1 / 80

Complex Lipid Management

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

walterkeller
Download Presentation

Complex Lipid Management

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Complex Lipid Management Tara Dall, MD, FNLA Diplomate, American Board Clinical Lipidology President Advanced Lipidology 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, National Lipid Association Advanced Lipid testing and Biomarkers 2011, 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 • 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. 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

  9. 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

  10. Canadian Treatment Targets Each 1.0 mmol/L reduction in LDL-C, is associated with a corresponding 20-25% reduction in CVD mortality and non-fatal myocardial infarction. (Cholesterol Treatment Trialists meta-analysis of 14 statin trials) Data from the PROVE-IT, TNT, A to Z, IDEAL and SEARCH trials have confirmed that lowering LDL-C to a mean of 2.0 mmol/L or less is associated with the lowest risk of recurrent CVD events in secondary prevention patient populations. A 50% relative reduction in LDL-C confers close to optimal benefit.

  11. 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

  12. Lipid-Lowering Pharmacotherapy Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486. Zetia [package insert] Merck/Schering-Plough Pharmaceuticals; 2005. Crestor [package insert] AstraZeneca; 2005. Lovaza [package insert] GlaxoSmithKline; 2010.

  13. 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

  14. Statin Efficacy * Available generically

  15. Statin Pharmacokinetics

  16. –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.

  17. Candidates for Optional LDL-C Goal of <70 mg/dL • Very high risk patients • Established atherosclerotic CVD Plus • multiple risk factors (esp. diabetes) • severe and poorly controlled risk factors (e.g., cigarette smoking) • metabolic syndrome • acute coronary syndromes Grundy SM et al. Circulation 2004;110:227–239.

  18. 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.

  19. 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

  20. Intestinally-Acting Agents: Mechanisms of Action

  21. 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.

  22. 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.

  23. 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.

  24. 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

  25. 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.

  26. Analyses of Cancer Data from Three Ezetimibe Trials • Background: Increase cancer risk in SEAS trial • Compared SEAS with data from SHARP and IMPROVE-IT • Results: No overall increase risk of cancer (313 active Rx vs. 326 control – no significant excess cancer at any particular site. Among patients assigned to ezetimibe there were more cancer deaths (not significant: 97 vs. 78 in control group; P = 0.07) but fewer cases of cancer (not significant: 216 vs. 254 in control group; P = 0.08) • Conclusion: Currently available data do not provide credible evidence of any adverse effect of ezetimibe on cancer risk. Peto R, et al. N Engl J Med. 2008;359:1357-1366.

  27. 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 (no outcomes data to support this but in some patients it is effective) • Retrial with hydrophilic statin with less p450 3 A4 interactions (Pravastatin, Rosuvastatin, Pitavastatin) • Consider every other day Rosuvastatin 5 mg

  28. 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.

  29. Vitamin D deficiency has been associated with ... • Increase in all CV events(F’ham Offspring,Wang, Circ 08) • Increase in MIs (Health Profs F/U Study, Giovannuci, AIM 08) • Increase stroke risk (LURIC, Pitz, Stroke 08) • Increased blood pressure (Foreman, HTN 07) • Increased PVD by ABI (NHANES data, ATVB, 08) • Increased CIMT (Targhan, Clin Endo 06)

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

  31. Even in high TG patients, more than 90% of total plasma apoB is associated with LDL particles, except in type III hyperlipidemia [1,2] LDL particle number (ApoB) is a stronger indicator of CHD risk vsLDL-Cin: Prospective epidemiologic trials [3-12] In assessing residual risk on statin or fibrate therapy in intervention trials [13-17]. LDL particle number (ApoB) is a stronger indicator of CHD risk vsnon HDL-C in: Prospective epidemiologic trials [8,11,18] In assessing residual risk on statin or fibrate therapy in intervention trials [13-15,]. Atherosclerosis.1991;89:109-16. ClinChemActa.1978;82:151-60. Circulation.1996;94:273-8. Circulation.1999;99:2517-22. Lancet.2001;358:2026-33. ArteriosclerThrombVascBiol.2002;22:1918-23. AJC.2005;997-1001. Diabetologica.2006;49:937-944. ArteriosclerThrombVascBiol.2007;27:661-670. JAMA.2005;294:326-33. JLipidRes.2007;48:2499-2505. JAMA.2007;298:776-785. Circulation.2000;101:477-84. Circulation.2002;105:1162-9. ArteriosclerThrombVascBiol.2000;20:2408-2413. JACC.1998;32:1648-1656. Circulation.2003;107:1733-1737. Lancet.2003;361:777-780. Outcome Associations of LDL Particle Number (ApoB) versus LDL Cholesterol (LDL-C)

  32. ADA/ACC 2008 Consensus Statement:Treatment Goals in Patients With Cardiometabolic Risk and Lipoprotein Abnormalities Goals Apo B LDL-C Non–HDL-C • Highest-Risk Patient • Known CVD • Diabetes plus ≥1 additional major CVD risk factora <70 mg/dL <100 mg/dL <80 mg/dL <100 mg/dL <130 mg/dL <90 mg/dL • High-Risk Patients • No diabetes or known CVD but ≥2 major CVD risk factorsa • Diabetes but no other major CVD risk factorsa “In individuals on statin therapy who continue to have low HDL-C or elevated non–HDL-C, especially if Apo B levels remain elevated, combination therapy is recommended. The preferred agent to use in combination with a statin is nicotinic acid…” aMajor risk factors beyond dyslipidemia include smoking, hypertension, and family history of premature CHD. Diabetes Care. 2008;31:811-822. 33

  33. AACE 2011 GuidelinesComprehensive Diabetes Care Treatment GoalsLipids Highest Risk: DM and CVD; High Risk: DM without CVD AACE Diabetes Care Plan Guidelines, Endocr Pract. 2011;17 (Suppl 2)

  34. 2011 Recommendations from the NLA Expert Panel on Clinical Utility of Inflammatory Markers and Advanced Lipoprotein Testing Summary of Recommendations for Measurement for Initial Clinical Assessment Davidson, et al. J Clin Lipidol 2011;5:338-367.

  35. 2011 Recommendations from the NLA Expert Panel on Clinical Utility of Inflammatory Markers and Advanced Lipoprotein Testing Summary of Recommendations for Measurement for On-Treatment Management Decisions Davidson, et al. J Clin Lipidol 2011;5:338-367.

  36. Clinical Cutpoints for LDL Percentile: 20th 50th 80th Optimal High LDL Cholesterol Percent of Subjects Framingham Offspring 70 100 130 160 190 220 250 mg/dL LDL Particle Number Percent of Subjects MESA 700 1000 1300 1600 1900 2200 2500 nmol/L

  37. Population Distributions of LDL-C, non-HDL-C, ApoB and LDL-P in Framingham Offspring Study ADA/ACC Cutpoints 1 High Risk Very High Risk The medical decision cutpoints should be set so that the apoB and LDL-P cutpoints are equivalent to those for LDL-C in terms of population percentiles. AACC Cutpoints 2 NCEP ATP-III Cutpoints 1 Brunzell, et al. Diabetes Care 2008;31(4):811-822. 2 Contois JH, et al. Clinical Chemistry 2009; 55:407-419

  38. Beyond LDL HDL and Triglycerides

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

  40. 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

  41. 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:

  42. Effect of Lifestyle Modifications on HDL-C Levels and HDL Components ABCA1, adenosine triphosphate-binding cassette transporter A1; apo A-1, apolipoprotein A-1, CETP, cholesterol ester transfer protein; HDL-C, high-density lipoprotein cholesterol; LCAT, lecithin-cholesterol acyltransferase; LDL-C, low-density lipoprotein cholesterol; LPL, lipoprotein lipase; MUFA, monounsaturated fatty acid; PUFA, polyunsaturated fatty acid. SI conversion factor: To convert HDL-C to mmol/L, multiply by 0.0259. Singh IM, Shishehbor MH, Ansell BJ. JAMA. 2007;298:786-798.

  43. Effect of Current Pharmacotherapies on HDL-C Levels and HDL Components Singh IM, Shishehbor MH, Ansell BJ. JAMA 2007;298:786-798.

  44. AIM HIGH

  45. What to do about Niacin post AIMHIGH? • Having an “LDL-Particle(NMR)” /”Apo B” vs “cholesterol” lens changes our perspective on studies like AIM HIGH • Baseline NORMAL apo B in AIM HIGH (not a clinical scenario lipidologists would add niacin) • Niacin is a powerful agent for LDL –P/Apo B reduction, this effect known and may be more important clinically then HDL cholesterol increase with niacin • Bottom line: continue using niacin

  46. Otvos comments regarding Niacin and AIM HIGH study • Niacin treatment has different effects on the cholesterol and particle measures of LDL and HDL. Niacin significantly raises HDL-C, but without increasing HDL particle number (HDL-P), and modestly reduces LDL-C but usually lowers LDL particle number (LDL-P) much more. Many clinicians invested in managing the particle abnormalities of their patients use niacin more for LDL-lowering than HDL-raising. The AIM-HIGH trial assessed the efficacy of increasing HDL-C and correcting other non-LDL lipid abnormalities with niacin in CHD patients with optimally-treated LDL-C, but the trial design did not allow the potential benefit of LDL-P lowering to be assessed. The lack of clinical benefit of niacin treatment in AIM-HIGH was generally considered a surprise, but was not surprising given the known effects of niacin on lipoprotein particles and lipoprotein-mediated cardiovascular risk Otvos, J clin lipidology Vol 5:5, 368-370. Sept 2011

  47. 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.

  48. Triglyceride Level Is Significant CVD Risk Factor:Recent Meta-Analysis of 29 Studies Groups CHD Cases CHD Risk Ratio* (95% CI) Duration of follow-up ≥10 years 5902 <10 years 4256 N = 262,525 Sex Male 7728 Female 1994 Fasting status Fasting 7484 Nonfasting 2674 Adjusted for HDL Yes 4469 No 5689 1.72 (1.56-1.90) Overall CHD Risk Ratioa 1 Increased Risk Decreased Risk 2 aIndividuals in top versus bottom third of usual log-triglyceride values, adjusted for at least age, sex, smoking status, lipid concentrations, and blood pressure (most) Sarwar N, et al. Circulation. 2007;115:450-458. 50

  49. ATP III Classification of TG Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.

  50. 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. Modified from Pejic R, et al., J Am Board Fam Med. 2006;19:310-316.

More Related