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Vitamin D Levels, MicrovascularComplications, and Mortality inType 1 DiabetesCHRISTEL JOERGENSEN , MD1PETER HOVIND , DMSC1,2ANNE SCHMEDES, PHD3

HANS-HENRIK PARVING , DMSC4PETER R OSSING , DMSC1

OBJECTIVE To evaluate vitamin D as a predictor of all-cause mortality, progression fromnormoalbuminuria to micro- or macroalbuminuria, and the development of background orproliferative retinopathy in patients with type 1 diabetes.

RESEARCH DESIGN ANDMETHODS A prospective observationalfollow-up study inwhich an inception cohort of type 1 diabetic patients was followed from onset of diabetes di-agnosed between 1979 and1984. Plasma vitamin D [25(OH)D3]levels were determined by highperformance liquid chromatography/tandem mass spectrometry in 227 patients before thepatients developed microalbuminuria. Values equal to or below the 10% percentile (15.5

nmol/L) were considered severe vitamin D de

ciency.RESULTS Median (range) vitamin D was 44.6 (1.7161.7) nmol/L.Vitamin D level was notassociated with age, sex, urinary albumin excretion rate (UAER), or blood pressure. Duringfollow-up, 44 (18%) patients died. In a Cox proportional hazards model, the hazard ratiofor mortality in subjects with severe vitamin D de ciency was 2.7 (1.16.7), P = 0.03, afteradjustment for UAER, HbA1c , and conventional cardiovascular risk factors (age, sex, bloodpressure, cholesterol, smoking). Of the 220 patients, 81 (37%) developed microalbuminuriaand 27 (12%) of these progressed to macroalbuminuria. Furthermore, 192 (87%) patientsdeveloped background retinopathy, whereas 34 (15%) progressed to proliferative retinopathy.Severe vitamin D de ciency at baseline did not predict the development of these microvascularcomplications.

CONCLUSIONS In patients with type 1 diabetes, severe vitamin D de ciency indepen-dently predicts all-cause mortality but not development of microvascular complications in theeye and kidney. Whether vitamin D substitution in type 1 diabetic patients can improve theprognosis remains to be investigated.

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H ypovitaminosis D is found to behighly prevalent worldwide (1). Re-cently, low levels of vitamin D havebeen associated with an increased risk of excess all-cause and cardiovascular mor-tality in the general population (2) as wellas in type2 diabetic patients (3). However,to our knowledge theassociation has neverbeen investigated in type 1 diabetic sub-

jects. The levels of plasma vitamin D (25-hydroxyvitamin D3 [25(OH)D3]) varies

considerably among individuals mainly because of differences in sun exposure,skin color, and the presence of risk factorssuch as diabetes or other comorbidities.

In patients with diabetes, an excessmortality in patients with diabetes com-plications hasbeen established (4). Devel-opment and progression of diabeticmicroangiopathy in terms of retinopathy

and nephropathy is known to be closely related to poor metabolic control, elevated

arterial blood pressure, and other risk fac-tors (5,6). Data from studies inexperimen-tal diabetic nephropathy indicate thatvitamin D insuf ciency may also be in-volved in thepathogenesis of albuminuria.In thegeneral population, an inverse asso-ciation is found between the level of vita-min D and the prevalence of albuminuria(7), and limited data from clinical trialsin nondiabetic chronic kidney disease(CKD) patients suggest that treatmentwithparicalcitol (vitaminD receptor analog[VDRA]) may reduce proteinuria (810).Furthermore, recently publisheddata sug-gest that administration of a VDRA on topof blockade of the rennin angiotensin al-dosterone system (RAAS) in patients withtype 2 diabetes and diabetic nephropathy lowers albuminuria (11). Diabetes is theleading cause of CKD and kidney failurein the Western world, but it is unclear if vitamin D insuf ciency contributes to therisk of developing diabetic nephropathy orother microvascular complications. Withthis study we aimed to investigate whethervery low levels of plasma 25(OH)D3 could

predict increased risk of excess mortality as well as development of microvascularcomplications in type 1 diabetic patients.

RESEARCH DESIGN ANDMETHODS Our study sample com-prised all patients newly diagnosed withtype 1 diabetes consecutively admittedto the Steno Diabetes Center between 1September 1979 and 31 August 1984.The inception cohort included 286 pa-tients. Nine patients wereexcluded; sevenbecause of serious mental illness and twobecause of microalbuminuria at the onsetof diabetes. Plasma 25(OH)D3 was ana-lyzed in samples from approximately 3years after diagnosis or the subsequently closest available sample (median [range]years after diagnose = 3.0 [2.39.1]) andbefore any of the patients developed mi-croalbuminuria. Samples were availablein 220 patients.

The patients attended the outpatientclinic every 3 or 4 months as part of routine follow-up. They were treated by diabetologists and nurses according topreviously described guidelines (12).

c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c

From the 1 Steno Diabetes Center, Gentofte, Denmark; the 2 Department of Clinical Physiology, Glostrup Hos-pital, Glostrup, Denmark; the 3 Departmentof Clinical Biochemistry, Lilleblt Hospital, Vejle, Denmark; andthe 4 Department of Medical Endocrinology, Rigshospitalet, Copenhagen University Hospital, Copenhagen,Denmark.

Corresponding author: Christel Joergensen, cijq@steno.dk.Received 30 December 2010 and accepted 27 January 2011.DOI: 10.2337/dc10-2459 2011 by the American Diabetes Association. Readers may use this article as long as the work is properly

cited,theuse iseducationaland notforpro t, andthe work is notaltered. See http://creativecommons.org/ licenses/by-nc-nd/3.0/ for details.

See accompanying editorial, p. 1245.

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They received no speci c intervention.Twenty-four hour urinary albumin excre-tion rate (UAER) was measured in eachpatient at least once a year (12). Develop-ment of persistent microalbuminuria andpersistent macroalbuminuria were de- ned as UAER between 30 and 300 mg/ 24 h and . 300 mg/24 h, respectively, inat least two of three consecutive samples,with an increase of at least 30% above thebaseline level (13,14).

Plasma 25(OH)D3 was measuredfrom samples stored at 2 20C until anal-ysis. All samples were treated and storedunder the same conditions. Plasma 25(OH)D3 is found to be stable when testedafter more than 10 years of storage (15),making long-term epidemiologic studiesof circulatingplasma 25(OH)D3 possible.Before initiation of the current study, wetested the stability of plasma 25(OH)D3in samples taken from this exact cohort. We analyzed plasma 25(OH)D3 in sam-ples taken from the same subjects at thesame time of year and stored for 5, 10, 15,20, and 25 years. No statistical signi cantdifference between mean levels of plasma25(OH)D3 was shown (data not shown).Plasma levels of 25(OH)D3 were de-termined by high performance liquidchromatography/tandem mass spectrom-etry (Department of Clinical Biochemis-try, Lilleblt Hospital, Vejle, Denmark). A plasma 25(OH)D3 value equal to or be-lowthe 10% percentile (15.5nmol/L) was

considered severe vitamin D de ciency in accordance with our previous study on vitamin D and mortality in type 2 di-abetes (3).

Patients were classi ed as smokersif they smoked more than one cigarettea day; smoking history was elicited by questionnaire. Retinopathy was assessedthrough dilated pupils and graded asabsent, background, or proliferative(12).

Statistical analysisBaseline data are from rst assessment 6months after the onset of type 1 diabetes,after initial glycemic stabilization. Vari-ables with skewed distribution are ex-pressed as medians (interquartile range);values for all other variables are means(SD).

For nonnormally distributed vari-ables, comparisons between groups wereperformed using the Mann-Whitney U test, and unpaired Student t tests wereused for normally distributed variables. A x 2 test was used for comparison of cat-egorical variables between groups.

To evaluate whether low vitamin Dlevels predicted all-cause mortality in anexplanatory model, a Cox proportionalhazards regression analysis was performed.Initially, a univariate analysis was per-formed using baseline variables (sex, age,plasma total cholesterol, systolic bloodpressure, UAER, smoking), all which havepreviously been shown to be associatedwith increased all-cause mortality. Resultsare described as hazard ratios (HRs) with95% CIs.

All time-to-event variables were ana-lyzed with a log-rank test and displayedasKaplan-Meier plots according to levels of vitamin D either above or below the lower10% percentile. Two-tailed P values# 0.05 were considered statistically sig-ni cant. All statistical calculations wereperformed using SPSS for Windows, ver-sion 14.0 (SPSS, Chicago, IL)

RESULTS We followed 220 patientsnewly diagnosed with type 1 diabetesfor a median (range) of 26.0 (1.029.0)years. The main baseline patient charac-teristics areshown in Table1. The median(range) vitamin D concentration was 44.6(1.7161.7) nmol/L.

The patients were divided into twosubgroups based on their vitamin D levelbeing either equal to and below or abovethevalue of the lower 10% percentile. Thecut off value for the lower 10% percentilewas vitamin D # 15.5 nmol/L in both men

and women, and 22 (10%) of the 220 in-cluded patients with a vitamin D valuebelow this level. Vitamin D level was notassociated with age, sex, UAER, andblood pressure, but a weak negative

association was found with HbA1c. (R =0.14, P = 0.04).

During follow-up, 44 (20%) of the220 patients died. Seven of the 22 (32%)patients with vitamin D levels # 15.5nmol/L died compared with 37 (19%) of the patients with vitamin D levels . 15.5nmol/L (P = 0.06). Figure 1 shows aKaplan-Meier curve for mortality accord-ing to a vitamin D level equal toandbelow or above the lower 10% percentile. In aCox proportional hazards model, the un-adjusted HR (95% CI) for mortality insubjects with vitamin D levels equal toor below the lower 10% percentile was2.0 (0.94.4), P = 0.1. The associationpersisted and became statistically signi -cant after adjustment for UAER, HbA1c ,and conventional cardiovascular risk fac-tors (age, sex, blood pressure, cholesterol,smoking) (covariate adjusted HR 2.7[1.16.7], P = 0.03). An analysis of vita-min D as a continuous variable in the Coxmodel could not demonstrate a signi -cant relation to all-cause mortality, sug-gesting the relationship is not linear overthe range of vitamin D values.

Microvascular complicationsDuring follow-up, 81 (34%) patients de-veloped persistent microalbuminuria. Of these patients, 6 (27%) had a vitamin Dlevel equal to or below the lower 10%percentile. Of the 81 patients who de-veloped microalbuminuria, 27 (12%)

progressed to persistent macroalbumin-uria, but only 2 of the patients with vitaminD levels equal to or below the lower 10%percentile progressed, corresponding to9%.

Table 1 Baseline clinical and laboratory characteristics of 220 type 1 diabetic patientsin accordance with levels of 25(OH)D3

25(OH)D3. 15.5 nmol/L

25(OH)D3# 15.5 nmol/L P

n 198 22Sex (male/female) 117/81 14/8 1.0 Age (years) 29 (14) 31 (16) 0.BMI (kg/m2 ) 20.6 (2.6) 20.2 (2.9) 0.5HbA1c (%) 9.8 (2.1) 10.6 (2.5) 0.1Urinary albumin excretion (mg/24 h) 9 (614) 9 (511) 0.3Serum creatinine (m mol/L) 80 (14) 77 (16) 0.3Systolic blood pressure (mmHg) 125 (17) 129 (16) 0.3Diastolic blood pressure (mmHg) 78 (11) 79 (10) 0.6Serum cholesterol (mmol/L) 5.5 (1.5) 5.6 (1.4) 0.7Smokers/nonsmoker/former smoker 85/63/50 11/7/4 0.7 Vitamin D, 25(OH)D3 (nmol/L) 46.6 (30.962.7) 11.4 (8.9 11.4) Data are n, means (SD), or medians (interquartile range).

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A Cox proportional hazards modelshowed that low vitamin D levels atbaseline did not predict the development

of micro- or macroalbuminuria (unad- justed HR 1.1 [0.52.4], P = 0.8 and HR 1.3 [0.35.4], P = 0.7, respectively).

A total of 192 (80%) patients devel-oped background retinopathy, and 18(82%) of the patients had vitamin D levelsequal to orbelowthe lower10% percentile.Of the 192 patients, 34 (15%) patientsprogressedto proliferative retinopathy,andone of these patients had low vitamin Dlevel at baseline, corresponding to 5%. Vitamin D levels equal to or below thelower 10% percentile at baseline did notpredict development of background reti-nopathy or proliferative retinopathy (HR 1.1 [0.71.7], P = 0.8 and HR 3.1 [0.422.9], P = 0.3, respectively).

After adjusting for progression pro-moters, the associations between severevitamin D de ciency at baseline and de-velopment or progression of microvascu-lar complications weakened further.

CONCLUSIONS In this 26-yearprospective observational follow-upstudy, we found very low levels of plasma25(OH)D3 (equal to or below the 10%

percentile) after onset of diabetes to be astrong and independent predictor of all-cause mortality in type1 diabetic patients.

This association was not only indepen-dent of glycemic control and conven-tional cardiovascular risk factors, butalso independent of UAER. Severe vita-min D de ciency at baseline did notpredict development or progression of microvascular complications in the eyeand kidney.

Our nding of an associationbetweensevere vitamin D de ciency and increasedrisk of mortality complement recent datafrom epidemiological studies suggestingsimilar associations in other popula-tions. For the general population, a cross-sectional study of 13,331 participantsfrom the National Health and NutritionExamination Survey (NHANES) III (2)showed low vitamin D levels to be associ-ated with all-cause mortality. A study of mainly nondiabetic CKD patients (16)found vitamin D to independently predictall-cause mortality and increased risk of progression to dialysis. Also among pa-tients with nondiabetic end-stage renaldisease, low levels of vitamin D havebeen associated with all-cause mortality (17).

In healthy subjects, vitamin D de- ciency mainly results from inadequatesunlight exposure, skin color, and inad-equate nutritional supply of vitamin Dcontaining foods. Seasonal variations invitamin D levels occur depending on geo-graphic latitude and sun exposure in par-ticularly. A study (18) done in the generalpopulation in a NorthernEuropean coun-try showed a seasonal variation of vitaminD insuf ciency of 73% and 29% for win-ter and summer, respectively. The differ-ence for vitamin D de ciency wassimilarly found to be 8% and 1%. Fur-thermore, several conditions such as obe-sity and absorption, liver, or kidney disorders pose an increased risk of devel-oping vitamin D de ciency.

The mechanisms of action behind theincreased mortality risk seen among pa-tients with the lower levels of vitamin D atbaseline are unclear. A growing amountof evidence indicates that vitamin D,through activation of the vitamin D re-ceptor, has clinically important noncal-cemic pleiotropiceffects. Activationof thevitamin D receptor is associated withsuppression of the RAAS (19), cardiacmyocyte hypertrophy (20), vascular cal-ci cation, and atherosclerosis lowering,anti-in ammatory (21), and immuno-modulatory actions. Also, an inverse re-lationship is found between vitamin Dand increased incident risk of certain can-cers as well as a higher mortality from

these cancers (1).Diabetic patients have a higher rate of cardiovascular morbidity and mortality compared with the general population.In a 10 year follow-up study of a cohortof 593 normoalbuminuric patientswith type 1 diabetes, we have previously shown that more than one-third died of known cardiovascular causes and 25%died of unknown, potentially cardiovas-cular causes (4), hence a large number of the observed deaths in the cohort of thecurrent study are likely to be from cardio-vascular causes.

In a cross-sectional study of type 2diabetic patients with mild kidney im-pairment, vitamin D de ciency wasshown to be strongly associated with ahigher prevalence of manifest cardiovas-cular disease when compared with nor-mal vitamin D status (22).

Several of the above mentioned path-ways may be important mechanisms incardiovascular health. In a recent study of type 2 diabetic patients (23), which inves-tigated the mechanism by which vitaminD de ciency mediates increased risk of

Figure 1 Kaplan-Meier curves of all-cause mortality in 220 type 1 diabetic patients in accor-dance witha vitamin D level equal to and belowor above thelower 10%percentile, 25(OH)D3 = 15.5nmol/L. Full black line, 25(OH)D3 . 15.5 nmol/L; dashed black line, 25(OH)D3# 15.5 nmol/L.

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cardiovascular disease, investigatorsfound a reduced vitamin D receptorsignaling to be a potential mechanismunderlying increased foam cell (macro-phages that ingested oxidized LDL) for-mation and accelerated cardiovasculardisease in diabetic compared with non-diabetic patients.

Given the observational design, thecurrent study does not elaborate furtheron underlying mechanisms but indirectly adds to the increasing amount of datasuggesting that vitamin D substitutionmight be a potential therapeutic target toprevent vascular disease progression.However, it is not possible to rule outthat low levels of vitamin D may resultfrom a singleyet unidenti ed factor that isat the same time responsible for the in-creased risk seen in this study.

The pathogenesis behind microvas-cular complications in diabetes is com-plex and thought to involve multiplepathways. Development of microalbumin-uria in diabetic patients is closely associ-ated with an increased risk of both renaland cardiovascular disease. It has beensuggested that microalbuminuria oftenregresses to normoalbuminuria, but inthis cohort, spontaneous and permanentregression to normoalbuminuria occurredin only 16% of the patients progressing tomicroalbuminuria, whereas 34% pro-gressed to persistent macroalbuminuriaduring follow-up (24). Of particular im-

portance to diabetic nephropathy is an ac-tivation of the intrarenal RAAS and theproin ammatory nuclear factor-k B path-way, both promoting progressive renaldamage. In a post hoc analysis, Agarwalet al. (10) found that administration of a VDRA compared with placebo causedreduction in albuminuria in nondiabeticCKD as measured by a dipstick method(P = 0.004). Importantly, the effects ap-peared to be independent of concomitanttherapies to inhibit theRAAS. Recently the VITAL study, a randomized controlledclinical trial with 281 type 2 diabetic pa-tients with diabetic nephropathy, hasshown that administration of a VDRA(paricalcitol) in addition to blockade of the RAAS causes sustained reduction inalbuminuria and thereby potentially hasclinically relevant renoprotective effectsin patients with diabetic nephropathy (11).

A cross-sectional study of 581 type 2diabetic patients shows signi cant as-sociation between the existence of pro-liferative retinopathy and a decrease in25(OH)D3. Also, investigators found a

decrease in 25(OH)D3 according to thenumber of microvascular complicationspresent (25). A cross-sectional designdoes not contribute to clari cation oncausality and effect, but fuels speculationthat lowlevels of vitaminD mightbe a riskmarker of development or progression of both diabetic nephropathy and/or reti-nopathy. In this study, however, we didnot nd low 25(OH)D3 levels to signi -cantly predict development or progres-sion of microvascular complications.This could be because of the lack of powerbased on a low number of events as theHR for both retinopathy and albuminuriawas above 1 in patients with severe vita-min D de ciency. It is also possible thata potentially damaging effect of low vitamin D is offset by optimized patienttreatment aiming at improving bloodglucose and lowering blood pressure in-clusive of RAAS blockade.

In our study, severe vitamin D de- ciency was de ned as the lower 10%percentile [plasma 25(OH)D3 # 15.5nmol/L] in both men and women. Inter-national consensus is lacking in regard tode nitions of what vitamin D levels areto be regarded as normal, insuf ciency,and de ciency. The limits for a physiolog-ical optimal vitamin D level are still a mat-ter of debate in the literature. Although25(OH)D3 is shown to be stable in storedsamples (15), storing could affect abso-lute concentrations because of evapora-

tion, thus we arbitrarily chose the lower10% percentile rather than an absolutevalue. We have previously used the samemethod to de ne the cutoff in a follow-upstudy in type 2 diabetic patients (3). Fur-thermore, we have recently analyzedplasma 25(OH)D3 in fresh samples from200 type 2 diabetic patients and we foundthe lower 10% percentile in these patientsto deviate only 0.1 nmol/L from the Dan-ish national de nition of severe vitamin Dde ciency existing at the time.

The stability of plasma 25(OH)D3levels in our samples was tested beforeanalysis as previously described. No sta-tistically signi cant difference in levelswas found when compared according toyears of storage.

Our study has some strengths andlimitations. One element of methodolog-ical strength is the prospective design andlong follow-up period as well as com-pleteness of follow-up. Given the obser-vational design, it is not possible to infercausality from the associations described.

Further limitations of our study arerelated to possible changes in the level of

vitamin D throughout the year. We didnot adjust for seasonal change. Nor didwe have baseline dataon physical activity,which could be related to outdoor activ-ity, sun exposure and thereby levels of vitamin D. Vitamin D levels are alsoin uenced by nutritional status. Unfortu-nately no nutritional parameters wereavailable except BMI, which was not re-lated to vitamin D levels (datanot shown). We were therefore not able to adjust forany of these possible cofounders, but ingeneral, the patients were young andhealthy apart from newly diagnosed type1 diabetes.

More observational studies areneeded to con rm this nding, but asmentioned, we have performed the sameanalysis in a cohort consisting of type 2diabetic patients and found similar resultsin regards to all-cause mortality anddevelopment/progression of diabetic ne-phropathy. Furthermore, in the study comprising type 2 diabetic patients, very low levels of 25(OH)D3 were also able topredict an increased risk of cardiovasculardisease. Another limitation to the currentstudy is that we do not have access to dataon the cause of death.

In conclusion, with the present pro-spective follow-up study we are now ableto show that baseline levels of 25(OH)D3equal to or below the 10% percentilepredict increased risk of all-cause mortal-ity in type 1 diabetic patients, as already

shown for the general population, inpatients with nondiabetic CKD and forpatients with type 2 diabetes (3). We werenot able to demonstrate an associationbe-tween baseline levels of 25(OH)D3 equalto or below the 10% percentile and devel-opment of microvascular complications intype 1 diabetic patients. Randomizedcontrolled clinical trials administrat-ing VDRA are necessary in order toprove causality between vitamin D statusand survival prognosis in diabeticpatients.

Acknowledgments This study was carriedout with nancial support from the Danish Di-abetes Association, the Paul and Erna SehestedHansen Foundation, the Aase and EjnarDanielsen Foundation, and the Per S. HenriksenFoundation. No potential con icts of interestrelevant to this article were reported.

C.J., H.-H.P., and P.R. designed the study on vitamin D in this cohort.P.H.,P.R., andC.J.collected data. A.S.measured plasma 25(OH)D3on baseline samples. C.J. analyzed data statis-tically. P.R., H.-H.P., and to some extent P.H.contributed to the analysis with suggestions

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and advice. C.J. drafted the manuscript. P.H.,H.-H.P., A.S., and P.R. critically reviewed andedited the manuscript.

The authors appreciate the expert technicalassistance from the laboratory technicians atthe Steno Diabetes Center. Christian Binder,Steno Diabetes Center, is acknowledged fordesign and inclusion of patients in this in-ception cohort.

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