Sánchez et al. Cardiovasc Diabetol (2019) 18:154 https://doi.org/10.1186/s12933-019-0962-6 Cardiovascular Diabetology ORIGINAL INVESTIGATION Open Access Characteristics of atheromatosis in the prediabetes stage: a cross‑sectional investigation of the ILERVAS project Enric Sánchez1†, Àngels Betriu2†, Carolina López‑Cano1, Marta Hernández1, Elvira Fernández2, Francisco Purroy3, Marcelino Bermúdez‑López2, Cristina Farràs‑Sallés4,5, Silvia Barril6,7, Reinald Pamplona8, Ferran Rius1, Cristina Hernández9,10, Rafael Simó9,10* and Albert Lecube1,10* on behalf of the ILERVAS project collaborators Abstract Background: Prediabetes has recently been associated with subclinical atheromatous disease in the middle-aged population. Our aim was to characterize atheromatous plaque burden by the number of affected territories and the total plaque area in the prediabetes stage. Methods: Atheromatous plaque burden (quantity of plaques and total plaque area) was assessed in 12 territories from the carotid and femoral regions using ultrasonography in 6688 non-diabetic middle-aged subjects without car‑ diovascular disease. Prediabetes was defined by glycosylated hemoglobin (HbA1c) between 5.7 and 6.4% according to the American Diabetes Association guidelines. Results: Prediabetes was diagnosed in 33.9% (n = 2269) of the ILERVAS participants. Subjects with prediabetes pre‑ sented a higher prevalence of subclinical atheromatous disease than participants with HbA1c < 5.7% (70.4 vs. 67.5%, p = 0.017). In the population with prediabetes this was observed at the level of the carotid territory (p < 0.001), but not in the femoral arteries. Participants in the prediabetes stage also presented a significantly higher number of affected territories (2 [1;3] vs. 1 [0;3], p = 0.002), with a positive correlation between HbA1c levels and the number of affected territories (r = 0.068, p < 0.001). However, atheromatosis was only significantly (p = 0.016) magnified by prediabetes in those subjects with 3 or more cardiovascular risk factors. The multivariable logistic regression model showed that the well-established cardiovascular risk factors together with HbA1c were independently associated with the presence of atheromatous disease in participants with prediabetes. When males and females were analyzed separately, we found that only men with prediabetes presented both carotid and femoral atherosclerosis, as well as an increase of total plaque area in comparison with non-prediabetic subjects. Conclusions: The prediabetes stage is accompanied by an increased subclinical atheromatous disease only in the presence of other cardiovascular risk factors. Prediabetes modulates the atherogenic effect of cardiovascular risk fac‑ tors in terms of distribution and total plaque area in a sex-dependent manner. Trial registration NCT03228459 (clinicaltrials.gov) Keywords: Cardiovascular risk factors, Glycosylated hemoglobin, Subclinical atheromatous disease, Prediabetes *Correspondence: rafael.simo@vhir.org; alecube@gmail.com † Enric Sánchez and Àngels Betriu contributed equally to this work 1 Endocrinology and Nutrition Department, University Hospital Arnau de Vilanova, Obesity, Diabetes and Metabolism (ODIM) research Group, IRBLleida, University of Lleida, Lleida, Spain Full list of author information is available at the end of the article © The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat​iveco​mmons​.org/licen​ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Sánchez et al. Cardiovasc Diabetol (2019) 18:154 Page 2 of 12 Background Methods The International Diabetes Federation has estimated that Study population, metabolic status and the selection in 2017 there were 451 million individuals with diabetes of patients plus 374 million people with impaired glucose tolerance A total of 6809 subjects were enrolled between January worldwide, with a total expenditure of USD 850 billion 2015 and December 2017 from 30 primary health care [1]. Cardiovascular (CV) disease is the main comorbidity centers in Lleida, Spain. The ILERVAS project is an ongo- of diabetes and is estimated to affect 32.2% of all subjects ing clinical trial dealing with subclinical atheromatous and is responsible for 27% of the total cost of treating dia- disease (ClinicalTrials.gov Identifier: NCT03228459) betes [2, 3]. At diagnosis, many patients with type 2 dia- [13]. The inclusion criteria were as follows: age betes have one or more additional classical risk factors for 45–70 years, no history of cardiovascular disease, and at macrovascular disease and many have evidence of overt least one cardiovascular risk factor (dyslipidemia, blood atherosclerosis [4]. In addition, all phases in the patho- hypertension, obesity, smoking habit or a first degree physiology of plaque formation are enhanced in type relative with premature (< 55 years old in men, < 65 in 2 diabetes, contributing to an accelerated process [5]. women) cardiovascular disease (myocardial infarction, However, symptoms are not always present, and the term stroke and peripheral arterial disease). The exclusion cri- “unrecognized diabetic cardiac impairment” has been teria were any type of diabetes, chronic kidney disease, proposed for individuals that develop CV disease without active neoplasia, a life expectancy of less than 18 months the classic angina-related or heart failure symptoms [6]. and pregnancy. Finally, compared with subjects without diabetes, ather- According to the current American Diabetes Asso- omatous disease in diabetes has special characteristics, ciation guidelines, prediabetes was defined as an HbA1c such as its being more extensive, and affecting multiple between 39 and 47 mmol/mol (5.7 to 6.4%) and normal and more peripheral blood vessels, that makes it more glucose metabolism as an HbA1c < 39 mmol/mol (< 5.7%) ­ 01®, Roche Diag- serious and aggressive [7]. [14]. The HbA1c test was performed in capillary blood The problem increases when we consider that many using a point-of-care device [Cobas B 1 of the atherogenic risk factors are already present in the nostics S.L., Sant Cugat del Vallès, Spain], based on a prediabetic stage, years before the diagnosis of type 2 dia- latex agglutination inhibition immunoassay procedure betes [8]. The milieu that favors CV disease in the predia- that meets the generally accepted performance criteria betes stage is more than hyperglycemia in the nondiabetic for HbA1c [15]. A total of 121 participants with previ- range and the effect of insulin resistance in the vessel ously undiagnosed type 2 diabetes [(HbA1c ≥ 48.0 mmol/ walls. It includes a cluster of different metabolic changes mol (≥ 6.5%)] were excluded from the investigation that that favors the development of atheromatous disease, was finally performed in 6688 subjects. such as low-grade chronic inflammation, endothelial Clinical data regarding the cardiovascular risk factors vasodilator and fibrinolytic dysfunction, and an athero- were obtained from an electronic database (Informa- genic lipoprotein profile [9, 10]. In this way, prospective tion System for the Development of Research in Primary cohort studies have shown how prediabetes [defined as Care, SIDIAP) that comprises anonymized and longitu- impaired fasting glucose, impaired glucose tolerance or dinal information from the Catalan Health Institute. The raised glycated hemoglobin (HbA1c)] is associated with prevalence of dyslipidemia was obtained from patients an increased risk of composite CV disease, coronary who during the study period had a diagnostic code for heart disease and stroke compared with normoglycemia disorders of lipoprotein metabolism according to of the [11]. Similarly, during an 8-years period and compared International Classification of Diseases codes. The inci- to individual with persistent normoglycemia, those who dence of blood hypertension was obtained from subjects shifted from normoglycemia to impaired fasting glu- who had an identification code for hypertensive diseases. cose had a significant increased risk of all-cause mortal- Obesity was defined by a body mass index (BMI) ≥ 30 kg/ ity [12]. Remarkably, the health risk increases in subjects m2. with values as low as 5.6 mmol/L for fasting glucose con- The prescribed antihypertensive, lipid-lowering and centration or 39 mmol/mol for HbA1c. On this basis, it antithrombotic treatments were extracted from pre- is of clinical relevance to evaluate the characteristics of scription- and pharmacy-invoicing databases provided subclinical atheromatous disease in the prediabetes stage by the Catalan Health Service, which are incorporated [11]. yearly into the SIDIAP database. Antihypertensive To shed light on this issue, we performed a cross-sec- medication agents included ACE inhibitors, diuretics, tional study in order to characterize atheromatous plaque ARA II, beta-blockers, calcium antagonists and other burden by the number of affected territories and the total antihypertensives. Lipid-lowering drugs included plaque area in the prediabetes stage. statins, fibrates, ezetimibe and omega-3 fatty acids. Sánchez et al. Cardiovasc Diabetol (2019) 18:154 Page 3 of 12 Antithrombotic treatment consisted of the use of anti- Statistical analysis coagulant or antiplatelet agents. Owing the non-normal distribution of the data detected by the Shapiro–Wilk test, quantitative data was expressed as the median [interquartile range]. Comparisons Evaluation of clinical variables between the prediabetes and non-prediabetes groups Height and body weight were measured without shoes were made using the Mann–Whitney U test for quantita- and in light clothing, and the body mass index (BMI) tive variables, and the Pearson’s Chi-squared test for cat- was obtained. A non-stretchable tape with a preci- egorical variables. The relationship between continuous sion of 0.1 cm was used to assess waist circumference. variables was assessed by the Spearman correlation test. According to a specified protocol, total cholesterol A multivariable logistic regression model for the pres- (mg/dl) levels were assessed in all participants from a ence of subclinical atheromatous disease for the devel- opment cohort was performed including the following REFLOTRON® Plus system (Roche non-fasting dried capillary blood test (fingertip punc- ture) using the ­ confounding elements: sex, age, HbA1c, total cholesterol, Diagnostics, GmbH, Germany) [13]. Quantification of systolic blood pressure, the BMI, waist circumference, the entire lipid profile (HDL cholesterol, LDL choles- smoking habit and medical treatments. The calibration terol and triglycerides) was evaluated only in subjects and discrimination of the multivariable logistic regres- in which total cholesterol was ≥ 200 mg/dL after fasting sion model were evaluated using the goodness of fit Hos- for 6 h or where total cholesterol ≥ 250 mg/dL regard- mer–Lemeshow test and the area under the Receiver less of fasting hours. Operating Characteristic curve, correspondingly. All “p” Blood pressure was measured in triplicate, after 5 min’ values were based on a two-sided test of statistical sig- rest using an automated device [Omron M6 Comfort nificance, and significance was accepted at the level of HEM-7221-E (Omron Healthcare, Kyoto, Japan)] at p < 0.050. All statistical analyses were performed using 2-min intervals, and the mean of the last 2 was calcu- SSPS statistical package (IBM SPSS Statistics for Win- lated. The smoking habit (non-smoker, current or former dows, Version 25.0. Armonk, NY, USA). smoker) was also documented. Smokers who stopped smoking ≥ 1 year prior to recruitment were considered former smokers. Results From the baseline sample of 6809 subjects, prediabetes was diagnosed in 33.3% (n = 2269) of the subjects. The Assessment of atheromatous plaque burden by ultrasound main clinical and metabolic data according to the HbA1c study values are displayed in Table 1. Participants with predia- Bilateral carotid (common, bifurcation, internal and betes were older and presented a higher ratio of women external arteries) and femoral (common and superficial and classical CV risk factors such as dyslipidemia, arteries) areas were explored. The pictures were obtained hypertension and obesity in comparison with the con- by qualified sonographers using an ultrasonic Doppler trol group. The prevalence of subclinical atheromatous Ultrasound Vivid-I (General Electric Healthcare, Wauke- disease in the entire population was significantly higher sha, WI, USA) equipped with probe broadband linear in subjects with prediabetes than in control participants 12L-RS that works at frequencies between 5 and 13 MHz. (70.4% vs. 67.5%, p = 0.017). This difference was at the Standardized and validated scanning and reading pro- expense of carotid territory (49.3% vs. 43.5%, p < 0.001), tocols were used to decrease inter-operator variability and disappeared when only the femoral territory was and type 2 errors [16]. To measure intra and inter rater evaluated (54.1% vs. 52.5%, p = 0.228). When each of the absolute agreement, Fleiss’ kappa for plaque presence six specific territories was analyzed in the left and right and intraclass correlation coefficient for plaque area were side, slightly marked differences were observed in the obtained (Additional file 1: Table S1). The readers were left arteries (Table 2). In addition, when only women unaware of the patients’ clinical histories. were analyzed, the increased prevalence of subclinical Subclinical atheromatosis was defined as the pres- atheromatous disease detected in postmenopausal con- ence of any plaque in the twelve assessed areas [17]. A trol women when compared to premenopausal control plaque was well-defined as a focal intima-media thick- women appeared to be attenuated among those with pre- ness ≥ 1.5 mm protuberant in the lumen [18]. Subjects diabetes (Additional file 1: Table S2). were categorized as having focal (1 territory), intermedi- We observed a significant correlation between ate (2 to 3 territories), or generalized (4 to 12 territories) HbA1c levels and the number of affected territories atheromatous disease. All plaques were measured, and (r = 0.068, p = 0.001), but not with the total plaque area the total plaque area (­ cm2) was assessed [19]. (r = − 0.008, p = 0.609). Participants with prediabetes Sánchez et al. Cardiovasc Diabetol (2019) 18:154 Page 4 of 12 Table 1 Main clinical, metabolic data, medical treatment and atheromatous disease characteristics in the study population according to the presence of prediabetes Prediabetes (n = 2269) Control group (n = 4419) p Women, n (%) 1290 (56.9) 2151 (48.7) < 0.001 Age (years) 59 [54;64] 57 [52;62] < 0.001 HbA1c (mmol/mol) 40 [39;42] 36 [33;37] < 0.001 HbA1c (%) 5.8 [5.7;6.0] 5.4 [5.2;5.5] < 0.001 Dyslipidemia, n (%) 1290 (56.9) 2214 (50.1) < 0.001 Total cholesterol (mg/dL) 206 [183;231] 203 [179;229] 0.002 LDL-cholesterola (mg/dL) 146 [133;164] 145 [129;162] 0.020 HDL-cholesterola (mg/dL) 53 [45;65] 55 [46;67] 0.009 Triglyceridesa (mg/dL) 148 [113;205] 133 [100;183] < 0.001 Lipid-lowering agents, n (%) 534 (23.5) 712 (16.1) < 0.001 Statins, n (%) 478 (21.0) 656 (14,8) < 0.001 Fibrates, n (%) 62 (2.7) 54 (1.2) < 0.001 Ezetimibe, n (%) 8 (0.3) 17 (0.3) 0.838 Omega-3 fatty acids, n (%) 6 (0.2) 0 (0.0) 0.001 Hypertension, n (%) 1048 (46.2) 1617 (36.6) < 0.001 Systolic BP (mm Hg) 132 [120;142] 129 [119;141] < 0.001 Diastolic BP (mm Hg) 81 [75;88] 81 [75;88] 0.764 Pulse pressure (mm Hg) 49 [42;58] 47 [40;56] < 0.001 Antihypertensives, n (%) 911 (40.1) 1305 (29.5) < 0.001 ACE inhibitors, n (%) 430 (18.9) 659 (14.9) < 0.001 ARA II, n (%) 230 (10.1) 334 (7.5) < 0.001 Diuretics, n (%) 441 (19.4) 586 (13.2) < 0.001 Beta-blockers, n (%) 196 (8.6) 216 (4.8) < 0.001 Calcium antagonists, n (%) 147 (6.4) 210 (4.7) 0.003 Other, n (%) 12 (0.5) 19 (0.4) 0.573 Obesityb, n (%) 817 (36.0) 1176 (26.6) < 0.001 BMI (kg/m2) 29.6 [26.7;33.1] 28.0 [25.1;31.2] < 0.001 Current or former smoker, n (%) 1211 (53.4) 2714 (61.4) < 0.001 Antithrombotics, n (%) 94 (4.1) 115 (2.6) 0.001 Number of CV risk factors 2 [1;3] 2 [1;2] < 0.001 Characteristics of atheromatous disease Presence of any plaque, n (%) 1597 (70.4) 2984 (67.5) 0.017 Carotid territory affected, n (%) 1112 (49.0) 1924 (43.5) < 0.001 Femoral territory affected, n (%) 1227 (54.1) 2321 (52.5) 0.228 Number of affected territories 2 [1;3] 1 [0;3] 0.002 Total plaque area, ­(cm2) 0.96 [0.52;1.62] 0.93 [0.56;1.55] 0.760 Stenotic lesions ≥ 50% 21 (0.9) 23 (0.5) 0.057 Data are expressed as a median [interquartile range] or n (percentage) HbA1c glycosylated hemoglobin, LDL low density lipoprotein, HDL high density lipoprotein, BP blood pressure, BMI body mass index, CV cardiovascular a Determination was done in cases in which total cholesterol was ≥ 200 mg/dL and after fasting for 6 h or total cholesterol ≥ 250 mg/dL regardless of fasting hours b Obesity was defined as a BMI ≥ 30 kg/m2 almost increased twice the number of affected territories 4 affected territories. In addition, no differences in the with plaque [2 (1 to 3) vs. 1 (0 to 3) territories, p = 0.002) carotid plaque area (0.22 [0.12;0.42] vs. 0.20 [0.11;0.41], compared with control subjects and, therefore, were p = 0.555), the femoral plaque area (0.68 [0.29;1.24] vs. more likely to be classified as individuals with general- 0.68 [0.34;1.18], p = 0.683) or the total plaque area (0.96 ized atheromatous disease (19.5% vs. 16.3%, p < 0.001). [0.52;1.62] vs. 0.93 [0.56;1.55], p = 0.760) were observed However, the vast majority (82.6%) presented less than between groups. Sánchez et al. Cardiovasc Diabetol (2019) 18:154 Page 5 of 12 Table 2 Prevalence of subclinical atheromatous disease associated with the presence of atheromatous disease in in each of the six specific territories in left and right participants with prediabetes (Table 3). When both sexes arteries according to the presence of prediabetes were assessed separately, the same parameters excluding Prediabetes Control p HbA1c accounted for subclinical atherosclerosis disease (n = 2269) group in females with prediabetes (Additional file 1: Table S3), (n = 4419) whereas only smoking status, age and systolic blood pres- Left arteries 1297 (57.2) 2395 (54.2) 0.021 sure were the independent variables in males (Additional Common carotid artery, n (%) 95 (4.2) 142 (3.2) 0.041 file 1: Table S4). Bifurcation carotid artery, n (%) 644 (28.4) 1118 (25.3) 0.018 Internal carotid artery, n (%) 350 (15.4) 546 (12.3) 0.002 Discussion External carotid artery, n (%) 31 (1.4) 69 (1.6) 0.534 In the present study we provide evidence that prediabe- Common femoral artery, n (%) 925 (40.8) 1775 (40.2) 0.636 tes modulates the atherogenic effect of cardiovascular Superficial femoral artery, n (%) 152 (6.7) 232 (5.3) 0.016 risk factors in terms of the distribution of plaques and Right arteries 1348 (59.4) 2513 (56.9) 0.046 the total atherosclerotic burden in a sex-dependent man- Common carotid artery, n (%) 68 (3.0) 129 (2.9) 0.376 ner. In this regard, our results suggest that prediabetes Bifurcation carotid artery, n (%) 659 (29.1) 1053 (23.8) < 0.001 and underlying insulin resistance act as an enhancer of Internal carotid artery, n (%) 322 (14.2) 578 (13.1) 0.240 the atherosclerotic process, but only in men with 2 or External carotid artery, n (%) 40 (1.8) 78 (1.8) 0.992 more classical CV risk factors. In addition, the distribu- Common femoral artery, n (%) 1018 (44.9) 1936 (43.8) 0.411 tion of plaques occurred mainly in the carotid territory Superficial femoral artery, n (%) 172 (7.6) 275 (6.2) 0.035 in women whereas a more severe and widespread plaque Data are expressed as a median [interquartile range] or n (percentage) burden was observed in men. Cardiovascular disease in prediabetes When the results were assessed according to sex, the The relationship between prediabetes and subclinical differences regarding subclinical atheromatous disease CV disease has been well-documented [20, 21]. In the were greater among males than females (Fig. 1). Men Heinz Nixdorf Recall Study, a population-based cohort with prediabetes presented not only a higher number of of 2184 without overt CV disease from Germany, par- plaques in both the carotid and femoral regions but also ticipants with prediabetes (fasting plasma glucose ≥ 6.1 an increase of affected territories and total plaque area in but < 7.0 mmol/l) showed a higher prevalence of coro- comparison with age-matched individuals without pre- nary artery calcification than normoglycemic partici- diabetes. By contrast, women with prediabetes only pre- pants [20]. However, the association between impaired sented a higher number of plaques in the carotid region fasting glucose and coronary artery calcification was less and a similar number of affected territories and total pronounced in women [20]. In the Multi-Ethnic Study of plaque area to age-matched women without prediabetes. Atherosclerosis, a cross-sectional study among 5121 par- In the entire population, the quantity of cardiovascular ticipants without type 2 diabetes or CV disease, those in risk factors was correlated with the number of affected the highest quartile of HbA1c showed significantly higher territories with atheromatous plaque (r = 0.223, p < 0.001) values for common and internal carotid intimal-medial and with the total plaque area (r = 0.192, p < 0.001). How- wall thickness in both sexes, but the association between ever, the presence of prediabetes only impacted on the HbA1c and carotid artery calcification was only present burden of subclinical atheromatous disease when sub- in women [21]. On the other hand, in a recent study with jects presented three or more CV risk factors (Fig. 2a). 6434 asymptomatic Korean individuals who underwent Notably, when the analysis was performed taking sex into a coronary computed tomographic angiography, predia- account, we observed that men with prediabetes and two betes was not associated with an increased risk of sub- or more CV risk factors displayed a significantly higher clinical coronary atherosclerosis [22]. Our study adds number of affected territories with atheromatous plaque information by providing the characteristics of the ath- in comparison with men free of prediabetes (Fig. 2b). eromatous process in a population of middle-aged sub- By contrast, we did not find any significant differences jects without previous vascular disease according to the between women with prediabetes and the control group presence of prediabetes. We describe how subjects with regardless of the number of CV risk factors (Fig. 2c). prediabetes suffer a higher prevalence of atheromatous Finally, the multivariable logistic regression model disease, mainly in the carotid territories, when compared showed that smoking habit, male sex, HbA1c, age, sys- with subjects with normal HbA1c. In addition, vascular tolic blood pressure, total cholesterol, BMI and lipid- disease in participants with prediabetes is characterized lowering and antihypertensive drugs were independently by the presence of plaques of a similar area in a higher Sánchez et al. Cardiovasc Diabetol (2019) 18:154 Page 6 of 12 Fig. 1 Atheromatous disease characteristics in the; a men and b women. Data are expressed as a median [interquartile range] or n (percentage) Sánchez et al. Cardiovasc Diabetol (2019) 18:154 Page 7 of 12 Fig. 2 Plot displaying the number of affected territories with atheromatous plaque according to the quantity of cardiovascular risk factors such as dyslipidemia, blood hypertension, obesity, smoking habit or a first degree relative with premature cardiovascular disease in the; a entire population, b men and c women Sánchez et al. Cardiovasc Diabetol (2019) 18:154 Page 8 of 12 Table 3 The multivariable logistic regression model hazard ratio for the presence of coronary artery calcified for presence of atheromatous disease in subjects plaque was only 1.07 (1.01 to 1.13) [23]. This result also in the prediabetes stage supports the modest effect of prediabetes itself as a CV Odds ratio (95% p risk factor. confidence interval) The different impact of prediabetes on atherosclerotic processes in men and women merits some comment. Sex First, it has been suggested that men and women may Women Ref. progress from normoglycemia to overt type 2 diabetes Men 3.37 (2.60 to 4.36) < 0.001 by different ways: more men than women had impaired Age (years) 1.10 (1.07 to 1.12) < 0.001 fasting glucose, whereas women more often had impaired Glycosylated hemoglobin (%) 1.92 (1.09 to 3.38) 0.024 glucose tolerance [24]. Also, in the Framingham Heart Total cholesterol (mg/dL) 1.01 (1.01 to 1.01) < 0.001 Study, the 4-year coronary heart disease event rate Lipid-lowering agents among participants with prediabetes differed accord- No Ref. ing to the prediabetes definition and the participants’ Yes 0.64 (0.50 to 0.83) 0.001 sex [25]. Whether or not the different transitional stage Systolic blood pressure (mm Hg) 1.01 (1.01 to 1.02) < 0.001 from normoglycemia to diabetes has a differential effect Antihypertensive treatment in the atherogenic process is an issue that remains to be No Ref. elucidated. Second, the relative contribution of ageing Yes 0.77 (0.62 to 0.96) 0.018 and menopause itself in the development of CV diseases Body mass index (kg/m2) 0.99 (0.96 to 1.01) 0.234 still remains uncertain [26]. It should be noted that the Waist ­circumferencea youngest women recruited in the LERVAS cohort were Normal Ref. 50 years old. Therefore, the relative protection of women High 1.05 (0.77 to 1.42) 0.762 against prediabetes-induced plaque formation seems to Smoking status be unrelated with estrogen levels. However, the inher- Never Ref. ent difference in circulating testosterone levels between Former 1.89 (1.49 to 2.41) < 0.001 men and women could not be ruled out as an underlying Current 5.23 (3.85 to 7.11) < 0.001 mechanism accounting for the widespread and signifi- Antithrombotic treatment cantly greater plaque detected in men [27]. No Ref. The predilection of prediabetes for the carotid territory Yes 0.82 (0.46 to 1.45) 0.491 deserves attention, particularly when its impact in CV Test of fit Hosmer–Lemeshow 0.586 disease may be markedly different. In an autopsy study, Area under de ROC curve 0.74 (0.72 to 0.76) < 0.001 Dalager et al. described different features in the micro- a High waist circumference was defined as ≥ 102 cm for men and ≥ 88 cm for scopic sections of the carotid and superficial femoral women arteries, probably reflecting different formation pathways [28]. Unlike the femoral arteries, the carotid bifurcation was prone to foam cell lesions and plaque formation, number of affected territories. Overall, our data reinforce and lipid core plaques were more much common in the the idea that CV disease is a progressive defect associated carotid territory in samples from patients who died of with glucose abnormalities, appearing and increasing coronary atherosclerosis [28]. Similarly, in vivo non- throughout the prediabetes stage. In fact, in the subjects invasive magnetic resonance plaque-imaging visual- with prediabetes, HbA1c positively correlates with the number of plaques. However, it should be noted that in ized significant differences in plaque composition, with the population included in our study the total plaque area larger necrotic cores as well as hemorrhaged areas in the was similar to age-matched control subjects. In addi- carotid arteries compared to the femoral arteries [29]. And in clinical practice, the significant correlation found tion, prediabetes was only a trigger for the number of between the stenosis of coronary segments and carotid affected territories when at least 3 classic CV risk factors plaque occurrence disappeared when femoral plaques were present. These findings seriously call into question were evaluated [30]. Therefore, carotid territories are the importance of insulin resistance and the prediabetes more prone to develop complicated plaques than femoral stage as primary factors of atherogenesis in the type 2 arteries, thus explaining different rates in the progression diabetes population. The lack of significance of the waist of atherosclerotic disease and the outcomes of CV events circumference in the multivariable logistic regression in subjects with prediabetes [11, 31]. In this way, results model in both sexes also argues against this assumption. from the Emerging Risk Factors Collaboration revealed In the Coronary Artery Risk Development in Young Adults that the risk of stroke in patients with diabetes mellitus Study, for each 5-year-long duration of prediabetes the Sánchez et al. Cardiovasc Diabetol (2019) 18:154 Page 9 of 12 is increased twofold compared with individuals without insulin resistance indices were strongly related to carotid diabetes mellitus [32]; the risk of recurrent stroke is also intima-media thickness, and plaque presence and area increased [33]. Prediabetes (defined as impaired glucose in patients without diabetes, but were without relevance tolerance or a combination of impaired fasting glucose when femoral atherosclerosis was evaluated [41]. More plus impaired glucose tolerance) has also been associ- recently, Altin et al. [43] showed how common carotid, ated with a higher future risk of stroke (relative risk 1.20, but not femoral, intima media thickness was significantly 95% confidence interval 1.07 to 1.35) [34]. The 10-year higher in 113 patients with insulin resistance (homeo- planned follow-up of the ILERVAS Project will give us stasis model assessment index > 2.5) free of CV disease relevant clinical information on this topic [13]. compared to 112 controls. In our population without Prediabetes duration has been associated with subclini- previous CV events, male participants with prediabetes cal atherosclerosis, suggesting that prevention strategies exhibited a higher prevalence of atheromatous plaque to reverse cumulative exposure to this metabolic transi- both in carotid and femoral territories in comparison tion stage are needed [35]. From the global 374 million with the control group. However, women with predia- people with prediabetes in 2017, only 1.95% will progress betes only presented a higher number of plaques in the to type 2 diabetes per year, suggesting that a substantial carotid region. These findings reinforce the rationale of number of subjects will continue unprotected against selecting the carotid territory for performing a screen- long-term intermediate glycemic elevations [1, 36]. Our ing of subclinical CV disease in those subjects with results suggest that men with at least 2 traditional risk prediabetes. factors represent the target prediabetes sub-population in which the efforts for testing the protective effects Limitations and strengths of anti-atherogenic therapeutic strategies should be This study has some limitations that need to be consid- addressed. ered. First, it is a cross-sectional analysis, so the nature of the study has not allowed us to establish causality. How- Potential pathogenic mechanisms ever, we will be doing a follow-up of the entire popula- The mechanisms which explain the burden of arterial tion until 2028. Second, the three accepted prediabetes plaque associated with prediabetes, and their impact on definitions according to the criteria of the American Dia- different arterial territories, are not yet fully understood. betes Association seem to identify different populations, The role of hemodynamic features and the underlying as often not all the tests identify prediabetes in the same blood vessel structure warrants attention, since vascu- individual [14, 45, 46]. Some advantages have been linked lar anatomy is not uniform for the thickness of intima- to HbA1c, such as that fasting is not required, and the media layer and the left carotid artery originates directly nonappearance of daily alterations in periods of illness or from the aortic arch and is therefore exposed to a con- stress, and its higher preanalytical stability [20]. In addi- stantly higher shear stress [37, 38]. In contrast to the tion, the prediabetes HbA1c-based definitions appears to femoral artery, a transitional zone has been described in be more specific and to provide modest improvements the carotid bifurcation, an artery segment between elas- in risk discrimination for CV disease and other clinical tic and muscular cell types where foam cell lesions and complications than definitions based on fasting plasma lipid core plaque develop at early ages [28, 39]. In addi- glucose [47]. Third, although we have tested HbA1c using tion, in vivo magnetic resonance imaging studies have a point-of-care instrument, the large population included described how the decrease of the lumen area by femo- in our study allowed us to define two well differentiated ral plaque progression is compensated for by positive populations, not only in their HbA1c values but also in remodeling, creating a dissimilar rate of progression of their anthropometric and clinical characteristics. In addi- luminal stenosis between the carotid and femoral arter- tion, we have no available data regarding the duration of ies [40]. The impact of metabolic changes associated with prediabetes in our population. Finally, LDL-cholesterol prediabetes in these selected segments, such as insulin was assessed regardless of the fasting state when total resistance, low-grade chronic inflammation, advanced cholesterol was ≥ 200 mg/dl or only after 6 h of fasting glycation end-products (AGEs) production, dyslipi- when ≥ 250 mg/dl, what it is not the standard recommen- demia or fibrinolytic dysfunction, in the carotid transi- dation. However, it is not very far from the recent new tional zone or in arterial remodeling is unclear [41–44]. lipid guidelines that summarizes that in adults ≥ 20 years The concentration of the endogenous secretory receptor old and not on lipid-lowering therapy (the 80.7% of our for the AGEs receptor in 220 patients with prediabetes population), measurement of either fasting or a non-fast- was significantly lower than in 99 control subjects and ing lipid profile is effective in estimating atherosclerotic was one of the main determinants of the intima-media cardiovascular disease risk and recording baseline LDL- thickness of the common carotid artery [42]. Similarly, cholesterol [48]. Sánchez et al. Cardiovasc Diabetol (2019) 18:154 Page 10 of 12 Conclusions committee (CEIC-1410). The study was conducted according to the ethical guidelines of the Helsinki Declaration and Spanish legislation regarding the In summary, prediabetes is associated with a significantly protection of personal information was also followed. increased burden of atheromatous disease in men with 2 or more CV risk factors. This finding points to this Consent for publication Not applicable. subpopulation as the main target for strategies aimed at reducing CV risk factors and HbA1c. In addition, our Competing interests results suggest that the global impact of prediabetes on The authors declare that they have no competing interests. the atherosclerotic process in the entire population is Author details quite limited. 1 Endocrinology and Nutrition Department, University Hospital Arnau de Vilanova, Obesity, Diabetes and Metabolism (ODIM) research Group, IRBLleida, University of Lleida, Lleida, Spain. 2 Vascular and Renal Translational Research Supplementary information Group, IRBLleida, RedinRen-ISCIII, Lleida, Spain. 3 Stroke Unit, University Supplementary information accompanies this paper at https​://doi. Hospital Arnau de Vilanova, Clinical Neurosciences Group. IRBLleida, University org/10.1186/s1293​3-019-0962-6. of Lleida, Lleida, Spain. 4 Applied Epidemiology Research Group, IRBLleida, Lleida, Spain. 5 Unitat de Suport a la Recerca Lleida, Fundació Institut Universi‑ tari per a la recerca a l’Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), Additional file 1: Table S1. Full results and methodological details Barcelona, Spain. 6 Respiratory Department, University Hospital Arnau de regarding intra and inter rate reliability for plaque presence and plaque Vilanova‑Santa María, Translational Research in Respiratory Medicine, IRBLleida, area by arterial territory. Table S2. Prevalence of subclinical atheromatous University of Lleida, Lleida, Spain. 7 Centro de Investigación Biomédica en Red disease in each of the six specific territories in women according the de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III (ISCIII), menopausal state. Table S3. The multivariable logistic regression model Madrid, Spain. 8 Experimental Medicine Department, IRBLleida, University for the presence of atheromatous disease among female subjects in the of Lleida, Lleida, Spain. 9 Endocrinology and Nutrition Department, University prediabetes stage. Table S4. The multivariable logistic regression model Hospital Vall d’Hebron. Diabetes and Metabolism Research Unit, Vall d’Hebron for the presence of atheromatous disease among male subjects in the Institut de Recerca (VHIR), Autonomous University of Barcelona, Pg. Vall prediabetes stage. d’Hebron 119‑129, 08024 Barcelona, Spain. 10 Centro de Investigación Biomé‑ dica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Madrid, Spain. Abbreviations AGEs: advanced glycation end-products; BMI: body mass index; CV: cardiovas‑ Received: 5 September 2019 Accepted: 2 November 2019 cular; HbA1c: glycosylated hemoglobin; SIDIAP: Information System for the Development of Research in Primary Care. Acknowledgements The ILERVAS project collaborators are: Ferran Barbé, José-Manuel Valdivielso, References Glòria Arqué, Jessica González, Ana Vena, Eva Miquel, Marta Ortega-Bravo, 1. Cho NH, Shaw JE, Karuranga S, Huang Y, da Rocha Fernandes JD, Ohl‑ Gerard Torres, Serafín Cambray, Manuel Portero-Otin, Mariona Jové, Montserrat rogge AW, Malanda B. IDF diabetes atlas: global estimates of diabetes Martínez-Alonso, Eva Castro, Pere Godoy. The authors would like to thank The prevalence for 2017 and projections for 2045. Diabetes Res Clin Pract. Health Bus Staff, Fundació Renal Jaume Arnó, and the Primary Care teams 2018;138:271–81. from Lleida for recruiting subjects and their efforts in the accurate develop‑ 2. American Diabetes Association. Economic costs of diabetes in the US in ment of the ILERVAS project. 2017. Diabetes Care. 2018;41:917–28. 3. Einarson TR, Acs A, Ludwig C, Panton UH. Economic burden of cardio‑ Authors’ contributions vascular disease in type 2 diabetes: a systematic review. Value Health. ES and ÀB recruited patients, collected and analysed data, wrote the first draft 2018;21:881–90. of the manuscript, and had final approval of the version for publication; CL-C, 4. Laakso M, Lehto S. Epidemiology of risk factors for cardiovascular MH, supervised the research, interpreted data, and critically reviewed the draft disease in diabetes and impaired glucose tolerance. Atherosclerosis. of the article; EF, FP, MB-L, CF-S, SB, RP and FR designed the study, supervised 1998;137:S65–73. the statistical analysis, interpreted data, critically revised draft of the article, 5. Yahagi K, Kolodgie FD, Lutter C, Mori H, Romero ME, Finn AV, Virmani R. and had final approval of the version for publication; CH and RS collected Pathology of human coronary and carotid artery atherosclerosis and and analysed data, contributed to the discussion and had final approval of vascular calcification in diabetes mellitus. Arterioscler Thromb Vasc Biol. the version for publication; AL designed the study, supervised the research, 2017;37:191–204. analysed and interpreted data, and wrote the manuscript. All authors read and 6. Schernthaner G, Lotan C, Baltadzhieva-Trendafilova E, Ceponis J, Clodi M, approved the final manuscript. Ducena K, Goncalvesova E, Guja C, Honka M, Janež A, Lalić N, Lehmann R, Nyolczas N, Pauklin P, Rynkiewicz A, Sergienko I, Duvnjak LS. Unrecog‑ Funding nised cardiovascular disease in type 2 diabetes: is it time to act earlier? This work was partially supported by grants from the Diputació de Lleida and Cardiovasc Diabetol. 2018;17:145. the Generalitat de Catalunya (2017SGR696 and SLT0021600250) and Menarini 7. Rana JS, Dunning A, Achenbach S, Al-Mallah M, Budoff MJ, Cademartiri F, Spain S.A. CIBER de Diabetes y Enfermedades Metabólicas Asociadas and Callister TQ, Chang HJ, Cheng VY, Chinnaiyan K, Chow BJ, Cury R, Delago CIBER de Enfermedades Respiratorias are initiatives of the Instituto de Salud A, Feuchtner G, Hadamitzky M, Hausleiter J, Kaufmann P, Karlsberg RP, Kim Carlos III. YJ, Leipsic J, Labounty TM, Lin FY, Maffei E, Raff G, Villines TC, Shaw LJ, Ber‑ man DS, Min JK. 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