2012 개원의와함께하는임상강좌 인슐린치료의기초 경희대학교의과대학내분비대사내과학교실 이상열 1922 년 1 월 22 일오전 11 시 Textbook of Diabetes, 4 th ed. Insulin Therapy Milestones Textbook of Diabetes, 4 th ed. 2012 개원의와함께하는임상강좌
특집 : 당뇨병환자의인슐린치료 Responses to Pharmacologic Treatment With Oral Agents Decrease in FBG (mg/dl) A1C ( from baseline) ulphonylureas 40-60 1.0-2.0% Repaglinide/nateglinide 30.3 1.1% Metformin 53 1.4% Rosiglitazone (across dose range) 25-55 0.1-0.7% Pioglitazone 20-55 0.3-0.9% α-glucosidase inhibitors 20-30 0.5-1.0% In contrast, insulin can be customised without dose limit to achieve target *FBG, fasting blood glucose. Adapted from Feld. Endocr Pract. 2002;8(suppl 1):41-82. 2 형당뇨병환자에서인슐린치료의적응증 KNDP 인슐린치료지침, 2011 순서 인슐린종류와작용기전속효성인슐린지속형인슐린혼합형인슐린 인슐린사용의실제인슐린사용법, 관리 2012 개원의와함께하는임상강좌
이상열 : 인슐린의종류와특징 인슐린종류와기전 2012 개원의와함께하는임상강좌
특집 : 당뇨병환자의인슐린치료 Normal Plasma Insulin Profile Incremental prandial insulin secretion Plasma levels Endogenous insulin Continuous basal insulin secretion Breakfast Lunch Dinner Time of day Adapted from McCall AL. In: Leahy JL, Cefalu WT, eds. Insulin Therapy. New York, NY: Marcel Dekker, Inc; 2002:193-222. Properties of Insulin Preparations Preparation Onset, h Peak, h Effective Duration, h hort-acting Aspart <0.25 0.5-1.5 3-4 Glulisine <0.25 0.5-1.5 3-4 Lispro <0.25 0.5-1.5 3-4 Regular 0.5-1.0 2-3 4-6 Long-acting Detemir 1-4 - a Up to 24 Glargine 1-4 - a Up to 24 NPH 1-4 6-10 10-16 Insulin combinations 75/25-75% protamine lispro, 25% lispro <0.25 1.5 h Up to 10-16 70/30-70% protamine aspart, 30% aspart <0.25 1.5 h Up to 10-16 50/50-50% protamine lispro, 50% lispro <0.25 1.5 h Up to 10-16 70/30-70% NPH, 30% regular 0.5-1 Dual b 10-16 a Glargine and detemir have minimal peak activity b Dual: two peaks one at 2-3 h and the second one several hours later. Human insulins do not closely match the endogenous insulin response Adapted from: Polonsky et al. J Clin Invest 1988;81:442 8 2012 개원의와함께하는임상강좌
이상열 : 인슐린의종류와특징 Insulin analogues address the limitations of human insulin Adapted from: Polonsky et al. J Clin Invest 1988;81:442 8 ( 초 ) 속효성인슐린 Regular Insulin 휴물린알 Insulin Lispro (Eli Lilly, 휴마로그 ) Insulin Aspart (Novo Nordisk, 노보래피드 ) Insulin Glulisine (anofi-aventis, 애피드라 ) tructure of Insulin Lispro A-chain 1 21 1 B-chain B28 LY B29 PRO 30 [Lys (B28), Pro (B29)] - Human Insulin Analog (recombinant DNA origin) 2012 개원의와함께하는임상강좌
특집 : 당뇨병환자의인슐린치료 tructure of insulin aspart Pro Asp Phe Phe Gly Arg Tyr Thr Asp Lys B28 B30 Thr A21 Asn Cys Tyr Gly Asn Ile Glu Val Leu Glu Gln Gln Tyr Cys Leu Cys Thr er er Ile Cys Glu Gly Cys Val Leu Tyr Leu Ala Glu Val Leu His er B1 Phe Val Asn Gln His Leu Cys Gly tructure of Glulisine Insulin glulisine differs from human insulin in that the amino acid asparagine at position B3 is replaced by lysine and the lysine in position B29 is replaced by glutamic acid. This is responsible for glulisine s more rapid absorption. 2012 개원의와함께하는임상강좌
이상열 : 인슐린의종류와특징 hort acting insulin analogues - time action profile - Initial assessment in 16 healthy subjects 0.3 IU/Kg C : Exogenous insulin concentration 초속효성인슐린유사체가 RI 에비해정말좋은걸까? Cochrane review, 2006 8,274 participants, 49 RCT only a minor benefit of short acting insulin analogues in the majority of diabetic patients treated with insulin No data for possible long-term effects 2012 개원의와함께하는임상강좌
특집 : 당뇨병환자의인슐린치료 초속효성인슐린유사체가 RI 에비해정말좋은가? Weighted mean differences 95% CI T1DM 1) HbA1c -0.1% (analogue favor) -0.2 to -0.1 CII -0.2% -0.3 to -0.1 Conventional insulin therapy -0.1% -0.1 to 0.0 2) hypoglycemia/pts/months -0.2-1.1 to 0.7 3) incidence of severe hypoglycemia T2DM RI: 46.1/100-py Analogue: 21.8/100-py 1) HbA1c 0.0% -0.1 to 0.0 2) hypoglycemia/pts/months -0.2-0.5 to 0.1 3) incidence of severe hypoglycemia RI: 1.4/100-py Analogue: 0.3/100-py 지속형인슐린 NPH (neutral protamine Hagedorn) 노보렛엔, 인슈라타드이노렛, 휴물린엔 Insulin Glargine (anofi-aventis, 란투스 ) Insulin Detemir (Novo Nordisk, 레버미어 ) Limitations of NPH: a relatively short action profile with a peak GIR, glucose infusion rate; GIR curves adapted from references; NPH, neutral protamine Hagedorn 2012 개원의와함께하는임상강좌
이상열 : 인슐린의종류와특징 Limitations of NPH: an action profile with variability, injection to injection Heise et al. Diabetes 2004;53:1614 20 Insulin Glargine A-chain A21 Asn Gly 1 1 B-chain 21 30 - Recombinant DNA technology - Asparagine at position A21 replaced by glycine : Provides stability - Addition of 2 arginines at the C-terminus of the B chain : oluble at slightly acidic ph (ph 4.0) B31, 32 Arg McKeage K et al. Drugs. 2001;61:1599-1624. Mechanism of Action: Glargine Injection of an acidic solution (ph 4.0) Microprecipitation of insulin glargine in subcutaneous tissue (ph 7.4) low dissolution of free insulin glargine hexamers from microprecipitates (stabilized aggregates) Protracted action Clear olution ph4 Dissolution Hexamers 10-3 M Capillary Membrane Insulin in Blood ph 7.4 Precipitation Dimers Monomers 10-5 M 10-8 M 1. Wang F, et al. Clin Ther 2003 Jun 1;25(6): 1541-1577 2. Home PD;Ashwell G, Diabetes Metab Res Rev 2002;18(uppl 3): 57-63 3. Lepore M et al. Diabetes Care 2000;49: 2142-2148 4. Mckeage K, Goa KL. Drugs.2001;61(11):1599-1624 5. Adapted from LANTU EMEA ummary of product characteristics 6. John R et al, Postgraduate Medicine 2003;113: no.6 2012 개원의와함께하는임상강좌
특집 : 당뇨병환자의인슐린치료 Insulin Pharmacodynamics NPH vs Ultralente vs Glargine vs CII mg/kg/min C insulin 4.0 3.0 NPH 2.0 1.0 Ultralente CII N=20T1DM Mean ±EM 24 20 16 12 8 4 µmol/kg/min 0 Glargine 0 4 8 12 16 20 24 Time (h) 0 Lepore M et al. Diabetes. 2000;49:2142-2148. Plasma Glucose Concentrations After C Injection of NPH, Ultralente, Glargine and CII 220 C insulin N=20T1DM Mean ±EM 12 mg/dl 200 180 160 140 NPH Ultralente Glargine 11 10 9 8 mmol/l 120 CII 7 0 4 8 12 16 20 24 Time (h) Lepore M et al. Diabetes. 2000;49:2142-2148. The structure of insulin detemir monomer Whittingham. Biochemistry 1997;36:2826 2012 개원의와함께하는임상강좌
이상열 : 인슐린의종류와특징 Insulin detemir: a unique mechanism of protraction Basal insulin analogues detemir and glargine share similar action profiles Bock. Diabetologia 2008;51(uppl. 1):Abstract 968 Basal insulin analogues share a similar action profile in type 1 and 2 diabetes Klein et al. Diabetes Obes Metab 2007;9:290 9 2012 개원의와함께하는임상강좌
특집 : 당뇨병환자의인슐린치료 Implications of reproducibility: a more predictable BG-lowering effect BG, blood glucose; GIR, glucose infusion rate; NPH, neutral protamine Hagedorn Heise et al. Diabetes 2004;53:1614 20 지속형인슐린유사체가 NPH 에비해정말좋은걸까? Meta analysis, 2009 6,178 (3,693 analogues / 2,485 NPH) T1DM pts 20 RCTs small effect on HbA1c also reduced the risk of nocturnal and severe hypoglycaemia Monami et al, DOM, 2009. 지속형인슐린유사체가 NPH 에비해정말좋은걸까? Monami et al, DOM, 2009. 2012 개원의와함께하는임상강좌
이상열 : 인슐린의종류와특징 지속형인슐린유사체가 NPH 에비해정말좋은걸까? Monami et al, DOM, 2009. 지속형인슐린유사체가 NPH 에비해정말좋은걸까? Meta analysis, 2008 5,735 (3,188 analogues / 2,547 RI) T2DM pts 14 RCTs does not seem to provide a better glycemic control in comparison with NPH insulin reduces the risk of nocturnal and symptomatic hypoglycemia Monami et al, DRCP, 2008. 지속형인슐린유사체가 NPH 에비해정말좋은걸까? Monami et al, DRCP, 2008. 2012 개원의와함께하는임상강좌
특집 : 당뇨병환자의인슐린치료 Premixed Insulin 기존인슐린혼합형 (RI + NPH) RI (30%) + NPH (70%) ( 휴물린, 믹스타드이노렛 ) 인슐린유사체혼합형 Lispro base ( 휴마로그믹스, 50%, 25%) Aspart base ( 노보믹스, 30%, 50%, 70%) Main insulin regimens : ultimate step Benefits of dual-release insulin replacement Mimics physiological insulin release Early release of rapid-acting insulin targets postprandial glucose Delayed release of intermediate-acting insulin fulfils basal insulin requirement Reduces hypoglycaemic risk < Conventional premix Improves HbA 1c in combination with oral medications implifies dosing Option of postprandial dosing 2012 개원의와함께하는임상강좌
이상열 : 인슐린의종류와특징 혼합형유사체제제가기존혼합형제제에비해효과적인가? Gough, DRCP, 2007. Practical Insulin Usage 인슐린제제 바이알 2012 개원의와함께하는임상강좌
특집 : 당뇨병환자의인슐린치료 인슐린제제 RI, NPH based, 펜 인슐린제제 속효성유사체단독, 펜 인슐린제제 지속형유사체단독, 펜 2012 개원의와함께하는임상강좌
이상열 : 인슐린의종류와특징 인슐린제제 유사체혼합형, 펜 인슐린의보관 개봉하지않은바이알, 펜 냉장보관 개봉 ( 사용 ) 인슐린 실온에서 1 개월유효 사용전확인할사항유효기간? 불순물 / 변질여부확인 비행기여행시반드시기내에가지고탑승 KNDP 당뇨병이해와관리, 2007 인슐린주사방법 실제인슐린사용연습이가능하도록부스에준비해두었습니다. KNDP 당뇨병이해와관리, 2007 2012 개원의와함께하는임상강좌
특집 : 당뇨병환자의인슐린치료 30G, 8 mm vs. 31G, 5 mm 인슐린흡수율에영향을미치는요인 운동 혈액순환속도, 인슐린흡수속도 예 : 허벅지에주사를맞고다리운동을한다면? 주사부위 복부 > 상완 > 대퇴 > 둔부 주사깊이 근육주사는흡수율 열 주사후사우나목욕등 혈액순환 마사지 주사부위를문지르지않는다 KNDP 당뇨병이해와관리, 2007 인슐린주사부위및교환순서 KNDP 당뇨병이해와관리, 2007 2012 개원의와함께하는임상강좌
이상열 : 인슐린의종류와특징 Recommended technique for the subcutaneous injection of insulin 5-12 mm Textbook of Diabetes, 4 th ed. 주사통증경감법 알코올이완전히마른후주사 알코올 통증 15 분정도실온보관후주사 차가운인슐린 통증 주사전공기방울완전제거 부정확한용량가능성, 통증 피부를빨리찌른다 찌르거나뺄때방향을바꾸지않는다 KNDP 당뇨병이해와관리, 2007 요약 및결론 2012 개원의와함께하는임상강좌
특집 : 당뇨병환자의인슐린치료 요약및결론 인슐린은당뇨병치료에서가장중요한치료방법의하나이다. 인슐린을이용한다양한치료방법이계속발전하고있다. 기존인슐린의단점이보완된다양한인슐린유사체가개발되었다. 요약및결론 인슐린유사체가기존인슐린에비해임상적으로효과적이라는근거는아직충분하지않다. 올바른인슐린사용을위해몇가지숙지해야할사항이있다. 2012 개원의와함께하는임상강좌