Focused Issue J Korean Diabetes 2018;19: Vol.19, No.1, 2018 ISSN 제 2 형당뇨병약제치료지침 2017 개정안 : Glu

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1 J Korean Diabetes 2018;19:35-40 Vol.19, No.1, 2018 ISSN 제 2 형당뇨병약제치료지침 2017 개정안 : Glucagon-Like Peptide-1 수용체작용제 김현진 충남대학교의과대학내분비대사내과 Glucagon-Like Peptide-1 Receptor Agonists for the Treatment of Type 2 Diabetes Mellitus: A Position Statement of the Korean Diabetes Association Hyun Jin Kim Division of Endocrinology and Metabolism, Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Korea Abstract Glucagon-like peptide-1 receptor agonists (GLP-1RAs) were recommended as a monotherapy or combination therapy with oral hypoglycemic agents or basal insulin in the position statement of the Korean Diabetes Association 2017 for pharmacological therapy, which was a change from the previous guideline that recommended them only as a combination therapy. Many randomized clinical trials and systematic reviews report that GLP-1RAs have considerable glucose-lowering effect and lead to weight reduction and low risk of hypoglycemia when used as a monotherapy or combination therapy. The results of cardiovascular outcome trials of long-acting GLP-1RAs (liraglutide, semaglutide) have demonstrated cardiovascular benefits in subjects with type 2 diabetes mellitus and a high risk of cardiovascular disease. The GLP-1RAs may be a choice of therapy when weight control and avoidance of hypoglycemia are important, and patients with high risk of cardiovascular disease might also favor choosing GLP-1RA. Keywords: Cardiovascular diseases, Diabetes mellitus, Glucagon-like peptide-1 receptor agonist, Hypoglycemia, Obesity, Practice guideline Corresponding author: Hyun Jin Kim Division of Endocrinology and Metabolism, Department of Internal Medicine, Chungnam National University School of Medicine, 266 Munhwa-ro, Jung-gu, Daejeon 35015, Korea, kimhj43@cnuh.co.kr Received: Jan. 28, 2018; Accepted: Feb. 2, 2018 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. Copyright c 2018 Korean Diabetes Association The Journal of Korean Diabetes 35

2 제 2 형당뇨병치료에서의 Glucagon-Like Peptide-1 수용체작용제 서론 대한당뇨병학회진료지침위원회는광범위한문헌검토를통하여 당뇨병진료지침 2015 를업데이트한 제2형당뇨병약제치료지침 2017 을발표하였다 [1]. Glucagon-like peptide-1 (GLP-1) 수용체작용제는병합요법으로만권고되었던이전진료지침과다르게, 경구약제또는기저인슐린과의병합요법과함께단독요법으로도권고되었다 [2]. 본글에서는 GLP-1 수용체의혈당강하효과, 대사에미치는영향, 심혈관결과에대한대규모임상연구들을요약하여 제2형당뇨병약제치료지침 2017 의근거를제시하고자한다. 본론 1. 혈당강하및대사효과 GLP-1 수용체작용제는혈당을강하시키는효과가강력하여공복혈당을 50 mg/dl까지, 당화혈색소를 0.5~1.3% 정도감소시킬수있다 [3,4]. Short-acting GLP-1 수용체작용제는위배출을지연시켜식후혈당강하효과가크며, long-acting GLP-1 수용체작용제는공복혈당감소효과가크다 [3,5]. 혈당의존적으로인슐린과글루카곤의분비를조절하기때문에저혈당의위험이낮다는장점이있고, 식욕억제효과가있어서평균 2~4 kg의체중감소의효과도있다 [6,7]. 또한임상연구를통해 GLP-1 수용체작용제치료가고밀도콜레스테롤을 0.01~0.02 nmol/l 증가시키고, 중성지방을 0.15~0.70 nmol/l 감소시킨다고보고되었다 [3]. GLP-1 수용체작용제의부작용은오심, 구토등의위장관증상이며, 급성췌장염의위험을보고한시판후보고서가있었지만, 이후대규모임상시험에서는 GLP-1 수용체작용제사용에의한급성췌장염의위험증가는확인되지않았다 [8-10]. Table 1은 GLP-1 수용체작용체의혈당강하효과, 대사효과등의특징을정리한것이다 [1]. 2. 심혈관결과제2형당뇨병환자에서심혈관질환은가장중요한사망원인이며, 심혈관질환의위험을낮추는것은당뇨병환자치료의중요한목적중하나로당뇨병환자의치료약제선택시심혈관질환에대한영향은고려해야할중요한인자중하나이다. GLP-1 수용체작용제의심혈관안전성을평가하 Table 1. GLP-1 receptor agonists for patients with type 2 diabetes mellitus Mechanism and common use Weight gain Hypoglycemia a HbA1c reduction (%) a Side effects Caution GLP-1 receptor agonist (exenatide, liraglutide, albiglutide, lixisenatide, dulaglutide) Glucose-dependent insulin secretion, postprandial glucagon secretion, postprandial hyperglycemia, delay gastric emptying, satiety Once or twice daily or once weekly SC injection No No 0.6~1.9 GI side effects (nausea, vomiting, diarrhea) Acute pancreatitis, C-cell hyperplasia, MEN2/MTC family or past history, severe renal or severe bowel disease Adapted from the article of Ko et al. Diabetes Metab J 2017;41: [1]. HbA1c, glycosylated hemoglobin; GLP-1, glucagon-like peptide-1; SC, subcutaneous; GI, gastrointestinal; MEN2, multiple endocrine neoplasia 2; MTC, medullary thyroid cancer. a Monotherapy. 36

3 김현진 는여러연구들이시행되어그결과들이발표되었는데 180 일이내에발생한급성관상동맥증후군환자 6,068명을대상으로한 Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) 연구에서 lixisenatide 투여군은대조군에비해심혈관질환의빈도를감소시키지는못했다 [8]. 하지만 long-acting GLP-1 수용체작용제인 liraglutide와 semaglutide의연구에서는심혈관질환의위험을줄였다. Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) 연구는심혈관위험이높은제2형당뇨병환자 9,340명을대상으로표준치료에 liraglutide와위약을추가하여심혈관결과를본것인데, liragluide는위약에비하여 3점주요해로운심혈관계사건 (3-point Major adverse cardiac events; 심혈관계사망, 비치명적심근경색, 비치명적뇌졸중 ) 을 13% 줄였다 (hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.78~0.97) [9]. Semaglutide의심혈관질환에대한평가를위해진행된 SUSTAIN-6 연구는 3,297명의심혈관질환위험이높은제2형당뇨병환자를대상으로하였고 3 점주요해로운심혈관계사건의유의한감소를보였다 (HR, 0.74; 95% CI, 0.58~0.95) [10]. 같은계열 GLP-1 수용체작용제의연구임에도불구하고심혈관결과에차이를보인것은약동학적및약력학적특성의차이에의한것으로생각된다. 또한연구대상, 기간등의연구디자인의차이도결과에영향을미쳤을것이다. 그러나, 이러한심혈관안전성을평가하기위한연구들은심혈관위험도가높은환자를대상으로비교적짧은기간동안이뤄지므로, 당뇨병진료를받는다수의환자를대변할수없다는일반화에대한문제가연구의제한점이다. 3. 미세혈관합병증에의영향 는신증의위험을감소시켰으나, semaglutide 투여군에서당뇨병망막증의빈도가증가하였다 [9.10]. 하지만망막증에대한영향을보기위한연구가아니었고미세혈관합병증을평가하기에는비교적짧은연구기간이었음을고려할때아직은 semaglutide의망막증에대한영향을결론내릴수는없으며추가적인임상연구가이뤄져야할것이다. 또한 GLP-1 수용체작용제의미세혈관합병증에대한영향을평가할수있도록디자인된임상연구가필요하다. 4. 권고안 1) GLP-1 수용체작용체는단독요법, 또는경구약제및기저인슐린과병용될수있다 1 단독요법으로서의 GLP-1 수용체작용체여러다른진료지침에서와마찬가지로 제2형당뇨병약제치료지침 2017 에서도메트포르민을경구약제단독요법시첫치료제로권고하고있다 [1]. 하지만메트포르민을사용할수없는경우에는 GLP-1 수용체작용체를포함한어떤계열의약제도사용가능하며, 동반질환, 목표혈당등의환자상태및약제의혈당강하효과, 부작용등을고려하여선택되어야한다. 많은연구들을통하여 GLP-1 수용체작용체의단독요법이효과적으로혈당을감소시킬뿐아니라체중감소효과가있고저혈당의위험이적다는것이확인되었다 [11,12]. 제2형당뇨병의치료에있어서체중관리와저혈당위험을최소화시키는것은중요한요소중하나이므로, 체중감소, 저혈당예방이중요한환자에서우선적으로 GLP- 1 수용체작용체를선택할수있겠다. 또한앞에서소개한심혈관결과들을고려할때심혈관질환의위험이높은환자에서도우선적으로고려할수있는약제이다. GLP-1 수용체작용제의미세혈관합병증에대한효과를일차적종말결과로디자인된임상연구결과는아직까지없다. LEADER와 SUSTAIN-6 연구에서이차종말결과로신증과망막증의결과를보았는데 liraglutide와 semaglutide 2 기저인슐린과병합요법으로서의 GLP-1 수용체작용체기저인슐린으로공복혈당은조절되나목표당화혈색소에도달하지못할때 GLP-1 수용체작용제를기저인슐린에추가할수있다. 많은임상연구에서 GLP-1 수용체작용 37

4 제 2 형당뇨병치료에서의 Glucagon-Like Peptide-1 수용체작용제 제와기저인슐린병합요법이식전인슐린과기저인슐린병합요법과비교할때, 당화혈색소감소효과는같거나우월하면서저혈당발생이적고체중조절이잘되는결과를보였다 [13-17]. 4B (the Basal Insulin Glargine plus Exenatide twice daily versus Basal Insulin Glargine plus Bolus Insulin Lispro) 연구는기저인슐린 (glargine) 으로혈당조절이불충분한제2형당뇨병환자를대상으로초속효성인슐린 (lispro) 하루 3회추가투여군과 exenatide 하루 2회추가투여군으로무작위배정하여관찰하였다. Exenatide 투여군은당화혈색소감소효과가비열등하였고저혈당발생률이적고체중감소효과가있었으며오심, 구토, 설사등의위장관부작용발생이많았다 [14]. 이런결과는한국인대상소그룹분석에서도관찰되었다 [15]. BEGIN:VICTOZA-ADD ON 연구에서는기저인슐린 (degludec) 으로혈당조절이불충분한환자에서 liraglutide 추가투여시에초속효성인슐린추가투여시보다당화혈색소감소가더컸으며, 저혈당빈도가적었고체중감소가관찰되었으며위장관부작용발생비율은높았다 [16]. 주 1회투여 GLP-1 수용체작용체인 dulaglutide의연구에서도기저인슐린과병용하였을때혈당강하효과가우수하고내약성도좋았다 [17]. 3 경구약제와병합요법으로서의 GLP-1 수용체작용체경구혈당강하제로목표혈당치에도달하지못한환자에서 GLP-1 수용체작용체를추가투여할수있다. Liraglutide 는메트포르민혹은설폰요소제에추가투여한경우나, 설폰요소제와메트포르민병합요법혹은티아졸리디네디온과메트포르민병합요법에추가투여했을때효과적으로혈당을감소시켰다 [18,19]. Dulaglutide도메트포르민, 설폰요소제, pioglitazone과의병합요법연구들에서효과적인혈당강하와체중감소효과를보였다 [20,21]. 최근발표된메타분석에서는경구혈당강하제에추가투여되는 GLP-1 수용체작용제와인슐린치료의효과를 head-to-head로비교하였는데 GLP-1 수용체작용제가혈당강하, 저혈당위험, 체중감소, 혈압조절, 지질조절등모든면에서우수함이증 명되었다 [22]. 결론 앞에서살펴본여러임상증거들을통해 GLP-1 수용체작용제가혈당강하와체중감소효과가있고저혈당의위험이적은혈당강하제임이확인되었으며, 단독요법또는경구약제및기저인슐린과병합요법으로제2형당뇨병환자의치료에권고된다. 특히체중조절이중요하고저혈당이나심혈관질환의위험이높은환자에서우선적으로고려될수있다. 향후심혈관질환의위험이낮은환자에서 GLP-1 수용체작용제의심혈관질환에대한영향을평가하는연구와한국인에서의효과와안전성을평가하는연구가수행되어야하겠다. REFERENCES 1. Ko SH, Hur KY, Rhee SY, Kim NH, Moon MK, Park SO, Lee BW, Kim HJ, Choi KM, Kim JH; Committee of Clinical Practice Guideline of Korean Diabetes Association. Antihyperglycemic agent therapy for adult patients with type 2 diabetes mellitus 2017: a position statement of the Korean Diabetes Association. Diabetes Metab J 2017;41: Kim HJ, Park SO, Ko SH, Rhee SY, Hur KY, Kim NH, Moon MK, Lee BW, Kim JH, Choi KM; Committee of Clinical Practice Guidelines of the Korean Diabetes Association. Glucagon-like peptide-1 receptor agonists for the treatment of type 2 diabetes mellitus: a position statement of the Korean Diabetes Association. Diabetes Metab J 2017;41: Nauck MA, Meier JJ, Cavender MA, Abd El Aziz M, Drucker DJ. Cardiovascular actions and clinical outcomes with glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. Circulation 38

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Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee University College of Medicine & Hospital E mail : ycell2@yahoo.co.kr Abstract