대한내과학회지 : 제 94 권제 5 호 2019 https://doi.org/10.3904/kjm.2019.94.5.396 What s new? 고지혈증치료가이드라인 연세대학교의과대학세브란스병원심장내과 이상학 Lipid-Lowering Therapy Guidelines Sang-Hak Lee Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea The major guidelines for lipid-lowering therapy (LLT) have been revised recently. Although higher cardiovascular risk-aggressive LLT with greater absolute clinical benefit is the main idea underlying all guidelines, there are some differences in the details among them. The US guidelines recommend pharmacological LLT based on a patient s risk category, independently of their low-density lipoprotein-cholesterol (LDL-C) level. However, the European and Korean guidelines consider the patient s risk category and LDL-C at the same time. Lifestyle modifications are suggested in parallel in all guidelines. The newest US guidelines have characteristically revived target LDL-C values in some patient s and indications for non-statin drugs (ezetimibe and PCSK9 inhibitors), whereas the European and Korean guidelines have maintained target LDL-C values as usual. It is universally accepted that statins are the first-line agent. Adding ezetimibe, bile acid sequestrants, or PCSK9 inhibitors is recommended as a second line treatment. Appreciating the trend and background of the newest LLT guidelines will be essential to maximize cardiovascular prevention in patients. (Korean J Med 2019;94:396-402) Keywords: Cholesterol; Atherosclerosis; Therapeutics; Lipoproteins 서론체계적인고지혈증치료지침 ( 지질강하치료지침 ) 은 30년내외의역사가있는데, 2000년대이후의임상시험자료를반영하여 2010년이후에세계각지에서지침이개정되었다. 특히미국에서는 2013년과 2018년에지침의새로운판이발표 되었는데, 타국가의지침이나미국의이전지침과도많이달라져서지침을보는독자들이조금혼란스러울수도있다. 국내에서는한국지질동맥경화학회에서 2018년에지침의최신판을발표하였다. 한국지침이국내외여러조건을반영한것이기는하나, 외국의대표적인최신지침을아는것도중요하기때문에본고에서는미국, 유럽, 한국의세가지지침 Received: 2019. 7. 6 Revised: 2019. 8. 5 Accepted: 2019. 8. 5 Correspondence to Sang-Hak Lee, M.D., Ph.D. Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea Tel: +82-2-2228-8460, Fax: +82-2-2227-7732, E-mail: shl1106@yuhs.ac Copyright c 2019 The Korean Association of Internal Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution - 396 - Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
- Sang-Hak Lee. Lipid-lowering therapy - 을핵심사항위주로비교하며기술하려고한다. 본론미국, 유럽, 한국지침개요국제적으로대표적인고지혈증치료지침은미국심장학회 (American College of Cardiology/American Heart Association) 지침과유럽심장학회 / 동맥경화학회 (European Society of Cardiology/ European Atherosclerosis Society) 지침이다. 미국지침은 2018년에개정되었고 [1], 유럽은 2016년지침이제일최근지침이다 [2]. 우리나라에서는한국지질동맥경화학회치료지침이 2018년에개정되었다 [3]. 미국지침은저밀도지단백콜레스테롤 (low-density lipoprotein-cholesterol, LDL-C) 수치와관계없이심혈관위험도에따라정해지는환자그룹에따라약물치료시작을결정하는것이 2013년판이후제일큰특징이라할수있다. 유럽지침은계산된심혈관위험도와 LDL-C 두가지를가지고약물치료시작을결정하는것이미국지침과의차이이다. 한국지침은 2004년에발간된미국의 National Cholesterol Education Program Adult Treatment Panel III 개정판을적극참고하여고안하였으나 [4], 지금의미국지침모양새와는꽤 다르다. 심혈관위험도를위험인자의종류와개수로판단하고, LDL-C 를고려하여약물치료를결정하는데, 타지침에비하여덜복잡하다 (Table 1). 물론어느나라지침이라하더라도최근 20여년간지질강하치료에대한여러대규모임상을기초로하였기때문에, 심혈관위험도가높을수록, 치료에따른절대이득이크므로강한지질강하치료가필요하다 라는뼈대는공통적이며 (Fig. 1), 세부사항이약간다르다고이해할수있다. 위험도평가 ( 층화 ): 어떤환자를선택하여치료할것인가? 위에서언급하였듯이지질강하치료여부와약물치료여부를결정할때첫단계는심혈관위험도를평가하는것이다. 심혈관위험도가높으면강한치료, 중간이면중간정도의치료가필요하고, 위험도가낮으면약물치료가불필요할때가많다. 미국지침은 2001-2004년까지는유럽지침과마찬가지로위험도에따라환자군을나누었으며위험도를층화할때위험인자 (risk factor) 의종류와개수를기준으로하였다. 하지만 2013년지침부터위험도층화보다는고위험환자군을몇군지정하여적극적인지질강하치료를권고하고있다 : 여기에는 1) 이차예방에해당되는임상적죽상경화성심혈관질환 (atherosclerotic cardiovascular disease, ASCVD) 환자, Table 1. Major points of the latest US, European, and Korean guidelines for lipid-lowering therapy Methods for risk stratification Drug- starting point Target levels of treatment Special points Consideration of the following items as major risk factors: ASCVD, diabetes, LDL-C 190, and high PCE score No cut-off value < 70 mg/dl plus a 50% reduction in LDL-C for the very high risk Items for non-statins, such as PCSK9 inhibitors and ezetmibe were newly added; revival of target levels; calcium score to refine risk Consideration of the following items as major risk factors: CVD, diabetes plus target organ damage, severe CKD, and high score on the SCORE chart 70 mg/dl for the very high risk < 70 mg/dl plus a 50% reduction in LDL-C for the very high risk Consideration of the following items as major risk factors: CAD, ischemic stroke, and PAD 70 mg/dl for the very high risk < 70 mg/dl for the very high risk ASCVD, atherosclerotic cardiovascular disease; PCE, pooled cohort equation; CVD, cardiovascular disease; CKD, chronic kidney disease; SCORE, European risk scoring system; CAD, coronary artery disease; PAD, peripheral artery disease; LDL-C, low-density lipoprotein-cholesterol. - 397 -
- 대한내과학회지 : 제 94 권제 5 호통권제 690 호 2019-2) LDL-C가 190 mg/dl 이상인심한고콜레스테롤혈증환자, 3) 당뇨병환자, 4) pooled cohort equation (PCE) 으로계산한심혈관위험도가높은환자가포함된다. 2018년최신지침에서는이런고위험환자군의뼈대는유지하였으나, 1) ASCVD 환자군에대한추가적으로층화하여 초고위험 ASCVD군 으로분류하고이들에대하여치료목표치를더엄격하게적용하였고, 2) PCE로계산한심혈관위험도가중등도인환자에서추가적인위험인자존재여부를고려하여약물치료를결 Figure 1. The need for stratified lipid-lowering therapy is based on the relationship between higher cardiovascular risk, aggressive lipid-lowering therapy, and greater absolute clinical benefit. In this figure, the more centrally located patient has a higher cardiovascular risk and obtains more clinical benefit from lipid-lowering therapy. DM, diabetes mellitus. 정하도록하였는데, 조금복잡하다 [1]. 유럽지침은위험인자와 European risk scoring system (SCORE) 을기초로환자군을분류하는데, 고위험군에서는둘중어느조건을사용해도상관없다. 네가지환자군으로분류하는데, 1) 초고위험군혹은 SCORE 10점이상, 2) 고위험군혹은 SCORE 5점이상 10점미만, 3) SCORE 1점이상 5점미만, 4) SCORE 1점미만이다. 초고위험군은다음조건중한개이상보유자인데, 심혈관질환, 표적장기손상이있는당뇨병, 중증만성신질환 (glomerular filtration rate [GFR] < 30) 이다. 고위험군은단일위험인자가심한정도인경우, 표적장기손상이없는당뇨병의대다수, 중등도만성신질환 (GFR 30-59) 이다. SCORE 는계산할때이용하는변수가미국의전통적위험도점수인 Framningham 위험도점수나 PCE와비슷하지만, 같지는않다 (Table 2) [2]. 한국지침은위험인자종류와개수에따라환자군을분류하며, 2004년미국지침을참고해서고안하였다. 1) 초고위험군은죽상경화성심혈관, 뇌혈관, 말초혈관질환, 2) 고위험군은경동맥질환, 대동맥류, 당뇨병, 3) 중증도위험군은위험인자 2개이상, 4) 저위험군은위험인자 0-1개인경우로정의한다. 최신지침끼리비교할경우에는미국보다는유럽지침의구조에더가깝다고할수있다. Table 2. Risk stratification of the latest guidelines Major points Specific patient s for LLT Combination of specific patient s and risk score for LLT Very high- risk -- CVD, DM with target organ damage, a severe CKD, or SCORE 10% High risk a -- Markedly elevated single RFs, most other DM, moderate CKD, or SCORE > 5% and < 10% Moderate risk Specific patient s or number of risk factors for LLT CAD, atherosclerotic ischemic stroke or TIA, and PAD Carotid artery disease, abdominal aortic aneurysm, DM -- SCORE 1% and < 5% Number of RFs 2 Low risk -- SCORE < 1% Number of RFs 0 1 LLT, lipid-lowering therapy; ASCVD, atherosclerotic cardiovascular disease; DM, diabetes mellitus; CVD, cardiovascular disease; CKD, chronic kidney disease; CAD, coronary artery disease; TIA, transient ischemic attack; PAD, peripheral artery disease; PCE, pooled cohort equation; RF, risk factor. a Patient s, such as ASCVD, DM, severe hypercholesterolemia, or PCE 7.5% were classified to always take LLT; very high risk ASCVD is defined by several conditions. - 398 -
- 이상학. 고지혈증의치료 - 생활습관교정 ( 비약물치료 ): 약물치료전과약물치료와동시에할치료미국지침은생활습관교정에대하여설명해놓았으나, 환자군에따라달리적용하지는않는다. 유럽지침은환자군과 LDL-C 수치에따라생활습관교정시작을결정하는데, 예컨대초고위험군은 LDL-C 수치와상관없이, 고위험군은 LDL-C 70부터, 중등도위험군은 LDL-C 100부터, 저위험군은 LDL-C 190부터이다. 한국지침에서는약물치료시작점은환자군마다다르지만, 생활습관교정은환자전체에권고하고있다. 생활습관교정은크게식사조절과운동으로구성되는데, 여기에는역대미국식사지침을소개한다. 미국식사지침은개정때마다약간씩수정되었는데, 핵심적인내용을정리하였다 (Table 3). 단, 한국인들의식사내용이서구와상당히다르고, 세대별차이도클수있으므로실제진료시에는환자마 다개별화된교육과권고를하는것이필요할것이다. 약물치료시작점과치료목표치 : LDL-C 수치얼마부터치료하고, 얼마까지내릴것인가? 언급하였다시피미국지침은약물치료대상환자군을위험도에따라이름을붙이지않으며, 치료대상환자군에서는약물치료를시작하는 LDL-C 수치가따로없다. 즉, LDL-C 수치가낮더라도해당환자군에서는약물치료를권고하고있다. 반대로유럽과한국은환자군을위험도를기초로환자군이름을붙이며, 위험군에따라서약물치료시작점을정해놓았는데, 이측면은유럽과한국지침이상당히비슷하다. 예컨대, 유럽지침에서는초고위험군에서 LDL-C 70 이상에서약물치료를시작하며 < 70인경우약물치료는고려가능하다고 ( 선택사항 ) 되어있다. 고위험군에서는 100 이상 Table 3. American diet recommendations Recommended to intake Recommended to avoid Items 2001 2006 2013 2019 Vegetables, fruits, whole grains; O I-A I-B low-fat dairy products Fish, particularly oily fish (> 2/week) O I-B Plant stanols/sterols, soluble fibers O < 7% calories from saturated fat; < 200 (or 300) mg cholesterol; reduce sodium; replace saturated to mono & polyunsaturated fats Limit sweets, red meats; Minimize processed meats, refined carbohydrates & sweetened beverages O O I-A IIa-B O I-A IIa-B Reduce trans-fats O I-A III Table 4. Starting points for pharmacological treatments in the latest guidelines Major points No starting point Depending on the risk category Depending on the risk category Very high risk -- LDL-C 70 LDL-C < 70 (optional) High risk -- LDL-C 100 LDL-C 70 (optional) Moderate risk LDL-C 70 LDL-C < 70 (optional) LDL-C 100 LDL-C 70 (optional) -- LDL-C 100 (optional) LDL-C 130 LDL-C 100 (optional) Low risk -- LDL-C 190 (optional) LDL-C 160 LDL-C 130 (optional) LDL-C, low-density lipoprotein-cholesterol. - 399 -
- The Korean Journal of Medicine: Vol. 94, No. 5, 2019 - 부터약물치료를권고하며 < 100인경우약물치료는선택사항이다. 초고위험군과고위험군에서한국지침의약물치료시작점은유럽과같다. 한국지침에서중등도와저위험군은 LDL-C가각각 130, 160 이상일때약물치료를권고한다. 그러나유럽지침에서는중등도와저위험군모두에서약물치료는선택사항이며이것도 LDL-C 가각각 100과 190 이상일때로제한하는것으로보아유럽지침에서는중등도이하에서는약물을덜쓰려고하는것이특징이다 (Table 4). 미국지침은이전판 (2013년) 에서 LDL-C의치료목표치를뚜렷하게제시하지는않았으나, 스타틴강도를고강도, 중간강도등으로나누어각각의강도를쓸경우 LDL-C가 50% 이상또는 30% 이상강하될것으로예상하였다. 미국지침의최신판 (2018 년 ) 에서는스타틴강도의분류를유지하여몇몇환자군에서각각의강도에따른 LDL-C 강하율을제시하는 동시에, 다른지침에서초고위험군으로분류되는 ASCVD 환자에대해서는 2013년판에없었던 LDL-C 치료목표치인 < 70을되살려냈다. 흥미로운점은이목표치에미달된환자를중심으로비스타틴계약물인에제티미브와 PCSK9 억제제권고가추가된것이다. 유럽지침은 LDL-C 치료목표치를전통적형식으로포함하고있으며비교적단순한데, 초고위험군에서 < 70과 50% 강하동시달성, 고위험군에서 < 100과 50% 강하동시달성, 중등도이하위험군에서는 < 115를제시하고있다. 한국은유럽지침과비슷하지만 LDL-C 수치만제시하며, 초고위험군, 고위험군, 중등도위험군, 저위험군에서각각 < 70, < 100, < 130, < 160을목표로하고있다 (Table 5). Table 5. LDL-C target value Major points Suggests statin intensity rather than specific LDL-C targets except for ASCVD; < 70 for ASCVD Depending on the risk category Depending on the risk category Very high risk a -- < 70 plus 50% reduction < 70 High risk a -- < 100 plus 50% reduction < 100 Moderate risk -- < 115 < 130 Low risk -- < 115 < 160 LDL-C, low-density lipoprotein-cholesterol; ASCVD, atherosclerotic cardiovascular disease; DM, diabetes mellitus; PCE, pooled cohort equation. a LDL-C reduction 50% or < 70 are recommended for patients with ASCVD; high-intensity statin (LDL-C > 50%) for LDL-C 190; moderate-intensity (LDL-C > 30 49%) for DM or PCE 7.5% and < 20%; LDL-C reduction > 50% for PCE 20%. Table 6. Recommended levels for pharmacological agents in the latest guidelines Recommendations Statins up to maximal tolerable dose are recommended to reach the goal. I I I Ezetimibe or bile acid sequestrants, or a combination, are considered for statin IIa IIa intolerance. If the goal is not reached, a statin combined with ezetimibe should be considered. IIa or IIb IIa IIa If the goal is not reached, a statin combined with a bile acid sequestrant should be IIb IIb IIb considered. A PCSK9 inhibitor may be considered in very high-risk patients with a persistently high LDL-C despite the maximal tolerable dose of statin, in combination with ezetimibe or in patients with a statin intolerance. IIa IIb IIb LDL-C, low-density lipoprotein-cholesterol. - 400 -
- Sang-Hak Lee. Lipid-lowering therapy - 권고약제 : 약물사용에우선순위와적응증이있다미국지침이바로전판 (2013년) 에서는스타틴외의약물을전적으로제외하였었는데, 이번판 (2018년) 에는스타틴관련내용이대부분이기는하지만일부상황에에제티미브와 PCSK9 억제제를권고하고있다. 각지침에서는기본적으로 LDL-C 치료목표를달성하기위해서내약가능한최고용량스타틴사용을권고하며, 스타틴부작용이발생하거나최고용량을쓰고도목표치달성에실패한경우에제티미브, 담즙산수지를스타틴에병합혹은단독투여하는것을원칙으로한다. 단, 초고위험군환자에서목표치달성에실패할경우스타틴에 PCSK9 억제제를병합투여하는것은선택사항으로포함된다. 이런사항들은미국, 유럽, 한국지침에대체적으로공통적인데, 미국지침은약제권고에대한설명이다소적다 (Table 6). 고중성지방혈증에대한조절약제는본고에서는자세히다루지않겠다. 예외적인환자군최근꾸준히증가하는환자군중대표적으로노인과만성신질환환자가있다. 이두조건은심혈관위험도의주요위험인자이며, 일차예방대상일경우이론적으로적극적지질강하치료가필요하다고할수있다. 하지만이두환자군은여러가지이유로인하여, 약물치료이득에대한임상시험증거가많지않다. 또한이들은다양한질환이흔히동반되며다약제복용가능성도높기때문에, 약물부작용빈도도높아질수있어서치료이득에서치료위해를뺀실이득 (net benefit) 이별로없을수도있기때문에심한고령등에서는적극적인지질강하치료에의문을제기하기도한다. 한편, 투석중인만성신질환환자에대한몇가지연구에서는치료이득이나타나지않아서, 투석중인환자에서는스타틴복용을새로시작하는것을권고하지않는다. 한국인에서지질강하치료를하였을때얻을수있는이득이미국이나유럽사람들과같을지, 다를지에대한정확한자료는없다. 단, 미국이나유럽의위험도점수가한국인에서심혈관위험도를과대평가할수있다는보고가있기때문에 [5], 특히일차예방대상자에서지질강하치료의절대이득이상대적으로작을가능성은있다. 한편서양사람보다더약한강도의스타틴을투여하였을때지질강하나임상적이득이비슷할것이라는추측은있으나역시증거는부족하다. 단, 최신미국지침에서도일본등동아시아인에서약물치료부작용을조심하라는언급이있기때문에 [1], 한국인에서환자개인특성을고려하여스타틴용량을소폭줄이는것도고려할수있을것이다. 흔히생길수있는중요한오류주요지침마다약간차이는있으나, 최신지침에서는당뇨병은조건없이혹은 LDL-C 100 이상부터약물치료를하라는것이통상적인권고사항이다. 하지만국내자료를보면당뇨병환자에서스타틴처방률은지침에따른대상환자에훨씬못미친다고보고된다 [6]. 당뇨병환자에대한이치료간극이지질강하치료에서흔한문제중하나로보인다. IMPROVE-IT 연구에서스타틴 / 에제티미브복합제의임상적이득이최초로보고되고, 이후스타틴 / 에제티미브복합제가여러가지추가로출시되면서국내에서도이런제형에대한처방이늘어나고있다. 하지만최신지침들에서보듯이지질강하치료에서일차적권고약제는스타틴이며, 고용량스타틴으로도목표치에도달하지못하거나부작용경험자에서병합요법을사용하는것이바람직하다는것을기억할필요가있다. 앞서언급하였지만지질강하의치료필요성과그강도는개별환자의심혈관위험도에따라결정되며, 대표적으로고강도스타틴이필요한환자군은심혈관질환 ( 협심증, 심근경색증, 허혈성뇌졸중등 ) 과거력이있는환자이다. 간혹저용량스타틴만복용하여도 LDL-C 치료목표치에쉽게도달되었다거나심지어약을안먹어도 LDL-C가 < 70 인환자에대해서는고용량스타틴복용이꺼려질수있으며, 실제진료에서도이런일이적지않을것이다. 하지만많은임상시험에기초한최신지침에서이런환자에서 LDL-C 수치와관계없이고강도스타틴을권고하고있는데, 따라서치료에따른환자의이득을위하여꼭이를따르는것이좋으리라생각된다. 결론지질강하치료는심혈관질환의일, 이차예방의핵심이며, 국내외최신지침의주요사항을숙지하는것이좋다. 고위험군에서강한치료를하면임상적이득이크다는원칙을기초로하여일차약물로스타틴을사용하게되며, 경우에따라비스타틴약물을병합할수있다. 특정환자군의치료 - 401 -
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