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1 이상지질혈증의관리 국립중앙의료원조영중

2 국내현황 Contents Statin Trial 관리목표 치료

3 SUMMARY of DIABETES FACT SHEET IN KOREA 2016 Year Data source KNHANES KNHANES NHIS KNHANES Year applied to Korean census * 2014 Co-working Institute CDC CDC NHIS CDC Prevalence of diabetes (%, n) 10.1% (3.2 M) 12.4% (4.0 M) 8.0% (2.7 M) 13.7% (4.8 M) Prevalence of IFG (%, n) 19.9% (6.2 M) 19.3% (6.1 M) 25% 24.8% (8.3 M) Awareness of diabetes (%) 73.4% 72% 70.7% No treatment for diabetes (%) 14.1% 11% 10.8% Treatment with insulin (%) 7.4% 11% 16.4% 8.9% Glycemic control (< 6.5%, %) 29.5% 27.9% 23.3% Hypertension (%) 54.6% 62.5% 54.7% Hypertension control (%) 37% 39.5% 69.1% Dyslipidemia (%) 79.6% 49.5% 31.6% Dyslipidemia control (%) 17.4% 49.8% Albuminuria (%) 27.3% 23.9% Chronic kidney disease (%) 10.0% 12.5% Diabetes in ESRD (%) 38.8% Diabetic neuropathy (%) 33.5% Diabetic retinopathy (%) 18.6% 15.9% Prevalence of obesity (%) 74.7% 44.4% 48.6% Available at

4 Hypercholesterolemia in Diabetes The prevalence and control rate of hypercholesterolemia in persons with diabetes are 31.6% and 49.8%, respectively. More than half of persons with diabetes do not reach the LDL-C goal of < 100 mg/dl Uncontrolled hypercholesterolemia 1 2 단위 (%) Prevalence 45.1 Control rate years 65 years Men Women Hypercholesterolemia is defined by total cholesterol 240 mg/dl or medication(s) and control rate is defined by low-density lipoprotein cholesterol (LDL-C) < 100 mg/dl based on KDA guideline.

5 Dyslipidemia Fact Sheet in Korea 2015, 한국지질 동맥경화학회

6 죽상동맥경화증의기전 대한당뇨병학회, EGDM slide

(lipoprotein or hepatic lipase) CETP : cholesteryl ester

7 인슐린저항성과이상지질혈증 Fat Cells Liver FFA CE IR X TG Apo B VLDL CE VLDL TG TG HDL Apo A-1 (hepatic lipase) Insulin sd LDL LDL Kidney (lipoprotein or hepatic lipase) CETP : cholesteryl ester transfer protein Lipids Online, 대한당뇨병학회, EGDM slide

8 Atherogenic dyslipidemia in T2DM Small dense LDL Atherogenic dyslipidemia Low HDL High TG

reduces CHD risk by 1% 1% increase in HDL-C reduces CHD risk by 3% 1 0

9 LDL-C, HDL-C 과심혈관질환발생 Framingham Heart Study The risk of CHD can be reduced by : Lowering LDL-C Increasing HDL-C 3 2 1% decrease in LDL-C reduces CHD risk by 1% 1% increase in HDL-C reduces CHD risk by 3% LDL-C (mg/dl) Castelli WP. Can J Cardiol. 1988;4(suppl A):5A

10 Primary and Secondary Prevention with Statin already established 30 4S - Pl Rx - Statin therapy Pl Placebo Pra pravastatin Atv atorvastatin Sim - simvastatin 4S - Rx Secondary Prevention TNT Atv80 PROVE-IT Atv JUPITER-Rosu 40 (1.0) 60 (1.6) LIPID - Rx CARE - Rx IDEAL-Sim HPS - Rx TNT Atv10 PROVE-IT - Pra IDEAL-Atv 80 (2.1) AFCAPS - Rx ASCOT - Rx 100 (2.6) ASCOT-PL JUPITER-Pl 120 (3.1) LDL-C achieved mg/dl (mmol/l) HPS - Pl AFCAPS - Pl CARE - Pl 140 (3.6) LIPID - Pl Primary Prevention (4.1) WOSCOPS Pl WOSCOPS - Rx 180 (4.7) 200 (5.2)

11 Primary and Secondary Prevention with Statin already established 30 4S - Pl Rx - Statin therapy Pl Placebo Pra pravastatin Atv atorvastatin Sim - simvastatin 4S - Rx Secondary Prevention TNT Atv80 PROVE-IT Atv JUPITER-Rosu 40 (1.0) 60 (1.6) LIPID - Rx CARE - Rx IDEAL-Sim HPS - Rx TNT Atv10 PROVE-IT - Pra IDEAL-Atv 80 (2.1) AFCAPS - Rx ASCOT - Rx 100 (2.6) ASCOT-PL JUPITER-Pl 120 (3.1) LDL-C achieved mg/dl (mmol/l) HPS - Pl AFCAPS - Pl MEGA-Rx CARE - Pl 140 (3.6) LIPID - Pl MEGA-Pl Primary Prevention (4.1) WOSCOPS Pl WOSCOPS - Rx 180 (4.7) 200 (5.2)

스타틴제제에의한심혈관질환예방 1 차예방 2 차예방 주요심혈관질환발생위험율 (%) N LDL-C 0-10 -20-30 -40 AFCAPS/

P < 0.001-31 P < 0.001-38 P < 0.001-25 P < 0.

12 스타틴제제에의한심혈관질환예방 1 차예방 2 차예방 주요심혈관질환발생위험율 (%) N LDL-C AFCAPS/ TexCAPS WOSCOPS 4S LIPID CARE % -26% -36% -25% -28% -38 P < P < P < P < P < WOSCOPS = West of Scotland Coronary Prevention Study La Rasa JC et al. JAMA 1999;282; 대한당뇨병학회, EGDM slide

CARDS trial ( 일차예방 ) : Atorvastatin 10 mg CumulativeHazard (%) 15 10 5 Placebo

001) (95% CI, -17 to -52) 48% RRR (P=.016) (95% CI, -11 to -69) 37% RRR (P=.

9 CARDS was stopped nearly 2 years early due to significant CV benefits with

13 CARDS trial ( 일차예방 ) : Atorvastatin 10 mg CumulativeHazard (%) Placebo (N=1410) 37% Atorvastatin 10 mg (N=1428) RRR (P=.001) (95% CI, -17 to -52) 48% RRR (P=.016) (95% CI, -11 to -69) 37% RRR (P=.007) (95% CI, -14 to -61) Years CARDS was stopped nearly 2 years early due to significant CV benefits with Atorvastatin Colhoun HM, Betteridge DJ, Durrington PN, et al. Lancet. 2004;364: Hitman GA, et al. Diabet Med. 2007;24: 대한당뇨병학회, EGDM slide

14 TNT trial ( 이차예방 ): Atorvastatin 10 mg vs 80 mg Cumulative incidence (%) Atorvastatin 10 mg (N=5006): End-of-Tx LDL-C=101 mg/dl Atorvastatin 80 mg (n=4995): End-of-Tx LDL-C=77.0 mg/dl Years 22% RRR HR=0.78 (CI, ) P< Cumulative incidence (%) Atorvastatin 10 mg (N=753): End-of-Tx LDL-C=98.6 mg/dl Atorvastatin 80 mg (n=748): End-of-Tx LDL-C=77.0 mg/dl 5 RRR HR=0.75 (CI, ) P< Years *Major CV events=chd death, nonfatal non procedure-related MI, resuscitated cardiac arrest, fatal or nonfatal stroke. Primary effecacy outcome: time to first occurrence of a major CV event. LaRosa JC et al. N Engl J Med. 2005; Shepherd J et al. Diabetes Care. 2006;29: 대한당뇨병학회, EGDM slide

LDL-C 치료목표와심혈관질환발생률 : Lower is still Better Clinical event rate TNT CARDS PROVE IT HPS Post CABG AFCAPS CARE LIPID 4S Risk Attributable to LDL-C 60 80 100 120 140 160 180 200 220 LDL Cholesterol

15 LDL-C 치료목표와심혈관질환발생률 : Lower is still Better Clinical event rate TNT CARDS PROVE IT HPS Post CABG AFCAPS CARE LIPID 4S Risk Attributable to LDL-C LDL Cholesterol mg/dl TNT = Treating to New Targets study, PROVE IT = Pravastatin or Atorvastatin Evaluation and Infection Therapy study, CARDS = Collaborative Atorvastatin Diabetes Study, Post CABG = Post Coronary Artery Bypass Graft Study 대한당뇨병학회, EGDM slide

16 2013 ACC/AHA guideline

18 HR 1.34 ( ) P value 0.07

19 Pooled Cohort Risk Assessment Equations : Predicts 10-year risk for a first ASCVD event

20 Intensity of Statin Therapy Statins and doses that are approved by the U.S. FDA but were not tested in the RCTs reviewed are listed in italics. Evidence from 1 RCT only: down titration if unable to tolerate atorvastatin 80 mg in IDEAL (47). Although simvasta n 80 mg was evaluated in RCTs, ini a on of simvasta n 80 mg or tra on to 80 mg is not recommended by the FDA due to the increased risk of myopathy, including rhabdomyolysis. Circulation. published online 2013 November 12

21 이상지질혈증치료지침 (2015) : 한국지질 동맥경화학회 위험도분류에따른 LDL 및 non-hdl 콜레스테롤의목표치위험도 LDL non-hdl (mg/dl) 초고위험군 <70 <100 관상동맥질환허혈성뇌졸중일과성뇌허혈발작말초혈관질환고위험군 <100 <130 경동맥질환 (50% 가넘는경동맥협착이확인된경우 ) 복부동맥류당뇨병중등도위험군 <130 <160 주요위험인자 2 개이상저위험군 <160 <190 주요위험인자 1 개이하

22 이상지질혈증관리목표 ( 대한당뇨병학회 2015) 일차목표 : LDL-C LDL-C < 100 mg/dl 심혈관질환이있거나고위험환자의경우 LDL-C < 70 mg/dl - 치료반응에따라기저 LDL-C 의 30-40% 감소 중성지방 < 150 mg/dl HDL-C > 40 mg/dl ( 남자 ) > 50 mg/dl ( 여자 ) Non HDL-C < 130 mg/dl Apo B < 90 mg/dl 혈중지질검사는당뇨병진단당시및매년시행

23 치료 ( 비약물요법 ) 생활습관교정 - 체중감량 ( 정상체중유지 ) -운동 -금연 - 식사요법 : 포화지방산, 콜레스테롤, 트랜스지방의섭취 n-3 지방산, 섬유소섭취 혈당조절개선 : 특히, 혈당조절이불량하면서중성지방이높은경우

24 약물치료 Statin Bile acid resin Ezetimibe Fibric acid derivative Omega-3 fatty acid Niacin

25 Statin HMG-CoA reductase inhibitor : 간의콜레스테롤합성을줄임 이상지질혈증의일차선택약제 심혈관질환의위험도에따라 LDL-C이목표수치에도달하도록용량조절 부작용 - 간기능이상 (ALT 상승 ) - 근육관련증상 ( 근육통, 근염등 ) - 드물게횡문근융해증 CK 측정 : may be useful at baseline in those at increased risk of muscle events and in patients with muscle symptoms -ALT 측정 : baseline measurement recommended

26 스타틴치료군과위약군으로분류 이중맹검으로 3.3 년진행후오픈라벨로전환해서 2.3 년 F/U 세, 10,240 명 복용약물을알기전 후의이상반응발생을비교

27 스타틴치료군과위약군으로분류 이중맹검으로 3.3 년진행후오픈라벨로전환해서 2.3 년 F/U 세, 10,240 명 복용약물을알기전 후의이상반응발생을비교

28 스타틴치료군과위약군으로분류 이중맹검으로 3.3 년진행후오픈라벨로전환해서 2.3 년 F/U 세, 10,240 명 복용약물을알기전 후의이상반응발생을비교

29 스타틴치료군과위약군으로분류 이중맹검으로 3.3 년진행후오픈라벨로전환해서 2.3 년 F/U 세, 10,240 명 복용약물을알기전 후의이상반응발생을비교 C/W nocebo effect

30 LDL-C lowering efficacy on FDA website

31 비스타틴약물요법 Ezetimibe - 소장에서콜레스테롤의흡수를억제 - 10 mg qd로복용 - 스타틴과의병합요법으로자주사용 ( 스타틴단독에비해 LDL-C을 15-20% 추가로감소시킴 ) - 스타틴을증량해도 LDL-C 목표에도달하지못할경우병용할수있다. - 부작용 : 주로위장관계증상 ( 복통, 설사, 속이부글거림등 ) - cyclosporin을사용하는환자에서는사용을피한다. (ezetimibe의혈중농도가올라가고, cyclosporin의혈중농도도증가 )

IMPROVE-IT trial (ezetimibe 10 mg/simvastatin 40 mg vs placebo/simvastatin 40 mg) Primary Composite Endpoint* Major Pre-specified Subgroups Event rate (%) 40 30 20 10 HR 0.936 CI (0.887-0.988) p=0.

32 IMPROVE-IT trial (ezetimibe 10 mg/simvastatin 40 mg vs placebo/simvastatin 40 mg) Primary Composite Endpoint* Major Pre-specified Subgroups Event rate (%) HR CI ( ) p=0.016 Simva 34.7% EZ/Simva 32.7% Simva EZ/Simva Male Female Age < 65 years Age 65 years No diabetes Diabetes Prior LLT No prior LLT Time since randomization (years) LDL-C > 95 mg/dl LDL-C 95 mg/dl year Ezetimibe/Simva Better Simva Better event rates *p-interaction = 0.023, otherwise > 0.05 *The primary composite endpoint : time to first CV death, nonfatal MI, UA requiring hospitalization, coronary revascularization ( 30 days post-randomization), or nonfatal stroke. Cannon CP et al. N Engl J Med 2015;372: 대한당뇨병학회, EGDM slide

33 비스타틴약물요법 Fibric acid derivative (Gemfibrozil, Fenofibrate) -PPAR-α를활성화시켜간에서지단백대사를조절하는유전자의전사과정을변화시켜작용 - 중성지방을감소시키는데가장효과적인약제 - 스타틴과병용시에는근육증상과횡문근융해증의발생위험이증가 : 스타틴과병용시에는 gemfibrozil 보다는 fenofibrate를선택 오메가-3 지방산 - 지방산의분해를촉진, 간에서 VLDL, 중성지방의합성을줄이고장으로의분비를촉진 -1일 2-4 g을한번또는두번에나누어복용

34 ACCORD-Lipid Trial Major fatal or nonfatal CV events, % % RRR, adjusted P= High triglycerides ( 204 mg/dl) and Low HDL ( 34 mg/dl) 17.6% (n=941) Of entire cohort High TG/low HDL-C subgroup had 70% higher event rate No benefit For less than Moderate dyslipidemia Simva Simva+Feno All others in entire cohort 82.4% (n=4548) of entire cohort Rosenblit PD. Curr Cardiol Rep 2012:14;112 ACCORD Study Group. N Engl J Med March 14, Epub. 대한당뇨병학회, EGDM slide

35 보험급여기준변경 (2014 Jan)

36 요약 일차약제는스타틴을사용하며, 스타틴만으로 LDL-C 목표치에도달하지못하는경우, 다른약제 (ezetimibe, bile acid binding resin, niacin 등 ) 을병용할수있다. LDL-C은목표치에도달했으나중성지방이목표치에도달하지못한경우다른기전의약제 (fibrate, 오메가-3 지방산 ) 를병용할수있다. 중성지방 >500 mg/dl인경우먼저혈당조절상태를개선시킨후 fibrate를이용하여치료한다.

37 경청해주셔서감사합니다!

Kjcg007( ).hwp

Kjcg007( ).hwp 25 Elderly People are the Major Target for Risk Reduction to Prevent Atherosclerotic Disease 동맥경화의정도 증상 (+) 증상 (-) 뇌졸중심근경색 위험인자 Hypercholesterolemia Hypertension Diabetes Mellitus Smoking Others 심장질환의고위험군이란?