Atherosclerosis is the main pathophysiological substrate of cardiovascular disease (CVD), which is the leading cause of morbidity and mortality in Western countries [1]. The prevalence of CVD increases not only with age but also with the presence of multiple concomitant risk factors, such as arterial hypertension, diabetes mellitus, dyslipidemia, obesity, and sedentary lifestyle [2]. When present together, high blood pressure and metabolic risk factors interact to produce the metabolic syndrome, which leads to a greater total CVD risk than the sum of its individual components [3]. Obesity and insulin resistance play a central role in the pathogenesis of metabolic syndrome [4]. The prevalence of obesity is high in all age groups and continues to rise in most Western countries. Of particular concern is the rising prevalence of weight-related disorders in children and adolescents, which can increase their risk of CVD in later life [5,6]. The economic burden of CVD, including healthcare and nonhealthcare-related costs, is increasing in most developed countries, thus highlighting the importance of these diseases in our milieu [7].

Since the 1980s, the improved survival of children with Down syndrome (DS) has resulted in dramatically improved life expectancy for a growing population of adults [8]. A population-based study in the United States revealed an increase in median age at death of adults with DS from 25 years in 1983 to 49 years in 1997 [9]. This "new" population of adults with DS raises unique clinical issues, which differ from those of the pediatric population with DS or the general population [10]. Obesity and dyslipidemia appear to be more prevalent in both children and adults with DS [11,12,13]. Murdoch et al. [14] found no significant differences in mean total cholesterol and triglyceride levels between adults with and without DS; however, other studies have observed a more atherogenic lipid profile in individuals with DS than in the general population [11,13]. Furthermore, a higher incidence of type 1 diabetes mellitus has also been observed in individuals with DS [15].

Despite the confluence of multiple risk factors for CVD, subclinical atherosclerotic damage, and cardiovascular events remain extremely rare in adults with DS [16,17,18]. In 1977, DS was reported to be an "atheroma-free model"; atheroma was completely absent at autopsy in five institutionalized adults with DS, while atheroma was present in institutionalized adults without DS [14]. Subsequent studies both supported [16] and contradicted this finding [19,20,21]. Based on carotid intima-media thickness or pulse wave velocity, recent studies found no increase in subclinical vascular damage in adults with DS compared to healthy controls, even though both groups had a similarly elevated risk of CVD [17,18]. However, most previous studies were cross-sectional evaluations of single CVD risk factors in small samples and insufficiently powered to generate any hypothesis for this relevant clinical discrepancy, which could have implications for protection from atherosclerosis in the general population. We present a cross-sectional study with a comprehensive assessment of multiple CVD risk factors, focusing on carbohydrate metabolism, lipids, and adiposity in a cohort of adults with DS. Our working hypothesis was that adults with DS would have a higher prevalence of obesity and subsequent metabolic disorders than adults without DS. Our objectives were to study the prevalence of weight-related and metabolic disorders (states of glycemic dysregulation such as impaired fasting glucose, diabetes mellitus, dyslipidemia, and metabolic syndrome) in adults with DS and to describe any differences with a cohort of healthy controls.

The study population comprised 102 participants (51 adults with DS and 51 controls). All participants were included in the analysis of clinical and anthropometric variables. Three adults with DS and 18 controls refused to provide a blood sample. Therefore, the laboratory results correspond to 48 adults with DS and 33 controls.

Abdominal obesity was highly prevalent among adults with DS in our study. Eight out of 10 adults with DS in our sample had a waist-to-height ratio greater than 0.5, and over two-thirds presented overweight or obesity according to their BMI. However, impaired glucose tolerance and insulin resistance were not more frequent among individuals with DS, and no relevant differences in lipid profile were found between the groups.

The proportion of weight-related disorders in our sample is somewhat lower than previously reported. Prasher [12] and Fujiura et al. [30] observed higher rates of obesity among adults with DS (47% of women and 48% of men and 43% of women and 25% of men respectively). Rubin et al. [31] found a higher rate of overweight individuals in this population (56% of women and 45% of men), whereas Melville et al. [11] reported a lower prevalence of obesity. However, direct comparisons with prior series are cumbersome owing to the use of different diagnostic BMI cutoff points. To our knowledge, this is the first report of weight-related disorders in adults with DS living in the community in a Mediterranean setting. In our study, adults with DS ate more daily fruit and vegetables and dietary fiber than controls. Regular use of olive oil in cooking accounted for the excess in dietary fat observed in both groups. These differences could have partially accounted for the lower prevalence of overweight and obesity compared with cohorts in which a Mediterranean diet was not followed [32].

Surprisingly, differences were not observed in insulin resistance parameters or in the lipid profile between groups, even though adults with DS presented higher rates of subclinical hypothyroidism and more regular use of medications which are known to predispose to metabolic disorders, such as selective serotonin uptake inhibitors or neuroleptics [33,34]. These findings contrast with those of prior studies, where lower HDL-C and higher triglyceride levels were consistently documented in children and adults with DS [12,13]. Nevertheless, when carefully evaluated, the mean differences in lipid levels observed in those studies, although statistically significant, were not clinically relevant. Furthermore, despite a higher prevalence of abdominal obesity, previous studies were unable to demonstrate a predominance of metabolic syndrome in adults with DS when compared to persons with other types of intellectual disability or healthy controls [35]. Moreover, the role of subclinical hypothyroidism in lipid metabolism when TSH levels are only moderately elevated (as in our cohort) remains open to debate [36]. Since TSH levels were not related to insulin resistance in our multivariate analysis, we believe that these factors did not play a major role in explaining present results. Moreover, other drugs, such as antipsychotics, were prescribed at a low dose. We agree with Adelekan et al. [13] that a possible explanation for these surprising findings could be the peculiar balance between leptin and adiponectin in individuals with DS. Corsi et al. [37] described relative leptin resistance and higher levels of adiponectin in individuals with DS. Surprisingly, Corsi et al. [37] found that leptin levels decreased with age, whereas adiponectin levels were higher in adults and elderly persons with DS. This pathogenic pathway has yet to be explored. The possible effect of a Mediterranean diet in our population could also explain their improved lipid profile [38].

Our study has several strengths. Biological siblings were used as controls, thus reducing the effect of potential genetic and environmental factors. We collected relevant metabolic and anthropometric variables and performed a multivariate analysis to correct our results for possible confounders. Our inclusion criteria were broad, enabling our results to be generalized to most adults with DS. Our study is also subject to a number of limitations. The loss of data related to the refusal to give a blood sample, especially in the control group, left a small sample for laboratory analysis, thus minimizing potential differences in insulin resistance indexes or in the lipid profile. Furthermore, families willing to participate in our study may have siblings with more complex medical needs.

In this study, the prevalence of weight-related disorders (abdominal obesity, overweight, and global obesity) was very high in adults with DS. However, the lipid profile and the prevalence of insulin resistance and metabolic syndrome in this group was very similar to that of controls. The effect of the Mediterranean diet and the role of the leptin-adiponectin pathway warrant further investigation.