07_( ) _김원준,박철영.hwp

DOI : 10.4093/kdj.2009.33.6.494 ORIGINAL ARTICLES 고중성지방혈증을동반한제2 형당뇨병환자에서 ω-3 지방산과 Simvastatin 병합요법과 Simvastatin 단독요법의지질및아포지단백크기와아형에대한비교연구 성균관대학교강북삼성병원내분비내과 1, 한양대학교구리병원내분비내과 2, 아주대학교병원내분비내과 3, 연세대학교노화과학연구소 4 김원준 1* 이창범 2* 박철영 1 박세은 1 이은정 1 이원영 1 오기원 1 박성우 1 김대중 3 김혜진 3 한승진 3 조홍근 4 Effects of Adding ω-3 Fatty Acids to Simvastatin on Lipids, Lipoprotein Size and Subspecies in Type 2 Diabetes Mellitus with Hypertriglyceridemia Won Jun Kim 1*, Chang Beom Lee 2*, Cheol Young Park 1, Se Eun Park 1, Eun Jung Rhee 1, Won Young Lee 1, Ki Won Oh 1, Sung Woo Park 1, Dae Jung Kim 3, Hae Jin Kim 3, Seung Jin Han 3, Hong Keum Cho 4 1 Department of Endocrinology and Metabolism, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, 2 Department of Endocrinology and Metabolism, Guri Hospital, Hanyang University School of Medicine, Guri, 3 Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, 4 Aging Research Institute, Yonsei University, Seoul, Korea Abstract Background: ω-3 fatty acids are known to improve lipid profiles, the distribution of lipoprotein subclasses, and secondary prevention against post-myocardial infarction. Rare reports have emerged of synergistic results of ω-3 fatty acids with simvastatin in cases of type 2 diabetes mellitus with hypertriglyceridemia. The purpose of this study was to determine the combined relationship of ω-3 fatty acids plus simvastatin on lipid, lipoprotein size and the types of subspecies. Methods: This randomized, multi-center, comparison study evaluated eight weeks of combination therapy (ω -3 fatty acids (Omacor) 4 g/day plus simvastatin 20 mg/day) or monotherapy (simvastatin 20 mg/day) for at least six weeks in 62 diabetic patients. Subjects with a triglyceride concentration of more than 200 mg/dl were eligible for inclusion. Results: No significant differences for ω-3 fatty acids + simvastatin versus simvastatin alone were observed for triglycerides (-22.7% vs. -14.3%, P = 0.292), HDL peak particle size (+2.8% vs. -0.4%, P = 0.076), LDL mean particle size (+0.4% vs -0.1%, P = 0.376) or LDL subspecies types, although the combination therapy showed a tendency toward lower triglycerides, larger HDL, and LDL particle sizes than did the monotherapy. There were no significant differences between the two groups in regard to HDL-C, LDL-C, or HbA1c levels. There were no serious adverse events and no abnormalities in the laboratory values associated with this study. 접수일자 : 2009 년 10 월 12 일, 통과일자 : 2009 년 12 월 10 일교신저자 : 박철영, 성균관대학교강북삼성병원내분비내과, E-mail: cydoctor@chol.com * 이연구는건일제약 의연구비지원으로이루어졌음. * 김원준과이창범은본논문에제 1 저자로공동기여하였음. 494

김원준외 11 인 : 고중성지방혈증을동반한제 2 형당뇨병환자에서 ω-3 지방산과 Simvastatin 병합요법과 Simvastatin 단독요법의지질및아포지단백크기와아형에대한비교연구 Conclusion: ω-3 fatty acids were a safeform of treatment in hypertriglyceridemic patients with type 2 diabetes mellitus. But, regarding efficacy, a much larger sample size and longer-term follow-up may be needed to distinguish between the effects of combination therapy and monotherapy. (Korean Diabetes J 33:494-502, 2009) Key words: Fatty acids, Hypertriglyceridemia, Omega-3, Simvastatin, Type 2 diabetes mellitus 서론당뇨병은심혈관계질환과동등한위험도를가진질환으로제2형당뇨병환자에서혈당을잘조절하면미세혈관합병증발생률을낮출수있었지만, 대혈관합병증발생률의감소에대해서는여러연구마다차이가있다 1-3). 이것은당뇨병이외에다른요인들이심혈관계질환에중요한역할을한다는것을의미하며, 당뇨병환자에서관찰되는고지혈증이심혈관계질환발생률및사망률과연관이있다는보고들이있다 4,5). 중성지방은대사성증후군과심혈관질환의발생에기여한다는증거는계속늘어나고있는가운데 6), 고밀도지단백콜레스테롤 (high density lipoproteins, HDL) 과저밀도지단백콜레스테롤 (low density lipoproteins, LDL) 의크기및아형도심혈관질환과연관이있다고보고있다. HDL은크기에따라 HDL 2b (9.7~23 nm) 부터 HDL 2a (8.8~9.7 nm), HDL 3a (8.2~8.8 nm), HDL 3b (7.8~8.2 nm), HDL 3c (7.2~7.8 nm) 의총 5개로나눌수있다. 5개의아형중크기가작을수록심혈관질환의고위험인자로밝혀져있으며, HDL 최대입자크기는 5개의 HDL 아형중가장밀도가높은입자의크기이다. HDL 2b 비율이상대적으로작을수록죽상경화증식이활발하며, HLD 2b 수치는곧제2형당뇨병에서의주요합병증인관상동맥질환의직접적인위험요인이라는보고가있다 7). LDL은상대적으로크기가크고밀도가작은 A형 (LDL 1과 LDL 2), 중간타입의 I형, 크기가작고밀도가큰 B형 (LDL 3~LDL 7) 으로구분되며, 그수치가정상일지라도, B형의비율이높을수록심혈관질환의고위험인자이다 8,9). 또한 B형은중성지방증가및 HDL 감소등에영향을미치고인슐린저항성을일으키는한부분으로고려되고있다. 1 g의캡슐에 eicosapentaenoic acid (EPA) 465 mg, docosahexaenoic acid (DHA) 375 mg, vitamin E 4 mg 이함유되어있는 ω-3 ethylester concentrate (Omacor ) 는 simvastatin이나 atrovastatin과병용투여할때, statin 계열 약물단독치료보다중성지방, non-hdl-c, 초저밀도지단백콜레스테롤 (VLDL-C) 을감소시켰고, 지단백입자의크기와아형분포를개선시켰다고보고되고있다 10-12). 본연구에서는 Simvastatin과 Omacor 병합요법과 Simvastatin 단독요법이고중성지방혈증을동반한제2형당뇨병환자에서중성지방의수치의변화와함께 HDL과 LDL 의아형에대한영향과차이를보고하는바이다. 대상및방법 1. 연구계획및대상본연구는제2형당뇨병과고지혈증을동반한한국인피험자를대상으로 Simvastatin 20 mg + ω-3 지방산 4 g/day 병합요법과 Simvastatin 20 mg 단독요법의유효성및안전성을비교평가하기위해 3개대학병원에서이루어진무작위배정, 비교형, 공개형제4상임상연구이다. 만 18~80세의남녀를대상으로, 최소 3개월이전제2형당뇨병으로진단되고고지혈증을동반한피험자를스크리닝하였으며, 제외기준에해당되지않으면, HbA1c 9.0% 이하이면서 6주이상 Simvastatin 20 mg/day를병용하고있고고중성지방혈증 200 mg/dl 이상이며, 4주내당뇨병약물의용량변화가없었고, 본시험참여에대해서면동의한피험자를대상으로진행하였다. 그리고, 제품설명서에서명시된투여금기에해당하는환자, 임상시험수행과결과해석에영향을미칠만한질환을가진환자, 동의가이루어지지않은환자들은연구대상에서제외하였다. 즉, 약제성분에과민한환자, 임신부나수유부, 피임제를사용하지않거나또는사용하지않을가능성이있는가임여성, 혈청 AST 또는 ALT 수치가정상수치의 2.5배이상인환자, 혈청크레아티닌수치가 177 μmol/l (2.0 mg/dl) 이상인신기능이상, 심혈관계, 간, 신경계, 내분비계또는기타심각한전신성질환을동반한자, 현재복용중인경구용혈당강하제, 고혈압약물외에추가적인약물의치료를요하거나용량변화가예상되는자, 지난 2개월간다른임상시험에참여한 495

자, 시험계획에동의하지않는자는연구대상에서제외하였다. 2. 연구방법 6주간의스크리닝기간을거쳐, 기초방문및투여 8주째에추적조사를위해병원에내원하여, 처방및검사를시행하였다. 1) 진단및약물투여본임상시험의대상자로적합함이확인된모든피험자는경구용혈당강하제와 Simvastatin을병용투여받았고, Simvastatin 20 mg/day 단독투여군과 Simvastatin 20 mg/day + Omacor 4 g/day 병용투여군에 1:1의비율로무작위배정되었다. 이후 8주의치료기간동안단독투여군은 1일 1회저녁에시험약물을투여하도록하였으며, 병용투여군은 1일 1회저녁에 Simvastatin 20 mg을투여하고, Omacor 1 g 캡슐 2개를 1일 2회아침 / 저녁에복용하도록하였다. 2) 관찰항목및자료수집방법성별, 연령, 신장 / 체중, 진단명, 식사요법여부, 흡연여부, 심혈관계질환가족력, 병력, 병용약제, 지질저하제의과거투여력등에대해서는스크리닝기간에구조화된증례기록지를이용하여수집하였다. 환자는스크리닝기간및기초방문및투여 8주째의평가방문을포함하여총 3회병원을방문하도록하였다. 중성지방변화의비교분석을 1차유효성평가변수로하였고, HDL과 LDL 아형변화의비교분석을 2차유효성평가변수로하였다. 그외에 HDL과 LDL 수치의변화를비교하였다. Gradient polyacrylamid gel electrophoresis (PAGE) 검사법을이용하여지질과아형분석을시행하였다. 대상환자군의부작용점검및안전성확보를위해외래방문시병력청취및혈당증가를포함한이상반응 ( 중증의증상 / 무증상, 저혈당포함 ), 활력징후 ( 체중포함 ), 이학적검사, 임상실험실검사치의변화를비교하였다. 3) 통계적분석본연구는 Omacor의유효성을평가하기위해, 중도탈락된환자들을포함하여 Intention to treat (ITT) 연구에포함시켰고, 안전성평가는한번이상의임상시험약을투여받은피험자를대상으로하였다. 기저치, 8주치에대하여정규성가정의만족여부에따라, 연속형자료는정규성가정의만족여부에따라, paired t-test 또는 Wilcoxon signed rank test를이용하여군내변화및 unpaired t-test 또는 Wilcoxon rank sum test를이용하여군간비교를하였다. 범주형자료는 McNemar's chi-square test를이용하여비교분석을실시하였다. 통계프로그램은 SAS v9.1 (SAS Institute Inc., Cary, NC, USA) 을사용하였다. 결과 1. 환자군의특성및평가대상국내 3개대학병원에서본연구에서적합한피험자 78명 ( 군당 39명 ) 을등록하였으며, 스크리닝된피험자중무작위배정되어 1회이상약물을투여한대상자는 62명이었다. 병용투여군과단독투여군에서모두남자가 74.2% (23/31명), 여자가 25.8% (8/31명) 으로성별이같은비율로분포되었으며, 두군간의통계적으로유의한차이는없었다. 평균연령은병용투여군에서 49.7 ± 11.3세, 단독투여 Table 1. Subject characteristics at baseline (n = 62) Parameter ω-3 fatty acids + Simvastatin Simvastatin (n = 31) (n = 31) P-value Sex Men 23 (74%) 23 (74%) 1.00 Women 8 (26%) 8 (26%) 1.00 Age (yr) 49.7 ± 11.3 52.0 ± 10.2 0.392 Body Mass Index (kg/m 2 ) 26.1 ± 2.7 26.6 ± 2.7 0.554 Waist Circumference (cm) 90.8 ± 9.3 92.4 ± 6.5 0.502 SBP (mm Hg) 125 ± 11.0 127 ± 11.7 0.464 DBP (mm Hg) 80.4 ± 6.2 82.6 ± 10.3 0.321 Smoking (%) 32.3 38.7 0.596 Alcohol intake (%) 61.3 54.9 0.607 DBP, diastolic blood pressure; SBP, systolic blood pressure. 496

김원준외 11 인 : 고중성지방혈증을동반한제 2 형당뇨병환자에서 ω-3 지방산과 Simvastatin 병합요법과 Simvastatin 단독요법의지질및아포지단백크기와아형에대한비교연구 Table 2. Plasma concentrations of standard lipid parameters and other laboratory values at baseline and at the end of the study Parameters ω-3 FAs + Simvastatin (n = 31) Simvastatin (n = 31) Baseline % Change Baseline % Change P-value TC 0.466 Mean (SD) 168.4 (35.3) -4.7 (17.8) 171.7 (37.9) -1.7 (14.2) Median 161.0-4.8 159.0-3.1 95% CI -11.2 to 1.9-6.9 to 3.5 TG 0.292 Mean (SD) 297.8 (109.1) -22.7 (32.7) 295.8 (110.7) -14.3 (30.1) Median 260-25.87 254-20.59 95% CI -34.7 to -10.7-25.3 to -3.2 HDL-Cholesterol 0.672 Mean (SD) 43.4 (7.9) 3.8 (16.8) 46.0 (9.2) 6.1 (25.5) Median 43 1.13 44.6 5.15 95% CI -2.4 to 9.9-3.3 to 15.5 LDL-Cholesterol 0.828 Mean (SD) 84.1 (29.4) -0.2 (34.2) 80.9 (32.7) 1.6 (28.1) Median 74.2-8.14 75 0 95% CI -12.7 to 12.4-8.8 to 11.9 Apo A1 0.897 Mean (SD) 137.6 (15.5) 1.6 (11.3) 144.8 (23.8) 2.0 (14.5) Median 136.02 0.86 141.01 0.77 95% CI -2.6 to 5.7-3.3 to 7.3 Apo B 0.553 Mean (SD) 90.5 (19.6) -1.7 (32.1) 89.3 (27.3) -5.8 (20.2) Median 84-4.72 80-2.25 95% CI -13.5 to 10.1-13.2 to 1.7 HbA1c 0.903 Mean (SD) 7.1 (1.2) 2.9 (8.7) 7.4 (1.2) 2.6 (8.5) Median 6.8 0.62 7.5 2.7 95% CI -0.4 to 6.2-0.5 to 5.8 Data are presented as mean (SD), median, or 95% confidence interval (CI). P values are for comparisons of percent change between combination and monotherapy, based on unpaired t-test. Apo A1, apolipoprotein A1; Apo B, apolipoprotein B. 군에서 52.0 ± 10.2세로두군간에통계적으로유의한차이가없었다. 그외에도체중, 키, BMI 수치, 허리둘레, 흡연력, 음주력에관한두군간의치료전특성은통계적으로유의한차이가없었다 (Table 1). 병발질환유무병용약물복용여부도두군간통계적으로유의한차이가없었다. 2. 유효성평가중성지방변화율에대한분석결과, 병용투여군은 -22.7% (P < 0.001), 단독투여군은 -14.3% (P = 0.013) 로, 두치료군내모두약물투여후중성지방수치가유의하게감소된것으로나타났다. 변화율에대한두군간의차이는통계적으로유의하지않았지만, 병용투여군이단독투여군보다 중성지방변화율이더컸다. 그밖에총콜레스테롤, HDL, LDL, ApoA1, ApoB 및 HbA1c 수치변화율에서두군간유의한차이는없었다 (Table 2). HDL 최대입자크기의평균변화량의경우병용투여군은 2.8% 증가하였으며, 단독투여군에서 -0.1% 로감소하였으나, 통계적으로유의한차이를보이지않았다. HDL 아형의비교에서, HDL 3a에서만유의하게병용투여군이단독투여군보다변화량증가폭이더작았다. 특히 HDL 2b의경우병용투여군에서의변화량감소폭이단독투여군의감소폭보다더작았으며 (-4.0% vs -6.1%), HDL 2a의경우두군에서모두유의하게증가하였으나 (P = 0.040 vs P = 0.003), 두군간유의한차이는없었다 (Table 3). HDL 수치는병합요법과단독요법의군내또는군간비교에서유의하지 497

Table 3. Concentrations of each HDL subfraction at baseline and at the end of the study Particle size and subfraction ω-3 FAs + Simvastatin (n = 31) Simvastatin (n = 31) Baseline % Change Baseline % Change P-value HDL peak particle size (nm) 0.076 Mean (SD) 8.8 (0.7) 2.8 (7.8) 8.9 (0.6) -0.4( 6.1) Median 8.9 1.1 8.9 0.0 95% CI 0.0 to 5.7-2.6 to 1.8 HDL 2b (%) 0.330 Mean (SD) 31.7 (2.2) -4.0 (8.9) 32.0 (2.5) -6.1 (7.7) Median 31.6-2.5 31.7-3.9 95% CI -7.2 to -0.7-8.9 to -3.2 HDL 2a (%) 0.949 Mean (SD) 21.9 (1.7) 4.9 (12.7) 22.5 (1.8) 4.7 (7.6) Median 22.3 3.0 21.9 4.0 95% CI 0.2 to 9.5 1.9 to 7.5 HDL 3a (%) 0.045 Mean (SD) 18.1 (1.4) 0.7 (8.7) 18.1 (1.2) 4.9 (7.3) Median 18.5-0.5 18.0 4.3 95% CI -2.5 to 3.9 2.2 to 7.5 HDL 3b (%) 0.060 Mean (SD) 12.7 (1.3) 1.0 (9.0) 12.4 (1.4) 5.8 (10.7) Median 13.0-1.4 12.1 2.3 95% CI -2.4 to 4.3 1.8 to 9.7 HDL 3c (%) 0.384 Mean (SD) 15.6 (2.7) 2.2 (26.3) 15.1 (2.7) -2.7 (16.3) Median 15.7-3.6 16.2-6.4 95% CI -7.5 to 11.8-8.7 to 3.3 Data are presented as mean (SD), median, or 95% confidence interval (CI). P values are for comparisons of percent change between combination and monotherapy, based on unpaired t-test. 않았다 LDL 입자크기의평균변화량은병용투여군에서 0.4% 더증가하였고, 단독투여군은 0.1% 로더감소하였으나, 통계적으로유의한차이는아니었다. LDL 1, LDL 2의변화량의경우병용투여군에서덜증가하는경향이었으나통계적으로유의하지않았고, LDL 3~5에서도유의한차이가없었다 (Table 4). 맥박의변화량은병용투여군에서는감소하였으며, 단독투여군의경우증가하였는데이는통계적으로유의한것으로나타났다 (P = 0.003). 그외혈압, 체온, 체중에대한변화량은치료군간통계적으로유의한차이는없었다. 3. 안전성평가병용투여군에서는이상반응및중대한이상반응을경험한피험자가나타나지않았으며, 단독투여군에서는이상반응 9.7% (3/31명), 중대한이상반응 3.2% (1/31명) 으로병용투여군보다는비율이높게나타났으나, 두치료군간차이는통계적으로유의하지않았다. 단독투여군에서발현된 중대한이상반응은흉통으로 2일후에자연적으로소실되었으며약제와는관련없는것으로판정되었고, 이상반응은소화불량이 3.2% (1/31명, 1건 ), 흉통이 3.2% (1/31명, 1건 ), 골절이 3.2% (1/31명, 1) 으로각각발현되었다. 고찰 Simvastatin만으로고중성지방혈증이치료되지않던환자군에게 ω-3 지방산을병합하면중성지방, 총콜레스테롤, 비고밀도-콜레스테롤의유의한감소가보고되고있다 13-15). 본연구에서는당뇨병을동반한고중성지방혈증환자들에게 ω-3 지방산병용투여가 simvastatin 단독투여보다중성지방을더감소시키는경향이었고, HDL 최대입자크기, LDL 평균입자크기를증가시키는경향이었으나, 통계적으로유의한차이는없었으며, HDL과 LDL 아형에서도 HDL 3a를제외하고통계적인유의성이없었다. 중성지방은 HDL 수치의하강과밀접한관련이있고, 개체를둘러싼생물학적변화에따라변동이매우심하여연 498

김원준외 11 인 : 고중성지방혈증을동반한제 2 형당뇨병환자에서 ω-3 지방산과 Simvastatin 병합요법과 Simvastatin 단독요법의지질및아포지단백크기와아형에대한비교연구 Table 4. Concentrations of each LDL subfraction at baseline and at the end of the study Particle size and subfraction ω-3 FAs + Simvastatin (n = 31) Simvastatin (n = 31) Baseline % Change Baseline % Change P-value LDL mean particle size (nm) n = 24 n = 23 n = 25 n = 24 0.376 Mean (SD) 265.0 (6.9) 0.4( 2.1) 265.3 (3.9) -0.1 (1.2) Median 266.3 0.1 266.5 0.2 95% CI -0.5 to 1.3-0.5 to 0.4 LDL 1 (mg/dl) n = 24 n = 23 n = 25 n = 24 0.390 Mean (SD) 18.3( 10.2) 0.5 (62.7) 17.0 (8.4) 13.4 (34.1) Median 17.5-9.1 16.0 19.0 95% CI -26.6 to 27.6-1.0 to 27.8 LDL 2 (mg/dl) n = 24 n = 23 n = 25 n = 24 0.339 Mean (SD) 15.8 (10.7) 3.5 (65.1) 16.6 (10.2) 18.7 (38.2) Median 13.0 0.0 13.0 11.3 95% CI -24.7 to 31.7 2.6 to 34.8 LDL 3 (mg/dl) n = 23 n = 21 n = 25 n = 24 0.370 Mean (SD) 5.4 (5.3) 65.5 (232.8) 5.4 (5.2) 17.5 (64.4) Median 3.0 16.7 3.0 5.6 95% CI -40.5 to 171.5-9.7 to 44.7 LDL 4 (mg/dl) * n = 12 n = 9 n = 12 n = 9 0.202 Mean (SD) 3.7 (4.1) -49.6 (78.2) 2.2 (1.8) 63.0 (226.4) Median 2.0-100.0 2.5 0.0 95% CI -109.7 to 10.5-111.0 to 237.0 LDL 5 (mg/dl) * n = 3 n = 2 n = 3 n = 2 0.617 Mean (SD) 4.0 (3.0) -64.3 (50.5) 1.0 (1.0) -100.0 (0.0) Median 4.0-64.3 1.0-100.0 95% CI -518.1 to 389.5-100.0 to -100.0 Data are presented as mean (SD), median, or 95% confidence interval (CI). P values are for comparisons of percent change between combination and monotherapy; P values are based on unpaired t-test except LDL 4 and LDL 5 (* Wilcoxon rank sum test). 구하기에어려운것으로알고있었으나 16), 최근중성지방의수치가기타다른지질수치에비하여변동폭이크지않다는논문도보고되고있다 17). ω-3 지방산이중성지방을감소시키는효과는잘알려져있다. 여러임상시험에서 ω-3 지방산의용량에따라중성지방의감소효과가나타나나, 대부분의연구에서 10~33% 의감소가보고되었다 18). 본연구에서병용투여군의중성지방의변화율 (-23%, P < 0.001) 은단독투여군 (-14%, P = 0.013) 에비해크게나타났으나, 두군간에통계적으로유의한차이를보이지는않았다. 혼합형고지혈증 ( 중성지방이 200~600 mg/dl이고, 비고밀도콜레스테롤이 ATPIII 권고수치보다높은경우 ) 을가진 78명의대상자들에게 ω-3 지방산을추가한병용요법과 simvastatin 단독요법의비교연구에서는중성지방의변화율차이가 -15% 였고, 다른지질관련수치의변화율의차이가 -20~-4% 였으며모두유의한차이를보였고 19), 다른연구에서도병합요법이고중성지방혈증과지질의아형개선에대해유효하다고제시하였다 15,20,21). 그런데, 고지혈증을가 진당뇨병환자들만을대상으로비교한연구는드물어, 8명을대상으로, fluvastatin 80 mg에 ω-3 지방산을병합한경우는 fluvastatin 단독보다중성지방감소와 HDL 증가, ApoB48 감소에서유의한차이를나타내었다 22). 62명을무작위배정한본연구에서는, simvastatin 기존복용환자에서도생활습관의교육과 statin 약제의꾸준한복용효과로추가적인중성지방의감소가유의하여, 중성지방의치료후농도는각군내에서각각 -78 mg/dl, -46 mg/dl씩유의하게감소되면서, 병용요법의효과가있었음에도뚜렷한차이를나타내지않았던원인으로보인다. HDL 입자크기가작을수록, HDL 2b 비율이작을수록심혈관질환의위험도가높아진다고보고되고있다 7). 본연구에서 HDL 최대입자크기평균변화량의경우병용투여군에서만 8주후증가하는양상을보였고, HDL 2b의경우치료군내및치료군간통계적으로유의하지않았고, HDL 2a의변화량의경우두군내에서모두유의하게증가하였으나치료군간변화량차이는유의하지않았다 (0.98% vs 499

1%, P = 0.972). 크기가작고밀도가큰 B형 (LDL 3~LDL 7) 이높을수록심혈관질환의위험이증가되고, 중성지방증가및 HDL 감소등에영향을미치고인슐린저항성을일으킨다고보고하였다 8,9). 본연구에서는병용투여군의 LDL 평균입자크기가단독투여군보다증가하는경향이었나, 유의한차이는없었다. LDL 1~5 아형을포함하여두군의유의한차이는없었다. 인슐린저항성을가진 2형당뇨병환자에서 lipoprotein lipase의효과가감소하고, 과체중인당뇨병환자에서간에서의 VLDL 생성이많아지며, VLDL의대사가감소하면서중성지방수치가높아진다. 8주간의치료기간동안당뇨병치료제의변화가없었던본연구에서당화혈색소및공복혈당수치에따라세부분석하였을때에두군간의유의한차이는없었다. 그런데, 당화혈색소를기준으로 7% 미만으로잘조절되었던그룹에서의병용요법과단독요법에비해 (-20% vs -24%, P = 0.976), 8% 이상으로조절되지않았던대상자에서각치료군내치료전후의중성지방수치가유의하게감소하였으나치료군간의유의한차이는없었다 (-35% vs -22%, P = 0.230). 당화혈색소가높은군에서중성지방이높아져고지혈증치료에더잘반응했던것으로보인다. HDL과 LDL 아형분석에서유의한차이는없었다. 본연구에서대상자수선정시, 유의수준 5%, 검정력 80% 에서두군간의중성지방변화량의차이 10%, 표준편차 15% 인경우군당 28명의피험자가필요한것으로산출되었으나 23), 실제표준편차에서많은차이를보여본임상결과의분석에대한 power는매우작은것으로나타났다. 본연구는당뇨병을동반한고지혈증환자를대상으로안전하게사용될수있는 ω-3 지방산과 simvastatin의병용요법과 simvastatin의단독요법의지질저하효과및그안전성을관찰한것으로, 8주간투여후병용투여군에서중성지방의감소효과가단독투여군보다더크며, HDL, LDL의입자크기가증가되는경향을보이나, 피험자수산정시예상한표준편차보다커지면서통계적인유효성의차이를보이기위해서는더많은대상군이필요하였다. Simvastatin 단독요법과비교하여안전성에서유의한차이가없었던 ω-3 지방산의병용투여가향후당뇨병환자의심혈관질환을예방할수있는지장기간투여효과에대한연구가필요하다. 요약연구배경 : ω-3 지방산은지질수치에긍정적인영향을줄뿐아니라, 심근경색후부정맥에서급사의위험성을낮추 는것으로알려져있다. 또한이약제는다른약제, 특히고지혈증치료의근간이되는 HMG-CoA 환원효소억제제와의병용요법에서가장문제가되는약물상호작용의가능성이매우적으며, 지단백입자의크기와아형분포를개선시켰다고보고되고있다. 저자등은 HMG-CoA 환원효소억제제만으로중성지방이조절안된제2형당뇨병환자에서, ω -3 지방산병용요법을시행하여중성지방감소효과와 HDL-C과 LDL-C의입자크기와아형변화를관찰하기로하였다. 방법 : 연구에동의한전체환자는 62명이었다. 단백뇨나 GFR 감소가없는 18~80세의제2형당뇨병환자를대상으로하였으며, 최근 6주간 simvastatin 20 mg을복용하였으나중성지방 200 mg/dl 이상, HbA1C < 9% 로조절되고, 최근 4주내에당뇨병약제의변화가없어야했다. 1주일에소주 2병해당량이상의알코올섭취자는제외하였다. 이환자들에게 simvastatin 20 mg에추가하여 ω-3 지방산을 8주간투여하였다. 정규성가정의만족여부에따라, t-test와윌콕슨순위합검정으로통계분석을이용하였다. 결과 : 8주간치료후병합요법군과단독요법군의중성지방수치의변화율에서유의한차이는없었고 (-22.7% vs -14.3%, P = 0.292), HDL 최대입자크기변화율 (+2.8% vs -0.4%, P = 0.076), LDL 평균입자크기변화율 (+0.4% vs -0.1%, P = 0.376), HDL 아형과 LDL 1~LDL 5 아형에서두군간의유의한차이는없었으나, 병합요법군에서중성지방수치가더낮아졌고, HDL과 LDL 입자크기가더증가하는경향이었다. 그밖의 HDL-C 수치, LDL-C 수치, 당화혈색소에서두군간의유의한차이는없었다. 약제병합요법의합병증은없었으며 CPK의증가는관찰되지않았다. 결론 : ω-3 지방산은, HMG-CoA 환원효소억제제만으로고중성지방혈증을보이는제2형당뇨병환자에서안전하게사용할수있는약제로, 병용시중성지방을더감소시키고 HDL과 LDL 입자크기를증가시키는경향이있으나, 더많은대상자에대한지질수치및아형변화의추가적인연구와 8주이상의장기적인연구결과를기대하여야겠다. 참고문헌 1. Malmberg K, Yusuf S, Gerstein HC, Brown J, Zhao F, Hunt D, Piegas L, Calvin J, Keltai M, Budaj A: Impact of diabetes on long-term prognosis in patients with unstable angina and non-q-wave myocardial 500

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