Presentation on theme: "New Concepts in the Evaluation and Treatment of Dyslipidemia Nathan D. Wong, PhD, FACC Professor and Director Heart Disease Prevention Program Division."— Presentation transcript:
New Concepts in the Evaluation and Treatment of Dyslipidemia Nathan D. Wong, PhD, FACC Professor and Director Heart Disease Prevention Program Division of Cardiology University of California, Irvine Past President, American Society for Preventive Cardiology
Chylomicron Remnants VLDL LDL-R HDL 2 HDL3DL 3 Particle Size (nm) Density (g/ml) Chylomicron VLDL Remnants Lipoprotein Particles Lp(a) IDL Only these lipoprotein particles found in plaque at biopsy
The Apo B-containing (non-HDL) Lipoprotein Family: All Atherogenic *ApoB is a component of all lipoprotein particles currently considered atherogenic 2 Apo = apolipoprotein; IDL = intermediate-density lipoprotein; VLDL = very low-density lipoprotein; Lp(a) = lipoprotein (a) 1. Olofsson SO et al. Vasc Health Risk Manag. 2007;3: Grundy SM. Circulation. 2002;106: Kunitake ST et al. J Lipid Res. 1992;33: Images available at: Accessed January Adapted with permission. ApoB* LDL ApoB-containing lipoproteins 1 – LDL—most common/most important – IDL – VLDL /VLDL remnants – Chylomicron remnants – Lp(a)
Rationale for therapeutic lowering of Apo B lipoproteins: decrease the probability of inflammatory response to retention Tabas I et al. Circulation. 2007;116: Williams KJ et al. Arterioscler Thromb Vasc Biol. 1995;15: Hoshiga M et al. Circ Res. 1995;77: Williams KJ et al. Arterioscler Thromb Vasc Biol. 2005;25: Merrilees MJ et al. J Vasc Res. 1993;30: Nakata A et al. Circulation. 1996;94: Steinberg D et al. N Engl J Med. 1989;320: High Plasma Apo B Lipoprotein Levels Promote Atherogenesis Blood Apo B lipoprotein particles Modification Macrophage Monocytes bind to adhesion molecules Smooth muscle Foam cell Inflammatory response
Lipid Atherogenesis HDL Liver Advanced fibrocalcific lesion Oxidative modification of LDL LDL + VLDL Cholesterol excreted Endothelial injury Adherence of platelets Release of PDGF High plasma LDL LDL infiltration into intima + Macrophages Foam cells Fatty streak LCAT APO-A1 Other growth factors
lipid core adventitia lipid core Anti-atherosclerotic therapy From Davies et al (1998) Unstable lesion Stable lesion
Total Cholesterol Distribution: CHD vs Non-CHD Population Castelli WP. Atherosclerosis. 1996;124(suppl):S1-S9. 1996 Reprinted with permission from Elsevier Science. 35% of CHD Occurs in People with TC<200 mg/dL Total Cholesterol (mg/dL) No CHD CHD Framingham Heart Study—26-Year Follow-up
Low HDL-C Levels Increase CHD Risk Even When Total-C Is Normal Risk of CHD by HDL-C and Total-C levels; aged 48–83 y Castelli WP et al. JAMA 1986;256:2835– < 4040–4950–59 60 < – –229 260 HDL-C (mg/dL) Total-C (mg/dL) 14-y incidence rates (%) for CHD
Sarwar N, et al. Circulation. 2007;115: a Individuals in top versus bottom third of usual log-triglyceride values, adjusted for at least age, sex, smoking status, lipid concentrations, and blood pressure (most) CHD Risk Ratio* (95% CI) 1.72 (1.56–1.90) 2 1 Duration of follow-up ≥10 years 5902 <10 years 4256 Sex Male 7728 Female 1994 Fasting status Fasting 7484 Nonfasting 2674 Adjusted for HDL Yes 4469 No 5689 N=262,525 GroupsCHD Cases Overall CHD Risk Ratio a Decreased Risk Increased Risk CHD=coronary heart disease HDL=high-density lipoprotein Triglyceride Level Is Significant CHD Risk Factor: Recent Meta-Analysis of 29 Studies (n=262,525) (Sarwar et al., Circulation 2007)
Triglyceride-rich lipoproteins carry cholesterol and promote atherosclerosis* Very–low-density lipoprotein (VLDL) is precursor to low-density lipoprotein (LDL) Hypertriglyceridemia (HTG) drives Cholesterol esters enrichment of VLDL (more atherogenic) ↓ LDL size (small, dense LDL are more atherogenic)* ↓ LDL-C (small, dense LDL carry less cholesterol)* ↓ High-density lipoprotein (HDL) size (small, dense HDL are unstable) HTG is linked to other proatherogenic states* Insulin resistance Proinflammatory state Prothrombotic state Prooxidative state Endothelial dysfunction *Reasons why non–HDL-C is stronger than LDL-C as predictor of cardiovascular disease How Can Hypertriglyceridemia be Atherogenic?
Apolipoprotein B LDL= 130 mg/dL Fewer Particles More Particles Cholesterol ester More apolipoprotein B Otvos JD, et al. Am J Cardiol. 2002;90:22i-29i. Correlates with: TC198 mg/dL LDL-C 130 mg/dL TG 90 mg/dL HDL-C 50 mg/dL Non – HDL-C148 mg/dL Correlates with: TC 210 mg/dL LDL-C 130 mg/dL TG 250 mg/dL HDL-C 30 mg/dL Non – HDL-C180 mg/dL TC=total cholesterol, LDL-C=low-density lipoprotein cholesterol, TG=triglycerides, HDL-C=high-density lipoprotein cholesterol Elevated Triglycerides Are Associated With Increased Small, Dense LDL Particles
Cholesterol per particle, BUT Subendothelial penetration Subendothelial binding Oxidized/modified LDL-receptor clearance LDL=low-density lipoprotein Why Is Small, Dense LDL More Atherogenic?
Very–low-density lipoprotein (VLDL) Made in the liver Triglycerides (TG) >> cholesterol esters (CE) Carries lipids from the liver to peripheral tissues HDL LDL IDL VLDL Atherogenic Lipoproteins Non-HDL; Apo B-100—containing Intermediate-density lipoprotein (IDL) Formed from VLDL due to lipase removal of TG Also known as a VLDL remnant Low-density lipoprotein (LDL) Formed from IDL due to lipase removal of TG CE >> TG High-density lipoprotein (HDL) Removes cholesterol from peripheral tissues Lp(a) Lipoprotein (a) Formed from LDL w/addition of apolipoprotein A Atherogenic and prothrombotic Non-HDL Includes All Atherogenic Lipoprotein Classes
Lp(a) in Atherogenesis: Another Culprit? Identical to LDL particle except for addition of apo(a) Plasma concentration predictive of atherosclerotic disease in many epidemiologic studies, although not all Accumulates in atherosclerotic plaque Binds apo B-containing lipoproteins and proteoglycans Taken up by foam cell precursors May interfere with thrombolysis Maher VMG et al. JAMA. 1995;274: Stein JH, Rosenson RS. Arch Intern Med. 1997;157:
Lp(a): An Independent CHD Risk Factor in Men of the Framingham Offspring Cohort RR=relative risk; HT=hypertension; GI=glucose intolerance. Bostom AG et al. JAMA. 1996;276: RR Lp(a) TC HDL-C HT GI Smoking
Placebo - Statin outcome trials High-risk CHD patients (high cholesterol) High-risk CHD patients (high cholesterol) Majority of CHD patients (broad range of cholesterol levels) Patients at high risk of CHD (high of CHD (high cholesterol) cholesterol) Patients at low Patients at low risk of CHD risk of CHD (low HDL-C) (low HDL-C) Primary prevention Secondary prevention WOSCOPS (pravastatin) AFCAPS/TexCAPS (lovastatin) 4S (simvastatin) HPS (simvastatin) CARE (pravastatin) LIPID (pravastatin) Continuum of risk Placebo MI rate per 100 subjects per 5 years PROSPER (pravastatin) Heart failure Heart failure CORONA GISSI-HF (rosuvastatin) End stage 53.7 JUPITER (rosuvastatin)
Cholesterol Treatment Trialists’ (CCT) Collaboration: Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis fo data from 90,056 participants in 14 randomized trials of statins (The Lancet 9/27/05) Over average 5 year treatment period (per mmol/L reduction—approx 40 mg/dl in LDL-C): 12% reduction in all-cause mortality 19% reduction in coronary mortality 23% reduction in MI or CHD death 17% reduction in stroke 21% reduction in major vascular events No difference in cancer incidence (RR=1.00). Statin therapy can safely reduce 5-year incidence of major coronary events, revascularization, and stroke by about 20% per mmol/L (about 38 mg/dl) reduction in LDL-C
HPS: First Major Coronary Event Nonfatal MI Coronary death Subtotal: MCE Coronary Noncoronary Subtotal: any RV Any MVE Coronary events Revascularizations Type of Major Vascular Event Statin- Allocated (n = 10269) Placebo- Allocated (n = 10267) 357 (3.5%) 574 (5.6%) 587 (5.7%) 707 (6.9%) 898 (8.7%)1212 (11.8%) 513 (5.0%)725 (7.1%) 450 (4.4%)532 (5.2%) 939 (9.1%) 1205 (11.7%) 2033 (19.8%)2585 (25.2%) 0.73 (0.67 0.79) P < (0.70 0.83) P < (0.72 0.81) P < Statin BetterPlacebo Better Heart Protection Study Collaborative Group. Lancet. 2002;360:7 22.
Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT)—TIMI 22 Study Follow-up (months) P =0.005 Recurrent MI or Cardiac Death 16% RRR Atorvastatin Pravastatin ACS=Acute coronary syndrome, CV=Cardiovascular, MI=Myocardial infarction, RRR=Relative risk reduction Cannon CP et al. NEJM 2004;350: HMG-CoA Reductase Inhibitor: Secondary Prevention 4,162 patients with an ACS randomized to atorvastatin (80 mg) or pravastatin (40 mg) for 24 months
TNT: Rationale (1.6)(2.1)(2.6)(3.1)(3.6)(4.1)(4.7)(5.2) Atorvastatin 80 mg Atorvastatin 10 mg Screening TNT ? Adapted from LaRosa et al. N Engl J Med. 2005:352: LDL-C, mg/dL (mmol/L) Patients With CHD Events (%)
TNT: Changes in LDL-C by Treatment Group FinalScreen P <.001 Baseline Mean LDL-C (mmol/L) Mean LDL-C level = 101 mg/dL (2.6 mmol/L) Mean LDL-C level = 77 mg/dL (2.0 mmol/L) LaRosa et al. N Engl J Med. 2005;352: Mean LDL-C (mg/dL) Study Visit (Months)
TNT: Primary Efficacy Outcome Measure: Major Cardiovascular Events* *CHD death, nonfatal non–procedure-related MI, resuscitated cardiac arrest, fatal or nonfatal stroke. LaRosa et al. N Engl J Med. 2005;352: HR=0.78 (95% CI 0.69, 0.89); P<.001 Proportion of Patients Experiencing Major Cardiovascular Event Atorvastatin 10 mg Atorvastatin 80 mg Relative risk reduction 22% Time (Years) Mean LDL-C level = 77 mg/dL Mean LDL-C level = 101 mg/dL
Recent Coronary IVUS Progression Trials Median change in percent atheroma volume (%) Mean LDL-C (mg/dL) REVERSAL pravastatin REVERSAL atorvastatin CAMELOT placebo A-Plus placebo ACTIVATE placebo Relationship between LDL-C and Progression Rate ASTEROID rosuvastatin Nissen SE, Nicholls S et al. JAMA 2006;295:1555–1565
Residual CVD Risk in Statin vs Placebo Trials 4 HPS Collaborative Group. Lancet. 2002;360: Shepherd J et al. N Engl J Med. 1995;333: Downs JR et al. JAMA. 1998;279: S Group. Lancet. 1994;344: LIPID Study Group. N Engl J Med. 1998;339: Sacks FM et al. N Engl J Med. 1996;335: LDL N %-28%-29%-26%-25% SecondaryHigh RiskPrimary Patients Experiencing Major CHD Events, % 4S 1 LIPID 2 CARE 3 HPS 4 WOSCOPS 5 AFCAPS/TexCAPS 6 Placebo Statin Many CHD Events Still Occur in Statin-Treated Patients 25-40% CVD Reduction Leaves High Residual Risk
Antioxidative Activity Antithrombotic Activity Potential Antiatherogenic Actions of HDL Anti-infectious Activity Endothelial Repair Chapman MJ et al. Curr Med Res Opin. 2004;20: Assmann G et al. Annu Rev Med. 2003;53: Antiapoptotic Activity Reverse Cholesterol Transport Cellular Cholesterol Efflux Anti-inflammatory Activity Vasodilatory Activity HDL Apo A-I Apo A-II
Should High-Density Lipoprotein Be a Target of Therapy? Should High-Density Lipoprotein Be a Target of Therapy?
MARS MAAS PLAC I LCAS PLAC I CCAIT LCAS MAAS MARS ASTEROID CCAIT * ASTEROID rosuvastatinMAAS simvastatin CCAIT lovastatin MARS lovastatin LCAS fluvastatinPLAC I pravastatin Change in % stenosis per year On-treatment HDL-C (mg/dL) Change in Percent Diameter Stenosis vs On-treatment HDL-C in QCA Trials Placebo Statin * Ballantyne CM, Nicholls S et al. Circulation 2008; Online
Should High-Density Lipoproteins Be a Target of Therapy ? ATP III Guidelines on HDL-C: “Current documentation of risk reduction through controlled clinical trials is not sufficient to warrant setting a specific goal value for raising HDL-C” (Grundy SM et al. Circulation. 2004;110: ) Failure of ACCORD, FIELD, AIM-HIGH and the experience with torcetrapib and dalcetrapib have raised doubts re: the value of raising HDL-C Still, The one best study of niacin effects on CVD (HPS- 2/THRIVE) is ongoing—results early in 2013 Investigational CETP inhibitors greatly increase HDL-C and might be shown to reduce CVD—clinical trials ongoing, results after 2017
HDL-C Risk Factor vs Risk Marker? Low HDL-C predicts high CVD Risk High HDL-C predicts anti-atherogenic effects: Anti-inflammatory Antioxidant Antithrombotic Pro-endothelial But clinical trials of HDL-C-raising agents so far have failed to prove CVD benefit—suggesting that HDL-C may be only a risk marker
Smoking Cessation −HDL-C levels are lower in smokers (by 7%-20%), and return towards normal 1-2 months after smoking cessation Whole Food Plant Based Diet—dietary fiber blunts adverse carb effect Weight Reduction −For every 3 kg (7 lb) of weight loss, HDL-C levels increase by 2-4%, but only after stabilization at new lower weight Exercise −Aerobic exercise (40 min, 3-4 x weekly) may increase HDL- C by 5-10% Rössner S et al. Atherosclerosis. 1987;64: Wood PD et al. N Engl J Med. 1988;319: Ornish D et al. JAMA. 1998;280: Lifestyle Modifications to Raise HDL-C Levels Cullen P et al. Eur Heart J. 1998;19: Kokkinos PF et al. Arch Intern Med. 1995;155: Kodama S et al. Arch Intern Med. 2007;167:
Available Agents for HDL-C Raising AgentHDL-C ↑ Primary Use Nicotinic acid15-35% HDL ↑ Fibrates 5-20% TG ↓ Statins 5-15% LDL ↓ Prescr. Om-3* 2-10% TG ↓ Bile-acid resins* 2-5% LDL ↓ Ezetimibe* 1-3% LDL ↓ Pioglitazone* 5-20% Glucose ↓ Estrogens* 10-25% Hot flashes -blockers* 10-20% BPH Alcohol* 5-15% Social, etc. *Lacking FDA-approved indication for HDL-raising. Belalcazar LM, Ballantyne CM. Prog Cardiovasc Dis. 1998;41: Insull W et al. Mayo Clin Proc. 2001;76: McKenney JM et al. Pharmacother. 2007;27:
Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) CHD Death or Nonfatal MI (%) Placebo 5.9 Fenofibrate P= % RRR 9,795 diabetic patients randomized to fenofibrate (200 mg) or placebo for 5 years A fibrate does not provide significant additional benefit* in diabetics Source: Keech A et al. Lancet 2005;366: *Unadjusted for concomitant statin use CHD=Coronary heart disease, MI=Myocardial infarction, RRR=Relative risk reduction Fibrate Evidence: Primary Prevention
Fibrate Evidence: Primary and Secondary Prevention Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid Trial 5,518 diabetic patients on statin therapy randomized to fenofibrate (160 mg) or placebo for 4.7 years On a background of statin therapy, a fibrate does not reduce CV events in diabetics CV death, nonfatal stroke or nonfatal MI (%/year) Placebo 2.4 Fenofibrate P=0.32 8% RRR Source: ACCORD study group. NEJM 2010;Epub ahead of print CV=Cardiovascular, MI=Myocardial infarction, RRR=Relative risk reduction
Is Niacin Useful in Low HDL-C?
HATS: Percent Change in Stenosis Change (%) *P = 0.16 for comparison with placebo; † P < 0.001; ‡ P = HATS = HDL-Atherosclerosis Treatment Study. Adapted from Brown BG et al. N Engl J Med. 2001;345: PlaceboAntioxidantSimvastatin/ Simvastatin / Vitamins*Niacin † Niacin/ Antioxidants ‡
Simvastatin-niacin 97% All placebos 76% RR = 0.10 P = HATS = HDL-Atherosclerosis Treatment Study. Adapted from Brown BG et al. N Engl J Med. 2001;345: HATS: Patients Free of Events Patients Free of Events (%) Years
Study Treatme nt n/N Control n/N Peto OR 95% Cl Peto OR 95% Cl ARBITER-6- HALTS 2/1879/ (0.08, 0.84) Guyton JR et al1/6761/ (0.02, 7.56) AFREGS0/711/ (0.00, 6.92) ARBITER-22/872/ (0.13, 6.65) HATS1/385/ (0.05, 1.26) UCSF_SCOR0/481/ (0.00, 6.96) STOCKHOLM72/279100/ (0.43, 0.88) CLAS1/945/ (0.05, 1.29) CDP287/ / (0.69, 0.94) Total Test for heterogeneity: P = 0.24, I 2 = 23.0% Test for overall effect: P < (0.65, 0.86) Subtotal excluding CDP 0.53 (0.38, 0.73) Log scale Meta-Analysis: Effects of Nicotinic Acid Pre-AIM-HIGH Trials: Major Coronary Events Many of these trials were tests of drug combinations that included niacin. Bruckert E et al. Atherosclerosis. 2010;210:
AIM-HIGH Design Purpose: “Rigorous test of the HDL hypothesis…” (not designed to be a test of niacin) Subjects: n=3414 men/women (85%/15%) w/ prior CVD event and HDL-C 35 (<42/53) LDL-C 74 (algorithm), TG 163 ( ) [median (range)] Randomized Therapy Extended-release niacin ( mg hs) vs “Placebo” (immediate-release niacin mg hs) Open-label titration/addition (keep LDL-C in mg/dL) Simvastatin 5-80 mg/d Ezetimibe 10 mg/d + extended release niacin ( mg) AIM-HIGH Investigators. N Engl J Med. 2001;365: AIM-HIGH Investigators. Am Heart J. 2011;161: e2.
Boden WE. N Engl J Med. epub 15 Nov 2011; doi /NEJMoa AIM-HIGH — Results HDL-C at Baseline and Follow-up
1 o Endpoint: CHD Death, nonfatal MI, ischemic stroke, high-risk ACS, hospitalization for coronary or cerebrovascular revascularization Boden WE. N Engl J Med. epub 15 Nov 2011; doi /NEJMoa AIM-HIGH — Results Primary Outcome
Fate of Niacin Beyond AIM-HIGH: HPS2- THRIVE : December 2012 Update HPS2-THRIVE evaluated extended-release niacin/laropiprant plus statin therapy versus statin therapy alone in patients at high risk for cardiovascular events HPS2-THRIVE did not reach the primary endpoint to reduce coronary deaths, non-fatal heart attacks, strokes, or revascularizations This finding, supportive of AIM-HIGH, suggests that niacin may not provide additional benefit to reduce CVD risk when patients are well-treated with statins
Emerging HDL-C Therapies CETP Antagonism
Role of CETP in Atherosclerosis Human CETP deficiency is usually associated with marked ↑ in HDL- C CETP activity is inversely correlated with plasma HDL-C Decreasing CETP activity has consistently inhibited atherosclerosis in animal models Barter PJ et al. Arterioscler Thromb Vasc Biol. 2003;23: Contacos C et al. Atherosclerosis. 1998;141: Guerin M et al. Arterioscler Thromb Vasc Biol. 2008;28: LIVERPERIPHERAL TISSUE CE TG Bile Foam cells RCT HDL ABC-A1 VLDL LDL PLASMA LDL-R ABC-G1 Free cholesterol CETP Athero- sclerosis LDL
Barter et al. N Engl J Med. 2007;357(13): Qiu X et al. Nat Struct Mol Biol. 2007;14(2): *Dalcetrapib development stopped May 7, 2012 due to lack of efficacy in the Dal-Outcomes CVD endpoint trial. CETP Inhibitors: 2 Down, 2 Remain CETP Evacetrapib ↑CVD (25%) but OK HDL function (off-target eff.?) *No ↓CVD, but OK HDL function, +/- anti athero? ↑HDL-C ~80% ~80% ~138%~30%
Lipid Effects of CETP Inhibitors/Modulators % Change from Baseline CETP Agent Dose (mg/day) HDL-C (%) LDL-C (%) TG (%) Torcetrapib Anacetrapib Evacetrapib Dalcetrapib Adapted from Cannon C et al. JAMA. 2011;306: Nicholls SJ et al. JAMA. 2011;306:
Torcetrapib “Beneficial” Effects on Lipoproteins Is the toxicity of torcetrapib related to the mechanism or the molecule? Placebo60 mg90 mg120 mg Barter PJ et al. N Engl J Med. 2007;357: HDL-C LDL-C +42% +49% +55% -20% -18% -1% +1%
Is the toxicity of torcetrapib related to the mechanism or the molecule? Atorvastatin only Torcetrapib plus atorvastatin Days After Randomization Patients Without Event (%) Barter PJ et al. N Engl J Med. 2007;357: Torcetrapib: Increased Cardiovascular and Non-cardiovascular Morbidity and Mortality HR = 1.25 P =
Torcetrapib Caused Off-target Hyperaldosteronism Torcetrapib arm of ILLUMINATE trial showed significant: 1 ↑ Systolic Blood Pressure: Mean ↑5.4 mmHg >15 mmHg ↑ SBP: 19.5% torcetrapib arm (vs 9.4% placebo arm, P 15 mmHg ↑ SBP: 19.5% torcetrapib arm (vs 9.4% placebo arm, P<0.001) ↓ serum potassium ↑ serum bicarbonate ↑ serum sodium ↑ serum aldosterone Inverse relationship of CVD and on-Rx-HDL-C preserved Conclusion: ↑ CVD in ILLUMINATE likely due to off-target actions of torcetrapib, not related to CETP inhibition 1,2 1. Barter PJ et al. N Engl J Med. 2007;357: Rosenson RS. Curr Athero Rep. 2008;10:
dal-OUTCOMES Results: Isolated ↑HDL-C LDL Cholesterol (mg/dL) HDL Cholesterol (mg/dL) Schwartz GG et al. N Engl J Med Nov 5. [Epub ahead of print]. No. at risk Placebo Dalcetrapib No. at risk Placebo Dalcetrapib Months
dal-OUTCOMES Results: No ↓CVD Schwartz GG et al. N Engl J Med Nov 5. [Epub ahead of print]. Year Cumulative Incidence of Primary Outcome (% of patients) No. at risk Placebo Dalcetrapib
Anacetrapib Effects on LDL-C and HDL-C HDL-C Baseline HDL-C (mg/dL) (SE) Anacetrapib Placebo Anacetrapib n = Placebo n = LDL-C Study Week Baseline LDL-C (mg/dL) (SE) Anacetrapib Placebo Anacetrapib n = Placebo n = % ( P <0.001) % ( P <0.001) Cannon CP et al. N Engl J Med. 2010;363: Study Week
The Role of PCSK9 in the Regulation of LDL Receptor Expression For illustration purposes only
Impact of an PCSK9 mAb on LDL Receptor Expression For illustration purposes only
Change in Calculated LDL-C at 2 Weekly Intervals from Baseline to Week Mean percentage change in calculated LDL-C from baseline to weeks 2, 4, 6, 8, 10, and 12 in the modified intent-to-treat (mITT) population, by treatment group. Week 12 estimation using LOCF method. LDL-C Mean ( SE) % Change from Baseline ∆ - 8.5% ∆ % ∆ % ∆ % ∆ % ∆ - 5.1% ∆ % ∆ %
LDL-C from Baseline to Week 12 by Treatment Group (mITT Population)
Antisense Oligonucleotides and Apo B Synthesis Inhibition Brautbar A and Ballantyne CM. Nat Rev Cardio 2011;8:253.
Mipomersen and LDL Lowering in Homozygous FH Baseline LDL-C: 405 mg/dl n=17 n=34 Raal F. Lancet 2010;375: mg SC/Q week
What’s New in the Cholesterol Guideline? 1)Focus on ASCVD reduction: 4 Statin Benefit Groups 2)New Perspective on LDL-C and/or Non-HDL-C Treatment Goals 3)Global Risk Assessment for Primary Prevention 4)Safety Recommendations 5)Role of Biomarkers and Noninvasive Tests 6)Future Updates to Guidelines
New Perspective on LDL–C & Non-HDL–C Goals Lack of RCT evidence to support titration of drug therapy to specific LDL–C and/or non-HDL–C goals Strong evidence that appropriate intensity of statin therapy should be used to reduce ASCVD risk in those most likely to benefit Quantitative comparison of statin benefits with statin risk Nonstatin therapies – did not provide ASCVD risk reduction benefits or safety profiles comparable to statin therapy
Why Not Continue to Treat to Target? Major difficulties: 1.Current RCT data do not indicate what the target should be 2.Unknown magnitude of additional ASCVD risk reduction with one target compared to another 3.Unknown rate of additional adverse effects from multidrug therapy used to achieve a specific goal 4.Therefore, unknown net benefit from treat-to- target approach
4 Statin Benefit Groups Clinical ASCVD* LDL–C >190 mg/dL, Age >21 years Primary prevention – Diabetes: Age years, LDL–C mg/dL Primary prevention - No Diabetes † : ≥7.5%‡ 10-year ASCVD risk, Age years, LDL–C mg/dL, *Atherosclerotic cardiovascular disease † Requires risk discussion between clinician and patient before statin initiation. ‡ Statin therapy may be considered if risk decision is uncertain after use of ASCVD risk calculator.
4 Statin Benefit Groups (Revised Figure) IA IB IA IIaB 1
Clinical Flow (Revised Figure-con’t)
Intensity of Statin Therapy *Individual responses to statin therapy varied in the RCTs and should be expected to vary in clinical practice. There might be a biologic basis for a less-than-average response. †Evidence from 1 RCT only: down-titration if unable to tolerate atorvastatin 80 mg in IDEAL (Pedersen et al). ‡Although simvastatin 80 mg was evaluated in RCTs, initiation of simvastatin 80 mg or titration to 80 mg is not recommended by the FDA due to the increased risk of myopathy, including rhabdomyolysis.
Primary Prevention Global Risk Assessment To estimate 10-year ASCVD* risk New Pooled Cohort Risk Equations White and black men and women More accurately identifies higher risk individuals for statin therapy Focuses statin therapy on those most likely to benefit You may wish to avoid initiating statin therapy in high-risk groups found not to benefit (higher grades of heart failure and hemodialysis) * 10-year ASVD: Risk of first nonfatal myocardial infarction, coronary heart disease death, nonfatal or fatal stroke
Risk Reduction as Related to 5-year Risk Categories Cholesterol Treatment Trialists’ Collaboration, The Lancet 2012
Thresholds for initiating statin therapy derived from 3 exclusively primary prevention RCTs Before initiating statin therapy, clinicians and patients engage in a discussion of the potential for ASCVD risk reduction benefits, potential for adverse effects, drug-drug interactions, and patient preferences Calculators don’t write Rx, physicians do! Primary Prevention Statin Therapy
Individuals Not in a Statin Benefit Group In those for whom a risk decision is uncertain: These factors may inform clinical decision making: Family history of premature ASCVD Elevated lifetime risk of ASCVD LDL–C ≥160 mg/dL hs-CRP ≥2.0 mg/L Coronary artery calcium (CAC) score ≥300 Agaston units Ankle brachial index (ABI)<0.9 Their use still requires discussion between clinician and patient
Monitoring Statin Therapy Adherence to medication and lifestyle, therapeutic response to statin therapy, and safety should be regularly assessed. This should also include a fasting lipid panel performed within 4 to 12 weeks after initiation or dose adjustment, and every 3 to 12 months thereafter. Other safety measurements should be measured as clinically indicated. I IIaIIbIII
The maximum tolerated intensity of statin should be used in individuals for whom a high- or moderate- intensity statin is recommended, but not tolerated.* * Several RCTs found that low and low-moderate intensity statin therapy reduced ASCVD events. In addition, the CTT meta-analyses of statin trials have shown that each 39 mg/dL reduction in LDL-C reduced CVD events by 22%. Therefore, the Panel considered that submaximal statin therapy should be used to reduce ASCVD risk in those unable to tolerate moderate- or high-intensity statin therapy. Optimizing Statin Therapy
In individuals who have a less-than-anticipated therapeutic response or are intolerant of the recommended intensity of statin therapy, the following should be performed: Reinforce medication adherence. Reinforce adherence to intensive lifestyle changes. Exclude secondary causes of hyperlipidemia. I IIaIIbIII Insufficient Response to Statin Therapy
It is reasonable to use the following as indicators of anticipated therapeutic response to the recommended intensity of statin therapy. Focus is on the intensity of the statin therapy. As an aid to monitoring: High-intensity statin therapy† generally results in an average LDL-C reduction of ≥50% from the untreated baseline; (recommendation cont. below) Insufficient Response to Statin Therapy (cont.) †In those already on a statin, in whom baseline LDL-C is unknown, an LDL-C <100 mg/dL was observed in most individuals receiving high intensity statin therapy.
Insufficient Response to Statin Therapy(cont.) (recommendation cont.) Moderate-intensity statin therapy generally results in an average LDL-C reduction of 30 to <50% from the untreated baseline; LDL-C levels and percent reduction are to be used only to assess response to therapy and adherence. They are not to be used as performance standards.
In individuals at higher ASCVD risk receiving the maximum tolerated intensity of statin therapy who continue to have a less-than-anticipated therapeutic response, addition of a nonstatin cholesterol-lowering drug(s) may be considered if the ASCVD risk-reduction benefits outweigh the potential for adverse effects. (recommendation cont. below) Insufficient Response to Statin Therapy (cont.)
Higher-risk individuals include: Individuals with clinical ASCVD‡ <75 years of age Individuals with baseline LDL-C ≥190 mg/dL Individuals 40 to 75 years of age with diabetes Preference should be given to nonstatin cholesterol- lowering drugs shown to reduce ASCVD events in RCTs. Insufficient Response to Statin Therapy (cont.) ‡ Clinical ASCVD includes acute coronary syndromes, or a history of MI, stable or unstable angina, coronary or other arterial revascularization, stroke, TIA, or peripheral arterial disease presumed to be of the atherosclerotic origin.
In individuals who are candidates for statin treatment but are completely statin intolerant, it is reasonable to use nonstatin cholesterol- lowering drugs that have been shown to reduce ASCVD events in RCTs if the ASCVD risk-reduction benefits outweigh the potential for adverse effects. I IIaIIbIII Insufficient Response to Statin Therapy (cont.)
Safety RCTs & meta-analyses of RCTs used to identify important safety considerations Allow estimation of net benefit from statin therapy o ASCVD risk reduction versus adverse effects Expert guidance on management of statin-associated adverse effects, including muscle symptoms Advise use of additional information including pharmacists, manufacturers prescribing information, & drug information centers for complex cases
Management of Muscle Symptoms on Statin Therapy It is reasonable to evaluate and treat muscle symptoms including pain, cramping, weakness, or fatigue in statin-treated patients according to the management algorithm To avoid unnecessary discontinuation of statins, obtain a history of prior or current muscle symptoms to establish a baseline before initiating statin therapy
Management of Muscle Symptoms on Statin Therapy (con’t) If unexplained severe muscle symptoms or fatigue develop during statin therapy: Promptly discontinue the statin Address possibility of rhabdomyolysis with: CK Creatinine urine analysis for myoglobinuria
Statin-Treated Individuals Nonstatin Therapy Considerations Use the maximum tolerated intensity of statin Consider addition of a nonstatin cholesterol-lowering drug(s) If a less-than-anticipated therapeutic response persists Only if ASCVD risk-reduction benefits outweigh the potential for adverse effects in higher-risk persons: Clinical ASCVD <75 years of age Baseline LDL–C ≥190 mg/dL Diabetes mellitus 40 to 75 years of age Nonstatin cholesterol-lowering drugs shown to reduce ASCVD events in RCTs are preferred
Non-Statin Therapies 1)Ezetimibe – Additional 15% lowering of LDL-C – No known benefit for reducing CVD events beyond statin therapy – awaiting IMPROVE-IT clinical trial 2)Bile Acid Resins 3)Niacin 4)Fibrates (Fenofibrate) 5)Therapies for HoFH (Lomitapide, Mipomersin) Emerging Therapies in Development 1)CETP Inhibitors (Anacetrapib and Evacetrapib) 2)PCSK9 Inhibitors
Three Principles Do not focus on LDL–C or non-HDL-C cholesterol levels as treatment goals o Lipid panel to monitor adherence For those shown to benefit, use statins – inexpensive (5 of 7 generic) medications proven to reduce ASCVD risk In primary prevention decisions, use a clinician- patient discussion to determine: global risk reduction strategy potential for benefit and harms of statin therapy Patient preferences (shared decision making)
Lifestyle management remains the cornerstone for reducing cardiovascular disease risk including achieving and maintaining optimal lipid levels
What’s New in Lifestyle? Recommendations based on in-depth systematic reviews. Previous reports used different methods and structure. More depth, less breadth. More emphasis on dietary patterns More data provided to support saturated and trans fat restriction saturated and trans fat restriction dietary salt restriction dietary salt restriction Evidence to support dietary cholesterol restriction in those who could benefit from LDL-C is inadequate.
Consume a dietary pattern that emphasizes intake of vegetables, fruits, and whole grains; includes low-fat dairy products, poultry, fish, legumes, nontropical vegetable oils and nuts; and limits intake of sweets, sugar-sweetened beverages, and red meats. Adapt this dietary pattern to appropriate calorie requirements, personal and cultural food preferences, and nutrition therapy for other medical conditions (including diabetes). Adapt this dietary pattern to appropriate calorie requirements, personal and cultural food preferences, and nutrition therapy for other medical conditions (including diabetes). Achieve this pattern by following plans such as the DASH dietary pattern, the U.S. Department of Agriculture (USDA) Food Pattern, or the AHA Diet. Achieve this pattern by following plans such as the DASH dietary pattern, the U.S. Department of Agriculture (USDA) Food Pattern, or the AHA Diet. LDL-C: Advise adults who would benefit from LDL-C lowering* to: I IIaIIbIII *Refer to 2013 Blood Cholesterol Guideline for guidance on who would benefit from LDL-C lowering.
Aim for a dietary pattern that achieves 5% to 6% of calories from saturated fat. Reduce percent of calories from saturated fat. Reduce percent of calories from trans fat. LDL-C: Advise adults who would benefit from LDL-C lowering* to: (cont.) I IIaIIbIII I IIaIIbIII *Refer to 2013 Blood Cholesterol Guideline for guidance on who would benefit from LDL-C lowering. I IIaIIbIII
Lipids: In general, advise adults to engage in aerobic physical activity to reduce LDL-C and non–HDL-C: 3 to 4 sessions a week, lasting on average 40 minutes per session, and involving moderate- to vigorous- intensity physical activity. BP: In general, advise adults to engage in aerobic physical activity to lower BP: 3 to 4 sessions a week, lasting on average 40 minutes per session, and involving moderate- to vigorous-intensity physical activity. Physical Activity I IIaIIbIII I IIaIIbIII
……even modest weight loss (3-5% of body weight) can result in clinically meaningful benefits for triglycerides, blood glucose, glycated hemoglobin, and development of diabetes (type 2)….
Lipid Management Recommendations Start dietary therapy (<7% of total calories as saturated fat and <200 mg/d cholesterol) Adding plant stanol/sterols (2 gm/day) and viscous fiber (>10 mg/day) will further lower LDL Promote daily physical activity and weight management. Encourage increased consumption of omega-3 fatty acids in fish or 1 g/day omega-3 fatty acids in capsule form for risk reduction. For all patients
Therapeutic Lifestyle Changes Nutrient Composition of TLC Diet NutrientRecommended Intake Saturated fat Less than 7% of total calories Polyunsaturated fatUp to 10% of total calories Monounsaturated fat Up to 20% of total calories Total fat25–35% of total calories Carbohydrate50–60% of total calories Fiber20–30 grams per day Protein Approximately 15% of total calories CholesterolLess than 200 mg/day Total calories (energy)Balance energy intake and expenditure to maintain desirable body weight
Possible Benefits From Other Therapies Therapy Result Soluble fiber in diet (2–8 g/d) (oat bran, fruit, and vegetables) Soy protein (20–30 g/d) Stanol esters (1.5–4 g/d) (inhibit cholesterol absorption) Fish oils (3–9 g/d) (n-3 fatty acids) LDL-C 1% to 10% LDL-C 5% to 7% LDL-C 10% to 15% Triglycerides 25% to 35% Jones PJ. Curr Atheroscler Rep. 1999;1: Lichtenstein AH. Curr Atheroscler Rep. 1999;1: Rambjor GS et al. Lipids. 1996;31:S45-S49. Ripsin CM et al. JAMA. 1992;267:
Dietary Adjuncts TLC for patients with LDL-C = 160 Walden CE et al. Arterioscler Thromb Vasc Biol 1997;17: Jenkins DJ et al. Curr Opin Lipidol 2000;11: Cato N. Stanol meta-analysis. Personal communication, Dietary Component LDL-C (mg/dL) Low saturated fat/dietary cholesterol –12 Viscous fiber (10–25 g/d) –8 –8 Plant stanols/sterols (2 g/d) –16 Total –36 mg/dl –36 mg/dl
% Reduction Triglyceride *P< * -21* Total Cholesterol Source: Abe Y et al. Arterioscler Thromb Vasc Biol 1998;18: patients with hypertriglyceridemia and low HDL-C treated with -3 fatty acid (4 grams/day) for 7 months -3 Fatty Acids Evidence: Effect on Lipid Parameters HDL-C=High-density lipoprotein cholesterol
Source: Yokoyama M et al. Lancet. 2007;369: Japan Eicosapentaenoic acid Lipid Intervention Study (JELIS) *Composite of cardiac death, myocardial infarction, angina, PCI, or CABG Years -3 Fatty Acids Evidence: Primary and Secondary Prevention 18,645 patients with hypercholesterolemia randomized to EPA (1800 mg) with a statin or a statin alone for 5 years -3 fatty acids provide CV benefit, particularly in secondary prevention CV=Cardiovascular, EPA=Eicosapentaenoic acid
CONCLUSIONS Many persons with normal total or LDL-C levels still suffer CHD events. While statin-based clinical trials significantly reduce risk of CHD, residual risk still exists. Non-HDL-C, which reflects all the atherogenic lipid fractions, appears to be a stronger predictor of CHD events than LDL-C. The measurement of non-HDL-C and its use as a secondary therapeutic target is warranted to better address residual CHD risk. Lifestyle therapies as well as pharmacologic approaches, particular combination therapy with statins and other agents, are important for optimizing the entire lipid profile.