1. Is HDL Therapy the Next Target to Reduce Cardiovascular Events 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 (All paid to institution, not individual): Abbott, AstraZeneca, Bristol-Myers Squibb, diaDexus, GlaxoSmithKline, Kowa, Merck, Novartis, Roche, Sanofi-Synthelabo, Takeda, NIH, ADA, AHA
Consultant: Abbott, Adnexus, Amylin, AstraZeneca, Bristol-Myers Squibb, Esperion, Genentech, GlaxoSmithKline, Idera Pharma, Kowa, Merck, Novartis, Omthera, Resverlogix, Roche, Sanofi-Synthelabo, Takeda
Speakers Bureau: Abbott, AstraZeneca, GlaxoSmithKline, Merck
Honorarium: Abbott, AstraZeneca, GlaxoSmithKline, Merck, Sanofi-Synthelabo, Takeda

3. HDL-C and Statin Trials
Do patients with low HDL-C benefit from statin therapy?
Are the effects of statins on HDL related to benefits on atherosclerosis progression and event reduction?
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 that targets HDL metabolism have additive effects on atherosclerosis/CVD events?

4. Case
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. HDL-C and Statin Trials
Do patients with low HDL-C benefit from statin therapy?

7. 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:

8. HDL-C and Statin Trials
Do patients with low HDL-C benefit from statin therapy?
Are the effects of statins on HDL related to benefits on atherosclerosis progression and event reduction?

9. Change in Percent Diameter Stenosis vs On-treatment HDL-C in QCA Trials-1
-0.8
-0.6
-0.4
-0.2
0.2
0.4
0.6
0.8 1
1.2
1.4
MARS
MAAS
PLAC I
LCAS
CCAIT
ASTEROID
Change in % stenosis per year
On-treatment HDL-C (mg/dL)
Placebo
Statin*
* ASTEROID rosuvastatin MAAS simvastatin
CCAIT lovastatin MARS lovastatin
LCAS fluvastatin PLAC I pravastatin
Ballantyne CM et al. Circulation 2008;117:2458–2466.

10. Beneficial Impact of Lowering LDL-C:HDL-C Ratio on Atherosclerosis
Change in PAV (%) 2 1 -1 -2
LDL-C:HDL-C during treatment 3
Nicholls S et al. JAMA 2007;297:499–508

11. 1300 patients with symptomatic CAD (angiographic stenosis >20%)
SATURN
1300 patients with symptomatic CAD (angiographic stenosis >20%)
LDL-C with (>80 mg/dL) or without (>100 mg/dL) statin use last 4 weeks
Rosuvastatin 40 mg (n =650)
Atorvastatin 80 mg (n=650)
Safety
Lipids Safety
IVUS
Lipids
Visit:
Week: 1 –4 3 4 13 5 26 6 39 7 52 8 65 9 78 10 91 11
104
Screening Period 2 –2
Atorva 40 mg
Rosuva 20 mg
Randomization Period

12. Percent change from baseline,
AFCAPS/TexCAPS: Percent Change in HDL-C, Apo A-I, and Apo B/Apo A-I at 1 Year
Percent change from baseline,
lovastatin – placebo
Gotto AM et al. Circulation 2000;101:477–484.

13. HDL-C and Statin Trials
Do patients with low HDL-C benefit from statin therapy?
Are the effects of statins on HDL related to benefits on atherosclerosis progression and event reduction?
Are low HDL-C/high TG still associated with increased CVD risk after high-efficacy statin therapy?

14. Low HDL-C and Risk for CVD in Statin Trials: CTT Meta-Analysis
Control (n = )
Treatmentb (n = )
5-Year Risk of Major
Vascular Eventsa, %
≤35
>42.5
HDL-C, mg/dL
aCombined outcome of nonfatal MI, CHD death,
nonfatal or fatal stroke, or coronary revascularization
bEvent rate per 1 mmol/L (39 mg/dL) reduction in LDL-C
Baigent C, et al. Lancet. 2005;366;

15. 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:

16. 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:

17. 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:

18. HDL-C and Statin Trials
Do patients with low HDL-C benefit from statin therapy?
Are the effects of statins on HDL related to benefits on atherosclerosis progression and event reduction?
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 that targets HDL metabolism have additive effects on atherosclerosis/CVD events?

19. Event Trials ACCORD AIM-HIGH HPS2-THRIVE dal-Outcomes
HPS-3 TIMI-55 REVEAL