1. Introduction
Metabolic syndrome (MS) is defined by the International Diabetes Federation (IDF) as a complex pathology characterized by several general features, such as abnormal body fat distribution, insulin resistance, atherogenic dyslipidaemia, proinflammatory state and prothrombotic state [
1]. Persistent insulin resistance often leads to the development of type 2 diabetes
mellitus (T2DM), a metabolic disease characterized by chronic hyperglycaemia, due to an impaired capacity of the utilization of glucose as an energy source, along with impaired gluconeogenesis and glycogenolysis [
2,
3]. This can lead to both micro and macrovascular complications in the long term. Microvascular complications include retinopathy (leading to total vision loss), neuropathy (leading to impaired wound healing and amputations in the lower limbs), nephropathy (possible renal failure), and sexual dysfunction (namely erectile dysfunction in men) [
4]. Macrovascular complications include peripheral and coronary artery disease, arrhythmias, diabetic cardiomyopathy, and cerebrovascular disease. Cardiovascular diseases are the leading cause of death in patients with T2DM [
5,
6].
Ageing of the population is a global phenomenon and Portugal is one of the European countries experiencing a considerable increase in the proportion of elderly people (i.e., individuals aged 65 and over). Ageing index, which measures the ratio of the elderly to the young population, has seen an exponential rise over the years, reaching 185.3% in 2022 [
7]. This demographic shift led to an increase in age-related diseases, including metabolic disorders such as T2DM [
8]. In this context, it becomes relevant to invest in the prevention of possible complications arising from metabolic syndrome.
Currently, several tools are available to assess cardiovascular (CV) risk [
9,
10,
11]. These tools consider various factors that can contribute to increased CV risk, including the presence of diabetes, blood pressure levels, LDL-cholesterol levels, age, sex, smoking status, prescribed medications, and the presence of complications. These tools show several advantages, such as a personalized risk assessment and a guidance to clinical decision related to the need of lifestyle modifications or the prescription of medication. However, they also have limitations, namely variable accuracy because they are based on average population data. Also, these tools may lead to over-reliance and do not consider all risk factors, such as family history or genetic markers.
The ADVANCE calculator evaluates the CV risk in T2DM patients diagnosed with metabolic syndrome [
12]. This tool is a specific calculator to assess the 10-year risk of suffering a cardiovascular event, for patients with diabetes. Using this calculator, we aimed to estimate how reducing systolic blood pressure and/or LDL-cholesterol until the recommended levels could decrease the CV risk and potentially revert the metabolic syndrome diagnosis in elderly patients.
4. Discussion
Given the higher susceptibility of elderly adults to cardiovascular (CV) diseases and their associated complications, it is crucial to identify and address modifiable risk factors to mitigate these health concerns. The current study examined a cohort of Portuguese elderly individuals diagnosed with both type 2 diabetes and metabolic syndrome, to estimate their CV risk and determine suitable clinical targets, i.e., key modifiable factors such hypertension and dyslipidaemia, to reduce the calculated risk.
As individuals age (a non-modifiable factor), the prevalence of type 2 diabetes tends to increase. In Portugal, diabetes affects over a quarter of the population aged 60-79 years, showing a greater prevalence in males [
18]. According to data from the Portuguese population survey, around one fifth of the general population and more than half of the elderly (aged 65 and over) have only four years of schooling [
19]. This low academic level agrees with the studied sample, which suggests that this sample can be considered representative of the elderly Portuguese population.
Our study demonstrates that aggressive blood pressure (BP) control, particularly lowering systolic BP below 120 mmHg, can substantially and significantly reduce the estimated 10-year cardiovascular risk for all participants. Lowering blood pressure to <130 mmHg also seems to have a significant impact on reducing 10-years CV risk. Considering the risks associated with more aggressive control (<120 mmHg) in patients with diabetes, this study shows that even the values recommended by the ADA [
14] and the European Society of Cardiology [
20] for blood pressure control (<130 mmHg) may have beneficial effects in reducing cardiovascular risk. More importantly, the combined effect of BP and LDL cholesterol interventions yields the most significant risk reduction. Our findings emphasize the potential benefits of multifaceted intervention strategies targeting both BP and lipid levels to mitigate cardiovascular risk in patients with diabetes and metabolic syndrome already reported in other studies [
20].
The ADA recommends the use of the American College of Cardiology/American Heart Association ASCVD risk calculator to calculate 10-year cardiovascular risk. However, it states that although this calculator includes diabetes as a risk factor, it does not consider the duration of the disease or the presence of long-term complications [
14]. The tool used in this study (ADVANCE) includes both factors in the calculation of cardiovascular risk [
12] and seems to be a good tool to help guide the therapy and goals of individuals with diabetes. In the present study, there was a positive correlation with the time since the diagnosis of T2DM (r=0.681,
p<0.001), when controlled for sex, suggesting that patients with a longer duration of the disease have a greater risk of these events. The positive correlations between age, time since T2DM diagnosis, and estimated CV risk underscore the progressive nature of cardiovascular risk accumulation over time in individuals with diabetes. Older individuals and those with a longer duration of diabetes exhibit a higher baseline risk for cardiovascular events, highlighting the importance of early and sustained intervention strategies to prevent or delay adverse outcomes in this vulnerable population [
21]. De Jong et al. [
22], in a prospective cohort study of UK Biobank participants, described that a 5-year increase in the duration of diabetes was associated with a cardiovascular risk increase of around 20%. Yao et al. [
23] also reported that the duration of diabetes increases the 10-year cardiovascular risk. Thus, it seems important that the calculation of the 10-year cardiovascular risk in patients diagnosed with diabetes should consider the time of diagnosis of the disease.
The current study revealed significant differences in body weight and abdominal circumference between males and females. These findings underscore the importance of considering sex-specific factors in the assessment and management of metabolic syndrome among elderly individuals with diabetes. Cardiovascular risk management must consider several factors, including patient´s sex, since this will be a factor to consider in risk stratification, the therapy implemented, and the expected outcomes in terms of metabolic health [
24]. Although the differences in BMI between the sexes were not statistically significant, the higher prevalence of men above the normal BMI range highlights the need for targeted interventions to address overweight and obesity and its associated cardiovascular risks in the elderly population with diabetes [
25,
26]. This finding could prompt a discussion on the role of BMI as a predictor of cardiovascular risk and the importance of comprehensive risk assessment beyond traditional measures. In a study that included 23,961 Chinese patients with diabetes, Hu et al. found that every 5 years of early diagnosis increased the risk of heart disease by 14%. This association was even higher in patients with obesity [
27], showing that BMI should be a factor to consider when calculating cardiovascular risk.
The observed sex disparities in smoking and alcohol consumption underscore the influence of lifestyle behaviours on cardiovascular health outcomes. According to 2019 data from the National Statistics Institute, tobacco was considered the first risk factor for premature death and lost years of healthy life in Portuguese men [
28]. In this national report, although the number of smokers decreased, an increase in the consumption of alcoholic beverages, compared to previous years, was observed. Smoking and alcohol consumption have a significant impact on metabolic syndrome components and cardiovascular risk, leading to the definition of intervention strategies targeting modifiable risk factors in elderly patients with diabetes [
20]. The fact that tobacco and alcohol consumption habits were higher in men than women, may be an important contributor to the increased risk observed in male.
Despite the absence of significant differences between the sexes in clinical parameters such as blood pressure, cholesterol levels, and glycaemic control, it is essential to consider the cumulative impact of these factors on cardiovascular risk in elderly individuals with diabetes [
24]. The finding of no significant sex differences in the prevalence of metabolic syndrome characteristics highlights the uniform burden of metabolic features among the individuals regardless of their sex.
Dyslipidaemia is a crucial factor considered within the diagnosis of metabolic syndrome, according to IDF [
1], and a major factor for developing a CV disease [
29]. The findings of this study suggest that while elderly patients may derive greater benefit from BP control, the effect of the intervention on LDL cholesterol may not appear as pronounced in this population. However, the impact of lowering lipid parameters in the elderly seems similar to the results observed in the prevention of CV events in younger individuals, and no additional safety concerns were found, which justifies the benefit of using lipid-lowering agents in older individuals [
30]. In fact, 56.3% of the patients evaluated in this study were treated for dyslipidaemia. It is important to note that the most recent tool developed to estimate cardiovascular risk in the European general and older population, respectively Score-2 and Score-2-OP, uses the total cholesterol value as an indicator for dyslipidaemia, allowing the estimation of absolute 10-year CVD event risk reduction from risk factor treatment [
29,
31]. However, although diabetes was considered a predictive factor for the construction of these tools, it is not an indicator considered on their operationalization. Hence, the ADVANCE tool was selected to calculate the 10-years risk of fatal CV event in the analysed elderly population with diabetes, based on previous studies [
12,
32,
33]. As mentioned, this calculator considers the time since diagnosis and the presence of long-term complications of diabetes, which are important factors in calculating the 10-year cardiovascular risk. Of note, although the waist circumference is a mandatory factor for the MS diagnosis according to the IDF [
1], it is not considered in any CV risk calculation tool, which may be important, especially in patients with metabolic syndrome. On the other hand, scores from non-alcoholic fatty liver disease (NAFLD) scoring systems like the Fatty Liver Index (FLI), which are strongly associated with high CVD risk [
34], do include waist circumference in their calculation [
35]. BMI is a required parameter when calculating 10-year cardiovascular risk using the DIAbetes Lifetime perspective (DIAL) model. However, the calculator model available online indicates that this tool may underestimate the 10-year and lifetime risk without a history of cardiovascular disease, and that the algorithm is being calibrated [
36]. Although the recalibration has already been published, the new algorithm is not yet available for online calculation [
37].
HbA1c levels, reflecting the glycemic control, are associated with the reduction of non-fatal CV events, such as stroke, and microvascular and macrovascular complications [
38,
39,
40]. For this reason, achieving good glycemic control is currently a recommended goal in the individualized approach to all individuals with diabetes [
41]. However, the IDF criteria for diagnosing MS do not take this parameter into account, but rather fasting blood glucose [
1]. Since HbA1c reflects the average of blood glucose values over the last 3 months, this could be a relevant parameter to consider for uncontrolled diabetes [
42], and therefore a criterion for MS.
The results of this study show that merely effective BP control (<130 mmHg) could lead to a substantial proportion of participants (34.5%) no longer meeting the criteria for a diagnosis of MS. Furthermore, this possible intervention alone could significantly reduce the cardiovascular risk in the studied population, compared to the current risk. This highlights the potential role of aggressive risk factor modification in ameliorating metabolic abnormalities and reducing the overall burden of CV risk in diabetic groups. The fact that the calculator used (ADVANCE) does not allow the control of all the parameters considered in the CV risk calculation and/or MS, such as HbA1c, HDL cholesterol, or total cholesterol, hinders the feasibility to quantitatively calculate the impact of changes in CV risk for each individual. This would be probably a complex task, since the therapeutic objectives for some of these parameters need to be defined, considering the individual characteristics of the patient. Perhaps including even further parameters that are not covered here, such as health literacy, as previously suggested [
43], could be important to reduce the CV risk.
Metabolic syndrome clustering may have an important role in the identification of priority intervention associated with cardiovascular risk, contributing to enhance the importance of early detection and intervention to mitigate adverse outcomes in this population. The burden of CV diseases attributable to metabolic risk factors has been growing during the last decades, and this trend is expected to continue, looking at the global aging and the increase in the life expectancy of the population [
44].
It is important to acknowledge the limitations of the study, such as the cross-sectional design and the use of population mean for albumin creatinine ratio parameter in the risk calculation on ADVANCE calculator due to the lack of information regarding this parameter.
Future research is essential, including longitudinal studies to assess the prospective trajectory of metabolic syndrome and its relationship with cardiovascular outcomes in elderly individuals with diabetes. It would also be important to develop tools, or upgrade the existing ones, that allow the adjustment of other important modifiable parameters in the cardiovascular risk of patients with diabetes and metabolic syndrome, such as HDL cholesterol, triglycerides, fasting glucose and/or HbA1c levels.