ORIGINAL ARTICLES 당뇨병이없는성인에서심혈관질환위험요소및대사증후군과당화혈색소의상관관계 조선대학교병원내분비대사내과, 산업의학교실 1, 조선대학교의과대학예방의학교실 2 김진화 최소라 1 이재록 신지혜 이상준 한미아 2 박종 2 배학연 김상용 Association of Hemoglobin A1c with Cardiovascular Disease Risk Factors and Metabolic Syndrome in Nondiabetic Adults Jin-Hwa Kim, So-Ra Choi 1, Jae-Rok Lee, Ji-Hye Shin, Sang-Jun Lee, Mi-Ah Han 2, Jong Park 2, Hak-Yeon Bae, Sang-Yong Kim Division of Endocrinology and Occupational & Environmental Medicine 1, Chosun University Hospital; and Department of Preventive Medicine 2, College of Medicine, Chosun University Abstract Background: Glycosylated hemoglobin(hba1c) is a useful index of mean blood glucose concentrations over the preceding 2 to 3 months. Elevated HbA1c levels(> 7%) are associated with a higher incidence of microvascular and macrovascular complications in patients with diabetes mellitus. However, the relationship between HbA1c and cardiovascualr disease risk in nondiabetic adults has been unclear. The aim of this study is to estimate the association of HbA1c with cardiovascular disease risk factors and metabolic syndrome in nondiabetic adults. Methods: The subjects of this study included 533 adults(180 males and 353 females) aged 20~70 years (mean age: 46.9 ± 10.12 years) without previously diagnosed diabetes who lived in Kangyang country. We examined baseline HbA1c levels and cardiovascular risk factors. Metabolic syndrome was defined based on International Diabetes Federation guidelines. Results: The prevalence of metabolic syndrome significantly increased as HbA1c increased. HbA1c revealed a significant correlation with age (r = 0.258, P < 0.001), BMI(r = 0.152, P < 0.001), waist circumference(r = 0.252, P < 0.001), fasting plasma glucose (r = 0.319, P < 0.001), systolic(r = 0.100, P = 0.021), diastolic(r = 0.115, P = 0.008) blood pressure, total cholesterol (r = 0.232, P < 0.001), triglyceride (r = 0.156, P < 0.001), LDL cholesterol (r = 0.216, P < 0.001), and HDL cholesterol(r = -0.167, P < 0.001). Multiple regression analysis showed that HbA1c had a association with age, fasting plasma glucose, and dyslipidemia. The receiver operating characterstics (ROC) curve analysis determined HbA1c of 5.35% to yield optimal sensitivity and specificity corresponding to the presence of metabolic syndrome. Conclusion: The HbA1c level is correlated with cardiovascular risk factors and prevalence of metabolic syndrome in nondiabetic adults. (KOREAN DIABETES J 32:435-444, 2008) Key Words: Cardiovascular disease, HbA1c, Metabolic syndrome 접수일자 : 2008 년 8 월 6 일, 통과일자 : 2008 년 9 월 29 일, 책임저자 : 김상용, 조선대학교병원내분비대사내과 * 본연구는 2006 년도조선대학교학술연구비지원에의하여연구되었음. 435
서론혈색소 A (hemoglobin A, HbA) 는베타체인의말단아미노산인발린 (valine) 이포도당과반응, 당화되어당화혈색소 (HbA1c) 가된다. 당화혈색소중당화된부분 (%) 은적혈구가포도당에노출된기간과혈액내포도당농도에의해결정되기때문에측정한시간보다수주전기간의평균혈당을반영하게된다 1). 당화혈색소는측정이간편하고비가역적이여서당뇨병환자들에서혈당조절의지표로널리이용되고있다. 당뇨병환자에서혈당상승및당화혈색소상승시심혈관질환으로인한사망위험률또한증가되며당화혈색소의증가는미세혈관및대혈관합병증증가와연관된다는보고들이있다 2-7). 그러나당뇨병이없는일반인구에서혈당상태와심혈관질환간의연관성에관해서는명확히밝혀져있지않으며특히, 당화혈색소와심혈관질환간의관계에관한연구는많지않다. 당화혈색소가당뇨병과는독립적으로동맥경화발생및심혈관질환의독립적인위험요소임을주장한연구들 8,9) 이있으며 Blake 등 10) 은 Women's Health Study 코호트를대상으로시행한전향적연구에서당뇨병이없는여성에서기저당화혈색소치가높은최상위군이낮은최하위군에비하여심혈관질환발생의상대위험도가 2.25라고보고하였다. 대사증후군은심혈관질환발생의주요위험인자인고혈당, 고혈압, 고지혈증, 복부비만이한개인에서군집되어나타나는현상으로 11) 대사증후군발병의예측과관리는심혈관질환의관리측면에서중요한의미를지닌다. 이에저자등은전라남도광양지역 20~70세의당뇨병이없는일반인구를대상으로당화혈색소와심혈관질환의위험요소간의연관관계를분석하고대사증후군발병과의상관성을평가하였다. 대상및방법 1. 대상 2006년 8월 7일부터 2006년 9월 17일까지전라남도광양에서편의추출된 20세에서 70세사이의성인 533명 ( 남성 180명, 여성 353명 ) 을대상으로하였다. 당뇨병의과거력이있거나급성질환을앓고있는환자, 암환자, 고혈압약제나고지혈증약제를복용중인환자들을제외하였으며진단되지않은당뇨병환자의가능성을고려하여공복혈당 126 mg/dl 이상, 당화혈색소가 7.0% 이상인경우를제외하였다. 조사원들에의한일차전화면담을통해조사개요에대해설명및참여를권유하였고검사전날에는이차전화면담을통해검사와사전준비사항등을환기시켰다. 검사를실시하기전모든대상자들에게조사내용이나향후관리에대해설명후동의서를얻었다. 2. 신체계측및생화학적검사대상자들의체중, 신장, 허리둘레등신체계측을시행하였고수축기혈압, 이완기혈압, 총콜레스테롤, 중성지방, high density lipoprotein (HDL) 콜레스테롤, 당화혈색소를측정하였다. 신체계측시신장, 체중은직립자세로신발을벗은상태에서신장은수동신장측정기를사용하여 0.1 cm 단위까지, 몸무게는체성분분석기 (Zeus 9.9, Jawon Medical Co.) 를사용하여 0.1 kg까지측정하였다. 허리둘레는줄자를이용하여직립자세에서늑골의최하부와장골능의최상부와의중간부위를통해측정하였다. 혈압은 10분이상안정상태를유지한후앉은자세에서수은혈압계로수축기혈압과확장기혈압을측정하였다. 수축기혈압은 Korotkoff phase 1을, 이완기혈압은 Korotkoff phase 5를기준으로하였고. 우측상완의혈압을 2회측정하여두값의평균값을구하였다. 모든대상자는 10시간이상금식하도록하였고혈액은정맥혈을추출하여보존제가첨가되지않은진공튜브에채취하였으며채취직후부터검사실에서원심분리하기전까지얼음에보관한채로수송하였다. 혈당은효소법으로 ADVIA 1650 (Bayer) 에서측정하였고, 총콜레스테롤, 중성지방, HDL 콜레스테롤은효소법에의해 ADVIA 1650 (Bayer) 에서측정되었고당화혈색소는 HPLC (high performance liquid chromatography) 법으로 HbA1c 전용 Kit (BIO-RAD) 를사용하여 BIO-RAD VARIANT II (BIO-RAD) 측정기기에서측정하였다. low density lipoprotein (LDL) 콜레스테롤은총콜레스테롤, 중성지방, HDL 콜레스테롤을이용하여아래의 Friedewald 공식에의해산출하였다 12). LDL 콜레스테롤 = 총콜레스테롤 ꠀ HDL 콜레스테롤 ꠀ 중성지방 / 5 3. 대사증후군의진단기준대사증후군은 2005년발표된 International Diabetes Feredation (IDF) 의진단기준에의하여진단하였다 13). 단허리둘레의기준은 World Health Organization (WHO) Western Pasific Region에서제시한아시아- 태평양지역기준을적용하였다 14). 대상자의허리둘레가남자는 90 cm 이상, 여자는 80 cm 이상이면서다음중두가지이상을동반하는경 436
김진화외 8 인 : 당뇨병이없는성인에서심혈관질환위험요소및대사증후군과당화혈색소의상관관계 우를대사증후군으로진단하였다. (1) 중성지방 150 mg/dl 또는중성지방의이상에대한치료를받고있는경우 (2) HDL 콜레스테롤 < 40 mg/dl ( 남자 ), < 50 mg/dl ( 여자 ) 또는 HDL 콜레스테롤의이상에대한치료를받고있는경우 (3) 수축기혈압 130 mmhg 또는이완기혈압 85 mmhg 또는항고혈압제를복용하는경우 (4) 공복혈당 100 mg/dl 또는제2형당뇨병을진단받은경우 4. 통계분석통계분석은 SPSS (Statistical Package for the Social Sciences, for windows version 13.0) 프로그램을이용하였고, 당화혈색소에따른네군의비교는 one-way ANOVA test 로시행하였으며사후검정은 Tukey's multiple comparison test로분석하였다. 당화혈색소와신체계측치및심혈관질환의위험요소간의관계는 Pearson's correlation analysis를시행하였으며이를통해확인된변수들을이용하여다중선형회귀분석 (multiple linear regression analysis) 을시행하였다. 당화혈색소와대사증후군및공복혈당기준치와의관계는수진자특성곡선 (receiver operating characterstics (ROC) curve) 을통하여민감도와특이도를구하였다. 유의수준은 P값이 0.05 이하인경우로하였다. 결과 1. 대상인구의특성남녀의성비는 1:1.961로여성이더많았으며평균연령은 46.9 ± 10.12세 (mean ± SD) 였다. 대상자들의연령대별분포는 20대가 3.93% (21명/533명) 로가장적었으며 40대가 39.96% (213명/533명) 로가장많았다. 평균체질량지수 (body mass index, BMI) 는 23.7 ± 3.21 kg/m 2 였고남성이여성보다유의하게높았으며, 평균당화혈색소 (hemoglobin A1c, HbA1c) 는 5.3 ± 0.36% 로남녀간의유의한차이는없었다. 그외남성이여성보다나이, 허리둘레, 공복혈당, 이완기혈압, 중성지방이유의하게높았고 HDL 콜레스테롤은유의하게낮았다 (Table 1). 2. 대사증후군의유병률대상인구에서 IDF 진단기준에따른대사증후군의전체유병률은 9.9% (53명/533명) 였다. 성별에따른대사증후군의유병률은남성에서 8.3% (15명/180명), 여성에서 10.8% (38명/353명) 로여성이더높았다. 연령대별대사증후군의 Table 1. Clinical characteristics of study subjects with respect to sex Total Male Female P value N 533 180 353 Age 20~29 21 11 10 30~39 98 22 76 40~49 213 61 152 50~59 137 54 83 60~70 64 32 32 Age (years) 46.9 ± 10.12 49.0 ± 11.14 45.9 ± 9.40 0.002 BMI (kg/m 2 ) 23.7 ± 3.21 24.1 ± 2.63 23.4 ± 3.45 0.018 WC (cm) 77.9 ± 8.85 83.1 ± 7.38 75.2 ± 8.35 < 0.001 FPG (mg/dl) 84.4 ± 10.02 86.8 ± 11.15 83.2 ± 9.17 < 0.001 SBP (mmhg) 116.0 ± 11.85 117.4 ± 11.53 115.3 ± 11.97 0.051 DBP (mmhg) 75.4 ± 8.96 77.0 ± 8.53 74.6 ± 9.07 0.003 TC (mg/dl) 187.7 ± 34.13 188.6 ± 33.73 187.2 ± 34.39 0.669 Triglyceride (mg/dl) 116.5 ± 87.48 147.0 ± 120.90 100.9 ± 58.40 < 0.001 LDL (mg/dl) 117.3 ± 33.37 114.9 ± 36.57 119. 7 ± 30.16 0.122 HDL (mg/dl) 46.5 ± 11.00 44.3 ± 10.86 47.6 ± 10.91 0.001 HbA1c (%) 5.3 ± 0.36 5.3 ± 0.34 5.3 ± 0.038 0.146 Data are means ± SD. BMI, body mass index; DBP, diastolic blood pressure; FPG, fasting plasma glucose; HDL, high density lipoprotein cholesterol; LDL, low density lipoprotein cholesterol; SBP, systolic blood pressure; TC, total cholesterol; WC, waist circumference. P values were obtained using the Student's t-test based on differences between male and female group. 437
Table 2. Comparison of cardiovascular risk factors of total study population according to quartile of HbA1c HbA1c quaritile 1st ( 5.0) 2nd (5.01~5.2) 3rd (5.21~5.45) 4th ( 5.46) N 138 140 122 133 Age (years) 43.9 ± 10.81 45.1 ± 9.14 49.6 ± 9.45 * 50.3 ± 9.29 * BMI (kg/m 2 ) 23.2 ± 3.71 23.4 ± 2.96 23.6 ± 2.69 24.4 ± 3.26 * WC (cm) 75.2 ± 8.37 76.9 ± 8.14 78.1 ± 8.50 * 81.4 ± 9.28 * FPG (mg/dl) 81.9 ± 9.32 81.6 ± 7.65 85.0 ± 8.23 * 89.5 ± 12.24 * SBP (mmhg) 115.6 ± 12.13 115.2 ± 11.13 115.3 ± 12.46 118.0 ± 11.62 DBP (mmhg) 75.2 ± 9.87 75.5 ± 8.99 73.2 ± 8.24 77.5 ± 8.13 TC (mg/dl) 175.5 ± 29.30 187.7 ± 33.18 * 190.1 ± 35.95 * 198.1 ± 34.52 * Triglyceride (mg/dl) 100.3 ± 53.65 114.8 ± 124.12 106.5 ± 54.53 144.1 ± 88.12 * LDL (mg/dl) 107.8 ± 27.48 116.7 ± 33.12 122.6 ± 31.97 * 125.3 ± 34.63 * HDL (mg/dl) 47.6 ± 11.30 47.9 ± 11.31 46.2 ± 10.82 43.9 ± 10.14 * Metabolic syndrome (n) 9 9 10 25 * P < 0.05, for different from 1st, P < 0.05, for different from 2nd, P < 0.05, for different from 3rd. Data are means ± SD. BMI, body mass index; DBP, diastolic blood pressure; FPG, fasting plasma glucose; HDL, high density lipoprotein cholesterol; LDL, low density lipoprotein cholesterol; SBP, systolic blood pressure; TC, total cholesterol; WC, waist circumference. Table 3. Comparison of cardiovascular risk factors according to quartile of HbA1c by sex HbA1c quaritile 1st ( 5.0) 2nd (5.01~5.2) 3rd (5.21~5.45) 4th ( 5.46) Male (n: 180) N 38 46 42 54 Age (years) 44.3 ± 13.39 46.2 ± 9.67 52.1 ± 9.99 * 52.4 ± 9.85 * BMI (kg/m 2 ) 23.3 ± 2.19 23.9 ± 2.54 24.2 ± 2.54 24.8 ± 2.92 * WC (cm) 79.2 ± 7.02 82.7 ± 5.86 83.8 ± 7.43 * 85.5 ± 7.78 * FPG (mg/dl) 84.6 ± 9.61 82.8 ± 6.96 87.5 ± 10.43 91.2 ± 13.88 * SBP (mmhg) 113.7 ± 9.61 118.3 ± 11.38 117.1 ± 14.12 11.5 ± 10.24 DBP (mmhg) 73.8 ± 8.65 78.5 ± 8.51 * 74.9 ± 8.18 79.6 ± 7.79 * TC (mg/dl) 166.0 ± 33.04 192.1 ± 32.85 * 188.8 ± 32.47 * 201.2 ± 28.47 * Triglyceride (mg/dl) 118.5 ± 59.18 168.7 ± 197.66 121.9 ± 64.10 168.2 ± 92.85 LDL (mg/dl) 99.3 ± 32.08 113.5 ± 42.61 119.6 ± 31.10 123.3 ± 35.25 * HDL (mg/dl) 43.0 ± 10.47 44.9 ± 11.59 44.8 ± 11.09 44.3 ± 10.53 Metabolic syndrome (n) 1 1 4 9 Female (n: 353) N 100 94 80 79 Age (years) 43.0 ± 9.72 44.5 ± 8.88 43.4 ± 9.01 * 48.9 ± 8.67 * BMI (kg/m 2 ) 23.2 ± 4.16 23.2 ± 3.12 23.3 ± 2.72 24.2 ± 3.47 WC (cm) 73.7 ± 8.39 74.1 ± 7.57 75.1 ± 7.46 78.5 ± 9.21 * FPG (mg/dl) 80.9 ± 9.04 81.0 ± 7.93 83.7 ± 6.50 88.3 ± 10.91 * SBP (mmhg) 116.3 ± 12.93 113.6 ± 10.74 114.4 ± 11.49 117.0 ± 12.44 DBP (mmhg) 75.7 ± 10.28 74.1 ± 8.89 72.3 ± 8.17 76.0 ± 8.09 TC (mg/dl) 179.1 ± 27.01 185.5 ± 33.30 190.7 ± 37.83 195.9 ± 38.14 * Triglyceride (mg/dl) 93.4 ± 49.99 88.5 ± 44.52 98.4 ± 47.22 127.7 ± 81.29 * LDL (mg/dl) 111.1 ± 24.93 118.3 ± 27.44 124.2 ± 32.50 * 126.6 ± 34.36 * HDL (mg/dl) 49.3 ± 11.16 49.5 ± 10.92 46.9 ± 10.67 43.8 ± 9.93 * Metabolic syndrome(n) 8 8 6 16 * P < 0.05, for different from 1st, P < 0.05, for different from 2nd, P < 0.05, for different from 3rd. Data are means ± SD. BMI, body mass index; DBP, diastolic blood pressure; FPG, fasting plasma glucose; HDL, high density lipoprotein cholesterol; LDL, low density lipoprotein cholesterol; SBP, systolic blood pressure; TC, total cholesterol; WC, waist circumference. 438
김진화외 8 인 : 당뇨병이없는성인에서심혈관질환위험요소및대사증후군과당화혈색소의상관관계 연령보정후유병률은 20대, 30대, 40대, 50대, 60대에서각각 0% (0명/21명), 5.1% (5명/98명), 8.0% (17명/213명), 13.1% (18명/137명), 20.3% (13명/64명) 로연령이증가함에따라대사증후군의유병률이증가하는양상을보였고 60대에서가장높은유병률을보였다 (P < 0.05) (data not shown). 3. 당화혈색소에따른심혈관질환의위험요소비교및대사증후군의유병률당화혈색소를 4분위 (quartile) 하여심혈관질환의위험요소및대사증후군의유병률을비교하였다. 1군은당화혈색소 5.0% 이하, 2군은당화혈색소 5.01% 에서 5.2%, 3군은당화혈색소 5.21% 에서 5.45%, 4군은당화혈색소 5.46% 이상으로분류되었다. 각각의군들을비교한결과당화혈색소 5% 이하인 1군에비하여당화혈색소 5.46% 이상인 4군에서연령, BMI, 허리둘레, 공복혈당, 총콜레스테롤, 중성지방, LDL 콜레스테롤의유의한상승이관찰되었고 (P < 0.05), HDL 콜레스테롤의유의한감소가관찰되었다 (P < 0.05)(Table 2). 2군 ( 당화혈색소 5.01~5.2) 과 3군 ( 당화혈색소 5.21~5.45) 의비교결과 3군의연령및공복혈당이유의하게높았고 (P < 0.05), 3군과 4군 ( 당화혈색소 5.46) 간의비교시 4군의허리둘레, 공복혈당, 이완기혈압, 중성지방이유의하게높았다 (P < 0.05)(Table 2). 성별에따른비교결과남녀모두 1군에비하여 4군에서연령, 허리둘레, 공복혈당, 총콜레스테롤, LDL 콜레스테롤은유의하게증가되었고 (P < 0.05), 남성에서는전체인구및여성과는다르게이완기혈압의유의한상승이관찰되었다 (P < 0.05)(Table 3). 대사증후군의유병률은당화혈색소의분위 (quartile) 가증가할수록증가하였다 (P for trend < 0.05)(Table 2, 3). 50대미만에서는대사증후군의증가가관찰되지않았으나 50대이상에서는당화혈색소의분위 (quartile) 이증가할수록증가하였다 (P for trend < 0.05) (Table 4). Table 4. Comparison of cardiovascular risk factors according to quartile of HbA1c by age HbA1c quaritile 1st ( 5.0) 2nd (5.01~5.2) 3rd (5.21~5.45) 4th ( 5.46) 20-49 (n: 332) N 105 94 65 68 Age (years) 39.1 ± 8.03 40.1 ± 5.90 42.3 ± 4.93 * 42.9 ± 4.99 * BMI (kg/m 2 ) 23.3 ± 4.04 23.2 ± 3.18 23.5 ± 2.91 24.1 ± 3.11 WC (cm) 74.7 ± 8.57 75.8 ± 8.22 77.4 ± 8.85 79.2 ± 8.64 * FPG (mg/dl) 81.0 ± 7.52 81.4 ± 6.87 84.1 ± 8.68 87.4 ± 10.45 * SBP (mmhg) 115.1 ± 12.21 114.1 ± 11.41 112.6 ± 11.72 115.1 ± 10.89 DBP (mmhg) 75.4 ± 9.58 74.8 ± 9.44 72.2 ± 8.61 75.2 ± 7.66 TC (mg/dl) 174.5 ± 27.21 182.5 ± 32.43 178.9 ± 34.75 191.2 ± 36.27 * Triglyceride (mg/dl) 92.8 ± 46.36 114.8 ± 139.71 100.2 ± 55.22 128.8 ± 88.06 LDL (mg/dl) 107.7 ± 24.91 112.7 ± 32.70 113.7 ± 32.07 121.8 ± 34.81 * HDL (mg/dl) 48.2 ± 10.91 46.9 ± 10.48 45.2 ± 9.56 43.7 ± 10.10 * Metabolic syndrome (n) 6 5 3 8 50~70 (n: 201) N 33 46 57 65 Age (years) 57.0 ± 6.23 55.2 ± 5.45 57.9 ± 5.75 58.1 ± 5.74 BMI (kg/m 2 ) 23.1 ± 2.45 23.8 ± 2.42 23.7 ± 2.42 24.7 ± 3.42* WC (cm) 76.9 ± 7.59 79.2 ± 7.52 78.9 ± 8.08 83.7 ± 9.43 * FPG (mg/dl) 84.7 ± 13.30 82.2 ± 9.09 86.1 ± 7.62 91.6 ± 13.62 * SBP (mmhg) 117.1 ± 11.96 117.4 ± 10.29 118.3 ± 12.69 121.1 ± 11.64 DBP (mmhg) 74.7 ± 10.87 76.9 ± 7.89 74.3 ± 7.71 79.8 ± 8.01 * TC (mg/dl) 178.6 ± 35.45 198.3 ± 32.48 * 202.8 ± 33.19 * 205.3 ± 31.26 * Triglyceride (mg/dl) 124.1 ± 67.60 114.9 ± 85.15 113.6 ± 53.31 160.2 ± 85.91 LDL (mg/dl) 108.2 ± 34.86 125.1 ± 32.75 132.8 ± 28.89 * 128.9 ± 34.34 * HDL (mg/dl) 45.6 ± 12.40 50.2 ± 12.67 47.3 ± 12.08 44.4 ± 10.25 Metabolic syndrome (n) 3 4 7 17 * P < 0.05, for different from 1st, P < 0.05, for different from 2nd, P < 0.05, for different from 3rd. Data are means ± SD. BMI, body mass index; DBP, diastolic blood pressure; FPG, fasting plasma glucose; HDL, high density lipoprotein cholesterol; LDL, low density lipoprotein cholesterol; SBP, systolic blood pressure; TC, total cholesterol; WC, waist circumference. 439
연령대에따른비교결과 50대미만에서는 1군에비하여 4군에서연령, 허리둘레, 공복혈당, 총콜레스테롤, LDL 콜레스테롤의유의한증가및 HDL 콜레스테롤의유의한감소가관찰되었고 (P < 0.05), 50대이상에서는 50대미만과다르게연령의유의한증가와 HDL 콜레스테롤의유의한감소는없었으나 BMI와이완기혈압은유의하게상승되었다 (P < 0.05)(Table 4). 4. 당화혈색소와심혈관질환위험인자간의상관관계당화혈색소는연령, BMI, 허리둘레, 공복혈당, 수축기혈압, 이완기혈압, 총콜레스테롤, 중성지방, LDL 콜레스테롤과유의한양의상관관계를나타내었고 HDL 콜레스테롤 과유의한음의상관관계를나타내었다 (Table 5). 상관관계를보인인자들에서다중선형회귀분석을시행한결과공복혈당, HDL 콜레스테롤, 연령, LDL 콜레스테롤, 중성지방이유의한독립변수였다 (Table 6). 5. 대사증후군및공복혈당 100 mg/dl을예측하기위한당화혈색소기준대상자에서대사증후군진단에상응하는당화혈색소치를 ROC 곡선을통하여추정한결과 5.35% (sensitivity; 0.547, 1-specificity; 0.319) 였고, 공복혈당 100 mg/dl에상응하는당화혈색소치는 5.45% (sensitivity; 0.614, 1-specificity; 0.219) 였다. 연령대별, 성별에따른추정치는 Table 7과같다. Table 5. Correlation between HbA1c and cardiovascular risk factors Correlation r P Age 0.258 < 0.001 BMI 0.152 < 0.001 WC 0.252 < 0.001 FPG 0.319 < 0.001 SBP 0.100 0.021 DBP 0.115 0.008 TC 0.232 < 0.001 Triglyceride 0.156 < 0.001 LDL 0.216 < 0.001 HDL -0.167 < 0.001 BMI, body mass index; DBP, diastolic blood pressure; FPG, fasting plasma glucose; HDL, high density lipoprotein cholesterol; LDL, low density lipoprotein cholesterol; SBP, systolic blood pressure; TC, total cholesterol; WC, waist circumference. Table 6. Multiple linear regression analysis between HbA1c and cardiovascular risk factors β P FPG 0.010 < 0.001 HDL -0.006 < 0.001 Age 0.005 < 0.001 LDL 0.003 < 0.001 Triglyceride 0.000 0.026 FPG, fasting plasma glucose; HDL, high density lipoprotein cholesterol; LDL, low density lipoprotein cholesterol. Table 7. Optimal HbA1c cutoff points from ROC curve HbA1c (%) cutoff point Sensitivity 1-specificity AUC Metabolic syndrome Total 5.35 0.547 0.319 0.646 Male 5.35 0.733 0.376 0.688 Female 5.25 0.579 0.435 0.632 FPG 100 mg/dl Total 5.45 0.614 0.219 0.682 Male 5.45 0.625 0.250 0.704 Female 5.55 0.600 0.156 0.650 AUC, area under the curve; FPG, fasting plasma glucose. 440
김진화외 8 인 : 당뇨병이없는성인에서심혈관질환위험요소및대사증후군과당화혈색소의상관관계 고찰및결론본연구에서는당뇨병이없는일반인구를대상으로당화혈색소가높은군에서낮은군에비하여심혈관질환의위험요소가증가하고대사증후군의유병률이유의하게증가함을관찰하였다. 특히, 공복혈당, HDL 콜레스테롤, 연령, LDL 콜레스테롤, 중성지방은유의한독립변수로당화혈색소와유의한연관성을보였다. 식생활및생활양식의서구화와함께우리나라의허혈성심질환으로인한사망률이 1990년인구십만명당 10.4명에서 2000년 21.5명으로 2배이상증가되며 15) 우리사회의중요한건강문제로대두되고있다. 대사증후군은심혈관질환발생의주요위험인자인고혈당, 고혈압, 고지혈증, 복부비만이한개인에서군집되어나타나는현상으로 11) 대사증후군의관리는심혈관질환의관리와연계된다. 특히, 고혈당은심혈관계질환의강력한독립인자로알려져있으며당뇨병이없는사람에비하여당뇨병이있는경우남성에서는 2~3배, 여성에서는 3~4배그위험도가증가된다 2,3). 당뇨병환자들을대상으로시행된 DCCT (Diabetes Control and Complicaation Trial) 4) 와 UKPDS (United Kindom Prospective Diabetes Study Group) 5) 연구에서엄격한혈당조절을시행한경우미세혈관합병증발생의감소가관찰되었고, 당뇨병환자에서심혈관질환으로인한사망위험률이혈당증가및당화혈색소의상승에따라증가된다는보고가있다 6,7). 당뇨병이없는인구에서혈당상태와심혈관질환의사망률간의연관성은명확히밝혀져있지않으나제2형당뇨병에서당뇨병이임상적으로진단되기적어도 4~7년이전에발병되어 16) 당뇨병진단당시당뇨병성망막병증 17), 당뇨병성신경병증 18), 당뇨병성신증 19) 등미세혈관합병증이동반되기도하며심혈관질환의위험율또한증가시킨다고보고되었다 20). DECODE (Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe) 21) 연구결과에서도고혈당과심혈관질환발병과의연관성이당뇨병진단기준인공복혈당 126 mg/dl이아닌공복혈당 110 mg/dl 에서부터시작하여직선적인상관관계가관찰되었다. 당화혈색소는지난 2~3개월동안의평균공복혈당과식후혈당을독립적을반영하므로 1) 당뇨병환자에서혈당관리의지표로검사되고있으며당뇨병에관한여러연구에서널리이용되고있다. 당뇨병이없는인구에서당화혈색소의인종간의차이가보고되었고 22), 당화혈색소가혈당상태이상의다양한대사상태를반영할가능성도제시되고있다 23). 당화혈색소가 HDL로부터콜레스테롤에스테르 (ester) 의이동을증가시켜 HDL 콜레스테롤감소의원인이되는 lipoprotein의당화증가의표지자임을보여주며당화혈색소와 HDL 콜레스테롤간의직접적인연관관계를제안한연구가있다 24). 본연구에서는당뇨병이없는일반인구에서당화혈색소와심혈관질환위험요소간의연관성및심혈관질환위험요소의군집상태인대사증후군과의관련성을파악하여당뇨병이없는일반인구에서당화혈색소가가지는의미를파악하고자하였다. 당화혈색소는변수를보정한후에도혈당상태뿐아니라연령, 지질상태와상관관계를나타내어심혈관질환의위험요소및대사증후군발병의예측자로서이용가능성을제시하였다. 당뇨병이없는사람들에서당화혈색소와심혈관질환과의연관관계는명확하지않으나당화혈색소가당뇨병이없는사람들에서도심혈관질환발생의독립적인위험인자임을제안하는연구들이있다. 당뇨병이없는 50세에서 75세사이의성인 2,363명을대상으로 8년간추적관찰한 Hoorn 연구 25) 에서경구당부하 2 시간후혈당과당화혈색소가심혈관질환으로인한사망위험률증가와연관이있었다. 사망위험률은당화혈색소 1.4% 에증가에따라 51% 증가되었고, 당화혈색소가증가할수록연령, 공복인슐린, 고혈압, BMI, 총콜레스테롤, LDL 콜레스테롤, 중성지방, 흡연률은증가하였고 HDL 콜레스테롤은감소하였다. 연령과성별보정후당화혈색소 6.5% 이상인군에서심혈관질환사망에대한상대적위험률은 3.58 (95% CI 1.60~8.00) 로상승되었다. Rancho Bernardo 연구 26) 에서는심혈관질환으로인한사망률예측에있어서당화혈색소가공복혈당과식후혈당치보다더좋다고보고하였으며, EPIC (European Investigation of Cancer and Nutrition)-Norfolk 연구 27) 에서는당뇨병이없는사람들에서변수를보정한후에도당화혈색소 1% 증가가심혈관질환위험률 21% 증가와연관된다고보고하였다. 또한당뇨병이없는사람들에서당화혈색소의증가가심혈관질환및사망률을예측할수있다고보고하며당화혈색소가혈압이나콜레스테롤처럼심혈관질환의위험요인이될수있음을제안하였다. Dilley 등 28) 은당뇨병이없는아시아인디언 1,620명을대상으로한연구에서당화혈색소와심혈관질환의위험인자간의연관성및대사증후군의증가를확인하였고특히, 연령, 허리둘레, 중성지방, LDL 콜레스테롤, 공복인슐린을독립변수로보고하였다. 또한당화혈색소를대사증후군발병 441
을예측할수있는요소로제안하며그기준치를 5.6% (sensitivity 67.6, specificity 55.7) 로제시하였다. 40세이상의한국인 22,465명을대상으로한연구 29) 에서도당화혈색소가높은군에서심혈관질환위험인자의유의한증가가관찰되었고대사증후군의유병률증가가확인되었다. 대사증후군의발병을추정할수있는당화혈색소의기준치는 5.45% (sensitivity 60.2, specificity 63.4) 였으며남성에서는 5.45% (sensitivity 56.5, specificity 67.5), 여성에서는 5.55% (sensitivity 63.8, specificity 69) 로본연구와차이가있었다. 본연구의임계점은전체인구에서 5.35% (sensitivity 54.7, specificity 68.1), 남성에서 5.35% (sensitivity 73.3, specificity 62.4), 여성에서 5.25% (sensitivity 57.9, specificity 56.5) 로더낮았는데이는대상군의기저평균당화혈색소치가남성 5.32%, 여성 5.41% 로본연구보다높았다는점이영향을미쳤을것으로사료된다. 또한공복혈당장애를추정할수있는당화혈색소치는남성에서 5.35% (sensitivity 61.7, specificity 63.1), 여성에서 5.45% (sensitivity 64.3, specificity 62) 로본연구의남성 5.45% (sensitivity 62.5, specificity 75.0), 여성 5.55% (sensitivity 60.0, specificity 84.4) 에비하여낮았다. 본연구와는달리대상자가 40세이상이어서연령이변수로작용하였을가능성을고려해볼수있으나연령차및성별에따른당화혈색소의변화추이및당화혈색소에대한다양한변수에대하여명확히밝혀져있지않아서이러한차이를정확히설명하기는어려울것으로사료된다. 본연구의결과당화혈색소의증가에따라대사증후군의유병률의유의한증가가관찰되어당뇨병이없는일반인구에서당화혈색소수치가상위에있는경우심혈관질환의위험요소및대사증후군의발생가능성을고려하여생활습관개선등관리가이루어져야할것을제안한다. 또한한국인에서의연구 29) 와본연구를고려하여당뇨병이없는일반인구에서당화혈색소가 5.25~5.55% 이상시대사증후군및당뇨병의전단계이며 30) 심혈관질환발생의위험성을 21) 지니는공복혈당장애에대한평가와관리가이루어져야할것을제안하며이에대한더많은연구가이루어져야할것이다. 특히당화혈색소는식사여부에상관없이하루중어느때나측정할수있어공복혈당측정이나경구당부하검사보다간편하게이용할수있다는장점을지닌다. 당화혈색소가당뇨병, 공복혈당장애및내당능장애의진단기준은아니나 30) 대사증후군및심혈관질환의위험을추측하는데이용해볼수는있을것으로사료된다. 본연구의대상에서진단되지않은당뇨병환자를제외시 키기위하여공복혈당 126 mg/dl 이상, 당화혈색소 7% 이상인사람들을제외하였으나경구당부하검사등이시행되지않아서진단되지않은당뇨병, 내당능장애를가진사람들이포함되었을가능성이있으며제외공복혈당기준을 126 mg/dl로하여공복혈당장애를가진사람들이포함되었을가능성이존재하여그영향에대한한계점을지닌다. 또한대상자의수가많지않고여성이많았으며연령분포가고르지않아본연구의결과를일반적으로적용하기는어려울것으로사료된다. 대사증후군의중요한바탕인인슐린저항성이평가되지않아서당화혈색소와인슐린저항성간의연관성을확인하기어려웠고혈관의동맥경화정도가측정되지않아서당뇨병이없는인구에서당화혈색소와동맥경화정도간의연관성을정확하게파악하지못하였다. 당화혈색소는결과의표준화가어렵고빈혈등혈색소에영향을미칠수있는질환에따라그수치가정확히검사되지않을수있다는단점을지니므로이에대한평가가요구된다. 본연구는단편적조사연구로본연구의결과만으로당화혈색소가심혈관질환의발생이나대사증후군발병과연관이있다고결론내리기에는한계가있을것으로사료되며이에대한더많은전향적연구가필요할것이다. 우리나라의당뇨병이없는일반인구에서당화혈색소의증가가대사증후군및심혈관질환의위험을예측할수있는하나의인자가될수있을것으로생각되며이에대한더많은연구가시행되어야할것이다. 요약배경 : 당뇨병환자에서혈당상승및당화혈색소상승시심혈관질환으로인한사망위험률또한증가되며당화혈색소의증가는미세혈관및대혈관합병증증가와연관된다는연구들이있다. 그러나당뇨병이없는일반인구에서혈당상태와심혈관질환간의연관성에관해서는명확히밝혀져있지않으며특히, 당화혈색소와심혈관질환간의관계에관한연구는많지않다. 이에저자등은전라남도광양지역 20~70세의당뇨병이없는일반인구를대상으로당화혈색소와심혈관질환의위험요소간의연관관계를분석하고대사증후군발병과의상관성을평가하였다. 대상및방법 : 2006년 8월 7일부터 2006년 9월 17일까지전라남도광양지역에거주하는 20~70세의당뇨병이없는성인 533명 ( 남성 180명, 여성 353명 ) 을대상으로하였다. 당화혈색소와심혈관질환의위험요소를조사하였고대사증후군은 International Diabetes Federation 기준을적용하여 442
김진화외 8 인 : 당뇨병이없는성인에서심혈관질환위험요소및대사증후군과당화혈색소의상관관계 정의하였다. 결과 : 남녀의성비는 1:1.961로여성이더많았으며평균연령은 46.9 ± 10.12세 (mean ± SD) 였고, 평균당화혈색소는 5.3 ± 0.36% 로남녀간의유의한차이는없었다. 당화혈색소의증가에따라대사증후군의유병률이유의하게증가하였고연령, BMI, 허리둘레, 공복혈당, 수축기혈압, 이완기혈압, 총콜레스테롤, 중성지방, LDL 콜레스테롤과유의한양의상관관계를나타내었으며 HDL 콜레스테롤과는유의한음의상관관계를나타내었다. 특히, 공복혈당, HDL 콜레스테롤, 연령, LDL 콜레스테롤, 중성지방은변수를보정한후에도유의한상관관계를보였다. 대사증후군진단에상응하는당화혈색소치를 ROC 곡선을통하여추정한결과 5.35% (sensitivity; 0.547, 1-specificity; 0.319) 였고, 공복혈당 100 mg/dl에상응하는당화혈색소치는 5.45% (sensitivity; 0.614, 1-specificity; 0.219) 였다. 결론 : 당뇨병이없는성인에서당화혈색소는심혈관질환의위험요소와유의한연관관계를보였고당화혈색소의증가에따라대사증후군유병률의유의한증가가관찰되어당뇨병이없는사람들에서당화혈색소가대사증후군및심혈관질환의위험을예측할수있는하나의인자로이용될수있을가능성을제안한다. 참고문헌 1. Krishnamurti U, Steffes MW: Glycohemoglobin: a primary predictor of the development or reversal of complications of diabetes mellitus. Clin Chem 47: 1157-65, 2001 2. Kannel WB, McGee DL: Diabetes and cardiovascular disease: the Framingham study. JAMA 241:2035-38, 1979 3. Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M: Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 339:229-34, 1998 4. Diabetes Control and Complications Trial Research Group: The absence of a glycemic threshold for the development of long-term complications: the prospective of the Diabetes Control and Complications Trial. Diabetes 45:1289-98, 1996 5. UK Prospective Diabetes Study (UKPDS) Group: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352:837-53, 1998 6. Laako M: Glycemic control and the risk for coronary heart disease in patients with non insulin dependent diabetes mellitus. The Finnish Studies. Ann Intern Med 124:127-30, 1996 7. Wei M, Gaskill SP, Haffner SM, Stern MP: Effects of diabetes and level of glycemia on all-cause and cardiovascular mortality. Diabetes Care 21:1167-73, 1998 8. Nakamura Y, Horii Y, Nishino T, Shiiki H, Sakaguchi Y, Kagoshima T, Dohi K, Makita Z, Vlassara H, Bucala R: Immunohistochemical localization of advaned glycosylation endproducts in coronary atheroma and cardiac tissue in diabetes mellitus. Am J Pathol 143:1649-56, 1993 9. Kanauchi M, Hashimoto T, Tsujimoto N: Advaned glycation end products in nondiabetec patients with coronary artery disease. Diabetes Care 24:1620-23, 2001 10. Blake GJ, Pradhan AD, Manson JE, Williams GR, Buring J, Ridker PM: Hemoglobin A1c level and future cardiovascular events among women. Arch Intern Med 164:757-61, 2004 11. Reaven GM: Role of insulin resistance in human disease. Diabetes 37:1595-07, 1998 12. Friedewald WT, Levy RI, Fredrickson DS: Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 18:499-502, 1972 13. International Diabetes Federation: The IDF consensus world wide definition of the metabolic syndrome. 2005 14. Western Pacific Regional Office of the World Health Organization, The International Obesity Task Force: The Asia-Pacific perspective: redefining obesity and its treatment. 2000 15. 통계청 : 2000년사망원인통계연보. 2001 16. Harris MI, Klein R, Welborn TA, Knuiman MW: Onset of NIDDM occurs at least 4-7 yr before 443
clinical diagnosis. Diabetes Care 15:815-19, 1992 17. Klein R, Klein BEK, Moss SE, Davis MD, DeMetz DL: The Wisconsin epidermiologic study of diabetic retinopathy. III. prevalence and risk of diabetic retinopathy when age at diagnosis is 30 or more years. Arch Opthalmol 102:527-32, 1984 18. Harris MI: Undiagnosed NIDDM; Clinical and public health issues. Diabetes Care 16:642-52, 1993 19. Ballard DJ, Humphrey IL, Melton LJ, Fronhnert PP, Chu PC, O'Fallon WN: Epidemiology of persistent proteinuria in type II diabetes mellitus. Populationbased study in Rochester, Minnesota. Diabetes 37: 405-12, 1988 20. Harris MI: Impaired glucose tolerancee in the U.S. population. Diabetes Care 12:464-74, 1989 21. The DECODE Study Group: Glucose tolerance and mortality: comparison of WHO and American Diabetes Association Diagnostic criteria. Lancet 354:617-21, 1999 22. Yates AP, Laing I: Age-related increase in hemoglobin A1c and fasting glucose in accomplished by a decrease in β-cell function without change in insulin sensitivity: evidence from cross-sectional of hospital personnel. Diabet Med 19:254-58, 2002 23. Osei K, Rhinesmith S, Gaillard T, Schuster D: Is glycosylated hemoglobin A1c a surrogate for metabolic syndrome in nondiabetic, first-degree relatives of African-American patients with type 2 diabetes?. J Clin Endocrinol Metab 88:4596-601, 2003 24. Bakker SJ, Dekker JM, Heine RJ: Association between A1c and HDL cholesterol independent of fasting triglycerides in a Caucasian population: evidence for enhanced cholesterol ester transfer induced in vivo glycation. Diabetologia 41:1249-50, 1998 25. de Vegt F, Dekker JM, Ruhe HG, Stehouwer CDA, Nijpels G, Bouter LM, Heine RJ: Hyperglycaemia is associated with all-cause and cardiovascular mortality in the Hoorn population: the Hoorn Study. Diabetologia 42:926-31, 1999 26. Park S, Barrett-Connor E, Wingard DL, Shan J, Edelstein S: GHb is a better predictor of cardiovascular disease than fasting or postchallenge plasma glucose in women without diabetes: the Rancho Bernardo Study. Diabetes Care 19:450-56, 1996 27. Khaw KT, Wareham N, Luben R, Bingham S, Oakes S, Welch A, Day N: Glycated haemoglobin, diabetes, and mortality in men in Norfolk cohort of European Prospective Investigation of Cancer and Nutrition (EPIC-Norfolk). Br Med J 322:15-18, 2001 28. Dilley J, Ganesan A, Deepa R, Deepa M, Sharada G, Williams OD, Mohan V: Association of A1c with cardiocascular diasease and metabolic syndrome in Asian indians with normal glucose tolerance. Diabetes Care 30:1527-32, 2007 29. Sung KC, Rhee EJ: Glycated haemoglobin as a predictor for metabolic syndrome in non diabetic Korean adults. Diabet Med 24:848-54, 2007 30. Expert committee on the diagnosis and classification of diabetes mellitus: Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 20:1183-97, 1997 444