효과적인경구혈당강하제의조합은? 대한당뇨병학회제 17 차연수강좌 ( ) 가천의대길병원내분비대사내과

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1 효과적인경구혈당강하제의조합은? 대한당뇨병학회제 17 차연수강좌 ( ) 가천의대길병원내분비대사내과 박이병

2 내용 배경 경구혈당강하제의병합이왜필요한가? (WHY?) 경구혈당강하제의병합은언제시작하나? (WHEN?) 경구혈당강하제의병합은어떻게하는것이좋은가?(HOW) 맺음말

3 배경 : drugs for treating diabetes In 1995 : sulfonylureas, insulin Currently 11 classes : sulfonylureas, meglitinides, glucagon-like like peptide-1 (GLP-1) receptor agonists, biguanides, amylin analogue, thiazolidinediones, bromocriptine, alpha-glucosidase inhibitors, dipeptidyl peptidase-4 4(DPP4) (DPP-4) inhibitors, colesevalam l (a bile-acid id sequestrant), and insulins Newer agents : more costly, some are only approved as adjunctive Combination pattern - 5.6% during during % taking three or more classes

4 경구혈당강하제의병합이왜 필요한가? (WHY)

5 UKPDS 10-Year Follow-up 10-Year Follow-up of Intensive Glucose Control in Type 2 Diabetes Rury R. Holman, F.R.C.P., Sanjoy K. Paul, Ph.D., M. Angelyn Bethel, M.D., David R. Matthews, F.R.C.P., and H. Andrew W. Neil, F.R.C.P. UKPDS 80 (N Engl J Med 2008;359; ) N Engl J Med 2008, 359:

6 조기혈당조절의 Legacy Effect UKPDS 연구종료후연장된추적관찰에서심근경색의위험과모든원인으로인한사망을줄이는것으로나타남 시험완료 8.5년 ( 중앙값 ) 후추적관찰시 모든종말점 모든당뇨병관련종말점 RRR: 12% 9% p: 미세혈관질환 RRR: 25% 24% p: 심근경색 RRR: 16% 15% p: 모든원인사망율 RRR: 6% 13% p:

7 복합위험인자치료 (Steno-2) :13 년추적관찰 Glycate edbin Hemoglob (%) 전통치료 집중치료 Chol /dl) Total (mg/ 300 전통치료 집중치료 lic BP mhg) Systo (mm 전통치료 집중치료 Chol g/dl) LDL (mg 전통치료 집중치료 Diast tolic BP (mm mhg) 전통치료 Trigly ycerides (mg g/dl) 집중치료 100 집중치료 추적관찰 ( 년 ) 추적관찰 ( 년 ) 전통치료 Gaede P et al. N Engl J Med 2008;358:

8 복합위험인자치료 (Steno-2) 5년의추적관찰기간중두군모두에서유사한복합위험인자관리가이루어졌으나, 임상적이익은이전에집중치료를받은환자들에서만증가되었음 사망의누적적발생률 (%) 위험군환자집중치료 80 전통치료 P = 0.02 P < 전통치료 추적관찰 ( 년 ) 집중치료 모든심혈관질환의누적발생률 (%) 위험군환자집중치료 80 전통치료 80 전통치료 집중치료 추적관찰 ( 년 ) Gaede P et al. N Engl J Med 2008;358:

9 Intensive control may reduce diabetic complications (meta-analysis) analysis) UKPDS PROactive ADVANCE VADT ACCORD 33,040 patients, follow-up 4.95 years Duration of T2DM 8 years mean HbA1c 7.8% at baseline 6.6%(INT) VS. 7.5%(STD) after follow-up Intensive glucose control : 17% reduction in non-fatal myocardial infarction : 15% reduction in coronary heart disease : 7% reduction in stroke (NS) : no increase on all-cause mortality Lancet 2009; 373:

10 Exposal of hyperglycemia may increase risk of diabetic complications cat o VADT in the context of the natural history of Type 2 diabetes Method: Intensive treatment (HbA1c < 6%) vs. conventional treatment (HbA1c < 9%) Stefano Del Prato : th ADA. Treatment - When Do We Start? What Do We Attack?

11 Early and Intensive treatment ACCORD, ADVANCE, VADT in 2008 Prematurely terminated UKPDS 10 year follow-up in 2008 Legacy effect The meta-analysis in % risk reduction of CV event & no effect on mortality Diabetes & Metabolism 36 (2010) 86 87

12 경구혈당강하제의병합은언제 시작하나? (WHEN)

13 Decline in β-cell function is associated with loss of glycemic control 9 Conventional HbA 1c (%) 8 7 Intensive % = normal range of HbA 1c Years from randomization UKPDS 33. Lancet 1998; 352:

14 ADOPT - HbA1c over time Rosiglitazone vs Metformin (-0.22 to -0.05), P=0.002 Rosiglitazone vs Glyburide ( to -0.33), P<0.001 NEJM 2006, 355,

15 The Practical Evidence of Antidiabetic Monotherapy Study (PEAM) : monotherapy in Drug-Naïve in Korea Diabetes Metab J Feb;35(1):26-33.

16 Earlier Use of Combination Therapy may achieve e target goal 10 Diet and exercise OAD* monotherapy Early combination approach OAD combinations OAD up-titration OAD + basal insulin Hb ba 1c (%) 9 8 OAD + multiple daily insulin injections 7 6 Duration of diabetes Del Prato S et al Int J Clin Pract 2005;59:

17 Control Hyperglycemia Needs for Early Combination Evidence based Medicine

18 대한당뇨병학회권고안 HbA1c 목표 < 6.5% 치료적생활습관교정 < 8.0% % > 10% 단독요법 * 조기병합요법또는인슐린요법 2~6 개월내목표에도달하지못하면 인슐린요법 + 경구혈당강하제 다른약제추가 3 제요법 인슐린추가다요소인슐린요법 ± 경구혈당강하제 * 1차치료 : 메트포르민을우선권하나환자의특성에따라다른약제선택도가능 ( 설폰요소제, DPP-4 억제제, 티아졸리딘디온, 알파글루코시다아제억제제, 메글리티나이드 ) 2차치료 : GLP-1 analogue 대한당뇨병학회, 당뇨병진료지침 2011

19 제2형당뇨병에서고혈당의관리 : 치료시작과조절에대한컨센서스알고리즘 미국당뇨병학회 (ADA)(7% 이하 ) 와유럽당뇨병학회 (EASD) 의 Consensus Statement Tier 1: 진단시 충분히입증된핵심치료법 생활습관 + metformin + 기저인슐린 생활습관 + metformin + 강화인슐린 생활습관 + metformin 생활습관 + metformin + Sulfonylurea 1 단계 2 단계 3 단계 Tier 2: 충분히입증되지않은치료법 생활습관 + metformin + pioglitazone 생활습관 + metformin + GLP- 1 agonist 생활습관 + metformin + pioglitazone + Sulfonylurea 생활습관 + metformin + 기저인슐린 Nathan DM et al. Diabetes Care 2009;32:

20 Glycemic Control Algorithm, Endocr Pract. 2009;15(No )

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23 경구혈당강하제의병합은어떻게 시작하나? (HOW)

24 *Comparison with hypoglycemic drugs Monotherapy vs. monotherapy Monotherapy vs. combination Combination vs. combination - HbA1c - weight - lipid profile - hypoglycemia and side effects - C-V risk and mortality, etc.

25 Combination vs. combination

26 Monotherapy versus Monotherapy Most oral diabetes medications had similar efficacy in achieving reductions in HbA1c, with absolute reduction by around 1 percent compared with baseline values. ADOPT

27 Combination Therapy versus Monotherapy All combination therapies were better at reducing HbA1c than monotherapy regimens, with between-group differences of about 1 percent. The strength of evidence was graded high for metformin versus metformin plus thiazolidinediones, and metformin versus metformin plus sulfonylureas, and graded moderate for metformin versus metformin plus DPP-4 inhibitors.

28 Combination Therapy Versus Combination Therapy The combination of metformin + thiazolidinedione had similar efficacy in reducing HbA1c compared to the combination of metformin + sulfonylurea, with moderate strength of evidence. Nine other combination therapy comparisons had low strength of evidence, making it difficult to draw firm conclusions. However, the majority showed similar efficacy in reducing HbA1c. Five combinations showed similar efficacy in reducing HbA1c: 1) metformin + repaglinide vs. metformin + thiazolidinedione, 2) metformin + sitagliptin vs. metformin + thiazolidinedione, 3) metformin + sulfonylurea vs. metformin + DPP-4 inhibitor, 4) metformin + thiazolidinedione vs. metformin + GLP-1 agonist, 5) metformin + GLP-1 agonist vs. metformin + basal insulin

29 경구혈당강하제선택에있어서고려사항 환자의연령 ( 여명, 저혈당의위험성 ) 동반질환, 합병증 당뇨병진단시기 현재혈당조절상태 약제별작용기전및장단점 경제적측면 부작용없이혈당조절 * 보험기준에준용해서처방은당연필수!

30 경구혈당강하제의병합요법 다른계열의약제를추가 약제의작용기전을고려 조절중당화혈색소가 65% 6.5% 를초과하면 2 차 ( 또는 3 차 ) 약제를추가 진단당시당화혈색소가 8% 를초과하면조기에병합요법을고려 병합요법실패시인슐린치료가추천되나환자의특성과상황에따라약제변경, 3제병합요법도고려해볼수있다.

31 경구혈당강하제의특성

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34 다양한병합요법 (1) 설폰요소제와메트포르민 - 인슐린분비능및인슐린감수성동시에개선 식후고혈당이문제될경우 : meglitinide, a-glucosidase inhibitor, GLP-1 receptor agonist나 DPP IV inhibitor의추가 설폰요소제 + 알파글루코시데이즈억제제 : 설폰요소제사용하면서 식후만조절이안될경우 비아나이드제 + 티아졸리딘디온계 : - 메트포르민단독요법으로혈당조절이잘되지않은경우, - 비만한환자나인슐린저항성이많은경우

35 다양한병합요법 (2) DPP IV inhibitor 의경우는다양한병합처방이가능 - 설폰요소제, 메트포민, 티이졸리딘디온계, 인슐린가병합가능 - DPP IV inhibitor + 메트포민병합 : 당화혈색소 1% 이상을감소, 저혈당없이체중을조절할수있으며베타세포의기능을보전하는등의다양한치료효과가증명되고있음 설폰요소제 + 메트포르민병합요법으로조절되지않은경우 - 알파글루코시다제억제제, 티아졸리딘디온계, DPP IV inhibitor 추가 설폰요소제 + 메글리티나이드 : 병용금기 메글리티나이드 + 알파글루코시다아제 : 작용기전을다르나둘다식후혈당조절을목표로하여병합하지말라는권고안도있으나환자에따라서병용가능함

36 다양한병합요법 (3) 부작용고려 저혈당이빈번한경우 : 설포닐요소제중단 소화기계부작용 : 메트포민, 알파글루코시데이즈억제제금지 비만, 심장질환동반된경우 : 티아졸린디온금지

37 고정복합제 설폰요소제 + 메트포르민 티아졸리딘디온 + 메트포르민 메트포르민 + DPP-4 억제제 * 최근에는 sitagliptin ti 과 simvastatin ti 의복합제 (Juvisync ) 미국 FDA 승인

38 맺음말 당뇨병합병증을예방하기위하여적절한혈당조절이필요하다. 혈당조절에적절하지못할경우, 경구혈당강하제를병합하거나조기에병합처방할수있다. 혈당강하제를병합할경우, 약제의특성과부작용등을고려해서처방한다. 보건복지부고시기준에맞게처방하는지혜가필요하다.

39 감사합니다!