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1 대한내과학회지 : 제 79 권제 3 호 21 Statin 치료시 LDL 콜레스테롤의직접측정값과계산값의비교 1 메리놀병원내과, 2 부산대학교의학전문대학원내과학교실 김현진 1 석지혜 1 강지현 1 권혁용 1 황치성 1 김명준 1 김미경 1 김태익 1 김인주 2 LDL cholesterols levels after statin treatment: A comparison of measured vs. estimated values Hyeon Jin Kim, M.D. 1, Ji Hye Suk, M.D. 1, Ji Hyun Kang, M.D. 1, Hyuk Yong Kwon, M.D. 1, Chi Sung Hwang, M.D. 1, Myoung Joon Kim, M.D. 1, Mi Kyung Kim, M.D. 1, Tae Ik Kim, M.D. 1, and In Joo Kim, M.D. 2 1 Department of Internal Medicine, Maryknoll Medical Center, 2 Department of Internal Medicine, Pusan National University School of Medicine, Busan, Korea Background/Aims: Lowering low-density lipoprotein cholesterol (LDL-C) is the primary target for the prevention of cardiovascular disease. Previous studies have shown that estimated LDL-C levels calculated using Friedewald s formula (FLDL-C) are closely correlated with directly measured LDL-C levels (DLDL-C). However, because statins not only reduce LDL-C, but also alter the levels of parameters used to calculate FLDL-C (i.e., total cholesterol, triglycerides, and high-density lipoprotein cholesterol), whether calculated LDL-C levels remain a reliable estimate of actual levels after statin treatment is unclear. Methods: Subjects included 985 patients at high risk of cardiovascular disease who had taken statins for more than 6 months. FLDL-C data were compared to DLDL-C data. Results: A strong correlation was observed between DLDL-C and FLDL-C data (R 2 =.879). However, the absolute values for FLDL-C and DLDL-C differed significantly according to a paired t-test, and 42.3% of patients showed a difference of greater than 1% between these two values. Among patients with diabetes, the percentage of patients deemed to have achieved target LDL-C levels differed significantly according to the method of LDL-C determination (p=.7). Conclusions: FLDL-C and DLDL-C data remained well correlated after statin treatment, although the absolute values differed significantly according to the LDL-C determination method. Furthermore, the percentage of subjects deemed to achieve target LDL-C levels differed significantly according to the method of determination among patients with diabetes. (Korean J Med 79: , 21) Key Words: LDL cholesterol; Diabetes mellitus; Statins 서 심혈관질환은전세계적으로중요한사망원인으로대두되고 론 있다 1). 심혈관질환의위험인자로는흡연, 고혈압, 가족력, 나이와이상지질혈증등이알려져있다 2-4). The National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) Received: Revised: Accepted: Correspondence to Mi Kyung Kim, M.D., Department of Internal Medicine, Maryknoll Hospital, Daecheong-dong 4-ga, Jung-gu, Busan 6-73, Korea kmkdoc@yahoo.co.kr

2 - The Korean Journal of Medicine: Vol. 79, No. 3, 21 - 은관상동맥질환의예방을위해이상지질혈증의조절을강조하고있으며, 특히 LDL 콜레스테롤 (low density lipoprotein cholesterol) 을일차치료목표로설정하고주요위험인자의수와 Framingham point score 를이용한위험도계산을바탕으로위험군을분류하여각각에대한 LDL 콜레스테롤의치료목표를제시하고있다. 이러한목표를달성하기위해서 ATP III 에서는모든성인에서최소한 5년마다일차적선별검사로서총콜레스테롤, HDL 콜레스테롤 (high density lipoproteincholesterol), 중성지방, LDL 콜레스테롤 (low density lipoprotein cholesterol) 을포함한네가지항목을공복상태에서측정할것을권고하고있다 4). 또한당뇨병을포함한허혈성심장질환의고위험군에서는 LDL 콜레스테롤의정확한수치를아는것이치료를결정하는데매우중요하다. LDL 콜레스테롤의측정의참고방법으로는베타정량법 (β -quantification) 이있으나, 이방법은검사가복잡하고시간이많이걸리며, 비싼기구들과숙련된검사인원이필요하기때문에일상적인검사로사용하기에는부적합하다 5-7). 현재 LDL 콜레스테롤측정을위해직접측정법인균질법 (homogenous assay) 과 Freidewald 공식에의한계산법이가장널리쓰이고있다. 이두가지방법으로측정한 LDL 콜레스테롤수치는일치하지는않지만좋은상관관계를보인다는연구들이발표되어왔었지만 5,8), 중성지방농도가아주높거나여러가지병적인상태에서는 Freidewald 공식을사용할수없다는것은이미잘알려져있다 5-13). Statin (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) 의사용은일차적으로 LDL 콜레스테롤의감소를목표로하지만, Friedewald 공식에이용되는세가지변수인총콜레스테롤, 중성지방, HDL 콜레스테롤의감소또는증가도역시관찰되며그변화폭들은각각다양하다 14). 이제까지직접측정법과 Friedewald 공식에의한계산법을비교한연구들에서는 statin 치료를고려해서분석하지않았으므로기존의연구결과가 statin을사용한후에도적용될수있을지는아직알수없다. 이에우리는 statin 치료후에 Friedewald 공식에따른계산값을직접측정법으로측정한 LDL 콜레스테롤결과와비교하여그차이를분석하고자하였다. 대상및방법 1. 대상 24년 5월에서 28년 12월까지메리놀병원내분비내과와심장내과진료를받고있는환자들중에서적어도 6개월 이상 statin을복용한 985명의환자들을대상으로연구하였다. 대상자들중 569명은당뇨병환자였고, 416명은당뇨는없으나 1년 Framingham risk가 2% 이상인고위험환자였다. 2. 방법대상자들은 8시간이상금식후채혈하였고, 총콜레스테롤, 중성지방, HDL 콜레스테롤, LDL 콜레스테롤을측정하였다. 총콜레스테롤은아산시약 (Asan Inc., Hwaseong, Korea) 을사용하여효소법으로, 중성지방, LDL 콜레스테롤, HDL 콜레스테롤은 DAIICHI 시약 (Tokyo, Japan) 을사용하여효소법으로측정하였다. 측정장비는 Hitachi (Hitachi hith-technologies Co., Tokyo, Japan) 자동화학분석기를사용하였다. FLDL-C 은 Friedewald 공식 [FLDL-C= 총콜레스테롤 -(HDL 콜레스테롤 + 중성지방 /5)] 을이용하여계산하였으며, LDL 콜레스테롤의직접측정치인 DLDL-C과비교하였다. %ΔLDL은아래의공식을이용하여계산하였다. %ΔLDL=[(FLDL-C-DLDL-C)/DLDL-C] 1 (FLDL-C: Friedwald 공식에의해계산된 LDL 콜레스테롤수치, DLCL-C: 직접측정법으로측정된 LDL 콜레스테롤수치 ) 3. 통계분석모든결과치는평균 ± 표준편차로표시하였고, 통계분석은 SPSS 프로그램 (version 12.) 을이용하였다. 모든통계학적인결과는 p 값이.5 미만인경우를유의성이있다고평가하였다. 결과대상환자들의기본적인특징은남성이 416명, 여성이 569명이었고, 569명 (57.8%) 이당뇨병을진단받고치료중이었다. 평균연령은 59.21±1.8세 (17~85세), 평균혈중크레아티닌수치는.89±.2 mg/dl (.5~1.5 mg/dl) 였다. 대상자들중 411명 (41.7%) 은 atorvastatin, 236명 (24.%) 는 rosuvastatin 을복용하였으며, 나머지는 fluvastatin, simvastatin, pitavastatin을복용하였다 ( 표 1). Statin 치료전과후의총콜레스테롤은각각 221.7±35.6 mg/dl, 154.5±26.4 mg/dl으로 29.2±13.4% 의감소를보였고, LDL 콜레스테롤은 4.2±16.7% 의감소, HDL 콜레스테롤은 2.5±23.7% 의증가, 중성지방은 6.4±55.4% 의감소를보였다 ( 표 2). Statin 치료후평균 DLDL-C 은 8.5±21.3 mg/dl 이었고, 평균

3 - Hyeon Jin Kim, et al. Statin treatment and calculated LDL-C - Table 1. Baseline characteristics of the subjects Total DM (+) DM (-) Number of patients (%) (57.8) 416 (42.2) Sex Male 416 (42.2) 235 (41.3) 181 (43.5) N (%) Female 569 (57.8) 334 (58.7) 235 (56.5) Age (yr) 59.21± ± ±1.5 Hypertension, N (%) 623 (63.2) 34 (53.4) 319 (76.7) Creatinine (mg/dl).89±.2.9±.2.9±.2 Statin, Atorvastatin 411 (41.7) 194 (34.1) 217 (52.2) N (%) Rosuvastatin 236 (24.) 152 (26.7) 84 (2.2) Fluvastatin 157 (15.9) 17 (18.8) 5 (12.) Simvastatin 142 (14.4) 16 (18.6) 36 (8.7) Pitavastatin 39 (4.) 1 (1.8) 29 (7.) Data are expressed as the mean±standard deviation (SD). Table 2. Lipid levels before and after statin treatment Before statin treatment After statin treatment Change from baseline (%) TC (mg/dl) 221.7± ± ±13.4 LDL-C (mg/dl) 139.± ± ±16.7 TG (mg/dl) 161.6± ± ±55.4 HDL-C (mg/dl) 45.4± ± ±23.7 Data are expressed as the mean±standard deviation (SD). TC, total cholesterol; LDL-C, low-density lipoprotein cholesterol; TG, triglyceride; HDL-C, high-density lipoprotein cholesterol. (A) Total (B) DM (+) (C) DM (-) FLDL (mg/dl) R 2 =.879 FLDL (mg/dl) R 2 =.88 FLDL (mg/dl) R 2 = DLDL (mg/dl) DLDL (mg/dl) DLDL (mg/dl) Figure 1. Correlation between directly measured low-density lipoprotein cholesterol (LDL-C) levels and estimated values calculated from Friedewald s formula after statin treatment. FLDL-C 은 82.1±23.3 mg/dl 이었다. 두수치를비교하였을때, 전반적인상관관계는양호하였으며 (R 2 =.879, p=.) 당뇨병군 (R 2 =.88, p=.) 과비당뇨병군 (R 2 =.876, p=.) 에서차이는보이지않았다 ( 그림 1). 그러나 DLDL-C 과 FLDL-C 을대응표본 T 검정으로비교하였을때당뇨군과비당뇨군 모두에서통계학적으로유의한차이가있었다 ( 표 3). %ΔLDL의평균값은전체대상자에서 2.9±15.4%, 당뇨병군에서 2.5±15.6%, 비당뇨병군에서 3.4±15.1% 이며, 분포는그림 2와같다. %ΔLDL가 ±5% 이상차이가나는경우는전체대상자에서 68.4%, 당뇨병군에서 69.3%, 비당뇨병군에서

4 - 대한내과학회지 : 제 79 권제 3 호통권제 61 호 21 - Table 3. Comparison of directly measured low-density lipoprotein cholesterol (LDL-C) levels and those calculated using Friedewald s formula after statin treatment No. DLDL-C (mg/dl) FLDL-C (mg/dl) Mean±SD Mean±SD p-values DM (+) ± ±23.3 <.1 DM (-) ± ±23.2 <.1 All ± ±23.3 <.1 p-values were calculated using a paired t-test. DLDL-C, directly measured LDL-C levels; DM, diabetes mellitus; FLDL-C, estimated LDL-C levels calculated from Friedewald s formula. (A) Total (B) DM (+) (C) DM (-) Cases (%) 15 1 Cases (%) 15 1 Cases (%) Percentage difference (%) Percentage difference (%) Percentage difference (%) Figure 2. Distribution of the percent differences of those achieving target low-density lipoprotein cholesterol (LDL-C) levels according to the LDL-C determination method. Table 4. Number of subjects deemed to have achieved target low-density lipoprotein cholesterol (LDL-C) levels after statin treatment according to the method of LDL-C determination FLDL (mg/dl) DM (+) DM (-) <1 1 Total <1 1 Total DLDL < (mg/dl) Total McNemar test p=.7 p= % 였으며 ±1% 이상차이가나는경우는각각 42.3%, 42.3%, 42.6% 였다. FLDL-C 의값이 DLDL-C의값보다낮게측정된경우는전체대상자에서 37.4%, 당뇨병군에서 38.8%, 비당뇨병군에서 35.3% 였다. Friedwald 계산값과직접측정값을고위험군환자의 LDL 콜레스테롤의치료목표인 1 mg/dl을기준으로나누어비교하였을때, 비당뇨병군에서는통계학적으로유의한차이가없었지만 (p=.132) 당뇨병군에서는통계학적으로유의한차이가있었다 (p=.7). 당뇨병군에서 statin 치료후에도 DLDL-C 이 1 mg/dl 이상으로실제로치료목표에도달하지못한 94명의환자들중 17.9% 인 15명이 FLDL-C 은 1 mg/dl 이하로치료목표에도달한것으로나타났다 ( 표 4). 고찰 LDL 콜레스테롤과심혈관질환과의상관관계가잘알려져있으며 LDL 콜레스테롤의수치를낮추는것이심혈관질환의발생률을줄인다는연구결과들이발표되고있다 15-19). 따라서심혈관질환의위험도평가및이상지질혈증의치료효과판정에있어서 LDL 콜레스테롤의정확한측정이매우중요하다. LDL 콜레스테롤의측정에는초원심분리법, 침전법, 전기영동법, 액체크로마토그래피법, 면역침전법및 Friedewald

5 - 김현진외 8 인. Statin 치료와 Friedewald 계산값 - 공식에의한계산법등다양한방법들이쓰여왔다. 참고방법인베타정량법은초원심분리와화학침전과정이필요하여일상적인검사로사용하기에는부적합하여 Friedewald 공식이널리사용되고있다 2,21). 이공식은혈장내중성지방이대부분초저밀도지단백콜레스테롤의형태로운반되며, 콜레스테롤과중성지방의비가 5:1로일정하다는것을전제로한다. 그러나혈장내킬로미크론이존재하거나중성지방이 4 mg/dl 이상에서는신뢰할수없다는것이잘알려져있다 21). 이상지질혈증의 1차치료제인 statin은 atherogenic lipoprotein, 특히 LDL 콜레스테롤의수치를감소시키며, Friedewald 공식에의한계산값을얻기위한변수인총콜레스테롤과중성지방을감소시키고, HDL 콜레스테롤을증가시키는효과가있다 14,24). ATP III에서는 statin 의효과로 LDL 콜레스테롤을 18~55% 감소시키고, 중성지방은 7~3% 감소시키며, HDL 콜레스테롤은 5~15% 증가시킨다고보고하였다 4). 본연구에서는총콜레스테롤, LDL 콜레스테롤, 중성지방, HDL 콜레스테롤이각각 -29.2±13.4%, -4.2±16.7%, -6.4±55.4%, 2.5±23.7% 의변화를보였다 ( 표 2). 최근의연구들은 Friedewald 공식의변수인총콜레스테롤, 중성지방, HDL 콜레스테롤수치에따른제한점을보고하고있으며, 심지어 LDL 콜레스테롤의농도에따른오차도보고하고있다. 몇가지연구들에서 Friedewald 공식과직접측정법을비교하여중성지방이 4 mg/dl 이하인경우에도통계학적으로유의한차이가있었다고보고하였다 5-7,1,11). Jun 등이 38,243명의한국인을대상으로시행한연구에서는중성지방뿐만아니라총콜레스테롤의농도에따라 Friedewald 공식에의한계산값과직접측정값의오차의범위가달라질수있다고보고하였고 12), Scharnagl 등은 LDL 콜레스테롤수치가낮은경우에도계산값이낮게측정된다고보고하였다 13). 많은대규모연구들에서 LDL 콜레스테롤을감소시켜심혈관질환의사망률과이환률을감소시킨다는것이증명되어온이후고위험환자들에게서의 statin은필수적인치료중의하나가되어왔다. Statin을복용한후에는 Friedewald 공식의세변수의변화가같이일어나므로, 위의연구들에의하면각콜레스테롤의변화에따라공식의신뢰도가달라질것으로예상된다. 그러나 statin 치료후이러한우려에대한이제까지의연구는거의찾아볼수가없었고, 두측정방법의관계에대한논문들은모두 statin 사용을하기전상태에대해서만보고되어왔다. Lindsey 등이 19,343 명을대상으로시행한연구에서 Friedewald 공식에의한계산값과균질법에의한직접측정값을비교하였을때계산값이측정값에비하여낮게측정되었으나강한연관성 (R 2 =.94) 을보였으며 8), Jeong 등이 33,792명을대상으로시행한연구에서도중성지방이높을수록오차는증가하고계산값과측정값사이의연관성은약해지는경향을보인다고보고하였으나계산값과측정값은강한연관성 (R 2 =.973, p<.1) 을보였다 5). 본연구는 statin 치료후의환자들을대상으로하였으며, 전반적인연관성은양호하였으나 (R 2 =.879) 이전의연구에비해서는상관계수가낮게측정되어연관성이낮아짐을알수있었다. Rubies-Prat 등은 Friedewald 공식에의한계산법과베타지단백정량검사에의한 LDL 콜레스테롤측정값을비교한연구에서 Friedewald 공식이제2형당뇨병환자에서심혈관질환의위험을평가하는데부정확하다고보고하였으며 25) Hirany 등은당뇨병환자를대상으로한연구에서 Friedewald 공식에의한계산값이면역침전법에의한직접측정값및베타지단백정량검사법에의한측정값보다신뢰도와정확도가낮다고보고하였다 26). 본연구에서는당뇨병군 (R 2 =.88) 과비당뇨병군 (R 2 =.876) 에서의상관관계의차이는보이지않았다 ( 그림 1). 두측정법사이의연관성은좋으나, 그절대적인수치에서는 DLDL-C과 FLDL-C 을대응표본 T 검정으로비교하였을때당뇨군과비당뇨군모두에서통계학적으로유의한차이가있었다 ( 표 3). %ΔLDL의평균값은전체대상자에서 2.9±15.4%, 당뇨병군에서 2.5±15.6%, 비당뇨병군에서 3.4±15.1% 이며, 분포는그림 2와같았다. %ΔLDL가 5% 이상차이가나는경우는전체대상자에서 68.4%, 당뇨병군에서 69.3%, 비당뇨병군에서 67.3% 로당뇨병군과비당뇨병군이비슷한분포를보였으며 ±1% 이상차이가나는경우도각각 42.3%, 42.3%, 42.6% 로비슷한분포를보였다. FLDL-C 의값이 DLDL-C 의값보다낮게측정된경우는전체대상자에서 37.4%, 당뇨병군에서 38.8%, 비당뇨병군에서 35.3% 로당뇨병군과비당뇨병군이별다른차이는없었다. FLDL-C 과 DLDL-C 을고위험군환자의 LDL 콜레스테롤의치료목표인 1 mg/dl을기준으로나누어비교하였을때, 비당뇨병군에서는통계학적으로유의한차이가없었지만 (p=.132) 당뇨병군에서는통계학적으로유의한차이가있었다 (p=.7). 당뇨병군에서는 statin 치료후에도 DLDL-C이 1 mg/dl 이상인실제로치료목표에도달하지못한 94명의환자들중 17.9% 인 15명이 FLDL-C 은 1 mg/dl 이하로치료목표에도달한것으로나타났다 ( 표 4). 이러한결과는 statin

6 - The Korean Journal of Medicine: Vol. 79, No. 3, 21 - 복용후치료효과판정을목적으로 Friedewald 공식을이용한계산값을이용하였을때당뇨환자중 17.9% 의환자들은치료를변경해야하거나용량조절을해야함에도불구하고적절한치료를받지못할가능성이있음을시사한다. 반면에 35명은 FLDL-C 이 1 mg/dl 이상으로치료목표에도달한것으로계산되어과잉치료를받을수있는것으로나타났다. Statin 치료후에 DLDL-C 이 1 mg/dl 이하인 475명의환자들중 92.6% 인 44명은 FLDL-C 역시 1 mg/dl 이하로높은일치율을보였다. 이러한치료효과판정에있어서의당뇨병군과비당뇨병군간의차이는 statin 치료후에대한연구결과를거의찾을수없고, 그기전에대한연구가드물기때문에그이유에대한설명은명확하지않다. 다만추정컨대, 제 2형당뇨병에서는중성지방의대사이상이흔한것으로알려져있고 29,3), statin 치료효과에있어서 LDL 콜레스테롤의감소율이중성지방의감소율에비해다소높기때문에치료후에도중성지방수치가높은경우가많을것으로생각되어계산식에의한값의차이가클것으로생각된다 4). 본연구의제한점은첫째, 후향적연구이므로고혈압, 갑상선질환, 심부전등의동반질환에의한영향과식이나운동, 비만, 흡연, 알코올등의생활습관의차이로인한영향을배제하기어렵다. 둘째, 본원을내원한환자들만을대상으로하여분석이시행되었으므로이러한결과가모든환자를대표할수는없을것이다. 셋째, statin 복용기간을통제하지못하였고, 각환자들의콜레스테롤수치를연속적으로측정하지못하여 statin 복용기간에따른차이를알기어렵다. 그러나 6개월이상복용한환자를대상으로하였기때문에 statin의효과에의한차이를비교하기에는부족하지않았을것으로생각된다. 결론적으로, Statin 치료후 Friedewald 공식으로계산한 LDL 콜레스테롤과직접측정한 LDL 콜레스테롤수치는비교적좋은연관성을보였으나, 각각의수치의비교에서는의미있는차이를보였다. 특히당뇨병군의치료효과판정에서는유의한차이가있었다. 향후 statin 치료의적정성을평가하거나치료변경여부를결정하는경우에 Friedewald 공식에의한계산값과 LDL 콜레스테롤의직접측정법의비교에대해서추가적인연구가뒷받침되어야할것으로생각된다. 요약목적 : LDL 콜레스테롤의수치를적정수준으로조절하는것이고지혈증에의한심혈관계질환의 1차적혹은 2차적 예방에매우효과적이다. Statin의사용은일차적으로 LDL 콜레스테롤의감소를목표로하지만, Friedewald 공식에이용되는세가지변수인총콜레스테롤, 중성지방과 HDL 콜레스테롤의변화도관찰된다. 이제까지직접측정법과 Friedewald 공식에의한계산법을비교한연구들에서는 statin 치료를고려해서분석하지않았으므로기존의연구결과가 statin을사용한후에도적용될수있을지는아직알수없다. 이에우리는 statin 치료후에 Friedewald 공식에따른계산값을직접측정법으로측정한 LDL 콜레스테롤결과와비교하여그차이를분석하고자하였다. 방법 : 메리놀병원내분비내과와심장내과진료를받고있는환자들중에서적어도 6개월이상 statin을복용한 985명의심혈관질환고위험군인환자들을대상으로연구하였다. 총콜레스테롤, 중성지방, HDL 콜레스테롤측정치를이용한 Friedewald 공식으로계산된 LDL 콜레스테롤수치를직접측정한 LDL 콜레스테롤수치와비교하였다. 결과 : Statin 치료후 DLDL-C은 8.5±21.3 mg/dl이었고, FLDL-C 은 82.1±23.3 mg/dl 이었다. 두수치를비교하였을때, 전반적인상관관계는양호하였으나 (R 2 =.879) paired t-test 상에서두값의차이는통계적으로유의하였고, 실제 42% 이상의환자에서 %ΔLDL이 ±1% 이상이었다. 계산값과직접측정값을당뇨병환자의 LDL 콜레스테롤의치료목표인 1 mg/dl을기준으로목표도달률을비교하였을때, 비당뇨병군에서는통계학적으로유의한차이가없었지만 (p=.132), 당뇨병군에서는통계학적으로유의한차이가있었다 (p=.7). 결론 : Statin 치료후 Friedewald 공식으로계산한 LDL 콜레스테롤과직접측정한 LDL 콜레스테롤수치는비교적좋은연관성을보였으나, 각각의수치의비교에서는의미있는차이를보였다. 특히당뇨병군의치료효과판정에서는유의한차이가있었다. 향후 statin 치료의적정성을평가하거나치료변경여부를결정하는경우에 Friedewald 공식에의한계산값과 LDL 콜레스테롤의직접측정법의비교에대해서추가적인연구가뒷받침되어야할것으로생각된다. 중심단어 : 저밀도지단백콜레스테롤 ; 당뇨병 ; 스타딘 REFERENCES 1) Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJ. Global and regional burden of disease and risk factors, 21: systematic analysis of population health data. Lancet 367: ,

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012임수진

012임수진 Received : 2012. 11. 27 Reviewed : 2012. 12. 10 Accepted : 2012. 12. 12 A Clinical Study on Effect of Electro-acupuncture Treatment for Low Back Pain and Radicular Pain in Patients Diagnosed with Lumbar