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Complex Lipid Management

Complex Lipid Management. Tara Dall, MD, FNLA Diplomate, American Board Clinical Lipidology President Midwest Lipid Association Delafield, WI www.advlip.com www.lecturepad.org (ongoing clinician education). Disclosures. Speakers Bureau 2012: Abbott, Liposcience, Santarus, HDL labs

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Complex Lipid Management

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  1. Complex Lipid Management Tara Dall, MD, FNLA Diplomate, American Board Clinical Lipidology President Midwest Lipid Association Delafield, WI www.advlip.com www.lecturepad.org (ongoing clinician education)

  2. Disclosures • Speakers Bureau 2012: Abbott, Liposcience, Santarus, HDL labs • 2011 GlaxoSmithKleine • Research support: none • OFF LABEL DISCUSSION: none

  3. Objectives • Review guidelines/consensus statements: NCEP ATP III, ADA/ACC, NLA, ATP IV (if available) • Discuss potential risk factors including triglycerides, HDLs • Identify successful strategies for the management of patients with complicated lipid disorders, high LDL, low HDL, high triglycerides, or combination disorders • Discuss recent combination therapy clinical trial data (ACCORD, AIM HIGH, SHARP)

  4. Complex Lipid Referral from Cardiology • 47 yr old Male with obesity, dyslipidemia, HTN, Sleep apnea • Statins stopped due to elevated LFTs • Lipid Panel • T Chol 301 mg/dl • HDL 29 mg/dl • Triglycerides 1457 • BP 160/90 • Medications • Fenofibrate 145 mg • Colesevalam 625 mg 6/d • Ezetamibe10 mg • Nicotinic Acid 500 mg • Amlodipine/Valsartan/HCTZ 10/320/25 • Aliskiren 300 • Nebivolol 20 mg • Clonidine 0.1mg • Statins stopped due to elevated LFTs

  5. Secondary Causes of Hypertriglyceridemia (Screen/Treat in All Cases) Diseases/States • Central/visceral adiposity • Insulin resistance/metabolic syndrome • PCOS • DM-2(esp. if poor control) • Sedentary Lifestyle • Endocrine disorders/states • Hypothyroidism • Hypercortisolism • Pregnancy • Renal disorders • Nephrotic syndrome • End-stage renal disease • Systemic Inflammation/Infection • Arthritis • HIV • Other? • Psychiatric disorders Drugs/Diet • Recreational • Ethanol • Marijuana • Diet • ↑Fructose/sucrose/starch • High fat (when TG >~700) • High calories? • Hormones • Oral estrogen (BCP & ERT) • Systemic glucocorticoids (not nasal or topical) • Blood Pressure/Lipid Rx • Beta blockers (most) • Thiazide diuretics • Bile-acid sequestrants • Miscellaneous • Cyclosporine • Retinoic-acid derivatives • HAART (PI and others) • Atypical anti-psychotics HAART = highly active antiretroviral therapy; PI=protease inhibitors.

  6. Emerging Risk Markers • hsCRP • LpPLA2 • Fibrinogen • Homocysteine • LDL Particle concentration (LDL-P) • Small dense LDL • Apo B • Lipoprotein (a)

  7. LDL Particles Cause Atherosclerosis Low Density Lipoprotein particles (LDL) are the causal agents in atherosclerosis.1 The more lipoprotein particles a person has, the higher the risk for plaque buildup that causes heart attacks, regardless of how much cholesterol those particles carry. 1 Fredrickson et al. NEJM 1967; 276: 148

  8. POLAR SURFACE COAT Phospholipid Free cholesterol Apo B This is an LDL particle (LDL-P) NONPOLAR LIPID CORE Cholesterol Ester Triglyceride This is LDL Cholesterol (LDL-C) LDL Cholesterol Is Not LDL!! A convenient analytic surrogate of LDL since 1972

  9. Chylo- microns 0.95 VLDL IDL 1.006 Chylomicron Remnants Density (g/ml) 1.02 LDL 1.06 HDL2 Lp(a) 1.10 HDL3 1.20 5 10 20 40 60 80 1000 Diameter (nm) Lipoprotein Subclasses Apo B ~ non HDL-C

  10. NON-HDL Cholesterol =Total cholesterol – HDL-Cholesterol “surrogate for Apo B/ LDL –P (NMR Particle concentration) when not available”

  11. Weight of Evidence:LDL-P/Apo B more predictive than LDL-Cholesterol Over 210 LDL-P related papers published to Date

  12. Up to 70% More Particles 100 mg/dL 100 mg/dL Large LDL Small LDL Cholesterol Balance Small LDL Particles Contain Less Cholesterol Than Large LDL Particles

  13. Up to 40% More Particles 100 mg/dL 100 mg/dL Normal Cholesterol Per Particle Less Cholesterol Per Particle Cholesterol Balance Even LDL Particles of the Same Size can Differ in Cholesterol Content

  14. 1.00 0.98 Framingham Heart Study Offspring Cohort 0.96 Low LDL-C n=1249 Event-free survival among participants with low-density lipoprotein cholesterol (LDL-C) above or below the median. Median values were 131 mg/dL for LDL-C 0.94 0.92 0.90 0.88 Probability of Event Free Survival 0.86 High LDL-C n=1251 0.84 0.82 How predictive is LDL-C with respect to event-free survival? 0.80 0.78 0.76 0.74 10 8 6 16 12 4 2 14 0 Years of Follow-up Cromwell W et al. J Clin Lipidol 2007;1:583-592

  15. 1.00 0.98 Framingham Heart Study Offspring Cohort 0.96 Event-free survival among participants with low-density lipoprotein cholesterol (LDL-C) above or below the median. Median values were 131 mg/dL for LDL-C 0.94 0.92 High LDL-C n=284 0.90 0.88 Probability of Event Free Survival 0.86 0.84 0.82 Low LDL-C n=282 0.80 Additional Data 0.78 0.76 0.74 10 8 6 16 12 4 2 14 0 Years of Follow-up Cromwell W et al. J Clin Lipidol 2007;1:583-592

  16. 1.00 Framingham Heart Study Offspring Cohort 0.98 Low LDL-P Event-free survival among participants with low-density lipoprotein cholesterol (LDL-C) and LDL particle number (LDL-P) above or below the median. Median values were 131 mg/dL for LDL-C and 1414 nmol/L for LDL-P. 0.96 Low LDL-C n=1249 0.94 Low LDL-P 0.92 High LDL-C n=284 0.90 0.88 Significant # of LDL-C / CV-risk disconnects High LDL-P LDL-P was strongly associated with increased CVD risk in both men and women (p<0.0001) When data for men and women were combined, LDL-P was approximately twice as strongly related to CVD incidence as LDL-C Probability of Event Free Survival 0.86 High LDL-C n=1251 0.84 High LDL-P 0.82 Low LDL-C n=282 ? Explanation 0.80 0.78 Particle number (LDL-P) is the key risk factor 0.76 0.74 10 8 6 16 12 4 2 14 0 Years of Follow-up Cromwell W et al. J Clin Lipidol 2007;1:583-592

  17. LDL-P/Apo B and LDL-C Discordance in MESA CVD Event Rates in Subgroups with Low LDL Discorcordant High LDL-P Residual Risk Concordant Discorcordant Low LDL-P Need Additional LDL-C Lowering? Otvos et al. J Clin Lipidol 2011;5:105-13

  18. ADA and ACC Consensus Statement on Lipoprotein Management in Patients with Cardiometabolic Risk LDL-C (mg/dL) Non-HDL-C (mg/dL) ApoB (mg/dL) TREATMENT GOALS Highest-risk patients, including those with 1) known CVD or 2) Diabetes plus one or more additional CVD risk factor < 70 < 100 < 80 High-risk patients, including those with 1) no diabetes or known clinical CVD but 2 or more additional major CVD risk factors or 2) Diabetes but no other CVD risk factors < 100 < 130 < 90 Brunzell JD, Davidson M, Furberg CD et al. Diabetes Care 2008;31:811-822

  19. NLA Expert Panel Advice: ApoB and LDL-P Initial Clinical Assessment LDL-P ApoB Low risk (<5% 10-year CHD event risk Not recommended Not recommended Intermediate risk (5-20% 10-year CHD event risk Reasonable for many patients Reasonable for many patients Consider for selected patients Consider for selected patients CHD or CHD Equivalent Reasonable for many patients Reasonable for many patients Family History Reasonable for many patients Reasonable for many patients Recurrent Events Davidson MH et al. J Clin Lipidol 2011;5:338-367

  20. NLA Expert Panel Advice: ApoB and LDL-P On-Treatment Management Decisions LDL-P ApoB Low risk (<5% 10-year CHD event risk Not recommended Not recommended Intermediate risk (5-20% 10-year CHD event risk Reasonable for many patients Reasonable for many patients Reasonable for many patients Reasonable for many patients CHD or CHD Equivalent Consider for selected patients Consider for selected patients Family History Reasonable for many patients Reasonable for many patients Recurrent Events Davidson MH et al. J Clin Lipidol 2011;5:338-367

  21. Apo B/LDL-P decreases more with: • niacin • fibrates • metformin • pioglitazone • omega 3 FAs • exercise • low carb diet • LDL Cholesterol decreases with: • statins • statin + ezetimibe • low fat, high carb diet Treatments that Alter the Cholesterol Content of LDL Change LDL-C and LDL-P (Apo B) Differentially BOTTOM LINE: USE COMBINATION DRUGTHERAPY to REDUCE APO B

  22. Existing LDL-C goals Optional LDL-C goals NCEP ATP III: LDL-C Goals(2004 Update modifications) Moderately High Risk ≥2 risk factors (10-yr risk 10-20%) Moderate Risk ≥2 risk factors (10-yr risk <10%) Lower Risk <2 risk factors High Risk CHD or CHD risk equivalents (10-yr risk >20%) 190 - goal 160 mg/dL 160 - goal 130 mg/dL goal 130 mg/dL LDL-C level 130 - goal 100 mg/dL or optional 100 mg/dL* 100 - or optional 70 mg/dL* 70 - *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 Circulation 2004;110:227-239

  23. Canadian Targets for LDL-C (or apoB): Nearly all clinical trials measure LDL-C as index of therapy. Recommendations: • Primary target is LDL-C decrease to < 2.0 mmol/L or 50% relative reduction • We recommend apoB < 0.80 g/L as primary alternate target In high- and moderate-risk subjects

  24. Statin Dose to Achieve LDL-C Reduction of 30–40% Grundy SM et al. Circulation 2005;112:2735–2752. Livalo [package insert] Kowa Pharmaceuticals; 2010

  25. Statins: Role in Therapy • The most effective agents to lower LDL-C, first-line therapy for most patients • Clinically proven to reduce mortality and recurrent cardiovascular events • Stabilizing plaques, reduces progression, partial regression • Most well tolerated

  26. –28% –37% –46%* –7% –4% –6% –7% –5% –6% –3% 10 mg –3% 20 mg 40 mg 80 mg The Majority of Statin LDL-C Efficacy Is at Starting Doses Atorvastatin Rosuvastatin Simvastatin Note far more LDL receptors are upregulated with the starter dose of the statin than occurs with doubling or even tripling the dose –5% –15% Mean % Change in LDL-C From Untreated Baseline † –25% –35% –45% –55% *P<0.001 vs atorvastatin 10 mg and simvastatin 20 mg and 40 mg. †P=0.026 vs atorvastatin 20 mg. Jones PH et al. Am J Cardiol.2003;92:152–160.

  27. Minimum Statin Dose to Achieve 50% LDL-C Reduction Jones PH et al. Am J Cardiol 1998;81:582–587. | Jones PH et al. Am J Cardiol 2003;92:152–160. | Ballantyne CM et al. Am J Cardiol 2004;93:1487–1494. Ballantyne CM et al. Am Heart J 2005;149:464-473.

  28. Simvastatin 80 mg no longer recommended FDA Safety Announcement 6/8/2011

  29. Simvastatin Restrictions • Contraindicated with simvastatin: • Itraconzole • Ketoconazole • Posaconazole • Erythromycin • Clarithromycin • Telithromcyin • HIV protease inhibitors • Nafazadone • Gemfibrozil • Cyclosporine • Danazole FDA Safety Announcement 6/8/2011

  30. Simvastatin Restrictions • Do not exceed 10 mg simvastatin with: • Amiodarone • Verapamil • Diltiazem FDA Safety Announcement 6/8/2011

  31. Simvastatin Restrictions • Do not exceed 20 mg simvastatin with: • Amlodipine • Ranolazine FDA Safety Announcement 6/8/2011

  32. Statin + bile acid binding resin Statin + ezetimibe Statin + niacin Statin + BAR ± ezetimibe ± niacin Bile acid binding resin or ezetimibe + niacin Bile acid binding resin + ezetimibe Combination Therapy to Reduce LDL-C

  33. Intestinally-Acting Agents: Mechanisms of Action

  34. Colesevelam + Atorvastatin: Efficacy† LDL-C HDL-C TG Change from Baseline (%) * * * * * † LDL-C and Total-C values are expressed as mean, whereas HDL-C and TG values are expressed as median. Atherosclerosis. 2001;158:407-416. * P < 0.05 vs placebo.

  35. Colesevelam Added to Metformin-based Therapy Reduces A1C in Patients With Type 2 Diabetes Colesevelam Added to Metformin + Non-insulin Antidiabetic Agent Colesevelam Added to Metformin (n=155) Baseline A1C 8.2% (n=145) Baseline A1C 8.0% Mean Treatment Difference A1C aP=0.002, colesevelam compared with placebo bP<0.001, colesevelam compared with placebo All subjects were stable on metformin-based therapy for ≥90 days. -0.5a -0.6b Bays HE, et al. Arch Intern Med. 2008;168:1975-1983.

  36. Advanced Lipidology protocol for Statin Intolerance • Rule out and treat secondary causes (ex. hypothyroidism, Vit D deficiency) • Assess which statins trialed previously and dose • Consider adding Co Q 10 Ubiquinol 300-600/day • Retrial with hydrophilic statin with less p450 3 A4 interactions (Pravastatin, Rosuvastatin, Pitavastatin) • Consider every other day Rosuvastatin 5 mg

  37. Low Vitamin D Levels are Associated with Reversible Myositis-myalgia in Statin Treated Patients • 38 of 82 patients with low vitamin D and myalgia symptoms were given vitamin D 50,000 units/week for 12 weeks while continuing statin therapy. • Vitamin D increased from 20.4 ± 7.3 to 48.2 ± 17.9 ng/mL (p<0.0001). • 92 % experienced resolutation of myalgias Ahmed W, et al. Translational Research. 2009;153:11-16.

  38. The Study of Heart and Renal Protection (SHARP): Eligibility • History of chronic kidney disease • not on dialysis: elevated creatinine on 2 occasions • Men: ≥1.7 mg/dL (150 µmol/L) • Women: ≥1.5 mg/dL (130 µmol/L) • on dialysis: hemodialysis or peritoneal dialysis • Age ≥40 years • No history of myocardial infarction or coronary revascularization • Uncertainty: LDL-C lowering treatment not definitely indicated or contraindicated • Randomized to 10/20 mg Eze-Simv vs. placebo Adapted from the SHARP slides available at www.sharpinfo.org from the presentation made by Colin Baigent and Martin Landray on behalf of the SHARP Investigators at the American Society of Nephrology, Denver November 20, 2010.

  39. SHARP: Major Atherosclerotic Events 25 Risk ratio 0.83 (0.74 – 0.94) Logrank 2P = 0.0022 20 Placebo 15 Eze/Simv Proportion suffering event (%) 10 5 0 1 2 3 4 5 Adapted from the SHARP slides available at www.sharpinfo.org from the presentation made by Colin Baigent and Martin Landray on behalf of the SHARP Investigators at the American Society of Nephrology, Denver November 20, 2010. Years of follow-up

  40. SHARP: Major Vascular Events Risk ratio & 95% CI Event Eze/simv Placebo (n = 4650) (n = 4620) Major coronary event 213 (4.6%) 230 (5.0%) Non-haemorrhagic stroke 131 (2.8%) 174 (3.8%) Any revascularization 284 (6.1%) 352 (7.6%) Major atherosclerotic event 526 (11.3%) 619 (13.4%) 16.5% SE 5.4 reduction (P = 0.0022) Other cardiac death 162 (3.5%) 182 (3.9%) Haemorrhagic stroke 45 (1.0%) 37 (0.8%) Other major vascular events 207 (4.5%) 218 (4.7%) 5.4% SE 9.4 reduction (P = 0.57) Major vascular event 701 (15.1%) 814 (17.6%) 15.3% SE 4.7 reduction (P = 0.0012) 0.6 0.8 1.0 1.2 1.4 Eze/simv better Placebo better Adapted from the SHARP slides available at www.sharpinfo.org from the presentation made by Colin Baigent and Martin Landray on behalf of the SHARP Investigators at the American Society of Nephrology, Denver November 20, 2010.

  41. Atherogenic Particles Apolipoprotein B MEASUREMENTS: Non-HDL-C ( TC – HDL) LDL Particle Concentration VLDL VLDLR IDL LDL Sm-Dense LDL TG-rich Lipoproteins

  42. Beyond LDL HDL and Triglycerides

  43. Relations of LDL Particles and LDL Cholesterol to Levels of HDL Cholesterol and Triglycerides Otvos et al., Amer J Cardiol 2002;90:22i-29i.

  44. Current HDL-C Cutpoints • NCEP ATP III: HDL Low if <40 mg/dL • Metabolic syndrome criteria (ATP III, IDF) • Men <40 mg/dL • Women <50 mg/dL • AHA Women’s Cardiovascular Health Guidelines: 50 mg/dL Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497. | Mosca L et al. Circulation 2011

  45. Clinical Diagnosis of the Metabolic Syndrome: 3 Risk Factors Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.

  46. AHA CVD Prevention Guidelines for Women 2011 Clinical Recommendations Major Risk Factor Interventions • Lipids - Lipoproteins: (Class I, Level B) • Optimal levels • LDL-C < 100 mg/dL • HDL-C > 50 mg/dL • TG < 150 mg/dL • Non HDL-C < 130 mg/dL • Pharmacotherapy for low HDL-C or high non–HDL-C* • Niacin or fibrate therapy (after LDL-C goal is reached) Mosca, L. et al. Circulation 2011;123:

  47. Non Pharmacologic Strategies to Raise HDL-Cholesterol • Low carb, moderate fat diet • Intense Freq Exercise • Weight loss • Smoking cessation

  48. Effects of Lipid-Modifying Drugs on HDL-C Statins  5 – 10% Niacin  15 – 35% Fibrates  2 – 15% Omega 3 FA  5-15%

  49. Beyond LDL: Combination TherapyStatin vs Statin/Niacin FATS10 YR WOSCOPS 4S CARE HPS FATS HATS 0 -10 -20 -24 -30 -25 -31 -34 -40 Percent -50 -60 -70 -80 -80 -90 -90 -95 -100 Reduction in CV Events Brown BG, et al. N Engl J Med. 2001;345:1583-1592.

  50. TRIGLYCERIDES

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