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