Review http://dx.doi.org/10.12997/jla.2015.4.1.1 pissn 2287-2892 eissn 2288-2561 Dyslipidemia in Older Adults and Management of Dyslipidemia in Older Patients Kwang-il Kim Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea JLA 노인과이상지질혈증 김광일 분당서울대학교병원내과 In Korea, the number of older adults, particularly of the very elderly people, is expected to be increasing for the upcoming years. This demographic change has profound implication for medical and health care systems. As more people live a longer life, it is important to understand the chronic diseases or health problems which affect the health status or quality of life among the older adults. It has been well established that cardio-cerebrovascular diseases have important roles and impacts on functional capacity and health status of older adults. Recently, many risk factors which increase the risk of cardio-cerebrovascular diseases have been identified. Among them, dyslipidemia is one of the most important risk factor for cardio-cerebrovascular disease. However, there remain several questions regarding the clinical importance of dyslipidemia in older adults, safety and efficacy issue in treating dyslipidemia with statin in older adults, and the relationship between genetic factors associated with lipid profile and longevity. In this review, I will discuss current evidence and data on the topic of dyslipidemia in older adults. Key Words: Dyslipidemia, Older adults, Cardiovascular disease, Statin 서론 우리나라는이미지난 2000년 65세이상의인구가 7.2% 를차지하여고령화사회 (aging society) 에진입하였고 2026년에는 20% 를넘어초고령사회 (super-aged society) 가될것으로전망된다. 특히 80세이상의초고령자의증가속도가두드러져서 2005년 80세이상의인구가전체인구중 1.4% 에불과하였지만 2050년에는전체인구의 14% 를차지할것으로예상된다. 1 우리나라의고령화는세계에서유래를찾아볼수없을정도로빠른속도로진행되고있기때문에노인에서흔한질환및노인의 삶의질과건강수준에영향을미치는질환에대한관심과적절한대비책이마련되어야할것이다. 이러한측면에서향후우리나라에서는심뇌혈관계질환의임상적중요성이더욱부각될것으로예상된다. 즉, 심뇌혈관계질환으로인한사망의대다수가노인에서발생하며, 신생물질환에의한사망은초고령자에서감소하는추세를보이는것에비해심뇌혈관질환에의한사망률은지속적으로증가하고, 심뇌혈관질환으로인해일상생활수행능력의장애를초래함으로써기능의존의위험성이증가된다는점을고려할때노인에서심뇌혈관계질환의중요성은앞으로더욱더강조될것이다. Received: Revised: Accepted: May 19, 2015 May 29, 2015 June 1, 2015 Corresponding Author: Kwang-il Kim Kim, Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Gumi-ro 166, Bundang-gu, Seongnam-si, Kyeongi-do 463-707, Korea Tel: +82-31-787-7032, Fax: +82-31-787-4052, E-mail: kikim907@snu.ac.kr This is an Open Access article distributed under the terms of the creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. www.lipid.or.kr Copyright c 2015 The Korean Society of Lipidology and Atherosclerosis 1
J Lipid Atheroscler 2015;4(1):1-6 JOURNAL OF LIPID AND ATHEROSCLEROSIS 220 210 200 190 180 170 160 150 140 130 Total cholesterol (mg/dl) Male Premenopausal female Postmenopausal female Not excluding people taking lipid-lowering agents 120 10-14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80+ Age Fig. 1. Distribution of total cholesterol in Korean adults for age, sex, and menopausal status 본원고에서는향후더욱더중요한임상문제가될심뇌혈관질환의위험요인인이상지질혈증에대해노화에따른변화, 스타틴치료에있어서젊은성인과차이, 그리고건강장수의지표로서고밀도지단백 (high density lipoprotein, HDL) 콜레스테롤의의의에대해알아보도록하겠다. 1. 연령증가에따른콜레스테롤수치의변화와임상적의의연령이증가함에따라혈중콜레스테롤수치의변화가관찰된다. 2 특히여성의경우에는폐경이라고하는특정시기를전후로하여, 혈중콜레스테롤과중성지방의수치가급격하게변화하게되고, 이러한변화가폐경이후여성에서심혈관질환의위험도가증가하는현상과관련되어있는것으로알려져있다 (Fig. 1). 3 따라서노인연령층에서는남자보다여자의혈중총콜레스테롤, 저밀도지단백 (low density lipoprotein, LDL) 콜레스테롤, 중성지방수치가높고, 여성에서폐경이후 HDL 콜레스테롤수치가급격하게감소하기때문에총콜레스테롤 /HDL 콜레스테롤수치도노인에서는여성이더높다는점을주목해야할것으로생각된다. 일반적으로노인에서는연령이증가할수록총콜레스테롤수치와 LDL 콜레스테롤수치가감소하게되며, 일부코호트연구결과에서는혈중콜레스테롤수치와사망률은역의상관관계를보여, 너무낮은혈중콜레스테롤수치가오히려노인에서는나쁜 3,572명을총콜레스테롤수치에따라 4 그룹으로나누어추적관찰한결과예상과는달리혈중총콜레스테롤수치가낮을수록사망률이높은결과를보였다. 4 이러한결과를토대로노인에서콜레스테롤의과도한저하는감염증, 암발생등의증가로인해사망률이증가될수있다는우려가제시되었다. 그러나콜레스테롤이낮았던그룹이보다고령이었고체중감소가동반된환자가많았다는점을고려할때콜레스테롤에의한차이라기보다는다른요소 ( 고령, 전신상태불량 ) 가환자의예후와관련되었다는분석이보다적합하다고생각된다. 특히고령의환자에서관찰되는낮은콜레스테롤수치는동반질환, 노쇠, 콜레스테롤대사의변화, 영양불량등이원인으로생각되며, 일부에서는콜레스테롤이낮은사람들이오래생존하기때문에관찰되는현상으로설명하기도한다. 그러나 Rancho Bernardo Study 등의종적관찰연구 (Longitudinal study) 에서도연령이증가할수록콜레스테롤수치가낮아진다는사실이밝혀지면서, 단순하게생존이증가함에따라나타나는현상은아닌것으로생각된다. 5 결론적으로노인에서는연령이증가할수록혈중콜레스테롤수치는감소하는경향을관찰할수있으나, 노인환자는젊은성인에비해심뇌혈관질환의발생위험이증가되어있기때문에노인에서관찰되는이상지질혈증도절대적인수치로비교하면중요한위험인자이며, 오히려치료를통해콜레스테롤수치를낮추었을때기대되는이득은더크다고할수있겠다 (Fig. 2). 6 예후와관련될수있다는우려가제시된적이있었다. 즉, 2001년발표된 Honolulu Heart Program 코호트연구결과에따르면 2 www.lipid.or.kr
Kwang-il Kim: Dyslipidemia in Older Adults and Management of Dyslipidemia in Older Patients Fig. 2. Comparison of relative (rel) and absolute (abs) risk reduction with statin therapy between patients aged <65 years and patients aged 65 years Table 1. Genetic variation modulate HDL metabolism and longevity Genes Polymorphisms Population Results APOA1 Msp1 Italian cohort Intron 14 G to A Japanese cohort LPL LPL HL ABCA1 PON1 Intron 14 G to A G445A Taq IB 1405V Pvu II Hind III - 514 C/T 219 R/K Codon 192 Ashkenazi Italian centenarians P allele was dominant in the oldest elderly Intron 14 splicing defect was less frequent in subjects >80 years old VV genotype was dominant in probands with longevity B allele was more frequent in centenarians 2. HDL 콜레스테롤과장수 HDL 콜레스테롤은콜레스테롤대사에관여하여여분의콜레스테롤을간으로수송하여담도를통해배설시킴으로써죽상동맥경화의위험성을감소시키지만, 그자체가항염증, 항산화, 항혈전기전을통해심혈관질환의발생위험을낮추는데에도기여한다. 한가지흥미로운사실은백세인과같이장수를하는대상자들이보여주는유전적특성중에 HDL 대사에관련된유전적변이가흔히관찰되며, 장수인가계에는 HDL 콜레스테롤수치가낮은사람이드물다는점이다 (Table 1). 7 또한장수인및그직계가족의경우단순히 HDL 콜레스테롤 수치뿐아니라입자의크기도보다크다는사실이밝혀짐으로써양적인변화뿐아니라, 질적으로도차이를보인다는사실이보고된바있다. 따라서일반적으로는연령이증가함에따라 HDL 콜레스테롤수치가감소하지만, 장수가계에서는 HDL 대사에관여하는유전적인변이를동반함으로써연령증가에따른 HDL 콜레스테롤수치가감소되지않는것이보다긴수명을유지할수있는원인으로생각된다. 하지만아직까지 HDL 콜레스테롤과수명의상관관계에대해서는직접적인인과관계가검증된단계가아니며, 추후 HDL 콜레스테롤수치를높여줄수있는약제를임상에서사용할수있게되면보다확실하게규명될수있을것으로생각된다. 8 www.lipid.or.kr 3
J Lipid Atheroscler 2015;4(1):1-6 JOURNAL OF LIPID AND ATHEROSCLEROSIS 3. 노인환자에서고콜레스테롤혈증의치료노인에서는이상지질혈증의유병률이증가하며, 관동맥질환의고위험군에해당되는경우가많아지질강하요법에의해많은이득을볼수있을것으로기대된다. 그러나최근까지도고령인구에서콜레스테롤과심혈관질환의상관관계, 특히사망률과의관계에대해서는논란이있어왔다. 또한노인에서스타틴을사용하였을때안전성과부작용발생위험에대한우려에대한의문이끊임없이제기되었다. 이러한논란은노인에서심혈관질환의예방을위한스타틴의유용성을검증하기위한연구결과가발표되면서많은부분해결되었지만, 아직까지도 80세이상의초고령자, 노쇠한노인등임상연구의대상에서제외된환자군에서콜레스테롤수치와심혈관질환및사망률의상관관계, 그리고스타틴치료의효용성에대해서는근거가부족한상태이다. 노인환자에서심혈관질환의발생위험이젊은성인에비해높은점을고려하면비록스타틴사용에따른상대적인위험도감소가노인환자에서낮다고하여도, 절대적인이득은오히려클수있고, 따라서노인환자에서스타틴의사용은비용-대비효능측면에서도효과적일것으로생각된다. 실제로 Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) 연구는 70세이상의환자를대상으로 pravastatin 의유용성과안전성을알아보고자수행된연구로노인환자에서도스타틴사용은심혈관질환의발생및심혈관질환에의한사망률을통계적으로유의하게감소시킴을보고하였다. 9 또한최근 JUPITER 연구의하위분석에서 LDL 콜레스테롤 130 mg/dl 미만이고 hscrp 2.0 mg/l 인 70세이상에서도 rosuvastatin 사용이심혈관질환의발생을감소시키는것으로관찰되어노인에서도스타틴이일차예방에유용할수있음을보여주었다. 10 하지만 60세-75세연령의전체미국인중 2013 년 ACC/AHA 치료지침에서제시하는스타틴을사용해야하는대상자에해당하는경우가 77% 에해당하고, 특히 10년심뇌혈관질환위험도 7.5% 이상인경우가절반정도이기때문에과연이러한권고가비용-대비효과측면에서유용한지, 그리고약제사용에의한이상반응의위험성은무시할만한정도인가에대한우려가제시되고있다. 11 한편, 심뇌혈관질환환자에서스타틴을사용한이차예방연구에서도젊은성인과비슷한유용성이있음이보고된바있다. 즉, TNT 연구와 CARDS 연구에서 65세이상의노인만을분석한하위연구에서도스타틴의사용이노인에서유의하게심혈관질환 의발생을줄였으며안전성측면에서도문제가없는것으로나타났다. 12,13 심근경색후관동맥질환발생에미치는 pravastatin의효과를알아보기위해수행된 Cholesterol and Recurrent Events (CARE) 연구에서주요관동맥질환, 관동맥질환에의한사망, 그리고뇌졸중등의주요심뇌혈관사건이유의하게감소함을관찰하였다. 14 이와같이심혈관질환을동반한노인환자에서스타틴의사용은젊은성인과비교하여도큰문제점없이유용한것으로알려져있다. 하지만노인수축기심부전환자를대상으로한 Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA) 연구에서는 rosuvastatin 사용이심혈관질환의발생및이로인한사망률을감소시키지는못하였다. 15 이러한연구결과들을종합하여미국의 2013 ACC/AHA 치료지침에서는 75세가넘는경우에이미스타틴을사용하고있고부작용이없는경우에는지속적으로사용할것을권장하였다. 이차예방에서는젊은이에게사용되는고강도스타틴은고령에서는근거가부족하므로사용하지말고, 중간강도의스타틴을사용할것을권장하였다. 일차예방에서는동반질환, 안전성검토, 치료의순위를감안하여스타틴투여여부를결정할것을권고하였다. 반면에 2011년 ESC/EAS 16 치료지침에서는노인도일차및이차예방모두에서젊은이와그효과면에서차이가없으므로같이치료하되, 동반질환이나다수의타약제를복용하는경우가많으므로약물상호작용과스타틴의부작용에주의할것을권장하였다. 하지만아직까지 75세이상, 특히동반질환이많고신체적으로건강하지못한노인들의경우임상연구에서제외되었기때문에실제이들환자를어떻게치료할것인가에대해서는근거가불충분하다고생각된다. 4. 노인환자에서스타틴치료와관련된논란들노인환자에서는스타틴사용에따른약물이상반응의위험성을고려해야한다. 특히노인환자는여러가지질병에동시에이환되어있으며, 장기기능저하로인해약물의흡수, 분포, 대사, 배설등약동학적변화가예상되며, 약물상호작용의위험성이증가하게된다. 특히스타틴사용후횡문근융해증이나간효소수치상승등의약물이상반응에대한우려가제시되었다. 하지만현재까지결과로는노인환자에서스타틴사용에따른이득은젊은성인환자와비교하여큰차이가없으며횡문근융해증이나간효소수치의상승과같은약물이상반응도유의하게증가하지는않아노인환자에서도스타틴을안전하게사용할수있을것으로보인다. 4 www.lipid.or.kr
Kwang-il Kim: Dyslipidemia in Older Adults and Management of Dyslipidemia in Older Patients 최근에는노인환자에서흔한문제인보행장애가스타틴을사용하는그룹에서보다더빈번하게발생하고, 이러한부작용이노인의전반적인일상생활수행능력을감퇴시킬수있다는우려가제시되고있다. 17 따라서이상지질혈증이동반되어있거나, 심혈관질환의고위험군인노인환자에서일차예방목적으로스타틴을사용하는것에대한근거는있으나, 스타틴의사용에따른비용- 대비효과및장기간사용하였을때안전성에대해서는아직까지계속적으로논란이제기되고있으며, 젊은성인에서는문제되지않는사소한이상반응의경우에도노인환자의삶의질과건강수준에는영향을미칠수있다는점을고려해야할것으로생각된다. 결론 연령이증가함에따라혈중콜레스테롤수치는변화하며, 이는콜레스테롤대사변화및동반질환, 영양상태등여러가지원인에의해나타나는현상으로생각된다. 하지만노인에서도이상지질혈증은심뇌혈관질환의중요한위험인자이며, 스타틴등의약제를사용하여치료하는것은비록젊은성인에비해상대적이득은적다고하여도, 절대적인이득은비슷하거나오히려더클수있다는점을주목할필요가있다. 하지만, 젊은성인에서는크게문제되지않는근골격계이상반응이노인환자에서는임상적으로의의가있을수도있기때문에보다많은노인환자를대상으로한임상연구가필요하겠다. 참고문헌 1. Statistics Korea. Population projections per Korea: 2010-2060. Daejeon: Statistics Korea; 2011. 2. Kannel WB, Vokonas PS. Demographics of the prevalence, incidence, and management of coronary heart disease in the elderly and in women. Ann Epidemiol 1992;2:5-14. 3. Park JH, Lee MH, Shim JS, Choi DP, Song BM, Lee SW, et al. Effects of age, sex, and menopausal status on blood cholesterol profile in the korean population. Korean Circ J 2015;45:141-148. 4. Schatz IJ, Masaki K, Yano K, Chen R, Rodriguez BL, Curb JD. Cholesterol and all-cause mortality in elderly people from the Honolulu Heart Program: a cohort study. Lancet 2001;358:351-355. 5. Ferrara A, Barrett-Connor E, Shan J. Total, LDL, and HDL cholesterol decrease with age in older men and women. The Rancho Bernardo Study 1984-1994. Circulation 1997;96:37-43. 6. Raffel OC, White HD. Drug insight: statin use in the elderly. Nat Clin Pract Cardiovasc Med 2006;3:318-328. 7. Arai Y, Hirose N. Aging and HDL metabolism in elderly people more than 100 years old. J Atheroscler Thromb 2004;11:246-252. 8. Walter M. Interrelationships among HDL metabolism, aging, and atherosclerosis. Arterioscler Thromb Vasc Biol 2009;29:1244-1250. 9. Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM, Cobbe SM, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002;360:1623-1630. 10. Glynn RJ, Koenig W, Nordestgaard BG, Shepherd J, Ridker PM. Rosuvastatin for primary prevention in older persons with elevated C-reactive protein and low to average low-density lipoprotein cholesterol levels: exploratory analysis of a randomized trial. Ann Intern Med 2010;152:488-496, W174. 11. Pencina MJ, Navar-Boggan AM, D'Agostino RB Sr, Williams K, Neely B, Sniderman AD, et al. Application of new cholesterol guidelines to a population-based sample. N Engl J Med 2014;370:1422-1431. 12. Wenger NK, Lewis SJ, Herrington DM, Bittner V, Welty FK; Treating to New Targets Study Steering Committee and Investigators. Outcomes of using high- or low-dose atorvastatin in patients 65 years of age or older with stable coronary heart disease. Ann Intern Med 2007;147: 1-9. 13. Neil HA, DeMicco DA, Luo D, Betteridge DJ, Colhoun HM, Durrington PN, et al. Analysis of efficacy and safety in patients aged 65-75 years at randomization: Collaborative Atorvastatin Diabetes Study (CARDS). Diabetes Care 2006;29:2378-2384. 14. Lewis SJ, Moye LA, Sacks FM, Johnstone DE, Timmis G, Mitchell J, et al. Effect of pravastatin on cardiovascular events in older patients with myocardial infarction and cholesterol levels in the average range. Results of the Cholesterol and Recurrent Events (CARE) trial. Ann Intern Med 1998;129:681-689. 15. Kjekshus J, Apetrei E, Barrios V, Böhm M, Cleland JG, www.lipid.or.kr 5
J Lipid Atheroscler 2015;4(1):1-6 JOURNAL OF LIPID AND ATHEROSCLEROSIS Cornel JH, et al. Rosuvastatin in older patients with systolic heart failure. N Engl J Med 2007;357:2248-2261. 16. European Association for Cardiovascular Prevention & Rehabilitation, Reiner Z, Catapano AL, De Backer G, Graham I, Taskinen MR, et al. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011;32:1769-1818. 17. Lee DS, Markwardt S, Goeres L, Lee CG, Eckstrom E, Williams C, et al. Statins and physical activity in older men: the osteoporotic fractures in men study. JAMA Intern Med 2014;174:1263-1270. 6 www.lipid.or.kr