Management of Hyperlipidemia Clinical Management Course 1/30/06 James M. May, M.D. Department of Medicine Vanderbilt University School of Medicine

GOALS : Rationale for treatment NCEP guidelines Diet therapy Drug therapy

N = number enrolled. TC LDL-C HDL-C 1 o prevention 2 o prevention Summary of Effects of Lipid Lowering on Coronary Events in Recent Statin Trials Nonfatal MI/CHD death CHD death All-cause mortality %+%+

Risk of increased LDL and CHD: 30% change in = 30% change in CHD Grundy, SM et al.. Circulation. 110: , 2004.

Event Reduction and LDL: At What LDL Level Does Risk Go to Zero? Primary Prevention Secondary Prevention O’Keefe, JH, et al. Am. J. Cardiol. 43: , 2004.

PI=placebo; Rx=treatment Shepherd J et al. N Engl J Med. 1995;333: S Study Group. Lancet. 1995;345: Sacks FM et al. N Engl J Med. 1996;335: Downs JR et al. JAMA. 1998;279: Tonkin A. Presented at AHA Scientific Sessions, Mean LDL-C level at follow-up (mg/dL) Relation Between CHD Events and LDL-C in Recent Statin Trials % with CHD event CARE-Rx LIPID-Rx 4S-Rx CARE-PI LIPID-PI 4S-PI 2° Prevention 1° Prevention WOSCOPS-PI WOSCOPS-Rx AFCAPS/TexCAPS-Rx AFCAPS/TexCAPS-PI

New Features of NCEP Guidelines: ATP III LDL remains primary treatment goal Diabetes: CHD risk equivalent Framingham projections of 10-year CHD risk – –Identify certain patients with multiple risk factors for more intensive treatment HDL cholesterol <40 mg/dL – –Raised from <35 mg/dL Multiple metabolic risk factors (metabolic syndrome)

Central obesity Glucose intolerance Atherosclerosis Hypertension Polycystic ovary syndrome Clinical Manifestations Lipid:Carbohydrate: Biochemical Abnormalities Fibrinolysis: Insulin resistance Hyperinsulinemia High TG Low HDL-C Small, dense LDL particles Increased PAI-1 The Insulin Resistance Syndrome

Laboratory: Fasting Lipid Profile 12-h fast Draw total cholesterol, HDL and triglycerides Calculate LDL = TC – HDL – TG/5 (accurate up to TG of 400 mg/dl) If TG > 400, measure LDL directly following ultracentrifugation.

Causes of Secondary Dyslipidemia Diabetes Hypothyroidism Obstructive liver disease Chronic renal failure Drugs: Raise TG, LDL and lower HDL: progestinsanabolic steroids thiazidesbeta-blockers corticosteroids

LDL Cholesterol Goals and Levels for Therapeutic Lifestyle Changes (TLC) and Drug Therapy Risk Category LDL Level for TLC (mg/dL) LDL Level for Drug Therapy (mg/dL) LDL Goal (mg/dL) 0–1 Risk Factor  160  190 (160–189: drug optional) < Risk Factors (10-year risk  20%)  130 (10-year risk 10–20%)  160 (10-year risk <10%) <130 CHD or CHD Risk Equivalents (10-year risk >20%)  100  130 (100–129: drug optional) <100 (<70 if very high risk patient)

Major CHD Risk Factors: NCEP-ATP III Positive risk factors Age – – Male  45 – – Female  55* Family Hx of premature CHD in 1st-degree relative: Male relative: <age 55 Female relative: <age 65 Cigarette smoking Hypertension: BP  140/90 mm Hg or on antihypertensive Low HDL-C: <40 mg/dL Negative risk factor HDL-C: >60 mg/dL * or having premature menopause without ERT. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 285: , 2001.

Therapeutic Lifestyle Changes TLC Diet – –Previous Step II Diet) Saturated fats <7% of total calories Dietary cholesterol <200 mg per day – –LDL-lowering therapeutic options Plant stanols/sterols (2 g/day) Viscous (soluble) fiber (10–25 g/day) Weight reduction Increased physical activity

mg/dl increase = 450 Calories r = 0.987, p < HDL (mg/dl) Exercise Calories/Week

Effects of Drug Therapy and Diet on Lipids * 84% reached NCEP LDL target (<130 mg/dL) † 63% reached NCEP LDL-C target (<100 mg/dL) Barnard RJ, et al. Exerpta Medica Brief Reports. 1997; TC (mg/dL) * † P<0.01 1° Prevention (n=40) 2° Prevention (n=53)

Mechanism of action of Lipid- Lowering Agents on Lipoproteins Agents LDL-C HDL-C VLDL-C Resins  15-40% (modest  )  secretion Niacin  10-15%  30-40%  30-40% Fibric acids (small  )  10-15%  50% Statins  25-50%  5-8%  20-50% Ezetimibe  18-20%  5-8%  15-20%

* Significantly less than atorvastatin 10 mg (P<0.02). † Significantly less than atorvastatin 20 mg (P<0.01). ‡ Significantly greater than mg-equivalent dose of comparative agents (P  0.01). Jones P et al. Am J Cardiol. 1998;81: Atorvastatin Fluvastatin Lovastatin Pravastatin Simvastatin Dose range (mg) Mean % LDL-C reduction * * * * * * * † † † ‡ ‡ ‡ The CURVES Trial: A Comparison of LDL-C Lowering Among Statins

BaselineWeek 2Week 4Last DB visit Mean %  in LDL-C P<0.05. DB=double blind. Nawrocki JW et al. Arterioscler Thromb Vasc Biol. 1995;15: mg 20 mg 40 mg 80 mg Atorvastatin Dose-Response Relationship in Primary Hypercholesterolemia

Drug Therapy in Primary Prevention If LDL goal not achieved, intensify LDL-lowering therapy Increase statin or add ezetimibe (or a bile acid sequestrant) 6 wks Rx: statin, or if severe LDL increase, statin + ezetimibe Initiate LDL-lowering drug therapy 6 wks If LDL goal not achieved, intensify drug therapy or refer to a lipid specialist Monitor response and adherence to therapy If LDL goal achieved, treat other lipid risk factors Q 4-6 mos

SUMMARY and CONCLUSIONS: LDL Lowering remains primary Stress: HDL, diabetes, & diet/exercise AHA step II is standard diet Statins as primary therapy Treat triglycerides, low HDL, especially if part of the “metabolic syndrome”

Patient EL: 52 yo White Female Patient referred for new onset diabetes and hyper- lipidemia. Diagnosis of diabetes was made on a routine exam, the patient complained only of mild fatigue. She denies weight loss, has nocturia x1, but no visual symptoms. She is on no special diet and gets no regular exercise. PMH: Hypertension for 5 years, no smoking ROS: post-menopausal, no chest pain or dyspnea FH: + for late onset diabetes in her mother, and a “cholesterol problem” in a sister “cholesterol problem” in a sister1

Medications: Cholestyramine, 4 g BIDCholestyramine, 4 g BID Glyburide, 5 mg BIDGlyburide, 5 mg BID Premarin, mg qdPremarin, mg qd Hydrochlorothiazide, 25 mg qdHydrochlorothiazide, 25 mg qd Physical Exam: Wt: 210 lbs. BP: 135/82 Exam significant only for obesity with abdominal fat distribution. No xanthomata or acanthosis. Normal circulatory and neurologic exams. 2

Initial Fasting Laboratory: T. Cholesterol 284 mg/dL Triglyceride 802 mg/dL HDL35 mg/dL Blood glucose244 mg/dL Hgb A1C9.6 % 3

Recommendations: ADA/AHA Step 1 diet instructionADA/AHA Step 1 diet instruction Home glucose monitoring: BIDHome glucose monitoring: BID Exercise program, 30 min x 3-5 times /wkExercise program, 30 min x 3-5 times /wk D/C cholestyramineD/C cholestyramine Continue other medsContinue other meds Return to clinic: 3 monthsReturn to clinic: 3 months 4

3 Month Return visit: Feels better. Home glucoses mg/dL Wt.: 215 lbs. Laboratory: T. Cholesterol262 mg/dL Triglyceride594 mg/dL  -Quant LDL154 mg/dL HDL36 mg/dL Hgb A1C8.4 % 5

Recommendations: Stress:Stress: Diet: ADA 1800 Cal. dietDiet: ADA 1800 Cal. diet Exercise: 30 min x 3-5 times /wkExercise: 30 min x 3-5 times /wk Weight lossWeight loss Rx: Metformin, 500 mg BIDRx: Metformin, 500 mg BID Return to clinic: 3 monthsReturn to clinic: 3 months 6

6 Month Return visit: Home glucoses mg/dL Wt.: 205 lbs., BP: 132/84 Laboratory: T. Cholesterol255 mg/dL Triglyceride325 mg/dL Calc. LDL150 mg/dL HDL40 mg/dL Hgb A1C7.2 % 7

Recommendation: Rx: atorvastatin, 10 mg qdRx: atorvastatin, 10 mg qd Return to clinic: 3 monthsReturn to clinic: 3 months 8

Laboratory: T. Cholesterol192 mg/dL Triglyceride252 mg/dL Calc. LDL98 mg/dL HDL44 mg/dL Hgb A1C7.4 % 9 Month Return visit: Home glucoses mg/dL Wt.: 204 lbs., BP: 124/80 9