with type 2 diabetes  and are in contrast with the finding that optimal treatment of ASCVD risk factors in these individuals is able to significantly reduce or even eliminate the excess risk of death and ASCVD events compared to non-diabetic controls [22, 23]. This suggests that the ESC stratification systems may overestimate mortality risk in a great number of people with type 2 diabetes. This interpretation is in keeping with a systematic review and network meta-analysis of randomised controlled trials  and a clinical practice guideline based on it , which stratified adults with type 2 diabetes into five risk categories using the Risk Equations for Complications of Type 2 Diabetes (RECODe) prediction model  and assigned those with ≤ 3 and > 3 additional ASCVD risk factors to the very low- and low-risk category, respectively. In both these categories, there was no clear evidence of a positive balance of benefits and harms of GLP-1 receptor agonists and SGLT-2 inhibitors , which therefore were not or only weekly recommended in patients with additional ASCVD risk factors but without established ASCVD or CKD .
At variance with those of other scientific societies [27, 28], both the 2019 and 2021 ESC guidelines recommend the use of a newly-developed, non-validated risk stratification system based on the presence of ASCVD risk factors, TOD and/or previous ASCVD event(s) instead of one of the ASCVD risk prediction tools that have been developed so far [11, 12], likely due to the numerous limitations of these algorithms, which result in insufficient performance . 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 [29, 30]. 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, most of them focus on specific ASCVD outcomes, especially myocardial infarction and stroke, without considering other ASCVD events, such as heart failure and peripheral artery disease. More importantly, they may not include variables that significantly affect risk, thus not allowing to appropriately classify patients at apparently lower risk such as those without established ASCVD. In fact, many of the most used algorithms, either derived from the general population, such as the Framingham Score , the Prospective Cardiovascular Münster Study (PROCAM) Score ,the Systematic COronary Risk Evaluation: High & Low cardiovascular (SCORE) Risk Charts , the Progetto Cuore , and the ASCVD Risk Estimator , or people with type 2 diabetes, such as the UK Prospective Diabetes Study (UKPDS) Risk Score  and the risk equation developed from the Swedish National Diabetes Register , do not include measures of TOD. Moreover, the remaining algorithms consider only measure(s) of kidney damage, such as the prediction tool derived from the Hong Kong Diabetes Registry for Coronary Artery Disease (eGFR) , the UKPDS model 2 (albuminuria and eGFR) , the QRESEARCH Cardiovascular Risk Algorithm (QRISK, CKD stage 3-to-5 in version 3) , the EstimatioN oF mORtality risk in type 2 diabetiC patiEnts (ENFORCE), a prediction model for all-cause mortality (albumin:creatinine ratio) , and the RECODe, a tool for predicting complications and death (serum creatinine and albumin:creatinine ratio ) , which was found to perform better than six of the above algorithms . The results of the present study point to a very high mortality risk associated with severe TOD, which in our analysis was related only to microangiopathy (DKD and DR) for both the 2019 and 2021 classifications, thus supporting the importance of including measures of TOD in the ASCVD risk prediction tools and arguing in favour of the use of the ESC classification system for stratifying patients with type 2 diabetes.
However, other TODs were not considered either in our analysis or in the ESC classification systems. One is peripheral neuropathy, which we could not include in the definition of microvascular disease according to the 2021 ESC guidelines (microalbuminuria plus retinopathy plus neuropathy)  because no data were available from the RIACE cohort on this complication. However, though presence of neuropathy is a powerful predictor of all-cause and ASCVD morbidity and mortality, it is generally undiagnosed because procedures are either semi-quantitative and not objective or laborious, time-consuming, and even invasive and, hence, difficult to implement in clinical practice . Another TOD that is not considered in the ESC classifications is non-alcoholic fatty liver disease, which has been shown to independently predict fatal and non-fatal ASCVD events . More importantly, macrovascular disease was not taken into account, as either left ventricular hypertrophy (which was considered in the 2019 classification but not in our analysis because of lack of data) or 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 ADA guidelines consider an index of high-risk if higher than 50% ; (b) functional imaging, i.e., radionuclide myocardial perfusion imaging, stress cardiac magnetic resonance imaging, or exercise or pharmacological stress echocardiography; (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 (10–20%) or low-to-intermediate 10-year risk (6–10%), with calcium score driving reclassification of these individuals to the low-risk or high-risk category . Conversely, the assessment of circulating biomarkers such as C-reactive protein, fibrinogen, or high-sensitivity cardiac troponin T is considered of limited clinical value when added to conventional ASCVD risk factors . The strong, independent association of microangiopathy, especially DKD, with measures of macroangiopathy such as left ventricular hypertrophy  and coronary calcification  may explain the higher mortality risk observed in patients with TOD only versus those with previous ASCVD event(s) only. It is in fact plausible that, in individuals with TOD due to microangiopathy (DKD and DR), the overall risk of death results from both overt microvascular and subclinical macrovascular disease. Therefore, in patients with type 2 diabetes, the presence of microangiopathy might serve to indicate the need for both noninvasive assessment of subclinical ASCVD and treatment with drugs providing protection from ASCVD and CKD such as GLP-1 receptor agonists and SGLT-2 inhibitors .
Strength of our study include the large sample size, the assessment of a wide range of clinical parameters, and the completeness of baseline and follow-up data. In addition, mortality data were not influenced by the use of GLP-1 receptor agonists and SGLT-2 inhibitors, as none these agents were available at the time of enrollment and only a negligible proportion of patients were treated with either one of these agents at the time of the census. However, there are several limitations. First, the lack of information on the causes of death did not allow detecting differences in ASCVD versus non-CVD deaths. Second, results may have been affected by the lack of information on left ventricular hypertrophy and diabetic neuropathy, which were taken into consideration 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.