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Hyperlipidemia/Dyslipidemia

Hyperlipidemia/Dyslipidemia. J.B. Handler, M.D. Physician Assistant Program University of New England. LDL- low density lipoprotein HDL- high density lipoprotein IDL- intermediate density lipprotein VLDL- very low density lipoprotein Lp(a)- lipoprotein a CAD- coronary artery disease

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Hyperlipidemia/Dyslipidemia

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  1. Hyperlipidemia/Dyslipidemia J.B. Handler, M.D. Physician Assistant Program University of New England

  2. LDL- low density lipoprotein HDL- high density lipoprotein IDL- intermediate density lipprotein VLDL- very low density lipoprotein Lp(a)- lipoprotein a CAD- coronary artery disease CHD=CAD= coronary heart disease CVD- cerebrovascular disease LFT- liver function test GI- gastrointestinal ETOH- alcohol D.M.- diabetes mellitus CK- creatine kinase NNT- number needed to treat ARR- absolute risk reduction IVUS- intravascular ultrasound RRR- relative risk reduction PAD- peripheral arterial disease PVD- peripheral vascular disease CVD- cerebrovascular disease ACS- acute coronary syndrome HTN- hypertension TLC- therapeutic lifestyle changes UAP- unstable angina pectoris PE- physical exam ACC- American College of Cardiology Abbreviations

  3. Lipids and Atherosclerosis • Thickened and hardened lesions of the medium and large muscular and elastic arteries; lipid rich. Lesions occur in the innermost layer of the artery (intima) and are largely confined to this region of the vessel. • Deposition of lipid within the artery is dependent on 2 major factors: • LDL: carries lipid to the arteries (LDL must be oxidized) • HDL: removes lipid from the arteries • The role triglycerides play is not as well understood, but considered a risk factor. See below.

  4. Lipoproteins • Lipoproteins carry lipids - Cholesterol, Triglyceride, Phospholipids. • Lipoproteins of importance: VLDL, (IDL), LDL, chylomicrons. • Apolipoproteins- Protein constituents of lipoproteins that add structural stability; may help mediate catabolism. Apolipoprotein B (LDL) increases coronary risk. • Lipid catabolism - 70% LDL removed in liver by LDL receptors.

  5. Cholesterol Biosynthesis • Liver and intestines - major sources of endogenously derived cholesterol. • Diet - exogenously derived cholesterol. • In liver- rate limiting step is converting HMG CoA to mevalonic acid by HMG CoA Reductase (role of “STATINS”). • Increase intake in dietary cholesterol - down regulation of LDL receptors  subsequent elevation of serum LDL cholesterol.

  6. Hypercholesterolemia • Diet and drug induced reductions of total and LDL Cholesterol can significantly reduce mortality and morbidity from Coronary Heart Disease. • Cholesterol reduction can slow progression of atherosclerosis, and in some cases, halt or reverse (isolated cases) its course.

  7. Lipids and Atherogenesis • Vascular injury from any source (smoking, HTN, DM) can lead to uptake of lipoproteins. • Elevation of LDL (oxidized) can lead to vascular injury resulting in premature atherosclerosis.

  8. Lipids and Atherogenesis • LDL oxidation necessary for endothelial damage. • HDL- Inverse correlation between serum HDL and atherosclerosis; reverse cholesterol transport and prevents oxidation of LDL- cardioprotective. • A low HDL level (dyslipidemia) is a strong riskfactor for CHD even when LDL and total cholesterol are normal. • Next major advance: safe drugs that substantially increase HDL levels, while reducing cardiac events (MI, Death).

  9. Hyperlipidemia- Clinical Findings • Often asymptomatic. • Atherosclerosis and disease- CHD, PVD, etc. • Eruptive xanthomas- red papules on buttocks seen with extremely high levels of chylomicrons or VLDL (triglycerides). • Tendinous xanthomas- Very high LDL- nodules on tendons (achilles, back of hand, patella). • Xanthelasma- yellow placques in skin around the eyes.

  10. Xanthelasma Images.google.com

  11. Dyslipidemias in Adults • Most cases are multifactorial • Influenced by diet, lifestyle and genes • Often detected in asymptomatic adults during routine blood screening • In patients with atherosclerosis involving the coronary arteries, carotids, aorta or periperal vessels, a high percentage will be found to have a dyslipidemia.

  12. Secondary Dyslipidemia • Diabetes Mellitus (discussed in Endocrine section) • Nephrotic Syndrome (Renal system) • Chronic Renal Failure • Hypothyroidism - high TG, low HDL

  13. Familial Dyslipidemia • At least six documented disorders all with accelerated atherosclerosis. • Example: Familial hypercholesterolemiaLDL receptor defect; heterozygous -total cholesterol at birth> 350 mg/dl;Homozygous - total cholesterol > 700mg/dl • PE: Tendon xanthomas, xanthelasma, cutaneous xanthomas • Most patients with lipid disorders carry genes that can predispose them to develop dyslipidemia when additional factors (diet, obesity, etc.) are present. Likely multiple genes involved.

  14. Rationale for Treatment • Primary prevention- Lowering cholesterol/LDL will prevent new onset CHD. Every 1% drop in cholesterol produces a 2-3% decrease in CHD risk. • Secondary prevention - Lowering cholesterol/LDL will prevent recurrent coronary events and decrease coronary and total mortality in the presence of existing CHD or equivalent(s). • Angiographic/IVUS trials retarded progression of of coronary lesions; regression in some.

  15. Primary Prevention • ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial) • 10,305 patients with HTN but without heart disease randomized to Placebo vs. Atorvastatin 10 mg/daily • Baseline LDL-133 mg/dL, treated LDL- 103mg/dL • Primary endpoints: Nonfatal MI and fatal CHD • Study ended prematurely at 3.3 years • Results: 36%  in primary endpoint (100 vs 154 events)

  16. Secondary Prevention • High risk prevention • Patients with known CHD have a 5-7x risk of recurrent MI. • Patients with known PAD, Carotid or Aortic disease have a 4-6x incidence of developing CHD and it’s consequences. • Other high risk subsets: DM, others (see below) • Goal: lower LDL to <100 mg/dl or less (below).

  17. Heart Protection Study • Patients with documented CHD or equivalent (DM, PAD). • >20,000 patients; placebo vs 40mg Simvastatin daily. • Baseline LDL 131-155 mg/dL. Rx with simvastatin resulted in: •  all cause mortality by 13% •  coronary death by 18% •  non fatal MI + coronary death by 27% •  coronary revascularization procedures by 24%. •  stroke by 25% . •  major vascular events by 24%

  18. Risk Stratification (NCEP) • Determine number of major risk factors besides elevated lipids. Excludes patients with documented CHD/PAD/CVD or diabetes (coronary risk equivalent). • Age/gender: men>45, women >55 • FH of premature CHD MI or SD in 1st degree relative: male<55, female < 65 • Hypertension whether treated or not • Current cigarette smoker • Low HDL: < 40 mg/dL • 2 or more risk factors calculate statistical risk for subsequent MI/death in next 10 years.

  19. Risk Stratification (NCEP) • For patients with 2 or more risk factors and no evidence yet of CHD: Determine 10 year CHD risk (for “hard CHD outcomes”- MI or coronary death) assessment using Framingham risk assessment tool. • Newest guidelines and options: NCEP ATP III, 7/04; amended in 2007.

  20. Risk Assessment Tool • Estimates 10 yr risk (%) of developing “hard” CHD (MI or coronary death) outcomes in patients without CHD. • Gender and age • Total or LDL cholesterol • HDL cholesterol • Smoker • Systolic blood pressure; on meds for HTN? • Tables based on Framingham Heart Study

  21. High Risk • Presence of CHD, PAD, CVD or DM (coronary risk equivalent even if no CHD yet documented). • Absence of clinical atherosclerosis with 2 or more risk factors (such as smoking or HTN) that give a greater than 20% chance of having an MI or coronary death within 10 years (risk factor tool). Remember IS case: Lenny L. • Goal: LDL< 100 mg/dL; initiate meds if > 100mg/dL. • Initiate TLC simultaneously. • Some High Risk patients will fall into the “Very High Risk subset (see below).

  22. Very High Risk • Established CHDwith: DM, multiple and poorly controlled risk factors (such as smoking), metabolic syndrome, orrecent ACS (MI or UAP). • Goal: LDL < 70mg/dL is a “therapeutic option”- a reasonable therapeutic strategy, on the basis of available clinical trial evidence. • This will require drug therapy, possibly 2 drugs (see below). • Initiate TLC if not already done. • Evidence: PROVE-IT trial (see below).

  23. Metabolic Syndrome (3 of 5 Factors) • Central obesity: waist circumference>88cm in women, >102 cm in men. • Hyperglycemia: FBS 110 mg/dL. • Hypertension: BP  135/85. • trig:  150 mg/dL. • HDL: 40 for men, 50 for women (any 3 of 5 meets criterion). • 3x risk of atherosclerosis. • Metabolic syndrome often associated with insulin resistance- to be discussed in Endocrine system.

  24. Is Greater Lowering Better? • PROVE IT-TIMI 22: Atorvastatin 80 mgs/d vs Pravastatin 40 mgs/d in patients with ACS (AMI or UAP). Prospective, randomized, double blind study of 4162 patients; 2 yr follow-up. • End-points: All cause mortality, MI, UAP, coronary revascularization, stroke. • Pravastatin group: mean LDL- 95mg/dL, 26.3% had primary end-point. • Atorvastatin group: mean LDL- 62mg/dL, 22.4% had primary end point. • ARR with Atorvastatin= 3.9%, NNT= 25 • RRR 16%

  25. Moderately High Risk • Absence of clinical atherosclerosis • 2 or more risk factors for CHD and a 10-20% risk of MI/Coronary Death within 10 years (risk factor tool). • Goal: LDL<130mg/dL • Therapeutic option: LDL<100mg/dL • Initiate TLC if not already started. • Initiate drug therapy for LDL>130 mg/dL.

  26. Moderate Risk • Absence of clinical atherosclerosis • 2 or more risk factors for CHD and a < 10% risk for MI/coronary death within 10 years (risk factor tool). • Goal: LDL<130mg/dL • Initiate TLC • Initiate drug therapy if LDL160 mg/dL

  27. Lower Risk • 0-1 risk factors • Do not need to calculate risk score as will be <10%. • Goal: LDL< 160 mg/dL • TLC • Initiate drug therapy if: LDL190mg/dL • Option: Initiate drug therapy if LDL 160mg/dL

  28. Other Goals • Total Cholesterol < 200mg/dL • HDL  40 (45) mg/dL in men;  50 (55) mg/dL in pre-menopausal women. • Bloodwork: Fasting Lipoprotein AnalysisTotal chol, Triglycerides, HDL, LDL LDL = TC - HDL - (Trig /5). • Can now measure “direct LDL”- does not require fasting; values usually lower (10%) than calculated LDL levels.

  29. Treatment Considerations • Age, weight and sex of patient • Presence or absence of CAD risk factors • Socioeconomic factors • Patient compliance • Availability of support personnel: dietary,educational, administrative

  30. Hypertryglyceridemia • Risk for developing CAD/CHD from elevated triglycerides alone is controversial; likely contributes when LDL-C is  or HDL-C is . • Pure hypertriglyceridemia associated with VLDL elevations is often accompanied by mild elevations of total and LDL-C (small dense LDL). • Inverse relationship between VLDL (triglycerides) and HDL. • Tryglycerides (>500 mg/dL) s risk of pancreatitis • Consensus: treat hypertriglyceridemia but lowering LDL-C much more important.

  31. Hypertriglyceridemia • Often associated with obesity, type 2 diabetes & metabolic syndrome; mildly  with some drugs: estrogen, corticosteroids, ß-Blockers (Non-selective) and thiazides. Increased by alcohol. • Very sensitive to diet, weight reduction and exercise. • Triglycerides > 200mg/dL may warrant additional Rx. Important to consider Rx if HDL is very low. • Rx with fibric acid agents or niacin.

  32. HDL • Cardioprotective; facilitates removal of cholesterol in tissues; also has direct protective effects. • Reduced in presence of obesity, smoking, inactivity. • Modest increase with weight reduction, regular exercise, smoking cessation, estrogen therapy in post menopausal women (avoid where possiblerisks), alcohol in low quantities. • Increased with some meds: fibric acid derivatives and niacin. Off label indication in patients with CHD and very low HDL levels

  33. Therapeutic Lifestyle Changes (TLC) • Smoking cessation • Decrease intake of saturated fats (details below) • Decrease total calories if overweight • Increase physical activity • Decrease sodium intake • Treat other risk factors if applicable

  34. Treatment of Dyslipidemia: Diet • The “typical” American diet is a major contributor to lipoproten disorders. • Dietary Cholesterol - Raises LDL - Egg yolks, animal fat, red meat, etc. • Dietary Fat- Saturated fat, saturated fatty acids and animal fat. • Ideal Diet: < 30% fat, <7% saturated fat, <200 mgs/day cholesterol. Fat replaced with carbohydrates. • Obesity - Minimum 10% weight reduction. • Result: 10% lowering of LDL, but varies.

  35. Drug Therapy - Hyperlipidemia • HMG CoA reductase inhibitors (statins) • Bile Acid sequestrants (resins) • Nicotinic Acid (niacin) • Fibric Acid derivatives (fibrates) • Cholesterol absorption inhibitor- Ezetimibe

  36. HMG CoA Reductase Inhibitors • Atorvastatin(Lipitor) 10-80 mg/D • Simvastatin (Zocor/generic) 10-80 mg/D • Rousuvastatin (Crestor) 5-40 mg/D • Lovastatin (Mevacor/generic) 10-80 mg/D • Pravastatin (Pravachol/generic) 10-80 mg/D • Fluvastatin (Lescol) 20-40 mg/D • Inhibit rate limiting step in cholesterol synthesis in liver; up regulate synthesis of LDL receptors - further reduction LDL cholesterol; LDL and TC lowered by 30-55%. • Some statins triglycerides and HDL but mildly.

  37. Statins - Side Effects • Increase in serum transaminase levels- must be monitored closely initial year. • GI disturbance infrequent • Myopathy – Dose related skeletal muscle complaints are most commonly reported adverse effects. • Myalgia is most common (1-5%) and benign. • Myositis with rhabdomyolysis is rare but can be life threatening; CK confirmation is essential to decision making; >10 ULN with myositis or rhabdo

  38. “Statin” Induced Myopathy • Mechanism unknown but dose related. Evaluate patients with muscle Sx ASAP hold drug and obtain CK. It may be as simple as lowering the dose. • Signs and symptoms: myalgia, muscle weakness, CK, rarely progressing to rhabdomyolysis, myoglobinemia, renal failure and death. • Cerivistatin (Baycol) was taken off market because of 31 reported deaths from rhabdomyolysis. • Risk of myopathy increased with a variety of drugs that inhibit statin metabolism: niacin, fibrates, bile acid sequestrants, ketoconazole, erythromycin, clarithromycin, cyclosporin and others.

  39. Statins: Pleiotropic Effects • Statins have beneficial effects independent of lipid lowering: • Placque stabilization • Anti-inflammatory effects • Reduce C-reactive protein levels • Protection of vessels subject to invasive coronary interventions

  40. Ezetimibe • Relatively new- released in 2003; inhibits intestinal absorption of dietary and biliary cholesterol • As monotherapy (randomized double blind study of 893 patients), 10 mg daily lowered LDL by up to 17%, triglycerides by 6% and increased HDL by 1.3(minimal)%. • Very well tolerated but avoid in patients with hepatic insufficiency.

  41. Ezetimibe • When added to a statin there was additional LDL cholesterol lowering of up to 25% likely a synergistic effect. • Ezetimibe plus low/moderate dose statin is more effective in lowering LDL cholesterol than doubling the dose of the statin. But…see controversies below. • Ezetimibe very low incidence of myopathy

  42. Ezetimibe- Recent Concerns • 1/14/08- Enhance Trial (Merck/Schering Plough), simvastatin vs simvastatin + ezetimibe. • Patients with familial hyperlipidemia: marked  in LDL-C. Simvastatin  LDL-C by 41% (2 yrs), simvastatin + ezetimibe  LDL-C by 58%. No difference in outcomes (MI or stroke), but study not powered for outcomes. • But: Carotid intima media wall thickness (IMT*) increased faster in group treated with combined therapy compared with simvastatin alone. ?Significance. • More trials needed. Opinion (ACC): Continue to use if LDL goal not reached with statin (hi dose) alone. *IMT- surrogate end point for clinical coronary events

  43. Bile Acid Sequestrants (Resins) • Bind bile in the intestine and stimulate conversion of cholesterol to bile acids in the liver; up regulate LDL receptors- result is decrease in LDL cholesterol. • Cholestyramine and Cholestipol- up to 12 scoops of powder in water daily. Colesevelam (Welchol) tablet form. Expensive. • Side effects - Constipation, GI Distress (flatulence, constipation, dyspepsia); less common with colesevelam • These drugs can also cause myopathy.

  44. Nicotinic Acid • Mechanism of action unclear (hepatic). • Lowers Triglycerides and to a lesser degree LDL cholesterol. • Modest (20-30% increase) elevation HDL. • Side effects: GI distress; flushing/itching, small elevations of LFT’s. • Pre-treat with ASA for itching/flushing • Caution: use in uncontrolled diabetes blood sugar. • Start with very low doses and work upwards • Increases the likelihood of myopathy when added to statins or bile acid sequestrants.

  45. Fibric Acid Derivatives • Gemfibrozil 600 mgs. 2x/dayPrimary effect - lower triglycerides • Fenofibrate: Once daily, may be more effective than gemfibrozil in lowering LDL and triglycerides. • Rx of low HDL (off label indication). HDL by 15-20%Consider fibrates in patients with CHD and very low (<30 mg/dL) HDL levels. Variable reduction in LDL. • Side effects: GI, myopathy, gallstones.

  46. Guidelines for Drug Therapy • Elevations of total and LDL cholesterol:Statin (TC and LDL decreased up to 50%) Goal based on degree of risk; statin dose increased to maximum as necessary (see below). • If goal not achieved, the addition of other agents (cholestyramine, niacin, ezetimibe, etc) will need to be determined on a case by case basis as supported by clinical trials, weighing the pros/cons, cost, side-effects, compliance and more. • Most experts recommend adding additional drugs to max dose statins to lower LDL to goals if necessary.

  47. Guidelines for Drug Therapy •  Triglycerides + mild hypercholesterolemia: Gemfribrozil, Fenofibrate or Niacin. Must control Diabetes, reduce smoking, reduce ETOH and lose weight if indicated. Add statin if LDL remains above goal. • Combination drugs (Advicor- extended release niacin plus lovastatin in fixed combination; Vytorin- simvastatin + ezetimibe) may play a role for some patients. • Very low HDL with CHD: consider fibric acid agent or niacin.

  48. References • Grundy, SM, et. Al., Implications of Recent Trials for National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation, 2004; 110: 227-239 • Canon, CP, et. al., PROVE IT TIMI trial; NEJM, 2004; 350:1495-1504

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