Table 1. Commonly used products for weight reduction Drug *Short- or long-term Action mechanism Classification by US Controlled Substances Act Orlista

Transcription

1 Review Korean J Obes 2015 March;24(1):17-27 pissn X eissn 장기간사용이허가된비만치료제의안전성 김경곤 * 가천의대가정의학과 Safety of Anti-Obesity Drugs Approved for Long-Term Use Kyoung Kon Kim* Department of Family Medicine, Gachon University College of Medicine, Incheon, Korea Because of the widespread use of ant-obesity medications, bariatricians need to be aware not only of common adverse events but also uncommon serious events in the pharmacotherapy of obesity. Safety and tolerability must be considered in selecting the drug, titrating the dosage, and monitoring patients. In Korea, orlistat and lorcaserine are the two anti-obesity drugs that can be used for long-term treatment, and in the US, liraglutide, phentermine/topiramate, and naltrexone/bupropion have been recently approved. In general, all of these drugs have very good safety and tolerability profiles. Common adverse events of these drugs are well understood, and they can be coped with or prevented by adjusting the dosage properly. In addition, patients can recover from serious events by stopping the medication. However, there are other serious side effects that need to be monitored for. These include liver injury, acute kidney injury, and pancreatitis for orlistat; valvulopathy for lorcaserine; thyroid C-cell pathology and pancreatitis for liraglutide; metabolic acidosis, urolithiasis, acute angle closure glaucoma, and teratogenic effects for phentermine/topiramate; and severe nausea and heart disease for naltrexone/bupropion. Key words: Safety, Adverse event, Orlistat, Lorcaserine, Liraglutide, Phentermine/topiramate, Naltrexone/bupropion 서론 비만인이섭취량을충분히줄이고활동량을획기적으로늘린다면, 거의모든비만인이체중을감량할수있고적정체중을유지할수있다. 하지만우리는그간의많은임상연구와경험을통해섭식량을제한하는방법 ( 식사요법 ) 이나신체활동량을늘리는방법 ( 운동요법 ) 과같은능동적방법에의한표준적치료방법으로만비만을해결하는것은충분치않다는것을잘알고있다. 1 비만인중에, 배고플때안먹고참을수있거나, 에너지밀도가높은음식을쉽게구할수있는환경에서굳이에너지밀도가낮은음식만을선택해서먹을사람은많지않다. 자동차나엘레베이터와같은이동수단에쉽게접근할수있는조건에서일부러규칙적이고충분히많은활동량을유지하려는사람역시소수에불과하다. 이와같이사람은태생적으로체중감량이쉽지않다는점과더불어, 비만이세계여러지역에서다른어 떤질병보다높은유병률을보인다는점때문에, 비만전문가들은많은사람들에게쉽게체중감량을유도할수있는약물요법을지속적으로모색하고있다. 현재비만치료에사용되는대표적인약물은 Table 1과같다. 이중, 우리나라에서장기간사용에대해허가를받은약물로는 orlistat과 lorcaserin이있는데, 이들의대표적인임상연구결과를보면, 획기적인정도는아니라할지라도, 위약만투여한경우에비해뚜렷한체중감량효과및부가적인대사관련개선효과가있다. 2,3 비만치료약물요법에대한임상연구에서위약군에도식사요법과운동요법이함께시행된다는것을감안하면, 약물요법이식사요법및운동요법과함께시행되었을때이와더불어추가적인체중감량효과가있는것은분명하다. 비만인에서약물을투여함으로써식사요법 / 운동요법을넘어서는체중감량을유도할수있다는것은, 최근미국에서허가받은 phentermine/topiramate (PHEN/TOPI), naltrexone/bupropi- Corresponding author Kyoung Kon Kim Department of Family Medicine, Gachon University Gil Medical Center, 21 Namdongdae-ro, Namdong-gu 774beon-gil, Incheon , Korea Tel Fax zaduplum@aim.com Copyright 2015 Korean Society for the Study of Obesity This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 17

2 Table 1. Commonly used products for weight reduction Drug *Short- or long-term Action mechanism Classification by US Controlled Substances Act Orlistat Long-term A reversible gastric and pancreatic lipase inhibitor that Not a controlled substance reduces the absorption of dietary fat Phentermine Short-term Sympathomimetic amine Schedule IV Diethylpropion Short-term Sympathomimetic amine Schedule IV Mazindol Short-term Sympathomimetic amine Not available in US Phentermine/topiramate (Qsymia ) Long-term Sympathomimetic amine/antiepileptic drug Schedule IV Lorcaserin (Belviq ) Long-term 5-HT2c receptor agonist Schedule IV Naltrexone/bupropion (Contrave ) Long-term Opioid antagonist/anti-depressant Not a controlled substance Liraglutide (Victoza ) Long-term GLP-1 analogue Not a controlled substance *Short-term therapy is considered as a few weeks, usually up to 12 weeks. on (NALT/BUPR), liraglutide 에서도마찬가지이다. 4-6 비만에대한약물요법에서는, 체중감량및대사개선과같은약물의유용성측면뿐아니라, 약물투여에대한안전성도함께고려해야한다. 비만은유병률이매우높은만성질환이기때문에, 비만치료약제는매우많은사람에게장시간투여된다. 또한, 비만은성별이나나이와무관하게나타나기때문에거의모든계층의사회구성원들이투여대상이될수있다. 이때문에발생빈도가적은부작용이라할지라도비만치료임상에서접하게될가능성이높으며, 심각한부작용에직면할가능성도배제할수없다. 따라서약물을이용하여체중감량을유도하고자하는전문가는자신이선택할약물의부작용에대해충분히인식하여야한다. 본고에서는우리나라에서장기간사용허가를받은 orlistat과 lorcaserin, 최근미국에서장기간사용허가를받은 PHEN/TOPI, NALT/BUPR, liraglutide 을안전성측면에서살펴보겠다. Orlistat Orlistat은가역적인위장관계지질분해효소 (lipase) 길항제로써, 음식에포함되어있는지방의분해와흡수를떨어뜨린다. Orlistat은이십년정도임상에서널리사용되어서이에대한임상경험이많이축적되어있고발현빈도가적은부작용에대해서도잘알려져있다. Orlistat에의한대부분의부작용은기름변, 기름이새어나오는방귀, 변실금, 대변횟수의증가, 복통등불쾌하거나불편한소화기계증상이다. 이들소화기계증상은약물작용기전자체에의한것같다. 소화기계부작용의강도는대체로경도에서중등도이다. 치료초기에나타나서지속적으로복용하는과정에서저절로사라지는부작용이많으며, 일회성이거나일시적인증상이상당수를차지하고, 반복적으로나타나는부작용은상대적으로적다. 비만인은합병증을가지고있는경우가많아서 orlistat이다른약물과병용투여될가능성이많다. Orlistat은식이지방흡수를억제하기때문에지방과연관성이높은약물의흡수나작용에영향을미칠 개연성이있다. Orlistat은지용성비타민 A, D, E, K와 β-carotene의흡수를저하시킬수있다. 2,7 마찬가지로지용성약물과의상호작용도간과할수는없다. Warfarin은지용성비타민인비타민 K에의해약효가영향을받는데, orlistat 복용으로기존에복용하던 warfarin 의효과가강화되었다는증례보고가있다. 8 약물상호작용에관한한연구에서는, orlistat이 cyclosporin 과상호작용을보였지만 amitriptyline, atorvastatin, losartan, metformin, phentermine 과상호작용을보이지않았다. 9 Cyclosporin 은친수성이매우나쁘고지방을부형제로사용하는경우가있는데, orlistat과병용투여시지질분해효소의작용저해로인해부형제분해가방해를받아서 cyclosporin의흡수가떨어지는것같다. 기존에혈압약을복용하던환자에서 orlistat을복용하는도중혈압이상승했다는보고가있는데, 이런경우역시 orlistat의혈압약에대한약물상호작용이원인일것으로추정할수있다. 10 Orlistat 사용에따른중대한부작용으로간손상유발가능성이제기된바있다. 11 Orlistat 투여와간손상사이에인과관계가있는지확실하지는않다. 12 하지만비만인에서는치료시점에이미비알코올성간염이있는환자가적지않으므로 orlistat 투여시에환자의간상태를미리평가하는것이바람직하다. 임상연구결과에의하면 orlistat 투여시담낭제거가필요했던담석증증례가발생했다 (Table 2). 하지만, orlistat 자체가담석증을유발하는것인지 orlistat에의한체중감량이담석증을유발하는것인지분명하지않다. 급격한체중감량을시도하는경우담즙에콜레스테롤이과포화되어담석증이발생하기쉽기때문이다. 한연구에서는 orlistat 을투여하면담즙의담즙산농도가감소하지않기때문에도리어담석발생을줄일수있다고주장했다. 15 Orlistat 투여에의해소변의 oxalate 농도가상승할수있고이때문에신장에 calcium oxalate 크리스탈이침착되어 oxalate 신증이발생할수있다. 16 소변에 oxalate가많이배출되는이유는장내에흡수되지않은지방과담즙산이많아지고이들이칼슘과반응하여장에서의 oxalate 흡수가증가하기때문인것같다. 18

3 Table 2. Adverse events (AEs) of orlistat Authors Number of subjects Duration (months) *Common AEs Serious AEs Serious AEs assessed as possibly related to drug Derosa et al. (2010) Malaise Fatty evacuation Perrio et al. (2007) 10 16,021 (orlistat) Prescription-event monitoring Ten most frequently reported reasons for stopping medication: diarrhea, intolerance, weight gain, unspecified side effects, abdominal pain, flatulence, unspecified gastrointestinal symptom, fecal incontinence, pregnancy, headache 18 deaths due to cardiovascular or cerebrovascular events Elevated liver function test (2) Hypertension (3) Pedal edema (1) Swollen ankle (3) Lichen planus of the tongue (1) Chanoine et al. (2005) adolescents 12 Fatty stool Pilonidal abscess (1) Symptomatic cholelithiasis that led to cholecystectomy Oily spotting Depression (2) Oily evacuation Asthma attack (1) seizure (1) Abdominal pain Admission for repair of deviated nasal septum (1) Fecal urgency Appendicitis (1) Flatus with discharge Cholelithiasis (1) Soft stool Gallbladder disorder followed by cholecystectomy (1) Increased defecation Adenoidal hypertrophy (1) Flatulence Aseptic meningitis (1) Fecal incontinence Sjöström et al. (1998) Fatty stool (25) (1) Increased defecation Oily spotting Soft stool Liquid stools Abdominal pain Fecal urgency Flatulence Flatus with discharge Fecal incontinence Oily evacuation Number in ( ) means number of cases with the adverse events. *Occurred at a rate of 5%, except Perrio et al. Orlistat 사용에의해췌장염이생겼다는보고가있는데췌장효소에대한국소적인영향이원인이었을것으로추정하지만이에대한발생원인이분명하지는않다. 17 Lorcaserine Lorcaserine은세로토닌수용체효현제로서, 세로토닌수용체중 5-HT 2c 수용체에선택성이매우높은약제이다. 세로토닌수용체는포만감과섭식행동을조절하는데, 이때문에비만치료의주요한표적이었다. 1970년대에체중감량을위해미국에서널리사용되던약물로 fenfluramine이있었는데이약제역시세로토닌을통해서작용하는약물이었다. 1990년대에 fenfluramine과 phentermine 병용요법 (fenphen) 이미국에서광범위하게사용되었으며, 1996년 fenfluramine에서부작용은적고체중감량효과는강할것으로추정한 fenfluramine 의이성체인 dexfenfluramine 이개발되었다. 하지만 dexfenfluramine 출시후얼마안되어 fen-phen 사용과관련된심장판막질환증례들이보고되었다. 18 이후이에관한정밀한역학적조사가이루어졌으며, 급기야 1997년 fenfluramine과 dexfenfluramine은심장판막질환을유발할위험이높다는이유로모두시장에서퇴출되었다. 1998년에게 19

4 재된식욕억제제투여환자에서의심장판막부전유병률조사연구에따르면대조군에서는 1.3%, 환자군에서 22.7% (dexfenfluramine 단독사용군에서 OR 12.7, dexfenfluramine + phentermine 사용군에서 OR 24.5, fenfluramine + phentermine 사용군에서 OR 26.3) 의빈도로심장판막부전이나타났다. 19 세로토닌성약물에대한과거의나쁜사례때문에 lorcaserine에대한세가지대규모 3상임상연구 (Table 3) 모두에서임상연구기간에심장초음파검사를이용하여연구참여자들의판막기능을추적관찰하였다. 세연구의통합분석결과를보면, 약물투여전과 1년투여시점을비교했을때, lorcaserine 투여군에서심장판막증의발생이위 약군에비해다소많았지만, 통계적으로유의하지는않았으며, 체중이많이빠질수록심장판막증발생위험이높았다. 22 세연구에참여한사람이 5,000명이상이며한사람당일년에세번 ( 치료시작전, 24 주, 52주 ) 의심장초음파검사를하여추적관찰하여얻은이데이터는심장판막에대한 lorcaserine의안전성에매우큰신뢰감을준다. 하지만, 통계적으로유의한수준은아니지만 lorcaserine 투여군에서판막증이더많이생기기는했다는점과, 수년간투여했을때에도괜찮을것인지를생각해볼때, lorcaserine 투여시환자의심혈관및호흡기계증상과징후에대해서주의깊게살펴야한다. Lorcaserine 에의한흔히발생하는부작용은 Table 3과같으며, 이 Table 3. Adverse events (AEs) of lorcaserin Authors Number of subjects Duration (months) *Common AEs Serious AEs Serious AEs assessed as possibly related to drug Smith et al. (2010) 3 (BLOOM) 3, Headache Cardiac disorder (2) Upper respiratory infection Gastrointestinal disorder (4) Dizziness General disorder (2) Nausea Hepatobiliary disorder (6) Constipation Immune system disorder (1) Fatigue Infection (7) Dry mouth Injury and poisoning (6) Metabolism Abnormal laboratory test (1) Metabolism disorder (1) Musculoskeletal disorder (8) Neoplasm (6) Nervous system disorder (4) Psychiatric disorder (1) Reproductive system or breast disorder (8) Respiratory disorder (3) Fidler et al. (2011) 20 (BLOSSOM) 4, Headache (76) Syncope (1) Upper respiratory infection Moderate depression (1) Nausea Acute anxiety attack (1) Dizziness Fatigue O Neil et al. (2012) 21 (BLOOM-DM) Headache 6.3% (10 mg BID) diabetic patients Back pain 8.4% (10 mg QD) Nasopharyngitis Nausea Urinary tract infection Cough Symptomatic hypoglycemia Fatigue Gastroenteritis Dizziness Influenza Procedural pain Hypertension Depression Number in () means number of cases with the adverse events. *Occurred at a rate of 5% in any treatment group and more frequently than in placebo group (P < 0.05). 20

5 는다른교감신경효현성식욕억제제들과대동소이하다. 증상은경증이며, 약제를중단하지않아도시간이지나면줄어든다. 정신건강상의부작용이나우울, 자살사고의발현은위약군과차이가없다. 약물투여에따른혈액검사결과와심전도의변화는두드러진것은없다. 당뇨병환자를대상으로한 3상임상연구는, lorcaserine 투여시저혈당이발생하지만심각한저혈당은생기지않는다고보고하였다. 21 설폰요소제를복용중인당뇨병환자에서저혈당이더자주생기며, 약제자체의효과라기보다는식욕억제에따른섭취량감소때문일것이다. Lorcaserine 은미국의 Controlled Substances Act에의한분류에서는 schedule IV 약물로분류되어있는데, benzodiazepine 이나 tramadol과같은등급이다. 우리나라에서도향정신성의약품으로간주된다. Lorcaserine은의존성이나남용의가능성이있을수있다고간주해야하며, 약물의관리에규제가따른다. 한연구에서는 lorcaserine 은권장용량을초과해서투여하면불쾌한느낌을주기때문에남용의가능성이낮다고주장했다. 23 다른약물과의뚜렷한상호작용은보고된바없다. 또, 다양한종 류의 cytochrome P450과 UDP-glucuronosyltransferase 들이 lorcaserine의대사에관여하기때문에, 다른약물과의상호작용발생가능성이낮다는보고도있다. 24,25 Liraglutide Liraglutide 는인크레틴의한종류인 glucagon-like peptide-1 (GLP- 1) 의유사체로, 체내의 GLP-1과는달리지속시간이길어서하루한번피하투여로사용한다. 체중감량을유도하는기전은, 포만감을유도하고배고픔을줄이며위배출시간을지연시킴으로써섭취량을줄이고, 대사량을늘임으로써체중을감량시킨다. 26 여러임상연구들을살펴볼때, liraglutide 는초기체중감량, bariatric surgery 및초저열량식이로유도된체중감량의유지, 비만인에서의심장대사지표의개선, Prader-Willi 증후군에서의혈당조절및체중감량의용도로사용할수있다. 미국에서는최근체중감량을위해사용할수있도록허가를받았지만우리나라에서는그렇지않은상태이다. 당뇨병치료에대해서 Table 4. Adverse events (AEs) of liraglutide Authors Number of subjects Duration (months) Common AEs Serious AEs Psychiatric AEs Astrup et al. (2009) *Nausea (1) 1.2 mg Insomnia (6) *Vomiting (4) 1.8 mg Depressed mood (3) *Fatigue (2) 2.4 mg Nervousness (2) *Gastroenteritis (1) 3.0 mg Astrup et al. (2012) (extension of Astrup et al. 6 ) Mild to moderate nausea-vomiting Cholelithiasis with acute Acute stress disorder (1) pancreatitis (1) Dyspepsia Breast cancer (1) Anxiety (4) Constipation Intestinal adenocarcinoma (1) Burnout syndrome (1) Upper abdominal pain Serious anaphylactic reaction (1, due to diclofenac/ misoprostol) Injection site disorders (pain, hematoma, irritation, discomfort) Symptomatic hypoglycemia (12) Antibodies to liraglutide (6) Jensterle Sever et al. (2014) PCOS patients 3 Mild nausea and diarrhea Hypoglycemic event Headache Rash at the injection site insomnia Atrial fibrillation (1, recovered) Uterine leiomyoma (1, recovered) Prostate cancer (1, recovered) Depressed mood (5) Depression (5) Eating disorder (1) Food aversion (1) Insomnia (7) Altered mood (2) Nervousness (2) Restlessness (1) Stress (4) Number in () means number of cases with the adverse events. *Occurred at a rate of 10% in any treatment group and more frequently than in placebo group (P < 0.05), Occurred at a rate of 5% in any treatment group and more frequently than in placebo group (P < 0.05). 21

6 사용하는용량은하루 0.6 mg 1회투여로시작하여단계적으로 0.6 mg씩증량하여최대하루 1.8 mg 1회를투여하는데, 일본의경우는 0.3 mg으로시작하여 0.3 mg씩증량하여최대 0.9 mg을투여한다. 체중감량의목적으로사용하는경우는좀더높은용량을사용하는데, 최대하루 3.0 mg 1회를투여한다는점이특이하다. Liraglutide 의몇가지임상연구에서나타난부작용들은 Table 4와같다. GLP-1 효현제이기때문에구역및구토가흔히발생한다. 보통은경도나중등도이며, 투여초기에증상이발생하고시간이지남에따라증상이호전되지만, 용량이높아지면발생빈도역시높아진다. 6 체중감량을위해사용하는경우는당뇨병치료에비해고용량을사용하기때문에초기에용량조절을하는과정에서심한구역 / 구토에대해주의할필요가있지만, 3.0 mg을투여하는경우에도저용량으로시작해서단계적으로용량을조절해나가는경우증상을감내할만하며삶의질을떨어뜨릴정도는아니다. 27 심박수는다소증가하며, 가벼운두근거림을느끼는사람들이있다. 임상연구에서는심방세동이발생한경우가있었다. 6 정신건강관련증상이흔하지는않지만위약군에비해많이나타났다. 불면의경우에는고용량사용시에더발생하는것으로보이지만, 그외증상은빈도수가낮아서발생패턴을추정하기어렵다. 경구용제제가아니기때문에 Table 4에서나타나는바와같이주사부위의부작용이발현하는경우가있다. Liraglutide 투여군은맥박이약간높으며, 심방세동이발생한경우도있다. 6 Liraglutide 에대한설치류에서의동물실험에서갑상선의 C 세포암이발생한사례가있는데, liraglutide 가갑상선 C 세포의 GLP-1 수용체를자극하기때문이다. 쥐 (rat) 의경우나이와성별에따라 C 세포의비정상증식이자연적으로발생한다. 30 설치류의이러한종특성이 liraglutide 의동물실험에서 C 세포이상소견이나타난원인으로보이지만, 사람에서도그러할지는불확실하다. 이러한점때문에 Liraglutide Effect and Action in Diabetes (LEAD) 연구를포함한다수의 3상임상연구에서연구참여자들에게 C 세포병리에민감도와특이도가높은혈청 calcitonin 농도를측정하였다. 5,000명이상의대상자를통합분석한결과를보면, 최장 2년, 최대일일 3.0 mg의 liraglutide를투여했을때, 연구자들은 liraglutide 가사람의 C 세포에서 calcitonin 분비를자극한다는증거는없다고결론내렸지만, liraglutide 투여군중하위집단에서혈청 calcitonin이위약군보다높은경우가있고, 투여기간이긴경우에는혈청 calcitonin이 20 ng/l 이상의농도를보인사람의빈도수가위약군보다많았다. 31 비만치료에 liraglutide를사용하는경우에는상대적으로고용량을장기간투여하게될가능성이많은데, 이경우에갑상선 C 세포이상발생에대해확실하게안전하다고보기는어렵다. 최소한갑상선수질암이나다발성내분비선종증의과거력이있거나위험도가높다고판단되는환자에서는 사용하지말아야한다. 인크레틴제제의사용이췌장염과연관이있다는우려가있다. 하 지만현재까지의데이터로볼때 liraglutide 투여와췌장염발생사이 의인과관계유무를판단하기어렵다. 32 Phentermine/topiramate 병용요법 (Qsymia ) Topiramate 는그자체로체중감량효과가있다는임상연구가발 표된바있지만, 어떤기전을통해체중감량이유도되는지는확실하 지않다. 33 Topiramate 의단점은체중감량을유도할만한충분한용 량을투여할경우이상감각등여러가지신경학적부작용이발생한 다는것이다. 마찬가지로 phentermine 역시용량을증가시키면체중 감량효과가더강해지지만그에상응하는부작용이함께증가한다. 이때문에부작용이잘안나타나는저용량으로 phentermine 과 topiramate 를함께사용하는병용요법이개발되었다. PHEN/TOPI 에대한주요 3 상임상연구들에서나타난부작용은 Table 5 와같다. PHEN/TOPI 투여시나타나는가장흔한부작용은 이상감각이지만, 실제로임상연구에서중도탈락한주요이유는불 면증, 과민, 불안, 두통, 집중저하, 우울, 입마름, 신장결석이다. 34 고용 량투여시에저용량투여시보다부작용발현이많으며, 임상연구중 도탈락자역시고용량투여군에서많다. 35 Gadde 등 35 의 3 상연구를 1 년더연장한연구결과를보면, 흔한부작용들은약물투여초기나 약물투여 2 년째에도같은종류의부작용들이나타나지만, 그발현 빈도는처음 1 년에비해훨씬줄어들며, 위약군에비해발현빈도에서 뚜렷한차이를보이는부작용은이상감각과구역정도뿐이다. 4 투여 기간이길어지면서환자가약물에적응하는것같다 (Table 5). Topiramate 는탄산탈수효소 (carbonic anhydrase) 를저해하는데 이때문에다양한부작용이발생한다. PHEN/TOPI 투여시이때문 에혈청중탄산염 (bicarbonate) 농도는감소하며임상적으로유의한 대사성산증이나타나기도한다. 혈청중탄산염농도는주로약물투 여초기에감소하며시간이지날수록점차정상화된다. 이외에도탄 산탈수효소저해작용때문에, 신장결석이발생할위험도있으며혈 청칼륨농도가낮아져서칼륨보충이필요한경우도생긴다. 이상감 각및입맛변화역시 topiramate 의탄산탈수효소저해작용때문인 것같다. 자살사고는증가하지않지만, 용량의존적으로우울및불안과관 련된증상은증가한다. 보통약물투여초기에나타나고, 약물투여를 중단하면사라진다. 뚜렷한기분장애가있는환자, 자살사고를가지 고있거나과거에자살시도를했던환자에서는투여하지말아야한다. 혈압은하강하고심박수는약간상승한다. 심박수상승은 phen- 22

7 Table 5. Adverse events (AEs) of phentermine/topiramate Authors Number of subjects Duration (months) Common AEs Serious AEs Psychiatric/cognitive AEs Allison et al. (2012) 34 (EQUIP) Gadde et al. (2011) 35 (CONQUER) 1, *Paresthesia Cholelithiasis (1) Insomnia (40, high dose) *Dry mouth Myelogenous leukemia (1) Depression (24, high dose) *Constipation Irritability (23, high dose) *Dysgeusia Anxiety (19, high dose) *Nasopharyngitis Disturbance in attention (18, high dose) *Blurred vision (low dose, P = 0.05) Jittery (7, high dose) *Alopecia *Hypoesthesia *Dry eye *Oral paresthesia *Dry skin *Anorexia *Decreased serum bicarbonate *Amenorrhea *Aphasia *Back injury *Decreased serum potassium *Parosmia 2, Dry mouth Anxiety (41, high dose) Paresthesia Irritability (34, high dose) Constipation Disturbance in attention (35, high dose) Dysgeusia Insomnia Dizziness Back pain Nausea Blurred vision Garvey et al. (2012) 4 (SEQUEL) (extension of CONQUER) Paraesthesia Nausea Number in () means number of cases with the adverse events. *Occured at a rate of 1% in any treatment group and more frequently than in placebo group (P < 0.05), Occured at a rate of 5% in any treatment group and more frequently than in placebo group (P < 0.05), In the second year, paresthesia occurred more in high dose group and nausea occurred more in low dose group than in placebo group (P < 0.05 by Fisher s exact test). termine의효과로보인다. 약물투여기간동안혈압과맥박을주기적으로측정할필요가있다. Topiramate는황산을포함하고있는데, 이런약물들은섬모체 (ciliary body) 의부종을유발해서급성폐쇄각녹내장을유발할수있다. 36,37 이는보통은약제투여시작초반에나타난다. 임상연구에서보고된부작용중흐려보임 (blurred vision) 도이러한작용과관계있을수있다. PHEN/TOPI 투여시에환자의시력변화와안구증상에주의를기울여야한다. EQUIP과 SEQUEL 임상연구중발생한 16건의임신의결과는, 세건은자연유산, 세건은인공유산, 그리고열건은건강한정상분만이었다. 하지만 topiramate는태아의구개열과구순열을일으킬수있기때문에, 임산부에게 PHEN/TOPI를투여해서는안된다. 두드러진약물상호작용은보고된것이없다. Phentermine 과 topiramate 의병용에대해서는임상경험이더축 적되어야하겠지만, 이두가지약제모두상당히긴기간동안광범위 하게사용되었기때문에부작용에대해잘알려져있다는것은강점 이다. 이들의병용제제는미국에서비만치료를위해승인받았지만, 우리나라에서는현재까지승인받은바없다. Naltrexone/bupropion 병용요법 (Contrave ) 체내에서체중조절의중요한정보는시상하부의궁상핵에모이는 데, 궁상핵의뉴론은크게체중을늘이는역할을하는 neuropeptide 23

8 Table 6. Adverse events (AEs) of naltrexone/bupropion Authors Number of subjects Duration (months) *Common AEs Serious AEs Psychiatric AEs Greenway et al. (2010) 5 (COR-I) 1, Nausea Heart failure (1) [placebo: low dose: high dose] Headache Death due to acute myocardial infarct (1) Insomnia 5.1%: 6.3%: 7.5% Constipation Anxiety 2.1%: 2.1%: 1.6% Dizziness Depression 1.1%: 1.6%: 0.5% Vomiting Dry mouth Hot flush Wadden et al. (2011) 38 (COR-BMOD) Nausea Cholecystitis (2) [placebo: high dose] Constipation Depression 2.5%: 0.3% Dizziness Dry mouth Tremor Upper abdominal pain Tinnitus Apovian et al. (2013) 39 (COR-II) 1, Nausea Seizure (1) [placebo: high dose] Contipation Myocardial infarction (1) Any psychiatric AEs 15.2%: 20.7% Headache Dry mouth Vomiting Dizziness Number in () means number of cases with the adverse events. *Occurred at a rate of 5% in any treatment group and more frequently than in placebo group (P < 0.05), P < Y (NPY) 와 Agouti-related protein (AgRP) 분비뉴론과, 반대로체중을줄이는역할을하는 pro-opiomelanocortin (POMC) 와 cocaine and amphetamine-regulated transcript (CART) 분비뉴론으로나눌수있다. Bupropion은도파민과노르에피네프린의재흡수를억제하는항우울제로써, POMC/CART 뉴론을자극하여식욕을떨어뜨린다. 하지만내인성 opioid인 β-endorphin은 POMC 뉴론에대해자가억제 (autoinhibition) 작용을하여 bupropion의식욕억제효과를떨어뜨린다. 여기에 opioid 길항제인 naltrexone을함께사용하면 bupropion의식욕억제효과를강화시킬수있는데, 이를이용하여개발된병용요법이 NALT/BUPR 제제이다. 가장흔하게나타나는부작용은구역인데, 주로 naltrexone 때문인것으로추정된다. 그외변비, 어지러움, 입마름, 떨림, 복통, 이명이자주나타난다. 이약제에의한구역감은간과하기어려운데, 임상연구참여자의 % 가구역감때문에중도탈락할정도이다. 5,38,39 혈압은체중감량정도에따라하강하지만, 맥박은변화없거나약간상승한다. Table 6에있는심대한부작용의증례들은연구자들이모두약제에의한것이아닌것으로판단했지만, 심혈관질환의위험요소를여러개가지고있던환자에서급성심근경색이발생한경우가있었다. 빈도수는낮지만심혈관질환위험이높은사람에서사용하는것은주의를기울일필요가있다. 미국에서는비만치료약물로승인받았지만, 우리나라에서는승인 받은바없으며, 아직임상사용례가충분하지않아서부작용발현에대해서앞으로더지켜봐야한다. 비만치료제의안전성에대해고려해야할점 비만약물요법에서다음몇가지문제점들을생각해봐야한다. 첫째, 이론적으로비만해결에묘책이라고생각되는약제들이뜻하지않은문제를일으키는경우가있다는점이다. 충분한사용례를면밀히검토한후에만해당약제의안전성과유효성을확인할수있기때문에, 임상연구결과만으로안전성을충분히평가하는것은무리가따른다. 둘째, 비만약물의경우유병률이매우높은비만의특성에따라매우많은사람들이복용하게되며, 비만이아닌정상인들이복용하는경우도많이발생한다는점이다. 또약제복용을중단하면체중재증가가발생하는경우가많기때문에장기간복용하는경우도많이발생한다. 투여증례가많고투여기간이길어지는만큼문제가발생할확률도높아지므로발생빈도가적은부작용이라도심각한부작용들은간과하지말아야한다. 셋째, 임상현장에서추천되는용량이상을투여하거나안전성과유효성에관한증거가불충분한병용요법을시행한다는점이다. 따라서권장용량에대해서만실시한임상연구결과가실제임상환경과같을수는없다. 본고에서언급한약제중 orlistat을제외하면, 모두장기간체중감 24

9 량에대한사용허가를받은것은최근의일이다. 약제사용시에유효성외에도안전성에대해주의깊게모니터링을해야만한다. 결론 Orlistat, lorcaserin, liraglutide, PHEN/TOPI, NALT/BUPR 모두내약성과안전성이뛰어난약제이다. 이들에대한흔한부작용들은잘알려져있으며, 적절한용량조절을통해서예방하거나대처할수있다. 경우에따라약물투여를중지함으로써부작용에서회복될수도있다. 하지만 orlistat 은간손상, 급성신증, 췌장염, lorcaserine 은심장판막증, liraglutide는갑상선 C세포이상, 췌장염, PHEN/TOPI 는대사성산증, 신장결석, 급성폐쇄성녹내장, 태아기형, 그리고 NALT/BUPR 은심한구역감과심장질환이, 사용시주의를기울여야하는심대한부작용이다. 요약 비만치료제는상당히많은사람들에게장기간투여되기때문에, 흔한부작용뿐만아니라드물게일어나지만심각한부작용도간과해서는안된다. 약물을선택하고용량을조절하고추적관찰하는데있어서안전성측면을우선적으로고려해야한다. 우리나라에서장기간사용이가능한비만치료제에는 orlistat 과 lorcaserine 이있으며, 미국의경우에는 liraglutide, phentermine/topiramate, naltrexone/bupropion이비만치료의목적으로장기간사용에대해허가를획득하였다. 이들약제는전반적으로모두내약성과안전성이뛰어난약제이다. 이들에대한흔한부작용들은잘알려져있으며, 적절한용량조절을통해서예방하거나대처할수있으며, 경우에따라약물투여를중지함으로써부작용에서회복될수도있다. 하지만 orlistat 은간손상, 급성신증, 췌장염, lorcaserine 은심장판막증, liraglutide 는갑상선 C세포이상, 췌장염, phentermine/topiramate는대사성산증, 신장결석, 급성폐쇄성녹내장, 태아기형, 그리고 naltrexone/bupropion은심한구역감과심장질환이, 사용시주의를기울여야하는심대한부작용이다. 중심단어 : 안전성, 부작용, orlistat, lorcaserine, liraglutide, phentermine/topiramate, naltrexone/bupropion Conflicts of Interest The author declares that there are no conflicts of interst. References 1. Miller WC, Koceja DM, Hamilton EJ. A meta-analysis of the past 25 years of weight loss research using diet, exercise or diet plus exercise intervention. Int J Obes Relat Metab Disord 1997;21: Torgerson JS, Hauptman J, Boldrin MN, Sjöström L. XENical in the prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Diabetes Care 2004; 27: Smith SR, Weissman NJ, Anderson CM, Sanchez M, Chuang E, Stubbe S, et al. Multicenter, placebo-controlled trial of lorcaserin for weight management. N Engl J Med 2010;363: Garvey WT, Ryan DH, Look M, Gadde KM, Allison DB, Peterson CA, et al. Two-year sustained weight loss and metabolic benefits with controlled-release phentermine/topiramate in obese and overweight adults (SEQUEL): a randomized, placebo-controlled, phase 3 extension study. Am J Clin Nutr 2012;95: Greenway FL, Fujioka K, Plodkowski RA, Mudaliar S, Guttadauria M, Erickson J, et al. Effect of naltrexone plus bupropion on weight loss in overweight and obese adults (COR-I): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2010;376: Astrup A, Rössner S, Van Gaal L, Rissanen A, Niskanen L, Al Hakim M, et al. Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study. Lancet 2009; 374: Sjöström L, Rissanen A, Andersen T, Boldrin M, Golay A, Koppeschaar HP, et al. Randomised placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients. European Multicentre Orlistat Study Group. Lancet 1998;352: MacWalter RS, Fraser HW, Armstrong KM. Orlistat enhances warfarin effect. Ann Pharmacother 2003;37: Zhi J, Moore R, Kanitra L, Mulligan TE. Pharmacokinetic evaluation of the possible interaction between selected concomitant medications and orlistat at steady state in healthy subjects. J Clin Pharmacol 2002;42: Perrio MJ, Wilton LV, Shakir SA. The safety profiles of orlistat and sibutramine: results of prescription-event monitoring studies in England. Obesity (Silver Spring) 2007;15: U.S. Food and Drug Administration. Orlistat (marketed as Alli and 25

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