What Else Do You Need to Know? Presenter Disclosure Information. Case 1: Cardiovascular Risk Assessment in a 53-Year-Old Man. Learning Objectives

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1 9: 1:am Understanding Dyslipidemia Testing and Screening: Importance of Lipoprotein Particle Analysis SPEAKER Matthew Sorrentino, MD, FACC Presenter Disclosure Information The following relationships exist related to this presentation: Matthew Sorrentino, MD, FACC, receives speaker honorarium for Takeda. Off-Label/Investigational Discussion In accordance with pmicme policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations. Learning Objectives Describe the pathogenesis of dyslipidemias in patients with diabetes and chronic kidney disease Understand the rationale for performing lipoprotein particle analysis in patients with high CV risk comorbidities Case 1: Cardiovascular Risk Assessment in a 3-Year-Old Man Patient history 3-year-old man Nonsmoker Physical examination BP: 1/9 mmhg Waist: in BMI: 9 kg/m Laboratory measurements TC: 7 mg/dl LDL-C: 1 mg/dl HDL-C: 3 mg/dl TG: mg/dl Non-HDL-C: mg/dl FPG: 113 mg/dl Case 1: Risk Assessment, cont d What Else Do You Need to Know? Secondary Causes of Hyperlipidemia Ruled Out Risk Assessment TSH: 3. µiu/ml Creatinine: 1. mg/dl Liver enzymes: normal 3 major risk factors: Age Low HDL-C High BP Metabolic syndrome: Low HDL-C High TG Increased waist circumference, BP, and FPG

2 Risk Calculator Risk Factor Units Value Sex M/F Age Years Race AA/WH Total Chol mg/dl HDL-C Mg/dl Systolic BP mmhg Treatment HBP Y/N Diabetes Y/N Smoker Y/N Based on: Guidelines_UCM_79_SubHomePage.jsp Risk Calculator Risk Factor Units Value Sex M/F M Age Years 3 Race AA/WH WH Total Chol mg/dl 7 HDL-C mg/dl 3 Systolic BP mmhg 1 Treatment HBP Y/N N Diabetes Y/N N Smoker Y/N N Based on: Guidelines_UCM_79_SubHomePage.jsp Predicted Risk (%) Risk 3-year-old man yr risk.9 Optimal Lifetime risk Lifetime Optimal Optimal values TC 17, HDL, SBP 11; Lifetime optimal risk at age yrs Lipoprotein Density Distribution Density g/ml HDL 3 HDL LDL Remnants IDL Lp(a) Chylomicron Remnants Chylomicron Chylomicron 1 1 Diameter, nm HDL=high density lipoprotein; LDL=low density lipoprotein =very low density lipoprotein; IDL= intermediate density lipoprotein; Lp(a)=lipoprotein (a) Segrest et al. Adv Protein Chem. 199;:33 39 HMG-CoA Reductase Inhibitors: Secondary Prevention Relationship between LDL-C Levels and Event Rates in Secondary Prevention Statin Trials of Patients with Stable CHD 3 Statin Placebo S 1 S LIPID CARE LIPID CARE 1 HPS HPS TNT (1 mg/d) TNT ( mg/d) Event (%) Is Lowering LDL-C Enough? Despite on-therapy LDL-C < mg/dl, a significant number of patients still have events. 1 Major statin trials consistently show % % risk reduction for cardiovascular events, regardless of baseline LDL-C levels. Despite LDL-C lowering, residual risk remains high for at least years following the index event. 1 There is a great need for further improvement in cardiovascular risk reduction. 3 LDL-C HPS: simvastatin mg CARE: pravastatin mg TNT: atorvastatin 1 mg or mg LIPID: pravastatin mg S: simvastatin 1- mg LaRosa JC, et al. NEJM ;3: Cannon CP, et al. N Engl J Med. ;3: LaRosa JC, et al. JAMA. 1999;: Assmann G, et al. Circulation. ;19(suppl III):-1.

3 Residual CVD Risk in Diabetic Patients Treated with Statins Low HDL-C is an Independent Predictor of CHD Risk Even When LDL-C is Low Major Vascular Event Rate % HPS: N=93 patients with DM.1. % Risk Reduction Residual CVD Risk Placebo Simvastatin Placebo Atorvastatin Collins R, et al. Lancet. 3;31:-1 Colhoun HM, et al. Lancet. ;3:-9 HPS=Heart Protection Study CARDS=Collaborative Atorvastatin Diabetes Study Acute CVD Event Rate % CARDS N= % Risk Reduction Residual CVD Risk Risk of CHD Gordon T, et al. Am J Med. 1977;: LDL-C HDL-C HDL-C as a Risk Factor Predicts Risk After Aggressive LDL-C Reduction CHD Risk of Patients in TNT* with On-Treatment LDL-C <7 mg/dl According to Quintile of On-Treatment HDL-C Hazard ratio (9% CI) versus Q Y Risk of Major CV Events (%) Q1 Q Q3 Q Q (<37) (37 to <) ( to <7) (7 to <) ( ) Quintile of HDL-C Level No. of Events No. of Patients 73 9 Barter P, et al. N Engl J Med. 7;37(13): Q. (.7-1.) Q3.7 (.3-.) Q. (.3-.) Q.1 (.3-.97) P=.3 * Treating to New Targets Trial Atherogenic Dyslipidemia in Diabetes and Metabolic Syndrome High Triglyceride Levels TG-rich remnant lipoproteins () Altered metabolism of LDL and HDL particles Remnants are atherogenic Haffner SM. Diabetes Care. 3; (suppl 1):S3-S. Garvey WT, et al. Diabetes. 3;:3-. Absolute LDL-C Levels Often not significantly increased Other LDL parameters significantly change Increased number of LDL particles Predominantly small, dense LDL particles Low HDL-C Levels May reduce reverse transport Pathogenesis of Dyslipidemia in the Metabolic Syndrome Dyslipidemia in Chronic Kidney Disease (CKD) intra-abdominal fat precedes development of insulin resistance. Ayyobi, Brunzell Am J Cardiol. 3;9(suppl):7J. IR leads to ApoB production TG-rich particles. IR leads to hepatic lipase activity hydrolysis of TG and PL in LDL and HDL leading to sd LDL and HDL (large buoyant subclass) IAF=intra-abdominal fat IR=insulin resistance TG=triglycerides; sd=small, dense ApoB=apolipoprotein B =very low density lipoprotein In general, patients with CKD do not have elevated LDL-C except in nephrotic syndrome and peritoneal dialysis, which are associated with elevated LDL-C CKD promotes delayed breakdown of TG-rich lipoproteins Patients with CKD have: Elevated TG, Low HDL-C, and Increased small, dense LDL Tsimihodimos et al. Am J Nephrol. ;:9

4 Mechanism of Dyslipidemia in CKD LDL Assessment Decreased activity of lipoprotein lipase and hepatic lipase Decreased activity of LDL receptor-related protein Increased TG Decreased LCAT activity Nephrotic increased HMG CoA reductase activity LCAT = lecithin cholesterol acyltransferase Tsimihodimos et al Am J Nephrol. ;:9. Decreased catabolism of TG-rich lipoproteins Clears TG-rich particles in liver Promotes TG transfer to LDL and HDL lowers HDL and increases TG-rich LDL modified to small dense LDL Impairs maturation of HDL particles Increases blood level of LDL LDL-C LDLd LDL Subfractions Calculated from the Friedewald formula LDL-C = TC [HDL + TG/] Fasting; unreliable if elevated TG Direct LDL Reliable nonfasting LDL phenotyping (pattern A/pattern B) LDL particle number (NMR) - LDLp LDL Phenotype Triglyceride Level Predicts LDL Pattern LDL heterogeneous in size, density, and composition Lipid content of LDL determines particle density TG content key determinant to density hydrolysis of TG leads to smaller denser particles Pattern A: predominance of large, buoyant LDL Pattern B: small, dense LDL particles (typically diameter less than. nm) Cumulative percent frequency 1 1 Phenotype A Phenotype B Triglycerides Sorrentino MJ. Advanced Lipid Testing in Hyperlipidemia in Primary Care. Humana Press, 11. Austin MA, et al. Circulation. 199;:9. LDL Particle Number Nuclear magnetic resonance (NMR) spectroscopy can directly measure LDL particle number (LDLp) LDLp < 1 nmol/liter thought to be optimal Frequent discrepancy between LDLp and LDL-C LDL-C underestimates number of small dense particles Measures of CVD Risk Other than LDL-C Non-HDL-C Subtract HDL from total cholesterol Sum of all potentially atherogenic particles Apolipoprotein B1 (ApoB) One molecule of ApoB per atherogenic particle (LDL, IDL, ) Represents total atherogenic particle number For most individuals, LDL accounts for 9% of all atherogenic particles so ApoB is an estimate of LDL particle number =very low density lipoprotein IDL=intermediate density lipoprotein Sorrentino MJ. Advanced Lipid Testing in Hyperlipidemia in Primary Care. Humana Press, 11. Sorrentino MJ. Advanced Lipid Testing in Hyperlipidemia in Primary Care. Humana Press, 11.

5 Non-HDL Cholesterol NCEP recommends Non-HDL-C as secondary target after LDL-C 1 Calculate when triglycerides > mg/dl Non-HDL-C target is 3 mg/dl greater than LDL-C goal Better predictor of CVD events than LDL-C High correlation with ApoB R value generally greater than. Reduction of Non-HDL-C correlates with CVD risk reduction regardless of treatment modality (1:1 relationship) 1 National Cholesterol Education Program (NCEP,) Adult Treatment Panel (ATP) III.. NIH Publication No Robinson et al. J Am Coll Cardiol. 9;3:31 Effect of LDL Particle Size and ApoB on CHD Risk Odds ratio for CHD apo B <1 mg/dl apo B >1 mg/dl >. nm <. nm LDL Peak Particle Diameter Lamarche B et al. Circulation. 1997;9:9 (Quebec Cardiovascular Study) Case -Year-Old Woman S.M. is a year old woman She seeks evaluation because she is concerned about her overall health She denies symptoms of myocardial ischemia She has been told that her blood pressure has run high in the past She denies a history of vascular disease or diabetes mellitus Mother had heart attack age Pertinent physical exam findings: BP 139/9; BMI 9. Fasting lipid profile: total cholesterol ; HDL-C ; TG1 ; LDL-C 19 BUN, Cr 1. Risk Calculator Risk Factor Units Value Sex M/F F Age Years Race AA/WH WH Total Chol mg/dl HDL-C mg/dl Systolic BP mmhg 139 Treatment HBP Y/N N Diabetes Y/N N Smoker Y/N N Based on: evention-guidelines_ucm_79_subhomepage.jsp Risk -year-old woman When to Use Advanced Lipid Testing (LDLp or ApoB) Predicted Risk (%) yr risk. Optimal Lifetime risk Lifetime Optimal Risk Profile Measure LDLp or Apo B? Low-risk patients Intermediate or CHD risk equivalent patients CHD patients at LDL-C goal No clear benefit Reasonable for many patients May be useful for determining whether to consider intensification of therapy (i.e. in discordant individuals) Optimal values TC 17, HDL, SBP 11; Lifetime optimal risk at age yrs; Lifetime risk calculated for individuals age -9 yrs LDLp=LDL particle number ApoB=apolipoprotein B Davidson MH, et al. J Clin Lipidol. 11;:33. (National Lipid Association)

6 American Diabetes Association Treatment Goals in Patients With Cardiometabolic Risk and Lipoprotein Abnormalities Highest Risk Patients High Risk Patients LDL-C Non-HDL-C ApoB <7 <1 < <1 <13 <9 Reasons Not to Use Advanced Lipid Testing Non-HDL-C is a strong predictor of CVD risk and is highly correlated with ApoB. (although some individuals may be discordant) Non-HDL-C is less costly No study has demonstrated improved outcomes using LDLp or ApoB targets compared with traditional lipid goals Highest Risk = Known CVD or diabetes plus at least 1 other risk factor High Risk = No diabetes or known clinical CVD but or more risk factors or diabetes but no other CVD risk factors ApoB=apolipoprotein B Brunzell JD, et al. Diabetes Care. ;31:11. (American Diabetes Association) Lipoprotein (a) Lipoprotein (a) Levels and CVD Risk Variant of LDL Contains ApoB and a unique glycoprotein [apolipoprotein (a)] linked to ApoB with homology to plasminogen Marked heterogeneity in density and size due to different isoforms of Apo(a) Marked ethnic differences Higher in African Americans but may be less atherogenic Higher CHD risk in individuals from the Indian subcontinent Lp(a) Concentration Desirable < 1 Borderline risk 1-3 High risk 31- Very high risk > Sorrentino MJ. Advanced Lipid Testing in Hyperlipidemia in Primary Care. Humana Press, 11. Sorrentino MJ. Advanced Lipid Testing in Hyperlipidemia in Primary Care. Humana Press, 11. When to Measure Lp(a) Consider in high risk sub-populations Caucasians and South Asians with strong family history of premature CHD Consider in patients on LDL-lowering therapy not able to reach goal or less than expected decline in LDL-C Friedewald calculated LDL-C includes Lp(a) May account for discrepancy b/w calculated LDL-C and some direct LDL-C assays HDL Sub-Fractions HDL is a risk factor for CVD but not a treatment target. Ultracentrifugation can separate HDL into two major sub-fractions. Gel electrophoresis separates HDL on basis of particle size. Conflicting data regarding HDL sub-fractions as risk marker. Currently no recommendations on using HDL subfractions to guide treatment. Sorrentino MJ. Advanced Lipid Testing in Hyperlipidemia in Primary Care. Humana Press, 11. Sorrentino MJ. Advanced Lipid Testing in Hyperlipidemia in Primary Care. Humana Press, 11.

7 Case 3 CAD and Discordant Lipids -year-old man with CAD DES to LAD at age Current meds: aspirin, rosuvastatin 1 mg/d Lipid Panel: TC LDLc LDLp HDL TG 13 mg/dl mg/dl 1 nmol/l mg/dl 7 mg/dl Plan intensify lipid lowering because of high LDLp despite LDLc at goal Advanced Lipid Testing: Summary No role in low-risk individuals May identify a high-risk population, especially if discordant from LDL-C Metabolic syndrome and diabetes Chronic kidney disease May modify treatment program for high risk patients May consider intensification of therapy or combination therapy in high-risk individuals with discordant results Questions?