대한내과학회지 : 제 87 권제 1 호 2014 http://dx.doi.org/10.3904/kjm.2014.87.1.9 특집 (Special Review) - 최신당뇨병치료약제 글루카곤양펩티드 -1 유사체 가천대학교길병원내과 엄영실 김병준 Glucagon-Like Peptide-1 (GLP-1) Agonist Young Sil Eom and Byung-Joon Kim Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea The prevalence of diabetes is increasing worldwide. Glycemic control has been shown to prevent microvascular complications. Many oral hyperglycemic drugs and insulin are being used in the treatment of diabetes, but the effects of those treatments are suboptimal. The two incretin hormones GLP-1 and GIP are released from L- and K-cells, respectively, in response to nutrient intake. GLP-1 stimulates glucose-dependent insulin release. Recently, incretin hormone-based therapies, including GLP-1 agonists and DPP-4 inhibitors, have been used as new treatment options to control glucose levels in patients with type 2 diabetes mellitus. The purpose of this article is to review the efficacy and safety of GLP-1 agonists in the treatment of type 2 diabetes. (Korean J Med 2014;87:9-13) Keywords: Glucagon-like peptide 1 analogue; Incretin; Type 2 diabetes 서론당뇨병은인슐린분비이상이나인슐린저항성에따른상대적인슐린결핍에의해혈중포도당조절기능을상실한대사성질환이다. 당뇨병인구는증가하는추세에있으며전세계적으로 20-79세의당뇨병환자가 2010년에 2억 8,500만명 (6.4%) 에서 2030년에는 4억 3,900만명 (7.7%) 로증가될것으로예상되고있다 [1]. 우리나라의경우에도 40년전 1.5% 였던당뇨병환자가 2011년 9.9% 로 6배이상급격히증가하는양상을보였다 [2]. 당뇨병의치료목표는혈당수치를정상수준으로조절및유지하여합병증을예방하고합병증을조기발견하여이에따라적절히치료하는것으로적절한혈당조절은미세혈관합병증을예방하는데효과가있다 [3]. 당뇨병치료를위해서는당뇨병의병태생리에맞는다양한약제가요구되는데, 특히혈당및체중조절을하면서베타세포의점진적인소실을막을수있는약제가필요하다. 최근에는인크레틴기반의약제 ( 글루카곤양펩티드-1 유사체와 DPP-4 억제제 ) 가개발되어사용되면서, 혈당조절, 체중조절및베타세포의보존이라는측면에서좋은효과를보여준다. Correspondence to Byung-Joon Kim, M.D., Ph.D. Division of Endocrinology, Department of Internal Medicine, Gachon University Gil Medical Center, 21 Namdong-daero 774beon-gil, Namdong-gu, Incheon 405-760, Korea Tel: +82-32-460-8903, Fax: +82-32-469-4320, E-mail: kbjoon4u@gilhospital.com Copyright c 2014 The Korean Association of Internal Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution - 9 - Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
- The Korean Journal of Medicine: Vol. 87, No. 1, 2014 - 본론인크레틴이란? 인크레틴은음식섭취후섭취된음식물의구성영양분에의해위장관에서분비되는호르몬으로췌장에서혈당치에의존적으로인슐린분비를촉진하는역할을한다 [4]. 인크레틴효과 (incretin effect) 란당분을정맥주사했을때보다경구로투여했을때인슐린분비자극이더강하게나타나는효과를말한다 [5]. 이러한인크레틴효과를나타내는위장관펩티드에는글루카곤양펩티드-1 (glucagon-like peptide-1, GLP-1) 과포도당의존형인슐린분비자극펩타이드 (glucose-dependent insulinotropic peptide, GIP) 가있다. GLP-1 은췌장에작용하여인슐린분비를증가시키며글루카곤분비를감소시켜혈당강하효과를나타내며위에서음식물의통과를지연시키고뇌에작용하여식욕을억제하여복합적으로혈당조절에관여하며체중감소에도도움이된다. 또한췌도베타세포의기능을호전시켜인슐린감수성에좋은영향을준다 (Fig. 1) [6]. 제2형당뇨병환자의경우인크레틴효과가감소되거나소실되어있어 [7], 인크레틴투여는인크레틴부족으로인한 초기인슐린분비이상을회복시켜혈당의호전을기대할수있었다. 하지만활성형 GLP-1 은반감기가 2분정도로매우짧았기에치료제로사용하기에는한계가있었다. 이러한한계를극복하기위해 GLP-1 을불활성시키는가수분해효소인 DPP-4 (dipeptidylpeptidase-4) 를억제하여활성형 GLP-1 의농도를유지시키려는노력과 GLP-1과비슷한구조를가지며 DPP-4에의해가수분해되지않는펩티드를찾고자하는노력이있었다. 현재전자에해당하는약물로 DPP-4 억제제들 (sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin, gemigliptin 등 ) 이개발되어사용되고있으며후자의경우 GLP-1 유사체들 (exenatide, liraglutide, lixisenatide, dulaglutide 등 ) 이개발되어사용되고있다. 글루카곤양펩티드-1 유사체 (GLP-1 analogues) 의임상효과초기 GLP-1 유사체로 exenatide와 lixisenatide가개발되어사용되었다. 이러한약제들은식후혈당에주로효과를나타내며혈당을개선시키는효과를보였으나하루 1-2회피하주사를해야한다는점에서사용에제한이있었다. 이에따라약제의작용시간을늘리는노력들이크게두가지로시도되었는데, 알부민이나의료용중합체에결합시켜피하주 Figure 1. The multiple actions of glucagon-like peptide-1. - 10 -
- Young Sil Eom, et al. Glucagon-like peptide-1 (GLP-1) agonist - Table 1. Comparison of short-acting GLP-1 agonists and Long-acting GLP-1 agonist Shoer-acting GLP-1 agonist Long acting GLP-1 agonist Compound Exenatide Liraglutide Lixisenatide Exenatide LAR Albiglutide Dulaglutide Half-life 2-5 h 12 h-several days Effects Fasting blood glucose level Moderate reduction Strong reduction Postprandial blood glucose levels Strong reduction Moderate reduction Fasting insulin secretion Moderate stimulation Strong stimulation Postprandial insulin secretion Moderate stimulation Moderate stimulation Glucagon secretion Reduction Reduction Gastric emptying rate Deceleration No effect Blood pressure Reduction Reduction Heart rate Small increase (0-2 bpm) Moderate increase (2-5 bpm) Body weight reduction 1-5 kg 2-5 kg Induction of nausea 20-50%, attenuates slowly (weeks to many months) 20-40%, attenuates quickly (4-8 wk) 사후흡수를지연시키는방법과신장에서의배설을지연시키는방법을통해 liraglutide, exenatide LAR, albiglutide, dulaglutide와같은장기작용 GLP-1 유사체가개발되었다 (Table 1). Exenatide (Byetta R, Amylin and Eli Lilly Pharmaceuticals) Exenatide 는제2형당뇨병치료를위해처음개발된 GLP-1 수용체유사제로 1992년미국독도마뱀 (Gila monster, Heloderma suspectum) 의침에서발견된펩티드이다. 39개의아미노산으로구성되어있으며, 인간의 GLP-1 과염기서열이 53% 유사성을가진다 [8]. 제2형당뇨병환자들중메트포르민, 설폰요소제또는티아졸리딘디온 (thiazolidinediones, TZD) 을복용하고있거나메트포르민과설폰요소제병합요법또는메트포르민과티아졸리딘디온병합요법으로치료함에도적절한혈당조절이되지않는경우에사용되며, 최근 FDA에서는운동이나식이요법으로조절되지않는환자에서첫번째단독요법으로사용을허가하였다. 보통시작용량은 5 µg을 1일 2회이며한달뒤 10 µg을 1일 2회로증량하여유지한다. 제2형당뇨병환자에서 30주간 exenatide를 10 µg 투여하였을때 0.8-0.9% 의당화혈색소감소및 1.6-2.8 kg의체중감소소견을보였다 [9]. 구역, 구토및식욕감소가가장흔한부작용이며, 약제의작용기전이기도하나치료중단의흔한원인이 되기도한다. Lixisenatide (Lyxumia R, Sanofi/Zealand Pharmaceuticals) Lixisenatide는 exendin-4의 C 말단부를변형하여작용시간을늘린, 엄격하게말한다면 exendin-4 유사체다. 2-4시간의짧은반감기를보이지만, GLP-1 수용체에강한결합력으로하루 1번사용이가능하다. 1일 1회 20 µg을사용할때가장좋은효능을나타낸다. GetGoal 연구들을살펴보면 0.7-0.9% 의당화혈색소감소효과및의미있는체중감소효과를보였으며, 구역및구토증상은약 20% 환자에서나타났다 [10,11]. Liraglutide (Victoza R, Novo Nordisk Pharmaceuticals) Liraglutide는 2009년 EU에서, 2010년 FDA에서제2형당뇨병환자에게메트포르민, 설폰요소제, 티아졸리딘디온과함께사용하도록허가된 GLP-1 유사체로, human GLP-1 와 97% 의동질성을가지며반감기가 13시간으로하루 1번주사하기에적합하다 [12]. Liraglutide Effect and Action in Diabetes (LEAD) 연구들을살펴보면 liraglutide 1.8 mg을다른혈당강하제와함께사용한군에서 1.0-1.5% 의당화혈색소감소및최대 3.7 kg의의미있는체중감소를보였다. 1.2 mg 사용한경우에도 1.8 mg 사용한군과비슷한혈당강하효과를보였으나체중감소는 2.8 kg으로상대적으로감소효과가적었다 - 11 -
- 대한내과학회지 : 제 87 권제 1 호통권제 647 호 2014 - (1.8 mg vs 1.2 mg, p = 0.011). 베타세포의기능에있어서는 HOMA-B와 PI/I ratio 호전양상을보였다 [13]. 최근정상인에서도저혈당의위험성이없이체중감소효과를보여체중조절제로서의가능성에대하여도연구중이다. Exenatide LAR (Bydureon R, Eli Lilly Pharmaceuticals) Exenatide LAR 는 exenatide 의마이크로입자 (microspheres) 를 D, L lactic-co-glycolic acid라는중합체에결합시켜피하주사후서서히흡수되도록개발된약제이다. 반감기는 4일이며 1주일에한번 2 mg을투여한다. DURATION-1 (Diabetes therapy Utilization Researching changes in A1C, weight and other factors Through Intervention with exenatide Once Weekly-1) 연구를살펴보면제2형당뇨병환자이면서적절한운동이나식이조절또는메트포르민, 설폰요소제, 티아졸리딘디온단독또는병합요법으로도당화혈색소가 7.0% 초과되는 295명의환자를대상으로주 1회 2 mg의 exenatide LAR 를사용하는군과 10 ug의 exenatide를하루 2회사용하는군을 30주간비교하였을경우주 1회사용군에서당화혈색소가더많이감소된결과를보였으며 (-1.9% vs. -1.5%, p = 0.0023), 3.7 kg 정도의체중감소가동반되었다 [14,15]. Albiglutide (Syncria R, GlaxoSmithKline Pharmaceuticals) 인간 GLP-1 이합체를인간알부민에결합하여 DPP-4에저항성을갖도록개발된약제로반감기는 6-8일이다. 용량에비례한혈당감소효과가있으며두통이가장흔히발생하고변비, 복부팽만감, 구토등이발생할수있다 [16,17]. Dulaglutide (Eli Lilly Pharmaceuticals) GLP-1을 IgG4의 Fc fragment 에결합시켜 DPP-4 가수분해에저항하도록만들어진장기작용 GLP-1 유사체로주 1회용법으로개발되었다. 1.52% 의당화혈색소감소효과및 2-2.5 kg의체중감소를보인다. 구역, 설사, 복부팽만이발생할수있다 [18,19]. GLP-1 유사체의췌장외효과 (Fig. 1) GLP-1 수용체는췌장의췌도외에도뇌, 폐, 위장, 시상하부, 심장및평활근세포그리고신장에분포되어있다. 위장관계에작용하여위장배출기능및위산분비억제효과가있으며 [6] 심혈관계측면에서는혈압감소및심근수축력증가등의효과를가진다 [13]. 또한 GLP-1 이사람의지방간을개선시킨다는보고가있다 [20,21]. 아시아인에서제2형당뇨병의특징및 GLP-1 유사체의효과한국인제2형당뇨병환자는백인에비해인슐린저항성은적고인슐린분비능장애가더큰경향을보인다. 당뇨병환자에서 GLP-1 분비는당뇨병이없는환자와차이가없으나 GLP-1 의당소비 (GI hormone induced glucose disposal) 에있어서는의미있는감소를나타낸다. 인크레틴유사체치료의혈당강하효과는백인과다르지않지만당질의소비가많고인슐린분비능저하가체중증가로인한인슐린저항성증가보다주된병리형태를지닌아시아인에서 GLP-1 유사체가좀더당뇨병치료에효과적으로사용될수있다 [22,23]. 결론 GLP-1 은포도당존성으로인슐린분비를촉진하고글루카곤분비를감소시켜체중감소효과를가진인크레틴호르몬으로위장관배출속도감소, 식욕억제등과효과도가진다. 이러한 GLP-1 유사체는 exenatide, lixisenatide과같은단기작용 GLP-1 유사체및 exenatide LAR, linaglutide, albiglutide, dulaglutide와같은장기작용 GLP-1 유사체로구분할수있다. 현재국내에서사용가능한 GLP-1 유사체로는 exenatide 와 liraglutide가있으며향후 exenatide LAR 와 lixisenatide가출시될예정이다. GLP-1 유사체는혈당강하효과뿐아니라체중감소에도효과적이며저혈당발생이거의없다는장점을가진약제로피하주사를해야한다는번거로움이있지만장기작용 GLP-1 유사체의개발로이러한문제는개선되고있다. 오심과구토와같은위장관부작용이동반되나지속적으로사용하면서호전되는양상을보임으로초기사용시위장관부작용에대해설명해주는것이치료에도움이될수있으며췌장암과췌장염발생에대해서는아직연관성이명확히밝혀진바는없지만췌장염병력이있는환자에서는사용에주의를요한다. 중심단어 : 글루카곤양펩티드-1 유사체 ; 인크레틴 ; 제2형당뇨병 - 12 -
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