How to best manage the patient with Low HDL Michael A Blazing MD Associate Professor of Medicine DUMC/DCRI
Disclosures Honoraria Consultant Research Pfizer, Merck, MSD Merck, CSL S-P/Merck, CSL
Cases - Primary Prevention CASE I 56 yo 5 6 with BMI 31 BP 145/84 LDL 114 HDL 34 Tg 230 FBS 115 CASE II 82 yo, HTN on HCTZ 5 11 with BMI 27 BP 126/76 LDL 134 HDL 32 Tg 140 FBS 85
Cases - Secondary Prevention Case III 66 yo Post MI 5 8 with BMI 28 BP 125/84 LDL 84 (before statin) HDL 34 Tg 160 FBS 95 CASE IV 66 yo Post Hx TIA, CEA 5 10 with BMI 22 BP 125/84 LDL 115 HDL 30 Tg 130 FBS 100
INHIBITION OF ATHEROSCLEROSIS BY HDL Monocyte HDL INHIBIT ADHESION MOLECULE EXPRESSION HDL INHIBIT MCP-1 1 EXPRESSION LDL Adhesion Molecule Cytokines MCP-1 LDL MODIFIED LDL HDL INHIBIT OXIDATION OF LDL ourtesy of Philip Barter Macrophage HDL PROMOTE CHOLESTEROL EFFLUX Foam Cell
Low HDL A 1% decrease in HDLc is associated with a 2% to 3% increase in CAD risk, and baseline HDLc levels are a more significant predictor of short term outcomes after ACS than baseline LDLc levels. Although there are genetic causes of low HDLc, it most often is associated with glucose intolerance 25% of American population is estimated to be IR Ratio of Tg/HDLc is the most characteristic feature of IR syndrome Felix-Getzik J Clinical Lipidology 2010; Lewis Circulation Research 2005
Prevalence of Low HDL in an ACS Population Of 250 consecutive patients with ACS admitted to Tufts between 2006 and 2008, 73% (183/250) had HDL < 40 44% (109/250) with HDL < 40 and LDL< 100 (black bars) 16% (40/250) with HDL < 40 and LDL< 70 (grey bars) Felix-Getzik J Clinical Lipidology 2010
Drugs that modify HDL levels Statins 0-5% ETOH 5% Fibrates 0-10% Niacin 10-30% CETP inhibitors 10-150% HDL infusion -????
Drugs that modify HDL levels and Statins 0-5% definitively reduce CV events
Residual risk on top of a statin CVD event risk across HDL Categories Low HDL is associated with higher residual risk despite statin treatment Cholesterol Treatment Trialists meta-analysis 90,000+ patients From Negi J. Clinical Lipidology 2010
Niacin-Statin clinical event reduction Brown et al NEJM 2001
HDL Raising - Niacin Effect 15-30% increase in HDL (dose related) 10-20% reduction in LDL 20-40% reduction in Tg Evidence CDP Significant reductions in MI, Stroke and CABG 11% mortality benefit at 11 years HATS Impressive event reduction in small number of patients ARBITER 3 Reduction in carotid IMT Risk??? Hepatic necrosis, Gout, Puritis, Flushing Clofibrate and niacin in coronary heart disease. JAMA (1975). Brown, B. G. et al. N. Engl. J. Med. (2001). Taylor, A. J et. al. Curr. Med. Res. Opin. 2006
Programs testing the HDL hypothesis - Niacin AIM HIGH - 3414 subjects with known vascular disease 2gm niaspan vs placebo (active run to min 1500mg tolerated) All participants received simvastatin 40-80mg Target LDL 40-80 Ezetimibe added if LDL too high (515 subjects) Original power based on 4 year event rate of 30% in placebo and 23% in active arms Annualized event rate 5.8% in niacin arm 5.6% in control Excess of strokes in niacin arm (28 vs 12) 9 of 28 niacin stokes were off of therapy Stopped early for futility
Programs testing the HDL hypothesis Niacin HPS2 Ongoing 25,000 subjects with known vascular disease 2gm ER niacin/laropiprant vs placebp All participants receive simvastatin 40 with 10mg EZ if needed Study in UK, China, Scandinavia Primary endpoint - composite of Cornary death, non fatal MI, stroke or revascularization.
HDL Raising - Fibrates Efficacy - 0-10% increase in HDL Evidence Positive Helsinki Heart Study DM Subgroup with all efficacy VA HIT Low LDL cohort Negative FIELD BIP ACCORD Consensus May be effective for low HDL, high Tg cohorts. No benefit in general low HDL population Frick et al N Engl J Med. 1987; Rubins et al NEJM 1999 ;Field Study Investigators Lancet 2005 Bezafibrate Infarction Prevention (BIP) study. Circulation. 2000 ; ACCORD NEJM 2010
HDL Raising Coming Attractions CEPT inhibitors Dalcetrapib Anacetrapib Apo A1 constructs Full protein Mimetic
Programs testing HDL Hypothesis - CETP CEPT and lipid movement CE rich HDL Apo B lipoproteins LDL or VLDL Net effect of CETP is to Transfer CE From HDL to Tg rich lipoproteins leaving HDL Tg rich and CE poor A 1 A 1 A 1 CE Tg A 1 A 1 CE Tg A 1 Tg rich HDL CETP Tg A 1 A 1 CE Tg A 1 CE Tg Renal degradation Small dense HDL Blocking CETP moves CE from LDL/VLDL to HDL in exchange for Tg. The prevention of Tg rich HDL reduces renal degradation and increases serum HDL
Comparing CETP lipid effects Torcet baseline* Total C LDLc HDLc Tg 156.8 79.7 48.6 127 Torcet Rx +4.9% -24% +60.2% -9% 151.5 81.2 40.5 127 Anacet baseline** Anacet Rx +13.9% -45.5% +139% -8.8% 76.9 41 131.7 Dalcet baseline*** Dalcet Rx -0.5% +33.4% -1.5% All lipid values are in mg/dl *Illuminate trial. Torcetripib 60mg +Atorvastatin 80 in all participants. NEJM 2007 **Anacetrapib 100mg + statin to LDL<100. NEJM 2010 ***Dalcetripib 900mg + Atorvastatin 10-80 to get LDL< 100mg/dl European Heart J 2010
Other programs/targets for testing HDL Infusion of pooled HDL Infusion of engineered HDL Milano Apo A1 mimetic peptides Up-regulate cellular HDL binding proteins ABCA1 ABCG1
Cases - Primary Prevention CASE I 56 yo 5 6 with BMI 31 BP 145/84 LDL 114 HDL 34 Tg 230 FBS 115 Metabolic syndrome Statin to LDL of 100 optional of 70 Fits into cohorts from Field (primary) or ACCORD (secondary) for benefit with a fibrate alone or with statin Field Study Investigators Lancet 2005; ACCORD Investigators NEJM 2009
Cases - Primary Prevention CASE II 82 yo, HTN on HCTZ 5 11 with BMI 27 BP 126/76 LDL 134 HDL 32 Tg 140 FBS 85 Elderly with CRF Matches criteria for PROSPER Elderly with low HDL had most benefit from statin for event reduction Statin Pravachol 40 minimum Personally LDL to < 100 Sheperd J, Lancet, 2002
Cases - Secondary Prevention Case III 66 yo Post MI 5 8 with BMI 28 BP 125/84 LDL 84 (before statin) HDL 34 Tg 160 FBS 95??? Gemfibrozil Fits criteria for VA HIT Just missed mortality benefit Significant reduction in composite of CV death, MI and stoke. Atorva 80 for PROVE IT
Cases - Secondary Prevention Case IV 66 yo Post Hx TIA, CEA 5 10 with BMI 22 BP 125/84 LDL 115 HDL 30 Tg 130 FBS 100 HPS, TNT Meets criteria for HPS Documented benefit for Death, Death or MI, MI and other Major Vascular events with Simvastatin 40 Would fit TNT Atorva 80 Reduction in major vascular events. No mortality reduction. HPS Lancet, LaRosa NEJM 200
Summary Low HDL is an independent and significant risk factor Unclear that HDL centered therapies are of any benefit except in specific populations For now statins should be the drugs of choice (drive down LDL) and Non-HDLc should be a secondary target that can be addressed with adjunct agents.=