Endocrine DOI 10.1007/s12020-015-0609-7
ORIGINAL ARTICLE
Hypovitaminosis D: a novel risk factor for coronary heart disease in type 2 diabetes? Giovanna Muscogiuri1 • Vincenzo Nuzzo2 • Adriano Gatti3 • Alfonso Zuccoli2 • Silvia Savastano1 • Carolina Di Somma4 • Rosario Pivonello1 • Francesco Orio5,6 Annamaria Colao1
•
Received: 9 November 2014 / Accepted: 15 April 2015 Ó Springer Science+Business Media New York 2015
Abstract Vitamin D (25(OH)D) levels have been associated with cardiovascular disease. Thus, the aim of our study was to investigate the association of 25(OH)D levels with coronary heart disease (CHD) in 698 consecutive type 2 diabetic outpatients. 698 consecutive type 2 diabetic outpatients (25.2 % men, age 66 ± 9 years) and 100 (90 % men, age 65 ± 13 years) age-matched non-diabetic volunteers were enrolled. 25(OH)D assay and the main cardiovascular risk factors were explored. 25(OH)D concentration was 22 ± 10 ng/ml in control subjects and 18.23 ± 10 ng/ml in diabetic patients (p \ 0.01). The prevalence of hypovitaminosis D was higher in diabetic patients than in control subjects (90 vs. 83 %, p \ 0.01). Diabetic subjects with hypovitaminosis D had higher prevalence of high values of A1C (p \ 0.01), BMI (p \ 0.01), LDL cholesterol (p \ 0.01), triglycerides (p \ 0.01), and glycemia (p \ 0.01) than their vitamin D-sufficient counterparts. 25(OH)D and HDL cholesterol were lower (p \ 0.01), while BMI (p \ 0.01), age (p \ 0.01), systolic (p \ 0.01) and diastolic blood pressure (p \ 0.01), diabetes duration (p \ 0.01), A1C (p \ 0.01),
& Giovanna Muscogiuri [email protected] 1
Dipartimento di Medicina Clinica e Chirurgia, Universita` di Napoli ‘‘Federico II’’, via S. Pansini 5, 80131 Naples, Italy
2
Internal Medicine Unit, San Gennaro Hospital, Naples, Italy
3
Diabetology Unit, San Gennaro Hospital, Naples, Italy
4
IRCCS SDN, Naples, Italy
5
Department of Endocrinology, University ‘‘Parthenope’’ Naples, Naples, Italy
6
Endocrinology of Fertile Age, ‘‘S. Giovanni di Dio e Ruggi d’Aragona’’ University Hospital Salerno, Salerno, Italy
glycemia (p \ 0.01), fibrinogen (p \ 0.01), triglycerides (p \ 0.01), and total (p \ 0.01) and LDL cholesterol (p \ 0.01) were higher in diabetic subjects with CHD than diabetic subjects without CHD. At the logistic regression analysis, the association of vitamin D with CHD was lost, while sex (p = 0.026), diabetes duration (p = 0.023), and age (p = 0.024) were the most powerful predictors of CHD. The current study demonstrates that 25(OH)D does not have a direct effect on CHD but may have an indirect effect mediated by cardiovascular risk factors such as diabetes duration, age, and sex. Keywords Vitamin D Hypovitaminosis D Obesity Coronary heart disease Cardiovascular disease Type 2 diabetes
Introduction The classical role of vitamin D is related to bone integrity [1]. However, in addition to its traditional calcium-related effects on the skeleton, hypovitaminosis D has been reported to have a detrimental effect on several other organ systems. In particular, several epidemiological studies have reported an association between low serum of 25(OH)D levels and an increased risk for cardiovascular disease (CVD) such as hypertension [2], stroke [3], and type 2 diabetes [4–6]. Strong evidence supporting the role of vitamin D in the pathogenesis of cardiovascular disease came from many longitudinal studies. The Framingham Offspring Study enrolled 1739 white subjects, free of cardiovascular disease, who were followed up for 5.4 years reporting a stepwise increase in cardiovascular risk across C15, 10 to \15 and \10 ng/ml [7]. A cross-sectional analysis of data from the Third National Health and
123
Endocrine
Nutrition Examination Survey (NHANES) reported a strong and independent association of 25(OH)D deficiency with increased prevalence of coronary heart disease (CHD), heart failure, and peripheral vascular disease [8]. However, the current available data are not straightforward. In fact a subset of the study performed by Messenger et al. [9] in 813 men reported that vitamin D deficiency (\15 ng/ml) was not significantly associated with cardiovascular disease compared to sufficiency ([30 ng/ml). To ascertain the association of hypovitaminosis D with cardiovascular disease, randomized controlled trials of vitamin D supplementation were performed. Although Forman et al. [10] demonstrated a beneficial effect of vitamin D supplementation on systolic blood pressure in black subjects, no effect on cardiovascular risk factors has been reported by Donneyong et al. [11] in a cohort of postmenopausal women. Meta-analyses of vitamin D supplementation studies not designed to assess cardiovascular outcomes as primary endpoints did not find an impact of vitamin D in reducing cardiovascular risk [12, 13]. Thus, the aim of our study was to investigate the association of vitamin D with CHD in a representative sample of type 2 diabetic outpatients, in whom, as well known, the incidence rates of CVD are very high.
Materials and methods We studied 698 consecutive type 2 diabetic outpatients (25.2 % men, age 66 ± 9 years) attending our clinic after exclusion of those with recent acute illness or advanced chronic liver or renal disease and those who were taking medications known to alter vitamin D metabolism. The control group consisted of 100 (90 % men, age 65 ± 13 years) age-matched non-diabetic volunteers. The local Ethics committee approved the protocol, and informed consent was obtained from all participants. In order to avoid seasonal influences on 25(OH)D levels, the study has been carried out from the beginning of November 2013 to the end of January 2014 . Study protocol Height and weight were measured wearing light clothing and no shoes. BMI was calculated as mass in kg divided by the square of height in meters (kg/m2). The presence of coronary (myocardial infarction, angina, or revascularization procedures) was confirmed by chart review, medical history, and examination. All patients had blood samples taken for routine analysis including biochemistry, hemochrome, electrolytes, and 25(OH)D levels the day of the interview. Blood measurements were done in the morning after an 8-h overnight fast. Biochemical blood
123
measurements were determined by standard laboratory procedures. The intra- and inter-assay coefficients of variation were below 10 % for all determinations. Serum levels of 25(OH)D were determined by chemiluminescence immunoassay radioimmunoassay (Liaison; Diasorin, Saluggia, Italy) (intra- and interassay coefficients of variations were 5.8 and 7.8 %, respectively). Statistical analysis The statistical analysis was performed by MedCalc Statistical Software (Mariakerke, Belgium. www.medcalc.be). Data are mean ± SD or frequencies. Statistical analyses included unpaired t test, v2 test, and logistic regression analysis. In logistic regression model, sex, age, BMI, diabetes duration, HbA1c (A1C), LDL cholesterol, HDL cholesterol, triglycerides, creatinine, 25(OH)D, and systolic and diastolic blood pressure were included as covariates. Vitamin D deficiency was defined as a serum 25(OH)D concentration \30 ng/ml.
Results The mean (±SD) 25(OH)D concentration was 22 ± 10 ng/ ml among control subjects and 18.2 ± 10 ng/ml among diabetic patients (p \ 0.01) (Table 1). The prevalence of hypovitaminosis D was higher in diabetic patients than in control subjects (90 vs. 83 %, p \ 0.001). Selecting 30 nmol/l as a cut-off point, diabetic subjects with hypovitaminosis D were similar for age and proportion of male/ female to diabetic subjects without hypovitaminosis D, but diabetic subjects with hypovitaminosis D were more likely to have increased prevalence of higher values of A1C (p \ 0.01), BMI (p \ 0.01), LDL cholesterol (p \ 0.01), triglycerides (p \ 0.01), and glycemia (p \ 0.01) than their vitamin D-sufficient counterparts. Age, diabetes duration, HDL cholesterol, and creatinine did not differ between the groups. Overall, 180 (25.8 %) of 698 diabetic patients were coded positive for CHD. The prevalence of CHD was greater among those with hypovitaminosis D (p \ 0.01). Similarly, 25(OH)D and HDL cholesterol were lower (p \ 0.01) among diabetic subjects with CHD (16.2 ± 8.4) than among diabetic subjects without CHD (18.9 ± 10.4). In addition, diabetic subjects with CHD were older (p \ 0.01) and had higher BMI (p \ 0.01), systolic (p \ 0.01) and diastolic blood pressure (p \ 0.01), diabetes duration (p \ 0.01), A1C (p \ 0.01), glycemia (p \ 0.01), fibrinogen (p \ 0.01), total (p \ 0.01) and LDL cholesterol (p \ 0.01) (Table 2). In diabetic patients, CHD was significantly associated with diabetes duration and this association was consistent when unadjusted [odds ratio 3.5 (95 % CI -1.1 to 4.0); p = 0.01], adjusted for age
Endocrine Table 1 Baseline characteristics of the study participants, grouped according to diabetic subjects and controls
Diabetic subjects
Controls
p
Number (% M)
698
100
Age (years)
66.9 ± 9.2
65.1 ± 13
BMI (kg/m2)
31.1 ± 6.14
32.2 ± 7.23
NS
SBP (mmHg)
135 ± 16.4
143 ± 21.5
\0.01
DBP (mmHg)
80.3 ± 10.9
81.1 ± 11.3
\0.01
NS
Diabetes duration (years)
16.9 ± 8.42
–
–
Glycemia (mg/dl)
95 ± 19.5
198 ± 85.1
\0.01
A1c (%)
4.15 ± 2.28
8.45 ± 2.63
\0.01
Fibrinogen (mg/dl)
355 ± 73.4
402 ± 125
\0.01
Total cholesterol (mg/dl)
197 ± 62.7
203 ± 48.6
\0.01
LDL cholesterol (mg/dl)
125 ± 50.3
128 ± 38.4
\0.01
HDL cholesterol (mg/dl)
50.1 ± 13.6
45 ± 13
\0.01
Triglycerides (mg/dl)
109 ± 51.8
170 ± 112
\0.01
25(OH)D
22 ± 10.7
18.2 ± 10
\0.01
SBP systolic blood pressure, DBP diastolic blood pressure, CHD coronary heart disease
Table 2 Baseline characteristics of the study participants, grouped according to CHD status
Table 3 Logistic regression analysis for metabolic and anthropometric parameters predicting CHD OR
95 % CI
Glycemia (mg/dl)
0.990
0.992–1.00
0.63
A1C (%)
0.89
0.96–1.00
0.28
\0.01
Age (years)
0.97
0.95–0.99
0.02
31.2 ± 5.75
\0.01
BMI (kg/m2)
1.02
0.994–1.00
0.79
142 ± 21.8
145 ± 20.5
\0.01
SBP (mmHg)
0.991
0.996–1.00
0.11
DBP (mmHg)
81.3 ± 11.6
80.7 ± 10.5
\0.01
DBP (mmHg)
1.05
0.98–1.00
0.43
Diabetes duration (years)
16.2 ± 8.47
18.8 ± 8.02
\0.01
Creatinine (mg/dl) Total cholesterol (mg/dl)
1.07 1.03
0.996–1.00 0.998–1.01
0.44 0.31
Triglycerides (mg/dl)
0.997
0.999–1.00
0.26
HDL cholesterol (mg/dl)
0.94
0.97–1.00
0.94
LDL cholesterol (mg/dl)
0.96
0.97–1.03
0.43
Sex
0.60
0.39–0.94
0.02
Diabetes duration (years)
0.96
0.95–0.994
0.02
25(OH)D (nmol/l)
0.37
0.44–2.68
0.84
Subjects without CHD
Subjects with CHD
p
Number (%)
518 (74.2 %)
180 (25.8 %)
\0.01
Age (years)
65.3 ± 9.52
68.4 ± 8.51
BMI (kg/m )
31 ± 6.28
SBP (mmHg)
2
Glycemia (mg/dl)
197 ± 83.1
199 ± 90.9
\0.01
A1c (%)
8.38 ± 2.63
8.64 ± 2.63
\0.01
Fibrinogen (mg/dl)
399 ± 126
411 ± 120
\0.01
Total cholesterol (mg/dl)
197 ± 50.6
205 ± 47.7
\0.01
126 ± 37.4
\0.01
p
LDL cholesterol (mg/dl)
123 ± 41.1
HDL cholesterol (mg/dl)
45.3 ± 12.8
44 ± 13.5
\0.01
The significant parameters were age, sex, and diabetes duration
Triglycerides (mg/ dl)
168 ± 113
174 ± 109
\0.01
SBP systolic blood pressure, DBP diastolic blood pressure, CHD CHD
25(OH)D (nmol/l)
18.9 ± 10.4
16.2 ± 8.40
\0.01
SBP systolic blood pressure, DBP diastolic blood pressure, CHD coronary heart disease
and body mass index [odds ratio 3.9 (95 % CI -1.5 to 4.7); p = 0.03], and adjusted for age, body mass index, and smoking [odds ratio 0.96 (95 % CI 0.95–0.99); p = 0.02]. In addition, predictors of CHD were also male sex [odds ratio 0.6 (95 % CI 0.39–0.94); p = 0.02] and age [odds ratio 0.97 (95 % CI 0.95–0.99); p = 0.02], whereas BMI, HbA1c (A1C), LDL cholesterol, HDL cholesterol,
triglycerides, creatinine, 25(OH)D, and systolic and diastolic blood pressure were not (Table 3).
Discussion In a representative sample of type 2 diabetic outpatients, we found a higher prevalence of hypovitaminosis D (defined as a serum 25(OH)D concentration \30 nmol/l) compared to controls, and in particular, serum 25(OH)D concentration was found to be lower in diabetic subjects
123
Endocrine
who had CHD compared to those without CHD. These findings confirm some previous evidence reporting that hypovitaminosis D is highly prevalent in people with type 2 diabetes [14, 15]. In addition, a recent metanalysis performed by Song et al. [16] confirmed an inverse and significant association between circulating 25(OH)D levels and risk of type 2 diabetes in different populations. Furthermore, our study found lower serum 25(OH)D levels in diabetic subjects with CHD compared to vitamin D-sufficient counterparts without CHD. This result was in agreement with previous studies that point out how the presence of hypovitaminosis D might be considered as a novel risk factor for cardiovascular disease. Wang et al. [18] performed a metanalysis including 65,994 participants demonstrating generally linear, inverse association between circulating 25(OH)-vitamin D ranging from 20 to 60 nmol/l and risk of CVD [17]. As previously reported by Anderson et al., this association may be also mediated by the tight link between hypovitaminosis D and cardiovascular risk factors such as diabetes, hypertension, hyperlipidemia, and peripheral vascular disease. In particular, Cigolini et al. [19] demonstrated that type 2 diabetic individuals with clinically relevant CVD had lower 25(OH)D concentrations than diabetic subjects without hypovitaminosis D, hypothesizing that the link between hypovitaminosis D and cardiovascular disease may be mediated by the tight relationship of vitamin D with inflammatory markers. This finding was subsequently confirmed by the same authors who demonstrated the association of lower 25(OH)D levels as that increased intima media thickness [20] and by Lee et al. [21] who reported an association of arterial stiffness with vitamin D deficiency in diabetic subjects. Joergensen et al. also reported the association of low levels of vitamin D with asymptomatic CAD in type 2 diabetic patients; however, this association was found only in patients with elevated urinary albumin excretion rate [22]. On the contrary, Bonakdaran and Varasteh failed to find an association between vitamin D deficiency and cardiovascular disease in diabetic subjects, although they found an association between vitamin D deficiency and inflammatory markers that could contribute to CVD [23]. In addition, a tight relationship between hypovitaminosis D and CVD has been also found in diabetic subjects with mild kidney dysfunction [24], as well as decreased 25(OH)D serum levels have been associated with cardiovascular markers and established cardiovascular disease in patients with advanced chronic kidney disease [25]. Many biologically plausible mechanisms related to vitamin D properties, including the regulation of the renin–angiotensin system, the suppression of proliferation of vascular smooth muscle cells, the improvement of insulin resistance, an anticoagulant and anti-fibrotic activity, the modulation of macrophage activity, and cytokine
123
production, have been proposed as a link between hypovitaminosis D and cardiovascular disease [26]. However, our results demonstrated that the association between vitamin D and CHD was lost after adjustment for the classical cardiovascular risk factors such as sex, age, BMI, diabetes duration, HbA1c (A1C), LDL cholesterol, HDL cholesterol, triglycerides, creatinine, 25(OH)D, systolic and diastolic blood pressure. Standard risk factors for CHD, such as age, diabetes duration, and sex were found to be strong predictors of CHD. As well known, age and sex are considered both predictors of CVD but they are also tightly related to vitamin D status [27]. Our results were in agreement with those reported by Carnevale et al. [28] that failed to find an association between vitamin D and PTH with intima media thickness in unselected patients. The most likely explanation for these results would be that low concentrations of 25(OH)D in respect to the other multiple well-known cardiovascular risk factors may play a marginal role in the pathogenesis of CHD. Accordingly, CHD would have limited value to test the association of vitamin D status and cardiovascular risk in diabetic subjects. The association of 25(OH)D with several cardiovascular risk factors such as hypertension [2], obesity [29], and insulin resistance [6, 30] suggests that the association between hypovitaminosis D may indirectly interact with vascular tree through its association with cardiovascular risk factors. In agreement with our hypothesis, Maple-Brown et al. [31] reported that hypovitaminosis D has been associated with adverse cardiometabolic risk profile in Aboriginal and Torres Strait Islander Australians, highlighting the association of hypovitaminosis D with several cardiovascular risk factors. This finding was further confirmed by vitamin D supplementation study in patients with type 2 diabetes. In fact, although vitamin D supplementation has been reported to increase 25(OH)D levels, it did not improve insulin resistance and arterial stiffness [32]. The association between hypovitaminosis D and cardiovascular disease has also been investigated in Caribbean patients with type 2 diabetes reporting that hypovitaminosis D was associated with an increased cardiometabolic risk [33]. This study has several strengths, including the large number of participants, the complete nature of the dataset, and the ability for the adjustment of multiple traditional CVD risk factors. However, there are some possible limitations to our study. First, the lack of assessment of calcium and PTH that could represent an indirect mediator of the effect of vitamin D on CHD. Second, the association between vitamin D and CHD may be strong only with lifelong deficiency. Since solar exposure in Italy takes place for the most number of months per year, our cohort may not reflect the effects of sustained life-long vitamin D deficiency. The current analyses were performed in an observational way, and thus, the lack of a followup may
Endocrine
prevent to identify the predictive role of hypovitaminosis D for CHD. Third, the analyses were focused on subjects with CHD thus excluding the potential association of 25(OH)D with other cardiovascular diseases such as cerebrovascular (ischemic stroke, recurrent transient ischemic attacks, or carotid endarterectomy) and peripheral (claudication, lower extremity amputation, or revascularization procedures) vascular disease. Finally, the control group was much smaller than diabetic patients and was age-matched but not sex-matched. In conclusion, our data showed that 25(OH)D does not have a direct link with CHD but could have an indirect association mostly mediated by cardiovascular risk factors such as age and sex. Additional investigations are necessary to evaluate the efficacy of vitamin D supplementation on CHD.
Disclosure This study has not received any specific support. None of the Authors have any conflict of interest to disclose.
References 1. I. Bhan, Vitamin D binding protein and bone health. Int. J. Endocrinol. (2014). doi:10.1155/2014/561214 2. R. Scragg, M. Sowers, C. Bell, Serum 25-hydroxyvitamin D, ethnicity, and blood pressure in the Third National Health and Nutrition Examination Survey. Am. J. Hypertens. 20(7), 713–719 (2007) 3. S. Pilz, H. Dobnig, J.E. Fischer, B. Wellnitz, U. Seelhorst, B.O. Boehm, W. Ma¨rz, Low vitamin D levels predict stroke in patients referred to coronary angiography. Stroke 39(9), 2611–2613 (2008) 4. G. Muscogiuri, G.P. Sorice, R. Ajjan, T. Mezza, S. Pilz, A. Prioletta, R. Scragg, S.L. Volpe, M.D. Witham, A. Giaccari, Can vitamin D deficiency cause diabetes and cardiovascular diseases? Present evidence and future perspectives. Nutr. Metab. Cardiovasc. Dis. 22(2), 81–87 (2012) 5. T. Mezza, G. Muscogiuri, G.P. Sorice, A. Prioletta, E. Salomone, A. Pontecorvi, A. Giaccari, Vitamin D deficiency: a new risk factor for type 2 diabetes? Ann. Nutr. Metab. 61(4), 337–348 (2012) 6. G. Muscogiuri, J. Mitri, C. Mathieu, K. Badenhoop, G. Tamer, F. Orio, T. Mezza, R. Vieth, A. Colao, A. Pittas, Mechanisms in endocrinology: vitamin D as a potential contributor in endocrine health and disease. Eur. J. Endocrinol. 171(3), R101–R110 (2014) 7. T.J. Wang, M.J. Pencina, S.L. Booth, P.F. Jacques, E. Ingelsson, K. Lanier, E.J. Benjamin, R.B. D’Agostino, M. Wolf, R.S. Vasan, Vitamin D deficiency and risk of cardiovascular disease. Circulation 117(4), 503–511 (2008) 8. J. Kendrick, G. Targher, G. Smits, M. Chonchol, 25-Hydroxyvitamin D deficiency is independently associated with cardiovascular disease in the Third National Health and Nutrition Examination Survey. Atherosclerosis. 205(1), 255–260 (2009) 9. W. Messenger, C.M. Nielson, H. Li, T. Beer, E. Barrett-Connor, K. Stone, J. Shannon, Serum and dietary vitamin D and cardiovascular disease risk in elderly men: a prospective cohort study. Nutr. Metab. Cardiovasc. Dis. 22(10), 856–863 (2012)
10. J.P. Forman, J.B. Scott, K. Ng, B.F. Drake, E.G. Suarez, D.L. Hayden, G.G. Bennett, P.D. Chandler, B.W. Hollis, K.M. Emmons, E.L. Giovannucci, C.S. Fuchs, A.T. Chan, Effect of vitamin D supplementation on blood pressure in blacks. Hypertension 61(4), 779–785 (2013) 11. M.M. Donneyong, C.A. Hornung, K.C. Taylor, R.N. Baumgartner, J.A. Myers, C.B. Eaton, E.Z. Gorodeski, L. Klein, L.W. Martin, J.M. Shikany, Y. Song, W. Li, J.E. Manson, Risk of heart failure among postmenopausal women: a secondary analysis of the randomized trial of vitamin D plus calcium of the women’s health initiative. Circ. Heart Fail. (2014). doi:10.1161/CIR CHEARTFAILURE.114.001738 12. L. Wang, J.E. Manson, Y. Song, H.D. Sesso, Systematic review: vitamin D and calcium supplementation in prevention of cardiovascular events. Ann. Intern. Med. 152(5), 315–323 (2010) 13. M.B. Elamin, N.O. Abu Elnour, K.B. Elamin, M.M. Fatourechi, A.A. Alkatib, J.P. Almandoz, H. Liu, M.A. Lane, R.J. Mullan, A. Hazem, P.J. Erwin, D.D. Hensrud, M.H. Murad, V.M. Montori, Vitamin D and cardiovascular outcomes: a systematic review and meta-analysis. J. Clin. Endocrinol. Metab. 96(7), 1931–1942 (2011) 14. L.G. Danescu, S. Levy, J. Levy, Vitamin D and diabetes mellitus. Endocrine 35(1), 11–17 (2009) 15. J. Mitri, A.G. Pittas, Vitamin D and diabetes. Endocrinol. Metab. Clin. North Am. 43(1), 205–232 (2014) 16. Y. Song, L. Wang, A.G. Pittas, L.C. Del Gobbo, C. Zhang, J.E. Manson, F.B. Hu, Blood 25-hydroxy vitamin D levels and incident type 2 diabetes: a meta-analysis of prospective studies. Diabetes Care 36(5), 1422–1428 (2013) 17. L. Wang, Y. Song, J.E. Manson, S. Pilz, W. Ma¨rz, K. Michae¨lsson, A. Lundqvist, S.K. Jassal, E. Barrett-Connor, C. Zhang, C.B. Eaton, H.T. May, J.L. Anderson, H.D. Sesso, Circulating 25-hydroxy-vitamin D and risk of cardiovascular disease: A meta-analysis of prospective studies. Circ. Cardiovasc. Qual. Outcomes. 5(6), 819–829 (2012) 18. J.L. Anderson, H.T. May, B.D. Horne, T.L. Bair, N.L. Hall, J.F. Carlquist, D.L. Lappe´, J.B. Muhlestein, Intermountain Heart Collaborative (IHC) Study Group, Relation of vitamin D deficiency to cardiovascular risk factors, disease status, and incident events in a general healthcare population. Am. J. Cardiol. 106(7), 963–968 (2010) 19. M. Cigolini, M.P. Iagulli, V. Miconi, M. Galiotto, S. Lombardi, G. Targher, Serum 25-hydroxyvitamin D3 concentrations and prevalence of cardiovascular disease among type 2 diabetic patients. Diabetes Care 29(3), 722–724 (2006) 20. G. Targher, L. Bertolini, R. Padovani, L. Zenari, L. Scala, M. Cigolini, G. Arcaro, Serum 25-hydroxyvitamin D3 concentrations and carotid artery intima-media thickness among type 2 diabetic patients. Clin. Endocrinol. (Oxf.) 65(5), 593–597 (2006) 21. J.I. Lee, S.J. Oh, W.C. Ha, H.S. Kwon, T.S. Sohn, H.S. Son, B.Y. Cha, Serum 25-hydroxyvitamin D concentration and arterial stiffness among type 2 diabetes. Diabetes Res. Clin. Pract. 95(1), 42–47 (2012) 22. C. Joergensen, H. Reinhard, A. Schmedes, P.R. Hansen, N. Wiinberg, C.L. Petersen, K. Winther, H.H. Parving, P.K. Jacobsen, P. Rossing, Vitamin D levels and asymptomatic coronary artery disease in type 2 diabetic patients with elevated urinary albumin excretion rate. Diabetes Care 35(1), 168–172 (2012) 23. S. Bonakdaran, A.R. Varasteh, Correlation between serum 25 hydroxy vitamin D3 and laboratory risk markers of cardiovascular diseases in type 2 diabetic patients. Saudi Med. J. 30(4), 509–514 (2009) 24. M. Chonchol, M. Cigolini, G. Targher, Association between 25-hydroxyvitamin D deficiency and cardiovascular disease in type 2 diabetic patients with mild kidney dysfunction. Nephrol. Dial. Transplant. 23(1), 269–274 (2008)
123
Endocrine 25. C. Garcı´a-Canto´n, E. Bosch, I. Auyanet, A. Ramı´rez, P. Rossique, C. Culebras, A. Sa´nchez, A. Toledo, M. Lago, N. Esparza, M.D. Checa, 25 hydroxyvitamin D levels and cardiovascular risk in a cohort of patients with advanced chronic kidney disease. Nefrologia 30(4), 435–442 (2010) 26. G. Targher, I. Pichiri, G. Lippi, Vitamin D, thrombosis, and hemostasis: more than skin deep. Semin. Thromb. Hemost. 38(1), 114–124 (2012) 27. S.S. Sherman, B.W. Hollis, J.D. Tobin, Vitamin D status and related parameters in a healthy population: the effects of age, sex, and season. J. Clin. Endocrinol. Metab. 71(2), 405–413 (1990) 28. V. Carnevale, R. Minonne, A. De Matthaeis, M.A. Annese, P. Tabacco, P. D’Arcangelo, G. D’Amico, A. Scillitani, Carotid intima-media thickness is not associated with vitamin D and PTH levels in patients admitted to an Internal Medicine Department. Endocrine (2014). doi:10.1007/s12020-014-0191-4 29. G. Muscogiuri, G.P. Sorice, A. Prioletta, C. Policola, S. Della Casa, A. Pontecorvi, A. Giaccari, 25-Hydroxyvitamin D concentration correlates with insulin-sensitivity and BMI in obesity. Obesity (Silver Spring) 18(10), 1906–1910 (2010)
123
30. G. Muscogiuri, C. Policola, A. Prioletta, G. Sorice, T. Mezza, A. Lassandro, S. Della Casa, A. Pontecorvi, A. Giaccari, Low levels of 25(OH)D and insulin-resistance: 2 unrelated features or a cause-effect in PCOS? Clin. Nutr. 31(4), 476–480 (2012) 31. L.J. Maple-Brown, J.T. Hughes, Z.X. Lu, K. Jeyaraman, P. Lawton, G.R. Jones, A. Ellis, A. Sinha, A. Cass, R.J. MacIsaac, G. Jerums, K. O’Dea, Serum vitamin D levels, diabetes and cardio-metabolic risk factors in Aboriginal and Torres Strait Islander Australians. Diabetol. Metab. Syndr. 6, 78 (2014) 32. O.H. Ryu, W. Chung, S. Lee, K.S. Hong, M.G. Choi, H.J. Yoo, The effect of high-dose vitamin D supplementation on insulin resistance and arterial stiffness in patients with type 2 diabetes. Korean J. Intern. Med. 29(5), 620–629 (2014) 33. F.L. Ve´layoudom-Ce´phise, L. Larifla, J.P. Donnet, S. Maimaitiming, J. Deloumeaux, A. Blanchet, C. Massart, N. Munoz-Bellili, S. Merle, R. Chout, F. Bonnet, L. Foucan, Vitamin D deficiency, vitamin D receptor gene polymorphisms and cardiovascular risk factors in Caribbean patients with type 2 diabetes. Diabetes Metab. 37(6), 540–545 (2011)
ORIGINAL ARTICLE
Hypovitaminosis D: a novel risk factor for coronary heart disease in type 2 diabetes? Giovanna Muscogiuri1 • Vincenzo Nuzzo2 • Adriano Gatti3 • Alfonso Zuccoli2 • Silvia Savastano1 • Carolina Di Somma4 • Rosario Pivonello1 • Francesco Orio5,6 Annamaria Colao1
•
Received: 9 November 2014 / Accepted: 15 April 2015 Ó Springer Science+Business Media New York 2015
Abstract Vitamin D (25(OH)D) levels have been associated with cardiovascular disease. Thus, the aim of our study was to investigate the association of 25(OH)D levels with coronary heart disease (CHD) in 698 consecutive type 2 diabetic outpatients. 698 consecutive type 2 diabetic outpatients (25.2 % men, age 66 ± 9 years) and 100 (90 % men, age 65 ± 13 years) age-matched non-diabetic volunteers were enrolled. 25(OH)D assay and the main cardiovascular risk factors were explored. 25(OH)D concentration was 22 ± 10 ng/ml in control subjects and 18.23 ± 10 ng/ml in diabetic patients (p \ 0.01). The prevalence of hypovitaminosis D was higher in diabetic patients than in control subjects (90 vs. 83 %, p \ 0.01). Diabetic subjects with hypovitaminosis D had higher prevalence of high values of A1C (p \ 0.01), BMI (p \ 0.01), LDL cholesterol (p \ 0.01), triglycerides (p \ 0.01), and glycemia (p \ 0.01) than their vitamin D-sufficient counterparts. 25(OH)D and HDL cholesterol were lower (p \ 0.01), while BMI (p \ 0.01), age (p \ 0.01), systolic (p \ 0.01) and diastolic blood pressure (p \ 0.01), diabetes duration (p \ 0.01), A1C (p \ 0.01),
& Giovanna Muscogiuri [email protected] 1
Dipartimento di Medicina Clinica e Chirurgia, Universita` di Napoli ‘‘Federico II’’, via S. Pansini 5, 80131 Naples, Italy
2
Internal Medicine Unit, San Gennaro Hospital, Naples, Italy
3
Diabetology Unit, San Gennaro Hospital, Naples, Italy
4
IRCCS SDN, Naples, Italy
5
Department of Endocrinology, University ‘‘Parthenope’’ Naples, Naples, Italy
6
Endocrinology of Fertile Age, ‘‘S. Giovanni di Dio e Ruggi d’Aragona’’ University Hospital Salerno, Salerno, Italy
glycemia (p \ 0.01), fibrinogen (p \ 0.01), triglycerides (p \ 0.01), and total (p \ 0.01) and LDL cholesterol (p \ 0.01) were higher in diabetic subjects with CHD than diabetic subjects without CHD. At the logistic regression analysis, the association of vitamin D with CHD was lost, while sex (p = 0.026), diabetes duration (p = 0.023), and age (p = 0.024) were the most powerful predictors of CHD. The current study demonstrates that 25(OH)D does not have a direct effect on CHD but may have an indirect effect mediated by cardiovascular risk factors such as diabetes duration, age, and sex. Keywords Vitamin D Hypovitaminosis D Obesity Coronary heart disease Cardiovascular disease Type 2 diabetes
Introduction The classical role of vitamin D is related to bone integrity [1]. However, in addition to its traditional calcium-related effects on the skeleton, hypovitaminosis D has been reported to have a detrimental effect on several other organ systems. In particular, several epidemiological studies have reported an association between low serum of 25(OH)D levels and an increased risk for cardiovascular disease (CVD) such as hypertension [2], stroke [3], and type 2 diabetes [4–6]. Strong evidence supporting the role of vitamin D in the pathogenesis of cardiovascular disease came from many longitudinal studies. The Framingham Offspring Study enrolled 1739 white subjects, free of cardiovascular disease, who were followed up for 5.4 years reporting a stepwise increase in cardiovascular risk across C15, 10 to \15 and \10 ng/ml [7]. A cross-sectional analysis of data from the Third National Health and
123
Endocrine
Nutrition Examination Survey (NHANES) reported a strong and independent association of 25(OH)D deficiency with increased prevalence of coronary heart disease (CHD), heart failure, and peripheral vascular disease [8]. However, the current available data are not straightforward. In fact a subset of the study performed by Messenger et al. [9] in 813 men reported that vitamin D deficiency (\15 ng/ml) was not significantly associated with cardiovascular disease compared to sufficiency ([30 ng/ml). To ascertain the association of hypovitaminosis D with cardiovascular disease, randomized controlled trials of vitamin D supplementation were performed. Although Forman et al. [10] demonstrated a beneficial effect of vitamin D supplementation on systolic blood pressure in black subjects, no effect on cardiovascular risk factors has been reported by Donneyong et al. [11] in a cohort of postmenopausal women. Meta-analyses of vitamin D supplementation studies not designed to assess cardiovascular outcomes as primary endpoints did not find an impact of vitamin D in reducing cardiovascular risk [12, 13]. Thus, the aim of our study was to investigate the association of vitamin D with CHD in a representative sample of type 2 diabetic outpatients, in whom, as well known, the incidence rates of CVD are very high.
Materials and methods We studied 698 consecutive type 2 diabetic outpatients (25.2 % men, age 66 ± 9 years) attending our clinic after exclusion of those with recent acute illness or advanced chronic liver or renal disease and those who were taking medications known to alter vitamin D metabolism. The control group consisted of 100 (90 % men, age 65 ± 13 years) age-matched non-diabetic volunteers. The local Ethics committee approved the protocol, and informed consent was obtained from all participants. In order to avoid seasonal influences on 25(OH)D levels, the study has been carried out from the beginning of November 2013 to the end of January 2014 . Study protocol Height and weight were measured wearing light clothing and no shoes. BMI was calculated as mass in kg divided by the square of height in meters (kg/m2). The presence of coronary (myocardial infarction, angina, or revascularization procedures) was confirmed by chart review, medical history, and examination. All patients had blood samples taken for routine analysis including biochemistry, hemochrome, electrolytes, and 25(OH)D levels the day of the interview. Blood measurements were done in the morning after an 8-h overnight fast. Biochemical blood
123
measurements were determined by standard laboratory procedures. The intra- and inter-assay coefficients of variation were below 10 % for all determinations. Serum levels of 25(OH)D were determined by chemiluminescence immunoassay radioimmunoassay (Liaison; Diasorin, Saluggia, Italy) (intra- and interassay coefficients of variations were 5.8 and 7.8 %, respectively). Statistical analysis The statistical analysis was performed by MedCalc Statistical Software (Mariakerke, Belgium. www.medcalc.be). Data are mean ± SD or frequencies. Statistical analyses included unpaired t test, v2 test, and logistic regression analysis. In logistic regression model, sex, age, BMI, diabetes duration, HbA1c (A1C), LDL cholesterol, HDL cholesterol, triglycerides, creatinine, 25(OH)D, and systolic and diastolic blood pressure were included as covariates. Vitamin D deficiency was defined as a serum 25(OH)D concentration \30 ng/ml.
Results The mean (±SD) 25(OH)D concentration was 22 ± 10 ng/ ml among control subjects and 18.2 ± 10 ng/ml among diabetic patients (p \ 0.01) (Table 1). The prevalence of hypovitaminosis D was higher in diabetic patients than in control subjects (90 vs. 83 %, p \ 0.001). Selecting 30 nmol/l as a cut-off point, diabetic subjects with hypovitaminosis D were similar for age and proportion of male/ female to diabetic subjects without hypovitaminosis D, but diabetic subjects with hypovitaminosis D were more likely to have increased prevalence of higher values of A1C (p \ 0.01), BMI (p \ 0.01), LDL cholesterol (p \ 0.01), triglycerides (p \ 0.01), and glycemia (p \ 0.01) than their vitamin D-sufficient counterparts. Age, diabetes duration, HDL cholesterol, and creatinine did not differ between the groups. Overall, 180 (25.8 %) of 698 diabetic patients were coded positive for CHD. The prevalence of CHD was greater among those with hypovitaminosis D (p \ 0.01). Similarly, 25(OH)D and HDL cholesterol were lower (p \ 0.01) among diabetic subjects with CHD (16.2 ± 8.4) than among diabetic subjects without CHD (18.9 ± 10.4). In addition, diabetic subjects with CHD were older (p \ 0.01) and had higher BMI (p \ 0.01), systolic (p \ 0.01) and diastolic blood pressure (p \ 0.01), diabetes duration (p \ 0.01), A1C (p \ 0.01), glycemia (p \ 0.01), fibrinogen (p \ 0.01), total (p \ 0.01) and LDL cholesterol (p \ 0.01) (Table 2). In diabetic patients, CHD was significantly associated with diabetes duration and this association was consistent when unadjusted [odds ratio 3.5 (95 % CI -1.1 to 4.0); p = 0.01], adjusted for age
Endocrine Table 1 Baseline characteristics of the study participants, grouped according to diabetic subjects and controls
Diabetic subjects
Controls
p
Number (% M)
698
100
Age (years)
66.9 ± 9.2
65.1 ± 13
BMI (kg/m2)
31.1 ± 6.14
32.2 ± 7.23
NS
SBP (mmHg)
135 ± 16.4
143 ± 21.5
\0.01
DBP (mmHg)
80.3 ± 10.9
81.1 ± 11.3
\0.01
NS
Diabetes duration (years)
16.9 ± 8.42
–
–
Glycemia (mg/dl)
95 ± 19.5
198 ± 85.1
\0.01
A1c (%)
4.15 ± 2.28
8.45 ± 2.63
\0.01
Fibrinogen (mg/dl)
355 ± 73.4
402 ± 125
\0.01
Total cholesterol (mg/dl)
197 ± 62.7
203 ± 48.6
\0.01
LDL cholesterol (mg/dl)
125 ± 50.3
128 ± 38.4
\0.01
HDL cholesterol (mg/dl)
50.1 ± 13.6
45 ± 13
\0.01
Triglycerides (mg/dl)
109 ± 51.8
170 ± 112
\0.01
25(OH)D
22 ± 10.7
18.2 ± 10
\0.01
SBP systolic blood pressure, DBP diastolic blood pressure, CHD coronary heart disease
Table 2 Baseline characteristics of the study participants, grouped according to CHD status
Table 3 Logistic regression analysis for metabolic and anthropometric parameters predicting CHD OR
95 % CI
Glycemia (mg/dl)
0.990
0.992–1.00
0.63
A1C (%)
0.89
0.96–1.00
0.28
\0.01
Age (years)
0.97
0.95–0.99
0.02
31.2 ± 5.75
\0.01
BMI (kg/m2)
1.02
0.994–1.00
0.79
142 ± 21.8
145 ± 20.5
\0.01
SBP (mmHg)
0.991
0.996–1.00
0.11
DBP (mmHg)
81.3 ± 11.6
80.7 ± 10.5
\0.01
DBP (mmHg)
1.05
0.98–1.00
0.43
Diabetes duration (years)
16.2 ± 8.47
18.8 ± 8.02
\0.01
Creatinine (mg/dl) Total cholesterol (mg/dl)
1.07 1.03
0.996–1.00 0.998–1.01
0.44 0.31
Triglycerides (mg/dl)
0.997
0.999–1.00
0.26
HDL cholesterol (mg/dl)
0.94
0.97–1.00
0.94
LDL cholesterol (mg/dl)
0.96
0.97–1.03
0.43
Sex
0.60
0.39–0.94
0.02
Diabetes duration (years)
0.96
0.95–0.994
0.02
25(OH)D (nmol/l)
0.37
0.44–2.68
0.84
Subjects without CHD
Subjects with CHD
p
Number (%)
518 (74.2 %)
180 (25.8 %)
\0.01
Age (years)
65.3 ± 9.52
68.4 ± 8.51
BMI (kg/m )
31 ± 6.28
SBP (mmHg)
2
Glycemia (mg/dl)
197 ± 83.1
199 ± 90.9
\0.01
A1c (%)
8.38 ± 2.63
8.64 ± 2.63
\0.01
Fibrinogen (mg/dl)
399 ± 126
411 ± 120
\0.01
Total cholesterol (mg/dl)
197 ± 50.6
205 ± 47.7
\0.01
126 ± 37.4
\0.01
p
LDL cholesterol (mg/dl)
123 ± 41.1
HDL cholesterol (mg/dl)
45.3 ± 12.8
44 ± 13.5
\0.01
The significant parameters were age, sex, and diabetes duration
Triglycerides (mg/ dl)
168 ± 113
174 ± 109
\0.01
SBP systolic blood pressure, DBP diastolic blood pressure, CHD CHD
25(OH)D (nmol/l)
18.9 ± 10.4
16.2 ± 8.40
\0.01
SBP systolic blood pressure, DBP diastolic blood pressure, CHD coronary heart disease
and body mass index [odds ratio 3.9 (95 % CI -1.5 to 4.7); p = 0.03], and adjusted for age, body mass index, and smoking [odds ratio 0.96 (95 % CI 0.95–0.99); p = 0.02]. In addition, predictors of CHD were also male sex [odds ratio 0.6 (95 % CI 0.39–0.94); p = 0.02] and age [odds ratio 0.97 (95 % CI 0.95–0.99); p = 0.02], whereas BMI, HbA1c (A1C), LDL cholesterol, HDL cholesterol,
triglycerides, creatinine, 25(OH)D, and systolic and diastolic blood pressure were not (Table 3).
Discussion In a representative sample of type 2 diabetic outpatients, we found a higher prevalence of hypovitaminosis D (defined as a serum 25(OH)D concentration \30 nmol/l) compared to controls, and in particular, serum 25(OH)D concentration was found to be lower in diabetic subjects
123
Endocrine
who had CHD compared to those without CHD. These findings confirm some previous evidence reporting that hypovitaminosis D is highly prevalent in people with type 2 diabetes [14, 15]. In addition, a recent metanalysis performed by Song et al. [16] confirmed an inverse and significant association between circulating 25(OH)D levels and risk of type 2 diabetes in different populations. Furthermore, our study found lower serum 25(OH)D levels in diabetic subjects with CHD compared to vitamin D-sufficient counterparts without CHD. This result was in agreement with previous studies that point out how the presence of hypovitaminosis D might be considered as a novel risk factor for cardiovascular disease. Wang et al. [18] performed a metanalysis including 65,994 participants demonstrating generally linear, inverse association between circulating 25(OH)-vitamin D ranging from 20 to 60 nmol/l and risk of CVD [17]. As previously reported by Anderson et al., this association may be also mediated by the tight link between hypovitaminosis D and cardiovascular risk factors such as diabetes, hypertension, hyperlipidemia, and peripheral vascular disease. In particular, Cigolini et al. [19] demonstrated that type 2 diabetic individuals with clinically relevant CVD had lower 25(OH)D concentrations than diabetic subjects without hypovitaminosis D, hypothesizing that the link between hypovitaminosis D and cardiovascular disease may be mediated by the tight relationship of vitamin D with inflammatory markers. This finding was subsequently confirmed by the same authors who demonstrated the association of lower 25(OH)D levels as that increased intima media thickness [20] and by Lee et al. [21] who reported an association of arterial stiffness with vitamin D deficiency in diabetic subjects. Joergensen et al. also reported the association of low levels of vitamin D with asymptomatic CAD in type 2 diabetic patients; however, this association was found only in patients with elevated urinary albumin excretion rate [22]. On the contrary, Bonakdaran and Varasteh failed to find an association between vitamin D deficiency and cardiovascular disease in diabetic subjects, although they found an association between vitamin D deficiency and inflammatory markers that could contribute to CVD [23]. In addition, a tight relationship between hypovitaminosis D and CVD has been also found in diabetic subjects with mild kidney dysfunction [24], as well as decreased 25(OH)D serum levels have been associated with cardiovascular markers and established cardiovascular disease in patients with advanced chronic kidney disease [25]. Many biologically plausible mechanisms related to vitamin D properties, including the regulation of the renin–angiotensin system, the suppression of proliferation of vascular smooth muscle cells, the improvement of insulin resistance, an anticoagulant and anti-fibrotic activity, the modulation of macrophage activity, and cytokine
123
production, have been proposed as a link between hypovitaminosis D and cardiovascular disease [26]. However, our results demonstrated that the association between vitamin D and CHD was lost after adjustment for the classical cardiovascular risk factors such as sex, age, BMI, diabetes duration, HbA1c (A1C), LDL cholesterol, HDL cholesterol, triglycerides, creatinine, 25(OH)D, systolic and diastolic blood pressure. Standard risk factors for CHD, such as age, diabetes duration, and sex were found to be strong predictors of CHD. As well known, age and sex are considered both predictors of CVD but they are also tightly related to vitamin D status [27]. Our results were in agreement with those reported by Carnevale et al. [28] that failed to find an association between vitamin D and PTH with intima media thickness in unselected patients. The most likely explanation for these results would be that low concentrations of 25(OH)D in respect to the other multiple well-known cardiovascular risk factors may play a marginal role in the pathogenesis of CHD. Accordingly, CHD would have limited value to test the association of vitamin D status and cardiovascular risk in diabetic subjects. The association of 25(OH)D with several cardiovascular risk factors such as hypertension [2], obesity [29], and insulin resistance [6, 30] suggests that the association between hypovitaminosis D may indirectly interact with vascular tree through its association with cardiovascular risk factors. In agreement with our hypothesis, Maple-Brown et al. [31] reported that hypovitaminosis D has been associated with adverse cardiometabolic risk profile in Aboriginal and Torres Strait Islander Australians, highlighting the association of hypovitaminosis D with several cardiovascular risk factors. This finding was further confirmed by vitamin D supplementation study in patients with type 2 diabetes. In fact, although vitamin D supplementation has been reported to increase 25(OH)D levels, it did not improve insulin resistance and arterial stiffness [32]. The association between hypovitaminosis D and cardiovascular disease has also been investigated in Caribbean patients with type 2 diabetes reporting that hypovitaminosis D was associated with an increased cardiometabolic risk [33]. This study has several strengths, including the large number of participants, the complete nature of the dataset, and the ability for the adjustment of multiple traditional CVD risk factors. However, there are some possible limitations to our study. First, the lack of assessment of calcium and PTH that could represent an indirect mediator of the effect of vitamin D on CHD. Second, the association between vitamin D and CHD may be strong only with lifelong deficiency. Since solar exposure in Italy takes place for the most number of months per year, our cohort may not reflect the effects of sustained life-long vitamin D deficiency. The current analyses were performed in an observational way, and thus, the lack of a followup may
Endocrine
prevent to identify the predictive role of hypovitaminosis D for CHD. Third, the analyses were focused on subjects with CHD thus excluding the potential association of 25(OH)D with other cardiovascular diseases such as cerebrovascular (ischemic stroke, recurrent transient ischemic attacks, or carotid endarterectomy) and peripheral (claudication, lower extremity amputation, or revascularization procedures) vascular disease. Finally, the control group was much smaller than diabetic patients and was age-matched but not sex-matched. In conclusion, our data showed that 25(OH)D does not have a direct link with CHD but could have an indirect association mostly mediated by cardiovascular risk factors such as age and sex. Additional investigations are necessary to evaluate the efficacy of vitamin D supplementation on CHD.
Disclosure This study has not received any specific support. None of the Authors have any conflict of interest to disclose.
References 1. I. Bhan, Vitamin D binding protein and bone health. Int. J. Endocrinol. (2014). doi:10.1155/2014/561214 2. R. Scragg, M. Sowers, C. Bell, Serum 25-hydroxyvitamin D, ethnicity, and blood pressure in the Third National Health and Nutrition Examination Survey. Am. J. Hypertens. 20(7), 713–719 (2007) 3. S. Pilz, H. Dobnig, J.E. Fischer, B. Wellnitz, U. Seelhorst, B.O. Boehm, W. Ma¨rz, Low vitamin D levels predict stroke in patients referred to coronary angiography. Stroke 39(9), 2611–2613 (2008) 4. G. Muscogiuri, G.P. Sorice, R. Ajjan, T. Mezza, S. Pilz, A. Prioletta, R. Scragg, S.L. Volpe, M.D. Witham, A. Giaccari, Can vitamin D deficiency cause diabetes and cardiovascular diseases? Present evidence and future perspectives. Nutr. Metab. Cardiovasc. Dis. 22(2), 81–87 (2012) 5. T. Mezza, G. Muscogiuri, G.P. Sorice, A. Prioletta, E. Salomone, A. Pontecorvi, A. Giaccari, Vitamin D deficiency: a new risk factor for type 2 diabetes? Ann. Nutr. Metab. 61(4), 337–348 (2012) 6. G. Muscogiuri, J. Mitri, C. Mathieu, K. Badenhoop, G. Tamer, F. Orio, T. Mezza, R. Vieth, A. Colao, A. Pittas, Mechanisms in endocrinology: vitamin D as a potential contributor in endocrine health and disease. Eur. J. Endocrinol. 171(3), R101–R110 (2014) 7. T.J. Wang, M.J. Pencina, S.L. Booth, P.F. Jacques, E. Ingelsson, K. Lanier, E.J. Benjamin, R.B. D’Agostino, M. Wolf, R.S. Vasan, Vitamin D deficiency and risk of cardiovascular disease. Circulation 117(4), 503–511 (2008) 8. J. Kendrick, G. Targher, G. Smits, M. Chonchol, 25-Hydroxyvitamin D deficiency is independently associated with cardiovascular disease in the Third National Health and Nutrition Examination Survey. Atherosclerosis. 205(1), 255–260 (2009) 9. W. Messenger, C.M. Nielson, H. Li, T. Beer, E. Barrett-Connor, K. Stone, J. Shannon, Serum and dietary vitamin D and cardiovascular disease risk in elderly men: a prospective cohort study. Nutr. Metab. Cardiovasc. Dis. 22(10), 856–863 (2012)
10. J.P. Forman, J.B. Scott, K. Ng, B.F. Drake, E.G. Suarez, D.L. Hayden, G.G. Bennett, P.D. Chandler, B.W. Hollis, K.M. Emmons, E.L. Giovannucci, C.S. Fuchs, A.T. Chan, Effect of vitamin D supplementation on blood pressure in blacks. Hypertension 61(4), 779–785 (2013) 11. M.M. Donneyong, C.A. Hornung, K.C. Taylor, R.N. Baumgartner, J.A. Myers, C.B. Eaton, E.Z. Gorodeski, L. Klein, L.W. Martin, J.M. Shikany, Y. Song, W. Li, J.E. Manson, Risk of heart failure among postmenopausal women: a secondary analysis of the randomized trial of vitamin D plus calcium of the women’s health initiative. Circ. Heart Fail. (2014). doi:10.1161/CIR CHEARTFAILURE.114.001738 12. L. Wang, J.E. Manson, Y. Song, H.D. Sesso, Systematic review: vitamin D and calcium supplementation in prevention of cardiovascular events. Ann. Intern. Med. 152(5), 315–323 (2010) 13. M.B. Elamin, N.O. Abu Elnour, K.B. Elamin, M.M. Fatourechi, A.A. Alkatib, J.P. Almandoz, H. Liu, M.A. Lane, R.J. Mullan, A. Hazem, P.J. Erwin, D.D. Hensrud, M.H. Murad, V.M. Montori, Vitamin D and cardiovascular outcomes: a systematic review and meta-analysis. J. Clin. Endocrinol. Metab. 96(7), 1931–1942 (2011) 14. L.G. Danescu, S. Levy, J. Levy, Vitamin D and diabetes mellitus. Endocrine 35(1), 11–17 (2009) 15. J. Mitri, A.G. Pittas, Vitamin D and diabetes. Endocrinol. Metab. Clin. North Am. 43(1), 205–232 (2014) 16. Y. Song, L. Wang, A.G. Pittas, L.C. Del Gobbo, C. Zhang, J.E. Manson, F.B. Hu, Blood 25-hydroxy vitamin D levels and incident type 2 diabetes: a meta-analysis of prospective studies. Diabetes Care 36(5), 1422–1428 (2013) 17. L. Wang, Y. Song, J.E. Manson, S. Pilz, W. Ma¨rz, K. Michae¨lsson, A. Lundqvist, S.K. Jassal, E. Barrett-Connor, C. Zhang, C.B. Eaton, H.T. May, J.L. Anderson, H.D. Sesso, Circulating 25-hydroxy-vitamin D and risk of cardiovascular disease: A meta-analysis of prospective studies. Circ. Cardiovasc. Qual. Outcomes. 5(6), 819–829 (2012) 18. J.L. Anderson, H.T. May, B.D. Horne, T.L. Bair, N.L. Hall, J.F. Carlquist, D.L. Lappe´, J.B. Muhlestein, Intermountain Heart Collaborative (IHC) Study Group, Relation of vitamin D deficiency to cardiovascular risk factors, disease status, and incident events in a general healthcare population. Am. J. Cardiol. 106(7), 963–968 (2010) 19. M. Cigolini, M.P. Iagulli, V. Miconi, M. Galiotto, S. Lombardi, G. Targher, Serum 25-hydroxyvitamin D3 concentrations and prevalence of cardiovascular disease among type 2 diabetic patients. Diabetes Care 29(3), 722–724 (2006) 20. G. Targher, L. Bertolini, R. Padovani, L. Zenari, L. Scala, M. Cigolini, G. Arcaro, Serum 25-hydroxyvitamin D3 concentrations and carotid artery intima-media thickness among type 2 diabetic patients. Clin. Endocrinol. (Oxf.) 65(5), 593–597 (2006) 21. J.I. Lee, S.J. Oh, W.C. Ha, H.S. Kwon, T.S. Sohn, H.S. Son, B.Y. Cha, Serum 25-hydroxyvitamin D concentration and arterial stiffness among type 2 diabetes. Diabetes Res. Clin. Pract. 95(1), 42–47 (2012) 22. C. Joergensen, H. Reinhard, A. Schmedes, P.R. Hansen, N. Wiinberg, C.L. Petersen, K. Winther, H.H. Parving, P.K. Jacobsen, P. Rossing, Vitamin D levels and asymptomatic coronary artery disease in type 2 diabetic patients with elevated urinary albumin excretion rate. Diabetes Care 35(1), 168–172 (2012) 23. S. Bonakdaran, A.R. Varasteh, Correlation between serum 25 hydroxy vitamin D3 and laboratory risk markers of cardiovascular diseases in type 2 diabetic patients. Saudi Med. J. 30(4), 509–514 (2009) 24. M. Chonchol, M. Cigolini, G. Targher, Association between 25-hydroxyvitamin D deficiency and cardiovascular disease in type 2 diabetic patients with mild kidney dysfunction. Nephrol. Dial. Transplant. 23(1), 269–274 (2008)
123
Endocrine 25. C. Garcı´a-Canto´n, E. Bosch, I. Auyanet, A. Ramı´rez, P. Rossique, C. Culebras, A. Sa´nchez, A. Toledo, M. Lago, N. Esparza, M.D. Checa, 25 hydroxyvitamin D levels and cardiovascular risk in a cohort of patients with advanced chronic kidney disease. Nefrologia 30(4), 435–442 (2010) 26. G. Targher, I. Pichiri, G. Lippi, Vitamin D, thrombosis, and hemostasis: more than skin deep. Semin. Thromb. Hemost. 38(1), 114–124 (2012) 27. S.S. Sherman, B.W. Hollis, J.D. Tobin, Vitamin D status and related parameters in a healthy population: the effects of age, sex, and season. J. Clin. Endocrinol. Metab. 71(2), 405–413 (1990) 28. V. Carnevale, R. Minonne, A. De Matthaeis, M.A. Annese, P. Tabacco, P. D’Arcangelo, G. D’Amico, A. Scillitani, Carotid intima-media thickness is not associated with vitamin D and PTH levels in patients admitted to an Internal Medicine Department. Endocrine (2014). doi:10.1007/s12020-014-0191-4 29. G. Muscogiuri, G.P. Sorice, A. Prioletta, C. Policola, S. Della Casa, A. Pontecorvi, A. Giaccari, 25-Hydroxyvitamin D concentration correlates with insulin-sensitivity and BMI in obesity. Obesity (Silver Spring) 18(10), 1906–1910 (2010)
123
30. G. Muscogiuri, C. Policola, A. Prioletta, G. Sorice, T. Mezza, A. Lassandro, S. Della Casa, A. Pontecorvi, A. Giaccari, Low levels of 25(OH)D and insulin-resistance: 2 unrelated features or a cause-effect in PCOS? Clin. Nutr. 31(4), 476–480 (2012) 31. L.J. Maple-Brown, J.T. Hughes, Z.X. Lu, K. Jeyaraman, P. Lawton, G.R. Jones, A. Ellis, A. Sinha, A. Cass, R.J. MacIsaac, G. Jerums, K. O’Dea, Serum vitamin D levels, diabetes and cardio-metabolic risk factors in Aboriginal and Torres Strait Islander Australians. Diabetol. Metab. Syndr. 6, 78 (2014) 32. O.H. Ryu, W. Chung, S. Lee, K.S. Hong, M.G. Choi, H.J. Yoo, The effect of high-dose vitamin D supplementation on insulin resistance and arterial stiffness in patients with type 2 diabetes. Korean J. Intern. Med. 29(5), 620–629 (2014) 33. F.L. Ve´layoudom-Ce´phise, L. Larifla, J.P. Donnet, S. Maimaitiming, J. Deloumeaux, A. Blanchet, C. Massart, N. Munoz-Bellili, S. Merle, R. Chout, F. Bonnet, L. Foucan, Vitamin D deficiency, vitamin D receptor gene polymorphisms and cardiovascular risk factors in Caribbean patients with type 2 diabetes. Diabetes Metab. 37(6), 540–545 (2011)
