Kathy What Is the Risk of Low HDL-C?

Targeting Better Cardiac Outcomes for High Risk Patients Daniel Soffer, MD, FNLA Clinical Associate Professor of Medicine Perelman School of Medicine at the University of Pennsylvania Philadelphia PA sofferd@uphs.upenn.edu Learning Objectives Evaluate recent clinical trials with respect to management of low HDL-C Examine the data on triglycerides and CVD risk to determine how aggressively to treat patients with elevated TGs Employ strategies for reducing CVD risk in patients with type 2 diabetes and hypertension Case 1: Kathy, 45 y/o female Pre-op consult for elective cholecystectomy Only complaint is intermittent RUQ pain Borderline HTN ; weight loss was recommended Habits/SH: Nonsmoker, social alcohol, intermittent exercise program, middle school teacher FHx: Father, CAD and MI age 65; Mother, DM PE: mean BP 138/86; BMI=30 Blood work (mg/dl): TC 200, HDL-C 36, LDL-C 124, TG 190; nonhdl-c 164 Glucose 102; remainder unremarkable No meds Is Kathy at Risk? Low risk (only 1 major risk factor) Framingham risk score (to be calculated if >2 RF s) = 1% Pooled cohort equation, 1.6% 10-yr risk, 39% lifetime risk http://cvdrisk.nhlbi.nih.gov/ Kathy What Is the Risk of Low HDL-C? What are her associated risks? Borderline elevated blood pressure ( 130/85) Low HDL-C (<50 mg/dl) Obesity (waist circumference >35 in?) Elevated triglycerides ( 150 mg/dl) Borderline fasting glucose The Framingham Heart Study demonstrated a strong inverse relationship between HDL-C and CHD It is estimated that for every increase in HDL-C by 1 mg/dl there is a 2% lower risk of CHD for men and 3% lower risk for women This patient has at least 3 or 4/5 criteria for the metabolic syndrome Gordon DJ, et al. Circulation. 1989;79:8-15. Third Report of the NCEP Expert Panel. JAMA. 2001;285:2486-2497.

Low HDL-c Is an Independent Predictor of CHD Risk Even When LDL-C Is Low [lumen] MCP, VCAM endothelium RCT glycoprotein matrix TNFα, IL-6 B CHD Risk A1 Ox- 100 160 220 LDL-C (mg/dl) 25 45 65 HDL-C 85 (mg/dl) Antioxidant Antiinflammatory Antithrombotic MMP, elastase Gordon T, et al. Am J Med. 1977;62:707-714. Steinberg D: Atheroscler Rev 1988, 18:1-23. Is Low HDL-C Simply a Marker of Increased Cardiovascular Risk? Low HDL-C levels common in Smokers Sedentary Obese Insulin resistant or diabetic High TG Chronic inflammatory diseases Isolated low HDL-C uncommon and not always harmful Marker for high apolipoprotein B (nonhdl-c, small dense LDL, high LDLp) HDL and apoai are directly atheroprotective Rader DJ and Tall AR. Nature Medicine. 2012;18:1344 1346. Prevalence of Low HDL Varies geographically/ethnically United States: 31% in men, 12% in women United States: 35% in Hispanic men United Kingdom: 23% in men, 8% in women China: 8% in men, 2% in women Low HDL-C is commonly associated with other risk factors: Cardiometabolic Risk Carroll MD, et al. Total and high-density lipoprotein cholesterol in adults: National Health and Nutrition Examination Survey, 2009 2010. NCHS data brief, no. 92.; 2012. Http://www.cdc.gov/nchs/data/databriefs/db92.htm. Bruckert E. Eur Heart J Suppl. 2006;8 (suppl F): F17-F22. Guidelines Define Low HDL-C as CV Risk Factor NCEP ATP III: Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) (2001) Implications of Recent Clinical Trials for the NCEP ATP III Guidelines (2004) ADA/ACCF Consensus statement on Lipoprotein Management in Patients with Cardiometabolic Risk (2008) 2013 ACC/AHA Cholesterol Guidelines NCEP ATP III (2001) and 2004 Update Treatment of low HDL-C (<40 mg/dl) First reach LDL-c goal, then: Intensify weight management and physical activity If triglycerides 200-499 mg/dl, achieve nonhdl-c goal In a high risk person with high TG or low HDL-C combining a fibrate or nicotinic acid with an LDL lowering drug can be considered NonHDL-C = TC HDL-C Third Report of the NCEP Expert Panel. JAMA. 2001;285:2486-2497.; Grundy, et al. Circulation. 2004;110:227-239.; ADA/ACCE Consensus. Brunzell JD, et al. JACC. 2008;51:1512-1524 Third Report of the NCEP Expert Panel. JAMA. 2001;285:2486-2497.; Grundy, et al. Circulation. 2004;110:227-239.

Non-HDL-C Triglyceride Cholesterol All atherogenic lipoproteins HDL LDL IDL VLDL Chylomicron remnant 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines APO A 1 APO B APO B APO B APO B 48 non HDL Circulation; November 2013 nonhdl C= Total cholesterol HDL C Figure courtesy of Michael Davidson, MD Recent Trials Addressing Treatment of Low HDL-C Niacin: The Coronary Drug Project Niacin AIM-HIGH (no benefit when LDL-C at target) HPS-2 THRIVE (no benefit, higher risk of myopathy) CETP inhibitors Torcetrapib (harm), dalcetrapib (no benefit) Other CETP inhibitors still in trials: anacetrapib, evacetrapib Fibrates ACCORD: benefit in subset with high TG/low HDL-C Event Rate (%) 35 30 25 20 15 10 5 14 27 26 Placebo Niacin 47 Barter PJ, et al. N Engl J Med. 2007;357(21):2109-22. Schwartz GG, et al. N Engl J Med. 2012; 367:2089-2099.; http://clinicaltrials.gov/ct2/show/nct01252953?term=anacetrapib&rank=7; http://clinicaltrials.gov/ct2/show/nct01687998?term=evacetrapib&rank=10; N Engl J Med. 2008;358:2545-2559.; The AIM-HIGH Investigators. N Engl J Med. 2011;365:2255-2267.; HPS2- THRIVE Collaborative Group. Eur Heart J. 2013; 34:1279-1291. The HPS2-THRIVE Collaborative Group N Engl J Med 2014; 371:203-212 0 Nonfatal MI/ Nonfatal MI Stroke/TIA CHD Death Total follow-up, adjusted for baseline characteristics, p<0.05, 5-year rate Coronary Drug Project Research Group. JAMA 1975;231:360 381. Canner PL et al. J Am Coll Cardiol 1986;8:1245-1255 CV Surgery HPS2 THRIVE: No Improvement in Major Vascular Events Event Randomized allocation ERN/LRPT Placebo (12838) (12835) Risk ratio & 95% CI Non-fatal MI 402 (3.1%) 431 (3.4%) 0.93 (0.82-1.07) 0.33 Coronary death 302 (2.4%) 291 (2.3%) 1.04 (0.89-1.22) 0.63 Major coronary event 668 (5.2%) 694 (5.4%) 0.96 (0.87-1.07) 0.51 p The HPS2-THRIVE Collaborative Group N Engl J Med 2014; 371:203-212 The short story is that NIACIN WAS INEFFECTIVE AND ASSOCIATED WITH SIGNIFICANT HARM. Ischaemic stroke 389 (3.0%) 415 (3.2%) 0.94 (0.82-1.08) 0.37 Haemorrhagic stroke 114 (0.9%) 89 (0.7%) 1.28 (0.97-1.69) 0.08 Any stroke 498 (3.9%) 499 (3.9%) 1.00 (0.88-1.13) 0.56 Coronary revasc 591 (4.6%) 664 (5.2%) 0.89 (0.80-0.99) 0.04 Non-coronary revasc 236 (1.8%) 258 (2.0%) 0.92 (0.77-1.09) 0.33 Any revascularization 807 (6.3%) 897 (7.0%) 0.90 (0.82-0.99) 0.03 Major vascular event 1696 (13.2%) 1758 (13.7%) 0.96 (0.90-1.03) 0.29 European Heart Journal (2013) 34: 1279 1291 0.8 1.0 1.2 ERN/LRPT better Placebo better

The HPS2-THRIVE Collaborative Group N Engl J Med 2014; 371:203-212 The short story is that NIACIN WAS INEFFECTIVE AND ASSOCIATED WITH SIGNIFICANT HARM. A more precise conclusion is that among participants with atherosclerotic vascular disease, the addition of extended-release niacin laropiprant to statin-based LDL cholesterol lowering therapy [simvastatin +/- ezetimibe, achieving avg LDLc 63 mg/dl and HDLc 44 mg/dl before randomization] did not significantly reduce the risk of major vascular events but did increase the risk of serious adverse events, particularly among the Chinese participants in the study. Niacin Trials: Questions Raised Why did these trials fail to show a difference? Coronary Drug Project showed benefit Atherosclerosis (angiographic and cimt) data previously suggested benefit Did we AIM too LOW with aggressive LDL-C therapy? If the LDL-C is <70 is there a benefit to raising HDL-C even though there is still increased residual risk? Who is the appropriate patient for niacin? Is there a specific subgroup that would benefit? Is HDL-C raising still a viable target of therapy? dal-outcomes: More Questions Raised Why did this trial fail to show a difference? No apparent off-target effects or harm as with torceptrapib Possibly due to lack of LDL benefit? Did we chose the wrong study population? High risk population on good evidence based regimen Are CETP inhibitors still worth investigating? Anaceptrapib/Evacetrapib in Phase 3 trials currently Is HDL-C raising still a viable target of therapy? Is HDL-C Still a Therapeutic Target? Low levels of HDL-C and apo AI remain strong predictors of increased risk of cardiovascular disease, even in patients with low LDL-C (but perhaps not very low LDL-C) LDL-C remains the primary target of lipid altering therapies NonHDL-C remains the secondary target HDL-C levels do not necessarily reflect HDL function Numerous HDL therapies still in clinical development that will help to answer many mechanistic questions Therapeutic Lifestyle Changes Weight management For every 7 lb weight loss, HDL-C levels increase by 1 mg/dl Increased physical activity Intensive aerobic exercise can modestly increase HDL-C levels by ~5% Smoking cessation Smoking lowers HDL-C levels 7% to 20% With cessation, HDL-C can return to normal after 30 to 60 days Dattilo AM, Kris-Etherton PM. Am J Clin Nutrition. 1992;56:320-328. Therapeutic Lifestyle Changes TLC Diet Low saturated fat (<7% of daily caloric intake) Low cholesterol (<200 mg/day) High fiber (10-25 g/day) Consider plant stanols/sterols (2 g/day) Very low fat diets will lower HDL-C Polyunsaturated fats may improve the antiinflammatory properties of HDL and should not necessarily be restricted (omega 3 and omega 6 FA) Alcohol intake raises HDL-C, but is not necessarily healthful Third Report of the NCEP Expert Panel. JAMA. 2001;285:2486-2497.

Kathy Plan (after cleared for elective surgery) Recommend TLC Repeat outpatient evaluation of all parameters in several months time Consider atherosclerosis imaging (eg CACS/cIMT) Consider statin therapy due to high lifetime risk Case 2: Melanie, a 28 y/o female Admitted with 1 wk of severe midepigastric abdominal pain/acute pancreatitis Medications: Oral contraceptive pill (OCP) SHx: Nonsmoker, rare alcohol FHx: Father with very high cholesterol PE: BP 120/80, BMI 26, rash on back and buttocks Fasting lipid profile (mg/dl) TC 210 HDL 38 TG 3540 LDL cannot be calculated, lipase is elevated Prevalence of Elevated Triglyceride Levels Hypertriglyceridemia Overall in the United States: 31% of adults have levels >150mg/dL (1.69 mmol/l) Mexican Americans: 35% Nonhispanic whites: 33% African Americans: 15.6% TG levels 200 mg/dl in 16.2% TG levels 500 mg/dl in 1.1% overall 9% in Mexican Americans aged 50 to 59 Primary / Genetic causes Lipoprotein Lipase, apolipoprotein C2 (LPL promotor) deficiency (chylomicrons or chylos + VLDL) Familial hypertriglyceridemia (VLDL) Familial combined hyperlipidemia (VLDL and LDL) Familial dysbetalipoproteinemia (Type III; remnants) Familial chylomicronemia syndrome (Type I) Miller M, et al. Circulation. 201;123:2292-2333. Secondary Causes of Hypertriglyceridemia Diseases/States Central/visceral adiposity, lipodystrophy DM/insulin resistance Sedentary lifestyle Endocrine d/o s (Cushings, hypothyroid) Kidney failure Liver disease HIV lipodystrophy Drugs/Diet Alcohol Diet Hormones Oral estrogen (BCP & ERT) Blood Pressure/Lipid Rx Retinoids Miscellaneous Management of Very Elevated TG No alcohol Weight loss of 5% to10% can lead to 20% reduction in TG levels Increased physical activity Dietary changes Need to remove almost all fat from diet until TG <1000 mg/dl Treat insulin resistance/deficiency/hyperglycemia Medications usually necessary for TG >1000 mg/dl Combination of lifestyle changes can help to lower TG by up to 50% Pejic R, et al., J Am Board Fam Med. 2006;19:310-316. Dattilo AM, Kris-Etherton PM. Am J Clin Nutrition. 1992;56:320-328. Miller M, et al. Circulation. 2011;123:2292-2333.

Effect of Pharmacologic Treatment on TG Drug % TG Reduction Fibrates 30-50 IR Niacin 20-50 Omega 3 FA 20-50 ER Niacin 10-30 Statins 10-30 Ezetimibe 5-10 Dietary Changes to Lower TG/nonHDL-C Reduce simple carbohydrates (VLDL): <50% of calories; reduce/eliminate fat (chylomicrons) Higher fiber Minimal added sugar (<5%) and fructose (<50 g) No trans fats Reduce saturated fats to <5% In acute setting may need supplementation with medium chain triglycerides Consider Mediterranean type diet (higher in MUFAs, PUFAs) Miller M, et al. Circulation. 2011;123:2292-2333. Dattilo AM, Kris-Etherton PM. Am J Clin Nutrition. 1992;56:320-328. Miller M, et al. Circulation. 2011;123:2292-2333. Fish Oil and Omega 3 Fatty Acids Dosing for hypertriglyceridemia is 4 g daily (2 g bid) w/food Expected TG lowering of ~30% to 45% Formulations Prescription: indicated at as an adjunct to diet to reduce TG levels in adults with very high levels ( 500 mg/dl) Omega 3 acid ethyl esters [Lovaza, Omtryg, Epanova]: 1 g capsules (approx 465 mg EPA and approx 375 mg DHA or ~850 mg combined) Icosapent ethyl [Vascepa]: EPA only, 1 g capsules TG and CVD Risk Elevated TG often clusters with other cardiometabolic risk factors Not directly atherogenic, but represents an important biomarker of CVD risk because of its association with atherogenic remnant particles sdldl, VLDL remnants There is an increased risk for pancreatitis when fasting TG level exceeds 1000 mg/dl OTC: Standard concentrations are 120 mg DHA and 180 mg EPA Miller M, et al. Circulation. 2011;123:2292-2333. NCEP ATP III Triglyceride Management >500 mg/dl First lower TGs to prevent pancreatitis Very low fat diet (15% of calories from fat) Weight management and physical activity Identify and correct secondary causes: STOP OCP! Consider pharmacologic therapy: fibrate, omega 3 FA, (and/or nicotinic acid ) When TGs <500 mg/dl, turn to LDL/nonHDL-cholesterol lowering therapy >200-499 mg/dl Consider adding drug if needed to reach nonhdl-c goal Intensify therapy with LDL-c lowering drug, or Add nicotinic acid, Ω3-FA s or fibrate Melanie Diagnosis Type V hyperlipoproteinemia with pancreatitis Plan Stop OCP Nutrition counseling for TG lowering diet Fibrate and prescription fish oil for rapid TG lowering Exercise Complete abstinence from alcohol Third Report of the NCEP Expert Panel. JAMA. 2001;285:2486-2497.

Case 3: Gus, a 49 y/o AA Male Seen in follow-up for history of mixed dyslipidemia, hypertension, diabetes, fatty liver, and obesity Feels well, but concerned about recent weight gain of 20 lbs over the past 1 year Habits: Nonsmoker, occasional beer on weekend FHx: Mother and brother have diabetes, HTN PE: BP 140/84, BMI 34, otherwise unremarkable Gus Medications: aspirin, amlodipine, HCTZ, lisinopril, metformin, multivitamin, vitamin D, fish oil Previously prescribed a statin but he stopped taking six months ago after hearing a story on the news Fasting blood work (mg/dl): - TC 212 HDL 38 LDLC 138 apob 138 - TG 180 nonhdl 174 - glucose 152 - HbA1C 7.6% LFTs minimally elevated Factors Contributing to Cardiometabolic Risk Overweight/Obesity Genetics Age Insulin Resistance Insulin Resistance Syndrome Lipids BP Glucose Smoking, Physical Inactivity Brunzell JD, et al. JACC. 2008;51:1513. Hypertension Cardiovascular Risk Global Diabetes/CVD Risk Abnormal Lipid Metabolism LDL ApoB HDL Triglycerides Age;Race;Sex, Family History Inflammation, Hypercoagulation LDL Cholesterol Goals LDL Cholesterol (mg/dl) Non HDL Cholesterol (mg/dl) Apolipoprotein B (mg/dl) Highest Risk <70 <100 <80 High Risk <100 <130 <90 Highest risk: Known clinical CVD or diabetes and one other risk factor (smoking, hypertension, or family history of CVD) High risk: Diabetes without other risk factors 2013 ACC/AHA Cholesterol Guidelines Treat with moderate to high intensity statin NCEP ATP III Update, Grundy SM, et al. Circulation. 2004;110:227-239.; ADA/ACCF Consensus. Brunzell JD, et al. JACC. 2008;51:1512-1524.; ADA 2010 Guidelines. Diabetes Care. 2010;33:S4-10 Achieving LDL Cholesterol Goals Statin therapy is first line Statin therapy should be added, regardless of baseline lipid levels, for the highest risk diabetic patients, especially those >40 years Categorical indication for moderate or high intensity statin based upon the present ACC/AHA Guidelines Many large scale clinical trials show a reduction in CHD events with statins in patients with diabetes NCEP ATP III Update, Grundy SM, et al. Circulation. 2004;110:227-239.; ADA 2010 Guidelines. Diabetes Care. 2010;33:S4-10. Gus Plan Counseled on diet/exercise; referred to nutritionist Started on atorvastatin 40 mg daily At four month follow-up: BP 132/80, 8 lb loss, BMI 33 Fasting blood work (mg/dl): - TC 154 - HDL 35 - LDL 87 - apob 90 - TG 162 - nonhdl 119 Glucose 141 HbA1C 7.3%

Options for Treating Residual Risk Residual LDL-C elevation Bile acid sequestrants Ezetimibe Niacin Modify statin therapy Atherogenic dyslipidemia Niacin Elevated triglycerides Fibrates Omega 3 fatty acids Take Home Points LDL-c/nonHDL-C; primary and secondary targets of lipid management Low HDL-C is strong CV risk marker but benefit from niacin added to statins/ezetimibe and use of CETP inhibitors have not demonstrated benefit in CV outcomes Rule out secondary cause of high TG Lower TG to <500 mg/dl to reduce risk of pancreatitis In highest risk DM patients, moderate to high intensity statin should be added