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1 Review Vol. 18, No. 1, March 2012 ISSN Copyright c The Korean Society of Hypertension 윤현주, 김계훈 전남대학교병원순환기내과 Current Issues on the Angiotensin II Receptor Blocker in Cardiovascular Disease Hyun Ju Yoon, MD, Kye Hun Kim, MD Department of Cardiology, Chonnam National University Hospital, Gwangju, Korea ABSTRACT To reduce cardio-cerebro-vascular and renal morbidity and mortality, the current guidelines on the treatment of hypertension recommend evaluating and managing total cardiovascular risks of the patient with hypertension, not just focused on reducing blood pressure itself. In this point of view, the angiotensin converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) are considered to be ideal drugs in the treatment of hypertension, because the angiotensin II plays a pivotal role in every stage of cardiovascular disease continuum. Many studies have shown that the ARBs were not only effective in lowering blood pressure, but also had another role in reducing morbidity and mortality of heart failure, myocardial infarction, stroke, diabetic nephropathy, chronic kidney disease, and the recurrence of atrial fibrillation, so called beyond blood pressure lowering effects or pleiotropic effects. However, these favorable effects of ARBs are counter-balanced by some debating issues, myocardial infarction paradox or cancer risk. Furthermore, the issue whether ARBs could replace the role of ACEIs in the treatment of cardiovascular diseases is not resolved yet. Because there have been no randomized studies proving the ARBs are better than ACEIs in terms of cardiovascular morbidity or mortality, the current status of the role of ARBs are an reasonable alternative of ACEIs. In this review, the current issues and status of ARBs will be discussed. (J Korean Soc Hypertens 2012;18(1):17-23) Key Words: Angiotensin receptor antagonists; Cardiovascular diseases 서론 안지오텐신 II는레닌-안지오텐신계 (renin-angiotensin system, RAS) 의주요한최종산물로안지오텐신 II type 1 (angiotensin II type 1, AT1) 수용체에결합하여혈관수축, 신세뇨관에서나트륨흡수증가, 수분저류, 내피세포기능저하, 산화적스트레스증가, 조직의섬유화및콜라젠침착증가등의효과를통해심혈관질환연속체 (cardiovascular disease continuum) 의다양한시점에서심 논문접수일 : , 수정완료일 : , 게재승인일 : 교신저자 : 김계훈주소 : 광주광역시동구제봉로 42번지전남대학교병원순환기내과 Tel: 062) , Fax: 062) christiankyehun@hanmail.net 혈관질환의발생이나진행에중심적인역할을하는매개체로알려져있다. 안지오텐신 II 수용체차단제 (angiotensin II receptor blocker, ARB) 는 RAS의 AT1 수용체에대한 J Korean Soc Hypertens 2012;18(1):

2 생리적인차단을통해탁월한강압효과와적은부작용으로현재고혈압의치료에서가장널리쓰이는약제이다. 또한 ARB는혈압강하효과이외에도항동맥경화효과, 내피세포기능개선, 항산화효과, 섬유화억제, 항염증효과등다양한다른효과들 (pleiotropic effects) 을통해심부전, 심근경색 (myocardial infarction), 심방세동등다양한심혈관질환의치료에서도좋은임상결과들이입증되고있다. 그러나 ARB의이러한다양한이점에도불구하고아직까지 ARB가심혈관질환사고의예방이나치료에서전환효소억제제 (angiotensin converting enzyme inhibitor, ACEI) 보다우월하다는연구결과들이아직까지없으며, ARB의사용이오히려심근경색을증가시킨다는소위 ARB-심근경색패러독스논란과암발생빈도의증가논란등으로그안정성에대한우려가제기되기도하였다. 따라서다른대규모임상결과들의뒷받침이있기전까지 ARB는고혈압을제외한다른심혈관질환에서는 ACEI 의사용이어려운경우에유용한대체약제로생각하는것이바람직할것이다. 여기에서는최근다양한연구들에의하여입증된 ARB 의혈압강하효과이외의심혈관보호효과및부가적인효과들에검토해보고, ARB의사용에대해문제로제기된논점들에대한최근까지의결과들을살펴보고자한다. 안지오텐신 II 수용체차단제의혈압강하이외의효과들 1. 안지오텐신 II 수용체차단제의신장보호효과혈압조절이외에가장알려진 ARB의효과는당뇨병성신장질환에서신장보호효과이다. 1) The Irbesartan Microalbuminuria Type 2 Diabetes in Hypertensive Patients 연구결과는 2형당뇨와미세알부민뇨를가진환자에게서 ARB 제제중하나인 irbesartan이육안적단백뇨및명백한신부전으로의진행을늦추는것을보여주었고, 2) losartan을이용한연구에서도당뇨병성신장병의진행을늦추는효과를나타내었다. 3) ARB와 ACEI 모두단백뇨 를줄이는효과를갖는것으로알려져있는데, 이들약제의복합처방이신장보호에더효과적인지에는논란이있다. The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) 연구에서는 ACEI인 ramipril과 ARB 제제인 telmisartan을사용하여 55세이상의고위험군 ( 동맥경화성혈관질환또는당뇨로인한표적기관손상이있는환자 ) 을대상으로 25,620명의환자들을 ramipril 10 mg (n = 8,576) 과 telmisartan 80 mg (n = 8,542) 또는두약제복합처방군으로 (n = 8,502) 무작위배정하여비교하였다. 신기능과단백뇨에대한추적관찰결과 ARB와 ACEI의단독처방에있어신기능등의변화 (composite of dialysis, creatinine doubling, and death) 에큰차이는없었지만복합처방에있어서는기대에미치지못하는결과를나타내었다. 이연구자들은혈관질환의발병가능성이높은고위험군환자에서 ARB와 ACEI의신장에미치는결과가비슷한정도이며병합요법이부가적인이득을주지않는다고주장하였다. 4,5) 그러나이연구군이심혈관질환과당뇨병을가진고혈압환자중심으로설계되어 ONTARGET 연구의결과를단백뇨가심하거나신기능저하가수반된만성신부전환자들에게그대로확대적용하기에는무리가있다는주장도제기되고있다. 6,7) 2. 안지오텐신 II 수용체차단제의심혈관계합병증예방효과 Losartan Intervention For Endpoint Reduction (LIFE) 연구는좌심실비대가있는고혈압환자를대상으로 losartan과 atenolol을비교하였는데비슷한혈압강하효과에도불구하고 losartan이 atenolol에비해뇌졸중발생을감소시켰고, 8) Study of Cognition and Prognosis in the Elderly 연구에서는노인고혈압환자에서 candesartan이위약에비교하여비치명적뇌졸중발생을유의하게감소시켰으며, 9) Acute Candesartan Cilexetil Therapy in Stroke Survivors Study 연구에서는 candesartan이위약과비교하여급성뇌졸중후심혈관계사고, 뇌혈관계사고를비롯한누적사고의발생률을유의하게감소시켰다. 10) ACEI를사용할수없는환자들을대상으로한 Candesartan in Heart 18 The Korean Society of Hypertension

3 윤현주 김계훈 Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) alternative에서는 candesartan군이위약군에비해의미있게심혈관계사망또는심부전으로인한입원율을감소시켰다. 11) The Valsartan Heart Failure Trial (Val-HeFT) 연구에서는 valsartan 투여로심부전에의한이환율이감소되었다. 12) ACEI와 ARB의병합치료에대한 CHARM-Added 연구와 Val-HeFT 하위분석에서는아직논란의여지가있다. 13) Add-on Effects of Valsartan on Morbi-Mortality (Kyoto Heart) 연구는고위험군 3,000명이상의피험자를 valsartan과 non-arb를사용하여평균 43개월동안추적관찰하였는데뇌졸중의발생및재발, 일과성뇌허혈발작 (transient ischemic attack), 협심증, 심근경색, 심부전, 신기능저하, 대동맥의박리성동맥류발생등을포함한심혈관계합병증발생을확인하였을때협심증과뇌졸중발생률이 valsartan 투여군에서더낮았으며, 당뇨병발생률도의미있게낮았다. 결론적으로, 양군의혈압조절효과는비슷하였으나심혈관사건의발생은 valsaltan군에서유의하게감소하는결과를보여주었다. 14) 동양인을대상으로한 Valsartan in a Japanese population with hypertension and other cardiovascular disease (Jikei Heart) 연구는관상동맥질환이나심부전을동반한 3,000명이상의고혈압환자를대상으로고혈압표준요법에 valsartan을추가하여심혈관계사건발생을 39% 나유의하게감소시켰음을보여주었다. 특히뇌졸중과협심증또는심부전으로인한입원율, 박리성대동맥류 (dissecting aortic aneurysm) 발생률을유의하게낮추는효과가있었다. 15) The Optimal Therapy in Myocardial Infarction with the Angiotensin II Antagonist Losartan (OPTIMAAL) 연구에서는 5,770명의전벽급성 ST 분절상승심근경색증환자, 재경색, 또는급성기에심부전을동반한고위험군심근경색증환자에서 captopril과 losartan의효과를평균 2.7년추적관찰하였는데 captopril군에서 losartan군보다낮은사망률을보였으며, 돌연심장사또는소생된심정지발생률에있어서도낮은경향을보였다. 그러나, 치명 적또는비치명적재경색또는전체입원률에있어서는차이가없었다. 반면에기침, 혈관부종, 발진및미각장애와같은부작용으로인해약제투여를중단한환자의비율은 losartan을투여받은군에서 captopril군에비해유의하게낮았다. 16) The Valsartan in Acute Myocardial Infarction (VALIANT) 연구는급성심근경색증발생후 10일이내에심부전증이발생한 14,808명의환자에서 24.7개월동안 valsartan과 captopril 및이두약제의병합요법의효과를비교하였다. 세군간에사망률의차이가없었으며, 심혈관계사망, 심근경색증의재발, 또는심부전으로인한입원률에서도차이는없어서 valsartan이 captopril과동등한효과를갖는것으로비열등성비교에서입증되었다. 부작용에있어서는두약제의병합요법을시행받은군에서약제관련유해사례의발생률이가장높았으며, 단독요법을시행받은군에서는저혈압과신기능저하가 valsartan군에서더흔하였으며, 기침, 발진, 미각장애는 captopril군에서더흔히발생하였다. VALIANT 연구에등록된환자를대상으로동맥경화사건의발생률을비교하였을때재경색률은 valsartan군과 captopril군에서유사하였다. 17) OPTIMAAL 연구와 VALIANT 연구모두급성심근경색증환자에서 ARB의 ACEI에대한우월성을입증하지는못하였지만, VALIANT 연구를통해 ARB가급성심근경색증후사망률및심근경색증의재발률을감소시키는데 ACEI와동등한효과를입증하였고, OPTIMAAL 연구에사용되었던 losartan의용량이상대적으로적었던점을고려한다면급성심근경색증환자에서 ACEI와유사한임상경과의개선효과를기대할수있을것이다. 3. 기타안지오텐신 II 수용체차단제의부가적인효과위에서언급한 ARB의부가적인효과외에도몇가지연구들이발표되고혹은진행되고있는데그중 US Department of Veterans Affairs system에서시행한 500 만명의자료를분석한결과 ARB를복용하는환자는다른항고혈압제를복용하는환자보다알츠하이머병의발병률이 35 40% 더낮다는자료가보고되기도하였다. 18) J Korean Soc Hypertens 2012;18(1):

4 ARB 중 candesartan은편두통을예방하는효능이있음이발표되었고, 이연구에서 ARB는위약과비교했을때더 tolerability한특성을가지고있었다. 19) 또한 ACEI 또는 ARB의투여가심방세동의발생에미치는효과에대한메타분석연구결과를살펴보면특히좌심실기능부전이있거나좌심실비대가있는환자에서심방세동의발생을감소시키는데효과적이라고도보고하고있다. 20) 안지오텐신 II 수용체차단제와심근경색패러독스안지오텐신 II의기능은 AT1 수용체를통해서혈관수축, 교감신경자극및알도스테론분비, 나트륨저류, 심근과혈관세포증식등일으키는반면 AT2 수용체는혈관확장등의효과를나타나는데, 이론적으로 ARB는 AT1의부정적인효과는줄이고 AT2의좋은효과를유지시킬수있어서 ACEI보다우월한기능이기대되었다. 그러나 CHARM alternative와 Valsartan Antihypertensive Long-term Use Evaluation Trial 연구에서 ARB가심근경색증발생의위험도를증가시키는임상적결과를바탕으로 Strauss 등 21) 은새로이 ARB의메타분석연구로 54,050명의데이터를분석한결과심근경색의위험도가 8% (p = 0.03) 증가된다는 ARB-심근경색패러독스를제기하였다. 22) 심근경색패러독스의기전으로는 ARB에의해 AT1 수용체가차단되고증가된안지오텐신 II에의해 AT2 수용체가지속적으로자극되면 matrix metalloproteinase-1의분비가증가하여죽상경화반파열의위험을증가시킬수있다는것이다. 21,23) 하지만이들의주장은이들의분석에포함된연구가 ARB에대한모든연구들, 특히 ARB가좋은결과를보였던연구들이제외되었으며, 이러한연구들을포함한다른메타분석에서는 ARB가심근경색의위험을증가시키지않는다는결과들이보고되면서가설이나논쟁거리로남아왔다. 24) 최근대규모임상연구인 ONTARGET trial에서관동맥질환또는당뇨병이동반된고혈압환자들을대상으로 ramipril, telmisartan, ramipril과 telmisartan combination의세그룹으로나누어추적관찰한결과심혈관계질환의사망률, 심근 경색, 뇌경색, 심부전으로인한입원율에서세군간에유의한차이가없음이보고되면서심근경색패러독스의논란이줄어들기시작하였고, ONTARGET을포함한 the Losartan Heart Failure Survival Study (Evaluation of Losartan in the Elderly I/II), OPTIMAAL, VALIANT, the Diabetics Exposed to Telmisartan And Enalapril 연구들의메타분석에서도심근경색증의발생빈도와심혈관질환에의한사망률이통계학적으로차이가없었으며다른여러메타분석에서도유사한결과를얻게되어 ARB- 심근경색패러독스는 nonsense라는주장까지나오게되었다 ) 하지만 ONTARGET 연구에서도통계적인유의성이검증되지는않았으나 telmisartan군에서 ramipril 군보다 7% 정도심근경색이더발생하는경향을보여준사실을고려한다면, 심혈관질환의고위험군환자에서심근경색증예방에있어 ARB가 ACEI에비해우월하다고할수는없을것으로판단된다. 더구나최근 Randomized Olmesartan and Diabetes Microalbuminuria Prevention trial의결과에서 ARB가위약군에비해제2형당뇨병환자에서 microalbuminuri의발생을지연시킬수있으나심근경색을포함한치명적인심혈관사고가유의하게많이발생되어고위험군환자에서 ARB의안정성과 ARB-심근경색패러독스가다시논란거리로대두되고있다. 28) 안지오텐신 II 수용체차단제의암발병에대한의혹 2010년 6월 Lancet Oncology에는 68,402명의환자를대상으로 ARB의효과를분석하여 (5개메타분석 ) 결론적으로 ARB 제제는발암유발가능성이있으며특히 telmisartan은고형암중에서도폐암을더많이유발할위험이높다는내용이보고되었다. 29) 이는 CHARM 연구를통해 candesartan 투약군에서치명적인암발생이유의하게증가했다고보고된이후, ARB의안전성, 특히발암가능성에대한의문이제기되어 Sipahi 등 29) 에의해 ARB 에관한무작위통제임상연구 (randomized controlled trial, RCT) 에관한자료를수집하여메타분석을시행하여 ARB가실제적으로암발생위험을증가시키는지를조사 20 The Korean Society of Hypertension

5 윤현주 김계훈 한것이었다. 안지오텐신 II는 AT1 수용체와 AT2 수용체에작용하여각각다른생리작용을나타내는데 ARB 약물이 AT1 수용체만강하게억제함으로써 AT2 수용체는오히려자극을받아발암성세포증식을촉진할것이라고발암기전을제시하였다. 이분석에서는새로운암의발생을 primary outcome, 특정장기고형암의발생과암으로인한사망을 secondary outcome으로정의하였는데, 새로운암발생위험은위약군에비해 ARB군에서유의하게더높았고, 전립선암이나유방암에서는유의한차이를발견할수없었으나, 폐암발생위험은위약에비해 ARB군에서유의하게더높았고암으로인한사망에서는위약과유의한차이가없었다. ARB의암발병에대한의혹이제기되면서미국 Food and Drug Administration (FDA) 에서기존의분석을재검토하는작업이진행되었다. Medline, Scopus, Cochrane 데이터베이스에서현재임상에서사용중인 7가지 ARB 에관한 RCT를검색하여총 2,057건을수집하고, 적합한 9건 ( 새로운암발생보고가포함된연구 5건, 특정암에관한보고가포함된연구 5건, 암으로인한사망에관한자료가포함된연구 8건 ) 의연구를분석대상에포함시켰다. Sipahi 등 29) 의분석의대상이된연구들의평균나이는 pre-hypertension에속한환자를대상으로진행된 Trial of Preventing Hypertension (TROPHY) 연구만평균연령이 48세로젊은편이었고, 나머지 LIFE, ONTARGET, Telmisartan Randomized Assessment Study in ACE intolerant subjects with Cardiovascular Disease, the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) 는약 66세였다. 8,30-32) 암자체가장기간에걸친잠복기를가진희귀이상반응이기때문에, 이들연구중추적조사기간이단기간인것은신뢰하기어렵다는의견도제기되었다. PRoFESS와 TROPHY 연구는평균연구기간이대략 2 3년사이였고, 이외 3개연구는 4년이상이었다. 메타분석을통한결과는평가지표까지취합하여분석했기때문에통계적으로검증되기어렵고, 임상자료에대한접근이메타분석에서는제한되어있기때문에문헌으로출간된통계치만합산하여연관성 만분석한자료는인과관계를규명하지못할뿐만아니라흡연및이상반응발생까지소요된시간을포함한중요인자에대한분석도할수없기때문에내재적한계가있다. 33) FDA의메타분석에서는임의표본을대상으로 ARB와다른약을비교실험한결과 ARB를투여한환자에게서새로운암의발생, 암과관련된죽음, 유방암, 폐암또는전립선암등이발생한다는증거를찾기어렵다고하였다. 확실한것은암을주요평가지표로전향적연구가진행되어야알수있을것이나, 현 ARB 계열의항고혈압제들을복용한환자들에게서발암률이증가할수있음을시사한연구사례들은근거가불충분하며암위험증가와연관성이없다는결론을도출하였다. 결론 RAS가많은심혈관질환의병태생리에서중요한역할을하기때문에 ACEI나 ARB에의한 RAS의차단은다양한심혈관질환을갖는환자들의예후를개선시킬수있음이많은연구들을통해입증되고있다. ACEI가주로기침으로기인하는불내성 (intolerance) 으로그사용에문제가되는경우가적지않은반면, ARB는탁월한순응도로고혈압등일부질환에서는일차약제로, 또한다른심혈관질환들에서는 ACEI의효과적인대체제가되었다. 그러나 ARB가 ACEI보다심혈관질환의치료에서우월하다는임상연구는아직없으며, ARB-심근경색패러독스에대한문제가아직도완전히해결되었다고보기는어렵다. 따라서현시점에서 ARB는고혈압등일부질환에서는일차적선택제로, 나머지심혈관질환에서는 ACEI 를사용할수없는경우의유용한대체제로생각하는것이바람직하다하겠다. ARB와 ACEI의병합요법은대부분의경우에서단독요법에비해추가적인이점을보이지못하고있으므로일부당뇨병성신질환환자에서단백뇨의감소를위해사용되는경우를제외하고는추천되지않으며, 병합요법이꼭필요한경우에도신기능과칼륨수치에대한주의깊은추적관찰이필요하다. J Korean Soc Hypertens 2012;18(1):

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untitled Korean J Fam Med. 2009;30:197-201 doi:10.4082/kjfm.2009.30.3.197 당뇨병이동반된고혈압환자에대한항고혈압제선택의변화 : 포항 경주 1 차의료연구망을중심으로 원저 윤주영, 이동욱 *, 정휘수, 박기흠, 이신형, 박정재, 김동익 1, 기재만 1, 조경래 1, 송준석 1, 최석 1, 우창호 1, 정태호 1, 정숙형 1,