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Differential Effect of Glycemia on theIncidence of Hypertension by SexThe Epidemiology of Diabetes Complications study

TINA COSTACOU, PHDTREVORJ. ORCHARD, MBBCH, MMEDSCI

OBJECTIVEdDiabetes Control and Complications Trial/Epidemiology of Diabetes Interven-tion and Complications analyses demonstrated that intensive insulin therapy was inversely as-sociated with incident hypertension. We thus sought to conrm these observations and, givensexdifferences in other type 1 diabetes complications andrisk factors, assessed whether anysuchassociations differ by sex.

RESEARCH DESIGN AND METHODSdParticipants of a prospectivecohort of childhood-onset type 1 diabetes, free of hypertension at study entry (baseline mean age, 28 years; diabetesduration, 19 years), were selected for study (n= 510). Hypertension incidence was dened asblood pressure .140/90 mmHg or use of hypertension medications in two consecutive visits.

Intensive insulin therapy was de

ned as three or more injections (or pump) and four or moreglucose tests daily. Baseline predictors of hypertension were examined using Cox proportionalhazards models. Models with time-dependent updated means of baseline signicant variableswere also constructed.

RESULTSdHypertension incidence over 18 years of follow-up was marginally higher in menthan in women (43.2 vs. 35.4%,P= 0.07). A signicant interaction was noted between sex andHbA1c, and separate models were constructed by sex. Multivariably, elevated HbA1cwas a sig-nicant predictor only in men (hazard ratio 1.48 [95% CI 1.281.71]). In time-dependentmodels, although a signicant effect of HbA1cwas also seen in women (1.21 [1.001.46]), theeffect of glycemic control on hypertension development remained stronger in men (1.59 [1.291.97], Pinteraction ,0.0001).

CONCLUSIONSdAlthough hyperglycemia is a risk factor for hypertension, its effect isstronger in men compared with women with type 1 diabetes.

Hypertension is the number one at-tributable risk factor for deathwithin the general population

worldwide (1) and remains particularlyprevalent among individuals with diabe-tes (2), despite the broad availability ofeffective treatment regimens (3). Amongindividuals with type 1 diabetes, the pres-ence of hypertension has been associatedwith a signicantly increased risk of bothmicrovascular (4) and macrovascular (5)

complications, and it also raises overallmortality risk (6). Given the increased in-cidence of cardiovascular and kidneycomplications in this population, the con-trol of arterial blood pressure is of

imminent importance, as is the manage-ment of risk factors for hypertension in-cidence itself.

Modiable lifestyle factors, such asobesity and physical inactivity, and di-etary factors, including excess alcoholconsumption, increased dietary sodiumintake, and inadequate fruit, vegetable, andpotassium intakes, have been shown tosignicantly increase the risk of new-onsethypertension in the general population

(3,7,8). Although, traditionally, individualswith type 1 diabetes were thought to be ofnormal or subnormal weight, the adop-tion of unhealthy lifestyle behaviors and/or intensive insulin therapy have led to an

increasing prevalence of overweight andobesity in individuals with this diabetestype (9). Moreover, the presence of hy-perglycemia has been suggested to fur-ther contribute to the excess risk ofhypertension in these individuals by pro-moting vascular stiffness (10). Indeed,analyses of the Diabetes Control andComplications Trial (DCCT) and itsobservational follow-up study, Epidemi-ology of Diabetes Intervention and Com-plications (EDIC), demonstrated thathyperglycemiaand intensive insulin ther-

apy are associated with incident hyper-tension (11), although sex differenceswere not evaluated. Differences in the in-cidence of and/or risk factors for vascularcomplications associated with hyperten-sion (i.e., kidney and heart disease) havebeen previously described by our groupamong individuals with type 1 diabetes(1214). We therefore aimed to assess theassociation between glycemia (HbA1c),glycemic control (intensive therapy), andthe development of hypertension in awell-characterized cohort study of indi-viduals with childhood-onset type 1 dia-betes, to conrm whether ndings fromthe DCCT/EDIC study are apparent inthe general type 1 diabetes population,and to determine whether any associationbetween glycemic control or intensive in-sulin treatment with incident hyperten-sion varies by sex.

RESEARCH DESIGN ANDMETHODSdParticipants from thePittsburgh Epidemiology of DiabetesComplications (EDC) study with arterialblood pressure,140/90 at study initiationwere selected for study (n = 510). The EDCis a historical cohort study based on inci-dent cases of childhood-onset (prior totheir 17th birthday) type 1 diabetes, diag-nosed or seen within 1 year of diagnosis(19501980) at the Childrens Hospital ofPittsburgh (15). This cohort has been pre-viously shown to be epidemiologicallyrepresentative of the type 1 diabetes pop-ulation of Allegheny County, Pennsylva-nia (16). The rst clinical assessment forthe EDC study took place between 1986and 1988, when the mean participant age

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From the Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania.Corresponding author: Tina Costacou,costacout@edc.pitt.edu.Received 13 April 2012 and accepted 7 July 2012.DOI: 10.2337/dc12-0708 2012 by the American Diabetes Association. Readers may use this article as long as the work is properly

cited,theuse iseducationaland notforprot,and the workis notaltered.See http://creativecommons.org/licenses/by-nc-nd/3.0/for details.

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E p i d e m i o l o g y / H e a l t h S e r v i c e s R e s e a r c hO R I G I N A L A R T I C L E

Diabetes Care Publish Ahead of Print, published online September 10, 2012

mailto:costacout@edc.pitt.eduhttp://creativecommons.org/licenses/by-nc-nd/3.0/http://creativecommons.org/licenses/by-nc-nd/3.0/http://creativecommons.org/licenses/by-nc-nd/3.0/http://creativecommons.org/licenses/by-nc-nd/3.0/mailto:costacout@edc.pitt.edu

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Tarrytown, NY). The DCA and Diamat as-says were also highly correlated (r= 0.95).Original HbA1 (19861998) and HbA1cvalues (19982004) were converted toDCCT-aligned standard HbA1cvalues us-ing regression formulae derived from du-plicate assays (DCCT HbA1c = [0.83 3Diamat HbA1] + 0.14 and DCCT HbA1c=[DCA HbA1c 2 1.13]/0.81). HDL choles-terol was determined enzymatically after

precipitation with heparin and manganesechloride, with a modication (20) of theLipid Research Clinics method (21). Cho-lesterol and triglycerides were measuredenzymatically (22,23). Non-HDL choles-terol was calculated as total minus HDLcholesterol. White blood cell (WBC) countwas obtained using a counter S-plus IV andbrinogen using a biuret colorimetric pro-cedure and a clotting method. Urinary

albumin was measured by immunonephe-lometry (24), and creatinine was assayedby an Ectachem 400 Analyzer (EastmanKodak Co., Rochester, NY). Glomerular l-tration rate was estimated by the ChronicKidney Disease Epidemiology Collaboration(CKD-EPI) creatinine equation (25). Itshould, however, be noted that serum creat-

inine was not calibrated in this study. All as-says were conducted during the cycle thatsamples were obtained, and thus, prolongedstorage would not have affected measure-ments performed in this study.

Statistical analysisAnalyses were conducted stratied bysex. Univariate associations were deter-mined using the Student t test for nor-mally distributed continuous variablesor Wilcoxon two-sample test for nonnor-mally distributed continuous variables.Thex2 or Fisher exact test, as appropriate,was used for univariate analysis of cate-gorical variables. Cox proportional haz-ards models with backward eliminationwere constructed to assess independentpredictors of hypertension incidenceamong traditional risk factors and uni-variately signicant variables. Cox pro-portional hazards models were alsoconstructed using time-dependent upda-ted means of variables signicant in mod-els using baseline characteristics. Survivaltime was dened as the time in years fromstudy entry to either incident hyperten-

sion or censorship during the 18-yearfollow-up. Nonnormally distributed var-iables were logarithmically transformedfor entry into multivariable models. Sta-tistical analyses were conducted usingStatistical Analysis Software (SAS), ver-sion 9.2 (SAS Institute, Cary, NC).

RESULTS

Incidence and univariatepredictors of hypertension in theentire cohortDuring 18 years of follow-up, 39.2% (n=200) of individuals developed incidenthypertension, for an incidence rate of31.2 per 1,000 person-years. Incidencewas slightly lower in women (35.4%)than in men (43.2%, P= 0.07). Table 1presents characteristics of male and fe-male participants at study entry by in-cident hypertension. In both sexes,compared with participants whose arte-rial blood pressure remained within a nor-mal range, those who subsequentlydeveloped hypertension were more likelyto be older and have elevated baseline

Figure 1dA: Incidence of hypertension by sex and tertiles of HbA1cat study entry. Among men,Pvalue = 0.004 and P value for trend = 0.0008. Among women,P value = 0.47 and P value fortrend = 0.31.B: Diabetes durationadjusted survival curves for hypertension by tertiles of HbA1cat study entry among men. The Pittsburgh EDC study (hazard ratio8.0 to ,9.22.42 [95% CI 1.434.10],Pvalue = 0.0009; hazard ratio .9.24.00 [2.356.80],Pvalue ,0.0001; log-rankPvalue,0.0001). C: Diabetes durationadjusted survival curves for hypertension by tertiles of HbA1cat

study entry among women. The Pittsburgh EDC study (hazard ratio 8.0 to ,9.21.18 [0.70

1.98],Pvalue = 0.54; HR.9.21.58 [0.972.58],P value = 0.07; log-rankP value = 0.22).

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men and postmenopausal women (29).This sex dimorphism and the observationof an important role of menopause haveled to the hypothesis that sex hormonesmay actas modulators of vascular functionand the pathogenesis of hypertension(30). Interestingly, a previous report alsosuggested that sex hormonebinding

globulin and total testosterone are higherin male, but not female, children andyoung adults with diabetes comparedwith nondiabetic siblings, a nding appar-ently related to the absence of endogenousinsulin (31). Whether such differencesmay account for the differential associa-tion between HbA1cand hypertension in-cidence by sex could, unfortunately, notbe evaluated, as hormonedata are notavail-able for EDC study participants. Moreover,as the associations reported in this manu-script were derived from a populationwhere the majority of women are premen-opausal, any conclusions made should berestricted to younger and middle-agedadults, as deviations from these relation-ships may be noted with longer follow-up, when more women would havereached menopause.

It has been suggested that the pres-ence of hyperglycemia contributes to theexcess risk of hypertension in individualswith diabetes by promoting vascular stiff-ness (10). Indeed, considerable evidencelinks hyperglycemia with increased uxthrough the polyol pathway and the re-

duction of glucose to sorbitol, increasedformation of advanced glycosylation endproducts, and, importantly, generation ofreactive oxygen species, which lead tovascular damage (10). Interestingly, ourresults suggest that the incidence ofnew-onset hypertension is higher inwomen compared with men among par-ticipants at better glycemic control buthigher in men compared with womenamong those at worse glycemic control.The reason why glycemic stress may dif-ferentially affect a persons risk for devel-oping hypertension based on their sex iscurrently unclear. As HbA1c has im-proved over follow-up, it is possible thatthe impact of male predominance for hy-pertension at high HbA1chas diminishedin time, in a similar manner to what wehave reported for renal disease (13) wherethe elimination of the male excess in ad-vanced renal disease in the more recentlydiagnosed cohort may be potentiallylinked to improved glycemic control. Alarge body of literature has provided evi-dence that in addition to structural dif-ferences, developmental/environmental

stressors may provoke a distinctive phys-iological response by sex (32). Thus, ashere, although only a weak difference inhypertension incidence exists by sex, thepathogenesis of blood pressure elevationis likelyto differbetween menand women.This is consistent with our earlier observa-tion of similar coronary artery disease in-

cidences between men and women despitedifferences in risk factors by sex (12) andour recent report that HDL cholesterolshows a different relationship to coronaryartery disease in women (U shaped) com-pared with men(inverselinear) in theEDCstudy, potentially explaining some of theloss of female protection against heart dis-ease seen in type 1 diabetes (14).

Despite previously reported associa-tions between BMI and hypertension in-cidence in the general population (26,27)as well as in type 1 diabetes (11), mea-sures of body fatness (WHR and, in sepa-rate models, BMI) were not selected in thenal prediction models in this study.However, AER, as measured at baselineand also as a time-dependent updatedmean over the follow-up period, was sig-nicantly associated with increased riskfor hypertension in both sexes. The cate-gorization of study participants intonormo- or microalbuminuric at the base-line assessment was also associated withincreased risk of hypertension in bothmen (almost fourfold increased risk) andwomen (twofold increased risk). AER was

strongly associated with the incidence ofhypertension also in the report from theDCCT/EDIC study (11). A direct associa-tion between plasma lipid concentrationsand hypertension incidence was also ob-served among women, although similarlystrong associations were not seen amongmen.

In conclusion, the results of thisstudysuggest that although hyperglycemia con-tributes to the development of hyperten-sion, this effect is much stronger in mencompared with women with type 1 di-abetes. The reasons for this difference arenot clear but merit further investigation assex differences appear to be common inthe natural history of type 1 diabetescomplications, including coronary arterydisease and kidney disease, both of whichare closely related to hypertension.

AcknowledgmentsdThis research was sup-ported by National Institutes of Health grantsDK-34818 and DK-082900.

No potential conicts of interest relevant tothis article were reported.

T.C. researched and analyzed data and wrotethe manuscript. T.J.O. researched data, con-tributed to the discussion, and reviewed andedited the manuscript. All authors haveread andapproved the nal version of the manuscript.T.C. is the guarantor of this work and, as such,had full access to all the data in the study andtakes responsibility for the integrity of the dataand the accuracy of the data analysis.

Preliminary analyses of this study were pre-sented at the Scientic Sessions of the AmericanHeart Association, Orlando, Florida, 1419November 2009.

The authors are indebted to the participantsof the Pittsburgh EDC study who have tire-lessly volunteered their time for more than 20years.

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