경구당뇨병약제복합처방 2012. 7. 1 연세대학교의과대학내과학교실세브란스병원당뇨병센터강은석
Contents 1. 경구용당뇨병약제종류 2. 복합처방 3. 보험인정기준 4. 개발중인경구용당뇨병약제
당뇨병환자의증가 당뇨병환자 : 2005 년 185 만 8 천명 2009 년 214 만 6 천명 4 년간약 28 만 8 천명, 연평균 3.7% 증가총진료비 : 2005 년 3,030 억원 2009 년 4,463 억원 4 년간약 1,433 억원, 연평균 10.2% 증가 당뇨병치료제시장이성장하고있음 건강보험심사평가원 2010
1. 경구용당뇨병약제종류 소화효소억제 α-glucosidase inhibitor 당신생억제 Metformin 인슐린저항성개선 Thiazolidinediones 인슐린분비촉진 Sulfonylurea, Meglitinde, GLP-1, DPP4- 억제제 Adapted from De Fronzo RA. Diabetes 1988; 37:667 687.
Sulfonylurea ( 혈당에무관하게 ) 췌장베타세포에서인슐린분비증가
Sulfonylurea 장점신속한효과, 뛰어난혈당강하능력, 가격저렴 단점저혈당발생체중증가고인슐린혈증이차성설폰요소제실패 ( 원인 : 체중증가, 운동부족, 점진적인인슐린저항성의증가, 인슐린분비의결핍 )
Meglitinides 장점 빠른효과 (10 분이내작용시작 ) 짧은작용지속시간적은저혈당빈도식후혈당조절용이식사직전에복용식사를거를때는약을복용안한다. 저혈당적음신기능이상시사용가능 단점 상대적으로약한혈당강하능력체중증가저혈당유발가능하루에여러번복용해야함
말초조직에서인슐린효과증진 비만환자에서처음사용약제 공복혈당감소에효과적 체중증가가없음 단독요법시저혈당발생하지않음 심혈관위험율을감소시킴 지방간개선효과 Metformin 장점
부작용 : 소화불량, 오심, 구토, 금속맛, 복부팽만감, 설사 소량부터서서히증량 약의대부분이신장으로배설, 신기능이상시에는사용못함 극히드물게치명적인유산혈증유발가능 CT 촬영시일시중단해야함 Metformin 단점 PET 촬영시정상, 악성감별힘들게함
말초조직에서인슐린효과증진 내장지방감소 Glitazone (Pioglitazone) 낮은저혈당빈도 단독요법시저혈당발생하지않음 동맥재협착억제 작용 고혈압및지질치개선효과
혈당강하효과를나타내기까지오래걸린다. (4 주이후에효과 ) Glitazone (Pioglitazone) 수분저류, 부종, 체중증가 심부전시사용금기 인슐린과같이사용시주의 간기능검사필요 (?) 단점 단독요법보다병합요법이효과적
Glitazones??? Diabetic MacularEdema ( 황반부종 ) Bladder cancer? Acute MI Heart Failure Arch Intern Med. Published online June 11, 2012
Glitazone and Macular Edema
Kaplan-Meier time to diabetic macular edema (DME) curves according to TZD use with or without insulin. In a comparison of TZD use with nonuse, the HR was 5.19 (95% CI, 4.31-6.25).
Alpha Glucosidase Inhibitors 기전 : 소장에서포도당흡수억제, 지연사용방법 : 매식사직전복용 특징 : 식후급격한혈당상승억제효과, 식후고혈당에효과 장점 : 저혈당, 체중증가없음. 혈청지질농도에영향이없음단점 : 평균혈당강하능이낮음. 부작용 : 위장증상 ( 복부팽만, 방귀, 설사 ) 소화기계증상금기 : 염증성장질환, 신기능장애시금기
GLP-1 and DPP4 Inhibitors T2DM Incretin response diminished Insulin Further impaired islet function Glucagon Hyperglycemia DPP-4 inhibitor Incretin activity prolonged Insulin Improved islet function Glucagon Improved glycemic control DPP-4=dipeptidyl peptidase-4; T2DM=type 2 diabetes mellitus Adapted from Unger RH. Metabolism. 1974; 23: 581 593. Ahrén B. Curr Enzyme Inhib. 2005; 1: 65 73.
DPP-4 Inhibitors and Body Weight kg Vildagliptin Glimepiride Between-group difference: 1.5 kg( p<0.001) Diabetes, Obesity and Metabolism 12: 780 789, 2010.
DPP-4 Inhibitors and Hypoglycemia patients experienced hypoglycaemia (%) 2.3% vs. 18.2% the number of hypoglycaemic events Vildagliptin+met Glimepiride+met 59 vs. 838 14 배 Diabetes, Obesity and Metabolism 12: 780 789, 2010.
Sitagliptin DPP-4 억제제공통특징혈당에의존적인인슐린분비촉진혈당이높을때만인슐린분비단독또는병합, 인슐린병합가능체중증가없음. 저혈당없음. Sitagliptin FDA approved on October 17, 2006 신기능저하시약물감량 ½, 1/4
Sitagliptin and Beta cell function 0.55 Proinsulin/insulin ratio 80 HOMA-β 75 0.5 70 Ratio (pmol/l / pmol/l) 0.45 0.4 0.35 p< 0.001* 65 60 55 50 45 40 p< 0.001* 35 0.3 Placebo Sitagliptin 100 mg 30 Placebo Sitagliptin 100 mg from baseline vs pbo = 0.078 (95% CI -0.114, -0.023) Hatched = Baseline Solid = Week 24 from baseline vs pbo = 13.2 (95% CI 3.9, 21.9) Raz I et al. Diabetologia 49:2564-2571, 2006, Aschner P et al. Diabetes Care 29:2638-2643, 2006
Sitagliptin Monotherapy in Korean 0.8 Placebo 0.6 Sitagliptin 0.4 Mean change of A1C from baseline(%) 0.2 0-0.2-0.4-0.6 Sitagliptin vs. placebo = -1.37% -0.8-1 0wks 6wks 12wks 18wks Yang et al. DRCP 2008 Group Sita (n=62) Plbo (n=31) Placebo Subtracted mg/dl FPG Placebo Subtracted mg/dl PPG -54.5-90.6
Vildagliptin and Insulin Resistance 0.8 HOMA-IR 0.7 0.6 0.5 0.4 0.3 0.2 0.1 * 0 Vildagliptin Glimepiride * P<0.001 between the groups Diabetes care 2010, 33, 730-2
Vildagliptin & Glucose Fluctuation MAGE Vildagliptin n = 20 Sitagliptin n = 18 100 * P <0.01 100 69 ± 18 80 70 ± 22 80 59 ± 16 MAGE (mg/dl) 60 40 20 34 ± 7 MAGE (mg/dl) 60 40 20 0 0 At baseline After 3 mo treatment At baseline After 3 mo treatment Patients were prior inadequately controlled by metformin max dose (3000 mg/d) and randomized to treat with either Vildagliptin 50 mg bid or Sitagliptin 100 OD on to metformin over a period of 3 mo. CSGM shows large MAGE decrements in the vildagliptin group compared with Sitagliptin group J Diabetes Complications. 2010 Mar-Apr;24(2):79-83
Saxagliptin and CV safety 5 Time to onset of first primary Major Adverse Cardiovascular Event (MACE) First adverse event (%) 4 3 2 1 Control All saxagliptin 0 0 24 37 50 63 76 89 102 115 128 Weeks Patients at risk Control 1251 935 860 774 545 288 144 123 102 57 All Saxagliptin 3356 2615 2419 2209 1638 994 498 436 373 197 Experience in patients with congestive heart failure of NYHA class I II is limited and there is no experience in clinical studies with saxagliptin in NYHA class III IV Frederich R, et al. Postgrad Med. 2010;122(3):16-27.
Linagliptin in Korean Patients
Linagliptin Could Reduce Albuminuria -29% p < 0.05 Addition of linagliptinsignificantly lowered albuminuriain patients with diabetic nephropathy ADA 2012, 953-P
Linagliptin and CV risk
Renal Impairment 환자에서 DPP4 억제제비교 30 < Cr Cl< 50 Cr Cl< 30 ESRD Sitagliptin 100 mg 50 mg (1/2 알 ) 25 mg (1/4 알 ) 25 mg (1/4 알 ) Vildagliptin50 mg*2 50 mgqd 50 mgqd 50 mgqd With Close monitor Saxagliptin 5 mg 2.5 mg (1/2 알 ) 2.5 mg (1/2 알 ) 2.5 mg (1/2 알 ) Linagliptin 5mg Full dose Full dose Full dose Alogliptin ½ dose ¼ dose ¼ dose
Hepatic Impairment 환자에서 DPP4 억제제비교 Mild/moderate Severe Sitagliptin 100 mg 100mg Full dose Not recommended Vildagliptin 50 mg*2 Not recommended Not recommended Saxagliptin 5 mg use with caution Not recommended Linagliptin 5mg 100% Full dose 100% Full dose Alogliptin 100% Full dose Not recommended
Contents 1. 경구용당뇨병약제종류 2. 복합처방 3. 보험인정기준 4. 개발중인경구용당뇨병약제
경구용당뇨병약제병용처방현황 2011 약사신문 2011
경구용당뇨병약제병용처방현황 2011 약사신문 2011
당뇨병진단시약물투여 단독요법 FPG 126 mg/dl, 2PPG 200 mg/dl, 또는 A1c 6.5% Metformin 투여시작 Sulfonylurea: Metformin 을쓸수없을때바로투여가능 병합요법 A1c 7.5%: 바로병합요법가능 (Met+1 종또는 SU+1 종, Metformin 못쓰는소견서필요, DPP4 억제제병합가능 ) 인슐린요법 A1c 9.0% 처음부터바로인슐린투여가능 : T1DM 감별안될때, LADA, DKA, NKHOC, Stroke, AMI, Acute disease state, infection, pregnancy
초기요법 2-4 개월뒤 FPG 130 mg/dl 또는 2PPG 180 mg/dl 또는 A1c 7.0% Met 또는 SU 포함 2 종병합가능, 이외의조합은저가 1 종은환자부담 Met + SU + TZD + DPP4 억제제 SU + Met + TZD + DPP4 억제제 아래조합은환자저가 1 종부담 TZD + Meglitinide ( 환자부담 ) TZD + DPP4 inhibitor ( 환자부담 ) Meglitinde + agi ( 환자부담 )
2 제복합
Metformin+ Sulfonylurea Metformin+ Meglitinide Metformin+ a-gi Metformin+ Pioglitazone Metformin+ DPP4 Inhibitor Sulfonylurea + a-gi 2 제복합 Sulfonylurea + Pioglitazone Sulfonylurea + DPP4 Inhibitor
3 제요법 : 2 제요법 2-4 개월뒤 A1c 7.0% Metformin + SU + 1 종 : 보험인정 TZD, Meglitinide, agi, DPP4 inhibitor 중 2 가지이상복합시저가 1 종환자부담 인슐린 + 경구용약제 2 종 (Insulin+SU+Met 조합이외에는저가경구용약제는환자부담 ) 인슐린 + Sitagliptin ( 환자전액부담 )
3 제요법 : 2 제요법 2-4 개월뒤 A1c 7.0% Metformin+ SU + 1 종 : 보험인정 Metformin+ SU + TZD Metformin+ SU + alpha GI Metformin + SU + DPP4 Inhibitor Metformin + SU + Meglitinide(X)
전액삭감 ( 허가사항이외투여 ) 식약청허가사항이외의투여 DPP4 Inhibitors + Meglitinide 병용투여 DPP4 Inhibitors + alpha-glucosidase inhibitor 병용투여 Thiazolidinedione 와 alpha-glucosidase inhibitor 병용투여 서방형제제분할, 분쇄하여투여시모두삭감 ( Diabex XR, Diamicron MR, Amary-Mex SR 등 ) 복합제 Amaryl-Mex SR 은 Diabex XR 과만병용가능 Aamary-M, Actosmet, Janumet, Galvusmet 는 Glupa (metformin 일반제제 ) 와만병용가능
Contents 1. 경구용당뇨병약제종류 2. 복합처방 3. 보험인정기준 4. 개발중인경구용당뇨병약제
4. 개발중인경구용당뇨병약제 아직도당뇨병약제가부족한가?
New DPP-4 Inhibitor Alogliptin Takeda Gemigliptin LG life science
Dapagliflozin Canagliflozin Empagliflozin Ipragliflozin SGLT2 Inhibitors 인슐린비의존적혈당감소베타세포기능과인슐린저항성에영향없음. 저혈당위험낮음, 체중감소효과???
GPR119 Agonist Reduction in food intake Reduction in body weight Regulate incretin and insulin secretion
Dual PPAR-gamma/alpha agonist Tesaglitazar -- 2006 STOP Muraglitazar -- 2006 STOP Aleglitazar phase 2 trial
Injections Long acting GLP-1 agonist - Liraglutide -- Novonordisk - Dulaglutide -- Lilly - Lixisenatide Sanofi - Albiglutide G S K - Taspoglutide Roche -2010 New Insulin - Insulin Degludec - Exubera(2007), Affrezza(2011)????
정리 1 당뇨병경구용약제는복합으로쓰는경우가많음. 2 효과적인약물조합 = 보험기준에합당한조합 3 DPP4 억제제의임상효과 4 실제약제 ( 조합 ) 선택은환자별로개별화필요 5 아직도부족한당뇨병약제