G Targher

M Cigolini

M Galiotto

MP Iagulli

S Lombardi

V Miconi

CIGOLINI, Massimo

TARGHER, Giovanni

V. Miconi

M. Galiotto

S. Lombardi

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Serum 25-Hydroxyvitamin D3Concentrations and Prevalence ofCardiovascular Disease Among Type 2Diabetic PatientsMASSIMO CIGOLINI, MD1MARIA PINA IAGULLI, MD1VALENTINO MICONI, MD1MICAELA GALIOTTO, MD1SIMONETTA LOMBARDI, MD1GIOVANNI TARGHER, MD2A ccumulating research suggests thatlow 25-hydroxyv i t amin D3[25(OH)D] concentrations may beinversely associated with type 2 diabetes(1–3), metabolic syndrome (4,5), insulinresistance (6), and cardiovascular disease(CVD) (7).Much remains to be learned, how-ever, about the relationships between vi-tamin D status, metabolic syndrome, andCVD. Furthermore, the published data inhumans arguing that hypovitaminosis Dis a CVD risk factor remain conflicting(8,9).Because this topic has received scantattention and the available information onassociations between vitamin D status andCVD among type 2 diabetic adults waslacking, we examined the relationshipsbetween serum 25(OH)D concentrationsand prevalent CVD in type 2 diabeticadults.RESEARCH DESIGN ANDMETHODS— We studied 459 con-secutive type 2 diabetic outpatients at-tending our clinic after exclusion of thosewith recent acute illness or advancedchronic liver or renal disease and thosewho were taking medications known toalter vitamin D metabolism. The controlgroup consisted of 459 (64% men, age61 6 years) age- and sex-matched non-diabetic volunteers.Biochemical blood measurementswere determined by standard laboratoryprocedures. Serum 25(OH)D concentra-tions were measured during wintermonths using an automated chemilumi-nescence immunoassay (DiaSorin Liai-son). Metabolic syndrome was definedaccording to the Adult Treatment PanelIII criteria (10). Presence of coronary(myocardial infarction, angina, or revas-cularization procedures), cerebrovascular(ischemic stroke, recurrent transient isch-emic attacks, or carotid endarterectomy),and peripheral (claudication, lower-extremity amputation, or revasculariza-tion procedures) vascular disease wasconfirmed by chart review, medical his-tory and examination, and vascular labo-ratory studies.Data are means  SD or frequencies.Skewed variables were logarithmicallytransformed to improve normality beforeanalysis. Statistical analyses included un-paired t test, 2 test, and logistic regres-sion analysis. In this latter analysis, CVDwas considered as an aggregate end pointinclusive of patients with at least one ath-erosclerotic manifestation. In fully ad-justed logistic regression models, sex, age,BMI, smoking, diabetes duration, HbA1c(A1C), LDL cholesterol, calcium, creati-nine, albumin excretion rate, use of med-ications, metabolic syndrome, andinflammatory markers (fibrinogen or C-reactive protein [CRP]) were also in-cluded as covariates. Hypovitaminosis Dwas defined as a serum 25(OH)D concen-tration 20 ng/ml (6,11,12).RESULTS— The mean (SD) 25 (OH)D concentration was 24.1  9.1 ng/ml(median 22.3, range 4.9–91.0) amongcontrol subjects and 19.7 10 ng/ml (17,3–76) among diabetic patients. The age-and sex-adjusted prevalence of hypovita-minosis D was higher in diabetic patientsthan in control subjects (60.8 vs. 42.8%,P  0.001).As shown in Table 1, diabetic patientswith hypovitaminosis D were more likelyto be women and had increased preva-lence of higher values of A1C, triglycer-ides, CRP, and fibrinogen than theirvitamin D–sufficient counterparts. Theproportion using insulin, lipid-lowering,or antiplatelet drugs was higher amongthose with hypovitaminosis D, whereasthe proportion using hypoglycemic drugswas similar in both groups. Age, BMI,waist circumference, diabetes duration,smoking, LDL cholesterol, creatinine, cal-cium, albuminuria, and metabolic syn-drome components did not differbetween the groups.Overall, 143 (31.1%) of 459 patientswere coded positive for CVD. Of these, 81patients had coronary heart disease, 51had cerebrovascular disease, and 41 hadperipheral vascular disease; many sub-jects had CVD in multiple sites. As shownin Table 1, the prevalence of CVD wasgreater among those with hypovitamino-sis D. Similarly, 25(OH)D was lower (P0.01) among those with CVD (17.9  9vs. 20.6  10 ng/ml), coronary disease(17  9 vs. 20.3  10 ng/ml), and cere-brovascular disease (16.9 7 vs. 20 10ng/ml) than among those without CVD.In logistic regression analysis, the as-sociation between hypovitaminosis D andprevalent CVD (odds ratio 1.70 [95% CI1.1–2.6], P 0.01) remained statisticallysignificant after adjustment for classicalrisk factors, A1C, metabolic syndrome,renal function tests, calcium, and use ofmedications (1.77 [1.1–2.9], P 0.023);additional adjustment for fibrinogen (orCRP) levels abolished this association(1.43 [0.9–2.3], P NS). Almost identi-cal results were obtained in models thatincluded the individual components of● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●From the 1Department of Medicine, Observatory of Clinical Epidemiology sen. Giacometti, Hospital ofArzignano, Arzignano, Vicenza, Italy; and the 2Diabetes Unit, Sacro Cuore Hospital, Negrar, Italy.Address correspondence and reprint requests to Giovanni Targher, MD, Diabetes Unit, Ospedale SacroCuore–don G. Calabria, Via Sempreboni, 5, 37024 Negrar (VR), Italy. E-mail: targher@sacrocuore.it.Received for publication 4 November 2005 and accepted 21 November 2005.Abbreviations: 25(OH)D, 25-hydroxyvitamin D3; CRP, C-reactive protein; CVD, cardiovascular disease.A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversionfactors for many substances.© 2006 by the American Diabetes Association.The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be herebymarked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.C a r d i o v a s c u l a r a n d M e t a b o l i c R i s kB R I E F R E P O R T722 DIABETES CARE, VOLUME 29, NUMBER 3, MARCH 2006metabolic syndrome and in models inwhich a more restrictive threshold to de-fine hypovitaminosis D (15 ng/ml) wasused (13).CONCLUSIONS— We found a highprevalence of hypovitaminosis D and astrong inverse association between25(OH)D concentrations and prevalentCVD among type 2 diabetic outpatients.Interestingly, our data suggest that theputative elevated CVD risk associatedwith hypovitaminosis D is probably me-diated by correlated elevations in plasmainflammatory markers. Moreover, sinceelevations of CRP and fibrinogen levelsincrease the risk for CVD (14), these find-ings could help to explain the CVD excesstypically observed during winter months,a period in which vitamin D status tendsto be poor (15), and suggest a rationale forvitamin D supplementation in preventionof CVD, especially in the elderly.Our findings are supported by fewavailable data in humans showing that25(OH)D levels are inversely related tocoronary artery calcifications (16,17) andare lower in patients with myocardial in-farction (7) and by experimental studies(18–22) suggesting that low 25(OH)D in-fluences the activity/expression of macro-phages and lymphocytes in atheroscleroticplaques, thus promoting chronic inflamma-tion in the artery wall. Interestingly, in tworecent clinical trials (23,24), vitamin D sup-plementation markedly reduced serum lev-els of CRP, interleukin-6, and tissue matrixmetalloproteinases. Additionally, low vi-tamin D3 concentrations result in eleva-tions of parathyroid hormone, which hasbeen linked to insulin resistance and sig-nificant increases in the serum levels ofmany acute-phase proteins (25).Evidently, these findings are all con-sistent with the proposition that hypovi-taminosis D and subsequent secondaryhyperparathyroidism may promote theacute phase response and may help to ex-plain how hypovitaminosis D might act asa risk factor for CVD.This study has some limitations. Be-cause our study was a cross-sectional one,the causative nature of the associationscannot be established. Additionally, para-thyroid hormone and 1,25(OH)D werenot measured in this study. Further inves-tigation is necessary to evaluate whetherhypovitaminosis D is associated with in-cident CVD among type 2 diabetic adultsand to determine possible mechanisms ofany preventive effect from vitamin D sup-plementation against CVD.References1. Boucher BJ, Mannan N, Noonan K, HalesCN, Evans SJ: Glucose intolerance andimpairment of insulin secretion in rela-tion to vitamin D deficiency in East Lon-don Asians. Diabetologia 38:1239–1245,19952. Isaia G, Giorgino R, Adami S: High prev-alence of hypovitaminosis D in femaletype 2 diabetic population (Letter). Dia-betes Care 24:1496, 20013. Scragg R, Sowers M, Bell C: Serum 25-hydroxyvitamin D, diabetes, and ethnic-ity in the Third National Health andNutrition Examination Survey. DiabetesCare 27:2813–2818, 20044. Boucher BJ: Inadequate vitamin D status:does it contribute to the disorders com-prising syndrome X? Br J Nutr 79:315–327, 19985. Ford ES, Ajani UA, McGuire LC, Liu S:Concentrations of serum vitamin D andthe metabolic syndrome among U.S.adults. Diabetes Care 28:1228–1230,20056. Chiu KC, Chu A, Go VL, Saad MF: Hypo-vitaminosis D is associated with insulinresistance and beta cell dysfunction. Am JClin Nutr 79:820–825, 20047. 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Am J ClinNutr 79:362–371, 2004Table 1—Baseline characteristics of the study participants, grouped according to vitamin DstatusVariablesWithouthypovitaminosis D25(OH)D:29.0  9 ng/mlWithhypovitaminosis D25(OH)D:13.6  3.3 ng/ml Pn 180 279 —Sex (% men) 74 57 0.001Age (years) 61  7 62  7 NSBMI (kg/m2) 29.2  4.5 29.7  5.1 NSWaist circumference (cm) 106.8  12 107  12 NSDiabetes duration (years) 11  8 12  8 NSDiet only (%) 17 14 NSOral hypoglycemic agents only (%) 64 57 NSInsulin treatment (%) 19 29 0.01Statin users (%) 20.6 31.2 0.01Aspirin users (%) 20.6 33.7 0.01Current smokers (%) 16.7 19.7 NSSystolic blood pressure (mmHg) 144  18 145  17 NSDiastolic blood pressure (mmHg) 80  7 80  8 NSA1C (%) 7.0  1.3 7.4  1.3 0.01(ln)triglycerides (mmol/l) 1.74  0.8 2.02  1.3 0.01HDL cholesterol (mmol/l) 1.33  0.3 1.36  0.4 NSLDL cholesterol (mmol/l) 3.49  0.9 3.40  0.9 NSCreatinine (mol/l) 74  15 76  18 NSCalcium (mmol/l) 2.35  0.1 2.38  0.2 NSFibrinogen (g/l) 4.02  0.9 4.56  0.9 0.001(ln)hs-CRP (mg/l) 3.85  5.4 5.10  6.7 0.001Microalbuminuria (%) 18 18.4 NSMacroalbuminuria (%) 5.8 6.5 NSAdult Treatment Panel III: metabolicsyndrome (%)78.7 84.2 NSCardiovascular disease (%)“Aggregate” end point 24.4 35.5 0.01Coronary 9.5 22.9 0.001Cerebrovascular 7.8 13.5 0.06Peripheral 9.9 8.0 NSData are the means  SD, unless otherwise indicated. 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Barsony J, Prufer K: Vitamin D receptorsand retinoid X receptors interactions inmotion. Vitam Horm 65:345–376, 200220. Pierce R, Kolodzie M, Parks W: 1,25-di-hydroxyvitamin D3 repress tropoelastinexpression by a posttranscriptional mech-anism. J Biol Chem 267:11593–11599,199221. Veldman C, Cantorna M, DeLuca H: Ex-pression of 1,25 dihydroxyvitamin D3 re-ceptor in the immune system. ArchBiochem Biophys 374:334–338, 200022. Willheim M, Thien R, Schrattbauer K,Bajna E, Holub M, Gruber R, Baier K,Pietschmann P, Reinisch W, Scheiner O,Peterlik M: Regulatory effects of 1alpha,25 dihydroxyvitamin D3 on the cytokineproduction of human peripheral bloodlymphocytes. J Clin Endocrinol Metab 84:3739–3744, 199923. Van den Berghe G, Van Roosbroeck D,Vanhove P, Wouters PJ, De Pourcq L,Bouillon R: Bone turnover in prolongedcritical illness: effect of vitamin D. J ClinEndocrinol Metab 88:4623–4632, 200324. Timms PM, Mannan N, Hitman GA,Noonan K, Mills PG, Syndercombe-CourtD, Aganna E, Price CP, Boucher BJ: Cir-culating MMP9, vitamin D and variationin the TIMP-1 response with VDR geno-type: mechanisms for inflammatory dam-age in chronic disorders? QJM 95:787–796, 200225. McCarty MF: Secondary hyperparathy-roidism promotes the acute phase respon-se:a rationale for supplemental vitamin Din prevention of vascular events in the el-derly. Med Hypotheses 64:1022–1026,2005Vitamin D status and CVD in diabetes724 DIABETES CARE, VOLUME 29, NUMBER 3, MARCH 2006

Serum 25-hydroxyvitamin D3 concentrations and prevalence of cardiovascular disease among type 2 diabetic patients.

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Serum 25-hydroxyvitamin D3 concentrations and prevalence of cardiovascular disease among type 2 diabetic patients.

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