To our knowledge, this is the first study to describe an optimization of CVRFs driven by an intervention with a carotid-US exploration in a T1D population compared to usual care. Despite a worse baseline cardiovascular risk profile (higher LDL-c), subjects undergoing carotid-US, showed an improvement of their lipid profile (increased rates of statin treatment, lower LDL-c levels and increased rates of patients in treatment goals) and significant cessation of smoking habit, compared to routine care. Intensity of changes in the lipid profile were proportional to the atherosclerosis findings in the carotid-US, allowing a tailored approach of treatment goals. Altogether highlights carotid-US as a potential tool for focusing on CVD risk prevention, beyond glycaemic control.
In spite of significant advances in diabetes care and reduction of CVD in the past decades, patients with T1D still have an excess early CVD morbidity and mortality compared to the general population(1,2). Cardiovascular risk increases in a stepwise fashion with each uncontrolled risk factor, even with good glycaemic control, underscoring the relevance of comprehensive cardiovascular risk management in this population(4). Although intensive lipid-lowering treatment is recommended for most patients with T1D (except young patients with short diabetes duration without additional CVRFs), in clinical practice, the rates of patients receiving these drugs and reaching treatment goals is insufficient(15–17). Our study suggests for the first time that carotid-US could help to improve overall management in T1D. Thus, performing carotid-US lead to a modification of lipid-lowering treatment in nearly 40% of patients, resulting in lower LDL-c which was maintained through the following year, while no differences were observed in patients following usual care. Since US is a simple and widely available procedure that does not involve radiation, it can be easily integrated in the endocrinology outpatient clinic. Considering that pragmatic clinical trials have confirmed the potential role of the visualization of the atherosclerotic process by US to improve overall CVD risk in primary prevention(29), this also could help to overcome the clinical inertia in CVD risk management in the T1D population.
Increasing age and LDL-c levels were independently related to the initiation or uptitration of lipid-lowering treatment at 1 year, in accordance with previous studies showing age, diabetes duration and LDL-c levels as CVRFs in T1D(2,17,30). Nevertheless, US-group allocation was the variable most strongly associated with intensification of lipid-lowering drugs, even after accounting for the former variables and others closely associated with CVD risk in the T1D population, such as traditional CVRFs or microvascular complications (Table 3). Further, undergoing carotid-US was also independently related with a more than 4.5-fold chance of LDL-c ≥40 mg/dL (≈1 mmol/L) decrease after 1 year, a secondary outcome that has been related to a significant decrease in CVD events in this population(10). Thus, US evaluation was associated not only with the initiation of lipid-lowering drugs, but also with improvement in lipoprotein profile to an extent that could be associated with hard clinical outcomes.
One of the main reasons for the low prevalence of statin treatment among T1D population could be the lack of a reliable instruments for selecting those most prone to suffer from future CVD(24). Although some clinical scores seem promising in this field(31,32), more studies are needed to ascertain their usefulness in populations other than those where they were described(33). This poor information about CVD in T1D seems contradictory with the recent ESC/EASD guidelines, in which high-intensity statin treatment is recommended for most of the patients with T1D(11). In contrast with these rather uniform recommendations, carotid-US could be used to tailor CVD prevention in this population. In fact, our results showed a stepped increase in the intensification of the lipid-lowering treatment as the atherosclerosis burden increased. Moreover, one out of three of our pre-selected high-risk T1D patients did not show subclinical atherosclerosis, making unnecessary the initiation of intensified cardioprotective treatment (and, thus, avoiding possible side effects from these drugs). Altogether highlights the usefulness of US as a tool for the future precision medicine that we are heading towards.
Interestingly, patients with carotid plaques in whom no modification of the lipid-lowering therapy was made, improved their LDL-c levels at 1 year. This did not happen in patients without plaque or controls. This could be explained by and increased physicians’ compromise and/or patient adherence after detecting the presence of subclinical atherosclerosis, improving overall treatment effectivity. This is in accordance with a study in general population that showed an improvement in CVD risk scores after 1 year of follow-up in patients who saw a pictorial representation of their carotid-US results and these were explained by a healthcare professional(29). Hence, carotid-US could also help to overcome non-adherence to cardioprotective drugs, a very important problem specially in primary prevention(34).
Another remarkable finding is that nearly one third of patients in the US group quitted smoking. This change was notable in those with no plaque but enlarged IMT. This group benefited from the intervention despite no changes in lipid profile at 1 year, but a reduced smoking rate, extending the benefits of subclinical atherosclerosis assessment. Smoking habit in T1D significantly and independently contributes to nephropathy progression(35), coronary heart disease and stroke(6). Strategies to reduce smoking habit are needed in clinical practice, especially in high-risk populations.
Nephropathy is a threatening complication of T1D. It frequently coexists with poor glycaemic control and classical CVRFs such as dyslipidaemia and smoking, which, in turn contribute to its development and progression(36,37). Nephropathy confers an extreme risk of CVD(11). Previous studies have shown that patients with T1D and nephropathy have higher plaque burden compared to those with normoalbuminuria(5).
In our sample, 13.5% had diabetic nephropathy. A subgroup analysis was performed in this extreme risk population. More than two thirds had an enlarged IMT or carotid plaques and all patients with plaques had a high plaque burden, in line with previous studies(5). Treatment was intensified in nearly half of the patients in the carotid-US group. Even with a worse initial cardiovascular profile (more smokers, higher LDL-c and higher rates of treatment with ACEi/ARB), patients selected for carotid-US had significantly lower LDL-c levels after 1 year and a higher proportion of patients under treatment goals (with no changes in the control group). Thus, performing carotid-US not only improves risk profile in general T1D population, but also in those specially at very-high risk.
Several strengths and limitations should be acknowledged. One of the main strengths is that, to our knowledge, this is the first study to describe an optimization of CVD risk profile after performing a carotid-US for the study of subclinical atherosclerosis in T1D. Likewise, this study included a control group following routine clinical practice, strengthening the relevance of our findings. Furthermore, in addition to IMT, carotid plaque was evaluated, which is a better predictor of CVD events, illustrating the robustness of our findings(38). Finally, a standardized CVD risk assessment protocol was performed in our study, limiting potential bias. Yet, our study also has some limitations. Of most relevance, its observational design precludes drawing conclusions on causality. Second, inclusion criteria were strict and only high CVD risk patients were selected, which may not be representative of the general T1D population. Third, nearly one third of patients fulfilling criteria for diabetic nephropathy were not receiving ACEi/ARB treatment, this was observed in up to 40% in patients not selected for carotid-US. Thus, initial stages of diabetic nephropathy still frequently go unrecognized/undertreated by endocrinologists and/or patients with diabetes. Additionally, this underscores the importance of comprehensive cardiovascular risk assessment (including nephropathy diagnosis and management) in this high-risk population in order to tackle CVD. Finally, the intensification of cardioprotective treatment according to US findings was not fully standardized. However, some pragmatic randomized trials using US as a visual tool for improving CVD risk in general population did not protocolize the treatment either, showing similar results(29). This underscores the usefulness of carotid-US evaluation in real clinical practice and highlights the need to protocolise patient management and treatment after weighing in carotid-US findings.