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Approach to Dyslipidemia

Approach to Dyslipidemia. Pathogenesis, Role in Atherosclerosis, Screening and Treatment Maryam Zamanian, MD. Covered Topics. Physiology of Lipid Metabolism Role of lipoproteins in atherosclerosis Hypolipidemic Agents ,indications, and side effects Screening and Risk Assessment

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Approach to Dyslipidemia

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  1. Approach to Dyslipidemia Pathogenesis, Role in Atherosclerosis, Screening and Treatment Maryam Zamanian, MD

  2. Covered Topics • Physiology of Lipid Metabolism • Role of lipoproteins in atherosclerosis • Hypolipidemic Agents ,indications, and side effects • Screening and Risk Assessment • Treatment Paradigms • Treatment of Special Populations • Emerging issues in Dyslipidemia

  3. Exogenous Pathway of Lipid Metabolism Cholest AA FA P, glycerol Vessel wall

  4. Endogenous Pathway of Lipid Metabolism

  5. HDL Metabolism

  6. Key Enzymes and Cofactors in Lipid Metabolism • HMG-CoA reductase-reduces HMG-CoA to mevalonic acid in the rate-limiting step of cholesterol biosynthesis (mainly liver and intestine) • Lipoprotein Lipase- digests TG core of CMC and VLDL • Hepatic Lipase-conversion of IDL to LDL • CETP-transfers cholesteryl esters from HDL to other lipoproteins in exchange for TG • LCAT(lecithin cholesterol acyl transferase) conversion of cholesterol to cholesterol esters • Apolipoprotein A-major protein of HDL activating many reactions • Apo-B-major protein of VLDL, IDL, and LDL • Apo-CII and Apo E obtained from HDL by CMC and VLDL for activation of LPL and receptor recognition respectively

  7. LDL Oxidation and Atherosclerosis

  8. Mechanism of Atherogenic Dyslipidemia Insulin resistance increased NEFA and glucose flux to liver Increased VLDL IR impairs LDLR Insulin resistance and decreased apo-B degradation Insulin resistance and decreased LPL FCHL DM II Metabolic syndrome

  9. Direct Association Longer residence time in plasma than normal sized LDL due to decreased recognition by receptors in liver Enhanced interaction with scavenger receptor promoting foam cell formation More susceptible to oxidation due to decreased antioxidants in the core Enter and attach more easily to arterial wall Endothelial cell dysfunction Indirect Association Inverse relationship with HDL Marker for atherogenic TG remnant accumulation Insulin resistance Increased Atherogenicity of Small Dense LDL

  10. High Density Lipoprotein and Atherosclerosis • Reverse cholesterol transport • Maintenance of endothelial function • Protection against thrombosis • With Apo A-I inhibits generation of calcium-induced procoagulant activity on erythrocytes by stabilizing cell membrane • Low blood viscosity via permitting red cell deformability • Anti-oxidant properties-may be related to enzymes called paraoxonase

  11. Specialized form of LDL (apolipoprotein (a) covalently bound to apo B by disulfide bridge) Structural similarity to plasminogen, thus interfering with fibrinolysis Macrophage binding and cholesterol deposition Measured by ELISA Cross-sectional and retrospective epidemiologic studies have shown association between excess Lp (a) and CHD while prospective results are conflicting Associated with unstable angina and presence of complex coronary lesions Commonly detected in premature CHD Possible role in target organ damage in presence of HTN Indications for screening: CHD and no other identifiable dyslipidemia Strong CHD family history and no other dyslipidemia HTN and early premature target organ damage Hypercholesterolemia refractory to statins and bile acid sequestrants Treatment guidelines Primary goal is to lower LDL to target and lowering to <80 may reduce risk If LDL cannot become optimized, then Lpa loweing with nicotinic acid (38%) shoud be tried Goal <20 in whites Lipoprotein (a)

  12. Primary Disorders of LDL-Cholesterol Metabolism • Familial hypercholesterolemia- defect in gene coding for apo B/E LDL receptor thus reduced clearance of LDL from circulation • Homozygotes with higher LDL-C levels • Excess LDL deposited in arteries as atheroma and in tendons and skin as xanthomata and xanthelasma • Hypercholesterolemia, normal TG, genetic or cellular confirmation of LDL receptor defect • Usually serum cholesterol levels AND premature CHD in first-degree or 2 second-degree relatives • Usually requires multiple drugs for treatment • Familial defective apolipoprotein B-100 • Mutation in apo-B 100 ligand and impaired binding to LDL receptor with decreased clearance of LDL and 2-3 fold increase • Similar clinical manifestation as FH and only distinguished by molecular biology techniques • Familial combined hyperlipidemia • Usually associated with metabolic syndrome • 1-2% general population • 1/3-1/2 familial causes of CHD and 10% of premature cases • Overproduction of hepatically derived apo-B 100 associated with VLDL +/- decreased LDL receptor activity • LDL phenotype B, increased TG, decreased HDL (atherogenic dyslipidemia) • Phenotypic heterogeneity depends on problems with VLDL or LDL metabolism • Elevated TG and cholesterol • Elevated LDL • Isolated hypertriglyderidemia (rise in VLDL)

  13. Statins • Competitive inhibitors of HMG CoA reductase, rate-limiting step in cholesterol biosynthesis • Reduction in intrahepatic cholesterol leading to increased LDL receptor turnover • Most powerful for lowering LDL cholesterol • Modest effect on raising HDL • Reduction in TG due to decreased VLDL synthesis and clearance of VLDL remnants by apo B/E (LDL) receptors • Reduction in oxidized and small dense LDL subfractions and reduce remnant lipoprotein cholesterol levels (reduction of CE transfer from LDL to VLDL)

  14. Comparable Efficacy of Statins Special considerations: No renal dosing: Atorvastatin and Fluvastatin Use in chronic liver disease: pravastatin or rosuvastatin Less drug interactions: pravastatin, fluvastatin, rosuvastatin (not metabolized via CYP3A4) Less muscle toxicity: Pravastatin and Fluvastatin Cost-effectiveness: Rosuvastatin, atorvastatin, fluvastatin

  15. Evidence in Primary Prevention

  16. Evidence in Secondary Prevention

  17. Mechanism of Benefit of Statins in Secondary Prevention • Regression of atherosclerosis • Plaque stabilization • Reduced inflammation • Decreased thrombogenicity • Reversal of endothelial dysfunction • Others • Reduced monocyte adhesion to endothelium • Reduced oxidative modification of LDL • Increased mobilization and differentiation of endothelial progenitor cells leading to new vessel formation

  18. Adverse Effects of Statins • In general, less than with other agents. Fairly tolerable and safe • Myopathy • Ranges from myalgias (2-11%), myositis(0.5%) to rhabdomyolysis (<0.1%) (possibly ARF) • Few weeks-4 months onset • Symptoms and CK should normalize over days to one month after d/c • Pravastatin and Fluvastatin less risk • Increased risk in • ARF/CRF • Obstructive liver disease • Hypothyroidism • Concomittant use of drugs interfering with CYP3A4?? • Gemfibrozil combined therapy • Hepatic • 0.5 to 3% persistent elevations in amino-transferases in first 3 months and dose-dependent • Several randomized trials have found no difference compared with placebo • FDA recommends LFTs before and 12 weeks after starting and with any dose elevation and periodically • CNS • Case reports of memory loss associated with statins (mainly lipophilic) • If memory loss and recent initiation of statin, then d/c and use a hydrophilic statin such as pravastatin or rosuvastatin • No significant difference with placebo in trials

  19. Fibric Acid Derivatives Decrease Triglycerides (35-50%) • Reduced hepatic secretion of VLDL through activation of PPAR-alpha receptors in liver • Stimulate lipoprotein lipase and thus clearance of TG-rich lipoproteins • Raise HDL (15-25%) • Direct stimulation of HDL apolipoprotein synthesis A-I,II • Increased transfer of apo A-I with diminished cholesterol transfer from HDL to VLDL • Increases LDL buoyancy • May also improve endothelial function and favorable effect on macrophage responses (possible reduction in CHD risk independent of effect on lipoproteins) • Agents • Gemfibrozil- 600 mg po BID (11% raise in HDL). Modest LDL reduction but little effect in combined hyperlipidemia. Can increase LDL in pure hypertriglyderidemia • Fenofibrate 200 mg capsules or iii caps 67 mg qd (renal dosing and can decrease Cyclosporin levels). Better for LDL lowering • Side effects • Gallstone formation • Dyspepsia, diarrhea, nausea, vomiting, abdominal pain, eczema, rash, vertigo and myalgias • Adverse drug interaction • Gemfibrozil- inhibits glucuronidation of lipophilic statins and increases levels thus increasde risk of myopathy. Also decreases warfarin by 30%

  20. Bile Acid Sequestrants Lower LDL (10-15%) BINDING BILE ACIDS IN INTESTINE CAUSING A DECLINE IN HEPATIC CHOLESTEROL POOL; THUS SYNTHESIS OF apo B/E (LDL) RECEPTORS Max doses cause 30% reduction Raise HDL Intestinal formation of nascent HDL Available agents Cholestyramine 8 grams/day. 24-30 grams/day can lower LDL up to 24% Colestipol 10 grams/day Colesevelam 1.5-4.5 grams/d Adverse effects Usually limit use Mainly GI (nausea, bloating, cramping)- least problematic with colesevelam Increased liver enzymes Also drug interactions (impair absorption) Digoxin, warfarin, and fat soluble vitamins (give one hour before or 4 hours after bile acid sequestrant) Contraindications: pts with elevated TG

  21. Nicotinic Acid • Mechanism of Action • Inhibits hepatic VLDL production and its metabolite LDL • Raises HDL by reducing lipid transfer of cholesterol from HDL to VLDL and by delaying HDL clearance • Increase in LDL size • Reduction in plasma fibrinogen levels • Formulations and dosing • Immediate release (crystalline): 100 TID and titrated to tolerance • Sustained release • Niacor • Niaspan: 500 mg qhs x one month and then titrated to 1000 mg usually given daily after evenng meal • 1-1.5 grams/day for HDL raising • 3 grams/day for VLDL and LDL lowering and possibly lowering lipoprotein a levels • OTC IR preps are cheaper and effective • OTC preps labeles “NO FLUSH” usually not efficacious • Side effects • Flushing (less common with controlled release) minimized with ASA 30 minutes before and limited in 7-10 days • Nausea, paresthesias, pruritis (20% each) • Elevation of hepatocellular enzymes and possible hepatotoxicity, jaundice and fulminant hepatitis (generally less common with Niaspan and crystalline niacin) • Insulin resistance and worsening hyperglycemia (less with crystalline Niaspan) • Hyperuricemia (AVOID IF H/O GOUT) • Hypotension in combination with other vasodialtors (can increase unstable angina)

  22. Ezetimibe(Zettia) • Mechanism: • impairs dietary and biliary cholesterol absorption at the brush border of the intestines without affecting TG or fat-soluble vitamins • possible Niemann-Pick C1 like protein involved in cholesterol transport • LDL decrease 15-20% • Trivial effects on HDL and TG • Also adjunctive therapy to statins but same effect with higher dose of statin as in one study 10 zettia and 10 atorvastatin same effect as 80 atorvastatin • Indications • Avoiding high doses of statins • Very high LDL (FCH) not sufficiently controlled on statins • Adverse effects • Only 20% absorption so lower side-effect profile • Higher incidence of myopathy and elevated transaminases when coadministered with a statin • Should not be used as the first-line agent in lowering LDL • Check LFTs prior to starting in combo with statins • No definite clinical outcome studies available

  23. Effect of Lifestyle Modification • Diet • Decreased saturated fat (decrease LDL) • Replacing saturated and trans unsaturated fats with unhydrogenated monounsaturated or polyunsaturated fats • Recommended diet • Dietary cholesterol <200 mg/d; total fat <30%; saturated fat <7% • CHO (whole grains, fruits,veggies) 50-60% total calories • Dietary fiber 20-30 g/d • Protein 10-25 g/day • Plant stanols/sterols 2 grams/day • Effect of LDL lowering should be evident in 6-12 months • Elevated BMI associated with decreased dietary response • Referral to dietitian helpful • Exercise • In a prospective study of 111 sedentary men and women with dyslipidemia randomized to different levels of exercise, decrease in VLDL TG and increase in LDL size observed. Increase in HDL and size and largest effect on LDL seen with high amount high intensity exercise • Mechanisms of benefit: reduction in CETP, elevation in LCAT, reduced hepatic lipase and elevated LPL activity • Possible effect on LDL particle size • Moderate intensity exercise (3-4 mi/hr) for 30 minutes on most days of the week

  24. Diet Supplements • Fish Oil (source of omega-3 polyunsaturated fatty acids) • Salmon, flaxseed, canola oil, soybean oil and nuts • At high doses > 6 grams/day reduces TG by inhibition of VLDL-TG synthesis and apolipoprotein B • Possibly decreases small LDL (by inhibiting CETP) • Several studies have shown lower risk of coronary events • 2 servings of fish/week recommended?? • Pharmacologic use restricted to refractory hypertriglyceridemia • Number of undesirable side effects (mainly GI) • Soy • Source of phytoestrogens inhibiting LDL oxidation • 25-50 grams/day reduce LDL by 4-8% • Effectiveness in postmenopausal women is questionable • Garlic • Mixed results of clinical trials • In combination with fish oil and large doses (900-7.2 grams/d), decreases in LDL observed • Cholesterol-lowering Margarines • Benecol and Take Control containing plant sterols and stanols • Inhibit cholesterol absorption but also promote hepatic cholesterol synthesis • 10-20% reduction in LDL and TC however no outcome studies • AHA recommends use only in hypercholesterolemia pts or those with a cardiac event requiring LDL treatment • Other agents include soluble fiber, nuts (esp. walnuts), green tea • Overall a combination diet with multiple cholesterol-lowering agents causes much more significant LDL reductions

  25. Measurement of Lipoproteins • Lipoprotein analysis 12-14 hours fasting • TC and HDL-C can be measured fasting or non-fasting • LDL-Cholesterol = Total cholesterol –VLDL (1/5 TG)-HDL • Validity depends on TG <400 mg/dL • Measured directly if patients have profound hypertrig • Errors in TC, HDL, and TG can affect values • Non-HDL cholesterol= TC – HDL-C • All cholesterol in atherogenic lipoproteins incl LDL, Lipoprotein a, IDL, VLDL • Acute phase response (i.e. MI, surgical trauma or infection) • Can reduce levels of TC, HDL, LDL, apo A+B through impairment of hepatic lipoprotein production and metabolism • Raise Lpa and TG • Lipoprotein analysis should be done as outpatient one month after event

  26. Screening Recommendations • Adult Treatment Panel III (NCEP) • Fasting lipid profile at least once q 5 years for all persons 20 y.o. or older • If non-fasting obtained and TC >200 or HDL <40, f/u panel recommended • If no known CHD and serum LDL <160 (0-1 risk factors) or LDL <130 (2 or more risk factors) then re-screen in 5 years • Borderline high cholesterol and <2 risk factors, re-screen in 1-2 years

  27. Risk Assessment • CHD equivalents: • Symptomatic carotid artery disease • Peripheral arterial disease • AAA • DM • Multiple risk factors that confer a 10-year risk of CHD > 20% • Identify major risk factors other than LDL: • Smoking • HTN BP >140/90 or on anti-hypertensive medication • Low HDL <40 mg/dL • Family history premature CHD (CHD in men 1st degree relative <55; women <65 y.o.) • Age (men > or =45; women >or =55) • Other potential risk factors • Chronic renal insufficiency (Cr > 1.5 mg/dL OR GFR <60 cc/min) per Up-To-Date • Obesity, physical inactivity, impaired fasting glucose, markers for inflammation • HDL > 60 mg/dL is a negative risk factor • If patient without CHD or equivalent has 2 or more major risk factors, then calculate the Framingham risk (age,TC,HDL,smoking,SBP)

  28. Validation study found Framingham CHD predictor worked well in white and black population but overestimated risk in Japanese American, Hispanic men and native American women and other studies have shown possible overestimation in European and Asian populations

  29. New Guidelines for LDL Goal

  30. Basis of New Guidelines in July 2004 • REVERSAL (secondary prevention) • Moderate tx (40 qd pravastatin) • Intensive tx (80 qd atorvastatin) • Coronary intravascular US after 18 months • Mod tx (: increase in atheroma volume 2.7%, mean LDL 110 mg/dL • Intensive tx: decrease in atheroma volume 0.4%, mean LDL 79 • No clinical outcomes • PROVE-IT: 4162 patients with ACS measuring clinical outcomes • Moderate tx (40 qd pravastatin): median LDL-C 96 • Intensive tx (80 qd atorvastatin): median LDL 62 AND 16% reduction of CV events (all cause death, MI, UA, revasc, stroke) • Benefit of pushing LDL below 70 • HPS: >20,000 patients with established CAD or CHD-equivalent • Simvastatin 40 qd • Placebo • 27% reduction in nonfatal MI and coronary death in Tx group • Patients w/o CHD but with CHD equivalents benefited from treatment • Benefit was present regardless of pretreatment LDL <100 • Application of New guidelines for LDL <70 • Very high risk (established CHD plus multiple major risk factors) • CHD + smoking • CHD +metabolic syndrome • ACS • 2004 ACC/AHA: for STEMI, LDL “substantially <100 mg/Dl”

  31. Elevated LDL • Statins are first choice and selection is based on extent of LDL reduction, cost and reduction in clinical CHD events as well as presence of renal impairment • 30-35% decrease in LDL-C with equivalent doses • Titrate statin dose at 3-4 week intervals • Doubling statin dose reduced LDL an additional 6% • Consider adding second agent instead of dose increase • Variable drug response depending on endogenous v. exogenous hypercholesterolemia • Second agents may include bile acid resins (15%), ezetimibe (20%), or plant stenol/sterol margarine (10%) • Niacin may be added as a third agent if needed

  32. Mixed (Combined Hyperlipidemia) • Elevated LDL and/ or triglycerides • Objective is to achieve LDL goals • With very high TG> 400, start with fibrate or niacin • Then treat LDL with statin • If LDL-C goal achieved, but TG>200, non-HDL-C should be targeted • Non-HDL goal 30 above LDL goal • Statin titration dose OR Statin-fibrate OR Statin-Niacin combinations more effective in this type of dyslipidemia but adverse reactions more common with combined treatment so benefit/risk ratio considered • Titration for mild TG elevations • Combination TX for moderate to severe TG elevations

  33. Normal <150 mg/dL; very high >500 mg/dL Evidence-Based Data Evidence-Based studies include Helsinki Heart Study and VA-HIT trial assessing efficacy of gemfibrozil and CV risk reduction from lowering TG In many large studies, elevated TG were determined to be independent risk factor for CHD Identify those with hyperchylomicronemia: TG >1000 mg/dL, eruptive xanthomas, pancreatitis Familial hypertrig (200-500) or combined hyperlipidemia Treatment Recommendations: After achievement of LDL goal (150-199): emphasize weight reduction and physical activity (200-499): non-HDL second target and pharmacologic tx for those with h/o MI or at high risk >500: prevention of pancreatitis with non-pharmacologic and pharmacologic therapy Isolated hypertrig tx indications Overt CHD Strong FH of CHD Multiple cardiac risk factors Statins (atorvastatin or rosuvastatin) if LDL elevated Fibrates or nicotinic acid Add fish oil for refractory cases Hypertriglyceridemia • Rule out secondary causes and eliminate • Obesity • DM • Nephrotic syndrome • Hypothyroidism • Estrogen replacement • Beta blockers • Glucocorticoids, cyclosporin

  34. Framingham Heart Study: MI risk increases by 25% per 5 mg/Dl decrease below mean HDL for men and women LIPID and CARE trials: 10 increase in HDL, 29% decrease in event rate in LDL <125 vs 10% decrease in LDL>125 Familial h/o premature CHD helpful in differentiating high from low risk pts with low HDL Causes: Familial forms Elevated CETP LPL deficiency Elevated hepatic TG lipase LCAT deficiency Insulin deficiency Drugs Beta blockers BDZ Anabolic steroids Evidence in Treatment VA-HIT trial: strong correlation of reduction in MI and CHD death with serum HDL achieved with gemfibrozil Simvastatin plus Niacin: higher reduction in events achieved than statin-only trial HPS: vascular event rate in baseline HDL <35 was 29.9% vs 20.9% for HDL >42 HDL < 40 mg/Dl; if metabolic syndrome <40 men and <50 women Treatment Indications of Isolated low HDL CHD OR CHD equivalent if first-degree relative early onset CHD and similar lipid profile Weight management, exercise, and smoking cessation Niacin +/- gemfibrozil CETP inhibitors (NEW and investigational) Isolated Low HDL

  35. Treatment Guidelines • Always Consider secondary causes of dyslipidemia (DM, hypothyroidism, obstructive liver disease, CRF or nephrotic syndrome or drugs) • All patients with LDL above goal start with adequate trial of lifestyle modification only but concomitant drug therapy may be appropriate if: • LDL >220 or > 190 if >= 2 risk factors • Pre-existing CHD or CHD equivalent • If CHD or risk equivalent and? significantly above goal, then start pharmacotherapy (preferably statin) immediately • If CHD or equivalent and LDL goal <100 not achieved on maximal statin (atorvastatin 80 or rosuvastatin 40), then additional agent should be added based on abnormalities in other lipoproteins • In no CHD or CHD equivalent, consider drug therapy with statin if after adequate lifestyle trial: • LDL >190 if 0 or 1 risk factor • LDL >160 if 2 or more risk factors if 10 yr risk <10%; 130 if risk 10-20% • If persistent elevation in LDL purely, then add bile acid sequestrant or zettia • In patients with ACS, atorvastatin 80 mg/day should be started soon after hospitalization • PROVE-IT TIMI 22 Trial, MIRACLE, A to Z trial • When LDL goal reached but TG >200, then consider non-HDL cholesterol and treat to goal 30 above LDL • In patients with ACS, atorvastatin 80 mg/day should be started soon after hospitalization (event reduction and LDL lowering effect) • PROVE-IT TIMI 22 Trial, MIRACLE, A to Z trial

  36. Elderly • Should be individualized based on chronologic and physiologic age • Secondary prevention studies support treatment • CARE :50% patients >60 derived similar benefits as in younger patients • HPS :% reduction in events similar in < or > 65 y.o. • Cardiovascular Health Study showed benefit in primary prevention in >65 y.o. • All major statin trials and VA-HIT trial have shown reduction of atherothrombotic stroke with lipid-lowering • ATP III recommends diet as first line of primary intervention but drugs can be considered if multiple risk factors possibly with LDL >160 • Underutilization of lipid-lowering drugs in elderly due to • Concern for safety (hapatic/renal impairment) • Time course to benefit

  37. Adults With DM • Both primary and secondary intervention trials have shown benefit and reduction of CVD in diabetic subgroups treated with lipid-lowering agents (HPS and CARE trial showed significant outcome improvement with statins even at LDL <116) • Despite their often elevated TG and low HDL due to insulin resistance, etc. LDL should be primary goal • Niacin-Statin combination can be particularly effective • LDL goal <100 and threshold for drug tx is 130 and optional 100-129 if diet effective • ADA 2004 guidelines: adults >40 y.o. and TC >135, statin to lower LDL by 30% • Based on HPS, drug therapy should not be postponed if LDL goal unlikely achieved by nonpharmacologic means • TZDs are insulin sensitizers and affect adipose tissue distribution by decrease in intraabdominal fat; shown to increase HDL and peak LDL buoyancy; rosiglitazone/atorvastatin led to reduction in TG/LDL and elevation in HDL (Promising but more studies required)

  38. Metabolic Syndrome • ATP III criteria: (3 or more) • Abdominal obesity (waist circumference >40 inches in men or >35 in women) • Hypertriglyceridemia (TG>150 mg/dL) • Low HDL <40 men; <50 women • SBP >130 or DBP >85 • Fasting glucose >110 mg/dL • Increased risk of DM and cardiovascular disease although there has been some controversy in the literature • Kuopio Ischemic Heart Disease Risk Factor Study: 1209 Finnish men (42-60 y.o.) without CVD, cancer or DM at baseline followed for 11.4 years. Results showed that CVD and all-cause mortality are increased in men with MS even in absence of CVD or DM at baseline • Dyslipidemia is atherogenic with low HDL, elevated TG, and small dense LDL • Treatment Recommendations: • Weight reduction and exercise • LDL goal is same as in patient w/o MS • If LDL goal reached, then focus on TG if >200? • Calculate non-HDL and goal is 30 above LDL goal • Fibrates and nicotinic acid are good choices for elevated TG

  39. Hyperlipidemia in Nephrotic Syndrome • Marked hypercholesterolemia • Increased apo B lipoprotein synthesis by liver due to decreased oncotic pressure • Decreased catabolism • Hypertriglyceridemia • Slow conversion of VLDL to IDL then LDL • Decreased LDL-receptor clearance of LDL and IDL • Associated Risks • Small study showed RR 5.5 for MI and 2.8 for coronary death • Possible progression of glomerular disease • Treatment rationale • Tx of underlying disease (i.e. steroids in minimal change disease) • Little benefit in diet therapy (vegetable soy diet rich in MUFA/PUFA) and low protein with 20-30 % reduction in lipids • Best drug tx is statins • ACE-Inhibitor or ARB by decreasing protein excretion cause 10-20% reduction in TC and LDL

  40. CRF and Dialysis • Hypertriglyceridemia • Diminished clearance due to apo C-III and reduction in lipoprotein lipase and hepatic triglyceride lipase • Usually not enough elevation to increase coronary risk • Diet modification preferable over drug therapy because of risk of rhabdomyolysis • Isolated marked hypertrig with cardiac risk factors may warrant drug therapy • Modest decline in HDL raising LDL/HDL ratio • Elevated Lipoprotein a • Increase in oxidative modification of LDL • Statins should be used to lower LDL <100 or better yet <80 as CKD considered CHD risk equivalent. Atorvastatin and fluvastatin better choices. Hydrophilic statins safer and dose adjustment needed with CrCl <30 • EPO appears to have modest hypolipidemia effect though unknown mechanisms

  41. Evolving Methods of Risk Assessment • Total/HDL cholesterol ratio • Ratio <4.0 advocated by the Canadian guidelines • Aggressive lowering LDL vs raising HDL • Better epidemiologic predictor of CV events than LDL (Lipid Research Clinics and Framingham Heart Study) however no trials based on this ratio • Non-HDL cholesterol (Total-HDL) • Includes all atherogenic cholesterol (LDL, lipoprotein a, IDL, VLDL) • Lipid Research clinics program showed slightly stronger predictor of CVD than LDL • Secondary target in pts with high triglycerides >200 mg/Dl (ATP III) • Goal 30 above LDL goal • Apolipoprotein measurement • Apo B/ Apo A-I found to be a better predictor of events than LDL and total/HDL in AMORIS study; best predictor of events on statins in AFCAPS/TexCAPS study • <0.7 considered target in Canadian guidelines • Most useful in the hypertriglyceridemic patient (elevated apoB levels) • Not universally available and much more expensive • Needs more cost-benefit analysis before routine use • May be useful for determining the efficacy of novel therapies • Hs-CRP • Intensity of atherosclerotic process • Recommendation of AHA, should be measured in the patient with intermediate Framingham risk (10-20%) with LDL below the cutoff point for tx • Would not add much to those already at high risk • questionable correlation with LDL levels

  42. Emerging Lipoprotein GoalTrials

  43. Investigational Issues • To what extent should plasma levels of LDL-C be lowered by therapy to afford optimal risk reduction? • Can risk assessment be improved by using novel risk measures (such as hs-CRP) to indicate patients at higher risk who may benefit from more aggressive intervention? • Should the metabolic syndrome be considered a high risk state warranting aggressive intervention irrespective of risk categorization using current scoring methods? • Awaiting prospective trials investigating the preventive benefits of lipid-altering treatment in metabolic syndrome (COMETS trial)

  44. References • Management of atherogenic dyslipidemia of the metabolic syndrome: evolving rationale for combined drug therapy. Endocrinology and Metabolism Clinics of North America 33 (2004) 525-544 • Obesity and dyslipidemia. Endocrinology and Metabolism Clinics of North America 32 (2003) 855-867 • Management of Metabolic Sydrome: statins. Endocrinology and Metabolism Clinics of North America 33 (2004) 509-523 • Emerging therapeutic strategies for the management of dyslipidemia in patients with the metabolic syndrome. The American Journal of Cardiology June 3, 2004 • Past, Present and Future Standards for Management of Dyslipidemia. The American Journal of Medicine March 22, 2004 • Cardiovascular Endocrinology: Special Features. Medical Management of Hyperlipidemia/Dyslipidemia. Journal of Clinical Endocrinology and Metabolism, June 2003 • Effects of Lipid-Altering Treatment in DM and the Metabolic Syndrome. American Journal of Cardiology June 3, 2004 • Statins as the cornerstone of drug therapy for dyslipidemia: Monotherapy and combination therapy options • Use of combination Therapy for Dyslipidemia: A Lipid Clinic Approach • Clinical relevance of the biochemical, metabolic, and genetic factors that influence low-density lipoprotein heterogenity. The American Journal of Cardiology October 2002 • Up-To-Date

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