Lipid Management: A Case-Based Approach. Overview. Simple Lipid Therapy Approach. Patients have lipid disorders of:

Transcription

1 Lipid Management: A Case-Based Approach Patrick E. McBride, M.D., M.P.H. Professor of Medicine, Cardiovascular Medicine Associate Director, Preventive Cardiology Program UW School of Medicine and Public Health Overview Patients have lipid disorders of: LDL VLDL (triglycerides) HDL Combined disorders Present different types of patients / discuss Simple Lipid Therapy Approach LDL Statins Resins Sterols Ezetimibe PCKS 9 inhibitors (statin intolerant) TG / HDL Fibrates Niacin Fish Oil

2 High-Risk Patients Atherosclerosis (premature) Genetic Cholesterol Disorders Diabetes mellitus Family History of premature atherosclerosis (< age yrs) Patient with multiple risk factors, including abnormal cholesterol levels Genetic Abnormalities Familial Hypercholesterolemia: LDL > 160 to > 200 mg / dl (> 95%ile for age) Low HDL syndromes: < mg / dl Hypertriglyceridemias: > 400 mg / dl Especially high-risk if > 1000 mg/dl (pancreatitis) Familial combined hyperlipidemia: High TG, Low HDL, moderately elevated LDL-C Usually have small, dense LDL and HDL 48 year old male with high TG, pancreatitis History of TG levels > 1000 mg/ dl fasting At least one pancreatitis episode History of sensitivity to high fat meals High alcohol intake Central obesity Disorder? Treatment?

3 Patient with Low HDL-C 21 year old male with family history of premature CHD in father: MI age 48 Total Chol 184, HDL 24, TG 150, LDL 130 BMI 27 Active 2 3 times per week Non smoker, occasional exercise Normal BP Young Male with high TG and Family History 11 yr old - TG of 474, HDL 22 mg/ dl Healthy, no other illness Father had MI age 37, developed severe ischemic cardiomyopathy same lipid disorder Treatment of Hypertriglyceridemia TG mg/dl Moderate risk of pancreatitis & hyperviscosity Secondary cause common diet + exercise + weight loss glycemic control First line: fibrate or niacin Second line: statins or fish oils

4 Treatment of Hypertriglyceridemia TG 1000 mg/dl Urgent need to lower to prevent pancreatitis and hyperviscosity syndrome Secondary cause common diet critical (approx. 15% fat needs referral) exercise + weight loss glycemic control First line: fibrate or niacin Second line: combination Third line: add fish oils or statin Helsinki Heart Study Triglycerides and CHD Event Reduction Gemfibrozil Placebo Relative Risk CHD Event TG < 200 TG > 200 TG < 200 TG > 200 LDL/HDL 5 LDL/HDL > 5 Manninen V, et al. Circulation 1992;;85:37 Treating TG & HDL Lowers Risk of Vascular Events* VA-HIT trial Patients with Vascular Events at 5 Years (%) Diabetic Patients % Risk Reduction 28.0 Non-diabetic Patients % Risk Reduction 18.0 Placebo Gemfibrozil Placebo Gemfibrozil N = 627 P = 0.05 N = 1,904 P = * Vascular events represent coronary heart disease, nonfatal MI, and confirmed stroke. Rubins HB, et al. N Engl J Med. 1999;;341(6):

5 THE CURRENT STATE OF NIACIN IN CARDIOVASCULAR DISEASE PREVENTION: A SYSTEMATIC REVIEW AND META-REGRESSION J Am Coll Cardiol. 2013;61(4): doi: /j.jacc Niacin Improves Clinical Outcomes Study CDP Regimen Niacin alone Key Outcomes 2 nd infarct over 6 yr;; total mortality at 15 yr IHD CLAS I and II Niacin, clofibrate Niacin, colestipol total and cardiac mortality over 5 yr CHD events and progression coronary atherosclerosis CAD regression in 16% CDP = Coronary Drug Project;; IHD = Stockholm Ischaemic Heart Disease Secondary Prevention Study;; CLAS I and II =Cholesterol-Lowering Atherosclerosis Study. Guyton JR. Am J Cardiol. 1998;;82:18U-23U. 48 year old Combined Dyslipidemia Overweight, sedentary Family history of brother age 55 CABG and father with MI age 63 Fasting blood glucose 107 Lipids: Total cholesterol 217, HDL 39, TG 196, LDL 139 Treatment?

6 Options Lifestyle education / counseling Diabetes Prevention Program Statin Statin + niacin? Statin + fibrate Diabetes Prevention Program 3234 patients with GINT / high FBG Randomized for 3 years to: Placebo Metformin Lifestyle intervention Results in reducing diabetes: Lifestyle 58% (NNT = 7) Metformin 31% (NNT = 14) N Engl J Med 2002;;346:393

7 Effects of the Mediterranean Diet in the Metabolic Syndrome 80 p< p< Mediterranean Control Mediterranean Control Weight (kg) hs-crp (mg/l) Before After Esposito K, et al. JAMA 2004;;292:1440 Mediterranean Diet Outcomes Improved Mortality Estruch R et al. N Engl J Med 2013;;368: Primary Prevention of Cardiovascular Disease with a Mediterranean Diet Incidence of Outcome Events in the Total Study Population Estruch R et al. N Engl J Med 2013;;368:

8 MRC/BHF Heart Protection Study Effects on 1 Endpoint by Baseline Feature Baseline feature STATIN (N=10,269) PLACEBO (N=10,267) RR and 95% CI Previous MI or CHD 1459 (21.8%) 1841 (27.5%) No prior CHD CVD 172 (18.7%) 212 (23.6%) PVD 327 (24.7%) 427 (30.5%) Diabetes 279 (13.8%) 367 (18.6%) ALL PATIENTS (19.9%) (25.2%) 24% decrease NNT = 19 (p<0.0001) STATIN better STATIN worse Lancet 2002;;360:7 49 year old female with family history of premature CHD Father had event at age 48, mother had CVA at age 61 Patient has high cholesterol Total cholesterol 221, HDL 57, LDL 133, TG 150 Lipoprotein (a) 109, hs CRP 2.2 CIMT increased thickness / plaque When to Consider Biomarkers? Family history of premature CHD Personal history of premature CHD, risk factors not clear Intermediate risk patient (6 19% CHD risk) - outcome would change your management

9 C-Reactive Protein (CRP) Acute phase protein produced by the liver 100-fold with infection or tissue destruction High-sensitivit y CRP (hscrp) May indicate chronic low levels of inflammation Atherogenesis and acute coronary syndromes are related to inflammation Classified as low (<1 mg/l), average (1-3 mg/l), and high (>3 mg/l) ~65 million Americans (37.7%) are >3 mg/l Risk marker, probably not a risk factor hscrp and CV Risk Women s Health Study Framingham 10-Year Risk (%) > <1.0 hs-crp (mg/l) Ridker PM, et al. N Engl J Med 2002;;347: JUPITER Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death Cumulative Incidence Number at Risk Rosuva s ta tin Placebo HR 0.56, 95% CI P < Number Needed to Treat (NNT 5 ) = Follow-up (years) Placebo 251 / 8901 Rosuvastatin 142 / ,901 8,631 8,412 6,540 3,893 1,958 1, ,901 8,621 8,353 6,508 3,872 1,963 1, Fewer Events

10 NNT for Jupiter Number needed to treat to prevent one event 5 yr. = yr. = 21 Considerations with Clinical Use of hscrp Strong association s with obesity, overweight, and diabetes mellitus do not do if ill High hscrp is rare in absence of high or borderline RF (4.4% men, 10.5% women) Yield for possible change of therapy based on screening all of U.S. 3-5% Limit to intermediate risk patients, borderline treatment cases, or to determine residual risk Measure at least twice, take lower value Miller M, et al. Arch Intern Med 2005;;165:2063 Guttormsen B, et al. Am J Cardiol 2007;;100:1130 High LDL, High HDL 60 year old female with LDL 190, HDL 72, normal triglycerides Family history premature CHD in father age 55, smoked, high cholesterol Patient: no smoking, regular exercise, no DM, normal body weight, normal BP 10 year risk CHD 2%, total CHD 7% Lifetime risk > 20%

11 Options Reassure no treatment Consider further risk stratification Family history / long-term risk intermediate hs-crp Coronary Calcium scan or CIMT NMR if triglycerides > 100 Lipoprotein (a) Outcomes of Evaluation Hs-CRP = 2.0, high Lp(a) 104 mg/dl CIMT presence of plaque;; vascular age > 80 years Prescribed statin, enhanced dietary recommendations Goal LDL < 130 mg/dl, optional < 100 mg/dl Patient with myalgias on statin 52 year old No history of heart disease 10 year risk > 10% LDL 165, HDL 41, TG 176 Trial of simvastatin 40 mg HS LDL 118, TG 142, HDL 44 Develops muscle aches

12 Approach to patient with myalgias History family? Friends? Symmetrical, diffuse myalgias (vs. localized) Evidence of weakness, fatigue Consider CK, secondary causes Reassurance / discussion if not localized review risk / benefit Natural statin Trial off of medication Myalgia rates Clinical trials = 3-5% Selection criteria may reduce rates Practice rates 10% - 15% Patients may be affected by bias from hearsay, internet, friends, fear of medicine TNT: Safety 10% All p< % 7.2% 5% 5.8% 5.3% 0% 1.2% 0.2% AST/ALT Adverse Events Drug discontinuation High-dose Low-Dose 5 cases of rhabdomyolysis, 2 on high dose, 3 on low dose Rate ~0.01%/year LaRosa JC, et al. NE JM 2005;; 352

13 Pharmacologic Therapy: Statins Safety: Myopathy Creatine kinase (CK) Elevation >10x ULN is observed in 0.1% of patients Monitor symptoms Risk of these events increases with dose escalation or in combination with fibrates or niacin Rhabdomyolysis (incidence = 1 in 10,000 patients) or renal failure may occur if drug is continued Reversed after discontinuation Maron et al. Circulation. 2000;;101: 207. LDL LDL Therapy Statin (trial of alternative / low dose high potency statin - qod Resins Sterols Ezetimibe Niacin at high dose / combination with resin (decrease LDL 40+%) Intensive Dietary Modification: Portfolio Diet 4 weeks Dietary Portfolio Plant sterols Soy Viscous fiber Almonds Control Statin Diet -31% P< % P<.001 vs lovastatin 20 mg LDL CRP Jenkins DJ, et al. JAMA. 2003;;290(4):

14 Mediterranean Diet Hu, FB. N Engl J Med 2003;;348:2595 Kris-Etherton P, et al. Circulation 2001;;103:1823 Increased physical activity Bread and cereal Nuts and legumes Daily fruit and vegetables Fish Less red meat (use poultry) Replace butter and cream with olive oil Genetic risk: 33-year-old female Obese, sedentary - no DM, HTN, tobacco FmHx: Mom CABG 63, Brother angioplasty 43 NO treatment for cholesterol prior to CABG Total Chol 428, LDL 354, TG 175, HDL 39 Familial hypercholesterolemia with exacerbation by lifestyle 5-Vessel CABG age 32 Statin + Resin + Niacin LDL year old male with high cholesterol Healthy, athletic, no other illness Total cholesterol 263, LDL 205, HDL 36, TG 82 Would you treat his cholesterol with medication if it did not respond to diet?

15 10 year old male Healthy, athletic, no other illness Total cholesterol 263, LDL 205, HDL 36, TG 82 Father MI age 27, 34 (CABG), 54 now with 2 blocked grafts and 35% EF Patient is now on simvastatin 20 mg HS with LDL 98, HDL 46 Genetic Risk Familial Hypercholesterolemia Male or Female with LDL > 220 has Familial Hypercholesterolemia prevalence 1/500 Gene mutations in LDL receptor CHD risk is > 10% by age 30 years old, > 30% by age 40, > 40-50% by age times the risk of an aged matched peer with similar risk 20% - 60% of parents current CAD Not responsive to diet or exercise J. Pediatrics 2011;;December Cholesterol Screening National Lipid Association 2011 Universal screening age 9 11 National Heart, Lung and Blood Institute (2011) Targeted screening before age 9 Universal screening at ages 9-11 Initial screen: Non-HDL cholesterol Total Cholesterol HDL Cholesterol = Non-HDL Non-HDL is more predictive than other lipid levels predicts atherosclerosis and future events in both children and adults Repeat at age if levels are normal

16 Yield of Targeted Cholesterol Screening Using Family History Prior NCEP and current AAP guidelines recommend targeted screening - Family history of premature CHD or dyslipidemia 35 45% of children / adolescent s had cholesterol screened based on targeted screen 30 60% of children / adolescent s with high blood cholesterol missed with targeted screen Family history not reliable or available Other factors (lack of adherence to guidelines, access, test variability, family resistance, etc) Atherosclerosis Change with Statin Children with FH ages 8 18 years (mean age 13 years, 54% girls, n = 214) 2 year randomized controlled trial Counseling + either pravastatin mg or placebo Safe, effective (24% LDL decrease) Significant difference in change of atherosclero sis progression between groups Minimal side effects no adverse effects on growth, sexual maturation, hormone levels, liver, muscle, etc Wiegman A. JAMA 2004;;292:331-7 F.H. Patient Young Female 20 year old female in good health On oral contraceptive Non smoker, exercises, good diet Grandfather heart attack at age 48, grandmother stroke at age 60 Mother with total cholesterol 274, LDL 204, HDL 50, TG 100 Patient: Total cholesterol 292, LDL 210, HDL 42, TG 200

17 Issues to consider: young female No studies on statins / chol meds in pregnancy Statins safe and effective in young Atherosclerosis starts in childhood Should use contraception during RX Long-term problem Suspend treatment during pregnancy and breast-feeding Summary Choose the optimal therapy for the risk of the patient and the type of cholesterol disorder Encourage lifestyle change Combination therapy is a useful strategy to achieve treatment goals Biomarkers / imaging can be considered if it would change management intermediate risk patients Thank You! Questions?

18 Additional Slides Metabolic Abnormalities Premature CHD Routine test Y Y Y N N N RR 2x 2-3x 4x 1.5x 2x 3x FH Hypoalpha FCH Apo E4 Hcy Lp(a) N 3x ALP Superko HR, Circulation 1996;;94: Frequency (%) Who Needs Lipoprotein Quantitation? Not needed if LDL-C above NCEP ATP III target Non-HDL-C above target (when TG > 200 mg/dl) Very useful if Strong family history of premature CHD Known CHD - treated to goal with recurrent event TG >150 with HDL-C >40 (male) or >50 (female) Other situations Residual risk at target - hidden risk?

19 Distribution of Adjusted Plasma Triglycerides LDL Density Cumulative Percent Prophecy Normal LDL-C Small Dense LDL-C Triglyceride (mg/dl) Austin M, et al. Circulation. 1990;;82: Effects of Medications on HDL concentration and size Statins small effects on HDL number - simva most, atorva least small and large HDL fractions are increased Niacin significantly raises HDL particle number increases large HDL Fibrates HDL increase depends on TG level small and large HDL fractions are increased