JMBS J Metab Bariatr Surg 2017;6(1):1-5 https://doi.org/10.17476/jmbs.2017.6.1.1 REVIEW ARTICLE 건양대학교병원외과 이상억 Weight Loss Medication in Bariatric Surgery Sang Eok Lee Department of Surgery, Konyang University Hospital, Daejeon, Korea Obesity is a chronic disease with serious health consequences, but weight loss is difficult to maintain through lifestyle intervention alone. Bariatric surgery is considered to be the most effective treatment modality in maintaining long-term weight reduction and improving obesity-related conditions in morbidly obese patients. Since the properly executed pharmacologic treatment is a good option for weight reduction. Surgeons should be aware of the efficacy and side effects of medical treatment. Key Words: Medication, Weight loss, Bariatric surgery 서론 최근제 2형당뇨와함께비만의유병율도한국에서급격하게증가하고있다. 경제협력개발기구 (Organization for Economic Cooperation and Development, OECD) 자료에의하면, 한국의비만유병율은체질량지수 25 kg/m 2 를기준으로하였을때, 31.8% 이며, 1990년대부터 2000년을지나면서급속한사회경제적인발전과더불어그유병율이급속히증가하였다 [1]. 비만에대한치료는생활습관의변화와약물치료, 수술등이있다. 식사조절과운동, 약물치료는많은병적비만환자에서일부효과는인정되지만, 장기간의성적은저조한편이다. 비만대사수술은수술후 12-18개월사이에초기체중의 20-35% 의감량을가져오게되는비만의확실한치료방법이라할수있다 [2]. 한국에 서의비만대사수술은서양에비해늦게시작되었지만, 비만인구의증가와더불어최근증가하고있으며, 국가조사에의해다기관에서시행한비만대사수술들을보고하고있다 [3]. 비만에대한약물요법에서, 체중감량과당뇨의개선등의약물치료후의유용한측면과더불어, 부작용에대한고려도동반되어야한다. 현재비만대사수술후에관리및약물치료에대해수술을시행하는의사들의경험이부족한실정이기때문에, 수술적치료와더불어, 비만치료에사용되는약물의종류와작용및부작용을미리알고있는것은, 병적비만과비만수술을시행받는환자를치료함에있어필수적인항목이라하겠다. 확실한결론에이르지는못하였지만, 비만대사수술전에체중감량이수술후결과에영향을미치는것으로대부분의의사들은믿고있다 [4]. 투고일 : 2016 년 12 월 7 일, 심사일 : 2017 년 5 월 25 일, 게재확정일 : 2017 년 5 월 26 일책임저자 : 이상억, 대전시서구관저동로 158 건양대학교병원외과우 : 35365 Tel: 042-600-8956, Fax: 042-543-8956, E-mail: srglee@hanmail.net CC This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyright 2017, The Korean Society for Metabolic and Bariatric Surgery
Vol. 6, No. 1, 2017 ORLISTAT (XENICAL R ) Orlistat는위장관및췌장에서지방질을분해하는효소인 lipase를억제하여음식에포함되어있는지방의분해와흡수를떨어뜨리는약물로미국식품의약품안전청 (Food and Drug Administration, FDA) 에서 1998년사용이허가되어현재까지사용중인약물이다 [5]. 주로 120 mg 하루 3번투여하는것이일반적이며, 용량이반으로줄인약도출시되고있다. 대부분의약물이대사과정을거치지않고대변으로배출되며, 전신적인약리작용은거의없으며, 극히일부가체내로흡수되어소변으로배출되는약물이다 [6]. Tetrahydrolipstatin이라는이름으로처음개발되었으며가수분해를촉매하는기능을가진 lipoprotein lipase (LPL) 을억제하여 LPL의하나인췌장효소인리파제와공유결합을하여그기능을억제하고, 경구로섭취한지방의흡수를저해하여체중감소효과를나타낸다 [7]. 체중감소효과와함께수축기및이완기혈압을낮추고, 총콜레스테롤과저밀도지단백을낮추며혈당을개선시키는등의심혈관계위험인자개선효과도있는것으로알려져있다 [8]. 기름변, 기름이새어나오는방귀, 변실금, 대변횟수의증가, 복통등불편한소화기계증상등이부작용으로나타날수있으며, 대부분경증이며치료초기에나타나서지속적으로복용하는과정에서저절로사라지는경우가많으며, 반복적으로나타나는부작용은비교적적다. 또한지방에용해되는지용성비타민인비타민 A, D, E, K의결핍이생길수있어약물복용 2시간전또는후로비타민보충해줄것을권장한다 [9,10]. Orlistat에대한임상연구로는 3,305명의스웨덴비만환자에서 4년간의이중맹검무작위시험에서위약을투여한군에비해 Orlistat를복용한군에서평균몸무게 2.7 kg의감소효과와, 제 2형당뇨의유병율을 9.0% 에서 6.2% 로줄이는결과를얻었다 [11]. Orlistat의체중감소효과에대한메타분석에서는약물투여로 2.9% 의체중감소효과를나타내었다고보고하였다 [11,12]. Orlistat는체내에흡수되는양이적고, 대변으로대부분배설되기때문에체내의부작용발생이많지않을것으로예상되지만, 위약대조군연구결과를보았을때에는부작용때문에중도탈락한증례가위약을투여한군에비해유의하게많았다 (7.7% vs. 4.7%) [13]. Orlistat는비타민 K의흡수를방해하고, 와파린작용을항진시킬수있고, 지질친화성이있는 amiodarone의흡수를감소시키는작용을할수도있다 [14]. 또한, 드물게나타날수있는부작용으로는급성췌장염, 급성수산염 (oxalate) 신증 (nephropathy) 에의한이차성세뇨관괴사가발생할수도있다 [15,16]. LORCASERIN (BELVIQ R ) 2012년미국식품의약품안전청에서새로운비만치료제로승인된 Lorcaserin은세로토닌수용체중 5-HT2c 수용체에대한선택적작용제로서시상하부에서 POMC (proopiomelanocortin) 의활성을일으켜포만중추를자극함으로써체중을감량시키는효과가있다 [17]. Lorcaserin의체중감량효과를연구한이중맹검전향적임상연구중에서 BLOOM trial이있는데, 52주동안 10 mg을하루 2회투여한군과위약을투여한군을비교해보았을때, 약물투여한군에서유의한체중감량효과를나타내었다 (5.8 kg vs. 2.2 kg, P<0.001) [18]. Lorcaserin은심장판막증의발생위험이높다는연구결과가있으므로투여시환자의심혈관및호흡기계증상과징후에대해서주의깊게살펴야한다 [19]. 3개월정도의짧은기간에복용하였을경우에는용량과비례하여체중감소효과가나타나면서심장판막질환의위험성이나타나지않는다는견해가일반적이다 [20]. Lorcaserin의부작용으로는두통, 상기도감염, 어지럼증, 오심, 변비, 피로, 저혈당등이있으며, 이는교감신경표현성식욕억제제들과대동소이하다 [18]. 증상은경증이며, 약제를중단하지않아도시간이지나면줄어든다. 당뇨병환자를대상으로한연구에서 Lorcaserin 투여시저혈당이발생할수있지만심각한수준은아니며, 특히 sulfonylurea를복용하는환자에서저혈당이자주발생하며, 약제자체의효과라기보다는식욕억제에따른섭취량감소로생각하고있다 [21]. Lorcaserin은우리나라에서향정신성의약품으로간주되며, 의존성이나남용의가능성이있을수있다고간주해야하며, 약물의관리와규제가필요한약물이다. PHENTERMINE/TOPIRAMATE (QSYMIA R ) Phentermine은 1959년에 FDA에서비만치료제로서단기간사용할수있게허가된약제로, 시상하부에서 serotonin에는영향을미치지않으면서 norepinephrine의분비를촉진하는작용을하는아드레날린성식욕억제제이다 [22,23]. Topiramate 는 1996년에간질치료제로, 2004년에편두통예방약으로사용이허가되었다. Phentermine은 phospholipidosis 등을일으킨보고가있었고, 1974년에사망자가발생하면서, 1981년많은나라에서퇴출된적이있었다. 2012년 FDA에서비만치료제로서승인된 Qsymia는 Phentermine과 topiramate의복합제로서 Qnexa라는이름으로임상연구가진행되었다. Topiramate는그자체로체중감량의효과는있지만아직정확한기전은알려지지않았는데, 체내의에너지요구량을증가 2
이상억 : 시키면서에너지효율성을감소시키고, 칼로리흡수를감소시킴으로써체중감소효과를나타내는것으로생각되고있다 [22]. 이약에대한 3상연구인 CONQUER trial에서는체질량지수 27-45 kg/m 2 정도의비만이있고고혈압, 지질이상, 당뇨나복부비만중, 2개이상을가진환자를대상으로하였다 [24]. PHEN 7.5/TPM 46.0을투여한저용량투여군에서 6.8% 의체중감량을나타내었고, PHEN 15.0/TPM 92.0을투여한고용량투여군에서는 8.8% 의체중감량을나타내었으나, 위약투여군에서는 1.9% 의체중감량만을보였다 [24]. 108주간진행된 SEQUEL trial에서는약물투여군에서장기간체중감량효과가위약투여군과비교할때유의하게유지되었다 [25]. 이약의단점은체중감소효과를충분이가져올만큼의용량을투여할경우이상감각등의신경학적인부작용이나타날수있다는것이다. 그이외오심, 어지럼증, 변비, 입마름등의부작용등도나타날수있다. 부작용으로입마름, 손발의이상감각, 변비, 어지러움, 불면증등이있다 [25]. 또한임산부의경우구순열등의기형이발생할수있어임산부의경우복용을삼가해야하며가임기여성의경우복용시임신을피하는것이좋겠다 [26]. LIRAGLUTIDE Liraglutide 는인크레틴의한종류인 glucagon-like peptide-1 (GLP-1) 의유사체로, 체내의 GLP-1과는달리지속시간이길어서하루한번 3.0 mg을피하투여로사용한다 [27]. 2014년에 FDA에서사용이허가된약물이다. Liraglutide는처음에는제 2 형당뇨환자에서, 하루 1.2-1.8 mg 투여하여 HbA1c를낮추는결과를보여당뇨치료제로개발되었다 [28]. Liraglutide는용량과비례하여, 체중감소효과를나타내게되는데, 중추신경계화소화기계에걸쳐광범위하게작용하게된다. 에너지요구량을증가시키기보다는포만감을유도하고에너지섭취량을감소시키고, 위배출시간을지연시킴으로써체중감소효과를나타내는약물이다 [29,30]. Pi-Sunyer 등 [27] 이보고한 56주간의이중맹검시험에서 liraglutide 복용군은 8.4 kg, 위약군에서는 2.8 kg 의체중감소를나타내었다. 이약물의부작용으로는오심, 구토, 설사, 변비가나타날수있으며, 담낭질환도발생할수있다 [27]. NALTREXONE/BUPROPION (CONTRAVE R ) Bupropion은 dopamine과 norepinephrine의재흡수를억제하는항우울제로서식욕억제효과를나타낸다 [31]. 여기에 opioid 길항제인 naltrexone을함께사용하면 bupropion의식욕억제효과를강화시킬수있는데, 이를이용하여개발된병용요법이다 [31]. Naltrexone/bupropion (NB) 의병합요법은식 욕을억제하게하는효과가있는 melanocyte 자극호르몬을 proopiomelanocortin (POMC) 에서신경자극을증가시킴으로써체중감소효과를나타내는것으로알려져있다 [32]. 또한이병합요법은음식섭취와같은행동들을조절하는도파민중변연계 (mesolimbic dopaminergic reward system) 에영향을주어효과를나타내게된다 [32]. NB를비만인환자에게사용한 3상임상연구를보면, COR-I 과 COR-II 연구가있다. 평균체중의변화가 NB 투약군에서는 6.1% 와 6.4% 였고, 위약투여군에서는 1.3% 와 1.2% 로유의하게 NB 투여군에서체중감소효과를많이나타내었다 [33,34]. 또다른연구인 COR-BMOD 연구에서는체중감소가 NB 9.3%, 위약군 5.1% 로역시이병합요법이효과적인체중감소를가져온다고하였다 [35]. 흔히나타나는부작용으로는구역, 변비, 어지러움, 입마름, 떨림, 복통, 이명이다 [36]. 비만수술전체중조절 미국비만대사외과학회 (the American Society of Metabolic and Bariatric Surgery, ASMBS) 와미국외과학회 (the American College of Surgeons) 에서는비만의치료와수술의질향상을위해 2012년임상가이드라인을발표하고, 수술과관련된내용들을 2014년에업데이트한이후에 2016년에도새로이업데이트를하였다. 이러한임상가이드라인의많은내용들은비만치료를체계화하고유기적인내과적외과적치료를실제로이행하는데그중요성을두고있다. 가이드라인은다학제진료를강조하고있는데, 의사, 간호사, 영양사등만이아니라각각의파트구성원들의유기적인팀웍을강조하고있다. 그중에서도, 수술전 / 후관리도중요하다. 수술전환자의체중관리 (Medical weight management, MWM) 가중요한데, 수술후합병증발생율을줄이기위한목적과함께수술후체중감소의극대화를가져오기위함이다. 수술전환자의체중관리는이상적으로는수술전부터치료에참여하게됨으로써식이및생활습관의변화를가져와서수술후결과를좋게하는것이다. 최근의대표적인수술전체중감량에대한연구는 Scandinavian Obesity Registry에서시행한 20,564명에대한대규모연구이다 [37]. Gerber 등 [37] 은수술후 1년째체중을살펴보았을때, 수술전체중감량을한환자는 BMI 45.7 kg/m 2 이상인환자에서체중감소가유의하게많다고발표하였다 (OR 2.39, P<0.001). 반면에, Horwitz 등 [38] 은수술전체중관리는수술후 1-2년후의체중감소와특별한연관성은없는것으로보고하였다. 일반적으로수술전의체중감량이수술후합병증감소와체중감량의극대화를가져온다고알려져있지만, 그에반대적인결과도있기때문에그효과를단 3
Vol. 6, No. 1, 2017 정짓기는어렵다. 하지만수술전부터식이습관이나비만을조절하는생활습관을몸에연습하는것은장기적으로보았을때는긍정적인면이많다고하겠다. 결론 비만치료에이용되는약제중 Orlistat, Locaserin, liraglutide, Qsymia, Contrave 등은모두내약성과안정성이뛰어난약제로이들에대한흔한부작용들이잘알려져있기때문에적절한용량조절을통해이러한부작용을예방하거나대처할수있다. 고도비만수술환자에서수술전후적절한약물요법을병용함으로써최적의결과를기대할수있을것으로생각되며, 추후이에대한지속적인모니터링및연구가필요하다. REFERENCES 1. Jang SI, Nam JM, Choi J, Park EC. Disease management index of potential years of life lost as a tool for setting priorities in national disease control using OECD health data. Health Policy 2014; 115:92-9. 2. Mechanick JI, Youdim A, Jones DB, et al. Clinical practice guidelines for the perioperative nutritional, metabolic, and nonsurgical support of the bariatric surgery patient--2013 update: cosponsored by American Association of Clinical Endocrinologists, the Obesity Society, and American Society for Metabolic & Bariatric Surgery. Surg Obes Relat Dis 2013;9:159-91. 3. Lee HJ, Ahn HS, Choi YB, et al. 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