Treating dyslipidemia in the high-risk patient

,

Applied Evidence

Treating dyslipidemia in the high-risk patient

J Fam Pract. 2010 February;59(2):E1-E9

By

Peter H. Jones, MD

How low should LDL levels be pushed and how important are other lipoproteins in our efforts to reduce CV risk? Here’s an update.

PDF Download

References

1. Rosamond W, Flegal K, Furie K, et al. For the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics 2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2008;117:e25-e146.

2. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. 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): final report. Circulation. 2002;106:3143-3421.

3. Rosamond WD, Chambless LE, Folsom AR, et al. Trends in the incidence of myocardial infarction and in mortality due to coronary heart disease, 1987 to 1994. N Engl J Med. 1998;339:861-867.

4. Fox CS, Evans JC, Larson MG, et al. Temporal trends in coronary heart disease mortality and sudden cardiac death from 1950 to 1999: the Framingham Heart Study. Circulation. 2004;110:522-527.

5. Smith SC, Jr, Allen J, Blair SN, et al. AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update. J Am Coll Cardiol. 2006;47:2130-2139.

6. Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90 056 participants in 14 randomized trials of statins. Lancet. 2005;366:1267-1278.

7. Ford I, Murray H, Packard CJ, et al. For the West of Scotland Coronary Prevention Study Group. Long-term follow-up of the West of Scotland Coronary Prevention Study. N Engl J Med. 2007;357:1477-1486.

8. Chen Z, Peto R, Collins R, et al. Serum cholesterol concentration and coronary heart disease in population with low cholesterol concentrations. BMJ. 1991;303:276-282.

9. O’Keefe JH, Jr, Cordain L, Harris WH, et al. Optimal low-density lipoprotein is 50 to 70 mg/dL: lower is better and physiologically normal. J Am Coll Cardiol. 2004;43:2142-2146.

10. 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.

11. Pedersen TR, Faergeman O, Kastelein JJP, et al. For the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) Study Group. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction. The IDEAL Study: a randomized controlled trial. JAMA. 2005;294:2437-2445.

12. Cannon CP, Braunwald E, McCabe C, et al. For the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350:1495-1504.

13. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomized placebo-controlled trial. Lancet. 2002;360:7-22.

14. Sever PS, Dahlöf B, Poulter NR, 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-LLA): a multicentre randomized controlled trial. Lancet. 2003;361:1149-1158.

15. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). JAMA. 2002;288:2998-3007.

16. Shepherd J, Blauw GJ, Murphy MB, et al. On behalf of the PROSPER study group. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomized controlled trial. Lancet. 2002;360:1623-1630.

17. Waters DD, LaRosa JC, Barter P, et al. Effects of high-dose atorvastatin on cerebrovascular events in patients with stable coronary disease in the TNT (Treating to New Targets) study. J Am Coll Cardiol. 2006;48:1793-1799.

18. Ridker PM, Cannon CP, Morrow D, et al. For the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE IT–TIMI 22) Investigators. Creactive protein levels and outcomes after statin therapy. N Engl J Med. 2005;352:20-28.

19. Grundy SM, Cleeman JI, Bairey Merz CN, et al. For the Coordinating Committee of the National Cholesterol Education Program. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110:227-239.

20. Nissen SE, Tuzcu EM, Schoenhagen P, et al. For the REVERSAL Investigators. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA. 2004;291:1071-1080.

21. Nissen SE, Nicholls SJ, Sipahi I, et al. For the ASTEROID Investigators. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA. 2006;295:1556-1565.

22. Kastelein JJP, Akdim F, Stroes ESG, et al. For the ENHANCE Investigators. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med. 2008;358:1431-1443.

23. Wiviott SD, Cannon CP, Morrow DA, et al. For the PROVE IT–TIMI Investigators. Can low-density lipoprotein be too low? The safety and efficacy of achieving very low low-density lipoprotein with intensive statin therapy: a PROVE IT-TIMI 22 substudy. J Am Coll Cardiol. 2005;46:1411-1416.

24. LaRosa JC, Grundy SM, Kastelein JJ, et al. For the Treating to New Targets (TNT) Steering Committee and Investigators. Safety and efficacy of atorvastatin-induced very low-density lipoprotein cholesterol levels in patients with coronary heart disease (a post hoc analysis of the treating to new targets [TNT] study). Am J Cardiol. 2007;100:747-752.

25. Kastelein JJP, van der Steeg WA, Holme I, et al. For the TNT and IDEAL Study Groups. Lipids, apolipoproteins, and their ratios in relation to cardiovascular events with statin treatment. Circulation. 2008;117:3002-3009.

26. Barter P, Gotto AM, LaRosa JC, et al. For the Treating to New Targets Investigators. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med. 2007;357:1301-1310.

27. Davidson MH, Stein EA, Bays HE, et al. Efficacy and tolerability of adding prescription omega-3 fatty acids 4 g/d to simvastatin 40 mg in hypertriglyceridemic patients: an 8-week, randomized, double-blind, placebo-controlled study. Clin Ther. 2007;29:1354-1367.

28. Brunzell JD, Davidson M, Furberg CD, et al. Lipoprotein management in patients with cardiometabolic risk: consensus conference report from the American Diabetes Association and the American College of Cardiology Foundation. J Am Coll Cardiol. 2008;51:1512-1524.

29. Miller M. Optimal treatment of dyslipidemia in high-risk patients: intensive statin treatment or combination therapy? Prev Cardiol. 2007;10:31-35.

30. Gordon DJ, Probstfield JL, Garrison RJ, et al. High-density lipoprotein cholesterol and cardiovascular disease: four prospective American studies. Circulation. 1989;79:8-15.

31. McKenney JM. Effect of drugs on high-density lipoprotein. J Clin Lipidol. 2007;1:74-87.

32. Paolini JF, Mitchel YB, Reyes R, et al. Effects of laropiprant on nicotinic acid-induced flushing in patients with dyslipidemia. Am J Cardiol. 2008;101:625-630.

33. Fruchart JC, Staels B, Duriez P. PPARS, metabolic disease, and atherosclerosis. Pharmacol Res. 2001;44:345-352.

34. 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. 2001;285:1585-1591.

35. Frick MH, Elo O, Haapa K, et al. Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med. 1987;317:1237-1245.

36. Durrington PN, Tuomilehto J, Hamann A, et al. Rosuvastatin and fenofibrate alone and in combination in type 2 diabetic patients with combined hyperlipidemia. Diabetes Res Clin Pract. 2004;64:137-151.

37. Athyros VG, Papageorgiou AA, Athyrou VV, et al. Atorvastatin and micronized fenofibrate alone and in combination in type 2 diabetes patients with combined hyperlipidemia. Diabetes Care. 2002;25:1198-1202.

38. Jones PH, Davidson MH. Reporting rate of rhabdomyolysis with fenofibrate + statin versus gemfibrozil + any statin. Am J Cardiol. 2005;95:120-122.

39. Barter PJ, Kastelein JJ. Targeting cholesteryl ester transfer protein for the prevention and management of cardiovascular disease. J Am Coll Cardiol. 2006;47:492-499.

40. Brousseau ME, Schaefer EJ, Wolfe ML, et al. Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol. N Engl J Med. 2004;350:1505-1515.

41. Tall AR, Yvan-Charvet L, Wang N. The failure of torcetrapib: was it the molecule or the mechanism? Arterioscler Thromb Vasc Biol. 2007;27:257-260.

42. Kastelein JJP, van Leuven SI, Burgess L, et al. For the RADIANCE 1 Investigators. Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia. N Engl J Med. 2007;356:1620-1630.

43. Nissen SE, Tardif J-C, Nicholls SJ, et al. For the ILLUSTRATE Investigators. Effect of torcetrapib on the progression of coronary atherosclerosis. N Engl J Med. 2007;356:1304-1316.

44. de Grooth GJ, Kuivenhoven JA, Stalenhoef AF, et al. Efficacy and safety of a novel cholesteryl ester transfer protein inhibitor, JTT-705, in humans: a randomized phase II dose-response study. Circulation. 2002;105:2159-2165.

45. Kuivenhoven JA, de Grooth GJ, Kawamura H, et al. Effectiveness of inhibition of cholesteryl ester transfer protein by JTT-705 in combination with pravastatin in type II dyslipidemia. Am J Cardiol. 2005;95:1085-1088.

46. Nissen SE, Tsunoda T, Tuzcu EM, et al. Effect of recombinant ApoA-1 Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA. 2003;290:2292-2300.

47. Nicholls SJ, Tuzcu EM, Sipahi I, et al. Relationship between atheroma regression and change in lumen size after infusion of apolipoprotein A-1 Milano. J Am Coll Cardiol. 2006;47:992-997.

48. Cesena FH, Faria-Neto JR, Shah PK. Apolipoprotein A-Imimetic peptides: state-of-the-art perspectives. Int J Atheroscler. 2006;1:137-142.

49. Singh IM, Shishehbor MH, Ansell BJ. High-density lipoprotein as a therapeutic target: a systematic review. JAMA. 2007;298:786-798.

PRACTICE RECOMMENDATIONS

• Clinical trials demonstrate that cardiovascular event rates diminish as low-density lipoprotein (LDL)-cholesterol and apolipoprotein B–containing particles are lowered with statin treatment. A

• The relationship between LDL-cholesterol and cardiovascular events seems to be linear, with no lowest threshold. A

• While LDL-cholesterol remains the primary target for coronary heart disease prevention, non–HDL-cholesterol is an important secondary target in patients with mixed dyslipidemia. A

Strength of recommendation (SOR)

A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series

Dyslipidemia is a primary contributor to coronary heart disease (CHD), the No. 1 cause of death in the United States.^1,2 Mortality rates from CHD have declined sharply over the last 3 decades as a result of improvements in acute care and in secondary prevention, notably by means of lipid-lowering statin therapy.^3,4 Studies confirm that the decline in cardiovascular events is largely due to decreases in low-density lipoprotein (LDL)-cholesterol and other atherogenic particles.^2,5 Still, despite these gains, CHD continues to be a major threat, and the search to find ways to lower CHD risk further continues. Additional avenues being explored include reducing triglycerides and raising high-density lipoprotein (HDL)-cholesterol through lifestyle intervention and other means in patients with mixed dyslipidemia whose statin therapy is already optimal.² This article reviews the LDL-cholesterol lowering “standard of care” and discusses the potential of addressing other lipoproteins to reduce the residual cardiovascular risk that frequently remains.

Lower LDL levels remain the primary target

The National Cholesterol Education Program (NCEP) has focused on reduction of serum levels of LDL-cholesterol for the primary and secondary prevention of CHD. This approach is biologically reasonable, because LDL is the major atherogenic lipoprotein and is directly implicated in the development of atherosclerosis. Further, the benefit of LDL lowering has been validated by the results of many randomized clinical trials using a combination of lifestyle changes and statins.²

Data on 90,000 patients confirm efficacy of lowering LDL
In an important meta-analysis, the Cholesterol Treatment Trialists’ (CTT) Collaborators compiled data from more than 90,000 people in 14 large-scale, randomized statin trials that included high-risk populations.⁶ The investigators found that each 39-mg/dL (1-mmol/L) reduction in LDL-cholesterol sustained over 5 years reduced the incidence of a first major coronary event by 23% and the incidence of CHD death by 19%. In the high-risk subgroup with preexisting CHD, a 39-mg/dL (1-mmol/L) reduction in LDL-cholesterol prevented 14 deaths per 1000 participants. These benefits were significant even in the first year of treatment (P<.0001) and were greater in subsequent years.⁶ The nearly linear relationship between lower LDL-cholesterol levels and fewer major vascular events held true regardless of baseline LDL-cholesterol levels, even when the baseline levels were <100 mg/dL.⁶

The greatest absolute benefit was noted in the high-risk and very-high-risk groups, especially in individuals with diabetes and those older than 75 years. Moreover, long-term follow-up comparing the original statin-treated participants with the original placebo group showed that lowering LDL-cholesterol continued to reduce cardiovascular risk for 10 years after the study ended.⁷

Optimal LDL levels may be even lower than we thought

FAST TRACK

Physiologically normal LDL-cholesterol levels may be lower than levels typically seen in family practice.

Observational studies have suggested that the relationship between cholesterol and CHD mortality has no apparent lower threshold, and that the physiologic norm for LDL-cholesterol may be lower than that typically seen in Western countries. For example, in a study done in the 1970s in an urban Chinese population of more than 9000 middle-aged men and women, the mean baseline total cholesterol level was 162 mg/dL, and only 7% of deaths were attributed to CHD in 13 years of follow-up.⁸ Nevertheless, there was an independent and strongly positive (P<.001) relationship between total cholesterol and risk of CHD death, starting at a level as low as 147 mg/dL, which may be equivalent to an LDL-cholesterol of 100 mg/dL. Some data indicate the physiologic norm for LDL-cholesterol levels may be in the range of 50 to 70 mg/dL, which is much lower than the US average of approximately 130 mg/dL.⁹

Lower LDL-cholesterol protects against atherosclerosis
Lifetime exposure to a lower LDL-cholesterol level may be responsible for a lower burden of atherosclerotic disease later in life. Analyses of data from major statin clinical trials indicate that atherosclerosis does not progress when LDL-cholesterol levels are maintained at <67 mg/dL, while other data suggest that CHD event rates could be minimized at LDL-cholesterol levels of 57 mg/dL for primary prevention and 30 mg/dL for secondary prevention.⁹

Intensive regimens yield better outcomes

Controlled clinical trials have compared more intensive and less intensive statin and lifestyle modification regimens in high-risk subjects, most of whom already had CHD. These trials found that lower LDL-cholesterol values achieved by more intensive regimens produced incremental CHD benefits.^10-16 Major findings of these trials are summarized in TABLE 1.