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1 당뇨병제 30 권제 4 호, 2006 원저 제 2 형당뇨병환자에서장기간의피오글리타존투여에따른임상적관찰 연세대학교의과대학내과학교실, 포천중문의과대학내과학교실 1 문재훈 김혜진 김수경 1 심완섭 강은석 이유미 안철우 임승길 김경래 이현철 차봉수 Long-term Effect of Pioglitazone Treatment in Patients with Type 2 Diabetes Jae Hoon Moon, Hye Jin Kim, Soo Kyung Kim 1, Wan Sub Shim, Eun Seuk Kang, Yumie Rhee, Chul Woo Ahn, Sung Kil Lim, Kyung Rae Kim, Hyun Chul Lee, Bong Soo Cha Department of Internal Medicine, Yonsei University College of Medicine, Department of Internal Medicine 1, Pochon CHA Univercity College of Medicine - Abstract - Background: Type 2 diabetes is characterized by impaired insulin secretion and/or insulin resistance. Thiazolidinediones have been shown to ameliorate insulin resistance. The purpose of the present study was to evaluate the long term serial effect of pioglitazone on anthropometrics and metabolic parameters in Korean type 2 diabetes patients. Methods: One hundred thirteen type 2 diabetes patients (male, 67; female, 46; mean age, 49.1 ± 10.8 years) were evaluated before and after 3 months, 6 months and 12 months of treatment with pioglitazone (Actos TM, 15 mg/day). Anthropometric parameters and metabolic variables were measured. Results: Body weight and body mass index (BMI) were increased in 3 months after pioglitazone treatment (body weight, 68.8 ± 12.2 vs 69.8 ± 11.9 kg, P < 0.01) without further increase. In women, body weight and BMI tended to increase more (body weight change after 3 months, 0.6 ± 1.7 kg vs 1.6 ± 1.7 kg, P < 0.01) and longer (3 months vs 6 months) than in men. Fasting plasma glucose (FPG) and HbA1c were decreased in 3 months after pioglitazone treatment (FPG, 7.97 ± 2.29 vs 6.94 ± 2.01 mmol/l, P < 0.01; HbA1c, 7.7 ± 1.5 vs 7.0 ± 1.1%, P < 0.01). Hypoglycemic effect of pioglitazone was prominent in women than in men (FPG change after 12 months, ± 2.54 vs ± 1.72 mmol/l, P < 0.001; HbA1c change after 12 months, -0.9 ± 1.3 vs -0.4 ± 1.1%, P < 0.05). Serum high-density lipoprotein cholesterol was increased after 3 months of pioglitazone treatment (1.16 ± 0.24 vs 1.31 ± 0.28 mmol/l, P < 0.01) without return until the end of this study. Serum triglycerides level decreased at 3 months (basal vs 3 months, 2.29 ± 1.86 vs 1.88 ± 1.21 mmol/l, P < 0.01) and 6 months (basal vs 6 months, 2.29 ± 1.86 vs 1.97 ± 1.40 mmol/l, P < 0.05) of pioglitazone treatment, but returned to basal level at 12 months. Liver enzyme, especially serum alanine transferase level decreased after 3 months of pioglitazone treatment (30.8 ± 23.7 vs 24.5 ± 18.5 IU/L, P < 0.01) without return until the end of this study. Hypoglycemic effect of pioglitazone was associated with basal BMI, fat contents and serum leptin level. Conclusion: Korean type 2 diabetes patients with pioglitazone use showed favorable metabolic effect for glycemic control, lipid metabolism and liverfunction, but pioglitazone induced body weight increase may be limited. (J Kor Diabetes Assoc 30:264~276, 2006) Key Words: Anthropometrics, Pioglitazone, Thiazolidinedione 접수일자 : 2005 년 9 월 13 일, 통과일자 : 2006 년 7 월 5 일, 책임저자 : 차봉수, 연세대학교의과대학내과학교실

2 - 문재훈외 10 인 : 제 2 형당뇨병환자에서장기간의피오글리타존투여에따른임상적관찰 - 서 론 대상및방법 제2 형당뇨병의병리기전은인슐린분비능저하및인슐린저항성으로알려져있다. 티아졸리딘디온 (thiazolidinedione) 제제는동물실험및임상실험에서인슐린저항성을개선시키는것이증명되었으며 1-5) 이러한티아졸리딘디온제제의인슐린저항성개선에대해많은연구가진행되었으나현재까지명확한작용기전은밝혀지지않았다. 티아졸리딘디온제제는세포의 peroxisome proliferator-activated receptor-gamma (PPAR-γ) 의 agonist로서, 여러종류의세포내 PPAR-γ와결합하여다양한유전자의발현을조절하는데 6), 특히지방세포의유리지방산생성을감소시키고아디포넥틴분비를증가시키며 7), adenosine monophosphate dependent protein kinase에도직접또는간접적으로영향을미치는것으로알려져있다 7). 또한혈당상승에영향이큰조직, 즉내장지방, 간, 근육및췌장의베타세포등에서지방축적을막고피하지방으로지방축적을유도하며 8-10), 이러한인슐린저항성개선효과외에도췌장베타세포의기능을향상시키는것으로도밝혀져제2형당뇨병의예방효과에대해서도주목받고있다 11). 현재까지이루어진동물및당뇨병환자를대상으로한많은연구에서티아졸리딘디온제제투여시에인슐린저항성의개선효과와함께체중증가 12-15) 및체지방량증가가 16-18) 동반되었음이보고되었다. 이에대한기전으로, 전지방세포를지방세포로분화시키는작용이내장지방조직보다피하지방조직에서활발히나타나고 10), 피하지방증가에따라체중및유리지방산저장능이증가하여근육과간에서의중성지방생성을저하시켜 8,9) 인슐린저항성을개선시키는것으로설명하기도한다. 일부대규모연구를통해티아졸리딘디온제제투여에따른임상경과를보고한바있으나 13,15,19) 신체계측과대사지표중한지표에치중하여관찰하거나치료전후의결과비교만을한연구가대부분이며장기간의티아졸리딘디온제제투여시에동반되는체중변화와이와연관된대사지표들의투여기간에따른변화에대해서는충분한연구가되어있지않다. 또한대상환자군이유럽및북미에국한되어, 한국인제2형당뇨병환자에서장기간티아졸리딘디온제제투여후의임상경과를관찰한예는극히드물다. 본연구에서는티아졸리딘디온제제인피오글리타존제제를 1년이상투여한한국인제2형당뇨병환자군을대상으로한코호트연구를통해투여기간에따른신체계측및대사지표의변화를관찰하고피오글리타존제제투여에높은효과를보이는환자군의특성을알아보고자하였다. 1. 연구대상연세대학교세브란스병원당뇨병센터에서미국당뇨병학회기준에따라제2형당뇨병으로진단된환자중최근 3개월간체중변화없이안정적용량의설폰요소제또는바이구아나이드제를투여하는환자를대상으로피오글리타존제제투여 (Actos TM, 15 mg/day) 를시작하면서본연구의코호트에순차적으로포함시켰다. 연구기간동안 83명 (73%) 의환자에서경구혈당강하제의변경은없었고, 11명 (10%) 은경구혈당강하제의용량이감소하였으며, 19명 (17%) 은경구혈당강하제중일부는감소하고일부는증가하였다. 연구기간동안피오글리타존제제는고정용량을유지하였다. 대상환자중간질환 ( 혈청 aspertate transaminase / alanine transaminase 수치가정상의 2배이상 ) 및신질환 ( 혈청 creatinine 수치가 2.0 mg/dl 이상 ) 의가능성이있는환자, 설폰요소제및바이구아나이드제제이외에혈당에영향을주는약제및지질대사개선제를사용하는환자는제외하였다. 최초코호트에포함된 218명의환자중정기적인추적관찰이이루어지지않은환자 92명, 추적기간중감염등의합병증에의해경구혈당강하제의용량을증량하거나인슐린을사용한환자 13명이탈락되었다. 연구기간은 2003년 3월부터 2004년 11월까지였다. 본임상연구는임상시험심사위원회의승인을받지않았다. 2. 연구방법선정된환자를대상으로피오글리타존제제투여전, 투여후 3개월, 6개월, 12개월에다음의지표를측정하였다. 1) 신체계측체중과키는신발을벗은상태에서가벼운옷차림으로 0.1 kg, 0.1 cm 단위까지측정하였고체질량지수를계산하였다. 허리둘레는가쪽엉덩뼈능선 (lateral iliac crest) 과가장아래갈비뼈사이의중간점에서측정하였으며엉덩이둘레는큰돌기 (great trochanter) 가가장돌출된부분에서측정하였다. 생체전기저항분석법 (bioelectrical impedance analysis) 의원리를이용한체성분분석기 (Inbody 2.0 Biospace Co., Ltd, Seoul, Korea) 를이용하여체성분분석을시행하였다. 고해상도초음파 (SA9900; Medison, Seoul, Korea) 를사용하여환자를바로눕게한후배꼽위 1 cm 위치에서 7.5 MHz probe로피하지방두께 ( 피부- 지방경계면에서백색선까지로정의 ) 를, 3.5 MHz probe로내장지방두께 ( 대동맥의전벽에서복직근내면까지로정의 ) 를측정하였다 20-22)

3 - 당뇨병제 30 권제 4 호, ) 대사지표대상환자의혈장에서공복및식후 2시간혈당 (glucose oxidase법 ), 당화혈색소 (HbA1c, high performance liquid chromatography), 인슐린 (RIABEAD II kit, Abbott, Japan), C-peptide, 요산, blood urea nitrogen (BUN), 크레아티닌, 총콜레스테롤, 중성지방, 고밀도지단백- 콜레스테롤, 저밀도지단백 -콜레스테롤, 렙틴 ( 방사선면역측정키트, Linco Research Inc., St. Charles, Mo., USA) 및 aspertate transaminase (AST), alanine transaminase (ALT) 수치를측정하였다. 인슐린저항성의지표로 homeostasis model assesment of insulin resistance (HOMA-IR) 을사용하였고다음과같은식으로계산하였다. HOMA-IR = [ 공복인슐린 (uu/ml) 공복혈당 (mmol/l) / 22.5] 3) 통계및분석모든자료의통계처리는개인용컴퓨터통계프로그램 SPSS 12.0 for Windows package를이용하였으며기술통계값은평균 ± 표준편차또는전체에대한백분율로표현하 였다. 남녀간의분석은독립표본 T 검정을, 치료기간에따른지표의변화분석에는대응표본 T 검정을이용하였다. 병용한경구혈당강하제의종류에따른분석은 ANOVA 분석을이용하였으며, 혈당강하효과와치료전지표의관계분석에는 Pearson 상관분석을사용하였다. P-value 가 0.05 미만인경우통계적으로유의한차이가있는것으로정의하였다. 결과 1. 연구대상환자군의임상적특성코호트에포함된환자중대상환자군의조건에부합하는환자는총 113명이었으며이중남자는총 67명 (59%), 여자는총 46명 (41%) 이었다. 피오글리타존제제투여전체질량지수는남녀간에통계적으로유의한차이를보이지않았고, 공복혈당및당화혈색소는여자가남자보다높았다 (P < 0.01). 내장지방의두께는남녀간차이를보이지않았으나피하지방두께및피하지방두께대내장지방두께의 Age (year) Weight (kg) * WHR HbA1c FPG (mmol/l) Total cholesterol (mmol/l) HDL cholesterol (mmol/l) LDL cholesterol (mmol/l) Triglyceride (mmol/l) AST (IU/L) ALT (IU/L) * HOMA-IR Fat SFT (cm) * VFT (cm) VSR * Muscle contents (kg) * Body composition Fat contents (kg) Fat proportion (%) * SU use (%) Oral hypoglycemics Biguanide use (%) SU+Biguanide use (%) Data are expressed as means ± Table 1. Baseline Characteristics of Subjects Total (n = 113) Male (n = 67) Female (n = 46) 49.1 ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± (19) 53 (47) 39 (34) 47.5 ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± (11) 37 (55) 23 (34) 51.5 ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± (30) 16 (35) 16 (35) SD.; BMI, body mass index; WHR, waist to hip circumference ratio; HbA1c, glycosylated hemoglobin; FPg, fasting plasma glucose; HDL, high density lipoprotein; LDL, low density lipoprotein; AST, aspartate transaminase; ALT, alanine transaminase; HOMA-IR, homeostasis model assessment insulin resistanace; SFT, subcutaneous fat thickness; VFT, visceral fat thickness; VSR, the ratio of VFT to SFT; SU, sulfonylurea. * P < 0.05 male versus female

4 - 문재훈외 10 인 : 제 2 형당뇨병환자에서장기간의피오글리타존투여에따른임상적관찰 - 비는여자에서남자보다유의하게높은결과를보였다 (P < 0.01). 체지방량은여자에서더높은경향을보였고 (P = 0.06), 근육및단백질량은남자가여자보다높았다 (P < 0.01) (Table 1). Total (n=113) Male (n = 67) Female (n = 46) Table 2. Changes of Body Weight and BMI after Pioglitazone Treatment Weight (kg) Weight (kg) Weight (kg) Baseline 3 Months 6 Months 12 Months 68.8 ± ± ± ± ± ± 3.4 Data are expressed as means ± SD.; BMI, body mass index. * P < 0.01 versus baseline. P < 0.01 versus 3 months ± 11.9 * 70.2 ± 11.8 * 70.3 ± 11.8 * 26.0 ± 3.4 * 26.2 ± 3.4 * 26.1 ± 3.5 * 73.9 ± 11.6 * 73.7 ± ± 3.2 * 25.7 ± ± ± ± 9.8 * 64.9 ± 10.3 * 65.2 ± 10.6 * 26.4 ± 3.5 * 26.8 ± 3.8 * 27.0 ± 4.0 * A B Fig. 1. Changes of body weight and BMI after pioglitazone treatment. A. Total study patients (n = 113). B. Male (n = 67) and female (n = 46) study patients. BMI, body mass index. * P < Table 3. Changes of Anthropometrics after 3 Months of Pioglitazone Treatment (n = 113) Muscle contents (kg) Fat contents (kg) Fat proportion (%) SFT (cm) VFT (cm) VSR Data are expressed as means ± of VFT to SFT. Baseline 3 Months P 46.1 ± ± ± ± ± ± ± ± ± ± ± ± 1.6 NS < < 0.05 < NS < SD.; SFT, subcutaneous fat thickness; VFT, visceral fat thickness; VSR, the ration

5 - 당뇨병제 30 권제 4 호, 피오글리타존제제투여기간에따른신체계측치의변화피오글리타존제제투여기간에따른체중및체질량지수의변화는 Table 2 및 Fig. 1과같다. 전체환자군에서체중은투여후 3개월에기저치보다증가하였으며 (68.8 ± 12.2 vs 69.8 ± 11.9 kg, P < 0.01) 이후로는의미있는체중증가는없었다. 남자에서는투여후 3개월에통계적으로유의한체중증가를보였고 (73.3 ± 11.7 vs 73.9 ± 11.6 kg, P < 0.01) 이후에는기저치와비교해도유의한차이를 보이지않았다. 여자에서는피오글리타존제제투여후 3개월부터체중증가가나타나기시작하여 6개월까지지속되었으며 (62.2 ± 9.6 vs 63.8 ± 9.8 vs 64.9 ± 10.3 kg, P < 0.01) 이후로는의미있는체중증가를보이지않았다. 피오글리타존제제투여전후의체성분분석및초음파를이용한복부지방두께측정결과는 Table 3과같다. 피오글리타존제제투여후 3개월에체지방량및체지방율모두증가하였으며 ( 체지방량, 20.5 ± 7.3 vs 21.7 ± 8.1 kg, P < 0.001; 체지방률, 29.5 ± 8.0 vs 30.3 ± 8.3%, P < 0.05), 복부피하지방두께는증가하였으나 (24.1 ± 8.6 vs 25.8 ± 9.0 cm, Table 4. Changes of FPG and Hba1c Levels, and HOMA-IR Indices after Pioglitazone Treatment Total (n = 113) Male (n = 67) Female (n = 46) FPG (mmol/l) HbA1c (%) HOMA-IR FPG (mmol/l) HbA1c (%) HOMA-IR FPG (mmol/l) HbA1c (%) HOMA-IR Baseline 3 Months 6 Months 12 Months 7.97 ± ± ± ± ± ± ± ± ± ± 2.01 * 7.19 ± 2.15 * 7.0 ± 1.1 * 6.9 ± 1.1 * 1.95 ± 1.10 * 6.75 ± 1.56 * 6.7 ± 0.9 * 6.87 ± ± 1.0 * 1.82 ± 1.21 * 7.23 ± 2.52 * 7.67 ± 2.48 * 7.5 ± 1.3 * 7.3 ± 1.2 * 2.13 ± 0.89 * 7.18 ± 2.28 * 7.1 ± 1.3 * 7.12 ± ± 1.1 * 7.28 ± 2.69 * 7.5 ± 1.4 * Data are expressed as means ± SD.; FPG, fasting plasma glucose; HbA1c, glycosylated hemoglobin; HOMA-IR, homeostasis model assessment insulin resistanace. * P < 0.01 versus baseline. Fig. 2. Hypoglycemic effects after pioglitazone treatment. A. Total study patients (n = 113). B. Male (n = 67) and female (n = 46) study patients. FPG, fasting plasma glucose; HbAlc, glycosylated hemoglobin. * P <

6 - 문재훈외 10 인 : 제 2 형당뇨병환자에서장기간의피오글리타존투여에따른임상적관찰 - P < 0.001) 내장지방두께는유의한차이가없어내장지방두께 / 피하지방두께의비는감소하였다 (2.8 ± 2.0 vs 2.4 ± 1.6, P < 0.001). 또한남자보다여자에서체지방량이더증가하는경향을보였다 (0.9 ± 2.1 vs 1.8 ± 2.7 kg, P = 0.06). 3. 피오글리타존제제의투여기간에따른혈당강하효과전체환자군에서공복혈당및당화혈색소의변화는기저치와비교하여투여후 3개월에통계적으로유의하게감소하였고 ( 공복혈당, 7.97 ± 2.29 vs 6.94 ± 2.01 mmol/l, P < 0.01; 당화혈색소, 7.7 ± 1.5 vs 7.0 ± 1.1%, P < 0.01), 이후에유의있는변화는없었다. 피오글리타존제제의혈당강하효과가남녀간의차이를보였으며, 12개월후의공복혈당및당화혈색소와각각의기저치를비교해보면남자보다여자에서유의하게공복혈당 (-0.09 ± 1.72 vs ± 2.54 mmol/l, P < 0.001) 및당화혈색소가 (-0.4 ± 1.1 vs -0.9 ± 1.3%, P < 0.05) 더감소하였다. 피오글리타존제제투여 6개월후 HOMA-IR은전체환자군및남자, 여자모두에서통계적으로유의하게감소하였으며, 역시여자에서유의하게더감소하였다 (-0.7 ± 1.6 vs -1.4 ± 1.3, P < 0.05) (Table 4, Fig. 2). 4. 피오글리타존제제의투여기간에따른지질대사개선효과혈청총콜레스테롤수치와저밀도지단백- 콜레스테롤수치는피오글리타존제제투여기간에따라유의한변화를보이지않았다. 고밀도지단백- 콜레스테롤은기저치와비교하여 3개월에유의한증가를보였고 (1.16 ± 0.24 vs 1.31 ± 0.28 mmol/l, P < 0.01) 이후기간동안지속적인증가는보이지않았다. 중성지방은기저치와비교하여 3개월에유의한감소를보였으며 (2.29 ± 1.86 vs 1.88 ± 1.21 mmol/l, P < 0.01), 6개월까지감소된수치를유지하다 (2.29 ± 1.86 vs 1.97 ± 1.40 mmol/l, P < 0.05) 투여후 12개월에는기저치와비교하여유의한차이를보이지않았다 (Table 5, Fig. 3). 이러한변화양상은남녀간의차이는보이지않았다 (data not shown). 5. 피오글리타존제제투여기간에따른혈중간효소수치의변화피오글리타존제제투여기간에따른혈중간효소수치즉혈중 AST, ALT 수치의변화는 Table 6, Fig. 4와같다. 혈중 AST 수치는피오글리타존제제투여후 3개월에기저 Table 5. Changes in Lipid Profiles after Pioglitazone Treatment (n = 13) Total cholesterol (mmol/l) HDL cholesterol (mmol/l) LDL cholesterol (mmol/l) Triglycerides (mmol/l) Data are expressed as means ± SD. Baseline 3 Months 6 Months 12 Months 4.92 ± ± ± ± 1.86 HDL, high density lipoprotein; LDL, low density lipoprotein. * P < 0.01 versus baseline. P < 0.05 versus baseline ± ± 0.28 * 2.75 ± ± 1.21 * 5.08 ± ± 0.30 * 2.86 ± ± ± ± 0.30 * 2.77 ± ± 2.05 Fig. 3. Changes in lipid profiles after pioglitazone treatment (n = 113). HDL, high density lipoprotein. * P < 0.01 versus baseline. P < 0.05 versus baseline

7 - 당뇨병제 30 권제 4 호, 치와차이를보이지않다가 6개월에유의한감소를보였고 (23.9 ± 12.6 vs 20.3 ± 7.6 IU/L, P < 0.01) 이후 12개월에는다시기저치와차이가없었다. 혈중 ALT 수치는투여후 3개월에기저치와비교하여유의한감소를보였고 (30.8 ± 23.7 vs 24.5 ± 18.5 IU/L, P < 0.01) 이후감소된수치 가유지되었다. 6. 피오글리타존제제의혈당강하효과를예측하는지표피오글리타존제제투여후혈당강하효과의차이가본연구에서측정한지표의기저치와관련이있는지알아보기 Table 6. Changes in Liver Enzymes after Pioglitazone Treatment (n = 113) Baseline 3 Months 6 Months 12 Months AST (IU/L) 23.9 ± ± ± 7.6 * 21.6 ± 12.1 ALT (IU/L) 30.8 ± ± 18.5 * 24.6 ± 20.3 * 23.7 ± 18.7 * Data are expressed as means ± SD. AST, aspertate transaminase; ALT, alanine transminase. * P < 0.01 versus baseline. Fig. 4. Changes in liver enzymes after pioglitazone treatment (n = 113). AST, aspertate transaminase; ALT, alanine transminase. * P < Fig. 5. Correaltions between FPG and basal parameters. FPG, 12 months fasting plasma glucose-baseline fasting plasma glucose; BMI, body mass index

8 - 문재훈외 10 인 : 제 2 형당뇨병환자에서장기간의피오글리타존투여에따른임상적관찰 - 위해, 체질량지수, 체지방률, 체지방량및혈청렙틴과피오글리타존제제투여후 12개월의공복혈당과기저치의차이와의관계를분석하였다 (Fig. 5). 약제투여전체질량지수가높을수록피오글리타존제제의혈당강하효과가크게나타났고 (r = , P = 0.01), 투여전체지방률, 체지방량이높을수록혈당강하효과가크게나타났다 (r = , P < 0,001; r = , P = 0.001). 또한투여전혈청렙틴수치가높을수록혈당강하효과가크게나타났다 (r = , P < 0.001). 7. 경구혈당강하제의종류에따른신체계측및대사지표변화의차이피오글리타존을투여하면서기존에사용한경구혈당강하제의종류에따른체중및체질량지수의변화는 Table 7 과같다. 설폰요소제만을병용한환자군에서체중및체질량지수의증가가더욱뚜렷하였으나 (P < 0.05), 바이구아나이드제만병용하거나설폰요소제와바이구아나이드제를같이병용한군에서도피오글리타존투여 3개월후체중및 체질량지수의증가를보여 (P < 0.01), 전체대상환자와각군에서모두동일한변화양상을보였다 (Fig. 6). 혈당강하효과및지질, 간효소수치등의대사지표의변화는경구혈당강하제의종류에따른차이를보이지않았다 (data not shown). 고찰제2형당뇨병은인슐린저항성과인슐린분비능감소로특징지어지며티아졸리딘디온제제는이러한인슐린저항성을개선시키는것으로알려져있다. 과거트로글리타존제제가간독성의부작용때문에시장에서사라진이후현재피오글리타존과로지글리타존이티아졸리딘디온계열의대표적인약제로쓰이고있다. 이전의여러연구에서피오글리타존투여후의체중및체질량지수변화가관찰된바있으며 12-15), 각연구에서모두피오글리타존투여후체중및체질량지수의증가내지는증가경향을보고하였다. 본연구에서도투여후체중및체질량지수의증가를보였다. Table 7. Changes of Body Weight and BMI after Pioglitazone Treatment in Each Oral Hypoglycemic Agent Use SU use (n = 21) Biguanide use (n = 53) SU+Biguanide use (n = 39) Weigh (kg) Weigh (kg) Weigh (kg) Data are expressed as means ± SD. BMI, body mass index; SU, sulfonylurea. * P < 0.01 versus baseline. Baseline 3 Months 6 Months 12 Months 58.4 ± ± ± ± ± ± ± 10.0 * 60.5 ± 10.2 * 61.8 ± 11.3 * 24.3 ± 2.9 * 24.5 ± 3.0 * 25.0 ± 3.7 * 71.0 ± 11.4 * 71.6 ± 11.5 * 71.7 ± 11.6 * 25.8 ± 3.4 * 26.0 ± 3.6 * 26.1 ± 3.6 * 73.4 ± 11.0 * 73.4 ± 10.5 * 27.1 ± 3.1 * 27.1 ± 3.2* 73.0 ± ± 3.2 * Fig. 6. Changes of body weight and BMI after pioglitazone treatment in each oral hypoglycemic agent use. SU, sulfonylurea use (n = 21); Met, metformin use (n = 53); SU+Met, sulfonylurea + metformin use (n = 39); BMI, body mass index. * P <

9 - 당뇨병제 30 권제 4 호, Smith 등 15) 은제2형당뇨병환자를대상으로피오글리타존제제 (45 mg/day) 투여후 6개월까지관찰한결과, 6개월까지 3.88 kg의지속적인체중증가와 3.55 kg의체지방량증가가나타나, 체중증가는대부분체지방의증가였음을보였다. 피오글리타존 (45 mg/day) 투여환자들을 3년간관찰한연구에서는 5 kg의체중증가및 30개월까지의체중증가를보였다 19). 본연구에서는전체환자군에서 3개월까지평균 1 kg의체중증가, 12개월까지 1.5 kg의체중증가를보였고 3개월이후에는증가양상은보였으나통계적으로유의한증가는없었다. 본연구에서피오글리타존제제투여후체지방량의증가가전체환자군에서평균 1.2 kg으로나타나체중의증가는대부분체지방량의증가임을기대할수있었다. 이러한체중의증가는피오글리타존제제의작용기전으로설명할수있는데, 피오글리타존은 PPAR-γ agonist 로서 4) 전지방세포를지방세포로분화시키고 23,24) 이러한작 용이내장지방보다피하지방에서더두드러져, 결과적으로지방저장고역할을하는인슐린에민감한지방세포의수를증가시켜인슐린저항성을호전시킨다 25,26). 초음파를이용한복부지방두께측정에서복부내장지방은유의한증가가없었으나피하지방은유의하게그두께가증가한것역시기존의연구에서밝혀진바있고 16,17,27), 이러한결과들을종합해보면체중및체지방량의증가는이러한지방세포의증가에기인하는것으로보인다. 본연구에서는체중증가의남녀차이를보였는데, 남자보다여자에서투여 3개월후체중증가가더크게나타났고 (0.6 ± 1.7 kg vs 1.6 ± 1.7 kg, P < 0.01) 체중이유의하게증가한기간도남자는 3개월, 여자는 6개월로여자에서더오랜기간동안체중증가가나타났다. 이러한남녀간의차이역시같은맥락으로설명할수있다. 본연구에서피오글리타존제제투여전의체지방량이여자에서더높은경향을보이고 (19.0 ± 7.2 vs 21.5 ± 6.9 kg, P = 0.06), 남자보다여자에서 3개월후의체지방량증가가더크게나타나는경향을보였다 (0.9 ± 2.1 vs 1.8 ± 2.7 kg, P = 0.06). 따라서체중증가의남녀차이는남녀간의체지방량의차이때문에피오글리타존의체중증가작용이체지방량이많은여자에서더두드러지게나타난결과로보인다. 피오글리타존제제의혈당강하효과는이미여러연구에서검증된바있으며본연구에서도피오글리타존투여후공복혈당및당화혈색소모두유의하게감소하였다. 또한본연구에서는남자보다여자에서피오글리타존의혈당강하효과및 HOMA-IR 감소효과가더두드러지게나타났는데, 이결과는다른연구결과와도일치하였다 18). 이러한남녀간의차이는체지방비율의차이로설명하기도하고 10,18,27) 또한성호르몬의영향으로설명하기도한다 28-30). 최근의연구에서는, 피오글리타존제제를투여한 rat에서성별에따라혈중피오글리타존농도및그활성대사물의농 도차이가있고이는백색지방조직에서의농도차이를반영함을보고하여피오글리타존의효과가남녀간에차이가나는것은남녀간피오글리타존의약동학적차이때문임을제시하기도하였다 31). 본연구의여자환자군에서나이에따른혈당강하효과의차이가없었으며 (data not shown) 이로써폐경유무와혈당강하효과간에유의한관계가없음을기대할수있다. 따라서본연구의결과를토대로볼때, 피오글리타존의혈당강하효과의남녀차는성호른몬의영향보다는남녀간의체지방량의차이와연관지어볼수있겠다. 제2형당뇨병에서지질대사이상이동반될수있음은잘알려진사실이다. 피오글리타존제제투여후이러한지질대사이상의개선이, 세부적인결과에차이는있지만, 여러연구에서보고된바있다. Hanefeld 등 32) 은설폰요소제와피오글리타존제제를복용한군과설폰요소제와바이구아나이드제제를복용한군을비교한연구에서양군에서모두이상적인혈당조절이되었음에도피오글리타존제제가고밀도지단백 -콜레스테롤및중성지방에더좋은영향을주었음을보고하였다. 또다른연구에서는피오글리타존제제, 바이구아나이드제제, 설폰요소제를사용하여혈당을조절하는세군을비교하여피오글리타존제제와바이구아나이드제제가혈당조절효과이외에부가적인고밀도지단백- 콜레스테롤및저밀도지단백 -콜레스테롤에개선효과가있었음을보였고 33), 정상인에서피오글리타존제제투여시저밀도지단백- 콜레스테롤의아형분포가개선됨을보고한연구도있다 34). 또한 Parhofer 등 35) 은설폰요소제로혈당조절이잘되는제2형당뇨병환자에서피오글리타존제제를투여하면서혈당에따라설폰요소제의용량을조절한결과피오글리타존제제의투여시고밀도지단백- 콜레스테롤이증가하고저밀도지단백 -콜레스테롤의아형분포가개선됨을보고하기도하였다. 본연구에서는피오글리타존제제투여후고밀도지단백- 콜레스테롤이증가하였고중성지방이감소하였으나총콜레스테롤및저밀도지단백- 콜레스테롤은유의한변화가없었다. 이러한피오글리타존제제의지질대사개선효과는인슐린저항성을개선시킴으로써얻어지는간접적인효과와 PPAR-α 효현작용으로얻어지는직접적인효과로설명할수있다 36). 즉피오글리타존제제는피하지방세포를늘려혈중유리지방산의저장용량을증가시키고, 간에서중성지방분비를감소시켜간접적으로지질대사를개선시킨다 37). 또한 PPAR-α는지질대사에있어중요한조절기능을가지고있고파이브레이트제제의중성지방감소효과를매개하는것으로알려져있는데 38), 피오글리타존제제는 PPAR-γ 효현작용뿐아니라 PPAR-α 효현작용도같이나타내므로피오글리타존의직접적인지질대사개선효과를기대할수있다. 최근인슐린저항성과지방간과의관련성이주목받고있

10 - 문재훈외 10 인 : 제 2 형당뇨병환자에서장기간의피오글리타존투여에따른임상적관찰 - 으며 39-42), 인슐린저항성을개선시키는티아졸리딘디온제제가간기능개선과지방간호전에효과가있음이보고되고있다. 설폰요소제를복용중인제2형당뇨병환자에서트로글리타존제제의지방간호전효과를보인연구 43), 제 2 형당뇨병환자에서피오글리타존제제투여시간의지방함량이 47% 감소한연구 44), 분리된간세포에서트로글리타존제제가중성지방생성을억제함을보인연구 45) 등이보고되었다. Kelly 등 46) 은트로글리타존을투여하는환자에서 gamma-glutamyl transpeptidase (gamma-gtp) 의감소가복강내지방량의감소와관계있음을보고하였고, 최근에는 Ono 등 47) 이트로글리타존과피오글리타존을투여한제2형당뇨병환자에서간효소수치및 gamma-gtp가감소함을보고하였다. 본연구에서도피오글리타존제제투여후간기능을대변하는혈중간효소수치의감소를보였고, 피오글리타존제제투여전초음파로지방간이진단된 6명의환자에서도 ALT가의미있게감소하였다. 앞선여러연구들의결과를종합해볼때이러한간기능개선효과는제 2형당뇨병환자에서지방간및지방간을유발할수있는대사상태의호전을반영하였다고기대할수있다. 본연구에서피오글리타존제제의투여후혈당강하효과는투여전체질량지수, 체지방률, 체지방량및투여전렙틴수치와상관관계가있었다. 앞서혈당강하효과의남녀간차이를보이는이유와도연관하여, 피오글리타존제제의작용기전상약리작용의주대상이지방조직이므로투여전체지방율이높고체지방량이많을수록혈당강하효과가크게나타남을설명할수있다. 따라서체질량지수및렙틴수치역시체지방량과연관이있으므로투여전체질량지수및렙틴수치가높을수록피오글리타존제제의혈당강하효과가크게나타난것으로보인다. 본연구에서피오글리타존제제와병용한경구혈당강하제의종류에따른신체계측및대사지표의변화양상은차이가없는것으로나타났으며, 다만설폰요소제단독으로병용한군에서체중증가가더크게나타났다. 이는설폰요소제의체중증가효과와, 바이구아나이드제의체중감소효과가영향을미친것으로기대된다. 결론적으로한국인제2형당뇨병환자에서 1년이상피오글리타존제제의투여는혈당강하, 지질대사개선및간기능개선에있어우수한효과를보였고체중증가는제한적으로나타났다. 또한이러한피오글리타존의효과는여성에서더두드러지게나타났고이중혈당강하효과는투여전체중및체지방량이높을수록크게나타났다. 요약연구배경 : 제 2형당뇨병의병인기전은인슐린저항성및인슐린분비능의저하로알려져있다. 본연구는인슐린저 항성을호전시키는것으로알려진티아졸리딘디온제제인피오글리타존제제를 1년이상투여한한국인제2형당뇨병환자군을대상으로한코호트연구를통해, 투여기간에따른신체계측및대사지표의변화를관찰하고자하였다. 방법 : 2003년 3월부터연세대학교세브란스병원에내원한 113명의제2형당뇨병환자에게피오글리타존제제를투여하면서전향적코호트연구를수행하였다. 대상환자군을투여전, 투여후 3개월, 6개월, 12개월에추적관찰하여신체계측및대사지표를측정하였다. 결과 : 대상환자군에서피오글리타존제제투여 3개월후체중및제질량지수의증가가나타났고 (68.8 ± 12.2 vs 69.8 ± 11.9 kg, P < 0.01) 이후지속적인체중및체질량지수의증가는없었으며이러한체중및체질량지수의증가는여자에서더크게 (3개월체중변화, 0.6 ± 1.7 kg vs 1.6 ± 1.7 kg, P < 0.01), 더오랜기간 (3개월 vs 6개월 ) 나타났다. 피오글리타존제제의혈당강하효과역시투여후 3 개월에나타났고 ( 공복혈당, 7.97 ± 2.29 vs 6.94 ± 2.01 mmol/l, P < 0.01; 당화혈색소, 7.7 ± 1.5 vs 7.0 ± 1.1%, P < 0.01), 남자보다여자에서그효과가두드러졌다. ( 공복혈당, ± 1.72 vs ± 2.54 mmol/l, P < 0.001; 당화혈색소, -0.4 ± 1.1 vs -0.9 ± 1.3%, P < 0.05). 고밀도지단백 -콜레스테롤수치는피오글리타존제제투여후 3개월에증가하여 (1.16 ± 0.24 vs 1.31 ± 0.28 mmol/l, P < 0.01) 지속적으로유지되었다. 중성지방은투여후 3개월에감소하고 (2.29 ± 1.86 vs 1.88 ± 1.21 mmol/l, P < 0.01) 6개월까지유지되다 (2.29 ± 1.86 vs 1.97 ± 1.40 mmol/l, P < 0.05) 다시증가하였다. 피오글리타존제제투여후간효소수치의감소도관찰되었으며, 특히 alanine transaminase 수치는투여후 3개월에감소하여 (30.8 ± 23.7 vs 24.5 ± 18.5 IU/L, P < 0.01) 이후유지되었다. 피오글리타존의혈당강하효과는투여전체질량지수및체지방률이높을수록크게나타났다. 결론 : 한국인제 2형당뇨병환자에서장기간피오글리타존제제의투여시혈당강하, 지질대사개선및간기능개선에있어우수한임상경과를보였고체중증가는제한적으로나타났다. 참고문헌 1. Saltiel AR, Olefsky JM: Thiazolidinediones in the treatment of insulin resistance and type 2 diabetes. Diabetes 45:1661-9, Iwamoto Y, Akanuma Y, KosakaK, Shigeta Y, Kuzuya T, Kaneko T: Effects of troglitazone: a new hypoglycemic agent in patients with NIDDM poorly controlled by diet therapy. Diabetes Care 19:151-6,

11 - 당뇨병제 30 권제 4 호, Suter SL, Nolan JJ, Wallace P, Gumbiner B, Olefsky JM: Metabolic effects of neworal hypoglycemic agent CS-045 in NIDDM subjects. Diabetes Care 15: , Lehmann JM, Moore LB, Smith-Oliver TA: An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma. J Biol Chem 270: , Nolan JJ, Ludvik B, Beerdsen P, Joyce M, Olefsky J: Improvement in glucose tolerance and insulin resistance in obese subjects treated with troglitazone. N Engl J Med 331: , Stumvoll M: Thiazolidinediones-some recent developments. Expert Opin Investig Drugs 12: , Camp HS: Thiazolidinediones in diabetes: Current status and future outlook. Curr Opin Investig Drugs 4:406-11, Neuschwander-Tetri BA, Brunt EM, Wehmeier KR, Oliver D, Bacon BR: Improved nonalcoholic steatohepatitis after 48 weeks of treatment with theppar-gamma ligand rosiglitazone. Hepatology 38: , Bajaj M, Suraamornkul S, Pratipanawatr T, Hardies LJ, Pratipanawatr W, Glass L, Cersosimo E, Miyazaki Y, DeFronzo RA: Pioglitazone reduces hepatic fat content andaugments splanchnic glucose uptake in patients with type 2 diabetes. Diabetes 52: , Adams M, Montague CT, Prins JB, Holder JC, Smith SA,Sanders L, Digby JE, Sewter CP, Lazar MA, Chatterjee VK, O'Rahilly S: Activators of peroxisome proliferator activated receptor have depot-specific effects on human preadipocyte differentiation. J Clin Invest 100: , Zimmet P: Addressing the insulin resistance syndrome: A role for the thiazolidinediones. Trends Cardiovasc Med 12:354-62, Hirose H, Kawai T, Yamamoto Y, Taniyama M, Tomita M, Matsubara K, Okazaki Y, Ishii T, Oguma Y, Takei I, Saruta T: Effects of pioglitazone on metabolic parameters, body fat distribution, and serum adiponectin levels in Japanese male patients with type 2 diabetes. Metabolism 51:314-17, Derosa G, Cicero AF, GaddiA, Ragonesi PD, Fogari E, Bertone G, Ciccarelli L, Piccinni MN: Metabolic effects of pioglitazone and rosiglitazone in patients with diabetes and metabolic syndrome treated with glimepiride: a twelve-month, multicenter, double -blind, randomized, controlled, parallel-group trial. Clin Ther 26:744-54, Shadid S, Jensen MD: Effects of pioglitazone versus diet and exercise on metabolic health and fat distribution in upper body obesity. Diabetes Care 26: , Smith SR, De Jonge L, Volaufova J, Li Y, Xie H, Bray GA: Effect of pioglitazone on body composition and energyexpenditure: a randomized controlled trial. Metabolism 54:24-32, Kelly IE, Han TS, Walsh K, Lean MEJ: Effects of a thiazolidinedione compound on body fat and fat distribution of patients with type 2 diabetes. Diabetes Care 22:288-93, Kawai T, Takei I, Oguma Y, Ohashi N, Tokui M, Oguchi S, Katsukawa F, Hirose H,Shimada A, Watanabe K, Saruta T: Effects of troglitazone on fat distribution in the treatment of male type 2 diabetes. Metabolism 48:1102-7, Akazawa S, Sun F, Ito M, Kawasaki E, Eguchi K: Efficacy of troglitazone on body fat distribution in type 2 diabetes. Diabetes Care 23: , King AB, Armstrong DU, Chinnapongse S: Clinical observations of weight gain associated with pioglitazone: 3 years. American Diabetes Association 63rd Scientific Sessions: New Orleans, LA, Suzuki R, Watanabe S, Hirai Y, Akiyama K, Nishide T, Matsushima Y, Murayama H, Ohshima H, Shinomiya M, Shirai K: Abdominal wall fat index, estimated by ultrasonography, for assessment of the ratio of visceral fat to subcutaneous fat in the abdomen. Am J Med 95:309-14, Armellini F, Zamboni M, Rigo L, Bergamo-Andreis IA, Robbi R, De MarchiM, Bosello O: Sonography detection of small intra-abdominal fat variations. Int J Obes Relat Metab Disord 15:847-52, Kim SK, Kim HJ, Hur KY, ChoiSH, Ahn CW, Lim SK, Kim KR, Lee HC, Huh KB, Cha BS: Visceral fat thickness measured by ultrasonography can estimate not only visceral obesity but also risks of cardiovascular and metabolic diseases. Am J Clin Nutr 79:593-9,

12 - 문재훈외 10 인 : 제 2 형당뇨병환자에서장기간의피오글리타존투여에따른임상적관찰 Lowell BB: PPARgamma: an essential regulator of adipogenesis and modulator of fat cell function. Cell 1999;99: Spiegelman BM, Flier JS: Adipogenesis and obesity: rounding out the big picture. Cell 87:377-89, Okuno A, Tamemoto H, Tobe K, Ueki K, Mori Y, Iwamoto K, Umesono K, Akanuma Y, Fujiwara T, Horikoshi H, Yazaki Y, Kadowaki T: Troglitazone increases the numberof small adipocytes without the change of white adipose tissuemass in obese Zucker rats. J Clin Invest 101: , Yamauchi T, Kamon J, Waki H, Murakami K, Motojima K, Komeda K, Ide T, Kubota N, Terauchi Y, Tobe K, Miki H, Tsuchida A, Akanuma Y, Nagai R, Kimura S, Kadowaki T: The mechanisms by which both heterozygous peroxisome proliferator-activated receptor gamma (PPARgamma) deficiency and PPARgamma agonist improve insulin resistance. J Biol Chem 276: , Mori Y, Murakawa Y, Okada K, Horikoshi H, Yokoyama J, Tajima N, Ikeda Y: Effect of troglitazone on body fat distribution in type 2 diabetic patients. Diabetes Care 22:908-12, Anderson LA: The effects of androgens and estrogens on preadipocyte proliferation in human adipose tissue: influence of gender and site. J Clin Endocrinol Metab 86: , Dieudonne MN, Pecquery R, Boumediene A, Leneveu MC, Giudicelli Y: Androgen receptors in human preadipocytes and adipocytes: regional specificities and regulation by sex steroids. Am J Physiol 274: , Dieudonne MN, Pecquery R, Leneveu MC, Giudicelli Y: Opposite effects of androgens and estrogens on adipogenesis in rat preadipocytes: evidence for sex and siterelated specificities and possible involvement of insulin-like growth factor1 receptor and peroxisome proliferator-activated receptor gamma2. Endocrinology 141:649-56, Fujita Y, Yamada Y, Kusama M, Yamauchi T, Kamon J, Kadowaki T, Iga T: Sex differences in the pharmacokinetics of pioglitazone in rats. Comp Biochem Physiol C Toxicol Pharmacol 136:85-94, Hanefeld M, Brunetti P, Schernthaner G, Mattews D, Charbonnel B: One-year glycemic control with a sulfonylurea plus pioglitazone versusa sulfonylurea plus metformin in patients with type 2 Diabetes. Diabetes Care 27:141-7, Lawrence J, Reid J, Taylor G, stirling C, Reckless J: Favorable effect of pioglitazone and metformin compared with gliclazide on lipoprotein subfractions in overweight patients with early type 2 diabetes. Diabetes Care 27:41-6, Winkler K, KonradT, Fullert S, Friedrich I, Destani R, Baumstark MW, Krebs K, Wieland H, Marz W: Pioglitazone reduces atherogenic dense LDL particles in nondiabetic patients with arterial hypertension: a double-blind, placebo-controlled study. Diabetes Care 26: , Parhofer KG, Otto C, Geiss HC, Laubach E, Goke B: Effect of pioglitazone on lipid in well controlled patients with diabetes mellitus type2-result of pilot study. Exp Clin Endocrinol Diabetes 113:49-52, Camp HS: Thiazolidinediones in diabetes: current status and futureoutlook. Curr Opin Investig Drugs 4:406-11, Shelness GS, Sellers JA: Very-low-density lipoprotein assembly and secretion. Curr Opin Lipidol 2:151-7, Keating GM, Ormond D: Micronised fenofibrate: an updated review of its clinical efficacy in the management of dyslipidemia. Drugs 62: , Goto T, Omura T, Takebe K, Kral JG: The influence of fatty liver on insulin clearance and insulin resistance in non-diabetic Japanese subjects. Int J Obes 19:841-5, Banerji MA, Buckley MC, Chaiken RL, Gordon D,Lebowitz HE, Kral JG: Liver fat, serum triglycerides and visceral adipose tissuein insulin-sensitive and insulin-resistant black men with NIDDM. Int J Obes 19:846-50, Marchesini G, Brizi M, Morselli-Labate AM, Bianchi G, Bugianesi E, McCullough AJ, Forlani G, Melchionda N: Association of nonalcoholic fatty liver disease to insulin resistance. Am J Med 107:450-5, Marchesini G, Brizi M, Bianchi G, Tomassetti S, Bugianesi E, Lenzi M, McCullough AJ, Natale S, Forlani G, Melchionda N: Non-alcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes 50: ,

13 - 당뇨병제 30 권제 4 호, Katoh S, Hata S, Matsushima M, Ikemoto S, Inoue Y, Yokoyama J, Tajima N: Troglitazone prevents the rise in visceral adiposity and improves fatty liver associated with sulfonylurea therapy-a randomized controlled trial.metabolism 50:414-7, Bajaj M, Suraamornkul S, Pratipanawatr T, Hardies LJ, Pratipanawatr W, Glass L, Cersosimo E, Miyazaki Y, DeFronzo RA: Pioglitazone reduces hepatic fat content and augments splanchnic glucose uptake in patients with type 2 diabetes. Diabetes 52: , Fulgencio JP, Kohl C, Girard J,Pegorier JP: Troglitazone inhibits fatty acid oxidation and esterification, and gluconeogenesis in isolated hepatocytes from starved rats. Diabetes 45: , Kelly IE, Han TS, Walsh K, Lean MEJ: Effects of a thiazolidinedione compound on body fat and fat distribution of patients with type 2 diabetes. Diabetes Care 22:288-93, Ono M, Ikegami H, Fujisawa T, Nojima K, Kawabata Y, Nishino M, Taniguchi H, Itoi-Babaya M, Babaya N, Inoue K, Ogihara T: Improvement of liver function parameters in patients with type 2 diabetes treated with thiazolidinediones. Metabolism 54:529-32,