ADA  ACC Consensus Statement Lipoprotein Management in Patients  with Cardiometabolic Risk

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. ADA and ACC Consensus Statement on Lipoprotein Management. Lipoproteins are the particles composed of cholesterol, triglycerides, phospholipids and apolipoproteins and they interact with the artery wall and set off the atherosclerotic cascadeWithin each category of lipoproteins, the size, density and lipid composition varyAtherosclerosis results from interactions between modified-lipoproteins and monocyte-derived macrophages, components of innate immunity and cel33756

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ADA ACC Consensus Statement Lipoprotein Management in Patients with Cardiometabolic Risk

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1. ADA & ACC Consensus Statement Lipoprotein Management in Patients with Cardiometabolic Risk Thomas Dayspring, MD, FACP Clinical Assistant Professor of Medicine University of Medicine and Dentistry of New Jersey New Jersey Medical School Attending in Medicine: St Joseph’s Regional Medical Center, Paterson and Wayne, NJ Diplomate: American Board of Clinical Lipidology Certified Menopause Clinician: North American Menopause Society North Jersey Institute of Menopausal Lipidology Wayne, New Jersey

2. ADA and ACC Consensus Statement on Lipoprotein Management Lipoproteins are the particles composed of cholesterol, triglycerides, phospholipids and apolipoproteins and they interact with the artery wall and set off the atherosclerotic cascade Within each category of lipoproteins, the size, density and lipid composition vary Atherosclerosis results from interactions between modified-lipoproteins and monocyte-derived macrophages, components of innate immunity and cellular elements of the artery There is a curvilinear relationship between increasing plasma cholesterol and incidence of CVD Measurements of cholesterol are indirect estimates of lipoproteins transporting cholesterol

3. ADA and ACC Consensus Statement on Lipoprotein Management

4. ADA and ACC Consensus Statement on Lipoprotein Management A plasma level of 25 mg/dL is sufficient to supply peripheral cholesterol needs Individuals with genetic mutations causing low LDL-C avoid CVD and are free of other abnormalities that might conceivably be linked to very low cholesterol levels The dyslipoproteinemia of insulin resistance is characterized by elevated VLDL, lower HDL-C and altered distributions of all lipoprotein classes Increased VLDL production and decreased clearance causing increased levels of large and intermediate VLDL particles Increased numbers of small, dense LDL particles which are easily oxidized, glycated and able to bond to intimal proteoglycans

5. ADA and ACC Consensus Statement on Lipoprotein Management Despite the usefulness of LDL-C for CVD prediction on a population level, the measure has limitations for individual risk assessment LDL-C is estimated using the Friedewald Equation, but this underestimates LDL-C as TG levels increase LDL-C = TC – [HDL-C + VLDL-C) VLDL-C = TG/5 However, the cholesterol content of LDL particles varies from person to person and is influenced by insulin resistance and hyperglycemia

6. ADA and ACC Consensus Statement on Lipoprotein Management A more accurate way to capture may be to measure LDL particles directly using Nuclear Magnetic Resonance (NMR) Cross-sectional and prospective studies show LDL-P is a better discriminator of risk than is LDL-C MESA (Multiethnic Study of Atherosclerosis) PLAC-1 (Pravastatin Limitation of Atherosclerosis in Coronary Arteries) WHS (Women’s Health Study) VA-HIT (Veteran’s Affairs HDL Intervention Trial) EPIC-Norfolk Population Study Framingham Offspring Study LDL size can also be measured. The association of small LDL and CVD may simply reflect the increased numbers of LDL particles in patients with small LDL. Hence it is unclear whether LDL size adds value to measurement of LDL-P

7. ADA and ACC Consensus Statement on Lipoprotein Management There is little evidence the insulin resistance or diabetes influences Lp(a) concentrations. The utility of routine measurement of Lp(a) is unclear More aggressive control of other lipoprotein parameters may be warranted in those with high concentrations of Lp(a)

8. ADA and ACC Consensus Statement on Lipoprotein Management Non HDL-C reflects the concentration of cholesterol within lipoproteins considered atherogenic and adds no expense and can be calculated from nonfasting specimens Non-HDL-C = TC – HDL-C or VLDL-C + LDL-C Many studies have demonstrated non-HDL-C is a better predictor of risk than is LDL-C STRONG Heart Study Physicians Health Study Framingham Cohort and Offspring Studies Multiple Risk Factor Intervention Trial (Mr FIT ) Lipid Research Clinics Prevalence Follow-up Study (LRCF)

9. ADA and ACC Consensus Statement on Lipoprotein Management Each Chylomicrons, VLDL, IDL, LDL and Lp(a) contains a single molecule of apolipoprotein B, making apoB measurement a marker of atherogenic particles Does not require fasting and assay is standardized In several epidemiological and post-hoc analyses of clinical trials apoB has been a better predictor of risk than LDL-C, particularly the on-treatment level of LDL-C Once LDL-C is lowered apoB may be a more effective way to assess residual CVD risk and to determine the need for medication adjustments The differences between apoB, LDL-C and non-HDL-C are more pronounced in patients with cardiometabolic risk, suggesting apoB is a more useful predictor among these patients

10. ADA and ACC Consensus Statement on Lipoprotein Management HDL-C levels are string inverse predictors of CVD events in diabetic and nondiabetic populations It has been difficult to determine whether raising HDL-C independently reduces CVD events, because all such interventions also affect concentrations of other lipoproteins Strategies to raise HDL-C remain a promising area of research that may be particularly valuable in patients with cardiometabolic risk Measurements of HDL subfractions or apoA-I appear to provide little clinical value beyond HDL-C

11. ADA and ACC Consensus Statement on Lipoprotein Management In the fasting state most TG are found in VLDL, so plasma TG are used as a surrogate measure of VLDL TG are a univariate predictor of CVD in many studies but often not an independent predictor in multivariate analyses This is because TG are linked to HDL and LDL abnormalities There are no clinical trial data establishing that lowering TG in individuals with or without diabetes independently leads to lower CVD event rates when one adjusts for HDL-C Chylomicron remnants may be atherogenic in a manner similar to VLDL remnants, but there is little population based evidence liking chylomicron remnants (measurements of which are not available) to CVD

12. ADA and ACC Consensus Statement on Lipoprotein Management HDL-C levels are strong inverse predictors of CVD events in diabetic and nondiabetic populations It has been difficult to determine whether raising HDL-C independently reduces CVD events, because all such interventions also affect concentrations of other lipoproteins Strategies to raise HDL-C remain a promising area of research that may be particularly valuable in patients with cardiometabolic risk Measurements of HDL subfractions or apoA-I appear to provide little clinical value beyond HDL-C

13. ADA and ACC Consensus Statement on Lipoprotein Management Good clinical practice calls for a comprehensive evaluation of current vascular health, factors related to dyslipoproteinemia and other factors affecting global risk Determine to the extent possible magnitude of future risk Identify modifiable prognostic risk factors Establish a treatment plan in terms of scope and intensity Subclinical disease may be determined by Coronary Calcification Carotid intima-media thickness Ankle-brachial index Other metabolic risk factors include BP, smoking, hyperglycemia, diet, inactivity, chronic renal disease Family history of premature CAD in siblings is a powerful risk predictor

14. ADA and ACC Consensus Statement on Lipoprotein Management The independent predictive power and clinical utility of C-reactive protein, fibrinogen and homocysteine are still unclear. CRP is often elevated in patients with cardiometabolic risk, but utility of its measurement in people already known to be at risk is unknown

15. ADA and ACC Consensus Statement on Lipoprotein Management Dyslipoproteinemia implies the presence of increased number of atherogenic lipoproteins and/or a reduced protective capacity of HDL beyond what is considered optimal It is present when triglycerides are high, HDL-C is low, and/or there is atherogenic particle excess (such as high LDL-C or small LDL-P) Lifestyle and pharmacologic therapy should be started concurrently in subjects with CVD and those with diabetes and multiple CVD risk factors regardless of baseline LDL-C Pharmacologic therapy is recommended for moderately high-risk primary prevention patients if LDL-C remains > 100 after several months of lifestyle changes

16. ADA and ACC Consensus Statement on Lipoprotein Management For patients who cannot tolerate a statin or the maximum statin therapy does not achieve treatment goals, other LDL-C lowering drugs include ezetimibe, bile-acid sequestrants or niacin. Each of these drugs enhance the LDL-C lowering of statins. BAS or niacin with statins selectively decrease small LDL particles BAS used alone can aggravate TG NCEP-ATP III established Non-HDL-C as a secondary target in those with hypertriglyceridemia or metabolic syndrome but the use of this measure has not been widely adopted Both LDL-C and Non HDL-C focus on cholesterol which is only a surrogate given that atherosclerosis is mediated by lipoproteins

17. ADA and ACC Consensus Statement on Lipoprotein Management Measurement of apoB or LDL-P by NMR may more closely quantitate the atherogenic lipoprotein load Studies suggest that both are better indices than LDL-C or non-HDL-C and more reliable indexes of on-treatment residual risk PLAC-1, WHS, AFCAPS-Tex-CAPS, AMORIS, INTER-HEART, 4S, LIPID Statins lower non-HDL-C more than they lower apoB and several studies show reaching apoB target usually requires more intensive therapy than achieving the equivalent level for non-HDL-C ApoB and LDL-P appear to be more closely associated with cardiometabolic risk factors than LDL-C

18. ADA and ACC Consensus Statement on Lipoprotein Management When both non-HDL-C and apoB are measured, the two are highly correlated, but only moderately concordant At any given level of non-HDL-C there will be wide variations of apoB levels and vice versa indicat9ing the correlation is of limited value for assessing individual risk This lack of concordance is particularly marked in patients with elevated triglyceride levels The panel concludes that routine use of non-HDL-C constitute a better index than LDL-C for identifying high risk patients

19. ADA and ACC Consensus Statement on Lipoprotein Management LDL-C should not be abandoned Many years of public and professional education geared towards LDL-C has resulted in its successful integration into the fabric of CVD prevention and treatment Non HDL-C should be provided on all laboratory reports and should also be used to ascertain risk in patients with low to moderate LDL-C levels (i.e., LDL-C < 130 mg/dL) Measurement of apoB is warranted in patients with cardiometabolic risk on pharmacologic treatment In particular apoB should be used to guide adjustments to therapy LDL-P as measured by NMR appears equally informative as apoB

20. ADA and ACC Consensus Statement on Lipoprotein Management Measurement of apoB is warranted in patients with cardiometabolic risk on pharmacologic treatment In particular apoB should be used to guide adjustments to therapy LDL-P as measured by NMR appears equally informative as apoB The panel recommends that the apoB goal be reached

21. ADA and ACC Consensus Statement on Lipoprotein Management

23. ADA and ACC Consensus Statement on Lipoprotein Management Elevations of TG and reduced HDL-C are the most common abnormalities of the standard lipid panel in subjects with obesity and insulin resistance-related cardiometabolic risk It has been difficult to demonstrate that lowering TG is independently associated with a reduction in CVD events Clinical trial evidence supporting treatment of low HDL-C is modest compared with that for LDL-C lowering For these reasons NCEP ATP-III recommended non HDL-C as a secondary target of treatment with a goal 30 mg/dL > than the LDL-C goal The panel recommends that the apoB goal be reached

24. ADA and ACC Consensus Statement on Lipoprotein Management The exception to not targeting TG is the relatively small proportion of patients with severe hypertriglyceridemia in whom the initial treatment priority is to reduce the risk of pancreatitis by combining fat restriction with fibrate, niacin or high-dose n-3 FA therapy A statin is the initial drug of choice for the vast majority of people with cardiometabolic risk who have high TG and low HDL-C In patients on statins who continue to have low HDL-C or elevated non-HDL-C, especially if apoB remains elevated, combination therapy is recommended

25. ADA and ACC Consensus Statement on Lipoprotein Management The preferred agent to use in combination with a statin is niacin because there is somewhat better evidence for reduction in CVD events with niacin than there is for fibrates Fibrates have been shown to reduce CVD events in some studies but not mortality N-3 fatty acid therapy lowers TG levels at high doses (= 4 grams/day) and may be another option to consider to lower non HDL-C in patients on statin therapy, but CVD outcome data are lacking for hypertriglyceridemic patients In diabetic patients, enhanced glycemic control may improve lipid and lipoprotein abnormalities, particularly hypertriglyceridemia

26. ADA and ACC Consensus Statement on Lipoprotein Management Niacin decreased CVD in the Coronary Drug Project and total mortality in an extended follow up Niacin in combination with bile-acid sequestrants was associated with regression of atherosclerosis and CVD events in several studies FATS, HATS, ARBITER 2, CLAS Although niacin has been associated with insulin resistance, in diabetes the use of low dose niacin (1500 mg/day) does not significantly increase A1C levels

27. ADA and ACC Consensus Statement on Lipoprotein Management In observational studies, low HDL-C is a powerful predictor of risk for CVD and remains a risk factor even in patients with low HDL-C Because a recent trial with a CETP inhibitor to raise HDL-C was terminated because of excess CV risk, it remains unclear if raising HDL-C per se reduces CV risk It may be that by increasing HDL-C by modifying the reverse cholesterol pathway may paradoxically increase CV risk, while other mechanisms to increase HDL-C may lead to a reduction in risk

28. ADA and ACC Consensus Statement on Lipoprotein Management Monotherapy with statins, fibrates, niacin and bile acid sequestrants have been shown to reduce CV events in clinical trials but there is not yet robust evidence for incremental benefits or risks of combination therapy compared with those of monotherapy Results of on-going and future trials of statin-niacin, statin-fibrate, and statin-n-e fatty acids will answer these questions Although statin therapy is highly effective in reducing CVD risk in primary and secondary prevention, there remain subsets of patients regarding whom more data are needed These include elderly, chronic kidney disease and young patients with cardiometabolic risk

29. ADA and ACC Consensus Statement on Lipoprotein Management Patients with cardiometabolic (CMR) risk factors have a high lifetime risk for CVD. They have low HDL-C, increased TG and/or increased numbers of small LDL particles The panel recommends for patients with CMR risk Statin therapy for the majority Guide therapy with measurements of apoB and treat to apoB goal

30. SUMMARY SLIDES

31. ADA and ACC Consensus Statement In Patients with Cardiometabolic Risk Lipoprotein abnormalities are common findings in patients with CMR. Measurement of LDL cholesterol may not accurately reflect the true burden of atherogenic LDL particles, especially in those with typical lipoprotein abnormalities of CMR. Even with adequate LDL cholesterol lowering, many patients on statin therapy have significant residual CVD risk. Treatment targets and the best approach for CVD risk reduction in this population need to be better defined. Some have advocated that assessment of other lipoprotein parameters might be more helpful than assessment limited to LDL-C or non-HDL cholesterol in these populations.

32. ADA and ACC Consensus Statement In Patients with Cardiometabolic Risk A more accurate way to capture the risk posed by LDL may be to measure the number of LDL particles directly using nuclear magnetic resonance (NMR) “Many cross-sectional and prospective studies show that LDL particle number is a better discriminator of risk than is LDL cholesterol.” Measurements of apoB or LDL particle number by NMR may more closely quantitate the atherogenic lipoprotein load. Some studies suggest that both are better indices of CVD risk than LDL cholesterol or non-HDL cholesterol and more reliable indexes of on-treatment residual CVD risk.

33. ADA and ACC Consensus Statement In Patients with Cardiometabolic Risk ApoB and LDL particle number also appear to be more discriminating measures of the adequacy of LDL lowering therapy than are LDL cholesterol or non-HDL cholesterol.” ApoB and LDL particle concentration also appear to be more closely associated with obesity, diabetes, insulin resistance, and other markers of CMR than LDL cholesterol or non-HDL cholesterol.”

34. LIPOSCIENCE PRESS RELEASE

35. Quantitating Lipoprotein Particles Cardiometabolic Risk (CMR) is associated with Type 2 Diabetes and CVD – obesity, insulin resistance, hyperglycemia and hypertension are risk factors that often cluster together. ApoB and LDL particle concentration appear to be more closely associated with these markers of CMR than LDL cholesterol or non-HDL cholesterol. Subsequently, lipoprotein abnormalities are commonly found in patients with CMR. According to the consensus statement, ApoB and LDL particle number by NMR appear to be more discriminating measures of the adequacy of LDL lowering therapies than are traditional LDL and HDL cholesterol measures.

36. Quantitating Lipoprotein Particles The American Diabetes Association (ADA) and the American College of Cardiology (ACC) issued a consensus statement today that states the measurement of LDL particle number by nuclear magnetic resonance (NMR) is one of the more accurate ways to evaluate cardiometabolic risk (CMR). The study, published in the April issue of Diabetes Care 2008;31:811-822, reinforces that LDL cholesterol may not be the best way to quantify a patient’s risk for cardiovascular disease (CVD).

37. Quantitating Lipoprotein Particles The NMR LipoProfile® test, developed by LipoScience, Inc., is the only test that quantifies LDL particle number (LDL-P) using Nuclear Magnetic Resonance. LDL particle information is used by clinicians to monitor the effect of lipid altering interventions, such as statins, in the management of a patient’s cardiovascular health by lowering LDL particle number (LDL-P).

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