1041105血脂管理與減少殘餘風險

Lipid management and residual risk reduction

/ Po-Chao Hsu, MD, PHD 2015/11/5

Topic outline Association between atherosclerosis and dyslipidemia What is residual risk?

Lipid metabolism Current lipid guideline of world and health insurance in

Taiwan Drug therapy for dyslipidemia Beyond LDL lowering therapy – If residual risk reduction exists?

(Fibrate, niacin, n-3 fatty acid, or CETP inhibitor) Trilipix: The first fibric acid derivative indicated for use in combination with a statin in Taiwan Take Home Message

Atherothrombosis: A Generalized and Progressive Process Thrombosis Unstable angina ACS MI Ischemic stroke/TIA

Atherosclerosis

Critical leg ischemia Intermitent claudication CV death

Stable angina/ Intermittent claudication Circulation. 2001;104:365-72

Importance of Cholesterol in Atherosclerosis

N Engl J Med. 1997;337:408–416.

Relationship Between Changes in LDL-C and HDL-C Levels and CHD Risk

1% decrease in LDL-C reduces CHD risk by 1%

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

Third Report of the NCEP Expert Panel. NIH Publication No. 01-3670 2001.

5 http://hin.nhlbi.nih.gov/ncep_slds/menu.htm

CHD Risk Increases as Plasma Cholesterol Increases MRFIT (n=356,222)1

Framingham Study (n=5,209)2

16

150

14

125

12

100

CHD 10 Mortality 8 Rate per 1,000 6

CHD Incidence 75 per 1,000 50

4

25

2 0 100

0 150

200

250

Serum Cholesterol, mg/dL

300

<204

205–234 235–264 265–294

>295

Serum Cholesterol, mg/dL

CHD = coronary heart disease; MRFIT = Multiple Risk Factor Intervention Trial.

1. Stamler J et al. JAMA. 1986;256:2823–2828.

2. Reprinted from Am J Med, Vol 76, WP Castelli, Epidemiology of coronary heart disease: the Framingham Study, pp. 4–12, Copyright 1984, with permission from Excerpta Medica Inc.

Relation Between CHD Events and LDL Cholesterol in Statin Trials PI = Placebo Rx = Treatment

Primary Prevention % of Paients with CHD Event

Secondary Prevention 4S-PI

25 TNT-Entry

20 4S-Rx 15

LIPID-PI CARE-PI

CARE-Rx

10

LIPID-Rx TNT

5

WOS-PI

WOS-Rx

AFCAPS-Rx AFCAPS-PI

0 50

70

90

110

130

150

170

190

210

LDL Cholesterol (mg/dL) AFCAPS: Lovastatin; 4S: Simvastatin WOS, LIPID, CARE: Pravastatin

Kastelein. Atherosclerosis 1999;143:S17-S21

Relationship between LDL-C levels and change in percent atheroma volume for several IVUS trials

1.8

REVERSAL

R2 = 0.97 P<0.001

pravastatin

CAMELOT placebo

1.2 Median change in Percent Atheroma Volume (%)

0.6

REVERSAL atorvastatin

A-Plus

Progression

placebo

0

Regression -0.6 ASTEROID rosuvastatin

-1.2 50

60

70

80 100 90 Mean LDL-C (mg/dL)

110

Ref: Nissen S et al. JAMA 2006; 295: e-publication ahead of print

120

What is residual risk?

Atherogenic dyslipidemia - The atherogenic triad Low HDL-C

The atherogenic triad High sd LDL-C

Expert Panel on Detection, Evaluation,and Treatment of High Blood Cholesterol in Adults JAMA 2001;285:2486-2497

High TG

Atherogenic Dyslipidemia in DM/MS

Framingham Study: Cholesterol and CHD

Castelli WP et al. JAMA 1986;256:2835-8

8-Year Incidence of Coronary Events in the Chin-Shan Community

Wang TD, Lee YT et al. Am J Cardiol 2001;88:737-43

Atherogenic dyslipidemia is an important contributor to macrovascular residual risk: HDL-C PROCAM study: Low HDL-C is an independent predictor of coronary heart disease risk even when LDL-C is low1

14 1 â&#x20AC;&#x201C; Assmann G et al. Eur Heart J Suppl 2006;8(SupplF):F40-6.

14

HDL-C Remains an Independent CHD Risk Factor After Aggressive LDL-C Reduction CHD risk of patients in TNT with on-treatment LDL-C < 70 mg/dL according to quintile of on-treatment HDL-C 5-Yr Risk of Major Cardiovascular Events (%)

Hazard ratio (95%) versus Q1 10

-39% P=0.03

9 8

Q2 Q3 Q4 Q5

7 6 5 4 3 2 1 0 Q1 (< 37)

Q3 Q4 Q2 (42 to < 47) (47 to < 55) (37 to < 42)

Q5 (â&#x2030;Ľ 55)

Quintile of HDL-C Level (mg/dl) No. of Events

57

50

34

34

35

No. of Patients

473

525

550

569

544

Barter P et al. N Engl J Med. 2007;357:1301-10.

0.85 (0.57-1.25) 0.57 (0.36-0.88) 0.55 (0.35-0.86) 0.61 (0.38-0.97)

LDL: same levels, but different CV risks

Otvos JD et al. Am J Cardiol. 2002;90:22i-29i

77% of macrovascular risk remains unaddressed despite effective LDL-C lowering with statins Statin meta-analysis Lowering LDL-C by 1 mmol/L(39 mg/dL) with statins reduces major coronary events by 23%, leaving an unaddressed CV residual risk of 77%

Baigent C et al. Lancet 2005;366:1267â&#x20AC;&#x201C;78.

Residual Cardiovascular Risk in Major Statin Trials CHD events occur in patients treated with statins

1 2 3

4S Group. Lancet. 1994;344:1383-1389.

LIPID Study Group. N Engl J Med. 1998;339:1349-1357.

Sacks FM, et al. N Engl J Med. 1996;335:1001-1009.

4 5 6

HPS Collaborative Group. Lancet. 2002;360:7-22.

Shepherd J, et al. N Engl J Med. 1995;333:1301-1307 Downs JR, et al. JAMA. 1998;279:1615-1622.

Residual CVD Risk in Patients Treated With Intensive Statin Therapy

1 2 3

*Mean or median LDL-C after treatment

Cannon CP, et al. N Engl J Med. 2004;350:1495-1504.

Pedersen TR, et al. JAMA. 2005;294:2437-2445.

LaRosa JC, et al. N Engl J Med. 2005;352:1425-1435.

Aggressive lowering of LDL-C with maximal doses of statins does not eliminate CV risk TNT study Despite intensive LDL-C lowering treatment with statins, CV relative risk is further reduced by only 22%

LaRosa JC et al. N Engl J Med 2005;352;1425-35.

While statins reduce CV risk, a substantial residual risk remains â&#x20AC;˘ A meta-analysis of 21 randomised clinical trials (N=129,526)

revealed that statin treatment prevented approximately 2 out of 10 major vascular events (relative risk reduction 22%, p<0.0001)1 CTT Meta-analysis: Effect of statins on major vascular events1

Statins prevent approximately 2 out of 10 events

1. Cholesterol Treatment Trialistsâ&#x20AC;&#x2122; Collaborators. Lancet. 2010;376:1670-81.

Remaining residual risk may be due to other modifiable and unmodifiable risk factors, including other lipid parameters, blood pressure, glycaemic control, weight and genetic predisposition

Beyond LDL as a Target non-HDL-C Addressed in guidelines as concept of "non-HDL-cholesterol" Not a new concept: Helsinki Heart Study of 1987 entry criteria

was high levels of non-HDL-C

1

Target non-HDL < 100 (but not routinely on lab request slip) ADA Expert Panel: Patients with type 2 diabetes and other risk

factors should also have non-HDL < 100; apoB goal < 90 mg/dl, LDL particle number < 1000 2

1. Frick et al. N Engl J Med. 1987;317:1237-1245.

2. Brunzell et al. Diabetes Care 31: 811-822

Non–HDL-C Superior to LDL-C in Predicting CHD Risk Non-HDL Non–HDL-C, mg/dL

<160

160-189

>190

<130

130-159

>160

Within non-HDL-C levels, no association was found between LDL-C and the risk for CHD. In contrast, a strong positive and graded association between non– HDL-C and risk for CHD occurred within every level of LDL-C Non–HDL-C is a stronger predictor of CHD risk than LDL-C

Relative CHD Risk

2.5 2 1.5 1 0.5 0 LDL

LDL-C, mg/dL Liu J, et al. Am J Cardiol. 2006;98:1363-1368.

PROCAM study: Fasting TG is an independent risk factor for CHD events

Assmann G et al. Eur Heart J 1998;19(Suppl M): M8-14

Elevated triglycerides contribute to macrovascular residual risk even when LDL-C is well controlled PROVE IT-TIMI 22 study Despite achieving LDL-C <70 mg/dL (1.8 mmol/L), patients with TG â&#x2030;Ľ150 mg/dL show a increase in the risk of death, MI or ACS compared to those with TG levels <150 mg/dL Miller M et al. J Am Coll Cardiol 2008;51:724-30.

Even when LDL-C is at goal, elevated TG levels are associated with a higher CHD risk • Despite achieving LDL-C goal with a statin, patients with

elevated TG have a significantly higher CHD risk1 PROVE IT-TIMI 22 post-hoc analysis: Effect of TG levels on CHD events in patients with LDL-C < 70 mg/dL1

27% higher relative risk

LDL-C <70 mg/dL TG levels ≥200 mg/dL

27% higher relative risk

vs. TG <200 mg/dL

of CHD events

Coronary events defined as death, myocardial infarction or recurrent acute coronary syndrome. Relative risk calculated from an adjusted hazard ratio for TG <200 mg/dL = 0.60 (95% CI 0.45–0.81) vs. TG ≥200 mg/dL = 0.76 (95% CI 0.52–1.12)

1. Miller M et al. J Am Coll Cardiol. 2008;51:724-30.

Elevated TG and low HDL-C represent an even greater risk for patients with type 2 diabetes ACCORD Lipid (prespecified subgroup analysis): Major vascular events in patients with T2D receiving simvastatin1

Proportion with event* (%)

20 15

17.3%

+70%

Simvastatin monotherapy

relative risk

10

10.1% 5

Mean LDL-C: 80 mg/dL

0

Elevated TG (â&#x2030;Ľ204 mg/dL) + Low HDL-C (â&#x2030;¤34 mg/dL) (n=456)

1. ACCORD Study Group. N Engl J Med. 2010;362:1563-74.

All others (n=2,284)

*Cardiovascular death, nonfatal myocardial infarction and nonfatal stroke

Lipid metabolism

Current lipid guideline of world and health insurance in Taiwan

Evolution of NHLBI Supported Guidelines

NCEP ATP I 1988

NCEP ATP II 1993

NCEP ATP III 2001

Updated NCEP ATP III 2004

AHA/ACC Update 2006

More Intensive Treatment Recommendations

Framingham MRFIT LRC-CPPT Coronary Drug Project Helsinki Heart CLAS

Angiographic trials (FATS, POSCH, SCOR, STARS, Ornish, MARS) Meta-analyses (Holme, Rossouw)

4S WOSCOPS CARE LIPID AFCAPS/ TexCAPS

NHLBI = National Heart, Lung, and Blood Institute.

NCEP ATP = National Cholesterol Education Panel Adult Treatment Panel.

AHA = American Heart Association.

ACC = American College of Cardiology.

HPS PROVE-IT ASCOT-LLA PROSPER ALLHAT-LLT

TNT IDEAL

Intensive LDL-C Goals for High-Risk Patients

Recommended LDL-C treatment goals ATP III Update 20041

AHA/ACC guidelines for patients with CHD*,2

<100 mg/dL: Patients with CHD or CHD risk equivalents (10-year risk >20%)1

<100 mg/dL: Goal for all patients with CHD†,2

<70 mg/dL: Therapeutic option for very high-risk patients1

<100 mg/dL

2006

Update

<70 mg/dL: A reasonable goal for all patients with CHD†,2

<70 mg/dL • If it is not possible to attain LDL-C <70 mg/dL because of a high baseline LDL-C, it generally is possible to achieve LDL-C reductions of >50% with more intensive LDL-C─lowering therapy, including drug combinations.

* And other forms of atherosclerotic disease.2 † Factors that place a patient at very high risk: established cardiovascular disesase (CVD) plus: multiple major risk factors (especially diabetes); severe and poorly controlled risk factors (eg, cigarette smoking); metabolic syndrome (triglycerides [TG] ≥200 mg/dL + non–HDL-C ≥130 mg/dL with HDL-C <40 mg/dL); and acute coronary syndromes.1 1. Grundy SM et al. Circulation. 2004;110:227–239.

2. Smith SC Jr et al. Circulation, 2006; 113:2363–2372.

ESC / EAS Guidelines LDL -C LDL-C

< 70 mg/dl mg/dl (< 1.8 mmol/l) or -C or >> 50% 50% LDL LDL-C reduction reduction

LDL -C LDL-C

< 100 mg/dl mg/dl mg/dl < 115 mg/dl (<2.5 mmol/l)

(< 3 mmol/l)

SCORE 10 - 5%

SCORE 5 - 1%

SCORE < 1%

Moderate Risk

Low Risk

SCORE ≥ 10% Documented

CVD

DM + ≥ 1 RF

and/or Severe TOD*

LDL -C LDL-C

Markedly elevated

DM 0 RF

Moderate RF

CKD

CKD

(< 30)

(30-60)

Very High Risk

High Risk

** TOD= TOD= target target organ organ damage damage (such (such as as microalbuminuria microalbuminuria 30-300 30-300 mg/24h) mg/24h) Joint Joint ESC ESC Guidelines.

Guidelines. Eur Eur J J Prev Prev Cardiol Cardiol 2012; 2012; 19: 19: 585-667 585-667

ESC/EAS ESC/EAS Guidelines.

Guidelines. Eur Eur Heart Heart J J 2011; 2011; 32: 32: 1769-1818 1769-1818

: Statin fibrate Statin

Statin Statin

fibrate gemfibrozil gemfibrozil fibrate statin

fibrate

ESC/EAS ESC/EAS Guidelines.

Guidelines. Eur Eur Heart Heart J J 2011; 2011; 32: 32: 1769-1818 1769-1818

2013 ACC / AHA Guidelines 4 Major Statin Benefit Groups 1. Clinical ASCVD (ACS or history of MI, stable or unstable angina, revascularisation, stroke, TIA, or PAD presumed to be of atherosclerotic origin)

2. LDL-C ≥ 190 mg/dL 3. Diabetes aged 40-75 y with LDL-C 70-189 mg/dL 4. Estimated 10-year ASCVD risk ≥ 7.5 % with LDL-C 70-189 mg/dL (and age 40-75 y)

2013 ACC/AHA Guideline: High-Moderate statin

Rosuvastatin 40mg is not indicated in Taiwan.

Stone NJ, et al. J Am Coll Cardiol. 2013: doi:10.1016/j.jacc.2013.11.002. Available at: http://content.onlinejacc.org/article.aspx?articleid=1770217. Accessed November 13, 2013.

2013 ACC/AHA Guideline: Summary

guideline RCT RCT , statin ASCVD ASCVD LDL nonnon-HDL goal Non-statin statin , ASCVD statin LDLâ&#x2030;Ľ 50%, statin LDL 30-50% Treat to target lower is best , treat to ASCVD risk

CHD = coronary heart disease.

2014 National Lipid Association(NLA) guideline

J Clin Lipidol. 2014 Sep-Oct;8(5):473-88

2014 National Lipid Association(NLA) guideline

J Clin Lipidol. 2014 Sep-Oct;8(5):473-88

2014 National Lipid Association(NLA) guideline Management of patients with hypertriglyceridemia For patients with very high triglycerides (>=500 mg/dL), the primary objective of therapy is to lower the triglyceride level to < 500 mg/dL to reduce the risk of pancreatitis.

For patients with hypertriglyceridemia who have high triglycerides (200 to 499 mg/dL) the primary objective of therapy is to lower levels of atherogenic cholesterol (non-HDL-C and LDL-C) to reduce risk for an ASCVD event.

J Clin Lipidol. 2014 Sep-Oct;8(5):473-88

2014 NICE guideline

Company Confidential Š 2012 Abbott

2014 NICE guideline – About Niacin

Company Confidential © 2012 Abbott

2014 NICE guideline â&#x20AC;&#x201C; About omega-3 fatty acid

Company Confidential Š 2012 Abbott

2014 NICE guideline – About Fibrate

Company Confidential © 2012 Abbott

2014 NICE guideline – About Fibrate

Company Confidential © 2012 Abbott

全民健康保險降膽固醇藥物 給付規定

(

) 102/8/1)

1醛

LDL-C 130mg/dl

100mg/dl

100mg/dl

2醛 ( ) ( ) 1.

1.

5.

( 2.

2. (

(TIA)

45

55

)

3.

3.

(

55

65 )

) 4.HDL-C<40mg/dL

(

) 102/8/1)

Drug therapy for dyslipidemia

HMG Reductase

B-100 B-48

51

Drugs: Options Lipid profile

First Choice

Second Choice

LDL-C↑↑ ↑↑

Statin

Ezetimibe Resins

LDL↑↑ ↑↑ and Triglycerdies↑ ↑

Statin

Niacin or fibrate

LDL↑ ↑ and Triglycerides↑↑ ↑↑

Statin

Statin + fibrate Statin + omega3

Triglycerides↑ ↑ and HDL-C↓ ↓

Fibrates or niacin

Triglycerides↑↑ ↑↑ and LDL↓ ↓

Fibrates

Lipid Management Pharmacotherapy TC

LDL

HDL

TG

Patient tolerability

↓ 19-37%

↓ 25-50%

↑ 4-12%

↓ 14-29%

Good

↓ 13%

↓ 18%

↑ 1%

↓ 9%

Good

Bile acid sequestrants

↓ 7-10%

↓ 10-18%

↑ 3%

Neutral or ↑

Poor

Nicotinic acid

↓ 10-20%

↓ 10-20%

↑ 14-35%

↓ 30-70%

Reasonable to Poor

↓ 19%

↓ 4-21%

↑ 11-13%

↓ 30%

Good

Therapy Statins* Ezetimibe

Fibrates

HDL-C=High-density lipoprotein cholesterol, LDL-C=Low-density lipoprotein cholesterol, TC=Total cholesterol, TG=Triglycerides *Daily dose of 40mg of each drug, excluding rosuvastatin.

Treatment approaches to residual vascular risk

Treatment options for reducing residual risk Diet Exercise Pharmacological interventions: combining statins

with treatments that improve TG and/or HDL-C levels may reduce residual risk Statin (+/-) Fibrates Nicotinic acid Omega-3 fatty acids CETP inhibitor

Which drug can reduce residual risk?

MICROvascular residual risk may be reduced with fibrates

1. Keech AC et al. Lancet 2007;370:1687-97.

2. Keech AC et al. Lancet 2005;366:1849â&#x20AC;&#x201C;61.

56 3. Colman P et al. EASD 2008; Abstract A-08-2532.

56

ACCORD-Lipid Simvastatin 20-40 mg + Fenofibrate 160 mg** (n=2,765)

5,518 patients with T2DM

Simvastatin 2040 mg*

Simvastatin 20-40 mg + Placebo (n=2,753)

Month 1

Mean 4.7-year follow-up

*According to patientsâ&#x20AC;&#x2122; LDL-C levels and CVD history **Bioequivalent to 200 mg micronised and 145 mg nanocrystal. Patients whose eGFR was 30-50 mL/min/1.73 m2 received a lower dose of fenofibrate, corresponding to 1/3 of the normal daily dose Ginsberg HN et al. Am J Cardiol 2007;99(12A):56i-67i.

ACCORD Study Group. N Engl J Med. 2010. Epub.

Outcomes Primary endpoint: Composite of CVD death, non-fatal MI and non-fatal stroke

Secondary endpoints: Expanded macrovascular outcome (primary outcome + any revascularization + hospitalization for heart failure) Total mortality Each of the separate components of the primary outcome

Ginsberg HN et al. Am J Cardiol 2007;99(12A):56i-67i.

ACCORD Study Group. N Engl J Med. 2010. Epub.

Baseline Characteristics Simvastatin + Fenofibrate (n=2,765)

Simvastatin + Placebo (n=2,753)

Overall (n=5,518)

Mean total cholesterol

175 (4.5)

176 (4.5)

175 (4.5)

Mean LDL-C

100 (2.6)

101 (2.6)

101 (2.6)

Mean HDL-C

38 (1.0)

38 (1.0)

38 (1.0)

Median triglycerides

164 (1.9)

160 (1.8)

162 (1.8)

114-232 (1.28-2.61)

112-227 (1.252.55)

113-229 (1.26-2.57)

Baseline lipids

Interquartile range Data presented as mg/dL (mmol/L)

Ginsberg HN et al. Am J Cardiol 2007;99(12A):56i-67i.

ACCORD Study Group. N Engl J Med. 2010. Epub.

Prespecified Primary and Secondary Outcomes

Ginsberg HN et al. Am J Cardiol 2007;99(12A):56i-67i.

ACCORD Study Group. N Engl J Med. 2010. Epub.

AC43

ACCORD Lipid Primary macrovascular outcome in prespecified subgroups (2) Subgroup

Simvastatin + Fenofibrate

Simvastatin + Placebo

P value for interaction

Hazard ratio (95% CI)

% of events (no. in group) Overall

10.5 (2,765)

11.3 (2,753)

9.4 (938) 9.9 (934) 12.4 (877)

12.2 (891) 11.2 (922) 10.6 (927)

0.12

12.2 (964) 10.1 (860) 9.1 (925)

15.6 (906) 9.5 (866) 9.0 (968)

0.24

9.9 (891) 10.5 (924) 11.1 (934)

11.3 (939) 9.9 (913) 12.8 (888)

0.64

12.4 (485) 10.1 (2264)

17.3 (456) 10.1 (2284)

0.06

8.7 (1,324) 12.2 (1,435)

10.6 (1,335) 11.9 (1,415)

0.20

LDL cholesterol ≤84 mg/dL 85-111 mg/dL ≥112 mg/dL

HDL cholesterol ≤34 mg/dL 35-40 mg/dL ≥41 mg/dL

Triglycerides ≤128 mg/dL 129-203 mg/dL ≥204 mg/dL

Triglyceride-HDL cholesterol combination TG ≥204 mg/dL + HDL-C ≤34 mg/dL All others

Glycated hemoglobin ≤8.0% ≥8.1%

0

Simvastatin + Fenofibrate better

ACCORD Study Group. N Engl J Med March 14, 2010. Epub.

1

2

Simvastatin alone better

Fenofibrate significantly reduced CV events in the elevated TG + low HDL-C subgroup by 31% In patients with TG â&#x2030;Ľ204 mg/dL and HDL-C â&#x2030;¤34 mg/dL 18

16

17.32%

-31% p=0.03

Proportion with event (%)

14

12

12.37% 10

Number needed to treat (NNT) for 5 years to prevent one CV event

8

20

6

4

2

0

Simvastatin

Simvastatin + fenofibrate

The primary endpoint of major CV events (CV death, nonfatal MI and nonfatal stroke) was not reduced significantly in the overall population (HR=0.92, 95% CI 0.79-1.08, p=0.32) ACCORD Study Group. N Engl J Med. 2010; 362(17):1563-74.

Elam MB et al. AHA 2010. Presentation 19724.

Results-Safety

Laboratory Measures, no. (%)

Simvastatin + Fenofibrate (N=2765)

1é&#x2020;&#x203A; Serum creatinine elevation 2é&#x2020;&#x203A; Women ever > 1.3 mg/dL CK ever > 10X ULN

Men ever > 1.5 mg/dL

p value

, 40 (1.5%)

0.21

6 (0.2%)

0.03

51 (1.9%)

59 (2.2%)

0.43

10 (0.4%)

9 (0.3%)

0.83

235 (28%) 698 (37%)

157 (19%) 350 (19%)

Statin fenofibrate 52 (1.9%) ALT ever > 3X ULN : ALT ever > 5X ULN 16 (0.6%) CK ever > 5X ULN

Simvastatin + Placebo (N=2753)

<0.001 <0.001

As noted in other fenofibrate trials,2,3 mean serum creatinine levels increased

ACCORD Study Group. N Engl J Med. 2010; 362(17):1563-74.

Elam MB et al. AHA 2010. Presentation 19724.

Macrovascular risk may be addressed by targeting triglycerides and HDL-C with fibrates Fibrates reduce CV

risk even further when TG levels are elevated and HDL-C levels are low

1 – Frick MH et al. N Engl J Med 1987;317:1237–45.

2 – The BIP Study Group. Circulation 2000;102:21–7.

3 – Rubins HB et al. N Engl J Med 1999;341:410–8.

4 – Keech A et al. Lancet 2005;366:1849-61.

5 – Scott R et al. Diabetes Care. 2009;31:493-98.

Fibrate /fibrate-statin meta-analysis

Sacks FM, Carey VJ, Fruchart JC: Combination lipid therapy in type 2 diabetes. N Engl J Med 2010, 363:692â&#x20AC;&#x201C;684.

Nicotinic acid produced superior regression of CIMT compared to ezetimibe in statin-treated patients ARBITER-6 Despite greater LDL-C reduction with ezetimibe, nicotinic acid was associated with superior regression of CIMT* in statin-treated patients *Carotid intima-media thickness, a surrogate marker of atherosclerosis 1â&#x20AC;&#x201C; Taylor AJ et al. N Engl J Med 2009;361:2113-22.

Niacin Reduces CVD Pre-AIM-HIGH Trials

stat sig 27%â&#x2020;&#x201C;

Many of these trials were tests of drug combinations that included niacin.

Bruckert E et al. Atherosclerosis. 2010;210:353-361.

AIM-HIGH study

N Engl J Med. 2011 Dec 15;365(24):2255-67.

AIM-HIGH Study design

Slide 69

AIM-HIGHâ&#x20AC;&#x201D;Results HDL-C at Baseline and Follow-up

Boden WE. N Engl J Med. epub 15 Nov 2011; doi 10.1056/NEJMoa1107579.

AIM-HIGHâ&#x20AC;&#x201D;Results Primary Outcome

1o Endpoint: CHD Death, nonfatal MI, ischemic stroke, high-risk ACS, hospitalization for coronary or cerebrovascular revascularization

Boden WE. N Engl J Med. epub 15 Nov 2011; doi 10.1056/NEJMoa1107579.

AIM-HIGH Early Termination Data, Safety and Monitoring Board chose early

termination Due to futility (likely lack of efficacy) - 1° Endpoint HR 1.02 Early concern: possible increased stroke rate signal Potential explanations for lack of observed efficacy: “Placebo” arm received IR niacin, ↑ statin dose & ↑

ezetimibe (poor test of HDL hypothesis) Early study termination (VA HIT also negative at 3 y) High prior statin use (94%, 40%>5y), prior niacin use

(20%) N Engl J Med. 2011 Dec 15;365(24):2255-67.

HPS2-THRIVE: Randomized placebo-controlled trial of ER niacin and laropiprant in 25,673 patients with pre-existing cardiovascular disease.

Jane Armitage on behalf of the HPS2-THRIVE Collaborative Group

Financial Disclosure: Grant to Oxford University. Designed, conducted and analysed independently of the grant source (Merck & Co). No honoraria or consultancy fees accepted.

25,673 high-risk patients with occlusive arterial disease from China, Scandinavia and UK Randomized comparison: ER niacin/laropiprant (ERN/LRPT) 2g daily versus placebo Primary end point: Major vascular events after median follow-up of 4 years Pre-specified safety analyses: Median follow-up of 3.4 years (to January 2012) Background LDL-lowering therapy with: Simvastatin 40mg (+/- ezetimibe 10mg) daily

HPS2-THRIVE: Design and randomization

Effect of ERN/LRPT on MAJOR VASCULAR EVENTS Patients suffering events (%)

20

Risk ratio 0.96 (95% CI 0.90 – 1.03) Logrank P=0.29

15

15.0% 14.5%

10

Placebo ERN/LRPT

5

0 0

1

2

Years of follow-up

3

4

nâ&#x20AC;&#x201C;3 Fatty Acids and Cardiovascular Outcomes in Patients with Dysglycemia The ORIGIN Trial Investigators Double-blind random study 12,536 patients who were at high risk for

cardiovascular events and had impaired fasting glucose, impaired glucose tolerance, or diabetes 1-g capsule containing at least 900 mg (90% or more) of ethyl esters of nâ&#x20AC;&#x201C;3 fatty acids or placebo daily The primary outcome was death from cardiovascular causes.

N Engl J Med 2012;367:309-18

N Engl J Med 2012;367:309-18

N Engl J Med 2012;367:309-18

CETP Inhibitors/Modulators Increase HDL-C May Reduce Atherosclerosis ?

Role of CETP in Atherosclerosis

LDL-R

LDL

VLDL CE CETP

Foam cells

TG ABC-A1 RCT Bile

LIVER

HDL PLASMA

Atherosclerosis

LDL

ABC-G1

Free cholesterol PERIPHERAL TISSUE

Human CETP deficiency

↑ in HDL-C (codominant) ↓CVD

Reducing CETP activity →↓atherosclerosis in animal models Barter PJ et al. Arterioscler Thromb Vasc Biol. 2003;23:160-167.

Contacos C et al. Atherosclerosis. 1998;141:87-98.

Guerin M et al. Arterioscler Thromb Vasc Biol. 2008;28: 148-154.

CETP Inhibitors and Modulators Evacetrapib

CETP

Lipid Effects of CETP Inhibitors/Modulators % Change from Baseline CETP Agent

Dose (Mg/day)

HDL-C (%)

LDL-C (%)

TG (%)

Torcetrapib

60

61

-24

-9

Anacetrapib

100

138

-40

-7

Evacetrapib

500

129

-36

-11

Dalcetrapib

600

31

-2

-3

Adapted from Cannon C et al. JAMA. 2011;306:2153-2155.

Nicholls SJ et al. JAMA. 2011;306:2099-2109.

Torcetrapib “Beneficial” Effects on Lipoproteins +55% +49% +42% HDL-C LDL-C +1% +1% -1% -18% Placebo

Barter PJ et al. N Engl J Med. 2007;357:2109-2122.

60 mg

90 mg

-20% 120 mg

Patients Without Event (%)

Torcetrapib: BUT Increased Cardiovascular and Non-cardiovascular Morbidity and Mortality

100

Atorvastatin only

98

HR = 1.25 P = 0.0001

96 94 92

Torcetrapib plus atorvastatin

90 0

0 90 180 630 720 810

270 360 450

Days After Randomization

Barter PJ et al. N Engl J Med. 2007;357:2109-2122.

540

Torcetrapib Caused Off-target Hyperaldosteronism Torcetrapib arm of ILLUMINATE trial showed significant:1 ↑ Systolic Blood Pressure: Mean ↑5.4 mmHg >15 mmHg ↑ SBP: 19.5% torcetrapib arm (vs 9.4% placebo arm, p<0.001)

↓ serum potassium ↑ serum bicarbonate ↑ serum sodium ↑ serum aldosterone

Conclusion: ↑ CVD in ILLUMINATE likely due to off-

target actions of torcetrapib, not related to CETP inhibition1,2 1. Barter PJ et al. N Engl J Med. 2007;357:2109-2122.

2. Rosenson RS. Curr Athero Rep. 2008;10:227-229.

Analysis of the Off-target Characteristics of Investigational CETP Inhibitors/Modulators Characteristic

Torcetrapib Anacetrapib

Dalcetrapib Evacetrapib

Clinical evidence of increased BP

Yes1

No2

No3

No7

Preclinical evidence of increased aldosterone production*

Yes3

No4

No3

No8

Preclinical evidence of aldosterone synthase (CYP11B2) mRNA induction*

Yes3

?

No3

?

Preclinical evidence of RAASassociated gene induction*

Yes5

?

No5

?

L-type Ca2+ channel activation*

Yes6

?

No6

?

1. Barter et al. N Engl J Med. 2007;357:2109-2122.

3. Stein et al. Am J Cardiol. 2009;104:82-91.

5. Stroes et al. Br J Pharmacol. 2009;158:1763-1770.

7. Nicholls et al. JAMA 2011;306:2099-2109

2. Masson D. Curr Opin Invest Drugs. 2009;10:980-987.

4. Forrest et al. Br J Pharmacol. 2008;154:1465-1473.

6. Clerc et al. J Hypertens. 2010: in press.

8. Cao et al. J Lipid Research. 2011;52:2169-2176

Dalcetrapib and Torcetrapib Appear to Differ in Mechanism of CETP Inhibition

dal

HDL

• Dalcetrapib binds to CETP, inducing a conformational change to CETP that hinders association to HDL1 • Dalcetrapib binds to CETP only2

CETP tor or ana HDL

• Torcetrapib binding to CETP is an irreversible high affinity complex of CETP inhibitor, HDL, and CETP2,3

NB: The clinical relevance of these differences is unknown; these compounds have not been studied in head-to-head clinical trials.

1Okamoto

H et al. Nature. 2000;406:203-207.

2008;199:231.

3Clark RW et al. J Lipid Res. 2006;47:537-552.

2Niesor

EJ et al. Atherosclerosis.

Termination of Dalcetrapib Clinical Trial 7/7/2012 â&#x20AC;&#x153;The dal-OUTCOMES trial evaluated the efficacy and safety profile of dalcetrapib when added to existing standard of care in patients with stable coronary heart disease following an acute coronary syndrome.

Following the results of the second interim analysis of the dalcetrapib dal-OUTCOMES Phase III trial the Independent Data and Safety Monitoring Committee (DSMC) has recommended stopping the trial due to a lack of clinically meaningful efficacy. No safety signals relating to the dalOUTCOMES trial were reported from the DSMC. As a result, Roche has decided to terminate the dal-OUTCOMES trial, as well as all other on-going studies in the dal-HEART program, including dal-PLAQUE 2â&#x20AC;? and dal-OUTCOMES 2. Additional information will be provided in due course as data become available.

Excerpt from letter to dal-OUTCOMES Investigators from Roche.

http://www.medscape.com/viewarticle/852516

Any safety & efficacy agents for T2DM with mixed dyslipidemia who have accepted statin treatment?

Introducing....

The first fibric acid derivative indicated for use in combination with a statin in Taiwan.

Allows you to confidently treat all three key lipid parameters in your high CV-risk* patients with mixed dyslipidaemia.

Trilipix速 is indicated as an adjunct to diet in combination with a statin to reduce TG and increase HDL-C in patients with mixed dyslipidemia and CHD or a CHD risk equivalent who are on optimal statin therapy to achieve their LDL-C goal.

*High-risk patients are those with CHD or a CHD risk equivalent, including those with type 2 diabetes

Trilipix (Choline fenofibric acid)

statin

(

Trilipix

TG 31% HDL 16醛3%

LDL 5醛1%

statin TG 46醛4% HDL 17醛4% ) Trilipix ( statin simva 40mg; atorva 40mg rosuva 20mg)

135 mg Trilipix (eGFR

3030-5栢 mL/min)

Trilipix (eGFR<30 mL/min)

LDL 40醛4%

45 mg

135 mg Regular dose

45 mg For patients with renal impairment*

fenofibrate fenofibric acid Trilipix fenofibric acid fenofibric acid PPAR lipoprotein lipase Apo CIII TG TG LDL small dense LDL particle size LDL PPARa HDLHDL-C Apo AI AII

Trilipix (fenofibric acid) Fenofibric acid

/

(glucuronic acid) fenofibric acid carbonyl (

Half-Life

CYP450 )

statin

20 hrs

fenofibric acid choline fenofibrate

fenofibrate

Trilipix 135mg

12

fenofibrate 160 or 200mg

mini-tablets

benzhydrol fenofibric acid

Trilipix â&#x20AC;&#x201C; choline fenofibrate Choline fenofibrate has an advantage over fenofibrate, in that it

dissociates to free fenofibric acid, allowing fenofibric acid to be rapidly and directly absorbed without requiring first-pass metabolism. In contrast, fenofibrate is an ester of fenofibric acid and requires enzymatic cleavage via first-pass metabolism to form fenofibric acid. Fenofibric acid the active metabolite of fenofibrate, contains a carboxylic acid moiety instead of an ester moiety and has relatively low potential for interaction with statins.

*INNOVATIONS IN ORAL SOLID DRUG DELIVERY, 2010

Trilipix – mini-tablets drug delivery system Mini-tablets in one system for greater flexibility The launch of new drugs which incorporate a number of mini-tablets provides a very flexible oral dosage option which can incorporate different mini-tablets, each one formulated individually and designed to release drug at different sites so that higher dose loading is possible within the gastro-intestinal tract. It is also possible to incorporate mini-tablets of different sizes so that high drug loading is possible. The Trilipix® fenofibrate product launched by Abbott in January 2009 is comprized of a number of mini-tablets. Another technology using a similar approach is the PRODAS® delivery system from Alkermesiii.

*NEW TRENDS IN DEVELOPMENT OF ORAL CONTROLLED RELEASE DOSAGE FORMS, 2012

Fenofibrate 160mg So-called â&#x20AC;&#x153;food effectâ&#x20AC;? complicates administration fenofibrate 160 mg: Absorption in fasting and fed conditions

Sauron R et al. Int J Clin Pharmacol Ther. 2006;44(2):64-70.

Trilipix vs fenofibrate in GI tract absorption

*Journal of Clinical Pharmacology, 2010;50:914-921

Trilipix vs fenofibrate in GI tract absorption

*Journal of Clinical Pharmacology, 2010;50:914-921

Trilipix vs fenofibrate in GI tract absorption

In conclusion: Fenofibric acid is well obsorbed throughout the GI tract and has greater bioavailability than fenofibrate in all GI regions.

*Journal of Clinical Pharmacology, 2010;50:914-921

The only Phase III trial programme to evaluate the combination of a fibric acid derivative and a statin Double-blind randomised trials1 (n=2,698)

Open-label extension Year 12 (n=1,895)

Open-label extension Year 23 (n=310)

12 weeks

52 weeks

52 weeks

Trilipix® + Moderate-dose statin

Trilipix® + Moderate-dose statin

Trilipix® (n=490)

Randomisation 2,715 patients with mixed dyslipidaemia

Trilipix® + Low-dose statin (n=490) Trilipix® + Moderate-dose statin (n=489) Low-dose statin (n=493) Moderate-dose statin (n=491) High-dose statin (n=245)

1. Jones PH et al. J Clin Lipidol. 2009;3(2):125-37. 2. Bays HE et al. J Clin Lipidol. 2008;2:426-35. 3. Kipnes MS et al. Clin Drug Investig. 2010;30(1):51-61. *Low-dose statin：simva 20mg ; atorva 20mg; rosuva 10mg *Moderate-dose statin：simva 40mg ; atorva 40mg; rosuva 20mg *High-dose statin：simva 80mg ; atorva 80mg; rosuva 40mg

All subjects had mixed dyslipidaemia The study population included men and women aged ≥18 years with

confirmed mixed (type IIb) dyslipidemia Fasting, off-treatment lipid levels for inclusion: TG ≥ 150 mg/dL HDL-C < 40 mg/dL for men and < 50 mg/dL for women LDL-C ≥ 130 mg/dL At baseline, the study population’s overall mean lipid levels reflected

the targeted mixed dyslipidemia, HDL-C (38.4 mg/dL) TG (282.2 mg/dL) LDL-C (157.3 mg/dL).

1. Jones PH et al. Clin Drug Invest. 2008;28:625-34.

Primary endpoints The mean percent change from baseline to week 12 in1: Triglycerides - combination vs. statin monotherapy HDL-C - combination vs. statin monotherapy LDL-C - combination vs. Trilipix速 monotherapy

For combination treatment to be considered successful, all three primary endpoints had to be significant1

1. Jones PH et al. Clin Drug Invest. 2008;28:625-34.

Trilipix® significantly improves all 3 key lipid parameters in combination with a low-dose statin Trilipix® + Low-dose statin: Efficacy through 12 weeks (pooled results)1 HDL-C

Mean change from baseline to 12 weeks (%) plus baseline and final value (mmol/L)

LDL-C

1.16

20

+18% 10

TG

8.7%

1.05 3.23

+7%

3.19

4.10

4.03

0

0.99

-5%

0.99

3.78

10

-17% 2.46

-20

-33%

-30

2.64

-44%

-40

Low-dose statin

1.66 -50

p<0.001

p<0.001

p<0.001

*Low-dose statin：simva 20mg ; atorva 20mg; rosuva 10mg

1. Jones PH et al. J Clin Lipidol. 2009;3(2):125-37.

Trilipix® 135 mg

Trilipix® 135 mg + Low-dose statin

Three times more patients achieved all key lipid goals with Trilipix®-statin combination therapy Post-hoc analysis: Percentage of patients achieving optimal lipid levels* after 12 weeks (LDL-C, HDL-C, TG, non-HDL-C and ApoB)

% of patients achieving optimal levels

25 20

3.1fold

18.5%

p<0.001

22.3%

3.3fold p<0.001

15 10

6.8%

6.0%

5 0

Low-dose statin

Trilipix® + Low-dose statin

Moderate-dose statin

Trilipix® + Moderate-dose statin

*Optimal levels were defined as: LDL-C <100 mg/dL, HDL-C >40 mg/dL for men and >50mg/dL for women, TG <150 mg/dL, non–HDL-C <130 mg/dL and ApoB <90 mg/dL

1. Mohiuddin SM et al. Curr Med Res Opin. 2011;27(5):1067-78.

*Low-dose statin：simva 20mg ; atorva 20mg; rosuva 10mg *Moderate-dose statin：simva 40mg ; atorva 40mg; rosuva 20mg

Long-term efficacy: Lipid improvements sustained through 2 years Open-label extension: Lipid levels through week 116 with Trilipix® + moderate-dose statin therapy (n=310), pooled results1

Mean change from baseline (%)

HDL-C +17.4%

LDL-C –40.4% TG –46.4% RCT = randomised controlled trials

Study design on slide 35

Similar long-term efficacy was observed with each of the three combinations1 1. Kipnes MS et al. Clin Drug Investig. 2010;30:51-61.

*Moderate-dose statin：simva 40mg ; atorva 40mg; rosuva 20mg

Combine with confidence: A favourable safety profile in combination with a statin Safety and tolerability comparable to Trilipix® and statin

monotherapy, with no new or unexpected safety concerns1 Randomised controlled trials: Key safety results after 12 weeks (n [%])1 Trilipix® monotherapy

Low-dose statin

Trilipix® + low-dose statin

Moderatedose statin

Trilipix® + moderate-dose statin

(n=490)

(n=493)

(n=490)

(n=491)

(n=489)

CPK >5x ULN

0 (0.0)

2 (0.4)

6 (1.2)

3 (0.6)

1 (0.2)

Rhabdomyolysis

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

Renal

Creatinine increased 50% and above ULN

9 (1.9)

3 (0.6)

13 (2.7)

1 (0.2)

15 (3.2)

Hepatic

ALT and/or AST >3x ULN on 2 consecutive visits

9 (1.9)

0 (0.0)

6 (1.3)

0 (0.0)

6 (1.3)

Adverse drug reaction

Muscular

There were no significant differences between combination therapy and the corresponding statin monotherapy ULN = upper limit of normal; CPK, creatine phophokinase; ALT, alanine transaminase; AST, aspartate aminotransferase 1. Kipnes MS et al. Clin Drug Investig. 2010;30:51-61.

*Low-dose statin：simva 20mg ; atorva 20mg; rosuva 10mg *Moderate-dose statin：simva 40mg ; atorva 40mg; rosuva 20mg

Favourable safety profile demonstrated through 2 years with Trilipix® + moderate-dose statin therapy No statistically significant difference in incidence was observed among treatment groups1 Open-label extension: Key safety results after 2 years (n [%])1 Trilipix® + Simvastatin 40 mg

Trilipix® + Atorvastatin 40 mg

Trilipix® + Rosuvastatin 20 mg

(n=50)

(n=86)

(n=174)

Rhabdomyolysis

0 (0.0)

0 (0.0)

0 (0.0)

CPK >5x ULN

0 (0.0)

1 (1.2)

4 (2.3)

CPK >10x ULN

0 (0.0)

1 (1.2)

3 (1.7)

Creatinine ≥2x baseline*

3 (6.0)

1 (1.2)

3 (1.7)

ALT >3x ULN

0 (0.0)

0 (0.0)

2 (1.1)

0 (0.0)

0 (0.0)

1 (0.6)

Adverse drug reaction

Muscular

Renal

on 2 consecutive visits

Hepatic AST >3x ULN on 2 consecutive visits

*Baseline for safety analyses was the treatment-naïve baseline value in the controlled studies at the time of randomisation following the 6-week washout period 1. Kipnes MS et al. Clin Drug Investig. 2010;30:51-61.

Fenofibrate versus Trilipix fenofibrate 160 mg

Trilipix® 135mg

Micronised

Choline fenofibrate

fenofibrate

(fenofibrate acid)

Absorption

4-5 hours

3 hours

Influence of Food

Increases with food intake

Not affected by food intake

Compliance

-

Less Likely to Skip or Forget Doses

Indicated for statin co-prescription

X

O

Long term safety & efficacy study with statins co-prescription

With simvastatin only

Rosuvastatin、 、Atorvastatin & Simvastatin

Chemical Difference

Photo

Structural formula

1. fenofibrate 160, 145 & Trilipix page inserrt 2. Kipnes MS et al. Clin Drug Investig. 2010;30:51-61.

Take Home Message LDL is still the primary goal of dyslipidemia therapy There seems no role for niacin, Omega-3 fatty acids, and CETP inhibitor therapy for dyslipidemia (Residual risk reduction) Residual risk reduction remains when TG remains high, HDL is low Fibrates might be the choice for the sub-group patients Trilipix: Not affected by food intake Long-term safety and efficacy seems better than fenofibrate The first fibric acid derivative indicated for use in combination with a statin in Taiwan.

Limitation: Self paid

Thanks for your attention