권고안 [1,2] 지침해설 I. 초기치료원칙 1. 당뇨병진단초기부터적극적인생활습관개선및적절한약물치료가필요하다. [A] 2. 환자의임상적특징, 약제의효능, 부작용, 비용을고려하여적절한당뇨병치료약제를선택한다. [E] II. 약제치료의원칙 1. 경구약제단독요법시첫치료제로메트

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1 J Korean Diabetes 2018;19:15-22 Vol.19, No.1, 2018 ISSN 제 2 형당뇨병환자의약제치료개정안 2017: 이상열 경희대학교의과대학내분비대사내과 Monotherapy in Type 2 Diabetes Mellitus Patients 2017: A Position Statement of the Korean Diabetes Association Sang Youl Rhee On Behalf of the Committee of Clinical Practice Guideline of the Korean Diabetes Association, Department of Endocrinology and Metabolism, Kyung Hee University School of Medicine, Seoul, Korea Abstract When starting initial medication in people with type 2 diabetes mellitus (T2DM), the appropriate drug should be selected considering characteristics of the patient, efficacy, side effects, and cost. It is generally recommended to use metformin as the first-line treatment oral hypoglycemic agent in T2DM patients. Metformin is recommended as the first treatment because of its excellent glucose lowering effect, relatively mild side effects, long-term safety, low risk of hypoglycemia, and small weight gain. If it is difficult to use metformin as a first-line treatment, appropriate drugs can be selected based on the clinical situation. Keywords: Diabetes mellitus, type 2, Hypoglycemic agents, Metformin, Practice guideline Corresponding author: Sang Youl Rhee Department of Endocrinology and Metabolism, Kyung Hee University School of Medicine, 23 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea, rheesy@khu.ac.kr Received: Dec. 28, 2017; Accepted: Jan. 24, 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 15

2 권고안 [1,2] 지침해설 I. 초기치료원칙 1. 당뇨병진단초기부터적극적인생활습관개선및적절한약물치료가필요하다. [A] 2. 환자의임상적특징, 약제의효능, 부작용, 비용을고려하여적절한당뇨병치료약제를선택한다. [E] II. 약제치료의원칙 1. 경구약제단독요법시첫치료제로메트포르민을사용한다. [A] 2. 첫치료제로메트포르민사용이어려운경우임상적상황을고려하여적절한약제를선택한다. [E] 3. 단독요법으로혈당조절목표도달에실패할경우작용기전이서로다른약제의병합요법을시행한다. [A] 배경 혈당을철저히조절하면당뇨병관련합병증을유의하게예방할수있음이여러연구에서확인되었다 [3,4]. 이러한연구결과는당뇨병환자의임상경과향상을위해적극적인혈당조절이필요함을설명하는이론적근거가된다. 하지만최근지나치게엄격한혈당조절이환자의부정적임상경과를초래할수있다는연구결과가보고되었다 [5-7]. 따라서당뇨병환자의다양한임상적상황을고려한개별화된혈당조절목표가필요하다 [8,9]. 생활습관개선은성공적인당뇨병관리를위해가장먼저시행되는치료수단이다. 당뇨병임상경과에대한생활습관개선의효과는여러연구에서입증되었다 [10,11]. 그러나베타세포기능이점차저하되는제2형당뇨병의병태생리적특성상, 생활습관개선만으로적절한혈당조절을유지하기는쉽지않다 [12]. 따라서많은환자에서적절한혈당조절을위해치료초기부터적절한약물을투여할필요가있다. 1. 생활습관개선으로충분한치료효과를얻지못한당뇨병환자에게을우선고려한다. 단일요법시행시, 약제에따라약 0.5~1.5% 의당화혈색소감소효과가확인된다 [13]. 그종류에따라다소차이가있으나, 일반적으로약제사용의최대효과는약 4~6개월후관찰된다 [14]. 대체로환자들의당화혈색소가높을수록약제사용에따른당화혈색소감소폭이커진다 [13]. 혈당이일반적권고수준 ( 당화혈색소 7.3% 이하 ) 에가까워지면당화혈색소의추가개선을위해식후혈당조절이중요하다 [15]. 일부연구결과식후혈당이공복혈당과독립적인심혈관질환및사망의위험인자임이확인되었다 [16,17]. 하지만식후혈당개선이추가적인심혈관질환위험개선효과가있는가에대한근거는명확하지않다. 최근새로운작용기전을가진약제가소개되고, 이와관련된여러임상시험결과가소개되면서당뇨병환자의초기치료제에대한다양한의견이제기되고있다. 어떤경구혈당강하제를우선선택해야하는지, 이후어떤약제를추가해야하는지에대해아직완전한결론에이르지못했다. 또한여러임상적상황에각각어떤약제의선택이합리적인지에대해서도아직충분한합의에도달하지못했다. 하지만임상적으로 어떤약제로혈당을조절해야하는지 보다 어떤목표까지혈당을조절해야하는지 가더욱중요한의미를가진다 [18]. 혈당과당화혈색소가목표에도달하지않더라도그개선정도에따라환자의예후를유의하게개선시킬수있다 [3]. 2. 메트포르민국내외주요당뇨병진료지침에서당뇨병환자의초기치료를위한경구혈당강하제로메트포르민을권고한다 [9,18-21]. 메트포르민은우수한혈당감소효과, 비교적적은부 16

3 이상열 작용, 장기간확인된안전성, 낮은저혈당위험, 적은체중증가등의이유로제2형당뇨병환자의첫선택약제로권고된다. 이러한권고는과체중인제2형당뇨병환자에서메트포르민단독요법이설폰요소제나인슐린단독요법과비교하여혈당강하효과는유사하면서체중증가와저혈당발생이적었다는코호트연구에근거한다 [22]. 잠재적심혈관질환예방효과도메트포르민을 1차치료제로선택하는이유에포함된다 [22,23]. 하지만메트포르민의심혈관질환예방효과에대해서는아직확고한결론에이르지못했다. 이후발표된여러관찰연구와메타분석에서도설폰요소제나티아졸리딘디온, dipeptidyl peptidase-4 (DPP-4) 억제제와비교하여당화혈색소감소, 부작용, 체중증가, 저혈당발생, 경제성, 심혈관질환발생등다양한측면에서메트포르민이초기경구약제로우선선택될수있는근거가확인되었다 [24-27]. 국내다기관임상연구결과에서도메트포르민단독요법의당화혈색소개선효과는설폰요소제또는티아졸리딘디온단독요법의효과와유사하였다 [28]. 이상의근거에따라본진료지침에서도제2형당뇨병환자의초기치료를위한경구혈당강하제로메트포르민을우선권고하였다. 중증간장애나신장애 (estimated glomerular filtration rate 기준 60 ml/min/1.73 m 2 미만시주의, 30 ml/ min/1.73 m 2 미만시금기 ), 중증감염, 탈수, 심폐부전등의임상적상황은메트포르민사용의금기에해당되어사용에주의가필요하다 [18,20]. 최근, 메트포르민사용이비타민 B12 결핍및빈혈과관련되어있다는연구가소개되었다 [29]. 따라서말초신경장애또는빈혈이동반된메트포르민사용자에게비타민 B12 측정을고려할수있다. 3. 메트포르민외다른경구혈당강하제메트포르민사용이금기이거나, 사용에어려움을경험하는환자에게메트포르민대신다른혈당강하제단독사용을고려한다. 최근새로운작용기전을가진약제가출시되어임상에서다양한경구혈당강하제사용이가능하다 (Table 1) [1]. 이들약제는작용기전이서로다를뿐만아니라부작용, 금기, 가격등의측면에서다양한차이를가진다. DPP-4 억제제는단독사용시저혈당발생이드물고, 부작용발생위험이낮아, 노인, 만성콩팥병환자등메트포르민단독사용이어려운환자의대체제로최근널리활용되고있다. 최근다른인종에비해아시아인의 DPP-4 억제제효과가우수하다는일부근거가제시되었다 [30]. 일부 DPP-4 계열약제에서심부전위험을증가시킨다는결과가확인되었으나, 체계적문헌고찰결과그위험이현저하지않고, 각약제별차이가존재하는것으로보인다 [31,32]. Sodium-glucose cotransporter 2 억제제는대규모임상연구에서당뇨병환자의심혈관질환위험과사망률을유의하게감소시키는결과를보여최근그사용빈도가증가하고있다 [33-35]. 하지만아직장기임상경과에대한연구결과가존재하지않고, 비뇨생식계감염, 탈수, 저혈압등의부작용발생가능성이있어노인, 만성콩팥병환자등일부대상자에서사용상주의가필요하다. 설폰요소제, 메글리티나이드, 티아졸리딘디온, α-glucosidase 억제제등기존에널리활용되고있는여러계열의약제역시단독요법의효과와안전성에대한다양한근거를확보하여메트포르민의효과적인대체제로사용가능하다 [27,36-38]. 결론 당뇨병치료는개인의필요성및선호도에따라개별화되어야하며, 약제는각약제의특이적장단점을고려하여선택되어야한다 [9]. 합리적인약제선택을위해나이, 당화혈색소, 공복및식후혈당, 비만또는대사증후군동반여부, 인슐린분비능, 저혈당발생위험, 간, 심장또는신장기능이상여부, 환자의선호도등다양한임상적상황을함께고려해야한다. 특히환자의임상경과에유의한영향을미칠수있는위험인자인체중증가에관심을가져야한다. 여러약제가체중증가를유발할수있어, 식사와운동을포함한생활습관개선이계속강조되어야한다. 17

4 Table 1. Oral antihyperglycemic agents for patients with type 2 diabetes mellitus used in Korea Biguanide (metformin) Sulfonylurea (gliclazide, glipizide, glimepiride, glibenclamide) Meglitinide (repaglinide, nateglinide, mitiglinide) DPP-4 inhibitor (sitagliptin, vildagliptin, saxagliptin, linagliptin, gemigliptin, alogliptin, teneligliptin, anagliptin) Thiazolidinedione (pioglitazone, lobeglitazone) SGLT-2 inhibitor (dapagliflozin, ipragliflozin, empagliflozin) α-glucosidase Inhibitor (acarbose, voglibose) Mechanism and common use Weight gain Hepatic glucose Neutral or production Start with lower decrease dose and titrate upward slowly Insulin secretion from β-cells Before meal Insulin secretion from β-cells, postprandial hyperglycemia Before each meal Postprandial incretin (GLP-1, GIP), glucosedependent insulin secretion, postprandial glucagon secretion, postprandial hyperglycemia, use regardless of mealtime Insulin sensitivity (muscle, adipose tissue), hepatic glucose production, once daily regardless of mealtime Renal glucose reabsorption, glucosuria Once daily regardless of mealtime Upper intestinal glucose absorption, postprandial hyperglycemia Before each meal Hypoglycemia a HbA1c reduction Side effects Caution (%) a No 1.0~2.0 GI side effects (anorexia, nausea, vomiting, diarrhea, cramping), vitamin B12 deficiency, lactic acidosis (rare) Contraindication in severe hepatic or renal insufficiency (egfr < 30 ml/min/1.73 m 2 ), severe infection, dehydration, heart failure. Major operation or iodine-contrast use within 48 hours Yes Yes 1.0~2.0 Severe hepatic or renal insufficiency, secondary failure Yes Yes 0.5~1.5 Severe hepatic or renal insufficiency No No 0.5~1.0 Angioedema, urticaria Acute pancreatitis Risk for heart failure (saxagliptin, alogliptin) Yes No 0.5~1.4 Edema, anemia, bone fracture, heart failure No No 0.5~1.0 Genitourinary tract infections, polyuria, dehydration, DKA No No 0.5~1.0 GI side effects (flatulence, diarrhea, bloating) Dose titration in severe hepatic or renal insufficiency Heart failure, severe hepatic or renal insufficiency Old age, heart failure, hypotension, diuretics use, not for severe CKD (egfr < 60 ml/min/1.73 m 2 ) Severe hepatic or renal insufficiency, chronic inflammatory bowel disease with malabsorption, severe infection Adapted from the article of Ko et al. Diabetes Metab J 2017;41: [1]. HbA1c, glycosylated hemoglobin; GI, gastrointestinal; egfr, estimated glomerular filtration rate; DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide 1; GIP, gastric inhibitory polypeptide; SGLT2, sodium-glucose cotransporter 2; CKD, chronic kidney disease; DKA, diabetic ketoacidosis. a Monotherapy. 18

5 이상열 감사의글 이원고는대한당뇨병학회에서발간하는 Diabetes & Metabolism Journal 학회지에수록된 Monotherapy in Patients with Type 2 Diabetes Mellitus (Diabetes Metab J 2017;41:349-56) 의내용을바탕으로재구성한것입니다. 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: Rhee SY, Kim HJ, Ko SH, Hur KY, Kim NH, Moon MK, Park SO, Lee BW, Choi KM, Kim JH; Committee of Clinical Practice Guideline of Korean Diabetes Association. Monotherapy in patients with type 2 diabetes mellitus. Diabetes Metab J 2017;41: UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352: Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008;359: Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME, Byington RP, Goff DC Jr, Bigger JT, Buse JB, Cushman WC, Genuth S, Ismail- Beigi F, Grimm RH Jr, Probstfield JL, Simons-Morton DG, Friedewald WT. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358: ADVANCE Collaborative Group, Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, Marre M, Cooper M, Glasziou P, Grobbee D, Hamet P, Harrap S, Heller S, Liu L, Mancia G, Mogensen CE, Pan C, Poulter N, Rodgers A, Williams B, Bompoint S, de Galan BE, Joshi R, Travert F. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358: Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, Zieve FJ, Marks J, Davis SN, Hayward R, Warren SR, Goldman S, McCarren M, Vitek ME, Henderson WG, Huang GD; VADT Investigators. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009;360: Ismail-Beigi F, Moghissi E, Tiktin M, Hirsch IB, Inzucchi SE, Genuth S. Individualizing glycemic targets in type 2 diabetes mellitus: implications of recent clinical trials. Ann Intern Med 2011;154: Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, Peters AL, Tsapas A, Wender R, Matthews DR. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2015;38: Look AHEAD Research Group, Wing RR, Bolin P, Brancati FL, Bray GA, Clark JM, Coday M, Crow RS, Curtis JM, Egan CM, Espeland MA, Evans M, Foreyt JP, Ghazarian S, Gregg EW, Harrison B, Hazuda HP, Hill JO, Horton ES, Hubbard VS, Jakicic JM, Jeffery RW, Johnson KC, Kahn SE, Kitabchi AE, Knowler WC, Lewis CE, Maschak-Carey BJ, Montez MG, Murillo A, Nathan DM, Patricio J, Peters A, Pi-Sunyer X, Pownall H, Reboussin D, Regensteiner JG, Rickman AD, Ryan DH, Safford M, 19

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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