Raising high-density lipoprotein cholesterol: where are we now?

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1 European Heart Journal Supplements (23) 5 (Supplement D), D17 D25 Raising high-density lipoprotein cholesterol: where are we now? Baylor College of Medicine, Houston, Texas, U.S.A. KEYWORDS Apolipoprotein; coronary heart disease; high-density lipoprotein cholesterol; statins Introduction In recent years, considerable attention has been paid to the importance of reducing levels of total cholesterol and low-density lipoprotein cholesterol (LDL-C) in order to reduce the risk for atherosclerosis and consequent coronary heart disease (CHD) in dyslipidaemic individuals. However, there is also considerable evidence that low levels of high-density lipoprotein cholesterol (HDL-C) are a contributory factor in the development of atherosclerosis and CHD. This association was initially recognized in early epidemiological studies. In the Framingham study, 1 for example, low HDL-C values were associated with increases in risk for CHD of approximately 7% in men and of more than 1% in women. Trials such as the Prospective Cardiovascular Münster (PROCAM) Correspondence: Christie M. Ballantyne, MD, Director, Center for Cardiovascular Disease Prevention, The Methodist DeBakey Heart Center, 6565 Fannin Street, MS A61, Suite A656B, Houston, TX 773, U.S.A. Low levels of high-density lipoprotein cholesterol (HDL-C) are acknowledged as an independent risk factor for coronary heart disease. Evidence from trials of fibrate and statin treatment indicate that increasing levels of HDL-C or apolipoprotein (apo)a-i, or decreasing the apob:apoa-i ratio produces significant benefit in reducing risk for coronary heart disease. These findings have indicated the potential need for defining therapeutic targets for HDL-C, apoa-i, or the apob:apoa-i ratio. Clinical trials have recently shown differences among statins in terms of their ability to raise levels of HDL-C and apoa-i and to reduce the apob:apoa-i ratio. Clinical trials are needed to test whether raising HDL-C or apoa-i and decreasing apob:apoa-i ratio should be goals in lipid-modifying therapy and to assist in defining specific target levels. 23 The European Society of Cardiology. Published by Elsevier Science Ltd. All rights reserved study 2 and the Framingham Offspring Study 3 demonstrated that low HDL-C is an independent predictor of risk after controlling for the presence of other CHD risk factors. More recently, the Atherosclerosis Risk in Communities (ARIC) study 4 has shown that HDL-C is a significant independent predictor of CHD risk. In this study, 12,339 middle-aged individuals without CHD were followed for CHD events for 1 years, with a total of 725 events being observed during follow-up. HDL-C, LDL-C and lipoprotein(a) were independent predictors of risk in both sexes, and triglyceride level was an independent predictor in women. As shown in Fig. 1, risk increased in a stepwise manner across quintiles of decreasing HDL-C levels in both men and women, with median values in the lowest risk (highest concentration) quintiles being 62 mg/dl in men and 81 mg/dl in women. There is increasing evidence that measurement of apolipoprotein (apo)a-i, the major apolipoprotein in HDL, also conveys important risk information. In the Apolipoprotein-related MOrtality RISk X/3/D $35./ 23 The European Society of Cardiology, Published by Elsevier Science Ltd. All rights reserved.

2 D18 Relative risk for CHD Relative risk for CHD Median: mmol/l mg/dl Median: mmol/l mg/dl Fig. 1 Relative risk for coronary heart disease (CHD) events according to HDL cholesterol quintile in men (top) and women (bottom) in the Atherosclerosis Risk in Communities (ARIC) study. (Data from Sharrett et al. 4 ) HDL-C=high-density lipoprotein cholesterol. (AMORIS) study, 5 for example, relative risk for fatal myocardial infarction among 175,553 individuals followed for more than 5 years decreased significantly in each progressively higher apoa-i concentration quartile in both men and women, mirroring the findings in the analysis of HDL-C. In that study, analysis of the interaction of apoa-i and apob showed increasing risk with decreasing apoa-i level quartiles and increasing apob level quartiles. HDL-C is now routinely measured in adult patients. The National Cholesterol Education Program Adult Treatment Panel III (ATP III) guidelines for lipid-lowering therapy 6 established an HDL-C below 4 mg/dl (1.3 mmol/l) as a major positive risk factor (increasing the categorical definition of low HDL-C from 35 mg/dl to the current level) and established HDL-C levels of 6 mg/dl or more as a negative risk factor (decreasing the total number of risk factors by one in risk scoring). Future guidelines may include some measure of apoa-i or apob:apoa-i ratio as a risk factor in a similar manner or provide specific therapeutic goals for HDL measures. In terms of current clinical practice, the issues to be confronted include identifying patients with low HDL-C levels who might benefit from pharmacological therapy, selecting optimal therapy and deciding whether raising HDL-C levels should be a specific goal of therapy. Adjusted for age and race; 12-year follow-up HDL-C quintiles in men Adjusted for age and race; 12-year follow-up HDL-C quintiles in women Effects on high-density lipoprotein cholesterol and CHD risk in fibrate treatment trials There is evidence that raising levels of HDL-C or apoa-i can reduce risk for CHD, particularly in patients with low levels of HDL-C. Some of this evidence is provided by trials of fibrates, supporting use of these agents in patients with low HDL-C levels or mixed dyslipidaemias. For example, the Veterans Affairs HDL Cholesterol Intervention Trial (VA-HIT) assessed the effects of gemfibrozil in preventing non-fatal myocardial infarction or CHD death in 2531 men with CHD who had low HDL-C values (<4 mg/dl [<1. mmol/l]) and low LDL-C levels (<14 mg/dl [<3.6 mmol/l). In the context of a 6% increase in HDL-C and a 31% decrease in triglycerides in gemfibrozil patients vs placebo patients and no difference in LDL-C between the two groups, gemfibrozil recipients had a significant 24% reduction in the primary endpoint over 5 years of follow-up. 7 It was estimated that every.13 mmol/l (5 mg/dl) increase in HDL-C was associated with a significant 11% reduction in risk for CHD events. 8 Post-hoc analyses from other fibrate trials have yielded evidence supporting the effectiveness of treatment in reducing CHD risk in patients with what may be termed the lipid triad that is, a profile consisting of low HDL-C and elevated

3 Raising high-density lipoprotein cholesterol: where are we now? D19 HDL-C: 1.8 mmol/l (42 mg/dl) Helsinki <1.8 mmol/l (42 mg/dl) HDL-C:.9 mmol/l (35 mg/dl) BIP <.9 mmol/l (35 mg/dl) Incidence of cardiac events (per 1 person-years) Gemfibrozil 2.3 > >2.3 Fig. 2 Post-hoc analyses from fibrate event trials. Shown are the incidence of cardiac events by high-density lipoprotein cholesterol (HDL-C) and triglyceride () levels in the gemfibrozil and placebo groups in the Helsinki Heart Study, and the probability of fatal or non-fatal myocardial infarction (MI) or sudden death according to HDL-C and levels in the bezafibrate and placebo groups in the Bezafibrate Infarction Prevention (BIP) study. (Adapted with permission from Manninen et al. 9 and the BIP Study Group 1.) triglyceride and LDL-C levels. The Helsinki Heart Study 9 assessed the effects of gemfibrozil vs placebo in 481 dyslipidaemic men (non-hdl-c 5.2 mmol/l) without CHD over a follow-up of 5 years. Baseline HDL-C was a significant predictor of CHD risk. Assessment of risk by dichotomized values of HDL-C (with a level of 1.8 mmol/l [42 mg/dl], representing the upper limit of the lowest tertile at baseline) and triglycerides showed that the highest risk for CHD events was in placebo patients with low HDL-C and elevated triglycerides (relative risk 2.43 as compared with high HDL-C/low triglycerides) and that gemfibrozil patients in this subgroup had the lowest CHD risk (relative risk.8 as compared with placebo patients with high HDL-C/low triglycerides; Fig. 2). The Bezafibrate Infarction Prevention Study 1 assessed the effects of bezafibrate vs placebo on risk for fatal or non-fatal myocardial infarction or sudden death over approximately 6 years in 39 patients with prior myocardial infarction or stable angina who had HDL-C levels of 45 mg/dl or less, total cholesterol levels of mg/dl, LDL-C levels of 18 mg/dl or less, and triglyceride levels of 3 mg/dl or less. In the context of an 18% increase in HDL-C levels and a 21% decrease in triglycerides with bezafibrate treatment, there was no significant difference between bezafibrate and placebo treatment groups with regard to frequency of the primary outcome measure. Analysis by high vs low HDL-C levels (cut point of 35 mg/dl) and high vs low triglycerides (cut point of 2 mg/dl) showed that the highest event rate was in the placebo group with low HDL-C and high Cumulative probability of fatal or nonfatal MI or sudden death (%) Bezafibrate 2.3 > >2.3 triglycerides followed by that in the high HDL-C/low triglyceride placebo group, and that the magnitude of risk reduction was greatest in the corresponding bezafibrate groups (Fig. 2). Effects on high-density lipoprotein measures and CHD risk in statin treatment trials Results of statin treatment trials also indicate elevated risk and increased benefit in patients with low HDL-C and elevated triglyceride levels. The Scandinavian Simvastatin Survival Study (4S) trial showed that simvastatin treatment resulted in a significant decrease in risk for CHD events in patients with prior CHD and elevated LDL-C levels. A post-hoc analysis 11 of the influence of low HDL-C and elevated triglycerides on outcome in the trial showed that patients with the lipid triad (n=458), consisting of those in the lowest HDL-C quartile (<1. mmol/l [39 mg/dl]) and highest triglyceride quartile (>1.8 mmol/l [159 mg/dl]) had more features of the metabolic syndrome than did those patients with isolated LDL-C elevation (n=545). In particular, the lipid triad group had a significantly greater body mass index and a greater prevalence of diabetes and hypertension (and were also more likely to be male, to be receiving calcium blocker or beta-blocker treatment, and to have had prior coronary intervention). patients with the lipid triad had the highest CHD event rate during the 5-year follow-up (35.9%), and the corresponding simvastatin group had the greatest

4 D2 Event rate (%) Lipid Triad HDL-C <1. >1.8 mmol/l n=221 reduction in event rate (19.% event rate, relative risk.48; Fig. 3). The event rate in the placebo patients with isolated LDL-C elevation was 2.8%, as compared with 18.% in the corresponding simvastatin group (relative risk.86). Overall, the treatment effect in patients with the lipid triad was significantly greater than that in patients with isolated LDL-C elevation. It is of considerable interest that event rates in placebo subgroups were very similar when analyzed according to the Event rate (%) Simvastatin P=.31 Isolated LDL HDL-C >1.34 <1.11 mmol/l Simvastatin n=237 n=261 n=284 Fig. 3 Major coronary event rates in simvastatin and placebo groups according to presence of lipid triad or isolated low-density lipoprotein (LDL)-cholesterol elevation in the Scandinavian Simvastatin Survival Study (4S). HDL-C=high-density lipoprotein cholesterol; =triglycerides. P value indicates difference between relative risks for lipid triad and isolated LDL-cholesterol elevation subgroups. (Reproduced from Ballantyne et al. 11 ) 18.1 presence of the lipid triad with diabetes and without diabetes, and the absence of the lipid triad with diabetes (Fig. 4), suggesting the common presence of metabolic syndrome and higher associated CHD risk in all of these groupings. Event rates in placebo patients in all of these subgroups were greater than in placebo patients with neither the lipid triad nor diabetes, and reductions in event rates tended to be greater in the corresponding simvastatin subgroups with the lipid triad, diabetes, or both. In the recently reported Heart Protection Study (HPS), 12 which assessed the effects of simvastatin treatment in more than 2, high-risk patients over 5 years, the rate of first major vascular event was highest in the lowest HDL-C tertile, with the largest absolute reduction in risk being observed in the corresponding simvastatin group. Overall, event rates for simvastatin vs placebo patients were 22.6% (818/3617 patients) vs 29.9% (164/3559 patients) in the lowest HDL-C tertile (<.9 mmol/l [35 mg/dl]); 2.% (56/2795 patients) vs 25.1% (72/2871 patients) in the middle tertile (.9 to <1.1 mmol/l [35 to <43 mg/dl]); and 17.% (655/3857 patients) vs 2.9% (81/3837 patients) in the highest tertile ( 1.1 mmol/l [43 mg/dl]). Overall, simvastatin treatment was associated with a 24% reduction in major vascular events in the setting of an average difference between simvastatin and placebo patients of 1. mmol/l in LDL-C, +.3 mmol/l in HDL-C, and.3 mmol/l in triglycerides. In the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS), 13 which was conducted in 665 patients without CHD who had average LDL-C and low HDL-C levels, lovastatin treatment resulted in a 37% reduction in risk for n: With lipid triad, with diabetes With lipid triad, without diabetes Without lipid triad, with diabetes Without lipid triad, without diabetes Fig. 4 Major coronary event rates in simvastatin and placebo groups according to presence or absence of lipid triad and diabetes. (Reproduced with permission from Ballantyne et al. 11 )

5 Raising high-density lipoprotein cholesterol: where are we now? D21 Events (%) HDL-C (mg/dl) Lovastatin Fig. 5 Rates of first major acute coronary events according to high-density lipoprotein cholesterol (HDL-C) tertile in lovastatin and placebo groups in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS). (Data from Gotto et al. 13 ) first major acute coronary event over approximately 5 years in the setting of a 6% increase in HDL-C and a 25% decrease in LDL-C levels. Baseline HDL-C was a significant predictor of risk. Analysis by HDL-C tertile showed that the highest event rate was among the lowest tertile of HDL-C in the placebo group (Fig. 5), with risk reduction in the corresponding lovastatin group being 45%; risk reductions in the lovastatin groups in the middle and highest tertiles were 44% and 15%, respectively. In addition to HDL-C, significant predictors of risk at baseline were apoa-i, apob, apob:apoa-i ratio, LDL-C:HDL-C ratio, and total cholesterol:hdl-c ratio. However, when lipid values at 1 year on-treatment were analyzed, only values for apoa-i, apob and apob:apoa-i ratio were significant predictors of risk; when percentage changes in lipid values at 1 year were analyzed, only percentage changes in apoa-i and apob:apoa-i were significant predictors. The differences between the lovastatin group and the placebo group at 1 year in HDL measures were +4.8% for HDL-C, +2.9% for apo A-I, and 23.6% for apob:apoa-i ratio. ApoA-I level was also found to be a significant predictor of risk for CHD death or non-fatal myocardial infarction at baseline and at 1 year on treatment in the Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) trial. 14 In that trial, which was conducted in more than 9 patients with CHD and total cholesterol levels of mmol/l, pravastatin treatment was associated with a 24% reduction in CHD death or non-fatal myocardial infarction. At 1 year, 4 pravastatin treatment increased HDL-C by 6% and apoa-i by 3%. On-treatment apoa-i value was significantly associated with risk for CHD death or non-fatal myocardial infarction on analysis adjusted for non-lipid risk factors, as were on-treatment values for total cholesterol, LDL-C, triglycerides, apob and total cholesterol:hdl-c ratio. However, the only on-treatment lipid values that were significant predictors on multivariate analysis were apoa-i level and total cholesterol level. Effects of statin therapy on highdensity lipoprotein cholesterol and apolipoprotein A-I Given the evidence that improvement in HDL-C and apoa-i levels is associated with preventive benefit in statin treatment trials, the relative effects of statins in altering these measures have become an area of interest. As a class, statins generally produce modest increases in HDL-C, although there are differences in this regard among available agents. For example, in a clinical trial performed in 826 patients with LDL-C levels greater than 16 mg/dl and triglyceride levels below 35 mg/dl, 15 simvastatin was found to raise HDL-C significantly more than atorvastatin at doses of 8 mg vs 4 mg and at doses of 8 mg vs 8 mg (Fig. 6). Simvastatin also increased apoa-i levels significantly more than did atorvastatin at doses of 4 mg vs 2 mg (5.6% vs 4.%), 8 mg vs 4 mg (5.7% vs 1.%), and 8 mg vs 8 mg (+2.5% vs 3.5%). Rosuvastatin is a new statin that has been shown to reduce LDL-C levels significantly more than atorvastatin, pravastatin and simvastatin. 16,17 In a study comparing rosuvastatin and atorvastatin across a range of doses in 374 hypercholesterolaemic patients (LDL-C 16 and <25 mg/dl and triglycerides <4 mg/dl), 18 rosuvastatin increased HDL-C levels significantly more than did atorvastatin at doses of 4 mg vs 4 mg (12.3% vs 4.1%) and 8 mg vs 8 mg (9.6% vs 2.1%), and significantly increased apoa-i at 8 mg versus 8 mg (9.2% versus 3.1%; Fig. 7). At doses of 1 8 mg, rosuvastatin reduced the apob:apoa-i ratio by %, as compared with % with atorvastatin. Logistic regression analysis showed that rosuvastatin was associated with a significantly greater 8.15% reduction in apob:apoa-i ratio across the dose range. Rosuvastatin also has been found to raise HDL-C significantly more than other statins Pooled data from phase III trials comparing rosuvastatin 1 mg with atorvastatin 1 mg over 12 weeks in

6 D22 Fig. 6 Changes in high-density lipoprotein cholesterol with simvastatin (SIM) and atorvastatin (ATV) treatment during a dose titration study. (Reproduced with permission from Illingworth et al. 15 ) Mean change from baseline (%) Mean change from baseline (%) HDL-C more than 7 patients with LDL-C 16 mg/dl and less than 25 mg/dl, and triglycerides <4 mg/dl indicate an increase of 8.9% with rosuvastatin vs 5.5% with atorvastatin. 19 In phase III trials comparing rosuvastatin 1 mg with pravastatin 2 mg and simvastatin 2 mg in more than 7 patients meeting these lipid criteria, rosuvastatin increased HDL-C by 9.1% as compared with 6.2% for pravastatin (P<.5) 2 and 6.2% with simvastatin (P<.5). 21 In an individual 12-week trial comparing rosuvastatin 1 mg (n=129) with atorvastatin 1 mg (n=127), 17 rosuvastatin increased apoa-i (7% vs 3%) and decreased apob:apoa-i ratio (37% vs 28%) significantly more than did atorvastatin. Furthermore, in a 12-week trial comparing rosuvastatin 1 mg (n=111) with pravastatin 2 mg (n=136) and simvastatin 2 mg (n=129), 16 rosuvastatin produced increases in apoa-i comparable to those with the other statins (5% vs 8.5 SIM 4 mg 7.3 ATV 2 mg * 9.7 SIM 8 mg 6.4 4% and 4%) and significantly decreased apob:apoa-i ratio as compared with both (42% vs 23% and 32%). Conclusion * Week ATV 4 mg *P<.1 vs atorvastatin; P<.1 vs atorvastatin; P<.5 vs atorvastatin. Mean change (%) presented as raw means. * Dose (mg) Apo A-I SIM 8 mg *P<.1 3. ATV 8 mg Rosuvastatin Atorvastatin Fig. 7 Changes in high-density lipoprotein cholesterol (HDL-C) and apolipoprotein (apo)a-i at 6 weeks according to dose of rosuvastatin or atorvastatin. (Reproduced from Schneck et al. 18 ) There is considerable evidence that a low HDL-C level is an independent risk factor for CHD. HDL-C levels should be measured in all adults to stratify CHD risk. There is accumulating evidence that patients derive benefit in terms of CHD prevention from increases in HDL-C or apoa-i, or decreases in apob:apoa-i ratio, achieved using drug therapy with fibrates and statins. Such findings suggest the potential need for defining therapeutic targets for HDL measures. Statins, the agents most widely used in lipid-lowering therapy, differ in their ability to increase HDL-C and apoa-i, and to reduce apob:apoa-i ratio. Further clinical trials

7 Raising high-density lipoprotein cholesterol: where are we now? D23 are needed to determine whether raising HDL-C or apoa-i, or improving the apob:apoa-i ratio should be adopted as goals of lipid-modifying therapy. References 1. Abbott RD, Wilson PW, Kannel WB, Castelli WP. High density lipoprotein cholesterol, total cholesterol screening, and myocardial infarction. The Framingham study. Arteriosclerosis 1988;8: Assmann G, Schulte H. Relation of high-density lipoprotein cholesterol and triglycerides to incidence of atherosclerotic coronary artery disease (the PROCAM experience). Prospective Cardiovascular Munster study. Am J Cardiol 1992;7: Wilson PW, Garrison RJ, Castelli WP, Feinleib M, McNamara PM, Kannel WB. Prevalence of coronary heart disease in the Framingham Offspring Study: role of lipoprotein cholesterols. Am J Cardiol 198;46: Sharrett AR, Ballantyne CM, Coady SA et al. Coronary heart disease prediction from lipoprotein cholesterol levels, triglycerides, lipoprotein(a), apolipoproteins A-I and B, and HDL density subfractions. The Atherosclerosis Risk in Communities (ARIC) Study. Circulation 21;14: Walldius G, Jungner I, Holme I et al. High apolipoprotein B, low apolipoprotein A-I, and improvement in the prediction of fatal myocardial infarction (AMORIS study): a prospective study. Lancet 21;358: Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 21;285: Rubins HB, Robins SJ, Collins D et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med 1999;341: Robins SJ, Collins D, Wittes JT et al. Relation of gemfibrozil treatment and lipid levels with major coronary events: VA- HIT: a randomized controlled trial. JAMA 21;285: Manninen V, Tenkanen L, Koskinen P et al. Joint effects of serum triglyceride and LDL cholesterol and HDL cholesterol concentrations on coronary heart diseae risk in the Helsinki Heart Study. Implications for treatment. Circulation 1992; 85: The BIP Study Group. Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery diseae. The Bezafibrate Infarction Prevention (BIP) Study. Circulation 2;12: Ballantyne CM, Olsson AG, Cook TJ, Mercuri MF, Pedersen TR, Kjekshus J. Influence of low high-density lipoprotein cholesterol and elevated triglyceride on coronary heart disease events and response to simvastatin therapy in 4S. Circulation 21;14: Heart Protection Study Collaborative Group. MRC/BHF Heart protection Study of cholesterol lowering with simvastatin in 2,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 22;36: Gotto AM Jr, Whitney E, Stein EA et al. Relation between baseline and on treatment lipid parameters and first acute major coronary events in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS). Circulation 2;11: Simes RJ, Marschner IC, Hunt D et al. Relationship between lipid levels and clinical outcomes in the Long-term Intervention With Pravastatin in Ischemic Disease (LIPID) Trial. To what extent is the reduction in coronary events with pravastatin explained by on-study lipid levels? Circulation 22;15: Illingworth DR, Crouse JR III, Hunninghake DB et al. A comparison of simvastatin and atorvastatin up to maximal recommended doses in a large multicenter randomized clinical trial. Curr Med Res Opin 21;17: Paoletti R, Fahmy M, Mahla G, Mizan J, Southworth H. Rosuvastatin demonstrates greater reduction of low-density lipoprotein cholesterol compared with pravastatin and simvastatin in hypercholesterolaemic patients: a randomized, double-blind study. J Cardiovasc Risk 21;8: Davidson M, Ma P, Stein EA et al. Comparison of effects on low-density lipoprotein cholesterol and high-density lipoprotein cholesterol with rosuvastatin versus atorvastatin in patients with type IIa or IIb hypercholesterolemia. Am J Cardiol 22;89: Schneck DW, Knopp RH, Ballantyne CM, McPherson R, Chitra RR, Simonson SG. Comparative effects of rosuvastatin and atorvastatin across their dose ranges in patients with hypercholesterolemia and without active arterial disease. Am J Cardiol 23;91: Wiklund O, Davidson M, Chitra R, Hutchinson H, Raza A. Rosuvastatin is more effective than atorvastatin in modifying lipid profiles and achieving National Cholesterol Education Program Adult Treatment Panel III LDL-cholesterol goals. Atherosclerosis Suppl 22;3: Barter P, Shepherd J, Brown WV, Bays H, Southworth H, Strutt K. Rosuvastatin significantly improves lipid parameters and ability to achieve low-density lipoprotein cholesterol goals compared with pravastatin. J Am Coll Cardiol 22;39(suppl B):142B. 21. Hamilton-Craig I, Schaefer E, Farnier M, Koren M, Southworth H, Pears J. Rosuvastatin produces significantly greater reductions in low-density lipoprotein cholesterol and more patients achieve treatment goals compared with simvastatin. J Am Coll Cardiol 22;39(suppl B):146B. Discussion Dr Stein: [Reads question from the audience.] Some statins, particularly atorvastatin, appear to increase HDL-C or apoa-i by smaller amounts at higher doses than at lower doses. Is it better to keep patients at lower doses on these drugs and get a better increase in HDL-C than to use higher doses and get a greater decrease in LDL-C? Dr Ballantyne: I think it depends on the clinical context. For patients with familial hypercholesterolaemia who have very high LDL-C concentrations, it makes sense to use the highest dose of atorvastatin to get the additional LDL-C reduction. Usually, HDL-C will still be up from baseline; usually, it s just that some of the increase at the lower doses is lost. So, in this context, I think lowering LDL-C and apob is of most benefit. One has the option of adding low doses of nicotinic acid, which is what I do, although I know this is not a popular drug in Europe.

8 D24 Dr Stein: What would you say the optimal apob:apoa-i ratio is, in general? Dr Ballantyne: I m probably not the right person to answer that question, since I ran the lipid lab that provided the data showing that apob and apoa-i were not predictive in the ARIC study data that were reanalyzed several times as a matter of fact. Chris [Dr Packard] what would you say the optimal ratio is? Dr Packard: I said before that one might consider doing something about the levels when apob is greater than 1 g/l and apoa-i less than 1 g/l. I would figure that targets of less than.5 g/l for apob and greater than 1.5 g/l for apoa- I would be good. Dr Stein: To add to that, one still needs to consider absolute values even if the ratio is being considered; it s a problem we run into with all ratios, whether they be total cholesterol:hdl or LDL:HDL. A ratio of 1 with values for apob of 2 g/l and apoa-i of 2 g/l is probably not a good thing to have, despite the high apoa-i value. Dr Stein: [New question.] Should we be assessing the structure or function of HDL-C rather than just the quantity? Dr Ballantyne: Ideally, from the viewpoint of understanding the pathogenesis of atherosclerosis, we could derive a lot of information from measuring particle size, number, function, and concentration. However, there are obviously practical issues involved in doing all of these measurements. Assessing functionality of HDL might be important for the rare cases of apoa-i Milano, or in the occasional patient with atherosclerosis who has high HDL and may have a CETP [cholesteryl ester transfer protein] deficiency. Unfortunately, there currently are no simple assays available for measuring functionality. Dr Stein: An issue that you briefly discussed is the combination of statins and fibrates to get better increases in HDL-C. Do we need a new class of HDL-raising agents? Dr Ballantyne: Obviously, that would be a very exciting target. We have good agents for lowering LDL-C and more in the pipeline. Nicotinic acid will never be widely used, I think, no matter what the formulation, because it is just a difficult drug to take but, one does get about a 3% increase in HDL with it. The potential for use of PPAR [peroxisome proliferator-activated receptor] agonists in combination with statins deserves a lot of attention. Other possibilities include the use of CETP inhibitors with statins. I believe that such approaches will end up giving us very impressive HDL increases. The question will then be what those approaches do in terms of reducing risk of atherosclerotic disease. Dr Stein: [Reads question from the audience.] Another audience question for you Christie [Dr Ballantyne], and some for the other panelists. Do you use a statin or fibrate to treat isolated low HDL-C in a patient with coronary disease in the setting of normal or low triglyceride levels? Dr Ballantyne: I start off with a statin and add niacin in those patients. Dr Stein: [Reads question from the audience.]: A question for Ole [Dr Faergeman]. In secondary prevention, is there any reason to measure lipids other than to confirm compliance with statin therapy? Dr Faergeman: I don t know if there is a good answer to that question. Certainly, I do not think that giving statins as a fire and forget strategy is a good idea, for at least the reason that one wants to see if the LDL-C is actually being reduced in the patient. Dr Ballantyne: I don t think one needs to have obtained lipid levels to start therapy in secondary prevention patients. But, I would get them anyway and do follow up measurements. We shouldn t forget that some people have very high triglyceride levels as the culprit, particularly those with diabetes, and that there is more than one lipoprotein abnormality associated with premature heart disease that could be missed if we don t measure lipids. With regard to triglycerides, for example, if someone has a triglyceride level of 1 or 2 mg/dl, the drug of choice is not a statin; the patient needs to have the elevated triglycerides treated first to prevent pancreatitis, and a fibrate is a better first choice. Dr Stein: I agree. I think something we have tended to overlook as we have concentrated more on the relationship of lipoproteins to coronary artery disease and prevention is that it s always important to measure triglycerides and cholesterol, because one can diagnose other abnormalities that may not even have an impact on coronary disease but that also need to be treated. Dr Pedersen: [Reads question from the audience.] Here s a question for Dr Faergeman. The HPS showed a 1 mmol/l reduction in LDL-C and the same reduction in risk for major vascular events irrespective of baseline LDL. Does that imply that a 2 mmol/l reduction in LDL would give double the benefit? Dr Faergeman: That risk reduction was relative risk reduction, not absolute risk reduction. But, the major question whether getting the LDL down further would increase the benefit was not

9 Raising high-density lipoprotein cholesterol: where are we now? D25 answered by HPS. That question has to be answered, I believe, by ongoing studies, such as TNT [Treating to New Targets], SEARCH [Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine], and IDEAL [Incremental Decrease in Endpoints through Aggressive Lipid Lowering]. Dr Ballantyne: A point needs to be made about the interpretation that benefits were the same irrespective of initial LDL-C in HPS. People just seem to be ignoring the fact that the placebo group had a very high drop-in rate, of over onethird being started on drug therapy. Unless practitioners in the U.K. are different from practitioners elsewhere in the world, I don t think that the patients dropping in were those with low LDL-C levels; they were more likely those with high LDL levels, who were more likely to go on to get lipid-lowering therapy. The treatment effects reported in the intent-to-treat analysis reflect this off-study lipid-lowering treatment in the placebo group. Without this, it is possible that the study would have shown greater prevention in patients with higher initial LDL levels. It would be really difficult to tease this out of the data. But, I think we should all understand that the way the trial was conducted makes it difficult to interpret the finding of similar benefit across the board.