60 yo white female Former smoker x 20 years Father had MI at age 42. Case 60 yo white female Former smoker x 20 years Father had MI at age 42. BP 127/79 mmHg on ACEI Seen in ER for chest pain earlier in the year. Ruled out for MI. ETT normal.

Case BMI: 28 kg/m2 Waist circumference: 39 inches (97.5 cm) Fasting lipids TC 239 mg/dl LDL-C 98 mg/dl TG 480 mg/dl HDL-C 45 mg/dl Glucose 104 mg/dL

Metabolic Syndrome (3 of 5 needed) Low HDL Male < 40 mg/dL Female < 50 mg/dLs Central Obesity Waist circumference > 40 (100 cm) in in men Waist circumference > 35inches (87.5 cm) in women TG > 150 mg/dL Hypertension Elevated fasting glucose (> 100 mg/dL)

DYSLIPIDEMIA: Pathway to Atherosclerosis  VLDL-TG Liver CETP  HL FFA Large, buoyant LDL, HDL Small, dense LDL, HDL  IAF

Two Hit Hypothesis: Role of Central Obesity / Insulin Resistance in Chronic Disease Expression ACE defect Insulin Secretion Defect DM2 HTN Insulin Resistance Central obesity FCHL PCOS  apo B secretion  Adrenal steroid

CAD risk is  2-3x … independent of LDL

What other labs do you want to know?

Case LFT’s, creatinine: NL TSH: 2.3 U/mL Hemoglobin A1c: 5.7% UA: no protein Non-traditional CAD risk factors: Lp(a) 18 mg/dl Homocysteine 9 mmol/L Apo B: 133 mg/dL

Diagnosis Familial Combined Hyperlipidemia Confirm by checking an Apo B level (> 120 mg/dl)

So, is she good to go? Fasting lipids TC 239 mg/dl LDL-C 98 mg/dl TG 480 mg/dl HDL-C 45 mg/dl Non-HDL-C 194 mg/dl

Triglyceride Disorders and Non-HDL Cholesterol Carr M C , and Brunzell J D JCEM 2004;89:2601-2607 ↑ portal vein FFA levels (with insulin resistance) → ↑production of apo B-particles. ↑ ↑ Atherogenic Particles

Lipid Research Clinic Follow-up Study: CVD Mortality by Non-HDL-C and LDL-C Cui Y et al. Arch Intern Med 2001;161:1413-1419. Non-HDL-C (mg/dL) Rate/ 10,000 <160 17.6 160 to <190 26.5 190 to <220 29.2 220 51.3 LDL-C (mg/dL) <130 25.4 130 to <160 22.8 27.7 190 40.1 LRC Follow-up Study: CVD mortality by non-HDL-C and LDL-C in women Non-HDL-C was a better predictor than LDL-C of cardiovascular mortality in women in the LRC Follow-up Study. Note that the data for non-HDL-C in women are stronger than the data for non-HDL-C in men. Reference: Cui Y, Blumenthal RS, Flaws JA, Whiteman MK, Langenberg P, Bachorik PS, Bush TL. Non-high-density lipoprotein cholesterol level as a predictor of cardiovascular disease mortality. Arch Intern Med 2001;161:1413-1419. 0 0.50 1.00 1.50 2.00 2.50 3.00 3.50 4.00 RR with 95% CI

Framingham Heart Study: Non–HDL-C Is Superior to LDL-C in Predicting CHD Risk Liu J, et al. Am J Cardiol. 2006;98:1363-1368 Within non–HDL-C levels, no association was found between LDL-C and the risk for CHD In contrast, a strong positive and graded association between non–HDL-C and risk for CHD occurred within every level of LDL-C Relative CHD Risk Non HDL-C and VLDL-C and Their Risk Predictive Values in CHD. Senior author Scott M. Grundy, chairman of the NCEP ATP III, published this study that analyzed data from the Framingham Heart Study (2693 men and 3101 women) in order to determine if non–HDL-C is a more useful predictor of CHD risk than LDL-C and if VLDL-C is an independent predictor of CHD risk. All subjects were aged ≥30 years of age and free of CHD at baseline, and incident CHD was the end point (618 men and 372 women). After multivariate adjustment, within non–HDL-C, no association was found between LDL-C and the risk for incident CHD. In contrast, a strong positive and graded association between non–HDL-C and risk for CHD was observed within every level of LDL-C. These results suggest that non–HDL-C is a stronger predictor of CHD risk than LDL-C and that VLDL-C may play a critical role in the development of CHD.1 These analyses were repeated within triglyceride levels <200 mg/dL and ≥200 mg/dL (data not shown here). Overall, the association with CHD incidence was stronger for non–HDL-C within every level of LDL-C than that for LDL-C within each level of non–HDL-C, regardless of whether triglyceride levels were <200 mg/dL or ≥200 mg/dL.1 Reference 1. Liu J, et al. Am J Cardiol. 2006;98:1363-1368. ≥190 160-189 <160 <130 130-159 ≥160 Non–HDL-C, mg/dL LDL-C, mg/dL

Treatment Goals for non-HDL Cholesterol When TG ≥ 200 mg/dL: LDL-C + 30 mg/dL Risk Category LDL-C Goal non-HDL Goal CAD/PVD (Secondary) < 70 mg/dL < 100 mg/dL CHD risk equivalent <100 mg/dL <130 mg/dL 2 Risk Factors 10-yr risk 10–20% <160 mg/dL <2 Risk Factors <190 mg/dL Treatment categories, LDL-C goals and cutpoints The primary goal of clinical lipid management is reduction of low-density lipoprotein cholesterol (LDL-C) to lower coronary heart disease (CHD) risk. Individuals who do not or cannot achieve this goal with therapeutic lifestyle change (TLC) alone are candidates for drug therapy. TLC is an important component of any lipid-lowering program. It can obviate the need for drug therapy, augment the LDL-C lowering achieved with drug therapy, and provide benefits beyond LDL-C lowering which contribute substantially to CHD risk reduction. As with all considerations in the Adult Treatment Panel III (ATP III) recommendations, the decision to initiate drug therapy should be consistent with the patient’s CHD risk. Those with the highest risk should be offered the most aggressive treatment to reduce the risk optimally. Conversely, in patients with the lowest risk, drug therapy may not be cost-effective. Patients with CHD or a CHD risk equivalent have the highest risk, exceeding 20% in 10 years, and are candidates for lipid-modifying drug therapy. Those with levels above 130 mg/dL can be given drugs simultaneously with TLC as lifestyle change alone is unlikely to achieve the treatment goal. Those with levels between 100 and 129 mg/dL should first be treated with TLC, and after an appropriate trial (e.g., 3 months), lipid-lowering drug therapy (for example, a statin or fibrate) may be initiated. Some clinicians prefer to initiate drug therapy simultaneously with TLC in patients being discharged from the hospital following a CHD event or with a CHD risk equivalent. In this case, the therapy can be adjusted on a subsequent visit if the treatment goal is not achieved or if it is exceeded. For CHD or CHD risk equivalent patients who were given LDL-C–lowering drug therapy and have an on-treatment LDL-C of 100–129 mg/dL, clinical judgment should be applied to choose from a number of options. The majority of participants in the statin endpoint trials had on-treatment LDL-C values in this range. Choices include intensifying TLC, adjusting the dose of the LDL-C–lowering drug, initiating nondrug treatment of the metabolic syndrome if it is present, or intensifying treatment of nonlipid risk factors. Patients with 2 or more major risk factors and a 10-year risk between 10 and 20% have an LDL-C goal of <130 mg/dL and should be given TLC; if it is unlikely that this alone will achieve the treatment goal, drug therapy may be initiated simultaneously. In most cases, TLC is tried for about 3 months before making decisions to advance to drug therapy. After adequate LDL-C reduction has been achieved, other risk factors, including obesity and sedentary lifestyle, should be addressed. Patients with 2 or more risk factors and a 10-year risk of <10% as well as patients with <2 risk factors (who mostly have a 10-year risk of <10%) should be treated with TLC unless LDL-C levels are very high, because drug therapy in these patients is the least cost-effective. If treatment goal cannot be achieved with TLC alone, consideration can be given to using lipid-lowering drug therapy. Reference: Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486-2497.

So, is she good to go? Fasting lipids TC 239 mg/dl LDL-C 98 mg/dl TG 480 mg/dl HDL-C 45 mg/dl Non-HDL-C 194 mg/dl Goal: < 130 mg/dL

What are your treatment options? Intensive Lifestyle Management Statins Atorvastatin 40 mg/dL TC 239 196 mg/dl LDL-C 98 81 mg/dl TG 480 365 mg/dl HDL-C 45 42 mg/dl Non-HDL-C 194 154 mg/dl Goal: < 130 mg/dl

Statins in Triglyceride Disorders Statins (as single agents) work poorly in triglyceride disorders, except: Atorvastatin and Simvastatin @ 80 mg dose In type 2 diabetes

What are your treatment options? Intensive Lifestyle Management Fibrate Fenofibrate 145 mg TC 239 185 mg/dl LDL-C 98 104 mg/dl TG 480 165 mg/dl HDL-C 45 48 mg/dl Non-HDL-C 182 137 mg/dl Goal: < 130 mg/dl

Fibrates and Triglyceride Disorders LDL went up What just happened?

Fibrates Increase TG Particle Processing by Enhancing Lipoprotein Lipase Activity  PCSK9  LpL  Apo CIII → → ↑

Fibrates and Triglyceride Disorders LDL went up Add in a statin or Zetia Bile acid resin binders may raise TG levels Can use niacin

What are your treatment options? Intensive Lifestyle Management Fibrate Fenofibrate 145 mg F + Crestor 30mg TC 239 185 mg/dl LDL-C 98 104 mg/dl TG 480 165 mg/dl HDL-C 45 48 mg/dl 165 mg/dl 88 mg/dl 158 mg/dl 49 mg/dl Non-HDL-C 182 141 mg/dl Goal: < 130 mg/dl 116 mg/dl

So, is she good to go? CAC score: 2200 Diffuse 3 vessel involvement LDL goal: < 50 mg/dL Non-HDL-C goal: < 80 mg/dL