Pharmacotherapeutics J Korean Med Assoc 2015 May; 58(5): 452-457 pissn 1975-8456 / eissn 2093-5951 http://dx.doi.org/10.5124/jkma.2015.58.5.452 신약중심의비만약물요법 노은 김민선 울산대학교의과대학아산병원내과 New and emerging drugs for the treatment of obesity Eun Roh, MD Min Seon Kim, MD Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea Obesity has become a global public health problem. The importance of obesity is highlighted by the fact that obesity-related comorbidities, such as type 2 diabetes, cardiovascular disease, and cancer, are a leading cause of death in Westernized countries. As endorsement of lifestyle modifications has proven to be inadequate to combat obesity, pharmacological treatment has become more critical for weight reduction as well as for the treatment of obesity-related morbidity and mortality. However, safety issues dampened the success of the development of antiobesity drugs, leaving orlistat as the single approved drug for long-term weight management until 2012, when two new anti-obesity drugs were approved by the FDA: lorcaserin and phentermine/topiramate. In 2014, another two drugs were approved by the US FDA for the treatment of obesity: naltrexone/bupropion and liraglutide. In this review, we describe the new FDA-approved anti-obesity drugs and briefly introduce other anti-obesity drugs still under development. (Word count: 144) Key words: Obesity; Drug; Development 서론 비만증의유병률이미국을비롯한세계여러나라들에서 놀라운속도로증가하고있다 [1]. 우리나라도예외는아니어서비만증을체질량지수 (body mass index, BMI) 25 kg/m 2 이상으로정의할때, 성인인구의 30.8% 가비만증을가지고있으며, 특히제2당뇨병환자의 44.4% 가비만증을동반하고있다 [2]. 비만증은제2형당뇨병, 고혈압, 심혈관질환, 수면무호흡증후군, 퇴행성관절질환, 유방암, 대장암등다양한 Received: March 16, 2015 Accepted: March 30, 2015 Corresponding author: Min Seon Kim E-mail: mskim@amc.seoul.kr Korean Medical Association 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. 질환의발생률을증가시키므로, 비만증의급격한증가는심각한보건의료의문제로인식되고있다 [1,3,4]. 비만증의치료로식이습관의교정및운동량증가를통한체중감량이우선적으로권장된다 [5]. 하지만이러한비약물적치료법만으로성공적인체중감량에도달하지못하거나, 심각한유병질환을동반하는증증비만증에서는약물치료가반드시필요하다 [6,7]. 비만증치료제에대한강력한필요성에도불구하고, 장기간사용이가능한효과적인비만치료제개발은그다지성공적이지못하였다. 지금까지개발된가장강력한비만치료제인 fen-phen은세로토닌계약제인 fenfluramine과교감신경흥분제인 phentermine의복합제제로탁월한체중감량효과를보였지만, fenfluramine이심장판막에존재하는 5-hydroxytryptamine 2B (5-HT 2B ) 수용체에작용하여심장판막질환을야기함이밝혀지면서 1997년에시판이중단되었 452 대한의사협회지
Roh E Kim MS New and emerging drugs against obesity Table 1. Newly-approved anti-obesity drugs Drug Dosage Mechanism of action Common adverse events Date of FDA approved Lorcaserin (Belviq) Phentermine/ topiramate (Qsymia) Naltrexone/ bupropion (Contrave) Liraglutide (Saxenda) 10 mg oral twice daily 5-HT 2c agonist Headache, upper respiratory tract infection, dizziness, nausea, constipation, and fatigue 7.5 mg of phentermine/46 mg of topiramate ER once daily 8 mg of naltrexone/90 mg of bupropion 2 tablets twice daily 3 mg subcutaneous injection once daily Phentermine (amphetamine that increases the release of noradrenaline, dopamine and serotonin)/ topiramate(anticonvulsant, precise mechanism of action unknown) Naltrexone (μ-opioid receptor agonist)/ bupropion (dopamine and noradrenaline reuptake inhibitor) Long-acting GLP-1 analog Dry mouth, unpleasant taste, diarrhea, constipation, vomiting, headache, insomnia Nausea, constipation, headache, vomiting, dizziness, insomnia, dry mouth, and diarrhea Nausea, diarrhea, constipation, hypoglycemia, headache, decreased appetite, pancreatitis, kidney failure, gallbladder problems and increased heart rate June 27, 2012 July 17, 2012 September 10, 2014 December 23, 2014 FDA, Food and Drug Administration; 5-HT 2c, 5-hydroxytryptamine 2C; ER, extended-release; GLP-1, glucagon-like peptide-1. Table 2. Anti-obesity molecules in clinical development Drug Mechanism of action Clinical development phase Agents acting through central mechanisms Zonisamide/ bupropion (Empatic) Zonisamide (carbonic anhydrase inhibitor)/bupropion (dopamine and noradrenaline reuptake inhibitor) Phase III ongoing Tesofensine Serotonin noradrenaline dopamine reuptake inhibitor Phase III ongoing Velneprit Neuropeptide Y5 receptor antagonist Phase II completed Agents acting through peripheral mechanisms Cetilistat Pancreatic lipase inhibitor NDA approved in Japan Beloranib methionine aminopeptidase 2 inhibitor Phase III ongoing NDA, new drug application. 미국식품의약국승인을받은새로운비만치료제 1. Lorcaserin (Belviq) Lorcaserin 은식욕조절중추인 시상하부에존재하는세로토닌수용체 5-HT 2C 에선택적으로작용하는약물로, 식욕억제물질을생산하는 proopiomelanocortin (POMC) 뉴런을흥분시켜포만 다 [8]. 그다음으로많이사용하던비만치료제인 sibutramine (Reductil) 은중추신경계에작용하여시냅스에서세포토닌 / 노르에피네프린재흡수를방해함으로써식욕억제작용을유도하는약물로심혈환질환의위험성을중가시킨다는이유로 2010년에사용이중지되었다 [9]. 또한 rimonabant를비롯한여러비만신약들이부작용과약한항비만효과로인하여개발이중단되거나, 사용이불허되었다. 그러다가미국식품의약국 (Food and Drug Administration, FDA) 은 2012년에 lorcaserin과 phentermine/topiramate 복합제를, 2014년에 naltrexone/bupropion 복합제와 liraglutide를비만치료제로사용할수있도록승인하였다. 따라서본리뷰에서는최근승인을받은비만치료약물들의작용기전과임상연구결과를기술하고 (Table 1), 아울러현재개발중인비만치료제에대해서간단히소개하고자한다 (Table 2). 감을유도하고, 체중감소를일으킨다 [10]. 2012년 6월에미국 FDA는 BMI 30 kg/m 2 이상, 혹은고혈압, 제2형당뇨병, 이상지혈증중한개이상을동반한 BMI 27 kg/m 2 이상인사람에서 lorcaserin 사용을허용하였다. 3,182명의비만혹은과체중을가진사람에생활습관교정과함께 52 주동안 lorcaserin 10 mg 혹은위약군을투여한대규모의다기관, 이중맹검임상연구 (Behavioral Modification and Lorcaserin for Overweight and Obesity Management, BLOOM trial) 에서치료종료시점에서 5.8 kg, 위약투여군은 2.2 kg의체중감소를보여주었다 [11]. 또한 1년간추가로 locaserine을복용하였을때감량한체중을유지하는효과가위약군에비하여우수하였다. BLOOM-DM 연구에서비만한제2형당뇨병환자에게 1년간 locaserine 10 mg을하루 1회, 혹은 2회투여하였을때 5% 이상인체중감량을도 신약중심의비만약물요법 453
J Korean Med Assoc 2015 May; 58(5): 452-457 달한사람의비율이각각 44.7%, 37.5% 로위약군 16.1% 에비하여유의하게높았고, 혈당도개선되었다 [12]. 부작용으로는오심, 두통, 현기증등이있으며, 2년동안진행된임상연구에서 fenfluamine과유사한심장판막의이상은관찰되지않았다. 2. Phentermine/topiramate extended-release (Qsymia) 이약제는아드레날린성식욕억제제인 phentermine과항간질약제인 topiramate 복합제이다. Topiramate는간질치료제로개발되어사용중체중감소를유발한다는사실이우연히발견되었는데, topiramate에의한체중감소의기전은아직명확히알려져있지않으나, 뉴런의 GABA 수용체를자극하거나, 다양한수용체나이온채널에결합하는능력과연관이있을것으로생각된다 [13]. 비만증에서 topiramate 를장기간사용한임상연구에서 topiramate는위약에비하여유의한용량의존적체중감소효과를보여주였다. 하지만용량이증가할수록인지장애, 이상감각등중추신경계및말초신경계에다양한부작용을일으키기때문에 topiramate의용량을줄여부작용을낮추고, phentermine 병용함으로써항비만효과를강화시킨복합제형이개발되었다 [14]. 미국 FDA는 2012년 7월에 BMI 30 kg/m 2 이상인사람이나, BMI 27 kg/m 2 이상이면서고혈압, 제2형당뇨병, 이상지혈증중하나이상의합병증을가진사람에서 phentermine/topiramate 처방을허용하였다. CONQUER 연구에서 1년동안 7.5 mg phentermine/46 mg topiramate 혹은 15 mg phentermine/92 mg topiramate을투여한사람에서평균 8.1 kg과 10.2 kg의체중감소가유도되었는데, 이는위약군에서 1.4 kg의체중감소에비하면현저하게높은수준이었다 [15]. 그후 2년간진행된 SEQUEL 연구에서 phentermine/topiramate 투여군에서유도된체중감소가대조군에비하여더잘유지됨이입증되었다 [16]. 흔한부작용으로는입마름, 감각이상, 변비, 불면등이있다. 3. Naltrexone/bupropion (Contrave) 이약제는알코올중독이나마약중독의치료제로 FDA 승 인을받은 naltrexone과항우울제혹은금연치료제로 FDA 승인을받은 bupropion의복합제이다. 2014년 9월에미국 FDA는 BMI 30 kg/m 2 이상이거나또는고혈압, 제2형당뇨병, 이상지혈증중하나이상을가진 BMI 27 kg/m 2 이상인사람에서 naltrexone/bupropion 사용을승인하였다. Naltrexone 은중추신경계존재하는 opioid 수용체억제제로 POMC 뉴런은내인성 opioid에의해억제를받고있는데, naltrexone은 opioid 수용체에작용하여이러한억제를차단함으로써결과적으로 POMC 뉴런의흥분성을증가시킨다 [17]. 한편 bupropion은시냅스에서도파민 / 노르에피네프린의재흡수를방해하는약물로, 시상하부 POMC 뉴런에서의작용을통하여음식섭취량을감소시키고, 에너지소비를증가시켜체중감소를유도한다 [17]. 또한 naltrexone/bupropion 복합제는음식에대한보상반응을조절하여맛있는고칼로리음식에대한갈망을감소시켜준다. 56주간 793명을대상으로체중감량을목적으로식이조절및운동요법과더불어 32 mg naltrexone/360 mg bupropion 복합제를복용한사람들에서 9.2-11.4 kg의체중감소가유도되었다. 위약을투여받은사람들에서같은기간동안평균 7.3 kg 체중감량이유도되어 naltrexone/ bupropion의항비만효과가입증되었다. 또한 10% 이상체중감량에성공한사람의비율이복합제제군에서 41.5%, 위약군에서 20.2% 로 naltrexone/bupropion 투여군에서더높았다 [18]. 현재까지알려진가장흔한부작용은오심이며, 그외변비, 두통, 현기증, 불면증등의부작용도보고되었다. 4. Liraglutide (Saxenda) Liraglutide는작용시간이긴 glucagon-like peptide-1 (GLP-1) 수용체의작용제로미국과유럽에서제2형당뇨병의치료제에사용하고있으며, 2014년 12월에미국 FDA 로부터 BMI 30 kg/m 2 이상이거나 BMI 27 kg/m 2 이상이면서고혈압, 제2형당뇨병, 이상지혈증등하나이상을가지고있는사람에서체중감량을위한 liraglutide의처방이승인되었다. GLP-1은음식섭취후회장과대장의내분비세포에서혈액으로분비되는장호르몬으로, 인슐린분비를 454 대한의사협회지
Roh E Kim MS New and emerging drugs against obesity 증가시키고, 글루카곤분비를억제함으로써식후혈당을낮추는데중요한역할을한다. 한편 GLP-1은위배출을지연시키고, 시상하부에서작용하여포만감을유발함으로써식욕억제작용을가진다 [19,20]. 당뇨병으로치료제로개발된 Victoza는 liraglutide 1.2 mg, 1.8 mg 제형인데반하여, 비만치료제인 Saxenda는 liraglutide 3 mg 주사제형으로 1일 1회투여한다. 당뇨병은없으나과체중혹은비만증을가진사람에게 2년동안 liraglutide 3 mg/day를투여하였을때위약에비해유의한체중감소효과를보였고, 당뇨병과대사증후군의발병을낮추고, 혈압과지질을개선하여심혈관질환의위험을감소시켰다 [21]. SCALE 연구에서저칼로리식이요법을통해체중을 5% 이상감량한사람들에서 56주간 liraglutide 3 mg을투여하였을때, 위약에비하여우수한체중감소유지효과와추가적인체중감량효과를보여주었다 [22]. 미국 FDA는 Saxenda를 16주동안투여했는데도체중이 4% 이상줄지않으면약물투여를중단하도록권고하였다. 부작용으로는오심, 설사, 변비, 식욕저하가흔하고, 췌장염, 신장기능저하, 담낭저하등이보고된바있다. 또한맥박상승이유발할수있어지속적인맥박상승을보이는경우약물중단이필요하다. 현재개발중인비만치료제 1. 중추신경계에작용하는약물들 Zonisamide/bupropion (Empatic) 은항전간제인 zonisamide와 bupropion의복합제로두약제의부작용, 즉 zonisamide에의한우울증유발과 bupropion의간질유발을두약제를병용함으로써완화시키고, 두약제의체중감소효과를한층강화시켰다. 729명의비만인에게 24주간 360 mg zonismide/360 mg bupropion 또는 120 mg zonisamide/360 mg bupropion을사용하였을때, 각각 7.5%, 6.1% 의체중감소를유발하여위약군 1.4% 에비하여유의한체중감량효과를보였다 [23]. 현재 3상연구가진행중이며, 오심, 두통, 불면등이흔한부작용이다. Tesofensin은시냅스에서세로토닌 / 노르아드레날린 / 도 파민의재흡수를억제하는약물로당초알츠하이머병이나파킨슨병의치료제로개발되었으나, 치료효과가만족스럽지않았다. 그러나부작용으로체중감소가보고되면서, 비만증에대한임상연구가진행되었고, 그결과음식물에대한욕구감소, 음식섭취량의감소, 체중감소를유발함이확인되었다 [24]. 161명을대상으로한소규모임상연구에서 tesofensin을일일 0.5 mg 혹은 1.0 mg을 24주간투여한사람에서체중이각각 11.3 kg, 12.8 kg 감소하였고, 위약군에서 2.2 kg 체중이감소하여, 이제까지개발된약제들에비하여 2배정도의높은체중감소효과를보여주었다 [24]. 이러한체중감소효과는밤동안에너지소비의증가, 24시간지방산산화율의증가에기인하는것으로생각된다 [25]. 또한 tesofensin 사용은복부비만, 혈중지질, 아디포넥틴, 인슐린, 혈당조절에긍정적변화를초래하였다. Tesofensin의부작용으로입마름, 불면, 변비, 오심, 맥박상승이있고, 고용량에서혈압상승이관찰되어추후대규모임상시험을통하여안전성을입증하는것이매우중요할것으로생각된다. 현재 3상연구가진행중이다. 2. 말초조직에작용하는약물들 Cetilistat은 orlistat과유사한약물로, 췌장의 lipase 를억제하여지방의흡수를억제하는약물이다. 2상연구결과 orlistat와비교하여유효성은비슷하고소화기계부작용이더적은것으로나타났다 [26]. 일본에서제2형당뇨병과이상지혈증을모두가진비만환자에서 52주간 cetilistat 120 mg 하루 3회를투여한 3상임상연구에서평균체중을 2.8%( 위약 1.1%) 감소시켰고, 혈당과지질이개선시켰다. 이에따라 2013년 9월일본에서제2형당뇨병과이상지혈증을동반한비만증환자들에서사용이승인되었다. Beloranib은 methionine aminopeptidase-2 억제제로간에서의지방산생합성을억제하고축적된지방을유용한에너지로전환시키는데기여한다. Beloranib을주 2회정맥주사하였을때유의한체중감량효과가있었다 [27]. 현재 beloranib 피하주사를이용한 3상연구진행중으로, 이약물의가장큰제한점은주사제라는것이다. 신약중심의비만약물요법 455
J Korean Med Assoc 2015 May; 58(5): 452-457 결론 비만증은이제우리나라에서도가장흔한대사질환으로 현재안전하고효과적인비만증치료제가없기때문에새로운비만치료제에관심이매우높다. 최근미국 FDA에서승인을받은비만치료제들은 lorcaserin을필두로조만간한국에도들어올예정이다. 이약물들은 2년정도의임상연구기간중심각한부작용은발견되지않았으나, 장기간사용을해야하는비만치료제의특성을감안할새로운비만치료제들의장기간사용이심혈관계에비치는부작용을향후면밀히살펴보아야할것이다. 한편비만증은복합적인요인에발생하므로다양한기전을통하여유의한체중감량을유도하는약물들의병용요법이필요할것으로생각된다. 비만의병태생리를더많이이해하게된다면, 새로운작용기전을가진다양한비만치료제가개발될수있을것이며, 머지않은미래에개인의비만증의특성에따른맞춤형비만치료가가능해질것으로기대해본다. 찾아보기말 : 비만 ; 약물요법 ORCID Eun Roh, http://orcid.org/0000-0001-8413-5006 Min Seon Kim, http://orcid.org/0000-0002-4881-0390 REFERENCES 1. World Health Organization. Obesity: preventing and managing the global epidemic: report of a WHO consultation. Geneva: World Health Organization; 2000. 2. Kim CS, Ko SH, Kwon HS, Kim NH, Kim JH, Lim S, Choi SH, Song KH, Won JC, Kim DJ, Cha BY; Taskforce Team of Diabetes Fact Sheet of the Korean Diabetes Association. Prevalence, awareness, and management of obesity in Korea: data from the Korea national health and nutrition examination survey (1998-2011). Diabetes Metab J 2014;38:35-43. 3. Tsigos C, Hainer V, Basdevant A, Finer N, Fried M, Mathus- Vliegen E, Micic D, Maislos M, Roman G, Schutz Y, Toplak H, Zahorska-Markiewicz B; Obesity Management Task Force of the European Association for the Study of Obesity. Management of obesity in adults: European clinical practice guidelines. Obes Facts 2008;1:106-116. 4. James WP. The epidemiology of obesity: the size of the problem. J Intern Med 2008;263:336-352. 5. Plodkowski RA, St Jeor ST. Medical nutrition therapy for the treatment of obesity. Endocrinol Metab Clin North Am 2003; 32:935-965. 6. Hensrud DD. Pharmacotherapy for obesity. Med Clin North Am 2000;84:463-476. 7. Bassett J, International Diabetes Institute; World Health Organization; Regional Office for the Western Pacific; International Association for the Study of Obesity; International Obesity Task Force. The Asia-Pacific perspective: redefining obesity and its treatment. Australia: Health Communications Australia; 2000. 8. Connolly HM, Crary JL, McGoon MD, Hensrud DD, Edwards BS, Edwards WD, Schaff HV. Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med 1997;337:581-588. 9. James WP, Caterson ID, Coutinho W, Finer N, Van Gaal LF, Maggioni AP, Torp-Pedersen C, Sharma AM, Shepherd GM, Rode RA, Renz CL; SCOUT Investigators. Effect of sibutramine on cardiovascular outcomes in overweight and obese subjects. N Engl J Med 2010;363:905-917. 10. Thomsen WJ, Grottick AJ, Menzaghi F, Reyes-Saldana H, Espitia S, Yuskin D, Whelan K, Martin M, Morgan M, Chen W, Al-Shamma H, Smith B, Chalmers D, Behan D. Lorcaserin, a novel selective human 5-hydroxytryptamine2C agonist: in vitro and in vivo pharmacological characterization. J Pharmacol Exp Ther 2008;325:577-587. 11. Smith SR, Weissman NJ, Anderson CM, Sanchez M, Chuang E, Stubbe S, Bays H, Shanahan WR; Behavioral Modification and Lorcaserin for Overweight and Obesity Management (BLOOM) Study Group. Multicenter, placebo-controlled trial of lorcaserin for weight management. N Engl J Med 2010; 363:245-256. 12. O Neil PM, Smith SR, Weissman NJ, Fidler MC, Sanchez M, Zhang J, Raether B, Anderson CM, Shanahan WR. Randomized placebo-controlled clinical trial of lorcaserin for weight loss in type 2 diabetes mellitus: the BLOOM-DM study. Obesity (Silver Spring) 2012;20:1426-1436. 13. Astrup A, Toubro S. Topiramate: a new potential pharmacological treatment for obesity. Obes Res 2004;12 Suppl:167S- 173S. 14. Gadde KM, Allison DB. Combination pharmaceutical therapies for obesity. Expert Opin Pharmacother 2009;10:921-925. 15. Gadde KM, Allison DB, Ryan DH, Peterson CA, Troupin B, Schwiers ML, Day WW. Effects of low-dose, controlledrelease, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial. Lancet 2011;377:1341-1352. 16. Garvey WT, Ryan DH, Look M, Gadde KM, Allison DB, Peterson CA, Schwiers M, Day WW, Bowden CH. Two-year sustained weight loss and metabolic benefits with controlledrelease phentermine/topiramate in obese and overweight adults (SEQUEL): a randomized, placebo-controlled, phase 3 extension study. Am J Clin Nutr 2012;95:297-308. 456 대한의사협회지
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