1. Current Status of HDL Therapy to Reduce Residual Cardiovascular Risk in the Statin-Treated Patient
Christie M. Ballantyne, MD
Center for Cardiovascular Disease Prevention
Methodist DeBakey Heart & Vascular Center
Baylor College of Medicine
Houston, Texas

2. Christie M. Ballantyne, MD Financial Disclosure
Grant/Research Support: Abbott, AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Genentech, Kowa, Merck, Novartis, Roche, Sanofi-Synthelabo, Takeda, NIH, ADA, AHA
Consultant: Abbott, Adnexus, Amarin, Amylin, AstraZeneca, Bristol-Myers Squibb, Esperion, Genentech, GlaxoSmithKline, Idera Pharma, Kowa, Merck, Novartis, Omthera, Pfizer, Resverlogix, Roche, Sanofi-Synthelabo, Takeda
Speakers Bureau: Abbott, GlaxoSmithKline, Merck
Honoraria: Abbott, Adnexus, Amarin, Amylin, AstraZeneca, Bristol-Myers Squibb, Esperion, Genentech, GlaxoSmithKline, Idera Pharma, Kowa, Merck, Novartis, Omthera, Pfizer, Resverlogix, Roche, Sanofi-Synthelabo, Takeda

3. HDL-C and Statin Trials
What is the risk associated with low HDL-C for MI and stroke? What are optimal levels?
Are low HDL-C/high TG still associated with increased CVD risk after high-efficacy statin therapy?
Does adding a second agent to statin therapy, which reduces TGs, non HDL-C or raises THL-C have additive effects on atherosclerosis/CVD events?

4. Case On exam: BMI 28.6, waist 40" Current meds:
62-year-old male with history of hypertension and hyperlipidemia admitted with unstable angina, had urgent PCI with stent for 95% proximal LAD lesion; multiple <50% lesions in RCA, Circ, and LAD
On exam:
BMI 28.6, waist 40"
Current meds:
lisinopril 20 mg/HCTZ 12.5 mg
ASA 325 mg

5. Lab Results on Arrival in ER
TC 203 mg/dL
TG 330 mg/dL
HDL-C 38 mg/dL
LDL-C 100 mg/dL
non-HDL-C 165 mg/dL
Glucose 115 mg/dL
Cr 1.2
BUN 20 mg/dL

6. What is the Optimal LDL-C? ARIC
Men
Women
Relative Risk for Incident CHD
LDL-C Quintiles
mmol/L
mg/dl
(median)
2.45 95
3.10
120
3.55
137
4.04
156
4.78
185
2.27 88
2.93
113
3.40
131
3.94
152
4.84
187
Adjusted for age and race, 12-year follow-up; N=12,339
Sharrett AR et al. Circulation 2001;104:

7. What is the Optimal HDL-C? ARIC
Men
Women
Relative Risk for Incident CHD
HDL-C Quintiles
mmol/L
mg/dl
(median)
0.80 31
0.97 38
1.11 43
1.27 49
1.60 62
1.01 39
1.25 48
1.44 56
1.69 65
2.09 81
Adjusted for age and race, 12-year follow-up; N=12,339
Sharrett AR et al. Circulation 2001;104:

8. Hazard Ratios for CHD or Ischemic Stroke across Quantiles of Usual HDL-C
12,785 cases;
68 studies)
Ischemic Stroke
(n=173,312;
2,534 cases;
32 studies)
Adjusted for age and sex
Adjusted for age, sex, SBP, smoking status, Hx DM, BMI, and lipids
Referent: highest quantile for HDL-C
Figure 1. Hazard Ratios for Coronary Heart Disease or Ischemic Stroke Across Quantiles of Usual Triglyceride, HDL-C, and Non–HDL-C Levels
Analyses for coronary heart disease were based on 302 430 participants (involving 12 785 cases) from 68 studies. Analyses for ischemic stroke were based on 173 312 participants (involving 2534 cases) from 32 studies. Regression analyses were stratified, where appropriate, by sex and trial group. Values with further adjustments were adjusted for age, systolic blood pressure, smoking status, history of diabetes mellitus, and body mass index; furthermore, analyses of loge triglyceride were adjusted for high-density lipoprotein cholesterol (HDL-C) and non–HDL-C levels, analyses of HDL-C were adjusted for non–HDL-C and loge triglyceride levels, and analyses of non–HDL-C were adjusted for HDL-C and loge triglyceride levels. Studies with fewer than 10 cases were excluded from analysis. Sizes of data markers are proportional to the inverse of the variance of the hazard ratios. The y-axes are shown on a log scale. The x-axes for triglyceride are shown on a log scale. Referent groups are lowest quantiles for triglyceride and non–HDL-C and highest quantiles for HDL-C. Error bars indicate 95% confidence intervals.
Emerging Risk Factors Collaboration. JAMA 2009;302:1993–2000.

9. Drugs That Raised HDL-C But Did Not Reduce CVD Events
Estrogen/progestin: WHI
HDL-C increased by 7.3% (vs. placebo)
CHD risk increased by 29%
Stroke risk increased by 41%
Torcetrapib: ILLUMINATE
HDL-C increased by 70.3% (vs. placebo)
CHD risk increased by 21%
Stroke risk increased by 8%
Writing Group for the WHI Investigators. JAMA 2002;288:321–333.
Barter PJ et al. N Engl J Med 2007;357:2109–2122.

10. Insights from GWAS with Levels of LDL-C, HDL-C, TG
Many new loci identified which are associated with lipid levels
Loci which are associated with LDL-C levels usually are associated with CHD
Loci associated with HDL-C and TG levels are not as consistently associated with CHD
Implication: not all pathways which alter HDL-C levels have the same impact on the pathogenesis of atherothrombotic CHD and therefore the same may be true of drugs which modify HDL metabolism
Chasman DI et al. PLoS Genet 2009;5:e | Kathiresan S et al. Nat Genet 2009;41:56–65. | Myocardial Infarction Genetics Consortium. Nat Genet 2009;41:334–341.

11. Event Reduction with Statin Therapy in Patients with Low vs. High HDL-C
Coronary Events (%)
52
38
39
<39
>44
<33
43
<43
40
34 4S
LIPID
CARE
WOSCOPS
AFCAPS
Adapted from Ballantyne CM et al. Circulation 1999;99:

12. Low HDL-C and CV Events: TNT
HDL-C Quintiles,a
mg/dL
5-Year Risk of Major CVD Events, %
Patients with LDL-C ≤70 mg/dL on statina,b Q1
<37 Q2
37 to <42 Q3
42 to <47 Q5
≥55 Q4
47 to <55
Hazard Ratio
Versus Q1*
0.85
0.57
0.55
0.61
39% Lower Risk
aOn-treatment level (3 months statin therapy); n = 2661
bMean LDL-C, 58 mg/dL; mean TG, 126 mg/dL
*P=.03 for differences among quintiles of HDL-C
Barter P, et al. New Engl J Med. 2007;357:

13. JUPITER: CVD Event Rates by Quartiles of HDL-C and apo A-I
Median LDL-C with rosuvastatin: 55 mg/dL
Ridker PM et al. Lancet 2010;376:

14. Effects on major vascular events per 1-mmol/L reduction in LDL-C by baseline HDL-C in 5 more-vs-less trials
PROVE IT
A to Z
TNT
IDEAL
SEARCH
Events per annum, %
≤1.0
1.0–1.3
≥1.3
HDL-C, mmol/L
Cholesterol Treatment Trialists' (CTT) Collaboration. Lancet 2010;376:

15. Event Trials JELIS ACCORD AIM-HIGH HPS2-THRIVE IMPROVE IT dal-Outcomes
TIMI 55 REVEAL
REDUCE IT

16. Addition of Eicosapentaenoic Acid (EPA) to Statin Therapy in Japanese Patients
JELIS Results
Statin (n = 9319)
Statin + EPA 1.8 g (n = 9326)
Major CHD Eventsa
Lipid Effects
Addition of Eicosapentaenoic Acid (EPA) to Statin Therapy in Japanese Patients.
This study tested the hypothesis that long-term use of eicosapentaenoic acid (EPA) is effective for prevention of major CHD events in hypercholesterolemic patients in Japan who consume a large amount of fish. A total of patients with a total cholesterol of >250 mg/dL were recruited from local physicians throughout Japan between 1996 and Patients were randomly assigned to receive either 1.8 g of EPA daily with a statin (n = 9326) or statin only (n = 9319) for a 4.6-year mean follow-up. The primary endpoint was any major CHD event [sudden cardiac death, fatal and nonfatal MI, unstable angina pectoris, angioplasty, stenting, or coronary artery bypass grafting (CABG)]. At mean follow-up of 4.6 years, 262 (2.8%) patients in the statin + EPA group and 324 (3.5%) in statin monotherapy group experienced a major CHD event, representing a 19% relative risk reduction in major CHD events with addition of EPA to statin therapy (P=0.011). Post-treatment LDL-C concentrations decreased by ~25% in both groups; thus, serum LDL-C was not a significant factor in a reduction of risk for major CHD events. Addition of EPA to statin therapy reduced TG by 9%, compared with a 4% reduction in TG with statin monotherapy (P<.001). There were only small changes in HDL-C in both treatment groups. In conclusion, the addition of EPA is a promising treatment for prevention of major CHD events, and especially nonfatal coronary events, in Japanese hypercholesterolemic patients. The mechanism by which EPA exerts its cardioprotection appears to be independent of a reduction in LDL-C. The beneficial effects of EPA may be related to an attenuation of thrombosis, inflammation, and arrhythmia, in addition to a reduction in triglycerides; however, the mechanism of EPA has not been elucidated. The authors caution that because the population was exclusively Japanese, the results cannot be generalized to other populations.1
Reference
1. Yokoyama M, et al. Lancet. 2007;369:
19% Reduction
P=.011
Event Rate, %
Change From Baseline, %
P<.001
LDL-C
HDL-C TG
4.6-year mean follow-up
aSudden cardiac death, fatal and nonfatal MI, unstable
angina pectoris, angioplasty, stenting, or CABG
Yokoyama M, et al. Lancet. 2007;369:

17. Patient subgroup - TG >150mg/dL and HDL <40mg/dL: JELIS
Saito, 2008

18. ACCORD - Lipid Primary Endpoint Secondary Endpoint
fenofibrate and simvastatin mg/d
Inclusion Criteria
LDL-C
estimated 60 to 180 mg/dL when untreated
HDL-C
<55 mg/dL for women/AA OR
<50 mg/dL for all other gender-race groups
Triglycerides
<750 mg/dL on no therapy OR
<400 mg/dL on treatment with lipid lowering drugs
Stable Type 2 DM
A1C 7.5% to 9% (more meds) OR ≤11% (fewer meds)
Age previous CVD events OR
Age with:
anatomical ASCVD, albuminuria, LVH OR
≥2 CVD risk factors
BMI ≤45; Cr ≤1.5
simvastatin mg/d
placebo and simvastatin mg/d
Month 1
Months
Primary Endpoint
First occurrence of major CVD event
nonfatal heart attack
nonfatal stroke
cardiovascular death
total mortality
cardiovascular mortality
CHD events
total stroke
congestive heart failure
Secondary Endpoint
ACCORD Study Group. N Engl J Med 2010;362:

19. Years Post-Randomization Years Post-Randomization
ACCORD Lipid Trial: Kaplan-Meier Estimates of Cumulative Incidence
0.20
0.15
0.10
0.05
0.00
Primary Outcome
0.20
0.15
0.10
0.05
0.00
Total Mortality
Cumulative Incidence
Years Post-Randomization
Years Post-Randomization
Placebo Fenofibrate
ACCORD Study Group. N Engl J Med 2010;362:

20. ACCORD: Primary Outcome By Treatment Group and Baseline Subgroups
Fenofibrate
Placebo
Feno to Placebo Hazard Ratio
Interaction P-value
% Events (# in Grp)
Overall
10.5% (2765)
11.3% (2753)
LDL-C Tertile
≤ 84 mg/dl
9.4% (938)
12.12% (891)
0.1212
mg/dl
9.9% (934)
11.2% (922)
≥ 112 mg/dl
12.4 (877)
10.6% (927)
HDL-C Tertile
≤ 34 mg/dl
12.2% (964)
15.6% (906)
0.2374
35-40 mg/dl
10.1% (860)
9.5% (866)
≥ 41 mg/dl
9.1% (925)
9.0% (688)
Trig Tertile
≤ 128 mg/dl
9.9% (891)
11.3% (939)
0.6422
mg/dl
10.5% (924)
9.9% (913)
≥ 204 mg/dl
11.1% (934)
12.8% (888)
Trig/HDL
TG204+ /HDL ≤ 34
12.4% (485)
17.3% (456)
0.0567
All others
10.1% (2264)
10.1% (2284)
A1c Median
≤ 8.0
8.7% (1324)
10.6% (1335)
0.2045
8.1+
12.2% (1435)
11.9% (1415)
ACCORD Study Group. N Engl J Med 2010;362:
Feno Better Placebo Better

21. Comparison of ACCORD subgroup results with those from prior fibrate studies
Trial
(Drug)
Primary Endpoint:
Entire Cohort
(P-value)
Lipid Subgroup Criterion
Primary Endpoint: Subgroup
HHS (Gemfibrozil)
-34% (0.02)
TG > 200 mg/dl
LDL-C/HDL-C > 5.0
-71%
BIP
(Bezafibrate)
-7.3% (0.24)
TG ≥ 200 mg/dl
-39.5%
FIELD
(Fenofibrate)
-11% (0.16)
TG ≥ 204 mg/dl
HDL-C < 42 mg/dl
-27%
ACCORD
-8% (0.32)
HDL-C ≤ 34 mg/dl
-31%
ACCORD Study Group. N Engl J Med 2010;362: 21

22. APOA5 variants and response to combination statin and fenofibric acid therapy in mixed dyslipidemia
2228 individuals with mixed dyslipidemia participating in a multicenter, randomized, double-blind, active-controlled study comparing fenofibric acid alone, fenofibric acid in combination with a statin, or statin alone for 12 weeks were genotyped for 304 candidate SNPs
Multivariate linear regression analysis was performed for percent change in HDL-C, apoA-I, and TGs
SNPs in APOA5–ZNF259 region rs (P = 1.8 × 10–7), rs (P = 3.6 × 10–6), rs (P = 4.5 × 10–5), and rs (P = 1 × 10–4) were significantly associated with HDL-C response to combination therapy, with similar association for apoA-I
Haplotype composed of minor alleles of rs , rs964184, and rs was associated with positive response to combination therapy (P = 8.7 × 10–7) and had a frequency of 18% in the study population
Brautbar AB et al. Atherosclerosis 2011;219:737–742.

23. Simvastatin + Niacin ER
Vascular Disease
Age >45 years
Atherogenic Dyslipidemia
(HDL<40 or 50; TG>149; LDL<160)
CV Death
NFMI
Stroke
ACS
Simvastatin
3-5 yr
Simvastatin + Niacin ER
2-year enrollment
LDL-C target <80 mg/dl both groups (may add ezetimibe if needed)
3300 patients from 60 sites (U.S. and Canada)
Study Start Date: September 2005
Planned Study Completion Date: approximately 2H 2012/1H 2013
Study Discontinuation Date: May 2011

25. Key issues on design Open label LDL-c reported to the sites
Year 3 LDL-c: P, N
Placebo contained 50 mg of IR niacin in each tab of 500 mg or 1000 mg
Year 3 HDL-c: 39.1 mg/dl (increase 11.8 % P) , 44.1 (increase 25% niacin)

27. Effect of very low dose niacin on HDL-C in patients on statin therapy
50 nondiabetic, nonsmoking patients on stable statin therapy for 3 months (39 completed 3-month study)
Randomized to receive niacin 50 mg BID or placebo
Primary endpoints: change in HDL-C and patient-reported adverse events
Wink J et al. Am Heart J 2002;143:

28. Effect of very low dose niacin on HDL-C in patients on statin therapy
Wink J et al. Am Heart J 2002;143:

29. ER niacin/laropiprant 2 g/40mg
HPS2-THRIVE (Heart Protection Study 2 – Treating HDL to Reduce Vascular Events)
Does ER niacin/laropiprant 2 g/40mg daily prevent vascular events in high-risk patients who are receiving intensive LDL-C lowering treatment?
ER niacin/laropiprant 2 g/40mg
simvastatin 40 mg or ezetimibe/simvastatin 10/40 mg
Planned at least 4 years of treatment
Placebo
Patient Population
Subjects
Primary End Point
Age 50-80
History of MI or cerebrovascular atherosclerotic disease or PAD or diabetes mellitus with any of the above or with other evidence of symptomatic CHD
20,000
UK (n=7500), Scandinavia (n=5000), China (n=7500)
Major vascular events during the scheduled treatment period (nonfatal MI or coronary death, nonfatal or fatal stroke, or revascularisation)
Study start: January 2007  Expected completion: January 2013

30. (Re-)Randomization within 10 days of hospital presentation
IMProved Reductions of Outcomes: Vytorin Efficacy International Trial (IMPROVE IT)
High-risk patients with acute coronary syndromes
NSTE-ACS
from
EARLY ACS centers
STEMI
from EARLY ACS and independent centers
NSTE-ACS
from
independent centers
(Re-)Randomization within 10 days of hospital presentation
Ezetimibe/simvastatin 10/40
Simvastatin 40
n = 18,000
2½-year minimum follow-up
1o Endpoint: CV Death / MI / Stroke / Hosp admission for ACS / Revasc > 30 days
Predicted median LDL-C achieved: ezetimibe/simvastatin 52 mg/dl; simvastatin 68 mg/dl
Estimated completion date: June 2013
Cannon et al. Am Heart J 2008;156:

31. Conclusions I
Low HDL-C/apo A-I levels are clearly associated with increased risk for CHD
Although epidemiological studies show that high HDL-C levels are associated with reduced CHD, not all genetic variants and therapies that raise HDL-C have reduced CHD events
Statins reduce CVD events in patients with low HDL-C

32. Conclusions II
Fibrates and omega 3 FAs in subgroup analysis have shown benefit in patients with low HDL-C/high TG
5. Addition of niacin (1.5 to 2.0 gms) to patients on statin therapy with low HDL-c and high TGs provided no greater benefit than low dose niacin and titrating patients with high dose statin/adding ezetimibe and using to treat LDL-C to goal
6. Ongoing trials will provide additional information on benefits of combination rx