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Review of the New 2013 ACC/AHA Guidelines on Lipid Management Kathleen Dively NP Associates In Cardiology Clinical Lipid Specialist FNLA.

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Presentation on theme: "Review of the New 2013 ACC/AHA Guidelines on Lipid Management Kathleen Dively NP Associates In Cardiology Clinical Lipid Specialist FNLA."— Presentation transcript:

1 Review of the New 2013 ACC/AHA Guidelines on Lipid Management Kathleen Dively NP Associates In Cardiology Clinical Lipid Specialist FNLA

2 Objectives Discuss and review major changes including the lack of target LDL Discuss the role of niacin and ezetimibe Dicuss the role of biomarker ie ApoB, CIMT Discuss the use of combination therapy Discuss the use of high dose statin therapy Discuss the management of residual risk Managing low-density lipoprotein (LDL) is an integral part of clinical practice. What remains controversial is whether we are using the best measure of LDL quantity for this purpose. This presentation is designed to address the following questions: 1. Are unrecognized (and under-treated) LDL particle elevations common and significant contributors to the residual risk of many patients with “acceptable” levels of LDL-C? 2. When cholesterol (LDL-C, non HDL-C) and particle number (LDL-P) measures of LDL quantity are discordant (esp. diabetes, metabolic syndrome), which is most predictive of observed cardiovascular risk? 3. Is LDL-P a more sensitive indicator of low risk than LDL-C or non-HDL-C? 4. Should LDL-P values be used to indicate a patient has achieved adequate LDL reduction treatment goals rather than LDL-C or non HDL-C ? 5. Does LDL size (“quality”) contribute independently to risk once LDL particle number is taken into account? 6. What therapies lower LDL-P? 2

3 Previous Guidelines The first priority of treatment is to treat LDL-C to goal (unless TG is >500) Non-HDL-C should be a secondary treatment target, if LDL-C at goal but TG is ≥200 mg/dL Always screen for residual risk , Look at more than the LDL-C Summary Reducing LDL-C to goal is the first priority of treatment A small proportion of patients with mixed dyslipidemia are receiving additional therapy beyond statin therapy, as recommended by several guidelines

4 Lifestyle/statin/other
Establish Goals of Therapy based on risk factors & Lab evaluation Multivariable Risk Assessment LDL Management Lifestyle/statin/other If above goal High Risk CHD/CHD Risk Equiv. (>20% 10-year risk) Treatment Assessment & Goal LDL-C < 100 (LDL-P < 1000)* Intermediate Risk 2+ Risk Factors (10-20% 10-year risk) Treatment Assessment & Goal LDL-C < 130 (LDL-P < 1300)* Step 2 involves the establishment of treatment goals for both LDL-C and LDL-P; once these goals are identified, baseline values for these parameters are obtained (Step 3) Three risk categories correlate with ATP-III LDL-C goals. Low risk (0-1 risk factors, and <10% 10-year risk) has an LDL-C goal of less than 160 mg/dL and an LDL-P goal of <1600. Intermediate risk (2+ risk factors, and 10-20% 10-year risk) has an LDL-C goal of less than 130 mg/dL, and an LDL-P goal of <1300. High risk (CHD or CHD risk equivalents such as diabetes or chronic kidney disease, and >20% 10-year risk) has an LDL-C goal of less than 100 mg/dL, and an LDL-P goal of <1000. The intermediate and high risk groups often have discordant levels of LDL-C and LDL-P Goals for HDL-C and triglycerides are the same for all three categories (HDL-C: >40 for male, >50 for female; triglycerides <150). Low Risk 0-1 Risk Factors (0-10% 10 year risk) Treatment Assessment & Goal LDL-C < 160 (LDL-P < 1600)* *Based on population equivalent cut points 1. Contois JH et al. Clin Chem. 2009;55: 2. Cromwell WC. In: Clinical Challenges in Lipid Disorders.Toth PP, Sica DA, editors. Oxford: Clinical Publishing; 2008.p 3. Cromwell WC, Barringer TA. Curr Cardiol Reports 2009;11(6):

5 ACC/AHA Guideline on the Assessment of Cardiovascular Risk
The last NCEP-ATPIII report was delivered in 2001 with an update in There has been no concensus reached with ATP IV so the 16 member group reconvened under the auspices of the ACC/AHA and were limited to review only level one research. In response to the 2011 report of the Institute of Medicine on the development of trustworthy clinical guidelines (1), the NHLBI Advisory Council (NHLBAC) recommended that the NHLBI focus specifically on reviewing the highest quality evidence Stone NJ et al. Task Force on Practice Guidelines. Circulation or JACC: on line 2013 Thomas Dayspring MD, FACP

6 Level I Evidence [ This definition,: Evidence obtained from at least one properly designed randomized controlled trial.‎ and therefore considered ( LIKELY reliable )

7 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Disease in Adults There is no evidence to support continued use of specific LDL-C and/or non–high-density lipoprotein cholesterol (non–HDL-C) treatment targets Stone NJ et al. Task Force on Practice Guidelines. Circulation or JACC: on line 2013

8 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Disease in Adults The following are no longer considered appropriate strategies: treat to target, lower is best. The new GL recommends: treat to level of ASCVD risk, based upon estimated 10-year or lifetime risk of ASCVD. The guidelines provided no recommendations for initiating or discontinuing statins in NYHA class II-IV ischemic systolic heart failure patients or those on maintenance hemodialysis. Stone NJ et al. Task Force on Practice Guidelines. Circulation or JACC: on line 2013

9 ACC/AHA Guidelines for 4 Classes of Statin Eligible Patients
Individuals with LDL> 190 mg/dl Age with LDL mg/dl without ASCVD assess 10 year risk, treat if > 7.5% Age with Diabetes and no ASCVD with LDL-C between mg/dl Individuals with clinical ASCVD No recommendations for CHF or hemodialysis patients. Stone NJ et al. Task Force on Practice Guidelines. Circulation or JACC: on line 2013

10 Statin Eligible Estimated that 44% of men 22% of women
Under the old guidelines about 15% are eligible

11 ACC/AHA Guideline on the Assessment of Cardiovascular Risk
The contribution to risk assessment for a first ASCVD event using ApoB, CKD, albuminuria, or cardiorespiratory fitness is uncertain at present CIMT is not recommended for routine measurement in clinical practice for risk assessment for a first ASCVD event Stone NJ et al. Task Force on Practice Guidelines. Circulation or JACC: on line 2013 Thomas Dayspring MD, FACP

12 ACC/AHA Guideline on the Assessment of Cardiovascular Risk
The use of ezetimibe is no longer recommended as a valid treatment for lipid management. The use of niacin was not addressed The use of fibrates and omega 3s were not addressed The use of combination therapy was not addressed due to lack of clinical evidence. Stone NJ et al. Task Force on Practice Guidelines. Circulation or JACC: on line 2013 Thomas Dayspring MD, FACP

13 ACC/AHA Guideline on the Assessment of Cardiovascular Risk
High-intensity statin therapy is defined as a daily dose that lowers LDL-C by ≥50% and moderate-intensity by 30% to <50%. All patients with ASCVD, should receive high-intensity statin therapy; or if not a candidate for high-intensity, should receive moderate-intensity statin therapy. Stone NJ et al. Task Force on Practice Guidelines. Circulation or JACC: on line 2013 Thomas Dayspring MD, FACP

14 ACC/AHA Guideline on the Assessment of Cardiovascular Risk
LDL-C ≥190 mg/dl : Should receive high-intensity or moderate-intensity statin therapy. Statin Intolerant: Other cholesterol-lowering agents can be considered to further lower LDL-C. Diabetics with a 10-year ASCVD ≥7.5%: Should receive high-intensity statins and <7.5% moderate-intensity statin therapy. Persons years with a ≥7.5% 10-year ASCVD risk: should receive moderate- to high-intensity statin therapy. Stone NJ et al. Task Force on Practice Guidelines. Circulation or JACC: on line 2013 Thomas Dayspring MD, FACP

15 ACC/AHA Guideline on the Assessment of Cardiovascular Risk
To the patients not in the 4 statin groups Individuals whose 10-year risk is <7.5% Family history of premature ASCVD, LDL-C >160 mg/dl, HS-crp ≥2 mg/dl, Coronary calcium score ≥300 Agatston units ankle-brachial index <0.9 Elevated lifetime risk of ASCVD may be used to enhance the treatment decision making. Stone NJ et al. Task Force on Practice Guidelines. Circulation or JACC: on line 2013 Thomas Dayspring MD, FACP

16 ACC/AHA Guideline on the Assessment of Cardiovascular Risk
Lifestyle modification (i.e., adhering to a heart healthy diet, regular exercise habits, avoidance of tobacco products, and maintenance of a healthy weight) remains a critical component of health promotion and ASCVD risk reduction, both prior to and in concert with the use of cholesterol-lowering drug therapies. Stone NJ et al. Task Force on Practice Guidelines. Circulation or JACC: on line 2013 Thomas Dayspring MD, FACP

17 Basically all targets have been removed
Risk stratification remains, but is much more lenient

18 Risk stratification, Statin eligible patients
10 year risk >7.5% (was > 20%)

19 Risk Factors, optimal levels
Total Cholesterol mg/dl HDL mg/dl Systolic b/p mmhg

20 Desk-top ACC Risk Calculator
10 year risk ages yr Life-time risk ages yr Pt age 55, non-smoker, TC 213, HDL50, systolic b/p 120 ( untreated), non-diabetic White women % African American women % White man % African American Man %

21 Risk Assessment Calculator/No targets of therapy

22 46 year old white male , Family history of HD .
TC 164 LDL79 HDL41 TRI 247 FBS 75

23 His 10 year risk with the new calculator was 2%.

24 Asymptomatic, Abnormal stress referred for LHC.
90% proximal LAD Pt was on lipitor and niaspan. Abnormal phytosterol levels. Changed to crestor. LVH by echo. b/p med changed LDLp 1245 (LDLc 75)

25 Given the strong evidence that statins reduce risk across the range of LDL levels, the best preventive strategy may be to use the patient’s global cardiovascular risk to determine treatment. The absolute benefit of statins is greatest for those at higher risk—and those at highest risk would tend to benefit most from higher dose or higher potency statins. The benefit diminishes with decreasing risk. A recent analysis of statins for primary prevention showed that a strategy using statins based on patient risk rather than LDL levels can prevent more cardiovascular events while treating fewer people with high dose statins. BMJ 2010;341:

26 “Clear, compelling evidence supports near-universal empirical statin therapy in patients at high cardiovascular risk (regardless of their natural LDL cholesterol values), but current clinical evidence does not demonstrate that titrating lipid therapy to achieve proposed low LDL cholesterol levels is beneficial or safe.” Ann Intern Med. 2006;145:

27 Evidenced Based Medicine
We conclude that there is clear and compelling evidence that most patients at high risk for cardiovascular disease should be taking at least a moderate dose of a statin if tolerated, even if their natural LDL cholesterol level is low We could find no published high-quality clinical evidence supporting titration of lipid therapy based on proposed LDL cholesterol targets We strongly suggest that those with access to these data conduct further analyses to provide more valid evidence on this important clinical and scientific question Hayward RA et al. Ann Intern Med. 2006;145:

28 The trials of cholesterol lowering treatments tested the effect of fixed doses of drugs, not a strategy of progressively intensifying lipid therapy without regard to strategy to reach specific target ranges Save a ton of money – No follow up lab tests! No follow up phone calls! BMJ 2010;341:

29 The first outcome trial ever done using a statin
4444 patients with angina pectoris or previous myocardial infarction and serum cholesterol 212 – 308 mg/dL on a lipid-lowering diet were randomized to double-blind treatment with simvastatin or placebo Dosage was adjusted, if necessary, at the 12-week and 6-month visits, on the basis of serum total cholesterol at 6 and 18 weeks. The goal of treatment was to reduce serum total cholesterol to mmol/L ( mg/dL) Patients in the simvastatin group whose serum cholesterol was out of range had their dose increased to 40 mg daily, as two 20 mg tablets, or reduced to one 10 mg tablet Pedersen TR. Lancet 1994;344:

30 The Politics of Evidence-Based Medicine
Evidence-based medicine has enabled payers, purchasers, and governmental authorities to use their financial clout to alter the practice of medicine. Traditionally doctors defined the standard of care. Now, armed with more and better information about medical practices, payers and purchasers can deny payment for medical services that they deem medically unnecessary or ineffective. In so doing, they redefine standards for appropriate medical practice. By Marc A. Rodwin, Indiana University Journal of Health Politics, Policy and Law, Vol. 26, No. 2, April 2001

31 Unmet Need: Persistent Incidence of CHD
Framingham Heart Study 26 year f/u, Indicates that Measuring Cholesterol Does Not Tell Us Enough 80% of subjects with cardiac events had lipid levels similar to subjects that were event free 35% of CHD occurs in people with TC<200 The problem with just measuring the cholesterol within particle subclasses is that cholesterol is not a great predictor of risk for an individual patient. If it were, heart attack deaths would be decreasing. This data from the Framingham Heart Study, 26 year follow-up data reveals that cholesterol levels were the same in 80 percent of patients who experienced a MI versus those who did not experience an event. In fact, 50% of people who had an MI in this study had normal cholesterol. Clearly we need a better tool to identify and manage patients with documented cardiovascular disease risk. Chol on the X axis 20/100 40/100 90/100

32 Should we consider a failure in detection of risk by “standard methods” an appropriate reason to increase the number of statin eligible patients and forfeit our present guidelines?

33 New ACC/AHA Guidelines
Lipids, there is no longer any support for treating to specific targets Obesity, There is no ideal diet for weight loss Risk Assessment, New calculator for 10 year risk assessment ages Ages life-time calculator. (my.americanheart.org/cvriskcalculator) Lifestyle, restriction of fat and sodium

34 Lifestyle/statin/other
Steps 2 & 3: Establish Goals of Therapy & Lab evaluation Multivariable Risk Assessment LDL Management Lifestyle/statin/other If above goal High Risk CHD/CHD Risk Equiv. (>20% 10-year risk) Treatment Assessment & Goal LDL-C < 100 (LDL-P < 1000)* Intermediate Risk 2+ Risk Factors (10-20% 10-year risk) Treatment Assessment & Goal LDL-C < 130 (LDL-P < 1300)* Step 2 involves the establishment of treatment goals for both LDL-C and LDL-P; once these goals are identified, baseline values for these parameters are obtained (Step 3) Three risk categories correlate with ATP-III LDL-C goals. Low risk (0-1 risk factors, and <10% 10-year risk) has an LDL-C goal of less than 160 mg/dL and an LDL-P goal of <1600. Intermediate risk (2+ risk factors, and 10-20% 10-year risk) has an LDL-C goal of less than 130 mg/dL, and an LDL-P goal of <1300. High risk (CHD or CHD risk equivalents such as diabetes or chronic kidney disease, and >20% 10-year risk) has an LDL-C goal of less than 100 mg/dL, and an LDL-P goal of <1000. The intermediate and high risk groups often have discordant levels of LDL-C and LDL-P Goals for HDL-C and triglycerides are the same for all three categories (HDL-C: >40 for male, >50 for female; triglycerides <150). Low Risk 0-1 Risk Factors (0-10% 10 year risk) Treatment Assessment & Goal LDL-C < 160 (LDL-P < 1600)* *Based on population equivalent cut points 1. Contois JH et al. Clin Chem. 2009;55: 2. Cromwell WC. In: Clinical Challenges in Lipid Disorders.Toth PP, Sica DA, editors. Oxford: Clinical Publishing; 2008.p 3. Cromwell WC, Barringer TA. Curr Cardiol Reports 2009;11(6):

35 Potential problems NO TARGETS OF THERAPY difficult for patient motivation , promotes apathy on the part of the provider NO ROUTINE LABS difficult for motivation, risk HIGH DOSE STATIN side effects HIGH RISK POPULATIONS ischemic CHF, CKD COMBINATION TX excluded WIDE SPREAD USE OF STATINS increased costs ETHNIC SPECIFIC ALGORITHMS not addressed INCREASED PAYOR DENIALS considered guidelines for us (not mandates) but do we really have a choice when payors deny

36 Ezetimibe (Zetia) Bowel absorption inhibitor
Works at the brush border of the small intestine.

37 X Cholesterol torsHo Liver Jejunum Ileum Colon Ezetimibe Duodenum
LDL apoB100 Liver Duodenum VLDL apoB100 Ezetimibe X Jejunum Ezetimibe reduces cholesterol absorption. This decreases the content of cholesterol in chylomicrons. In the circulation, chylomicrons deliver triglycerides to muscle and fat tissue, but return to the liver with a full complement of cholesterol that was absorbed by the intestine. Therefore, ezetimibe reduces the flux of cholesterol from the intestine to the liver. Because this cholesterol is packaged and resecreted by the liver into the blood as VLDL particles, containing apo B-100, and because VLDL particles are the precursor particles of LDL in plasma, reduced flux of cholesterol to VLDL particles will lower LDL cholesterol. This mechanism is distinct from that of statins, which promote the clearance of LDL principally in the liver. Evidence that ezetimibe reduces LDL production may be inferred from a study in which patients with homozygous familial hypercholesterolemia were treated with ezetimibe plus statin therapy. The efficacy of statins is reduced in these individuals, in whom the LDL receptor is functionally absent. However, the efficacy of ezetimibe is largely unaffected. It is important to consider that ezetimibe therapy may lead to increased LDL receptor expression in individuals with functional LDL receptors, and that this may comprise a component of the mechanism by which ezetimibe lowers plasma LDL cholesterol and triglyceride concentrations. Reference: Gagne C, Gaudet D, Bruckert E, for the Ezetimibe Study Group. Efficacy and safety of ezetimibe coadministered with atorvastatin or simvastatin in patients with homozygous familial hypercholesterolemia. Circulation 2002;105: Ileum CM Remnant apoB48 CM apoB48 Colon

38 Niacin effectiveness in reducing events.
Fats trial ( Familial hypercholesterolemia ) % Hats trial (HDL atherosclerosis tx ) % AFREGS (airforce regression) % Aim High ( no residual risk) Not rec due to no level one evidence (Placebo blind controlled , randomized studies ). These studyies were not powered for outcomes. But the Risk Event Reduction is impressive with studies involving niacin in patients with residual risk. Average LDL at entry was 71 and tri 161 with non hdl of 106

39 RESIDUAL RISK IS NOT ADDRESSED

40 Evidence of Residual CVD Risk
136,905 hospitalizations for (non-CHF) CAD and lipids w/in 24 hrs of admit (at 541 hospitals) Over 50% of patients with LDL-C <100 mg/dL and 17.6% with LDL-C <70 mg/dL For patients without h/o CAD, 72.1% with LDL-C <130 mg/dL and 41.5% with LDL-C <100 mg/dL The evidence for residual cardiovascular risk has been well documented. Sachdeva et al published a landmark analysis from AHA’s Get with The Guidelines CAD Program and database that documented that over 50% of CAD patients hospitalized for acute coronary events had LDL-C < 100 mg/dL, and close to 20% had LDL-C < 70 mg/dL. For patients without a history of heart disease, 72.1% had LDL-C < 130 mg/dL and over 40% had LDL-C < 100 mg/dL. This adds further support to the concept that there is an opportunity to better manage these “at-risk” patients Sachdeva A, et al. Am Heart J 2009; 157:111-7.e2. From AHA’s Get with The Guidelines (GWTG) CAD Program and database;

41 Residual Cardiovascular Risk in Major Statin Trials
ACCESS Medical Group Residual Cardiovascular Risk in Major Statin Trials Major Coronary Events, % Patients Experiencing Residual Cardiovascular Risk in Major Statin Trials. In all of these major statin trials, significant residual cardiovascular risk remains even after reducing LDL-C. According to Libby, in the best of circumstances, the decrease in cardiovascular events due to statin treatment still allows two-thirds of cardiovascular events to occur. Libby concludes, “To address the majority of cardiovascular events that still occur despite our most powerful existing therapies, we must combine lifestyle change and evaluate new pharmacological strategies that will move us toward the goal of eradicating cardiovascular disease in the future.”1 4 s simvastatin, LIPID, pravastatin. CARE pravastatin, HPS simvastatin, WOS pravastatin, AFCAPS/TEXCAPS lovastatin Reference 1. Libby PJ, et al. J Am Coll Cardiol, 2005:46: N 4444 9014 4159 20 536 6595 6605 LDL -35% -25% -28% -29% -26% -25% Secondary High Risk Primary Adapted from Libby PJ, et al. J Am Coll Cardiol, 2005:46:

42 Should we consider a failure in detection of risk by “standard methods” an appropriate reason to increase the number of statin eligible patients and forfeit our present guidelines?

43 NO!

44 Groups that have come out with position statements in support of lipoprotein testing
American Diabetes Association / American College of Cardiology Foundation Consensus Statement [3] American Association for Clinical Chemistry Lipoproteins & Vascular Diseases Working Group Recommendations [1] American Association of Clinical Endocrinologists Guidelines for Management of Dyslipidemia [4] National Lipid Association Expert Recommendations [5] Canadian Cardiovascular Society Guidelines [6] ESC/EAS Guidelines for the Management of Dyslipidemia [7] 1] Contois JH Clin Chem 2009;55: ] Otvos et al. J Clin Lipidol 2011;5: ] Brunzell JD et al. j Am Coll Cardiol 2008;51: ] Jellinger PS et al. Endocr Pract 2012;18(suppl 1), European Society of Cardiology and European Athrosclerosis society

45 What’s the difference between Lipoproteins and Cholesterol ?

46 = Lipoprotein = Cholesterol

47 Question #1: What causes traffic jams to occur on a highway ?
Number of cars not the number of passengers =

48 “LDL” should not imply LDL-Cholesterol
The LDL Particle NONPOLAR LIPID CORE Cholesterol Ester Triglyceride POLAR SURFACE COAT Phospholipid Free cholesterol Apo B LDL-Cholesterol = the weight of the constituent cholesterol within the particle LDL does not always imply LDL-cholesterol. There are 3 measures related to LDL: LDL-C, ApoB, and LDL-P. A lipoprotein particle has two main components - a nonpolar lipid core that contains some amount of cholesterol ester and triglyceride; and a polar surface coat made up of phospholipids and a small amount of free cholesterol. All particles (LDL, HDL, or VLDL) share this structure. There is one molecule of ApoB on each LDL, VLDL and IDL particle. ApoB can provide an estimation of LDL, but is not specific for LDL. LDL particles are the most atherogenic. LDL is a particle that carries varying amounts of cholesterol. Because LDL particles vary in composition, or how much cholesterol they carry, LDL cholesterol is not a reliable indicator of atherogenic LDL particle concentrations, although LDL cholesterol has been used as a surrogate measure of LDL particles since 1972

49 Cholesterol Molecules Apoprotein B-100
Triglyceride Molecules Cholesterol Molecules Triglyceride Molecules This is an actual lipoprotien molicule as seen by an electron microscope LDL A Particle LDL B Particle

50 LDL-C can vary with particle size
At the same LDL cholesterol, more small LDL vs. large LDL particles present Up to 70% More Particles Cholesterol Balance 100 mg/dL 100 mg/dL Large LDL Small LDL Because of variability in the amount of cholesterol carried inside LDL particles, LDL-C often does not reflect accurately LDL-P. Two processes are primarily responsible for this phenomenon. First, small sized LDL particles carry less cholesterol per particle than large sized particles. For LDL particles differing by 3 nm in diameter, there is approximately 40% less core cholesterol in the smaller versus larger particle. Thus, the person with the smaller LDL particles will require almost 70% more particles to carry the same amount of LDL-C than the person with the larger particles. Otvos JD et al. Am J Cardiol 2002;90(suppl):22i-29i Cromwell WC et al. J Clin Lipidology. 2007;1(6): Otvos JD et al. Am J Cardiol 2002;90(suppl):22i-29i Cromwell WC et al. J Clin Lipidology. 2007;1(6):

51 LDL particle number (LDL-P), as opposed to size, is a key driver of atherogenic plaque formation
Endothelial Cell Arterial Wall A gradient driven process, LDL particles invade the arterial wall and set in motion the cascade of events that leads to atherosclerosis1,2 After adjustment for LDL-P concentration, particle subclass and size do not impact outcomes 3 LDL Particle Endothelial Gap Lipoprotein movement is a gradient driven process and an excessive number of LDL particles sets the stage for large amounts of cholesterol to enter the sub-endothelial space. The higher the number of lipoprotein particles (LDL-P), the greater the risk for atherosclerosis / CHD. The number of particles is more important in driving the atherogenic process than the size of the particle. In a systematic literature review by Ip et al (Ann Intern Med. 2009;150: ), the authors concluded that higher LDL particle number has been shown to be associated with cardiovascular disease incidence, but studies have not determined whether any measures of LDL subfractions add incremental benefit to traditional risk factor assessment. The authors go to state that the routine use of clinically available LDL subfraction tests to estimate cardiovascular disease risk is premature. 1. Fredrickson et al. NEJM 1967; 276: 148 2. Brunzell, et al. Diabetes Care. 2008;4: 3. Ip et al . Ann Intern Med. 2009;150:

52 Lipoprotein Particles
ACCESS Medical Group Lipoprotein Particles Chylo- microns 0.95 VLDL Chylomicron Remnants 1.006 LDL IDL Density (g/ml) 1.02 LDL Cholesterol Triglycerides (mainly) 1.06 A VLDL rmnant or IDL is catabolized by hepatic lipases to produce a triglyceride depleted lipoprotein called LDL. If triglycerides are high the LDL particle may receive tri form other lipoproteins via CETP. And the tri enriched LDL is further degraded to a small dense LDL particle which has 3 potential fates. It can return to the liver via LDL receptors or it can move to other cells for hormone production or it may infiltrate an impaired endothelium and become oxidized stimulating the production of foam cells. Your non-HDL cholesterol includes all these lipoprotiens minus the HDL. HDL 1.10 HDL Cholesterol 1.20 5 10 20 40 60 80 1000 Diameter (nm)

53 Why Alternate Measures of LDL Quantity are Not Equivalent
Concordance: LDL-C and LDL-P “agree” (i.e., are equally high or low) Either LDL measure is an equally good guide to LDL treatment decision-making. Discordance: LDL-C and LDL-P “disagree” (i.e., the values differ, either in their relationship to the normal range or to each other) Which LDL measure should guide clinical decision-making? Managing low-density lipoprotein (LDL) is an integral part of clinical practice. But is the best measure of LDL being used to guide our clinical decision-making? Historically, the cholesterol content of LDL particles (LDL-C) has been used to assess patient LDL levels. LDL can now be quantified differently by measuring the number of LDL particles (LDL-P). LDL-C and LDL-P levels in most patients are concordant (ie, in good agreement: comparably high, intermediate, or low). In such cases, either of the 2 measures of LDL quantity is an equally good guide to LDL treatment decision-making. Importantly, the cholesterol content of LDL particles is not fixed, but varies considerably from person to person. Multiple studies show the cholesterol contained in LDL particles differs >2-fold between patients, as well as varying in the same patient over time in response to drug treatment or lifestyle change. Because of this variability in the cholesterol content of LDL particles, there is frequent disagreement, or discordance, between LDL cholesterol (LDL-C) and LDL particle number (LDL-P). In some patients, LDL-C is low while LDL-P is much higher. In others, LDL-P may be low despite LDL-C not being low. The key question is - should clinical decision-making be guided by LDL-C or LDL-P when these 2 measures of LDL quantity disagree? Recent data from Framingham and MESA address this question. As a result, one measure (LDL-C versus LDL-P) may not simply substitute for the other.

54 CHD Event Associations of LDL-P versus LDL-C
Framingham Offspring Study This figure shows 15 year event-free survival among Framingham Offspring participants as a function of concordant or discordant LDL-C and LDL-P values above or below the median. Median values were 131 mg/dL for LDL-C and 1414 nmol/L for LDL-P. x axis –years of f/u Y axis is event free survival In the setting of high LDL-P, similar CHD event rates are present regardless of high or low LDL-C. Conversely, low CHD events are present in the setting low LDL-P CHD regardless of high or low LDL-C levels. These data demonstrate that both LDL-P and LDL-C are similarly associated with CHD events when these measures are concordant. However, when LDL-P and LDL-C are discordant, only LDL-P is predictive of CHD events. Cromwell WC et al. J Clin Lipidology 2007;1(6):

55 Friedwald Equation (is used to calculate the bad cholesterol, LDL)
ACCESS Medical Group Friedwald Equation (is used to calculate the bad cholesterol, LDL) LDL Cholesterol=Total chol-(HDL)-(TG/5) It assumes all the TG is carried on VLDL And the TG/CHOL ratio of VLDL is constant at 5:1 NOT TRUE when TG>200, DM or metabolic syndrome exist with ^ Chilomycrons, get falsely low HDL and LDL. When the LDL- lipoprotein is more triglyceride rich

56 Triglycerides > 150mg/dl FBG > 100 ( or DM)
Metabolic Syndrome Triglycerides > 150mg/dl FBG > 100 ( or DM) Waist circumference > 35 inches in a women or 40 inches in a man HTN (>130/85 mmHg) or taking B/p medication HDL-C <40mg/dl males or <50mg/dl females NCEP Definition of Metabolic Syndrome 2001 Guidelines

57 How NMR Lipoprotein Analysis works

58 NMR Lipoprotein Analysis
Lipoprotein subclasses of different size broadcast lipid NMR signals that are naturally distinguishable. The measured amplitudes of these signals provide subclass quantification. NMR spectroscopy provides the capability to directly quantify the various lipoproteins in plasma in a rapid, automated manner by taking advantage of the slightly different (but very reproducible) frequencies and shapes of the NMR signals emitted by the lipoproteins of the different-size VLDL, LDL, and HDL subclasses. A rapid (<1 sec) spectral deconvolution process is used to derive the amplitudes of each of the subclass signals. These amplitudes are directly proportional to the number of subclass particles emitting the signal, irrespective of differences in the cholesterol content of the particles. In this way, NMR is able to quantify the particle concentrations of the various lipoprotein subclasses, as well as total VLDL, LDL, and HDL particle concentrations (VLDL-P, LDL-P, HDL-P). Jeyarajah EJ et al. Clin Lab Med 2006;26:47-70

59 NMR Measures LDL Particle Number, Not LDL Cholesterol
Measured LDL-C 90 mg/dL Measured LDL-C 90 mg/dL Importantly, changes in the core cholesterol and triglyceride content do not impact the signals from the individual lipoprotein subclasses. As a result, NMR is able to provide accurate measures of lipoprotein particle number irrespective of whether these particles contain normal or decreased amounts of core cholesterol. LDL NMR Signals LDL particles 900 nmol/L LDL particles 1600 nmol/L

60 Principles for determining appropriate LDL testing guided by landmark publication
Value of the new reference test is best examined in cases of disagreement (discordance) between the new and standard tests. Clinical consequences of disagreements between new and standard test requires a fair “umpire” test. Fair umpire tests include clinical events or disease progression. LDL-C has been used for nearly 50 years to assess and manage cardiovascular risk. LDL particle number as a measure of LDL in patients with established risk has been available for over 10 years, and has warranted comparison to LDL-C. To determine the clinical value of a new versus “standard” test, a “fair umpire” is needed to determine which of the two test results is more clinically informative when they disagree (are discordant). Since there is no “gold standard” LDL test available for analytic comparison, fair umpire tests for evaluating LDL-C and LDL-P discordance must be clinical outcomes studies examining associations with atherosclerotic endpoints. Glasziou P et al. Ann Intern Med 2008;149:

61 Multiple Outcome Studies Demonstrate Difference Between LDL-P and LDL-C
This slide summarizes the results of the 10 published studies that have compared LDL-P and LDL-C in terms of their associations with both subclinical and clinical CVD outcomes. We will share the key findings from two of these studies, the Framingham Offspring Study and MESA, as they were large studies that included the analysis of the associations of both concordant and discordant subsets of the total study population with clinical outcomes (per the bullets under the Annals of Internal Medicine article featured on the previous slide) 61

62 Relationship of LDL Particle Number with CHD Outcomes

63 Framingham Offspring Study
Long-running NIH/NHLBI observational study of residents of Framingham, MA to determine risk factors for future cardiovascular disease (CVD) Blood samples obtained in (exam 4) Lipids measured by traditional chemical methods Lipoprotein particles measured by NMR spectroscopy Correlated with CVD occurrence during a 15-year follow up 3,066 subjects 431 CVD events (MI, stroke, CHD death, angina, congestive heart failure) Discordance defined as either above or below the median for LDL-C and LDL-P The Framingham study is a long-running NIH/NHLBI observational study of the residents of Framingham Massachusetts that has been following cardiovascular disease longitudinally. A study by Cromwell et al, published in the Journal of Clinical Lipidology in 2007, focused on lipid and lipoprotein analyses, obtained from blood samples from 3,066 patients obtained between , and then performed correlation analyses with CVD events over a 15 year follow-up period. There were 431 documented CVD events which included MI, stroke, CHD death, angina, and congestive heart failure. Discordance was defined as either being above or below the median percentile for LDL-C and LDL-P measures. Cromwell WC et al. J Clin Lipidology 2007;1(6):

64 CHD Event Associations of LDL-P versus LDL-C
Framingham Offspring Study This figure shows 15 year event-free survival among Framingham Offspring participants as a function of concordant or discordant LDL-C and LDL-P values above or below the median. Median values were 131 mg/dL for LDL-C and 1414 nmol/L for LDL-P x axis –years of f/u In the setting of high LDL-P, similar CHD event rates are present regardless of high or low LDL-C. Conversely, low CHD events are present in the setting low LDL-P CHD regardless of high or low LDL-C levels. These data demonstrate that both LDL-P and LDL-C are similarly associated with CHD events when these measures are concordant. However, when LDL-P and LDL-C are discordant, only LDL-P is predictive of CHD events. Cromwell WC et al. J Clin Lipidology 2007;1(6):

65 Multi-Ethnic Study of Atherosclerosis (MESA)
Large NHLBI observational study of the pathogenesis and progression of subclinical atherosclerosis. N= 6,814 asymptomatic men and women free of cardiovascular disease at entry 38% White 28% African-American 22% Hispanic 12% Asian 319 CVD events (MI, CHD death, angina, stroke, stroke death, or other atherosclerotic or CVD death) occurred during 5.5-yr follow-up (n=5598). The Multi-Ethnic Study of Atherosclerosis (MESA) is an ongoing NHLBI study of the characteristics of subclinical cardiovascular disease (disease detected non-invasively before it has produced clinical signs and symptoms) and the risk factors that predict progression to clinically overt cardiovascular disease or progression of the subclinical disease. It is considered by many to be the “contemporary” version of Framingham with a more diverse patient population. Study participants include a diverse, population-based sample of 6,814 asymptomatic men and women aged Approximately 38 percent of the recruited participants are white, 28 percent African-American, 22 percent Hispanic, and 12 percent Asian, predominantly of Chinese descent. The current study focuses on the relationship of alternate LDL measures (LDL-C and LDL-P) with baseline carotid intima-media thickness (cIMT) and incident cardiovascular events (MI, CHD death, angina, stroke, stroke death, or other atherosclerotic or CVD death) during a 5.5 year follow-up period. Otvos et al. J Clin Lipidol 2011;5:105-13

66 MESA: Study Design Baseline assessments:
LDL particle number (LDL-P) measured by NMR spectroscopy Calculated LDL cholesterol (LDL-C) Carotid intima-media thickness (IMT) Associations of LDL-C and LDL-P with CVD events (prospective) and carotid IMT (cross-sectional) were determined Overall population Concordant subgroup Discordant subgroup Discordance defined as LDL-C and LDL-P levels differing by 12 percentile units, to give equal-sized concordant and discordant subgroups. Data from MESA was used to examine differences in disease associations between LDL-C and LDL-P as they relate prospectively to incident CVD events among individuals with concordant or discordant levels of these 2 LDL measures. The findings were supplemented by cross-sectional associations of LDL-C and LDL-P in the same population with carotid intima-media thickness (IMT), an indicator of subclinical atherosclerosis. Since “discordance” is a subjective term with no absolute definition, the magnitude of disagreement between LDL-C and LDL-P defined as “discordant” in this study was 12 percentile units, so as to make half the population concordant and half discordant. Otvos et al. J Clin Lipidol 2011;5:105-13

67 MESA: Conclusions The cholesterol content of LDL particles varies greatly, causing LDL-C in many individuals to over-represent or under-represent LDL particle concentrations. LDL-C and LDL-P were both significantly associated with incident CVD overall. For individuals with concordant levels of LDL-C and LDL-P, both measures of LDL quantity were (as expected) equally predictive of risk. For individuals with discordant levels, only LDL-P was significantly associated with incident CVD. Carotid IMT also tracked with LDL-P rather than LDL-C when these measures were discordant. CONCLUSIONS: The cholesterol content of LDL particles varies greatly, causing LDL-C in many individuals to over-represent or under-represent LDL particle concentrations. LDL-C and LDL-P were both significantly associated with incident CVD overall. For individuals with concordant levels of LDL-C and LDL-P, both measures of LDL quantity were (as expected) equally predictive of risk. For individuals with discordant levels, only LDL-P was significantly associated with incident CVD. Carotid IMT also tracked with LDL-P rather than when these measures were discordant. Otvos et al. J Clin Lipidol 2011;5:105-13

68 VA-HIT Background Purpose: Randomized, double-blind trial to determine if increasing low HDL-C will decrease CHD events Subjects: 2531 men with CHD, low HDL-C (31.5 mg/dL), and low LDL-C (111 mg/dL) Therapy: Gemfibrozil (1.2 g/d) vs. placebo The purpose of the VA-HIT was a randomized, double-blind trial to determine if increasing low HDL-C will decrease CHD events Subjects were 2531 men with CHD, low HDL-C (31.5 mg/dL), and low LDL-C (111 mg/dL) Therapy in the trial was fibric acid, gemfibrozil (1.2 g/d) vs. placebo Otvos, et al. Circulation 2006;113:

69 VA-HIT: Principal Results
Gemfibrozil treatment resulted in a 22% decrease in nonfatal MI + CHD death 31% decrease in stroke No increase in adverse events The principal results were the following: Gemfibrozil treatment resulted in a 22% decrease in nonfatal MI + CHD death and 31% decrease in stroke. No increase in adverse events Otvos, et al. Circulation 2006;113:

70 VA Hit Trial Demonstrated that gemfibrozil reduced 5-yr rate of new CHD events. No effect on LDL-C, HDL-C only raised 6%, tri lowered 31% Increased LDL size and decreased LDL particles number (LDL-P) The decrease in particle number was predictive for CHD future events. There was a case control substudy of the VA-Hit trial presented at the American Heart Association that used NMR spectroscopy to help identify why the men that were treated with Gemfibrozil had a decrease in Coronary events even though there was not a significant change in the LDL-c. What they found in this nested case control substudy of VA-HIT was that the gemfirozil effected the LDL and HDL subclass particles as measured by the NMR spectroscopy. The lipoprotein changes may help to explain the reduction in major CHD events and death. Low Density Lipoprotien and high density lipoprotein particle subclasses predict coronary events and are favorable changed by gemfibrozil therapy in the veterans affairs high density lipoprotein intervention trial.

71 VA-HIT: Alternative Measures of LDL and HDL As Predictors of CHD Events
Odds Ratio per 1-SD Increment Odds Ratio per 1-SD Decrement The following results, clearly demonstrated that it was LDL-P and HDL-P that showed higher association versus LDL-C, apo B, non-HDL-C, and ApoA-1. LDL-C Non-HDL-C ApoB LDL-P* HDL-C ApoA-1 HDL-P* Adjusted for treatment, age, hypertension, smoking, BMI, and diabetes *p<0.001 Otvos, et al. Circulation 2006;113:

72 Consensus and Recommendations

73 2008 ADA/ACC Consensus Statement on Lipoprotein Management in Patients with Cardiometabolic Risk
“… the cholesterol content of LDL particles varies from person to person and is influenced by metabolic abnormalities such as insulin resistance and hyperglycemia.” “Hence, measurement of LDL cholesterol may not accurately reflect the true burden of atherogenic LDL particles, especially in those with the typical lipoprotein abnormalities of cardio-metabolic risk.” “Measurements of apoB or LDL particle number by NMR may more closely quantitative the atherogenic lipoprotein load. Some studies suggest that both are better indices of CVD risk than LDL cholesterol or non-HDL cholesterol …” Selected statements from the Consensus Statement on Lipoprotein Management in Patients with Cardiometabolic Risk Report from the American Diabetes Association and the American College of Cardiology include the following: “Measurement of LDL cholesterol (the cholesterol within LDL particles) has been the standard approach to approximate LDL levels.” “However, the cholesterol content of LDL particles varies from person to person and is influenced by metabolic abnormalities such as insulin resistance and hyperglycemia.” Hence, “measurement of LDL cholesterol may not accurately reflect the true burden of atherogenic LDL particles, especially in those with the typical lipoprotein abnormalities of cardio-metabolic risk.” Brunzell et al. Diabetes Care (4):

74 New Guidelines for Lipid Targets in patients with type II Diabetes
ApoB <80mg/dl LDL-p <1000nm/l American Association of clinical endocrinology comprehensive diabetes management 2013 consensus statement

75 Recommendations for Using LDL Particle Number Measures as Targets of Therapy
American assoication of clinical endocrinology Garber AJ, et al. Endocr Pract 2013;19(Suppl 2):1-48.

76 Groups that have come out with position statements in support of lipoprotein testing
American Diabetes Association / American College of Cardiology Foundation Consensus Statement [3] American Association for Clinical Chemistry Lipoproteins & Vascular Diseases Working Group Recommendations [1] American Association of Clinical Endocrinologists Guidelines for Management of Dyslipidemia [4] National Lipid Association Expert Recommendations [5] Canadian Cardiovascular Society Guidelines [6] ESC/EAS Guidelines for the Management of Dyslipidemia [7] 1] Contois JH Clin Chem 2009;55: ] Otvos et al. J Clin Lipidol 2011;5: ] Brunzell JD et al. j Am Coll Cardiol 2008;51: ] Jellinger PS et al. Endocr Pract 2012;18(suppl 1), European Society of Cardiology and European Athrosclerosis society

77 NLA Expert Panel Recommendations

78 Recommendations from the NLA Expert Panel on Clinical Utility of Inflammatory Markers and Advanced Lipoprotein Testing Measurement for On-Treatment Management Decisions The National Lipid Association convened a panel of clinical experts in 2011 to evaluate the use of selected biomarkers in clinical practice as either tools to improve risk assessment or as markers to adjust therapy once a decision to treat had been made. These panel recommendations are intended to provide practical advice to clinicians who wrestle with the challenges of identifying the patients who are most likely to benefit from therapy, or intensification of therapy, to provide the optimum protection from CV risk. This slide summarizes the panel’s recommendations for patients currently receiving treatment for lipid management Describe the 5 categories in Gray in the first column: Low risk (patients with 0-1 risk factors and < 5% 10-year CHD event risk on the basis of NCEPATP III Framingham risk scoring) Intermediate risk (patients with 2 or more risk factors or 5%-20% 10-year CHD event risk on the basis of NCEPATP III Framingham risk scoring) CHD or CHD equivalent (i.e., diabetes, atherosclerotic CV disease [CVD], or more than 20% 10-year CHD event risk by ATP III Framingham risk scoring) Patients with a family history of premature CHD Patients with CVD and recurrent events despite apparently ‘‘optimal’’ medical therapy. The color codes refer to the corresponding recommendations: Red = Not Recommended Blue = Reasonable for Many Patients Yellow = Consider for Selected Patients Green = Recommended for Routine Measurement Davidson, et al. J Clin Lipidol 2011;5:

79 Recommendations from the NLA Expert Panel
Unrecognized (and under-treated) LDL particle elevations are common and a significant contributor to the residual risk of many patients with “acceptable” levels of LDL-C. When LDL-C and LDL-P levels are discordant (esp. diabetes, metabolic syndrome), risk tracks with LDL-P, not LDL-C. LDL-P values should be used to indicate a patient has achieved adequate LDL reduction, because LDL-P is a significant independent predictor of CHD end points. In conclusion: Unrecognized (and under-treated) LDL particle elevations are common and a significant contributor to the residual risk of many patients with “acceptable” levels of LDL-C. When LDL-C and LDL-P levels are discordant (esp. diabetes, metabolic syndrome), risk tracks with LDL-P, not LDL-C. LDL-P values should be used to indicate a patient has achieved adequate LDL reduction, because LDL-P is a significant independent predictor of CHD end points. LDL size (“quality”) does not contribute independently to risk once LDL particle number is taken into account. LDL-P is a more sensitive indicator of low risk than LDL-C or non-HDL-C, and therefore a more discriminating LDL treatment target. LDL-P may be lowered not only by statins, but by lifestyle change and combination drug therapy. Davidson, et al. J Clin Lipidol 2011;5: 79 79

80 Approach to Utilization of Lipids and LDL Particle Number in Clinical Practice

81 Clinical Cut-points for LDL
Percentile: th 50th 80th Optimal High LDL Cholesterol Percent of Subjects Framingham Offspring 1 mg/dL LDL Particle Number Population data are used to compare the relationships between different levels of LDL-C and LDL-P. The clinical cut-points for LDL-C, which are the 20th , 50th, and 80th percentile values in the Framingham Offspring Study, are compared here to the corresponding LDL-P cut-points as provided by population data from the Multi-Ethnic Study of Atherosclerosis (MESA). The green bars represent optimal levels (0-20th percentile) of LDL cholesterol (Framingham) and LDL Particle Number (MESA), the yellow bars represent numbers moderately elevated levels (20th to 80th percentiles), and the red bars represent high levels (>80th percentile). Percent of Subjects MESA 2 nmol/L 1 Otvos JD, Jayarajah E, Cromwell, WC. Amer J Cardiol 2002;90(8A):22i-29i. 2 Otvos JD et al. J Clin Lipidol 2011;5: 81

82 Approach to Utilization of Lipids and LDL Particle Number in Clinical Practice
Step 1: Assess clinical CHD risk Step 2: Establish goals of therapy appropriate for degree of clinical risk present (Lipids and LDL Particle Number) Step 3: Laboratory evaluation Step 4: Consider therapeutic lifestyle changes and medications as indicated to achieve targets: Primary target: LDL Secondary targets: non-HDL and TG Step 5: Assess response to therapy and modify intervention as indicated to achieve LDL-P target From a clinical perspective, lipids and LDL particle number can be incorporated into medical decision making by following the following step-wise process: Step 1: Assess clinical CHD risk (High, Moderate, Low) Step 2: Establish goals of therapy appropriate for degree of clinical risk present Step 3: Laboratory evaluation Step 4: Consider therapeutic lifestyle changes and medications as indicated to achieve targets: Primary target: LDL Secondary targets: HDL and TG Step 5: Assess response to therapy and modify intervention as indicated to achieve LDL-P target Cromwell WC et al. Lipid and Lipoprotein Disorders: Current Clinical Solutions Baltimore: International Guidelines Center; 2009.

83 Risk Factors : CV disease
Smoking Obesity Sedentary lifestyle HTN Hyperlipidemia Family History of premature heart disease Age , men > 45yrs or women > 55yrs

84 Step 1: Assess Clinical Risk (using NCEP ATP-III Guidelines)
Multivariable Risk Assessment High Risk CHD/CHD Risk Equiv. (>20% 10-year risk)** Intermediate Risk 2+ Risk Factors* (10-20% 10-year risk)** Low Risk 0-1 Risk Factor* (0-10% 10 year risk)** Step 1 involves the classification of cardiovascular risk. Framingham (and ATP III) assessment allows for classification related to the number of risk factors and the 10-year risk. Traditional risk factors include age, gender, smoking, hypertension, low HDL-C and family history. Three risk categories correlate with ATP-III LDL-C goals. Low risk (0-1 risk factors, and <10% 10-year risk) has an LDL-C goal of less than 160 mg/dL. Intermediate risk (2+ risk factors, and 10-20% 10-year risk) has an LDL-C goal of less than 130 mg/dL. High risk (CHD or CHD risk equivalents such as diabetes or chronic kidney disease, and >20% 10-year risk) has an LDL-C goal of less than 100 mg/dL. *Risk factors are age (>45M;>55W), smoking, hypertension, low HDL-C, family history **10-year risk given by age, gender, TC, HDL-C, SBP/hypertension, and smoking Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:

85 Lifestyle/statin/other
Steps 2 & 3: Establish Goals of Therapy & Lab evaluation Multivariable Risk Assessment LDL Management Lifestyle/statin/other If above goal High Risk CHD/CHD Risk Equiv. (>20% 10-year risk) Treatment Assessment & Goal LDL-C < 100 (LDL-P < 1000)* Intermediate Risk 2+ Risk Factors (10-20% 10-year risk) Treatment Assessment & Goal LDL-C < 130 (LDL-P < 1300)* Step 2 involves the establishment of treatment goals for both LDL-C and LDL-P; once these goals are identified, baseline values for these parameters are obtained (Step 3) Three risk categories correlate with ATP-III LDL-C goals. Low risk (0-1 risk factors, and <10% 10-year risk) has an LDL-C goal of less than 160 mg/dL and an LDL-P goal of <1600. Intermediate risk (2+ risk factors, and 10-20% 10-year risk) has an LDL-C goal of less than 130 mg/dL, and an LDL-P goal of <1300. High risk (CHD or CHD risk equivalents such as diabetes or chronic kidney disease, and >20% 10-year risk) has an LDL-C goal of less than 100 mg/dL, and an LDL-P goal of <1000. The intermediate and high risk groups often have discordant levels of LDL-C and LDL-P Goals for HDL-C and triglycerides are the same for all three categories (HDL-C: >40 for male, >50 for female; triglycerides <150). Low Risk 0-1 Risk Factors (0-10% 10 year risk) Treatment Assessment & Goal LDL-C < 160 (LDL-P < 1600)* *Based on population equivalent cut points 1. Contois JH et al. Clin Chem. 2009;55: 2. Cromwell WC. In: Clinical Challenges in Lipid Disorders.Toth PP, Sica DA, editors. Oxford: Clinical Publishing; 2008.p 3. Cromwell WC, Barringer TA. Curr Cardiol Reports 2009;11(6):

86 Pharmacologic Options for Reaching LDL Particle Number Goals Step 4
Presents a pharmacotherapy algorithm from Rosenson et al. Atherosclerosis. 2010; 213:1-7. Adapted from Rosenson et al. Atherosclerosis. 2010; 213:1-7.

87 Step 5: Assess Response to Therapy
If not at Lipid and LDL Particle Number goal – modify therapy and repeat laboratory tests in 3 months Following therapeutic changes, repeat laboratory testing every 3 months until goal values for lipid and LDL Particle Number are achieved Once at goal – continue therapy and repeat laboratory tests in 1 year If patients are not at Lipid and LDL Particle Number goal consideration should be given to modifying therapy and repeating laboratory tests in 3 months to assess response to therapy. Following therapeutic changes repeat laboratory testing every 3 months should be considered until goal values for lipid and LDL Particle Number are achieved. Once at goal the patient can be continued on therapy with repeat laboratory tests performed on an annual basis. Cromwell WC, Barringer TA. Curr Cardiol Reports 2009;11(6):

88 Contributors to residual risk
Unrecognized (and under-treated) LDL particle elevations are common and a significant contributor to the residual risk of many patients with “acceptable” levels of LDL-C. When LDL-C and LDL-P levels are discordant, risk tracks with LDL-P, not LDL-C, especially in higher risk patients with diabetes and metabolic syndrome. LDL-P measurement with findings of discordance between LDL- P and LDL-C yield actionable data for medical decision-making regarding treatment, e.g., statin increase or decrease, combination therapy, etc. In conclusion: Unrecognized (and under-treated) LDL particle elevations are common and a significant contributor to the residual risk of many patients with “acceptable” levels of LDL-C. When LDL-C and LDL-P levels are discordant (esp. diabetes, metabolic syndrome), risk tracks with LDL-P, not LDL-C. Achievement of LDL-P treatment goals is superior to LDL-C or non HDL-C values to indicate a the patient has achieved adequate LDL reduction. LDL size (“quality”) does not contribute independently to risk once LDL particle number is taken into account. LDL-P is a more sensitive indicator of low risk than LDL-C or non-HDL-C, and therefore a more discriminating LDL treatment target. LDL-P may be lowered not only by statins, but by lifestyle change and combination drug therapy. 88

89 ACCESS Medical Group

90 The primary objective of this study was
To evaluate treatment patterns between patients monitored with LDL-c alone and patients monitored with LDL-c and LDL-p results. The secondary objectives of this study were: To determine the number and type of cardiovascular events and procedures To determine the percentage of patients with LDL control according to NCEP Adult Treatment Panel III Guidelines To determine the percentage of patients with diabetes with A1C control according to ADA

91 Inclusion Criteria Diabetes or metabolic syndrome
At least 4 lipid profiles in the 4 years follow-up

92 Gender Distribution

93 Age Distribution

94 Most Prevalent Comorbid Conditions

95 Average LDLc in the Previous 3 Years

96 Conclusions Trending towards decreased CVD events in the group using LDLp to guide therapy. Lower dose statin and more combination tx noted in the group where LDLp guided treatment.

97 L-TAP: Majority of Patients With CHD Do Not Reach NCEP LDL-C Targets
25 n = 4,888 20 18 16.6 14.4 15 13 11.2 % of patients 9.9 9.4 10 7.9 5 Pt were assess from 5 regions of the unitied states. They had to be on lipid lowering therapy for at least 3 months. There were 4800 patients  >160 LDL-C (mg/dL) on-treatment Pearson TA et al. Arch Intern Med. 2000;160: Other L-TAP data courtesy of TA Pearson.

98 LIPID CLINIC YEARLY DATA BASE RETROPECTIVE ANALYSIS

99 Lipid Clinic LDL-C Goal Attainment
July 20009 March 20019 November 20014 August 20024 May 20034 October 20044 Goal Met LDL Goal < 160 66.7% (2/3) 92.3% (12/13) 84.6% (22/26) 92.3% (24/26) 89.4 % (59/66) 86.1% (130/151) LDL Goal < 130 58.8% (10/17) 65.8% (25/38) 75.3% (55/73) 69.6% (55/79) 66.7% (66/99) 71.7% (104/145) LDL Goal < 100 41.4% (12/29) 47.1% (40/85) 55.7% (102/183) 51.6% (116/225) 48.5% (159/328) 54.8% (249/454) OVERALL 49% (24/49) 56.6% (77/136) 63.5% (179/282) 59.1% (195/330) 57.6% (284/493) 64.4% (483/750) This was a data base analysis,,, all data from all patients in the lipid clinic

100 Overall Office LDL Goal Attainment
Data from the National Health and Nutrition Examination Survey (NHANES III – Phase I, conducted between 1989 and 1991) showed that 17% of adults with CHD and 45% of patients with two or more risk factors were meeting their LDL cholesterol goal. The Lipid Treatment Assessment Project (L-TAP) showed that 18% of patients with CHD and 37% of patients with two or more risk factors met their LDL cholesterol goal.11 The overall rate of LDL cholesterol goal attainment for this office was 62.3% (185/297). Of those patients with CHD or CHD risk equivalents, 53.4% (102/191) met their LDL cholesterol goal, exceeding the national rate of goal attainment. Of those patients with two or more risk factors for CHD, 76.5% (62/81) met their LDL cholesterol goal, also exceeding the national rate of goal attainment.

101 Patient Case Study

102 Ms R is a pleasant 55 yr old white female with a history of CAD, hypertension, & hyperlipidemia. She had an MI and stent placement on 2 occasions prior to seeing me. She has been followed at by my Lipid Clinic since October She has maintained a 10 lb. Weight loss and a low risk NMR profile with diet, exercise and medication. She has had no recurrent events.

103 What is Mrs R’s goal of therapy?
High risk < 70 LDL -C <700 LDL-P

104 10/25/2000 2/14/2005 Goal T Chol 234 190 Triglyceride 305 53 LDL -C 104 93 LDL-Particle LDL-P size 1197 20.6 723 22.0 < 700 HDL-C 67 92 Blood Sugar 140 80

105 http://www.medpagetoday.com 11/14/2013
Robert Superko Trials have not been designed to address such a strict interpretation but reasonable conclusions, regarding benefit of lipoprotein manipulation, can be made from an abundance of heterogeneous clinical trials A weakness of this strict constructionist approach is that it ignores the very large number of individuals treated with a statin who continue to have a cardiovascular event The new guidelines ignore individuals who continue to have a CHD event despite statin treatment. This is the new guidelines greatest failure in my opinion as such an approach creates the danger of ignoring the traditional pathophysiologic/clinical trial approach to understanding disease and treatments that are in the best interest of the individual patient, and worships at the altar of Randomized Clinical Trial strict interpretation 11/14/2013

106 Although we are enamored of the notion that we live in the world of truth in evidence-based medicine, the real truth is that we know very little. Instead, we understand a great many things with a great deal of probability. For us to practice better medicine and perform superior research, we must all accept this fact. There is no end to science; it is an evolutionary discipline. The best we can do at any moment is be familiar with the totality of the literature and practice medicine based upon its trends as well as our knowledge of human physiology and hard-won clinical experience. In this process, let us be forever vigilant not to slay the intuitive provider. Clin. Cardiol. 35, 5, 259–260 (2012)

107 Parachutes reduce the risk of injury after gravitational challenge, but their effectiveness has not been proved with randomized controlled trials In fact our search strategy did not find any randomised controlled trials of the parachute This slide depicts the seriousness of limiting our medical practices to only level one evidence. Meaning using meds and methods that have only been supported by randomized, placebo blind controlled trials. Would you like to volunteer for the placebo group without the parachute? Does one size fit all . Hopefully we realize that each patients case is different. They don’t all fit in the same mold We think that everyone might benefit if the most radical protagonists of evidence based medicine organized and participated in a double blind, randomised, placebo controlled, crossover trial of the parachute Gordon C S Smith, Jill P Pell BMJ 2003;327:1459–61

108 Future updates needed 1. Treatment of high triglycerides.
2. Whether on-treatment markers such as apoB, Lp(a), LDL-particles are useful in guiding decisions. 3. Optimal age for starting treatment for reducing lifetime risk of ASCVD. 4. Tx options for pts with HF, hemodialysis. 5. Long term effects of statin associated new onset diabetes in our patients

109 Questions? kathleen@dively.org www.lecturepad.org Dr Thomas Dayspring


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