Original Article| Volume 10, ISSUE 1, P72-81.e1, January 2016

Deficient serum 25-hydroxyvitamin D is associated with an atherogenic lipid profile: The Very Large Database of Lipids (VLDL-3) study

Published:September 23, 2015DOI:


      • We examine the association between vitamin D (25[OH]D) and an extended lipid panel.
      • We compare deficient 25(OH)D.
      • We adjust for age, sex, HbA1c, insulin, creatinine, and blood urea nitrogen.
      • Deficient 25(OH)D is associated with 5% lower high-density lipoprotein cholesterol.
      • Deficient 25(OH)D is associated with 9% to 26% higher atherogenic lipids.


      Cross-sectional studies have found an association between deficiencies in serum vitamin D, as measured by 25-hydroxyvitamin D (25[OH]D), and an atherogenic lipid profile. These studies have focused on a limited panel of lipid values including low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG).


      Our study examines the relationship between serum 25(OH)D and an extended lipid panel (Vertical Auto Profile) while controlling for age, gender, glycemic status, and kidney function.


      We used the Very Large Database of Lipids, which includes US adults clinically referred for analysis of their lipid profile from 2009 to 2011. Our study focused on 20,360 subjects who had data for lipids, 25(OH)D, age, gender, hemoglobin A1c, insulin, creatinine, and blood urea nitrogen. Subjects were split into groups based on serum 25(OH)D: deficient (<20 ng/mL), intermediate (≥20–30 ng/mL), and optimal (≥30 ng/mL). The deficient group was compared to the optimal group using multivariable linear regression.


      In multivariable-adjusted linear regression, deficient serum 25(OH)D was associated with significantly lower serum HDL-C (−5.1%) and higher total cholesterol (+9.4%), non–HDL-C (+15.4%), directly measured LDL-C (+13.5%), intermediate-density lipoprotein cholesterol (+23.7%), very low–density lipoprotein cholesterol (+19.0%), remnant lipoprotein cholesterol (+18.4%), and TG (+26.4%) when compared with the optimal group.


      Deficient serum 25(OH)D is associated with significantly lower HDL-C and higher directly measured LDL-C, intermediate-density lipoprotein cholesterol, very low–density lipoproteins cholesterol, remnant lipoprotein cholesterol, and TG. Future trials examining vitamin D supplementation and cardiovascular disease risk should consider using changes in an extended lipid panel as an additional outcome measurement.

      Graphical abstract


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        • Murray C.J.
        • Vos T.
        • Lozano R.
        • et al.
        Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990-2010: a systematic analysis for the global burden of disease study 2010.
        Lancet. 2012; 380: 2197-2223
        • Pekkanen J.
        • Linn S.
        • Heiss G.
        • et al.
        Ten-year mortality from cardiovascular disease in relation to cholesterol level among men with and without preexisting cardiovascular disease.
        N Engl J Med. 1990; 322: 1700-1707
        • Kannel W.B.
        Range of serum cholesterol values in the population developing coronary artery disease.
        Am J Cardiol. 1995; 76: 69C-77C
        • McBride P.
        Triglycerides and risk for coronary artery disease.
        Curr Atheroscler Rep. 2008; 10: 386-390
        • Gordon D.J.
        • Rifkind B.M.
        High-density lipoprotein—the clinical implications of recent studies.
        N Engl J Med. 1989; 321: 1311-1316
        • Ponda M.P.
        • Huang X.
        • Odeh M.A.
        • Breslow J.L.
        • Kaufman H.W.
        Vitamin D may not improve lipid levels: a serial clinical laboratory data study.
        Circulation. 2012; 126: 270-277
        • Vacek J.L.
        • Vanga S.R.
        • Good M.
        • Lai S.M.
        • Lakkireddy D.
        • Howard P.A.
        Vitamin D deficiency and supplementation and relation to cardiovascular health.
        Am J Cardiol. 2012; 109: 359-363
        • Jorde R.
        • Figenschau Y.
        • Hutchinson M.
        • Emaus N.
        • Grimnes G.
        High serum 25-hydroxyvitamin D concentrations are associated with a favorable serum lipid profile.
        Eur J Clin Nutr. 2010; 64: 1457-1464
        • Skaaby T.
        • Husemoen L.L.
        • Pisinger C.
        • et al.
        Vitamin D status and changes in cardiovascular risk factors: a prospective study of a general population.
        Cardiology. 2012; 123: 62-70
        • Zerwekh J.E.
        Blood biomarkers of vitamin D status.
        Am J Clin Nutr. 2008; 87: 1087S-1091S
        • Giovannucci E.
        • Liu Y.
        • Hollis B.W.
        • Rimm E.B.
        25-hydroxyvitamin D and risk of myocardial infarction in men: a prospective study.
        Arch Intern Med. 2008; 168: 1174-1180
        • Wang T.J.
        • Pencina M.J.
        • Booth S.L.
        • et al.
        Vitamin D deficiency and risk of cardiovascular disease.
        Circulation. 2008; 117: 503-511
        • Grandi N.C.
        • Breitling L.P.
        • Brenner H.
        Vitamin D and cardiovascular disease: systematic review and meta-analysis of prospective studies.
        Prev Med. 2010; 51: 228-233
        • Leu M.
        • Giovannucci E.
        Vitamin D: epidemiology of cardiovascular risks and events.
        Best Pract Res Clin Endocrinol Metab. 2011; 25: 633-646
        • Kienreich K.
        • Tomaschitz A.
        • Verheyen N.
        • et al.
        Vitamin D and cardiovascular disease.
        Nutrients. 2013; 5: 3005-3021
        • Chowdhury R.
        • Kunutsor S.
        • Vitezova A.
        • et al.
        Vitamin D and risk of cause specific death: systematic review and meta-analysis of observational cohort and randomised intervention studies.
        BMJ. 2014; 348: g1903
        • Theodoratou E.
        • Tzoulaki I.
        • Zgaga L.
        • Ioannidis J.P.
        Vitamin D and multiple health outcomes: umbrella review of systematic reviews and meta-analyses of observational studies and randomised trials.
        BMJ. 2014; 348: g2035
        • Wang H.
        • Xia N.
        • Yang Y.
        • Peng D.Q.
        Influence of vitamin D supplementation on plasma lipid profiles: a meta-analysis of randomized controlled trials.
        Lipids Health Dis. 2012; 11: 42
        • Wang L.
        • Song Y.
        • Manson J.E.
        • et al.
        Circulating 25-hydroxy-vitamin D and risk of cardiovascular disease: a meta-analysis of prospective studies.
        Circ Cardiovasc Qual Outcomes. 2012; 5: 819-829
        • Melamed M.L.
        • Michos E.D.
        • Post W.
        • Astor B.
        25-hydroxyvitamin D levels and the risk of mortality in the general population.
        Arch Intern Med. 2008; 168: 1629-1637
        • Manson J.E.
        • Bassuk S.S.
        Vitamin D research and clinical practice: at a crossroads.
        JAMA. 2015; 313: 1311-1312
        • Martin S.S.
        • Blaha M.J.
        • Elshazly M.B.
        • et al.
        Friedewald-estimated versus directly measured low-density lipoprotein cholesterol and treatment implications.
        J Am Coll Cardiol. 2013; 62: 732-739
        • Rizzo M.
        • Berneis K.
        Should we measure routinely the LDL peak particle size?.
        Int J Cardiol. 2006; 107: 166-170
        • Ahmed H.M.
        • Elshazly M.B.
        • Martin S.S.
        • Blaha M.J.
        • Kulkarni K.R.
        • Jones S.R.
        Ratio of dense to buoyant LDL subclass is associated with LDL density phenotype (VLDL-5).
        Open Chem Biomed Methods J. 2013; 6: 1-5
        • Twickler T.
        • Dallinga-Thie G.M.
        • Chapman M.J.
        • Cohn J.S.
        Remnant lipoproteins and atherosclerosis.
        Curr Atheroscler Rep. 2005; 7: 140-147
        • Twickler T.B.
        • Dallinga-Thie G.M.
        • Cohn J.S.
        • Chapman M.J.
        Elevated remnant-like particle cholesterol concentration: a characteristic feature of the atherogenic lipoprotein phenotype.
        Circulation. 2004; 109: 1918-1925
        • Lamon-Fava S.
        • Herrington D.M.
        • Reboussin D.M.
        • et al.
        Plasma levels of HDL subpopulations and remnant lipoproteins predict the extent of angiographically-defined coronary artery disease in postmenopausal women.
        Arterioscler Thromb Vasc Biol. 2008; 28: 575-579
        • Kawakami A.
        • Yoshida M.
        Remnant lipoproteins and atherogenesis.
        J Atheroscler Thromb. 2005; 12: 73-76
        • Liu L.
        • Wen T.
        • Zheng X.Y.
        • et al.
        Remnant-like particles accelerate endothelial progenitor cells senescence and induce cellular dysfunction via an oxidative mechanism.
        Atherosclerosis. 2009; 202: 405-414
        • Jones S.R.
        • Martin S.S.
        • Brinton E.A.
        Letter by Jones et al regarding article, “Elevated remnant cholesterol causes both low-grade inflammation and ischemic heart disease, whereas elevated low-density lipoprotein cholesterol causes ischemic heart disease without inflammation”.
        Circulation. 2014; 129: e655
        • Del Valle H.B.
        • Yaktine A.L.
        • Taylor C.L.
        • Ross A.C.
        Dietary Reference Intakes For Calcium and Vitamin D.
        National Academies Press, Washington, DC2011
        • Forouhi N.G.
        • Ye Z.
        • Rickard A.P.
        • et al.
        Circulating 25-hydroxyvitamin D concentration and the risk of type 2 diabetes: results from the European prospective investigation into cancer (EPIC)-norfolk cohort and updated meta-analysis of prospective studies.
        Diabetologia. 2012; 55: 2173-2182
        • Forouhi N.G.
        • Luan J.
        • Cooper A.
        • Boucher B.J.
        • Wareham N.J.
        Baseline serum 25-hydroxy vitamin D is predictive of future glycemic status and insulin resistance: the Medical Research Council Ely Prospective Study 1990-2000.
        Diabetes. 2008; 57: 2619-2625
        • Esteghamati A.
        • Aryan Z.
        • Esteghamati A.
        • Nakhjavani M.
        Vitamin D deficiency is associated with insulin resistance in nondiabetics and reduced insulin production in type 2 diabetics.
        Horm Metab Res. 2015; 47: 273-279
        • Kajbaf F.
        • Mentaverri R.
        • Diouf M.
        • Fournier A.
        • Kamel S.
        • Lalau J.D.
        The association between 25-hydroxyvitamin D and hemoglobin A1c levels in patients with type 2 diabetes and stage 1-5 chronic kidney disease.
        Int J Endocrinol. 2014; 2014: 142468
        • Al-Timimi D.J.
        • Ali A.F.
        Serum 25(OH) D in diabetes mellitus type 2: relation to glycaemic control.
        J Clin Diagn Res. 2013; 7: 2686-2688
        • Kostoglou-Athanassiou I.
        • Athanassiou P.
        • Gkountouvas A.
        • Kaldrymides P.
        Vitamin D and glycemic control in diabetes mellitus type 2.
        Ther Adv Endocrinol Metab. 2013; 4: 122-128
        • Kovacic J.C.
        • Castellano J.M.
        • Farkouh M.E.
        • Fuster V.
        The relationships between cardiovascular disease and diabetes: focus on pathogenesis.
        Endocrinol Metab Clin North Am. 2014; 43: 41-57
        • Tak Y.J.
        • Lee J.G.
        • Song S.H.
        • et al.
        The relationship between the level of serum 25-hydroxyvitamin d and renal function in patients without chronic kidney disease: a cross-sectional study.
        J Ren Nutr. 2015; 25: 88-96
        • Kaptein E.M.
        • Yi S.S.
        • Endres D.B.
        • Kaptein J.S.
        • Chan L.S.
        Serum 25-hydroxyvitamin D deficiency: a risk factor for chronic kidney disease in ambulatory indigent patients.
        Endocr Pract. 2014; 20: 236-243
        • Damasiewicz M.J.
        • Magliano D.J.
        • Daly R.M.
        • et al.
        Serum 25-hydroxyvitamin D deficiency and the 5-year incidence of CKD.
        Am J Kidney Dis. 2013; 62: 58-66
        • Sarnak M.J.
        • Levey A.S.
        • Schoolwerth A.C.
        • et al.
        Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention.
        Hypertension. 2003; 42: 1050-1065
        • Alani H.
        • Tamimi A.
        • Tamimi N.
        Cardiovascular co-morbidity in chronic kidney disease: current knowledge and future research needs.
        World J Nephrol. 2014; 3: 156-168
        • Martin S.S.
        • Blaha M.J.
        • Toth P.P.
        • et al.
        Very large database of lipids: rationale and design.
        Clin Cardiol. 2013; 36: 641-648
        • Friedewald W.T.
        • Levy R.I.
        • Fredrickson D.S.
        Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge.
        Clin Chem. 1972; 18: 499-502
        • Kulkarni K.R.
        Cholesterol profile measurement by vertical auto profile method.
        Clin Lab Med. 2006; 26: 787-802
        • Holick M.F.
        • Binkley N.C.
        • Bischoff-Ferrari H.A.
        • et al.
        Evaluation, treatment, and prevention of vitamin D deficiency: an endocrine society clinical practice guideline.
        J Clin Endocrinol Metab. 2011; 96: 1911-1930
        • Fraser A.
        • Williams D.
        • Lawlor D.A.
        Associations of serum 25-hydroxyvitamin D, parathyroid hormone and calcium with cardiovascular risk factors: analysis of 3 NHANES cycles (2001-2006).
        PLoS One. 2010; 5: e13882
        • Ooi E.M.
        • Afzal S.
        • Nordestgaard B.G.
        Elevated remnant cholesterol in 25-hydroxyvitamin D deficiency in the general population: Mendelian randomization study.
        Circ Cardiovasc Genet. 2014; 7: 650-658
        • Lamarche B.
        • Tchernof A.
        • Moorjani S.
        • et al.
        Small, dense low-density lipoprotein particles as a predictor of the risk of ischemic heart disease in men. Prospective results from the Quebec cardiovascular study.
        Circulation. 1997; 95: 69-75
        • Campos H.
        • Genest Jr., J.J.
        • Blijlevens E.
        • et al.
        Low density lipoprotein particle size and coronary artery disease.
        Arterioscler Thromb. 1992; 12: 187-195
        • Austin M.A.
        • Breslow J.L.
        • Hennekens C.H.
        • Buring J.E.
        • Willett W.C.
        • Krauss R.M.
        Low-density lipoprotein subclass patterns and risk of myocardial infarction.
        JAMA. 1988; 260: 1917-1921
        • Reid I.R.
        Effects of calcium supplementation on circulating lipids: potential pharmacoeconomic implications.
        Drugs Aging. 2004; 21: 7-17
        • Zemel M.B.
        • Shi H.
        • Greer B.
        • Dirienzo D.
        • Zemel P.C.
        Regulation of adiposity by dietary calcium.
        FASEB J. 2000; 14: 1132-1138
        • Wortsman J.
        • Matsuoka L.Y.
        • Chen T.C.
        • Lu Z.
        • Holick M.F.
        Decreased bioavailability of vitamin D in obesity.
        Am J Clin Nutr. 2000; 72: 690-693
        • Ertugrul D.T.
        • Yavuz B.
        • Cil H.
        • et al.
        STATIN-D study: comparison of the influences of rosuvastatin and fluvastatin treatment on the levels of 25 hydroxyvitamin D.
        Cardiovasc Ther. 2011; 29: 146-152
        • Perez-Castrillon J.L.
        • Vega G.
        • Abad L.
        • et al.
        Effects of atorvastatin on vitamin D levels in patients with acute ischemic heart disease.
        Am J Cardiol. 2007; 99: 903-905
        • Wood A.D.
        • Secombes K.R.
        • Thies F.
        • et al.
        Vitamin D3 supplementation has no effect on conventional cardiovascular risk factors: a parallel-group, double-blind, placebo-controlled RCT.
        J Clin Endocrinol Metab. 2012; 97: 3557-3568
        • Ponda M.P.
        • Dowd K.
        • Finkielstein D.
        • Holt P.R.
        • Breslow J.L.
        The short-term effects of vitamin D repletion on cholesterol: a randomized, placebo-controlled trial.
        Arterioscler Thromb Vasc Biol. 2012; 32: 2510-2515
        • Bjelakovic G.
        • Gluud L.L.
        • Nikolova D.
        • et al.
        Vitamin D supplementation for prevention of mortality in adults.
        Cochrane Database Syst Rev. 2014; : CD007470
        • Ford J.A.
        • MacLennan G.S.
        • Avenell A.
        • et al.
        Cardiovascular disease and vitamin D supplementation: trial analysis, systematic review, and meta-analysis.
        Am J Clin Nutr. 2014; 100: 746-755
        • Vimaleswaran K.S.
        • Berry D.J.
        • Lu C.
        • et al.
        Causal relationship between obesity and vitamin D status: bi-directional mendelian randomization analysis of multiple cohorts.
        PLoS Med. 2013; 10: e1001383
        • Afzal S.
        • Brondum-Jacobsen P.
        • Bojesen S.E.
        • Nordestgaard B.G.
        Genetically low vitamin D concentrations and increased mortality: Mendelian randomisation analysis in three large cohorts.
        BMJ. 2014; 349: g6330
        • Yokoyama Y.
        • Barnard N.D.
        • Levin S.M.
        • Watanabe M.
        Vegetarian diets and glycemic control in diabetes: a systematic review and meta-analysis.
        Cardiovasc Diagn Ther. 2014; 4: 373-382
        • Carter P.
        • Gray L.J.
        • Talbot D.
        • Morris D.H.
        • Khunti K.
        • Davies M.J.
        Fruit and vegetable intake and the association with glucose parameters: a cross-sectional analysis of the let's prevent diabetes study.
        Eur J Clin Nutr. 2013; 67: 12-17
        • Jorde R.
        • Grimnes G.
        Vitamin D and metabolic health with special reference to the effect of vitamin D on serum lipids.
        Prog Lipid Res. 2011; 50: 303-312
        • Miettinen M.E.
        • Kinnunen L.
        • Leiviska J.
        • et al.
        Association of serum 25-hydroxyvitamin D with lifestyle factors and metabolic and cardiovascular disease markers: population-based cross-sectional study (FIN-D2D).
        PLoS One. 2014; 9: e100235
      1. National Health and Nutrition Examination Survey. 2007-2008 Data Documentation, Codebook, and Frequencies: Glycohemoglobin. Available at: Updated 2012. Accessed July, 2015.