J Korean Diabetes 2018;19:71-75 Vol.19, No.2, 2018 ISSN 2233-7431 인제대학교의과대학부산백병원내과학교실 Paradigm Changes in Diabetes Management Guidelines: American Diabetes Association 2018 Jeong Hyun Park Department of Internal Medicine, Busan Paik Hospital, Inje University College of Medicine, Busan, Korea Abstract The management of type 2 diabetes mellitus should comprise healthy lifestyle modifications along with tailored pharmacologic treatment. Traditionally, the American Diabetes Association (ADA) s Diabetes Management Guidelines have not prioritized specific anti-diabetic drugs over others with regard to cardiovascular disease (CVD) and mortality prevention. Recently, two novel anti-diabetic medications proved to be significantly protective against future CVD and mortality, regardless of the glycemic levels achieved in type 2 diabetic patients with pre-existing CVD. The 2018 ADA Guidelines recommend SGLT2 inhibitor and/or GLP-1 receptor agonist be used for type 2 diabetes patients with atherosclerotic CVD after metformin monotherapy failure. Considering the value of CVD protection in the management of diabetes mellitus, this minor guideline adjustment could have far-reaching implications. Keywords: Agonist, Cardiovascular diseases, Diabetes mellitus, Glucagon-like peptide-1 receptor, Inhibitor, Mortality, Sodium-glucose transporter 2 Corresponding author: Jeong Hyun Park Department of Internal Medicine, Busan Paik Hospital, Inje University College of Medicine, 75 Bokji-ro, Busanjin-gu, Busan 47392, Korea, E-mail: pjhdoc@chol.com Received: Apr. 27, 2018; Accepted: May 22, 2018 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/bync/4.0/) 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 71
서론 당뇨병은매우복잡한만성질환으로, 지속적인의학적치료를통해다방면에걸친다양한급만성의위험들을경감시켜야한다. 급성합병증을예방하고, 만성합병증의발생위험을보다효율적으로경감시키기위해서는의료기관에서의진료이외에일상생활에서의자가관리에대한교육도지속적으로이루어져야만한다. 미국당뇨병학회 (American Diabetes Association, ADA) 의 Standards of Medical Care in Diabetes 는임상의사, 당뇨병환자, 과학자, 의료보험관련인및그외에관심이있는모든사람들을대상으로당뇨병관리와관련된요소, 치료방법및그치료들의목표, 그리고치료의질을평가하는방법들에대해기술하고있다. 하지만이것은임상진료에서의결정을대신할수있는것은아니며, 환자개개인의다양한특성및의료진의개별적인상황에따라선별적으로적용이되어야함도명시하고있다. ADA에서는매년이권고안을개정하고있다. 2018년에도개정된내용이발표되었고 2017년과비교해서몇가지내용들에부분적인수정이이루어졌지만, 이전과는달리 2018년권고안에서는굉장히중요한개념의변경이이루어진부분이있다. Section 8의혈당조절을위한약물치료접근 (8. Pharmacologic approaches to glycemic treatment) 이라는부분에서당뇨병치료약물의선택에있어기존에유지되어오던개념과는완전히다른방식의접근이제시되기시작했다 (Fig. 1, Table 1) [1]. 본글에서는이부분의변경이갖는의학사적인의미및미래전망에대해간략히다루어보도록하겠다. 당뇨병치료의목표를찾기위한노력의시기 1920년대초반, 인슐린의발견이후당뇨병환자의고혈당에대한정량적인치료가비로소시작될수있었다. 하지만그이후에도대략 70년이상당뇨병환자의혈당치를어느정도까지조절하는것이최선인지는아무도알지못했 다. 막연하게혈당이높은것보다는낮은것이좋을것이고, 낮은중에서도정상에가까운것이좋을것이라는다분히상식선에서의목표가실제치료에도사용되었다. 목표에대한과학적인해답이제대로제시가된것은 1990년대중반에발표된제1형당뇨병환자들을대상으로한 DCCT (Diabetes Control and Complications Trial) 연구와 2000년에발표된제2형당뇨병환자들에시행된 UKPDS (United Kingdom Prospective Diabetes Study) 연구결과였다. 이후 2000년대후반까지보다더정상에가까운혈당치를엄격하게유지하는것이만성합병증의예방에더좋은가를검증하는연구결과들이계속발표되었다. 하지만이들 treat-to-target (TTT) design 연구들은엄격한혈당조절이미세혈관합병증의발생위험은의미있게경감시켜줄수있지만심혈관질환의위험을감소시킬수있음을증명하는것에는실패하였으며, 오히려엄격한혈당조절에의해심각한저혈당의발생위험이증가할수있음을알려주었다. 당뇨병치료약물의효과에대한개별적검증시기 2000년대후반, 당뇨병치료를위한약물들이심혈관질환의발생위험을높일수도있다는논란이발생하였으며, 미국식품의약국 (U.S. Food and Drug Administration) 에서는모든당뇨병치료약물들은실제환자에서심혈관질환의위험을증가시키지않음을반드시증명하도록하였다. 이후새로이개발되는모든약물들은모두무작위위약대조이중맹검전향적임상시험 (randomized placebo controlled double blind prospective clinical trial) 을시행하게되었고, 임상연구들은 TTT design을벗어나혈당조절의차이보다는특정약물의심혈관질환에대한효과를검증하는형태로이루어지게된다. 그이후최소수천명에서많게는만명이상의환자들이수십개국가들에서함께참여하는대규모임상연구들이지난 10년간다수시행되었다. 유감스럽게도이들연구의대부분에서중립적인결과들이도출되었지만, 72
박정현 Fig. 1. The American Diabetes Association 2018 antihyperglycemic therapy in type 2 diabetes: general recommendations. Adapted from the article of American Diabetes Association (Diabetes Care 2018;41:S73-85) [1] with original copyright holder s permission. A1C, HbA1c; ASCVD, atherosclerotic cardiovascular disease. 최근몇년간당뇨병환자의심혈관질환복합지표와사망률을유의하게개선시킬수있는약물들에대한임상연구결과들이보고되었다. 2015년 New England Journal of Medicine에발표 된 EMPA-REG OUTCOME 연구는 SGLT2 억제제인 empagliflozin을과거심혈관질환이있었던고위험군제2형당뇨병환자들에게투여함으로써심혈관질환에대한복합종말점과심혈관질환에의한사망등을매우유의하게감소 www.diabetes.or.kr 73
Table 1. Drug-specific and patient factors to consider when selecting antihyperglycemic treatment in adults with type 2 diabetes (SGLT2 inhibitor and GLP-1 RA) Weight change ASCVD SGLT-2 inhibitors Loss Benefit: canagliflozin, empagliflozin CV effects CHF Benefit: canagliflozin, empagliflozin Cost High Oral/SQ Oral GLP-1 RAs Loss Neutral: lixisenatide, exenatide extended release Neutral High SQ Benefit: liraglutide Adapted from the article of American Diabetes Association (Diabetes Care 2018;41:S73-85) [1] with original copyright holder s permission. CV, cardiovascular; ASCVD, atherosclerotic cardiovascular disease; CHF, congestive heart failure; SQ, subcutaneous; RAs, receptor agonists. 시켜줄수있음을보고하였다 [2]. 이것은 1921년인슐린이발견되어당뇨병치료에사용된이후, 지금까지사용되어온모든약물들을통틀어서최초로증명된직접적인심혈관질환및사망률감소효과라고평가될수있다. 2016년역시 New England Journal of Medicine에발표된 LEADER trial에서는 GLP-1 receptor agonist인 liraglutide를역시고위험군제2형당뇨병환자들에게하루한번주사로투여해서역시심혈관계복합종말점들과심질환에의한사망을유의하게감소시킬수있음이발표되었다 [3]. 2018 ADA 약물치료권고안의수정 이들두연구의결과들은그중요성이곧인정이되어세계각국가들의진료지침에바로반영이되었고, ADA 역시약물선택에대해서는보수적이던기존의입장을선회해서 atherosclerotic cardiovascular disease (ASCVD) 가있는고위험군제2형당뇨병환자에서메트폴민치료로적절히혈당조절이되지않을때, 심혈관질환과사망률감소를위해 SGLT2 억제제나 GLP1 receptor agonist를먼저고려하도록하는내용으로 2018년도약물치료권고안을수정하게된다. 심혈관질환과사망률을감소시킬수있는것으로확인된 이들약물들모두동일계열에서유사한효과가있는지의여부는아직까지확실하지않다. 이들약물이최근발표된임상연구들에서보여준효과는스타틴계열의약물을사용한저밀도지단백콜레스테롤의감소나고혈압환자에서혈압조절이줄수있는심혈관질환및사망률의절대적위험도감소와대략유사한정도로알려져있다. 당뇨병환자에서심혈관질환의발생과이로인한사망이가장중요한임상적문제로대두되어있는상황에서이들약제들이보여준효과의임상적의미와가치는감히짐작하기가어려울정도로클수있다고개인적으로는판단한다. 현재미국에서는동맥경화증이동반되어있는당뇨병환자에서는혈액콜레스테롤검사를할필요없이모든환자들에게스타틴을투여하고, 이후굳이혈액지질을추적할필요도없다는권고안을이미사용하고있다. 마찬가지로, SGLT2 억제제와 GLP1 receptor agonist들의효과와부작용에대한평가가잘이루어진다면당뇨병에서도유사한방식의진료권고안이만들어질가능성도충분히있다고본다. 비록간접적인비교이기는하지만, 이들치료로얻을수있는심혈관질환및사망에대한절대위험의감소는대략유사한것으로알려져있기때문이다. 74
박정현 결론 REFERENCES 당뇨병에서심혈관질환은가장중요한사망원인의하나이다. 하지만철저한혈당조절은심혈관질환을효율적으로감소시키지못하였다. 최근 SGLT2 억제제와 GLP-1 receptor agonist의임상시험에서고위험군당뇨병환자의심혈관질환과사망률을유의하게억제할수있음이보고되었다. 2018년 ADA에서는 ASCVD가이미있는고위험군당뇨병환자에서메트폴민치료로적절히혈당조절이되지않을때 SGLT2 억제제나 GLP-1 receptor agonist들을먼저고려하도록권고하고있다. 이것은당뇨병치료의역사에서대단히중요한사건이며, 향후전세계모든당뇨병진료지침들의큰패러다임변화를예고하는전주곡일수도있다고본다. 1. American Diabetes Association. 8. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes-2018. Diabetes Care 2018;41(Suppl 1):S73-85. 2. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117-28. 3. Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, Nissen SE, Pocock S, Poulter NR, Ravn LS, Steinberg WM, Stockner M, Zinman B, Bergenstal RM, Buse JB; LEADER Steering Committee; LEADER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375:311-22. www.diabetes.or.kr 75