New Concepts in the Evaluation and Treatment of Dyslipidemia

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  • At the end of this educational program, it is intended for the participant to be able to: Discuss the etiology and risk markers of atherogenesis including the role of cholesterol and the metabolic syndrome Review current NCEP goals and AHA/ACC guidelines for cholesterol and cholesterol lowering Evaluate the efficacy and safety profiles of various cholesterol lowering strategies including diet and lifestyle regimens and the use of statins, fibrates, niacin, cholesterol absorption inhibitors and cholesterol binding resins Examine the results of important cholesterol lowering clinical trials and understand their relevance in clinical practice Debate the need for aggressive cholesterol lowering and the utility of various therapeutic strategies
  • By reporting single values for lipoprotein cholesterol levels, the traditional lipid panel implies that lipoproteins such as HDL, LDL,… are single entities. This slide illustrates that all lipid sub-fractions are present in a continuum of size and density, with an especially large gradient for the triglyceride-rich lipoproteins IDL, VLDL, and chylomicrons. Technologies that sort by particle size (NMR and GGE) cannot separate IDL and Lp(a) from LDL-R, as these particles have overlapping size. They do differ by density so ultracentrifugation is the best way to separate total LDL into its 3 components. Total LDL is made up of Lp(a), IDL and real LDL or R-LDL-R. We define R-LDL as total LDL-C minus Lp(a)-C minus IDL-C. Each requires different therapies, confers different risk and has different inheritance. Both Lp(a) and IDL are more atherogenic than LDL itself. They do not respond to statins and both are highly inherited and implicated in premature CAD. Lp(a), “the widowmaker” doubles risk but when another lipid risk factor, such as dense LDL, is also present the risk leaps to 25x. It may be useful to point out that Lp(a) cannot be accurately measured in most commercial laboratories because the immunoassay kits are sensitive to the size heterogeneity of the apoprotein(a) due to variation in the # of kringle repeats. Lp(a) rises in renal failure and is probably partly responsible for the terrible CAD in ESRD patients. High IDL requires combination therapy with a statin plus niacin. Density 1.006-1.019 g/ml. Lp(a) and R-LDL are density range 1.019-1.063 g/ml. Lp(a) and small/dense LDL overlap in the density range 1.050-1.063 g/ml. Note that Lp(a) has overlaps with IDL and large R-LDL when GGE is used because of its different electrophoretic mobility – while the actual Lp(a) size is 21nm-25nm. Dense, small LDL is called Pattern B and increases risk 4x. Intermediately dense LDL is called Pattern A/B and doubles risk. HDL2 is the most protective HDL sub-fraction. HDL3 may be mildly protective to inert. You may have normal HDL but still have low HDL2 and not know it. Exercise and wine raise HDL2, as does niacin, fenofibrate and simvastatin. Atherogenic remnant lipoproteins include IDL and VLDL3 (small/dense). These are elevated in Metabolic Syndrome and NIDDM, and respond to low carbohydrate diets. If Lp(a), IDL or small/dense LDL pattern B are found, then first degree relatives should be tested. Note that large LDL may be confused with Lp(a) and IDL with size-based (vs. density based) separation methods as Lp(a) and IDL overlap with large R-LDL in size.
  • Neither hypertension nor hypercholesterolemia are well controlled in the United States. NHANES 1999-2000 collected data on awareness, treatment, and control of hypertension and hypercholesterolemia. As shown here, although 70% of documented hypertensives in the United States were aware of their hypertension, 59% were treated for hypertension, and only 34% had their hypertension controlled as defined by BP <140/90 mm Hg. 30 Also collected in the 1999-2000 NHANES were data on awareness, treatment, and control of hypercholesterolemia (<200 mg/dL) in 4148 individuals  20 years of age who had their cholesterol measured or who reported being on lipid-lowering medication. 32 Of the participants in the study, 39.6% (unadjusted) were aware of their hypercholesterolemia. Among those who were aware, 36.8% were using cholesterol-lowering agents (not shown). Finally, of those taking lipid medications, 47% were controlled (not shown). Accordingly, of 100 individuals with hypercholesterolemia, 39.6% were aware of their situation, 14.5% reported using lipid-lowering drugs, and only 6.8% had total cholesterol levels <200 mg/dL. The age-adjusted percentage of individuals reporting current use of lipid-lowering agents was 9.0% in men and 6.8% in women. 30. Chobanian AV, Bakris GL, Black HR, et al, and the National High Blood Pressure Education Program Coordinating Committee. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 Report. JAMA . 2003;289:2560-2572. 32. Ford ES, Mokdad AH, Giles WH, Mensah GA. Serum total cholesterol concentrations and awareness, treatment, and control of hypercholesterolemia among US adults: findings from the National Health and Nutrition Examination Survey, 1999 to 2000. Circulation . 2003;107:2185-2189.
  • Data from the Framingham Heart Study show the continuous relationship between risk of developing CVD over 8 years and levels of cholesterol. 9 Other assumptions for this model are that the patient was a 40-year-old man, who was ECG left ventricular hypertrophy (LVH) negative, and with no glucose intolerance, and who was not a current smoker. As illustrated on this slide, the relationship between level of total cholesterol (TC) and CVD risk is graded and continuous. Risk is not confined to the upper centiles. 9 9. Kannel WB. Importance of hypertension as a major risk factor in cardiovascular disease. In: Genest J, Koiw E, Kuchel O, eds. Hypertension. Physiopathology and Treatment. New York, NY: McGraw-Hill; 1977:888-910.
  • Slide 3. Total cholesterol distribution: CHD vs non-CHD population In the Framingham Heart Study, as many as one third of all coronary heart disease (CHD) events occurred in individuals with total cholesterol <200 mg/dL. Considering that the average U.S. cholesterol level is approximately 210 to 220 mg/dL, almost half of all heart attack events and all stroke events that will occur in the United States next year will in fact occur among individuals with below-average lipid levels. For this reason, our research group has sought in our large-scale prospective epidemiologic studies to understand better other markers associated with cardiovascular risk. Reference: Castelli WP. Lipids, risk factors and ischaemic heart disease. Atherosclerosis 1996;124(Suppl):S1-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8831910&dopt=Abstract Keywords: cholesterol distribution, Framingham Heart Study Slide type: graph
  • Epidemiologic studies have also established specific lipid parameters as important risk factors for CAD. In the Münster Heart Study (also known as PROCAM), which included 17,437 men and 8065 women who were followed for more than 8 years, the incidence of CAD was Positively correlated with increasing serum levels of low-density-lipoprotein cholesterol (LDL-C) and triglycerides (TG) Negatively correlated with increasing high-density-lipoprotein cholesterol (HDL-C) concentrations The correlation between levels of LDL-C and incidence of CAD was particularly strong: Incidence of CAD increased from 2.3% in individuals with LDL-C <133 mg/dL to 10% in individuals with LDL-C >163 mg/dL. Assmann G, Cullen P, Schulte H. The M ünster Heart Study (PROCAM). Results of follow-up at 8 years . Eur Heart J . 1998;19(suppl A):A2-A11.
  • Speaker’s Notes/Talking Points: Low high-density lipoprotein cholesterol (HDL-C) levels (< 40 mg/dL) are associated with an increased risk of coronary heart disease (CHD) even if the total cholesterol (Total-C) level is < 200 mg/dL. This slide shows the CHD incidence over 14 years among Framingham Study subjects who were aged 48–83 years at baseline. 1 Among those with HDL-C levels < 40 mg/dL and Total-C < 200 mg/dL, 11.24% experienced a CHD event. This incidence was virtually the same as that (11.91%) for subjects with HDL-C levels between 40–49 mg/dL and Total-C  260 mg/dL. References 1. Castelli WP, Garrison RJ, Wilson PW, et al. Incidence of coronary heart disease and lipoprotein cholesterol levels: the Framingham Study. JAMA. 1986;256:2835–2838.
  • Slide 5 Effects of Increasing TC Levels on the Risk for CHD in the Presence of Other Risk Factors. The Framingham Heart Study showed the effects of increasing total cholesterol levels on the risk for CHD in the presence of other risk factors in men aged 50 years. As shown, low HDL-C poses an even greater risk than smoking, hyperglycemia, and hypertension.
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  • Allocation to simvastatin also produced an extreme 38% proportional reduction in incidence of first nonfatal myocardial infarction following randomization (357 [3.5%] simvastatin vs 574 [5.6%] placebo; p<0.0001). Combining this with the effect on coronary death rate, there was a 27% proportional reduction in the incidence rate of ‘major coronary events’ (MCE): (898 [8.7%] vs 1212 [11.8%]; p<0.0001). Simvastatin treatment also resulted in a highly significant 24% proportional reduction in the incidence rate of first revascularization procedure following randomization (939 [9.1%] simvastatin vs 1205 [11.7%] placebo; p<0.0001). A 30% proportional reduction in the incidence rate of coronary revascularization occurred (513 [5.0%] vs 725 [7.1%]; p<0.0001), and there was also a significant 16% proportional reduction in the incidence rate of noncoronary revascularization (450 [4.4%] vs 532 [5.2%]; p=0.006). Major vascular events of any kind were reported in significantly fewer patients allocated to simvastatin compared to placebo (2033 [19.8%] vs 2585 [25.2%]; p<0.0001).
  • The primary objective of the lipid-lowering arm was to assess and compare the long-term effects on the the combined endpoint of non-fatal MI and silent MI, and fatal CHD of a statin (plus antihypertensive treatment) compared with placebo (plus matched antihypertensive treatment) among patients with total cholesterol concentrations of 250 mg/dL or less. The primary endpoint of non-fatal MI/fatal CHD was significantly lower by 36% (hazard ratio (HR) 0.64 [95% CI 0.50-0.83], P = 0.0005) in the atorvastatin group than in the placebo group. The proportional effect of atorvastatin on the primary endpoint did not significantly differ regardless of baseline cholesterol level. Further, there was no significant interaction between gender of the participants and the impact of statin on the primary endpoint. Sever PS, et al, for the ASCOT investigators. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial – Lipid Lowering Arm (ASCOT-LLT): a multicentre randomised controlled trial. Lancet . 2003;361:1149-1158.
  • The primary hypothesis of the TNT study was that incremental reduction in cardiovascular risk can be achieved by lowering LDL-C levels beyond currently recommended minimum targets. 1 Reference 1. Waters DD, Guyton JR, Herrington DM, McGowan MP, Wenger NK, Shear C, for the TNT Steering Committee Members and Investigators. Treating to New Targets (TNT) study: does lowering low-density lipoprotein cholesterol levels below currently recommended guidelines yield incremental clinical benefit? Am J Cardiol . 2004;93:154-158.
  • During the open-label period, LDL-C was reduced by 35% in the overall patient population, from 152 mg/dL (3.9 mmol/L) to 98 mg/dL (2.6 mmol/L). 1 Following randomization, mean LDL-C in the atorvastatin 10-mg group was maintained at approximately baseline level for the duration of the treatment period, with an average of 101 mg/dL (2.6 mmol/L) across the 5 years of follow-up. 1 After 12 weeks of treatment, LDL-C was further reduced to a mean level of 77 mg/dL (2.0 mmol/L; P <.001) among patients receiving atorvastatin 80 mg. 1 The LDL-C level in the 80-mg group remained relatively stable over the course of the study. 1 Reference 1. LaRosa JC, Grundy SM, Waters DD, et al, for the Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med . 2005;352:1425-1435.
  • Over the course of the study, there was a highly significant reduction in the composite efficacy outcome of major cardiovascular events in the atorvastatin 80-mg group compared with the atorvastatin 10-mg group. 1 The Kaplan-Meier analysis showed a hazard ratio of 0.78 (95% CI 0.69, 0.89; P <.001). 1 This represented a 22% reduction in relative risk in the atorvastatin 80-mg group relative to the atorvastatin 10-mg group, over and above the low absolute event rate of 10.9% recorded in the atorvastatin 10-mg group. 1 There was no statistical interaction for age or sex in the primary outcome measure. 1 Reference 1. LaRosa JC, Grundy SM, Waters DD, et al, for the Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med . 2005;352:1425-1435.
  • This graphs shows the second order relationship of LDL+HDL and cardiovascular event risk reduction, using data from major clinical trials of lipid-lowering therapy. The percent change from baseline (or placebo) for LDL+HDL is added using absolute values. This is plotted against the relative risk reduction in composite endpoints from each of the trials. The trend line indicates that these variables are highly correlated. In fact, it appears that the percent absolute change in LDL+HDL during treatment in these clinical trials accounts for 76% of the effect on cardiovascular event relative risk reduction vs placebo in this crude analysis.
  • 5.43
  • 5.44
  • The change in CIMT from baseline to 12 months was 0.044 mm in the placebo group ( P <0.001) and 0.014 mm in the ER-niacin group ( P =0.023). Thus, the increase in CIMT was 3-fold greater in the placebo than in the ER-niacin group. There was a trend towards significance for the between-group comparison of the rate of progression for the placebo and ER-niacin groups ( P =0.08).
  • The major risk factors for CAD are Age over 45 for men and over 55 for women Smoking Hypertension (BP  140/90 mm Hg or antihypertensive medication) HDL-C <40 mg/dL Family history of premature CAD Before the age of 55 in a first-degree male relative Before the age of 65 in a first-degree female relative Although it is a well-established risk factor, LDL-C is not included because it is recognized to be modified by other major risk factors. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA . 2001;285:2486-2497.
  • NCEP ATP III guidelines recognize the presence of CAD risk equivalents (eg, diabetes, atherosclerotic disease in other vascular beds, combination of several risk factors) that are associated with a 10-year risk equivalent to that of established CAD (>20%). Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA . 2001;285:2486-2497.
  • NCEP ATP III guidelines define 3 categories of risk, according to the number of risk factors and evidence of CAD or CAD risk equivalent. For individuals with 0 or 1 risk factor, the 10-year risk for CAD is <10%, and there is no need to calculate the absolute risk. For individuals with 2 or more risk factors, the 10-year risk for CAD varies from <10% to 10%-20%, and the absolute risk needs to be calculated to determine the appropriate management. For individuals with established CAD or a CAD risk equivalent, the 10-year risk of a coronary event is >20%, and there is no need to calculate the absolute risk. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA . 2001;285:2486-2497.
  • The NCEP ATP III guidelines recommend the use of therapeutic lifestyle changes (TLC) and pharmacologic therapy according to the LDL-C goals and calculated risk. In individuals with an LDL-C goal of <160 mg/dL, initiation of TLC and pharmacologic therapy is recommended at LDL-C levels of  160 mg/dL and  190 mg/dL, respectively. In individuals with an LDL-C goal of <130 mg/dL, initiation of TLC is recommended at LDL-C level of  130 mg/dL, regardless of their 10-year risk of developing CAD. Initiation of pharmacologic therapy is recommended at LDL-C level of  160 mg/dL in patients with a 10-year risk of <10% and at LDL-C level of  130 mg/dL in those with a 10-year risk of 10%-20%. In individuals with an LDL-C goal of <100 mg/dL, initiation of TLC and pharmacologic therapy is recommended at LDL-C levels of  100 mg/dL and  130 mg/dL, respectively. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA . 2001;285:2486-2497.
  • In patients with elevated TG (  200 mg/dL), cholesterol content of atherogenic remnant lipoprotein particles (chylomicron remnant, VLDL remnant) may be increased, and LDL-C alone may not be an adequate risk predictor. In these individuals, measurement of non – HDL-C (calculated by subtracting HDL-C from TC) is recommended, and its reduction is defined as a secondary therapeutic goal. Non – HDL-C goals are set at 30 mg/dL above the LDL-C goal in each risk category. For individuals with 0 or 1 risk factor: <190 mg/dL For individuals with  2 risk factors and a 10-year risk of 0%-20%: <160 mg/dL For individuals with established CAD or a CAD risk equivalent: <130 mg/dL Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA . 2001;285:2486-2497.
  • NCEP ATP III guidelines recommend therapeutic lifestyle changes (TLC) as an essential component of lipid-lowering. Diet Reduced intake of saturated fat (<7% of total calories) Reduced intake of cholesterol (<200 mg/d) Use of plant stanols/sterols Use of soluble fiber Weight reduction Increased physical activity Patients at high risk are likely to require both TLC and pharmacologic therapy. Statins Fibrates Niacin Bile acid sequestrants These agents target different aspects of lipid metabolism and have been shown to reduce the risk of CAD. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA . 2001;285:2486-2497.
  • The NCEP ATP III guidelines recommend incorporation of plant sterol and stanol esters into patients’ diet in order to reduce plasma levels of LDL-C. Plant sterol and stanol esters have a low degree of intestinal absorption, and block cholesterol absorption by inhibiting incorporation of dietary/biliary cholesterol into micelles, producing LDL-C reductions of 10%-15%. 1 Plant sterol and stanol esters may reduce the absorption of lipid-soluble vitamins. 2 Plant stanol esters are saturated derivatives of sterol esters and have a lower degree of absorption. 1 Nguyen TT. The cholesterol-lowering action of plant stanol esters. J Nutr . 1999;129:2109. Gylling H, Puska P, Vartiainen E, Miettinen TA. Retinol, vitamin D, carotenes and alpha-tocopherol in serum of moderately hypercholesterolemic population consuming sitostanol ester margarine. Atherosclerosis. 1999;145:279-285.
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  • Dietary adjuncts This slide shows that in a hypothetical patient with an LDL-C of 160 mg/dL, average reductions in LDL-C obtained by a diet lower in saturated fat and dietary cholesterol and the addition of viscous fiber and plant stanol/sterol esters could reduce LDL-C to <130 mg/dL. This is the goal for many patients with multiple risk factors and may obviate the need for cholesterol-lowering drug therapy or an increase in dosage of cholesterol-lowering drug therapy. References: Walden CE, Retzlaff BM, Buck BL, McCann BS, Knopp RH. Lipoprotein lipid response to the National Cholesterol Education Program Step II diet by hypercholesterolemic and combined hyperlipidemic women and men. Arterioscler Thromb Vasc Biol 1997;17:375-382. Jenkins DJ, Kendall CW, Axelsen M, Augustin LS, Vuksan V. Viscous and nonviscous fibres, nonabsorbable and low glycaemic index carbohydrates, blood lipids and coronary heart disease. Curr Opin Lipidol 2000;11:49-56. Cato N. Stanol meta-analysis. Personal communication, 2000.
  • Patient compliance with prescribed therapy is influenced by numerous factors, including the number of daily doses and medications, the occurrence and severity of side effects, incompatibility of the treatment with the patients’ daily routine, and inadequate physician-patient communication (ie, patient education). In addition, the high cost of therapy also reduces patient compliance.
  • Lipid-modifying therapies include HMG CoA reductase inhibitors (statins), fibrates, bile acid sequestrants (resins), nicotinic acid and its derivatives, and probucol. Statins are highly effective in lowering LDL-cholesterol and have a good tolerability profile. 1-3 Data presented in this slide does not include rosuvastatin. Bile acid sequestrants are potent cholesterol-modifying agents. Adverse events such as gastrointestinal bloating, nausea and constipation limit compliance to the bile acid sequestrants. 1,2 Nicotinic acid , a B-complex vitamin, is effective at reducing both LDL cholesterol and triglyceride concentrations, and increasing HDL cholesterol levels. To be effective, it must be given in pharmacologic doses. The value of nicotinic acid has been limited by the incidence of adverse events, which include flushing, skin problems, gastrointestinal distress, liver toxicity, hyperglycaemia and hyperuricemia. 1,2 Fibrates are effective triglyceride-lowering and HDL-raising drugs. However, in the majority of patients they are only moderately successful in reducing LDL-cholesterol. 1,2 Probucol is not available in most countries. It has only a modest LDL-cholesterol-lowering effect, and there is no evidence that it reduces CHD risk and there are limited long-term tolerability data. 1,2 Ezetimibe is the first of a novel class of selective cholesterol-absorption inhibitors. Ezetimibe may be useful in patients who are intolerant to other lipid-modifying therapies, and in combination with a statin in patients who are intolerant to large doses of statins or need further reductions in LDL cholesterol despite maximum doses of a statin. 4 References 1. Yeshurun D, Gotto AM. Southern Med J 1995; 88(4) :379–391. 2. National Cholesterol Education Program. Circulation 1994; 98(3) :1333–1445. 3. Knopp RH. N Engl J Med 1999; 341 :498–511. 4. Gupta EK, Ito MK. Heart Dis 2002; 4 :399–409.
  • Niacin reduces hepatic HDL catabolism and VLDL production. Niacin is primarily used to treat low HDL-C and elevated TG. HDL-C is increased by 15%-35%. TG is reduced by 20%-50%. Niacin also reduces LDL-C by 5%-25%. Side effects of niacin include hepatotoxicity, hyperglycemia, hyperuricemia, upper gastrointestinal distress, and flushing. Niacin is contraindicated in patients with liver disease, gout, or peptic ulcer. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA . 2001;285:2486-2497.
  • Fibrates inhibit production of TG by the liver and increase HDL-C production. Plasma level of TG is reduced by 20%-50%. Plasma level of HDL-C is increased by 10%-20%. Depending on the patient’s plasma TG concentration, fibrates have a variable effect on plasma LDL-C concentration. Side effects associated with fibrates include dyspepsia, gallstones, and myopathy; their incidence is increased in combination with statins. Fibrates are contraindicated in patients with severe renal or hepatic disease. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA . 2001;285:2486-2497.
  • The effect of statins on various lipid parameters are shown here. Depending on the molecule, statins reduce LDL cholesterol concentrations by 18 to 55% and triglycerides by 5 to 15%. HDL cholesterol concentrations are increased by 5 to 15% (although high-dose atorvastatin has a neutral effect on HDL cholesterol). The incidence of side effects is generally low, although myopathy and increases in liver enzymes can occur, especially with high statins doses. Muscle symptoms and rhabdomyolysis are more likely when certain fibrate drugs are used with statin therapy. Liver disease is an absolute contraindication to statin use. Certain drugs may interact with statins depending on the pathways through which they are metabolized.
  • Key point: In general, Rule of 6 : Each doubling of the dose of a statin drug produces approximately a 6% decrease in LDL-C. The potency of the statin drugs varies, with fluvastatin being the least potent and atorvastatin the most potent of the currently available compounds. 8 The effect of the statins on LDL-C is dose related. The recommended starting dose of each statin drug results in a mean reduction in LDL-C of approximately 19% to 37%. Thereafter, a doubling of the dose of the statin drug lowers LDL-C approximately 6%. Titration to the maximum approved dose produces a mean reduction of approximately 31% to 51%. 8 Statins are indicated as an adjunct to diet to reduce elevated total cholesterol, LDL-C, apolipoprotein B, and triglyceride levels and to increase high-density-lipoprotein (HDL)-C in patients with primary hypercholesterolemia (heterozygous familial and nonfamilial) and combined hyperlipidemia (Fredrickson types IIa and IIb) after a trial of diet and other nondrug therapy has proved inadequate.
  • This slide shows the percentage change from baseline in LDL-C at week 6 by drug and dose range comparison. Rosuvastatin 10-40 mg reduced LDL-C significantly more than atorvastatin across the dose range of 10-80 mg ( P< .002) a ligning the maximum doses of each drug. 2 Rosuvastatin 10 mg resulted in a statistically significant greater percent reduction in LDL-C compared with atorvastatin 10 mg; simvastatin 10 mg, 20 mg, or 40 mg; or pravastatin 10 mg, 20 mg, or 40 mg ( P< 0.002). Rosuvastatin 20 mg treatment resulted in a statistically significant greater percent reduction in LDL-C compared with atorvastatin 20 mg or 40 mg ( P< 0.002); pravastatin 20 mg or 40 mg, or simvastatin 20 mg, 40 mg, or 80 mg ( P< 0.002). Rosuvastatin 40 mg treatment resulted in statistically significantly greater percent reductions in LDL-C compared with atorvastatin 40 mg, pravastatin 40 mg, or simvastatin 40 mg or 80 mg ( P< 0.002). Reference Jones PH, Davidson MH, Stein EA, et al. Comparison of the Efficacy and Safety of Rosuvastatin Versus Atorvastatin, Simvastatin, and Pravastatin Across Doses (STELLAR Trial) Am. J. Cardiology 2003; 93:152-160. 2. Data on file, DA-CRS-02 AstraZeneca Pharmaceuticals LP, Wilmington, DE. 215665 11/03
  • Summary (I) In patients at high or moderately risk, therapeutic lifestyle change is an integral part of risk reduction. If an LDL-C –lowering drug is used, the intensity of therapy should achieve an additional LDL-C reduction of at least 30–40% beyond diet.
  • At their starting dosages, all of the currently available statins reduce levels of LDL cholesterol and triglycerides, and increase levels of HDL cholesterol. Rosuvastatin is the most potent at LDL lowering. Reference Product Data Sheets
  • Combinations of lipid-lowering agents may help patients achieve their LDL cholesterol goals, which happens infrequently on statin monotherapy, especially for patients who have the most aggressive goals (those with CHD or CHD risk equivalents). Studies have shown that few physicians uptitrate statin dosages as necessary to achieve LDL cholesterol goals. Furthermore, using high does of statins increases the risk of muscle symptoms and liver enzyme abnormalities. Finally, use of combinations of drugs with different mechanisms may address lipid abnormalities in patients with mixed dyslipidemias.
  • The combination of statins, which inhibit cholesterol synthesis, and intestinal-acting agents, which reduce intestinal absorption of dietary/biliary cholesterol or intestinal reabsorption of bile acids, is an attractive therapeutic strategy for lowering of LDL-C, because of their complementary mechanisms of action (statins block the compensatory increase in hepatic cholesterol synthesis that occurs in response to inhibition of intestinal cholesterol absorption). Combination therapy may have additive (or synergistic) LDL-C – lowering effects, thus effectively increasing the likelihood of reaching LDL-C goals. Combination therapy may also allow the use of lower statin doses in order to achieve target LDL-C levels, thereby reducing the potential for adverse effects.
  • Bile acid sequestrants reduce LDL-C by 15%-30%, raise HDL-C by 3% -5% , but may increase TG in patients with hypertriglyceridemia. Side effects associated with bile acid sequestrants include gastrointestinal distress or constipation, which may often lead to decreased compliance. Additionally, first-generation agents (such as cholestyramine) reduce absorption of other drugs. Bile acid sequestrants are contraindicated in patients with dysbetalipoproteinemia and in individuals with elevated TG (particularly those with TG >400 mg/dL).
  • A bile acid sequestrant introduced more recently, colesevelam, is effective at lower doses and is associated with fewer GI disturbances than previous agents in this class. Colesevelam has been reported to reduce intestinal absorption of  -carotene. Colesevelam regimen consists of 4-6 large tablets per day, which may decrease compliance. Davidson MH, Dicklin MR, Maki KC, Kleinpell RM. Colesevelam hydrochloride: a non-absorbed, polymeric, cholesterol-lowering agent. Expert Opin Investig Drugs . 2000;9:2663-2671.
  • Colesevelam (3.8 g/d) significantly reduced LDL-C by 15% ( P <0.001 vs placebo) and significantly increased HDL-C by 3% ( P =0.04 vs placebo). TG concentrations vs baseline were significantly increased in both the placebo and colesevelam groups (by 5% and 10%, respectively), although the difference between the placebo and colesevelam groups was not statistically significant. Insull W Jr, Toth P, Mullican W, et al. Effectiveness of colesevelam hydrochloride in decreasing LDL cholesterol in patients with primary hypercholesterolemia: A 24-week, randomized controlled trial. Mayo Clin Proc . 2001;76:971-982.
  • Despite their ability to reduce LDL-C, clinical use of both bile acid sequestrants and plant stanol and sterol esters is limited by several factors. Principal limitations of bile acid sequestrants include inadequate compliance, relatively poor GI tolerability, reduced absorption of lipid-soluble vitamins, and potential for increase in TG in patients with hypertriglyceridemia. Plant stanol and sterol esters are limited by the lack of selectivity for cholesterol, and some patients may find it difficult to incorporate them into their diet. In addition, these agents have been reported to reduce absorption of lipid-soluble vitamins.
  • Inclusion Criteria Age 30-75 years Familial Hypercholesterolemia: Genotyping Diagnostic criteria WHO Untreated LDL-C levels > 210 mg/dL (5.43 mmol/l) Patients on lipid-lowering treatment LDL-c after washout > 210 mg/dL (5.43 mmol/l) Exclusion Criteria High-grade carotid stenosis History carotid endarterectomy Carotid stenting Congestive heart failure III/IV
  • <0.01 -45.3 ± 0.8 -31.9 ± 0.8 Total Cholesterol <0.01 -55.6 ± 0.9 -39.1 ± 0.9 LDL-cholesterol <0.01 -29.8 -23.2 Triglycerides (median) 0.05 10.2 ± 1.0 7.8 ± 0.9 HDL-cholesterol <0.01 -46.7 ± 0.9 -33.1 ± 0.9 Apo B 0.56 6.3 ± 0.8 6.9 ± 0.8 Apo A1 P value Ezetimibe 10 mg/ simvastatin 80mg Simvastatin 80 mg
  • New Concepts in the Evaluation and Treatment of Dyslipidemia

    1. 1. New Concepts in the Evaluation and Treatment of Dyslipidemia Nathan D. Wong, PhD, FACC Professor and Director Heart Disease Prevention Program Division of Cardiology University of California, Irvine
    2. 2. Learning Objectives <ul><li>Discuss the role of cholesterol, lipoproteins, and the metabolic syndrome in coronary heart disease </li></ul><ul><li>Examine the results of important cholesterol lowering clinical trials and understand their relevance in clinical practice </li></ul><ul><li>Review current NCEP goals for lipid management </li></ul><ul><li>Evaluate the efficacy and safety profiles of various cholesterol lowering strategies including diet and lifestyle regimens and pharmacologic agents </li></ul>
    3. 3. Most Myocardial Infarctions Are Caused by Low-Grade Stenoses <ul><ul><li>Pooled data from 4 studies: Ambrose et al, 1988; Little et al, 1988; Nobuyoshi et al, 1991; and Giroud et al, 1992. (Adapted from Falk et al.) </li></ul></ul><ul><ul><li>Falk E et al, Circulation , 1995. </li></ul></ul>
    4. 4. Lipoproteins <ul><li>Water-soluble way to transport hydrophobic lipids </li></ul><ul><li>Envelope of phospholipids and free cholesterol </li></ul><ul><li>Triglyceride and cholesteryl ester-rich core </li></ul><ul><li>Vary in size and density </li></ul>From: Braunwald et al, Heart Disease: A Textbook of Cardiovascular Medicine 6 th ed. , 2001
    5. 5. Lipoprotein Particles 1.20 1.100 1.063 1.019 1.006 0.95 5 10 20 40 60 80 1000 LDL-R HDL3 DL 3 Particle Size (nm) Density (g/ml) Chylomicron VLDL Remnants Lp(a) IDL Chylomicron Remnants VLDL HDL 2 Only these lipoprotein particles found in plaque at biopsy. 1.050
    6. 6. Lipid Atherogenesis HDL Liver Advanced fibrocalcific lesion Oxidative modification of LDL LDL + VLDL Cholesterol excreted Endothelial injury Adherence of platelets Release of PDGF High plasma LDL LDL infiltration into intima + Macrophages Foam cells Fatty streak LCAT APO-A1 Other growth factors
    7. 7. Genetic Causes of Dyslipidemia <ul><li>Type I – Familial Hyperchylomicronemia </li></ul><ul><ul><li>Fasting triglycerides > 1000 mg/dl </li></ul></ul><ul><ul><li>Defect in lipoprotein lipase or apo CII </li></ul></ul><ul><ul><li>Not necessarily at increased risk of CAD </li></ul></ul><ul><li>Type II - Familial Hypercholesterolemia (type II) </li></ul><ul><ul><li>LDL-C > 95 th percentile for age and gender </li></ul></ul><ul><ul><li>CAD in men by 3 rd or 4 th decade </li></ul></ul><ul><ul><li>Defect in LDL receptor </li></ul></ul><ul><ul><li>Autosomal dominant inheritance </li></ul></ul><ul><ul><li>Prevalence 1:500 </li></ul></ul><ul><li>Familial Defective apo B 100 </li></ul><ul><ul><li>Defective apo B alters LDLr handling </li></ul></ul><ul><ul><li>Previously undetecable from FH </li></ul></ul>
    8. 8. Genetic Causes of Dyslipidemia <ul><li>Type III – Hyperlipoproteinemia </li></ul><ul><ul><li>Increased TC, VLDL, decreased HDL; Increased VLDL:TG </li></ul></ul><ul><ul><li>Defect in apo E results in increased concentration of remnant particles </li></ul></ul><ul><ul><li>Rare </li></ul></ul><ul><li>Type IV – Familial Hypertriglyceridemia </li></ul><ul><ul><li>Increased TC (due to VLDL), TG, decreased LDL, HDL </li></ul></ul><ul><ul><li>Results from hepatic overproduction of VLDL </li></ul></ul><ul><ul><li>Prevalence 1:100 – 1:50; Association with CAD not as strong as FH </li></ul></ul><ul><ul><li>Heterogeneous inheritance </li></ul></ul><ul><ul><li>Very sensitive to diet and EtOH </li></ul></ul><ul><li>Type V </li></ul><ul><ul><li>Increase in chylomicrons and VLDL </li></ul></ul><ul><ul><li>Rare </li></ul></ul>
    9. 9. Genetic Causes of Dyslipidemia <ul><li>Familial Combined Hyperlipidemia </li></ul><ul><ul><li>Increased TC, LDL and/or triglycerides; decreased HDL </li></ul></ul><ul><ul><li>Most common genetic dyslipidemia: prevalence 1:50 </li></ul></ul><ul><ul><li>Heterogenous inheritance </li></ul></ul><ul><ul><li>Accounts for 10-20% of patients with premature CAD </li></ul></ul><ul><li>Defects in HDL Metabolism </li></ul><ul><ul><li>Most often low HDL is secondary to other dyslipidemia </li></ul></ul><ul><ul><li>Not all associated with increased CAD risk (e.g. apo AI Milano ) </li></ul></ul><ul><ul><li>Tangier’s Disease </li></ul></ul><ul><ul><li>CETP defects result in increased HDL </li></ul></ul>
    10. 11. Compliance with Lipid Treatment Guidelines <ul><li>About half U.S. population has LDL-C >130 mg/dL </li></ul><ul><li>Less than half those eligible undertake treatment </li></ul><ul><li>Only a third of those treated achieve their LDL-C goals </li></ul><ul><li>40% of patients surveyed who saw a physician in preceding 2 years were unaware of their lipid status </li></ul><ul><li>Only 20-25% of CVD patients in the U.S. are reported to be on treatment for dyslipidemia </li></ul><ul><li>AHA Heart Disease and Stroke Statistics: 2004 Update </li></ul><ul><li>NHANES II Behavioral Risk Factor Survey </li></ul>_______________________________________________________________ ______________________________________________________________ __________________________________________________________________
    11. 13. Total Cholesterol Distribution: CHD vs Non-CHD Population Castelli WP. Atherosclerosis . 1996;124(suppl):S1-S9.  1996 Reprinted with permission from Elsevier Science. 35% of CHD Occurs in People with TC<200 mg/dL 150 200 Total Cholesterol (mg/dL) 250 300 No CHD CHD Framingham Heart Study—26-Year Follow-up
    12. 14. Lipid Parameters and Risk of CAD Over 8 Years (PROCAM) Incidence (%) >49 40-49 <40 <133 133-163 >163 <105 105-166 >166 HDL-C LDL-C TG Assmann et al. Eur Heart J . 1998;19(suppl A):A2. mg/ dL
    13. 15. Low HDL-C Levels Increase CHD Risk Even When Total-C Is Normal Risk of CHD by HDL-C and Total-C levels; aged 48–83 y Castelli WP et al. JAMA 1986;256:2835–2838 0 2 4 6 8 10 12 14 < 40 40–49 50–59  60 < 200 230–259 200–229  260 HDL-C (mg/dL) Total-C (mg/dL) 14-y incidence rates (%) for CHD 11.24 11.91 12.50 11.91 6.56 4.67 9.05 5.53 4.85 4.15 3.77 2.78 2.06 3.83 10.7 6.6
    14. 16. Lp(a) in Atherogenesis: Another Culprit? <ul><li>Identical to LDL particle except for addition of apo(a) </li></ul><ul><li>Plasma concentration predictive of atherosclerotic disease in many epidemiologic studies, although not all </li></ul><ul><li>Accumulates in atherosclerotic plaque </li></ul><ul><li>Binds apo B-containing lipoproteins and proteoglycans </li></ul><ul><li>Taken up by foam cell precursors </li></ul><ul><li>May interfere with thrombolysis </li></ul>Maher VMG et al. JAMA . 1995;274:1771-1774. Stein JH, Rosenson RS. Arch Intern Med . 1997;157:1170-1176.
    15. 17. Lp(a): An Independent CHD Risk Factor in Men of the Framingham Offspring Cohort RR=relative risk; HT=hypertension; GI=glucose intolerance. Bostom AG et al. JAMA . 1996;276:544-548. 1.9 1.8 1.8 1.2 2.7 3.6 RR 0.1 1 10 2 5 0.2 0.5 Lp(a) TC HDL-C HT GI Smoking
    16. 18. LDL Particle Size Subclass: Fasting triglycerides of 175 mg/dl or greater or TG/HDL ratio >3 is a good surrogate of small, dense LDL particle side IDL L3 L2 L1 large, buoyant small, dense A B AB
    17. 19. Accumulation of Other Risk Factors Compound Effects of Dyslipidemia on Risk of CHD Low HDL Smoking Hyperglycemia Hypertension No Other Risk Factors Schaefer EJ, adapted from the Framingham Heart Study CHD Risk Per 1000 (in 6 years) Serum Cholesterol (mg/dL)
    18. 20. Primary and Secondary Prevention Trials With Statins Adapted from Ballantyne CM. Am J Cardiol. 1998;82:3Q-12Q . 2° prevention placebo 2° prevention statin 1° prevention placebo 1° prevention statin 0 5 10 15 20 25 30 80 90 100 110 120 130 140 150 160 170 180 190 200 LDL-C Achieved (mg/dL) AFCAPS AFCAPS WOSCOPS WOSCOPS CARE CARE LIPID LIPID 4S 4S Event Rate (%) HPS HPS
    19. 21. Cholesterol Treatment Trialists’ (CCT) Collaboration: Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis fo data from 90,056 participants in 14 randomized trials of statins (The Lancet 9/27/05) <ul><li>Over average 5 year treatment period (per mmol/L reduction—approx 40 mg/dl in LDL-C): </li></ul><ul><ul><li>12% reduction in all-cause mortality </li></ul></ul><ul><ul><li>19% reduction in coronary mortality </li></ul></ul><ul><ul><li>23% reduction in MI or CHD death </li></ul></ul><ul><ul><li>17% reduction in stroke </li></ul></ul><ul><ul><li>21% reduction in major vascular events </li></ul></ul><ul><ul><li>No difference in cancer incidence (RR=1.00). </li></ul></ul><ul><li>Statin therapy can safely reduce 5-year incidence of major coronary events, revascularization, and stroke by about 20% per mmol/L (about 38 mg/dl) reduction in LDL-C </li></ul>
    20. 22. Meta-analysis of Statin Trials HDL-C LaRosa JC et al. JAMA . 1999;282:2340-2346. 5 0 -5 -10 -15 -20 -25 -30 -35 -28 + 5 -13 -31 -29 -21 LDL-C TG Coronary Events Fatal CHD Total Mortality Change (%)
    21. 23. Statin Trials: Therapy Reduces Major Coronary Events in Women n = number of women enrolled. * 4S = primarily CHD death and nonfatal MI; CARE = coronary death, nonfatal MI, angioplasty, or bypass surgery; AFCAPS/TexCAPS = fatal/nonfatal MI, unstable angina, or sudden cardiac death. Miettinen TA et al. Circulation . 1997;96:4211-4218. Lewis SJ et al. J Am Coll Cardiol . 1998;32:140-146. Downs JR et al. JAMA . 1998;279:1615-1622. 4S (n=827) CARE (n=576) AFCAPS/TexCAPS (n=997) 2  Prevention 1  Prevention -50 -45 -40 -35 -30 -25 -20 -15 -10 -5 0 5 10 Major coronary events* -34 -46 -46 %  P =0.012 P =0.001
    22. 24. Effects of Statins on Stroke: A Meta-analysis of Primary- and Secondary-Prevention Trials Crouse JR et al. Arch Intern Med. 1997;157:1305-1310. * P =0.001. † 95% confidence interval of percentage of relative reduction. Relative reduction in rates (%) 1° Prevention (-42 to -27) † 2° Prevention (13-45) † Combined (11-40) †
    23. 25. HPS: First Major Coronary Event 0.4 0.6 0.8 1.0 1.2 1.4 Nonfatal MI Coronary death Subtotal: MCE Coronary Noncoronary Subtotal: any RV Any MVE Coronary events Revascularizations Type of Major Vascular Event Statin- Allocated (n = 10269) Placebo- Allocated (n = 10267 ) 357 (3 .5%) 574 (5 .6%) 587 (5 .7%) 707 (6 .9%) 898 (8 .7%) 1212 (11 .8%) 513 (5 .0%) 725 (7 .1%) 450 (4 .4%) 532 (5 .2%) 939 (9 .1%) 1205 (11 .7%) 2033 (19 .8%) 2585 (25 .2%) 0.73 (0.67  0.79) P < 0.0001 0.76 (0.70  0.83) P < 0.0001 0 .76 (0.72  0.81) P < 0.0001 Statin Better Placebo Better Heart Protection Study Collaborative Group . Lancet. 2002;360:7  22.
    24. 26. HPS — Simvastatin: Vascular Events by Baseline LDL-C Event Rate Ratio (95% CI) Statin Better Statin Worse www.hpsinfo.org 0.76 (0.72 –0.81) P < 0.0001 358 (21.0%) 282 (16.4%) <100 871 (24.7%) 668 (18.9%) 100–129 2585 (25.2%) 2033 (19.8%) All patients 1356 (26.9%) 1083 (21.6%)  130 Placebo (n = 10,267) Statin (n = 10,269) Baseline LDL-C (mg/dL) 0.4 0.6 0.8 1.0 1.2 1.4
    25. 27. HPS: Incidence of MI and stroke in diabetic patients without prior disease Collins R et al. Presented at the American Heart Association Scientific Sessions. November 13, 2001. <0.0001 p value 369 (18.7%) Placebo (n=1976) 28% Relative reduction (adjusted) 279 (13.9%) Simvastatin (n=2006)
    26. 28. Collaborative Atorvastatin Diabetes Study (CARDS) <ul><li>2838 patients aged 40-75 with type 2 diabetes, no prior CVD, but at least 1 of the following: retinopathy, albuminuria, smoking, or hypertension </li></ul><ul><li>Randomization to 10 mg atorvastatin or placebo </li></ul><ul><li>Mean follow-up 3.9 years </li></ul><ul><li>Reduction in all CVD events of 37% (p=0.001), all cause mortality 27% (p=0.059). CHD events reduced 36% and stroke 48%. </li></ul>Colhoun HM et al., The Lancet 2004; 364: 685-696
    27. 29. ASCOT: Primary Endpoint: Nonfatal MI/Fatal CHD Sever PS et al, for the ASCOT Investigators. Lancet . 2003;361:1149-1158. 0 1 2 3 4 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Years Cumulative Incidence (%) 36% reduction HR = 0.64 (0.50-0.83) Atorvastatin 10 mg Number of events 100 Placebo Number of events 154 P = 0.0005
    28. 30. TNT: Rationale (1.6) (2.1) (2.6) (3.1) (3.6) (4.1) (4.7) (5.2) Atorvastatin 80 mg Atorvastatin 10 mg Screening TNT ? Adapted from LaRosa et al. N Engl J Med. 2005:352:1425-1435. LDL-C, mg/dL (mmol/L) Patients With CHD Events (%)
    29. 31. TNT: Changes in LDL-C by Treatment Group Final Screen 0 3 12 24 36 48 60 P <.001 Baseline Mean LDL-C (mmol/L) Mean LDL-C level = 101 mg/dL (2.6 mmol/L) Mean LDL-C level = 77 mg/dL (2.0 mmol/L) LaRosa et al. N Engl J Med. 2005;352:1425-1435. Mean LDL-C (mg/dL) Study Visit (Months) 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0
    30. 32. TNT: Primary Efficacy Outcome Measure: Major Cardiovascular Events* * CHD death, nonfatal non – procedure-related MI, resuscitated cardiac arrest, fatal or nonfatal stroke. LaRosa et al. N Engl J Med. 2005;352:1425-1430. HR=0.78 (95% CI 0.69, 0.89); P <.001 Proportion of Patients Experiencing Major Cardiovascular Event 0 0.05 0.10 0.15 Atorvastatin 10 mg Atorvastatin 80 mg Relative risk reduction 22% 0 1 2 3 4 5 6 Time (Years) Mean LDL-C level = 77 mg/dL Mean LDL-C level = 101 mg/dL
    31. 34. Are LDL and HDL Effects Additive? R2 = 0.8512 0 20 40 60 80 100 0 10 20 30 40 50 60 70 80 % Absolute Change in LDL+HDL % CV Event RRR 4S VA HIT DAIS BIP AFCAPS/ TexCAPS WOSCOPS LIPID CARE, HPS HHS CDP ASCOT ALLHAT PROSPER 2 nd Order Relationship HATS FATS FATS F/U
    32. 35. HATS: Percent Change in Stenosis -1.0 -0.5 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 Change (%) * P = 0.16 for comparison with placebo; † P < 0.001; ‡ P = 0.004. HATS = HDL-Atherosclerosis Treatment Study. Adapted from Brown BG et al. N Engl J Med. 2001;345:1583-1592. Placebo Antioxidant Simvastatin/ Simvastatin / Vitamins* Niacin † Niacin/ Antioxidants ‡
    33. 36. Simvastatin-niacin 97% All placebos 76% RR = 0.10 P = 0.03 0 1 2 3 0 70 80 90 100 HATS = HDL-Atherosclerosis Treatment Study. Adapted from Brown BG et al. N Engl J Med. 2001;345:1583-1592. HATS: Patients Free of Events Patients Free of Events (%) Years
    34. 37. ARBITER 2: Primary Endpoint Carotid IMT Across 12 Months <ul><li> CIMT at 12 months </li></ul><ul><li>Statin vs ER niacin + statin P = 0.08 </li></ul><ul><li>Intent-to-treat analysis of statin vs. ER niacin + statin P = 0.048 </li></ul><ul><li>Non-Insulin resistant pts only: statin vs. ER niacin P = 0.026 </li></ul>Taylor AJ, et al. ARBITER 2: A double-blind, placebo-controlled study of extended-release niacin on Atherosclerosis progression in secondary prevention patients treated with statins. Circulation . 2004 68% decrease in progression 0 0.01 0.02 0.03 0.04 0.05 0.06 0.07 Change in CIMT (mm +/- SEM) ER Niacin Placebo
    35. 38. How low to go? Recent Findings from PROVE-IT and REVERSAL <ul><li>PROVE-IT (Cannon CP et al., NEJM 2004; 350: 1495-1504) </li></ul><ul><ul><li>randomized 4162 ACS pts to 80 mg atorvastatin vs. 40 mg pravastatin </li></ul></ul><ul><ul><li>median on-treatment LDL-C of 62 mg/dl vs. 95 mg/dl. </li></ul></ul><ul><ul><li>16% reduction of combined death, MI, unstable angina req. hosp., stroke, and revas in 30 days on atorvastatin </li></ul></ul><ul><li>REVERSAL (Nissen SE et al., JAMA 2004; 291: 1071-80) </li></ul><ul><ul><li>randomized 654 pts to atorvastatin 80 mg vs. pravastatin 40 mg; 502 and evaluable IVUS at baseline and after 18 mos on treatment. </li></ul></ul><ul><ul><li>On-treatment LDL-C 79 mg/dl on atorvastatin and 110 mg/dl on pravastatin. </li></ul></ul><ul><ul><li>Those on atorvastatin showed significantly less progression of atheroma volume </li></ul></ul>
    36. 39. Late Breaking Clinical Trial, ACC 3/8/05 Treating to New Targets (TNT) Study <ul><li>10,001 pts with CAD randomized to 10 mg atorvastatin (n=5006) vs. 80m mg atorvastatin (n=4995) for 4.9 years, reducing LDL-C to 101 mg/dl and 77 mg/dl, respectively </li></ul><ul><li>Total major cardiovascular events were 10.9% on low dose atorvastatin vs. 8.7% on high dose atorvastatin, representing a 22% reduction in risk </li></ul><ul><li>Provides evidence that treatment to a lower target below the recommended 100 mg/dl goal will provide additional benefit in preventing cardiovascular events </li></ul>N Engl J Med, 3/8/05
    37. 40. NCEP ATP III: Evaluation— Major Risk Factors for CAD <ul><li>Age (men  45 y; women  55 y) </li></ul>Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA . 2001;285:2486. <ul><li>Cigarette smoking </li></ul><ul><li>Hypertension (BP  140/90 mm Hg or antihypertensive medication) </li></ul><ul><li>HDL-C <40 mg/dL </li></ul><ul><li>Family history of premature CAD </li></ul><ul><ul><li><55 y in first-degree male relative </li></ul></ul><ul><ul><li><65 y in first-degree female relative </li></ul></ul>
    38. 41. NCEP ATP III: Evaluation— CAD Risk Equivalents <ul><li>Diabetes </li></ul>Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA . 2001;285:2486. <ul><li>Atherosclerotic disease </li></ul><ul><ul><li>Peripheral artery disease </li></ul></ul><ul><ul><li>Abdominal aortic aneurysm </li></ul></ul><ul><ul><li>Symptomatic carotid artery disease </li></ul></ul><ul><li>CAD 10-year risk >20% </li></ul>
    39. 42. NCEP ATP III: Evaluation — Need for Framingham Calculation Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA . 2001;285:2486. No >20% CAD or CAD risk equivalent Yes 0%-10%  2 RF No <10%  1 RF Need for Framingham Calculation 10-Year Risk for CAD Risk Profile Yes 10%-20%
    40. 43. Assessing CHD Risk in Men Note: Risk estimates were derived from the experience of the Framingham Heart Study, a predominantly Caucasian population in Massachusetts, USA. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA . 2001;285:2486-2497. Step 2: Total Cholesterol TC Points at Points at Points at Points at Points at (mg/dL) Age 20-39 Age 40-49 Age 50-59 Age 60-69 Age 70-79 <160 0 0 0 0 0 160-199 4 3 2 1 0 200-239 7 5 3 1 0 240-279 9 6 4 2 1  280 11 8 5 3 1 Point Total 10-Year Risk Point Total 10-Year Risk <0 <1% 11 8% 0 1% 12 10% 1 1% 13 12% 2 1% 14 16% 3 1% 15 20% 4 1% 16 25% 5 2%  17  30% 6 2% 7 3% 8 4% 9 5% 10 6% Step 7: CHD Risk ATP III Framingham Risk Scoring © 2001, Professional Postgraduate Services ® www.lipidhealth.org Step 1: Age Years Points 20-34 -9 35-39 -4 40-44 0 45-49 3 50-54 6 55-59 8 60-64 10 65-69 11 70-74 12 75-79 13 HDL-C (mg/dL) Points  60 -1 50-59 0 40-49 1 <40 2 Step 3: HDL-Cholesterol Systolic BP Points Points (mm Hg) if Untreated if Treated <120 0 0 120-129 0 1 130-139 1 2 140-159 1 2  160 2 3 Step 4: Systolic Blood Pressure Step 5: Smoking Status Points at Points at Points at Points at Points at Age 20-39 Age 40-49 Age 50-59 Age 60-69 Age 70-79 Nonsmoker 0 0 0 0 0 Smoker 8 5 3 1 1 Age Total cholesterol HDL-cholesterol Systolic blood pressure Smoking status Point total Step 6: Adding Up the Points
    41. 44. Assessing CHD Risk in Women Point Total 10-Year Risk Point Total 10-Year Risk <9 <1% 20 11% 9 1% 21 14% 10 1% 22 17% 11 1% 23 22% 12 1% 24 27% 13 2%  25  30% 14 2% 15 3% 16 4% 17 5% 18 6% 19 8% Note: Risk estimates were derived from the experience of the Framingham Heart Study, a predominantly Caucasian population in Massachusetts, USA. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA . 2001;285:2486-2497. TC Points at Points at Points at Points at Points at (mg/dL) Age 20-39 Age 40-49 Age 50-59 Age 60-69 Age 70-79 <160 0 0 0 0 0 160-199 4 3 2 1 1 200-239 8 6 4 2 1 240-279 11 8 5 3 2  280 13 10 7 4 2 Step 7: CHD Risk Step 2: Total Cholesterol ATP III Framingham Risk Scoring © 2001, Professional Postgraduate Services ® www.lipidhealth.org Step 1: Age Years Points 20-34 -7 35-39 -3 40-44 0 45-49 3 50-54 6 55-59 8 60-64 10 65-69 12 70-74 14 75-79 16 HDL-C (mg/dL) Points  60 -1 50-59 0 40-49 1 <40 2 Step 3: HDL-Cholesterol Systolic BP Points Points (mm Hg) if Untreated if Treated <120 0 0 120-129 1 3 130-139 2 4 140-159 3 5  160 4 6 Step 4: Systolic Blood Pressure Step 5: Smoking Status Points at Points at Points at Points at Points at Age 20-39 Age 40-49 Age 50-59 Age 60-69 Age 70-79 Nonsmoker 0 0 0 0 0 Smoker 9 7 4 2 1 Age Total cholesterol HDL-cholesterol Systolic blood pressure Smoking status Point total Step 6: Adding Up the Points
    42. 45. NCEP ATP III Guidelines: Treatment  1 RF  2 RFs equivalent CAD risk Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA . 2001;285:2486. Risk Category (10-year risk 0%-10%) (10-year risk 10%-20%) CAD or <160 <130 <100 <130 LDL - C Goal (mg/dL)  160  130  100  130 LDL - C Level to Initiate TLC (mg/dL) LDL - C Level to Initiate Drug Therapy (mg/dL)  190  160  130  130
    43. 46. NCEP ATP III: Setting Goals— Secondary – Non-HDL-C  1 RF <190  2 RFs (CAD risk  20%) <160 CAD or CAD risk equivalent <130 (CAD risk >20%) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA . 2001;285:2486.   Risk Category Non–HDL-C Goal (mg/dL) (Patients With TG  200)
    44. 47. NCEP ATP III Guidelines: Treatment Therapeutic Lifestyle Change (TLC) Improve diet Weight reduction Physical activity Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA . 2001;285:2486. Pharmacologic Treatment Statins (HMG-CoA reductase inhibitors) Fibrates Niacin Bile acid sequestrants
    45. 48. I have some bad news for you. While your cholesterol has remained the same, the research findings have changed.
    46. 49. Lipid Management Goal LDL-C should be less than 100 mg/dL Further reduction to LDL-C to < 70 mg/dL is reasonable *Non-HDL-C = total cholesterol minus HDL-C If TG > 200 mg/dL, non-HDL-C should be < 130 mg/dL* I I I IIa IIa IIa IIb IIb IIb III III III I I I IIa IIa IIa IIb IIb IIb III III III I I I IIa IIa IIa IIb IIb IIb III III III IIa IIa IIa IIb IIb IIb III III III
    47. 50. Grundy, S. et al. Circulation 2004;110:227-39. Lipid Management Goals: NCEP ATP=Adult Treatment Panel, CHD=Coronary heart disease, LDL-C=Low-density lipoprotein cholesterol, TLC=Therapeutic lifestyle changes > 100 mg/dL (<100 mg/dL: consider drug options)  100 mg/dL <100 mg/dL if TG > 200 mg/dL, non-HDL-C should be < 130 mg/dL High risk: CHD or CHD risk equivalents (10-year risk >20%) and All patients Initiate TLC > 100 mg/dL (<100 mg/dL: consider drug options) Consider Drug Therapy <70 mg/dL, non-HDL-C < 100 mg/dL LDL-C and non-HDL-C Goal Risk Category Very high risk: ACS or established CHD plus: multiple major risk factors (especially diabetes) or severe and poorly controlled risk factors
    48. 51. Lipid Management Recommendations Start dietary therapy (<7% of total calories as saturated fat and <200 mg/d cholesterol) Adding plant stanol/sterols (2 gm/day) and viscous fiber (>10 mg/day) will further lower LDL Promote daily physical activity and weight management. Encourage increased consumption of omega-3 fatty acids in fish or 1 g/day omega-3 fatty acids in capsule form for risk reduction. For all patients I I I IIa IIa IIa IIb IIb IIb III III III I I I IIa IIa IIa IIb IIb IIb III III III I I I IIa IIa IIa IIb IIb IIb III III III IIa IIa IIa IIb IIb IIb III III III
    49. 52. Lipid Management Recommendations If baseline LDL-C > 100 mg/dL, initiate LDL-lowering drug therapy If on-treatment LDL-C > 100 mg/dL, intensify LDL-lowering drug therapy (may require LDL lowering drug combination) If baseline is LDL-C 70 to 100 mg/dL, it is reasonable to treat to LDL < 70 mg/dL Assess fasting lipid profile in all patients, and within 24 hours of hospitalization for those with an acute event. For patients hospitalized, initiate lipid-lowering medication as recommended below prior to discharge according to the following schedule: When LDL lowering medications are used, obtain at least a 30-40% reduction in LDL-C levels. I I I IIa IIa IIa IIb IIb IIb III III III I I I IIa IIa IIa IIb IIb IIb III III III I I I IIa IIa IIa IIb IIb IIb III III III IIa IIa IIa IIb IIb IIb III III III
    50. 53. Lipid Management Recommendations If TG are 200-499 mg/dL, non-HDL-C should be < 130 mg/dL Further reduction of non-HDL to < 100 mg/dL is reasonable Therapeutic options to reduce non-HDL-C: More intense LDL-C lowering therapy I (B) or Niacin (after LDL-C lowering therapy) IIa (B) or Fibrate (after LDL-C lowering therapy) IIa (B) If TG are > 500 mg/dL, therapeutic options to prevent pancreatitis are fibrate or niacin before LDL lowering therapy; and treat LDL-C to goal after TG-lowering therapy. Achieve non-HDL-C < 130 mg/dL, if possible I I I IIa IIa IIa IIb IIb IIb III III III I I I IIa IIa IIa IIb IIb IIb III III III I I I IIa IIa IIa IIb IIb IIb III III III IIa IIa IIa IIb IIb IIb III III III I I I IIa IIa IIa IIb IIb IIb III III III I I I IIa IIa IIa IIb IIb IIb III III III I I I IIa IIa IIa IIb IIb IIb III III III IIa IIa IIa IIb IIb IIb III III III
    51. 54. Event Rate Ratio (95% CI) Statin Better Statin Worse 0.76 (0.72 –0.81) P<0.0001 Heart Protection Study (HPS) HMG-CoA Reductase Inhibitor: Secondary Prevention 20,536 patients with CAD, other occlusive arterial disease, or DM randomized to simvastatin (40 mg) or placebo for 5.5 years CAD=Coronary artery disease, CI=Confidence interval, DM=Diabetes mellitus, HPS Collaborative Group. Lancet 2002;360:7-22 358 (21.0%) 282 (16.4%) <100 871 (24.7%) 668 (18.9%) 100–129 2585 (25.2%) 2033 (19.8%) All patients 1356 (26.9%) 1083 (21.6%)  130 Placebo (n = 10,267) Statin (n = 10,269) Baseline LDL-C (mg/dL) 0.4 0.6 0.8 1.0 1.2 1.4
    52. 55. Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT)—TIMI 22 Study ACS=Acute coronary syndrome, CV=Cardiovascular, MI=Myocardial infarction, RRR=Relative risk reduction Cannon CP et al. NEJM 2004;350:1495-1504 HMG-CoA Reductase Inhibitor: Secondary Prevention 4,162 patients with an ACS randomized to atorvastatin (80 mg) or pravastatin (40 mg) for 24 months 3 6 9 12 15 18 21 24 27 30 Follow-up (months) 30 25 20 15 10 5 0 P =0.005 Recurrent MI or Cardiac Death 16% RRR Atorvastatin Pravastatin
    53. 56. LaRosa JC et al. NEJM. 2005;352:1425-1435 LDL-C=Low density lipoprotein cholesterol; TNT=Treating to New Targets; HPS=Heart Protection Study; CARE=Cholesterol and Recurrent Events Trial; LIPID=Long-term Intervention with Pravastatin in Ischaemic Disease; 4S=Scandinavian Simvastatin Survival Study. Statin Placebo Relationship between LDL Levels and Event Rates in Secondary Prevention Trials of Patients with Stable CHD HMG-CoA Reductase Inhibitor: Secondary Prevention 30 25 20 15 10 5 0 0 70 90 110 130 150 170 190 210 LDL-C (mg/dL) TNT (atorvastatin 80 mg/d) TNT (atorvastatin 10 mg/d) HPS CARE LIPID LIPID CARE HPS Event (%) 4S 4S
    54. 58. Therapeutic Lifestyle Changes in LDL-Lowering Therapy: Major Features <ul><li>Saturated fats <7% of total calories </li></ul><ul><li>Dietary cholesterol <200 mg per day </li></ul><ul><li>Plant stanols/sterols (2 g per day) </li></ul><ul><li>Viscous (soluble) fiber (10–25 g per day) </li></ul><ul><li>Weight reduction </li></ul><ul><li>Increased physical activity </li></ul>
    55. 59. Plant Sterol and Stanol Esters <ul><li>Low absorption </li></ul><ul><li>Reduce LDL-C by 10%-15% </li></ul><ul><li>May interfere with absorption of lipid-soluble vitamins </li></ul><ul><li>Plant stanol esters </li></ul><ul><ul><li>Saturated derivatives of plant sterol esters </li></ul></ul><ul><ul><li>Very low absorption </li></ul></ul>Nguyen. J Nutr . 1999;129:2109.
    56. 60. Therapeutic Lifestyle Changes Nutrient Composition of TLC Diet <ul><li>Nutrient Recommended Intake </li></ul><ul><li>Saturated fat Less than 7% of total calories </li></ul><ul><li>Polyunsaturated fat Up to 10% of total calories </li></ul><ul><li>Monounsaturated fat Up to 20% of total calories </li></ul><ul><li>Total fat 25–35% of total calories </li></ul><ul><li>Carbohydrate 50–60% of total calories </li></ul><ul><li>Fiber 20–30 grams per day </li></ul><ul><li>Protein Approximately 15% of total calories </li></ul><ul><li>Cholesterol Less than 200 mg/day </li></ul><ul><li>Total calories (energy) Balance energy intake and expenditure to maintain desirable body weight </li></ul>
    57. 61. Effect of Mediterranean-style diet in the metabolic syndrome <ul><li>180 pts with metabolic syndrome randomized to Mediterranean-style vs. prudent diet for 2 years </li></ul><ul><li>Those in intervention group lost more weight (-4kg) than those in the control group (+0.6kg) (p<0.01), and significant reductions in CRP and Il-6. </li></ul><ul><li>After 2 years, 40 pts in intervention group still had features of metabolic syndrome compared to 78 pts in the control group </li></ul>Esposito K et al. JAMA 2004; 292(12): 1440-6.
    58. 62. Dietary Approaches to Stop Hypertension (DASH) <ul><li>Diet high in fruits and vegetables and low-fat dairy products lowers blood pressure more than a sodium-restricted diet </li></ul><ul><li>7-8 servings/day of grain/grain products, 4-5 vegetable, 4-5 fruit, 2-3 low- or non-fat dairy products, 2 or less meat, poultry, and fish. </li></ul><ul><li>NEJM 1997; 366: 1117-24. </li></ul>
    59. 63. Comparison of Atkins, Ornish, Weight Watchers, and Zone diets for weight loss and heart disease risk reduction: a randomized trial <ul><li>160 subjects randomized, 40 to each diet, for 2 months of maximum adherence, and self-selected adherence for rest of year </li></ul><ul><li>After 1 year, mean wt loss 2.1 kg for Atkins, 3.2 kg for Zone, 3.0 kg for Weight Watchers, and 3.3 kg for Ornish. </li></ul>Dansinger et al., JAMA 2005; 293: 43-53.
    60. 64. Comparison of diets (cont.) <ul><li>53% completed Atkins, 65% Zone, 65% Weight Watchers, and 50% Ornish </li></ul><ul><li>Each diet significantly reduced LDL-C/HDL-C ratio by about 10%, no sig effects on blood pressure or glucose. </li></ul><ul><li>Weight loss related to self-reported dietary adherence or type of diet; decreases in total/HDL-C, CRP, and insulin significantly related to weight loss </li></ul>
    61. 65. Possible Benefits From Other Therapies Therapy Result <ul><li>Soluble fiber in diet (2 – 8 g/d) (oat bran, fruit, and vegetables) </li></ul><ul><li>Soy protein (20 – 30 g/d) </li></ul><ul><li>Stanol esters (1.5 – 4 g/d) (inhibit cholesterol absorption) </li></ul><ul><li>Fish oils (3 – 9 g/d) </li></ul><ul><li>(n-3 fatty acids) </li></ul> LDL-C 1% to 10%  LDL-C 5% to 7%  LDL-C 10% to 15%  Triglycerides 25% to 35% Jones PJ. Curr Atheroscler Rep. 1999;1:230-235. Lichtenstein AH. Curr Atheroscler Rep. 1999;1:210-214. Rambjor GS et al. Lipids. 1996;31:S45-S49. Ripsin CM et al. JAMA. 1992;267:3317-3325.
    62. 66. Dietary Adjuncts <ul><li>TLC for patients with LDL-C = 160 </li></ul>Walden CE et al. Arterioscler Thromb Vasc Biol 1997;17:375-382. Jenkins DJ et al. Curr Opin Lipidol 2000;11:49-56. Cato N. Stanol meta-analysis. Personal communication, 2000. – 36 mg/dl Total – 16 Plant stanols/sterols (2 g/d) – 8 Viscous fiber (10–25 g/d) – 12 Low saturated fat/dietary cholesterol LDL-C  (mg/dL) Dietary Component
    63. 67. A Model of Steps in Therapeutic Lifestyle Changes (TLC) <ul><li>Reinforce reduction in saturated fat and cholesterol </li></ul><ul><li>Consider adding plant stanols/sterols </li></ul><ul><li>Increase fiber intake </li></ul><ul><li>Consider referral to a dietitian </li></ul><ul><li>Initiate Tx for Metabolic Syndrome </li></ul><ul><li>Intensify weight management & physical activity </li></ul><ul><li>Consider referral to a dietitian </li></ul>6 wks 6 wks Q 4-6 mo <ul><li>Emphasize reduction in saturated fat & cholesterol </li></ul><ul><li>Encourage moderate physical activity </li></ul><ul><li>Consider referral to a dietitian </li></ul>Monitor Adherence to TLC Visit N Visit I Begin Lifestyle Therapies Visit 2 Evaluate LDL response If LDL goal not achieved, intensify LDL-Lowering Tx Visit 3 Evaluate LDL response If LDL goal not achieved, consider adding drug Tx
    64. 68. Factors Influencing Noncompliance <ul><li>Number of daily doses and medications </li></ul><ul><li>Occurrence and severity of side effects </li></ul><ul><li>Incompatibility with patients’ daily routine </li></ul><ul><li>Inadequate physician-patient communication </li></ul><ul><li>Cost </li></ul>
    65. 69. Questran ® Prescribing Information, Colestid ® Prescribing Information, WelChol ® Prescribing information, Niaspan ® Prescribing Information, Lopid ® Prescribing Information, TriCor ® Prescribing Information, Lipitor ® Prescribing Information, Zocor ® Prescribing Information, Mevaco ® r Prescribing Information, Lescol ® Prescribing Information, Pravacol ® Prescribing Information; Zetia ® Prescribing Information. Effect of Lipid-modifying Therapies TC–total cholesterol, LDL–low density lipoprotein, HDL–high density lipoprotein, TG–triglyceride. * Daily dose of 40mg of each drug, excluding rosuvastatin. Good  9%   1%   18%  13% Ezetimibe Good  14-29%  4-12%  25-50%  19-37% Statins* Good   30%  11-13%   4-21%   19% Fibrates (gemfibrozil) Poor to reasonable  30-70%  14-35%  10-20%  10-20% Nicotinic acid Poor Neutral or   3%   10-18%   7-10% Bile acid sequestrants Patient tolerability TG HDL LDL TC Therapy
    66. 70. Pharmacologic Therapy: Niacin <ul><li>Reduces HDL catabolism and VLDL production </li></ul><ul><li>Primarily used to treat low HDL-C (15%-35%  ) and elevated TG (20%-50%  ) </li></ul><ul><li>LDL-C  5%-25% </li></ul><ul><li>Side effects </li></ul><ul><ul><li>Hepatotoxicity, hyperglycemia, hyperuricemia, upper GI distress, flushing, itching </li></ul></ul><ul><li>Contraindicated in patients with liver disease, gout, peptic ulcer </li></ul>Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA . 2001;285:2486.
    67. 71. Pharmacologic Therapy: Fibrates <ul><li>Inhibit hepatic TG production and increase HDL production </li></ul><ul><li>Used to treat elevated TG (20%-50%  ) and low HDL-C (10%-20%  ) </li></ul><ul><li>Variable effect on LDL-C </li></ul><ul><li>Side effects </li></ul><ul><ul><li>Dyspepsia, gallstones, myopathy </li></ul></ul><ul><ul><li>Increased with statins </li></ul></ul><ul><li>Contraindicated in patients with severe renal or hepatic disease </li></ul>Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA . 2001;285:2486.
    68. 72. Drug Therapy <ul><li>HMG CoA Reductase Inhibitors (Statins) </li></ul><ul><li>Reduce LDL-C 18–55% & TG 7–30% </li></ul><ul><li>Raise HDL-C 5–15% </li></ul><ul><li>Major side effects </li></ul><ul><ul><li>Myopathy </li></ul></ul><ul><ul><li>Increased liver enzymes </li></ul></ul><ul><li>Contraindications </li></ul><ul><ul><li>Absolute: liver disease </li></ul></ul><ul><ul><li>Relative: use with certain drugs </li></ul></ul>
    69. 73. Effect of Statin Therapy on LDL-C Levels: “The Rule of 6” Illingworth DR. Med Clin North Am . 2000;84:23-42.
    70. 74. Percentage Change From Baseline in LDL-C at Week 6 by Dose (ITT) 1,2 Atorvastatin Rosuvastatin 10 mg 20 mg 40 mg 80 mg Dose <ul><li>*P<. 002 vs atorvastatin 10 mg; simvastatin 10 mg, 20 mg, 40 mg; pravastatin 10 mg, 20 mg, 40 mg </li></ul><ul><li>** P< .002 vs atorvastatin 20 mg, 40 mg; simvastatin 20 mg, 40 mg, 80 mg; pravastatin 20 mg, 40 mg </li></ul><ul><li>† P< .002 vs atorvastatin 40 mg; simvastatin 40 mg, 80 mg; pravastatin 40 mg </li></ul><ul><li>Jones PH, Davidson MH, Stein EA, et al. Am. J. Cardiology 2003; 93: 152-160. </li></ul><ul><li>Data on file, DA-CRS-02 AstraZeneca Pharmaceuticals LP, Wilmington, DE. </li></ul>* ** † Mean Percent Change From Baseline in LDL-C (  SE) Pravastatin Simvastatin – 60 – 50 – 40 – 30 – 20 – 10 0
    71. 75. When LDL-lowering drug therapy is employed in high-risk or moderately high risk patients, intensity of therapy should be sufficient to achieve a 30–40% reduction in LDL-C levels.
    72. 76. Grundy et al. Circulation. 2004;110:227-239. Doses of Statins Required to Attain 30-40% Reduction of LDL-C 39 10 Atorvastatin 39-45 5-10 Rosuvastatin 25-35 40-80 Fluvastatin 35-41 20-40 Simvastatin 34 40 Pravastatin 31 40 Lovastatin LDL Reduction, % Dose, mg/d
    73. 77. Why combination therapy? <ul><li>Few patients achieve LDL-C goal on monotherapy </li></ul><ul><li>Uptitration of dosage is rare </li></ul><ul><li>LDL-C goals are getting more aggressive </li></ul><ul><li>High-dose statins increase risk of side effects </li></ul><ul><li>Can address mixed dyslipidemia (e.g., few pts achieve adequate control of HDL-C and triglycerides on monotherapy) </li></ul>
    74. 78. Options for Patients who Fail to Reach LDL-C Goal on Statin Monotherapy <ul><li>Niacin </li></ul><ul><li>Bile acid sequestrant </li></ul><ul><li>Cholesterol absorption inhibitor </li></ul>Addition of:
    75. 79. Combination Therapy With Intestinal- Acting Agents and Statins: Rationale <ul><li>Statins inhibit compensatory increase in cholesterol synthesis induced by blockade of cholesterol absorption </li></ul><ul><li>May increase ability to reach LDL-C goals </li></ul><ul><li>May allow use of a lower statin dose </li></ul>
    76. 80. Bile Acid Sequestrants <ul><li>Major actions </li></ul><ul><ul><li>Reduce LDL-C 15%-30% </li></ul></ul><ul><ul><li>Raise HDL-C 3% -5% </li></ul></ul><ul><ul><li>May increase TG </li></ul></ul><ul><li>Side effects </li></ul><ul><ul><li>GI distress/constipation </li></ul></ul><ul><ul><li>Decreased absorption of other drugs (1st generation) </li></ul></ul><ul><li>Contraindications </li></ul><ul><ul><li>Dysbetalipoproteinemia </li></ul></ul><ul><ul><li>Elevated TG (especially >400 mg/dL) </li></ul></ul>
    77. 81. New Bile Acid Sequestrant : Colesevelam <ul><li>Lower dose for effect </li></ul><ul><li>Fewer GI complaints than with other bile acid sequestrants </li></ul><ul><li>Reduces absorption of  -carotene </li></ul><ul><li>Requires 4-6 tablets/day </li></ul>Davidson et al. Expert Opin Investig Drugs . 2000;9:2663.
    78. 82. Colesevelam Monotherapy: Efficacy Insull et al. Mayo Clin Proc . 2001;76:971. * P <0.001 vs placebo. † P =0.04 vs placebo. % Change from baseline at wk 24 TG HDL-C LDL-C * † Placebo (n=88) Colesevelam 3.8 g/d (n=95)
    79. 83. Limitations of Current Intestinal-Acting Agents <ul><li>Bile acid sequestrants </li></ul><ul><ul><li>Noncompliance </li></ul></ul><ul><ul><li>GI tolerability </li></ul></ul><ul><ul><li>Reduced absorption of lipid-soluble vitamins </li></ul></ul><ul><ul><li>May increase TG in patients with hypertriglyceridemia </li></ul></ul><ul><li>Plant stanol and sterol esters </li></ul><ul><ul><li>Lack of selectivity </li></ul></ul><ul><ul><li>Some patients may find difficult to incorporate into diet </li></ul></ul><ul><ul><li>May reduce absorption of lipid-soluble vitamins </li></ul></ul>
    80. 84. Ezetimibe — Localizes at Brush Border of Small Intestine <ul><li>Ezetimibe, a selective cholesterol absorption inhibitor, localizes and appears to act at the brush border of the small intestine and inhibits cholesterol absorption </li></ul><ul><li>This results in </li></ul><ul><ul><li>A decrease in the delivery of intestinal cholesterol to the liver </li></ul></ul><ul><ul><li>A reduction of hepatic cholesterol stores and an increase in clearance of cholesterol from the blood </li></ul></ul>
    81. 85. Ezetimibe and Statins Complementary Mechanisms <ul><li>Ezetimibe reduces the delivery of cholesterol to the liver </li></ul><ul><li>Statins reduce cholesterol synthesis in the liver </li></ul><ul><li>The distinct mechanism of ezetimibe is complementary to that of statins </li></ul><ul><li>The effects of ezetimibe, either alone or in addition to a statin, on cardiovascular morbidity or mortality have not been established </li></ul>Knopp RH. N Engl J Med. 1999;341:498–511.
    82. 86. Coadministration: Simvastatin + Ezetimibe Mean Percent Change in LDL-C From Baseline Placebo (n = 11) -30 -20 -10 0 SIMVA 10 mg (n = 12) SIMVA 10+ EZE 10 mg (n = 11) -34.9* -51.9*† -3.2 -40 -50 -60 * P < 0.01 vs placebo † P < 0.01 vs simvastatin 10 mg Stein, E. Eur Heart J. 2001;3(suppl E):E14. 17%
    83. 87. ENHANCE Background <ul><li>Patients with FH have a greatly increased risk of developing premature coronary artery disease and an increased rate of progression of intima-media thickness (IMT) </li></ul><ul><li>Primary Outcome: change in the carotid IMT, an average of the right and left common carotid arteries, carotid bulbs, and internal carotid arteries </li></ul><ul><li>Secondary Outcomes: regression in mean carotid IMT, new plaque formation, and various individual measurements of the carotid artery </li></ul>Kastelien J. N Engl J Med . 2008; 358: 1431- 43.
    84. 88. ENHANCE Study Design RANDOMI ZAT I ON 0 24 Months 3 6 9 12 15 18 21 Pre-randomization Phase FH: LDL-c ≥ 210 mg/dL Screening and Fibrate Washout Placebo Lead-In/ Drug Washout Weeks -6 -10 to -7 IMT assessment N = 720 Kastelien J. N Engl J Med. 2008; 358: 1431- 43. Ezetimibe 10 mg-Simvastatin 80 mg Simvastatin 80 mg Simvastatin 80 mg Ezetimibe 10 mg-Simvastatin 80 mg
    85. 89. ENHANCE LDL Changes -16.5 % incremental reduction in LDL Kastelien J. N Engl J Med . 2008; 358: 1431- 43. Simvastatin Eze-Simva Months -40 0 6 12 18 24 -50 -60 -70 0 -10 -20 -30 10 Percentage change from baseline P<0.01 141 + 53 319 + 65 Eze-Simva 193 + 60 318 + 66 Simva 24 Months (mg/dL) Baseline (mg/dL)
    86. 90. ENHANCE Primary Outcome : Mean cIMT Kastelien J. N Engl J Med . 2008; 358: 1431- 43. 0.29 0.0111 ±0.0038 0.0058 ±0.0037 Change from baseline (mm) 0.29 0.71 ±0.15 0.70 ±0.14 Mean cIMT, 24 mo 0.64 0.69 ±0.13 0.70 ±0.13 Mean cIMT, baseline P value Simvastatin plus ezetimibe (n=338) Simvastatin monotherapy (n=342) Mean intima-media thickness of carotid artery (mm)
    87. 91. ENHANCE Mean cIMT during 24 months of therapy Mean cIMT (mm) Longitudinal, repeated measures analysis Kastelien J. N Engl J Med . 2008; 358: 1431- 43. 6 12 18 24 0.60 0.70 0.75 0.80 0.65 Months P=0.88 Simvastatin Eze-Simva
    88. 92. ENHANCE Conclusion <ul><li>Despite the observed improvements in lipid parameters, there were no significant differences in the change in carotid IMT between ezetimibe/simvastatin and simvastatin alone. </li></ul><ul><li>Reason(s) for this discrepancy currently remains unknown, however: </li></ul><ul><li>1. Measurement technique may not be accurate enough to reflect changes in atherosclerotic burden </li></ul><ul><li>2. Ezetimibe lacks vascular benefit despite the observed LDL-c and hsCRP reduction </li></ul><ul><li>3. The population studied may have been at too low a risk to detect changes, limiting the ability to detect a differential response </li></ul>Kastelien J. N Engl J Med. 2008; 358: 1431- 43.

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