Enfoque farmacológico del HDL colesterol

ENFOQUE FARMACOLOGICO DEL HDL-COLESTEROL SEC - 2010 Lina Badimon Barcelona Cardiovascular Research Center (CSIC-ICCC) IIB-Sant Pau, Hospital de la Santa Creu i Sant Pau

Octubre 2010

EN LA ERA DE LAS ESTATINAS • Supervivencia – Aprox. 30% reducción muerte • Presentacion de eventos cardiovasculares – Aprox. 34% reducción de eventos coronarios

Major CVD Events in Statin-Trials

La Rosa JC et al. JAMA 1999; 282: 2340-46

Treatment of Hyperlipemia High LDL-C Therapeutic Lifestyle Change Drug Therapy Therapy of Choice: Statin RESIDUAL RISK: WHAT ELSE? HDL ?

CV events and HDL despite statins Residual high risk for CV events despite statin therapy among patients with low HDL-C levels

CV events and HDL despite statins Residual high risk for CV events despite statin therapy among patients with low HDL-C levels

INTER-HEART Study: Risk Factors for MI Risk Factor

Odds Ratio adjusted for all other risk factors

APO-B/APO-A1 (Quintile 5 vs 1)

3.25 (2.81 - 3.76)

Current smoking

2.87 (2.58 - 3.19)

Diabetes

2.37 (2.07 – 2.71)

Hypertension

1.91 (1.74 – 2.10)

Abdominal obesity

1.62 (1.45 – 1.80)

Psychosocial stress

2.67 (2.21 – 3.22)

Daily vegetables/fruit

0.70 (0.62 – 0.79)

Exercise

0.86 (0.76 – 0.97)

Alcohol Usage

0.91 (0.82 – 1.02) Yusuf S et al. Lancet. 2004;364:937-952

LDL-C Levels versus Events in Landmark Statin Trials % with CHD event

25

4S-P Secondary P

20

Primary P

LIPID-P

4S-S

15 10

TNT-ATOR80 Prove-it-Ator

5 0

PROSPER-S CARE-SLIPID-S

JUPITER-R

1.0 (40)

1.6 (60)

AFCAPS-S

2.1 (80)

2.8 (110)

Prava

PROSPER-P

TNT-ATOR10 Prove-it Prava HPS-S ASCOT-S*

Simva

CARE-P HPS-P

WOSCOPS-S

WOSCOPS-P

Atorva

ASCOT-P*

3.4 (130)

Rosu

AFCAPS-P

JUPITER-P

3.9 (150)

LDL-C, mmol/L (mg/dL)

4.4 (170)

Lova

4.9 (190)

5.4 (210)

S = statin treated P = placebo treated *Extrapolated to 5 years

Atherothrombosis: A Generalized and Progressive Process Endothelial dysfunction

Thrombosis

LDL-CHOLESTEROL

Unstable angina ACS MI Ischemic stroke/TIA

HDL-CHOLESTEROL

Atherosclerosis

Critical leg ischemia Intermitent claudication CV death

Stable angina/ Intermittent claudication

Badimon L et al 2008

REMODELLING INDUCED BY LDL IN THE VESSEL WALL

Loss of SMC Content in Advanced Plaques versus Early Lesions human coronary arteries m

m

fp

early lesions

advanced lesions

70 60

Îą-actin

50 40

%

a-actin CD68

30 20

CD68

10 0 AIT

I-II

III

IV-V

Types of Lesions

VI

VII-VIII

agLDL impair migration of human coronary VSMC VSMC + /- agLDL (16 hours)

0h double sided scrape-wound

Padro et al. Cardiovasc Res 2007

agLDL affects subcellular F-actin organization during cell attachment control VSMC

agLDL

1 hour

+ /- agLDL (16 hours)

released

3 hours

Seeded FCS-coated dishes 1.5 x105 cells - /+ agLDL 6 hours

F-Actin: Allexa -594 Phalloidin MRLC: FITC ; Colocalization

Padro et al. Cardiovasc Res 2008

LDL-C and change in percent atheroma volume (IVUS)† 2

REVERSAL5

1.5

pravastatin

CAMELOT4 placebo

Change in Percent Atheroma Volume* (%)

1 ACTIVATE1 placebo

0.5

A-Plus2

REVERSAL5

placebo

atorvastatin

Progression

0 50

60

70

90

Mean LDL-C (mg/dL)

-0.5 -1

80

100

110

120

Regression

ASTEROID3 rosuvastatin

†ASTEROID and REVERSAL investigated active statin treatment; A-PLUS, ACTIVATE AND CAMELOT investigated non-statin therapies but included placebo arms who received background statin therapy (62%, 80% and 84% respectively). *Median change in PAV from ASTEROID and REVERSAL; LS mean change in PAV from A-PLUS, ACTIVATE AND CAMELOT 1 Nissen S et al. N Engl J Med 2006;354:1253-1263. 2 Tardif J et al. Circulation 2004;110:3372-3377. 3 Nissen S et al.

JAMA 2006;295 (13):1556-1565 4 Nissen S et al. JAMA 2004;292: 2217–2225. 5 Nissen S et al. JAMA 2004; 291:1071–1080

Treatment of Hyperlipemia High LDL-C Therapeutic Lifestyle Change Drug Therapy Therapy of Choice: Statin RESIDUAL RISK: WHAT ELSE?

COMBINATION LIPID-ALTERING DRUG THERAPY WITH STATINS • Ezetimibe and statins • Bile acid sequestrants and statins • PPAR agonists and statins • Fish oils and statins • Niacin and statins • CETP inhibition and statins

RESIDUAL RISK after LDL lowering

Lipid Deposition in Atherosclerosis imbalance between chol influx and efflux

J Clin Invest 1990;85:1234-41.

Nissen et al. JAMA 2006;295:1556-65.

Trial evidence supporting the raise of HDL CORONARY DRUG PROJECT (NIACIN ↑ 25% HDL) LIPID RESEARCH CLINICAL TRIAL (CHOLESTRYRAMINE ↑ 3% HDL) HELSINKY HEART TRIAL (GENFIBROZIL ↑10% HDL) VETERANS HDL INTERVENTION TRIAL (GENFIBROZIL ↑6% HDL)

Imaging/Angiographic studies FATS (nicotinic acid) HATS (nicotinic acid) REVERSAL (statin) ASTEROID (statin) Apo A-I Milano (Apo A-I) ERASE (rHDL)

Estrogens?

Torcetrapib????

EFFECTS OF LIPID-MODIFYING DRUGS

Parhofer KG, Vascular Health and Risk Management 2009:5

FIBRATES AND STATINS

ACCORD-Lipid Study Design • Lipid Trial question: whether combination therapy with a statin plus a fibrate would reduce cardiovascular disease compared to statin monotherapy in people with type 2 diabetes mellitus at high risk for cardiovascular disease.

Henry C. Ginsberg, MD College of Physicians & Surgeons , Columbia University, New York For The ACCORD Study Group

ACC - March 2010

• All participants on open-labeled simvastatin, 20 to 40 mg/day – Simvastatin dose complied with lipid guidelines • Patients randomized to double-blind placebo or fenofibrate, 54 to 160mg/day – Dosing based upon eGFR level • Only blinded ACCORD trial • Observed Follow-up: 4 to 8 years (mean 4.7 years)

ACCORD: Systemic lipid levels Mean LDL-C

Mean Total Cholesterol 200

120

190

110 100 Feno

170

Placebo

160

80

150

70

140 0 N = 5483

1 5180

2

3

4

5

6

7

4988

4783

5250

3377

1668

491

Feno

90

l /d g m

l /d g m

180

Placebo

60

Years PostRandomization

0

1

N = 5483

5180

Mean HDL-C

3

4

5

6

4988

4783

5250

3377

1668

7

Years PostRandomization

491

Median Triglycerides

42

170

41

160 150

40

Feno Placebo

39

l /d g m

l /d g m

2

Feno

140

Placebo

130

38

120

37 0 N = 5483

1 5180

2

3

4

5

6

4988

4783

5250

3377

1668

7 491

Years PostRandomization

110 0 N = 5432

1

2

3

4

5180

4988

4783

5250

5 3377

6

7

1668

491

Years PostRandomization

Primary Outcome Fenofibrate (N=2765)

Placebo (N=2753)

Rate Events (%/yr)

Rate Events (%/yr)

N of

N of

HR (95% CI) P Value

mary Outcome: Major Fatal or Nonfatal Cardiovascular Event

291

2.24

310

2.41

0.92 (0.79 - 1.08)

0.32

Prespecified Secondary Outcomes Fenofibrate (N=2765) N of Rate Events (%/yr)

Placebo (N=2753) N of Rate Events (%/yr)

HR (95% CI)

P Value

Outcome Primary + Revasc + hospitalized CHF

641

5.35

667

5.64

0.94 (0.85-1.05)

0.30

Major Coronary Event

332

2.58

353

2.79

0.92 (0.79-1.07)

0.26

Nonfatal MI

173

1.32

186

1.44

0.91 (0.74 - 1.12)

0.39

Total Stroke

51

0.38

48

0.36

1.05 (0.71 - 1.56)

0.80

Nonfatal Stroke

47

0.35

40

0.30

1.17 (0.76 - 1.78)

0.48

Total Mortality

203

1.47

221

1.61

0.91 (0.75 - 1.10)

0.33

Cardiovascular Death

99

0.72

114

0.83

0.86 (0.66 - 1.12)

0.26

Fatal/Nonfatal CHF

120

0.90

143

1.09

0.82 (0.65 - 1.05)

0.10

Fish Oils and Statins • Marine fish oils rich in omega-3 fatty acids lower triglyceride levels and may be effective in combination with statins to treat patients with combined hyperlipidemia • Fish oils plus statin may often be an alternative to fibrate plus statin • Fish oils may have other cardiovascular effects complementary to those of statins, such as: – Reduction in malignant ventricular dysrhythmias – Increased heart rate variability – Antithrombotic effects – Improved endothelial reactivity/relaxation – Anti-inflammatory effects – Slight lowering of blood pressure Bays HE et al. Expert Opin Pharmacother 2003;4:1901-1938.

Kris-Ethrton PM et al. Circulation 2002;106:2747-2757.

Fish Oils Indications: Adjunctive therapy to diet Hypertriglyceridemia (Type IV and V) With statins or other LDL-C– lowering drugs in mixed hyperlipidemia Efficacy: Decrease TG 30–40% LDL-C remains the same or increases Little change in HDL-C Side Effects: GI upset and a “fish burp” Intervention Lyon Heart Study (dietary), GISSI Trials: Prevenzione Trial, others

ApoA-I Milano and CAD Double-blind, placebo-control multicenter study (n=47) End-point: IVUS coronary artery Treatment: 5 weekly doses of 15 or 45 mg/Kg ETC-216

Atheroma Burden

Baseline

F/U

change

Placebo

34.8 ± 8

34.9 ± 9.7

0.14 %

Treatments

38.9 ± 7

37.9 ± 6.9 -1.06 %*

18 months of ATORVA-80 resulted in only 0.4% regression Nissen S et al. JAMA 2003;290:2292-2300

Delipidated HDL and Plaque Regression 28 ACS patients ; Autologous delipidated HDL HDL apheresis/reinfusion 7 times once-a-week Pre-beta HDL: 5.6 to 92.8% Alpha HDL: 92.8 to 20.9%

R. Waksman EuroPCR 2008 in Barcelona May 2008

Niacin Niacin had demonstrated to significantly increase HDL levels but its clinical use is significantly hampered by the flushing episodes.

ARBITER-3 even showed plaque regression when Niacin was combined with statin (Taylor A et al.)

EFFECTS OF NICOTINIC ACID ON LIPOPROTEINS

Parhofer KG, Vascular Health and Risk Management 2009:5

SELECTED RANDOMIZED CONTROLLED TRIALS OF NICOTINIC ACID

Parhofer KG, Vascular Health and Risk Management 2009:5

ARBITER 6

Taylor AJ, N engl j med 361;22, 2009

Baseline CHO 146 mg/dl HDL 43 mg/dl LDL 82 mg/dl TGL 124 mg/dl

Taylor AJ, N engl j med 361;22, 2009

ARBITER 6

Maccubbin D, Int J Clin Pract. 2008 Dec;62(12):1959-70

Maccubbin D, Int J Clin Pract. 2008 Dec;62(12):1959-70

Emerging Strategies to raise HDL CETP Inhibitors +/Apo A-I Milano ($$$$$) PPAR’s Agonists alpha - fibrates gamma - glitazones Rimonabant (removed from market) Non-flushing Niacin (Cordaptive/ /Tredaptive) Apo A-I mimetics LXR/RXR activation SR-B1 overexpression ABC 1 gene overexpression

Reverse Cholesterol Transport

Brewer B, NEJM 2004;350:1491

CETP-Inhibitors: Torcetrapib ď ś

IVUS-based study to be completed in 2006 N= 1,100 patients; non-obstructive CAD ( 20-50%) Randomized into Atorva vs. Atorva/torcetrapib Angiogram and IVUS at baseline and 1-year

WITHDRAWN

ď ś

ILLUMINATE Phase III trial with n=13,000 CHD patients Multi-center, randomized, parallel group evaluation treatments: Atorva vs. Atorva/torcetrapib End-point: occurrence of major CV events.

Cholesteryl Ester Transfer Protein Inhibition in Cardiovascular Risk Management: Ongoing Trials will End the Confusion.

Cholesteryl ester transfer protein (CETP) contributes to an atherogenic lipoprotein profile by redistributing cholesteryl esters from high density lipoprotein (HDL) toward apolipoprotein Bcontaining lipoproteins, especially when the concentration of acceptor triglyceride-rich lipoproteins is elevated.

However, this lipid transfer protein may have antiatherogenic proprerties as well.

Experimental evidence is accumulating which suggests that the atheroprotective reverse cholesterol transport pathway, whereby cholesterol is removed from peripheral macrophages to the liver for metabolism and biliary excretion, is stimulated by CETP in vivo.

CETP could also play a role in host defense against infection and inflammatory processes.

Moreover, recently published observational studies show that higher CETP levels may confer cardiovascular protection, whereas reported associations of cardiovascular disease (CVD) with CETP gene variations are equivocal.

The concept that HDL cholesterol raising through inhibition of CETP may ameliorate CVD risk has been challenged by the failure of the CETP inhibitor, torcetrapib.

Adverse clinical outcome associated with the use of this CETP inhibitor has been attributed to offtarget effects, which relate to stimulation of aldosterone.

Other CETP inhibitors, such as dalcetrapib and anacetrapib, are unlikely to increase blood pressure.

Dalcetrapib is less potent than anacetrapib, which doubles HDL cholesterol.

Both inhibitors considerably lower LDL cholesterol.

Serious concerns remain about the validity of the concept that HDL cholesterol raising by means of CETP inhibition is a viable strategy.

Results of ongoing clinical trials with these drugs will have to be awaited before making up the balance between possible benefits and harms related to pharmacological CETP inhibition

Kappelle PJ, van Tol A, Wolffenbuttel BH, Dullaart RP. Cardiovasc Ther. 2010 Jul 14. [Epub ahead of print]

COMBINATION LIPID-ALTERING DRUG THERAPY WITH STATINS • Ezetimibe and statins • Bile acid sequestrants and statins • PPAR agonists and statins • Fish oils and statins • Niacin and statins • CETP inhibition and statins

Proteomic Analysis of HDL Protein

First dimension - IEF pI 4

7

120 kDa

Apo A-I

Albumin

Trypsin digestion

Alpha 1 antitrypsin PON 1 ApoJ

Apo A-IV

Peptides Cr2/C3d Complex Apo E Apo A-I

Haptoglobin

Apo A-IV

Apo M

Mass spectrometry ďƒ˜ MALDI-TOF Mass fingerprint

Databases

10 Second dimension PAGE-SDS 12% Cubedo J, Padro T, Badimon L. 2010

Protein Identification

Best Treatment In Atherosclerosis

ATHEROSCLEROSIS PROGRESSION Lower LDL-Cho

REGRESSION Raise HDL-Cho

NCEP ATP III: LDL-C Goals High Risk

Moderately High Risk

Moderate Risk

Lower Risk

CHD or CHD risk equivalents

≥ 2 risk factors

≥ 2 risk factors

< 2 risk factors

(10-yr risk >20%)

(10-yr risk 10-20%)

(10-yr risk <10%)

190 Target 160 mg/dL

LDL-C level

160 Target 130 mg/dL 130 -

Target 100 mg/dL

100 -

70 -

Target 130 mg/dL

or optional 100 mg/dL**

or optional 70 mg/dL*

*Therapeutic option in very high-risk patients and in patients with high TG, non-HDL-C<100 mg/dL; ** Therapeutic option; 70 mg/dL =1.8 mmol/L; 100 mg/dL = 2.6 mmol/L; 130 mg/dL = 3.4 mmol/L; 160 mg/dL = 4.1 mmol/L Grundy SM et al. Circulation 2004;110:227-239.

ALGORITHM FOR TREATING PATIENTS WITH DIFFERENT FORMS OF DYSLIPIDEMIA

Parhofer KG, Vascular Health and Risk Management 2009:5

Sandra Camino Maísa García Montse Gómez-Pardo Roberta Lugano Vicenta LLorente-Cortés Laura Nasarre Marta Otero Teresa Padró Esther Peña

BARCELONA CARDIOVASCULAR RESEARCH CENTER CSIC-ICCC HOSPITAL DE LA SANTA CREU I SANT PAU