Objectives: Hypercholesterolemia:

Transcription

1 Hypercholesterolemia: Pathophysiology and Therapeutics Robert J. Straka, Pharm.D. FCCP Associate Professor College of Pharmacy University of Minnesota Objectives: Hypercholesterolemia: Pathophysiology and Therapeutics By the end of this presentation, learners should be able to: 1. Discuss the epidemiology and pathophysiology of atherosclerosis 2. Describe the risk factors for developing (ASCVD) 3. Discuss NCEP ATP III treatment algorithms for patients with hyperlipidemia (and optional goals based on the white paper) 4. Compare antihyperlipidemic medications in terms of efficacy, side effects, cost, outcomes, major study results and implications regarding education of the patient 4. Based on a patient case, provide and defend a rational approach to selecting a pharmacotherapeutic treatment plan incorporating clinical evidence and cost data where applicable (10 yr risk, therapeutic goals etc.) Lipids: Hyperlipidemia Epidemiology Estimated 105 M American adults have hyperlipidemia (cholesterol levels of > 200 mg/dl) 39% males (15% F) have < 40mg/dL 42M have cholesterol levels of > 240 mg/dl A 10% decrease in total-c may reduce by 30% the incidence of CHD Risk of AMI in Male and Female is highest at lower (<37mg/dL in M and 47mg/dL in F) regardless of total-c, conversely those with higher (>53mg/dL in M or >67mg/dL in F) are at lower risks for AMI (Adapted from Neaton et al.) CAD Risk Is Incremental Lipoproteins Composition: Phospholipid, free cholesterol & protein on surface and a core made up of primarily triglyceride & cholesterol esters Apolipoproteins are proteins on the surface which regulate their transport and metabolism Apo A Apo B Function of Cholesterol and role of lipoproteins: Cell membranes, bile acid synthesis, steroid hormone precursor Classes Chylomicrons Very-low-density (VLDL) Lipoproteins Intermediate density lipoprotein (IDL) Low-density (LDL) High-density (HDL) Significance Premature coronary artery disease (CAD) Pancreatitis (hypertriglyceridemia) (VLDL + IDL + LDL-C) = non Apo B particles

2 Low as a Potent Predictor of CHD Although strong epidemiological evidence that protects against CHD exists, there has not been a cause and effect relationship proved From analysis of 4 epi trials, for each 1mg/dL increase in HDL- C, a 2% decrease in CHD risk in men and 3% decrease in women may occur 11% of US men have isolated Low levels (NHANES III), but up to 17-36% of high risk pts. LDL-C management does not completely remove the risk imparted by low Harper C Jacobson T Arch Intern Med 1999;159: Risk of CHD by HDL and LDL Levels: Framingham Heart Study 3x 2x 1x Rel. Risk of CHD (2.59) 160 (4.14) 220 (5.67) 85 (2.20) 65 (1.68) 45 (1.16) 25 (0.65), mg/dl (mmol/l) LDL-C, mg/dl (mmol/l) Arch Intern Med. 1999;159: Relative Risk of CHD over 4 years follow-up in men yrs old Lipoprotein & Lipid Concentrations V6 V5 V4 V3 V2 V1 VLDL-C (TG/5) ApoB-lipoproteins IDL-C L3 L2 L1 LDL-C Total Cholesterol TC = Non LDL-C C + C = TC C + VLDL-C Handbook of lipoprotein Testing 2 nd Ed 2000 AACC Press Washington DC + Reported LDL-C ApoAI-lipoproteins H5 H4 H3 H2 H1 Coronary Remodeling Lipid-Rich Plaque Progression Compensatory expansion maintains constant lumen Expansion overcome: lumen narrows Normal vessel Minimal CAD Moderate CAD Severe CAD (Adapted from Glagov et al.) Glagov et al, N Engl J Med,, With permission from Davies. In: Colour Atlas of Cardiovascular Pathology. 1986;86.

3 Most Myocardial Infarctions Are Caused by Low-Grade Stenosis Pooled data from 4 studies: Ambrose et al, 1988; Little et al, 1988; Nobuyoshi et al, 1991; and Giroud et al, (Adapted from Falk et al.) NCEP ATP III Objectives: By the end of this section, learners should be able to: 1) Be able to recommend a treatment approach for a patient with hypercholesterolemia according to current NCEP ATP III guidelines 2) Be able to apply the guidelines to a specific patient case (calculating 10 yr risk, identifying LDL-C and non goals etc.) 3) Demonstrate familiarity with key therapeutic options for managing hypercholesterolemia and results of key studies and novel approaches to therapy Falk E et al, Circulation, New Features of ATP III Built on ATP II Designation of a CHD risk equivalent category for aggressive LDL-C lowering Deployment of a Framingham based risk assessment to identify certain patients with 2 risk factors for more intensive treatment Identification of patients with multiple metabolic risk factors (the metabolic syndrome) who become candidates for intensified therapeutic lifestyle changes (TLC) ATP III: Features Continues to identify LDL-C as the primary target of cholesterol-lowering therapy Increased emphasis on: CHD risk status and CHD risk equivalents Diabetes: CHD risk equivalent Framingham projections of 10-y CHD risk Metabolic syndrome as a risk factor for CHD Intensified therapeutic lifestyle changes (TLC) Adherence to therapy Step #1 Determine Fasting Lipid Levels of LDL-C,, TG, TC LDL-C (mg/dl) TG (mg/dl) <100 Optimal <150 Normal Above, near optimal Borderline high Borderline high High High 500 Very high 190 Very high TC (mg/dl) (mg/dl) <200 Desirable <40 Low Borderline high 60 High 240 High Step #2 Identify Presence of CHD or CHD Risk Equivalents CHD Myocardial infarction Myocardial ischemia Stable angina Unstable angina PTCA Coronary by-pass surgery CHD risk equivalents Peripheral artery disease Abdominal aortic aneurysm Thrombotic stroke Transient ischemic attacks Diabetes risk >20% All of these listings are associated with >20% risk of a CHD event in 10 years LDL-C goal is < 100mg/dL

4 Patients With Diabetes Are at Even Greater Risk for CHD Patients With Diabetes Without History of CHD Have Incidence of MI Comparable to Patients Without Diabetes With CHD History 7-Year MI Incidence, % 50% 40% 30% 20% 10% 0% 45% MI = myocardial infarction. Haffner SM et al. N Engl J Med. 1998;339: CHD 18.8% Diabetes No diabetes 20.2% No CHD 3.5% N=2,432 Step #3 Determine Major CHD Risk Factors Other Than LDL-C According to ATP-III Positive risk factors Age Men 45 Women 55 Family history of premature CHD (first-degree relative) Male relative age <55 years Female relative age <65 years Negative risk factor High : 60 mg/dl Cigarette smoking Hypertension: BP 140/90 mm Hg or on antihypertensive medication Low : <40 mg/dl Negates one other risk factor Step #4 Framingham Point Scale for Estimating 10-Year CHD Risk if > 2 risk factors (Men/Women) Age = -9/ = -4/ = 0/ = 3/ = 6/ = 8/ = 10/ = 11/ = 12/ = 13/16 Total cholesterol <160 0/0 0/0 0/0 0/0 0/ /4 3/3 2/2 1/1 0/ /8 5/6 3/4 1/2 0/ /11 6/8 4/5 2/3 1/ /13 8/10 5/7 3/4 1/2 Systolic blood pressure If Untreated If Treated <120 0/0 0/ /1 1/ /2 2/ /3 2/ /4 3/6 60 = -1/ = 0/ = 1/1 <40 = 2/2 Smoker No 0/0 0/0 0/0 0/0 0/0 Yes 8/9 5/7 3/4 1/2 1/1 Total points: < >17 risk (%) for men: < Total points: < risk (%) for women: < JAMA. 2001;285: Patient Risk Categories Based on the 10-year Risk Assessment >20% 10% 20% <10% High risk risk equivalent Moderate risk Low risk JAMA. 2001;285: Step #5 Establish Risk Category and Determine Goal: Risk Category CHD or CHD risk equivalents (10-y risk >20%) 2+ Risk factors (10- y risk <20%) 0-1 Risk factor LDL-C Goal (mg/dl) <100 <130 <160 LDL-C Level for Initiation of TLC (mg/dl) LDL-C Level for Consideration of Drug Therapy (mg/dl) 130 ( : drug optional) 130: 10-y risk 10%-20% 160: 10-y risk <10% 190 ( : LDL-C-lowering drug optional) Determined using the Framingham Risk Scoring system. Therapeutic lifestyle changes. Some experts will use drug therapy is TLC does not achieve LDL-C <100 mg/dl; others usedrugs to modify and triglycerides. Implications of Recent Clinical Trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines Scott M. Grundy, James I. Cleeman,C. Noel Bairey Merz, H. Bryan Brewer, Jr, Luther T. Clark, Donald B. Hunninghake, Richard C. Pasternak, Sidney C. Smith, Jr, Neil J. Stone For the Coordinating Committee of the National Cholesterol Education Program Endorsed by the NHLBI, ACC, and AHA Circulation. 2004;110:

5 ATP III LDL cholesterol cutoffs for lifestyle interventions and drug therapy in different risk categories Risk category High risk: CHD or CHD risk equivalents (10-year risk >20%) Moderately high risk: two or more risk factors (10-year risk 10%-20%) Moderate risk: two or more risk factors (10-year risk <10%) Low risk: <1 risk factor LDL cholesterol goal <100 mg/dl (with an optional goal of <70 mg/dl) <130 mg/dl (with an optional goal of <100 mg/dl) <130 mg/dl <160 mg/dl Initiate therapeutic lifestyle changes >100 mg/dl >130 mg/dl >130 mg/dl >160 mg/dl Consider drug therapy >100 mg/dl (consider drug options if LDL-C <100 mg/dl) >130 mg/dl (consider drug options if LDL-C mg/dl) >160 mg/dl >190 mg/dl (consider drug options if LDL-C mg/dl) Step #6 Therapeutic Lifestyle Changes (TLC) and/or Step #7 Consider Drug Therapy TLC Reduce saturated fat intake to <7% of total calories and cholesterol to <200 mg/day Utilize other therapeutic options for LDL-C lowering such as plant stanols/sterols (2 g/day) and (soluble) fiber (10 25 g/day) Maintain an appropriate body weight Establish a regular exercise plan Pharmacologic intervention Drug therapy may be started simultaneously Grundy SM et al. Circulation; available at JAMA. 2001;285: Nutritional Components of TLC Diet Nutrient Saturated fat Polyunsaturated fat Monounsaturated fat Total fat Carbohydrates (esp. complex carbs) Fiber Protein Cholesterol Trans fatty acids also raise LDL-C and should be kept at a low intake. Recommended intake <7% of total calories Up to 10% of total calories Up to 20% of total calories 25% to 35% of total calories 50% to 60% of total calories grams/day ~ 15% of total calories <200 mg/day Step # 8 Identify Patients With The Metabolic Syndrome (Any 3 or more of the following are needed for diagnosis) Risk category Defining level Abdominal obesity (Waist circumference ) Men >102 cm (>40 in) Women >88 cm (>35 in) TG 150 mg/dl Men <40 mg/dl Women <50 mg/dl Blood pressure 130 / 85 mmhg Fasting glucose 100 mg/dl Diagnosis is established when 3 of these risk factors are present. Abdominal obesity is more highly correlated with metabolic risk factors than is BMI. Some men develop metabolic risk factors when circumference is only marginally. Updated based on Grundy et al, Circulation 2005;112: Treatment of the Metabolic Syndrome Weight control Physical activity Rx of hypertension ASA for patients with CHD Rx of elevated TGs Rx of low

6 Relative Risk of Death in Patients With Metabolic Syndrome Compared With Those Without Metabolic Syndrome Relative risk CHD mortality CVD mortality All-cause mortality 0.0 NCEP NCEP WHO WHO Waist >102 cm Waist >94 cm WHR >0.90 or Waist 94 cm BMI 30 P<.05. Subjects with metabolic syndrome (n= ) 179) vs subjects without metabolic syndrome (n= ). 1103). Lakka H-M M et al. JAMA ;288: Step # 9 Treat Elevated Triglycerides Classification of Serum Triglycerides Normal Borderline high High Very high <150 mg/dl mg/dl mg/dl 500 mg/dl Primary aim to lower LDL-C Intensify weight management, increase physical activity, if LDL target is reached and TG still exceed 200mg/dL, then set secondary goal for non-hdl Fibrate or nicotinic acid if TG > 500mg/dL Elevated Triglycerides ( 200 mg/dl) Risk category Non- goal (mg/dl) CHD and CHD risk equivalent <130 2 risk factors < risk factors <190 Non- = Total Cholesterol Non holesterol Non = total-c - Strongly correlated with CHD events Strongly correlated with apo B levels Takes into account all atherogenic lipoproteins VLDL-C IDL-C remnant particles LDL-C Apo B Cholesterol Ester Same LDL-C Levels, Different Cardiovascular Risk Large LDL Fewer Particles Correlates with: TC 198 mg/dl LDL-C 130 mg/dl TG 90 mg/dl 50 mg/dl Non- 148 mg/dl LDL= 130 mg/dl Small, Dense LDL More Particles Correlates with: TC 210 mg/dl LDL-C 130 mg/dl TG 250 mg/dl 30 mg/dl Non- 180 mg/dl More Apo B Otvos JD, et al. Am J Cardiol. 2002;90:22i-29i. Management of Low Low : <40 mg/dl (no specific goal defined for raising ) Targets of therapy All persons with low : achieve LDL-C goal; then set non goal decrease weight, increase physical activity (if metabolic syndrome is present) Those with TG mg/dl: achieve non- goal as secondary priority Those with TG <200 mg/dl: consider drugs for raising (fibrates, niacin) Non- goal is set at 30 mg/dl higher than LDL-C goal.

7 Patient Case 53 yo WM 6 1, 210 lbs (95.5Kg) waist circumference 40 with a BMI 27.7kg/sqm with a family history positive for CHD on both father and mother s side is seen 12/02 by Family physician secondary to a suggestion by a colleague BP 153/98, smoker 1ppd (>20yrs) Lipid Panel: Tot. C 230mg/dL, LDL 187mg/dL, HDL- C 26mg/dL, TG 84 mg/dl Recommendations? Framingham Point Scale for Estimating 10-Year CHD Risk (Men/Women) Age = -9/ = -4/ = 0/ = 3/ = 6/ = 8/ = 10/ = 11/ = 12/ = 13/16 Total cholesterol <160 0/0 0/0 0/0 0/0 0/ /4 3/3 2/2 1/1 0/ /8 5/6 3/4 1/2 0/ /11 6/8 4/5 2/3 1/ /13 8/10 5/7 3/4 1/2 Systolic blood pressure If Untreated If Treated <120 0/0 0/ /1 1/ /2 2/ /3 2/ /4 3/6 60 = -1/ = 0/ = 1/1 <40 = 2/2 Smoker No 0/0 0/0 0/0 0/0 0/0 Yes 8/9 5/7 3/4 1/2 1/1 Total points: < >17 risk (%) for men: < Total points: < risk (%) for women: < JAMA. 2001;285: Patient Risk Categories Based on the 10-year Risk Assessment >20% 10% 20% <10% High risk risk equivalent Moderate risk Low risk Classification of LDL-C,, TG, TC LDL-C (mg/dl) TG (mg/dl) <100 Optimal <150 Normal Above, near optimal Borderline high Borderline high High High 500 Very high 190 Very high TC (mg/dl) (mg/dl) <200 Desirable <40 Low Borderline high 60 High 240 High JAMA. 2001;285: Formulas Friedwall s Equation for calculating LDL-C: ( LDL ) = ( Total - HDL ) - ( TRG / 5 ) Note: not useful or accurate if Trigs exceed 400mg/dL Eg: T-Chol=240mg/dL, HDL=50mg/dL, TG= 150mg/dL what is LDL-C? Answer: (240-50)-(150/5)=160mg/dL Units: -Traditional -- mg / dl -SI -- mmol / L Conversion: (mg / dl) x = (mmol / L) eg. 100mg/dL x = 2.59 (NEJM 312:20, )