Combination therapy to control cholesterol?

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The benefits of adding a second or third drug to a statin are unproven at best and may have potential downsides instead, this expert maintains.

The HMG-CoA reductase inhibitors, commonly known as the “statins,” are widely used and successful therapies.

Developed nearly 20 years ago, the statins’ ability to lower LDL and help prevent cardiovascular events has made them popular around the world. In a series of landmark clinical trials, drugs of the statin class were shown to reduce initial and recurrent MI, cardiac mortality, and even total mortality.1-3 Subsequent studies comparing statins at higher doses or with greater potency for lowering LDL demonstrated that in high-risk patients, lowering LDL dramatically to levels <70 mg/dL reduced cardiac events even further.4-6

These studies led the National Cholesterol Education Program (NCEP) to revise its guidelines to recommend lower LDL targets.7 The new recommendations have placed renewed emphasis on setting target LDL at significantly lower levels than previously sought, leading many clinicians to consider adding another cholesterol-reducing agent in certain patients.

Combination therapy

Combining several medications to control a long-term medical problem (e.g., hypertension) is a widely used strategy. However, there is an important difference between treatments of hypertension and hyperlipidemia. In hypertension, BP numbers are targeted. In cholesterol management, while the evidence clearly shows that initial treatment with statin therapy is aimed at a significant lowering of LDL, most of the interest in combination therapy is aimed at correcting abnormalities in one of the other lipid fractions (e.g., triglycerides or HDL).

The only justification for using any therapy comes from its proven effectiveness to reduce disease. Therefore, the ultimate goal of cholesterol management is not the correction of the lipid numbers but the reduction in heart attack and other cardiac end points. While this result is seen with statin therapy, it is not clearly proven in clinical trials with many of the other therapies. The benefit of adding a second or third drug to a statin is unproven and may have potential downsides instead.

By way of example, torcetrapib was once a new agent with enormous promise. It increased HDL approximately 60% and lowered LDL an additional 20% when added to ongoing statin therapy. Research was abruptly halted in December of 2006 when, one year into a long-term study, excess death and cardiovascular problems were noted in the torcetrapib group.8

Two further studies on torcetrapib have since been published. Both confirmed an increase in HDL of 52%-61%, and a reduction of LDL by an additional 20% but no change in the progression of coronary or carotid atherosclerosis.9-11

This shows that adding a second agent to a statin may not necessarily be helpful. Furthermore, why did the additional 20% reduction in LDL achieved by torcetrapib not prove protective in its own right? This is the same level of LDL reduction seen with ezetimibe (Zetia). The finding raises an interesting possibility. Perhaps LDL reduction produced by another agent does not reduce cardiac events as well as a statin-induced reduction. This supports the theory that the statins have “pleiotropic” properties that protect the vascular system beyond their very positive effects on LDL. These appear to include anti-inflammatory properties as well as “plaque stabilization” factors and probably include a number of other properties not yet considered.

Goals of combination therapy

Since there are different goals for different types of combination therapies, the discussion will be separated into three topics: combination therapy to lower LDL, raise HDL, and lower triglycerides.

Lowering LDL

Of the three combination therapies, adding secondary therapy to a statin to enhance the lowering of LDL has the most support. However, this is based on the results of statin-only trials, not combination trials of statins with another agent.

The most recent NCEP guidelines drew on two recent trials to recommend a dramatically lower target LDL of <70 in certain very high-risk patients (those having either a recent acute coronary syndrome or multiple risk factors, including diabetes, metabolic syndrome, and cigarette smoking).3-5

Two other trials also demonstrated the value of much lower LDL on statin therapy in patients with known coronary heart disease (CHD) or significant risk factors for CHD but without recent acute coronary syndrome.6,7

Lowering the LDL of a high-risk patient to <70 can be a challenge. For the traditional practitioner, the easiest way of reaching the goal is to become comfortable with moderate-to-high doses of the most potent statins (i.e., rosuvastatin [Crestor] 10-40 mg for reduction of about 60% and atorvastatin [Lipitor] 20-80 mg for a reduction of about 50%).12

Ezetimibe alone and combined with simvastatin (Vytorin) is the agent most often added to statin therapy to lower LDL. While many clinicians assume that LDL reductions produced by ezetimibe confer the same MI protection as LDL reductions produced solely by a statin, this has not been proven. Now details of the first study to look at the use of ezetimibe have been released by the manufacturers.13 It is the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial, which evaluated 720 patients with severe hereditary LDL elevations. One group received simvastatin 80 mg and placebo, while the other received simvastatin 80 mg and ezetimibe 10 mg, the most potent Vytorin combination.

The addition of ezetimibe to simvastatin did significantly lower LDL, but the growth of the carotid plaque in the ezetimibe group—as measured by intima-media thickness (IMT)—was no better than in the simvastatin-alone group, and it actually trended toward more build-up in the ezetimibe group. Granted, the study was not definitive since it used a surrogate marker (carotid IMT) for atherosclerotic disease. However, it challenges the assumption that ezetimibe will reduce heart attacks equivalent to the statins.

What’s a careful practitioner to do? First, do not use Vytorin as a substitute for a more potent statin. Since there were no safety problems with ezetimibe in ENHANCE, I will continue to use it only as a supplement to the highest tolerated dose of the most potent statin, usually rosuvastatin 40 mg. Tell patients that we do not know if this will help reduce their risk of heart attack until the definitive trial is finished in several years.

The only other agents for lowering LDL alone are the bile-acid sequestrants (e.g., cholestyramine, colestipol, and colesevelam). These have very limited use at present, and GI side effects make them very difficult to tolerate.14

Raising HDL

Low HDL is recognized as a potent risk factor for MI and other cardiac ischemic events.15 When and how it should be treated remains unsettled. Furthermore, while the definition of low HDL as <40 mg/dL (possibly <50 mg/dL in women) is commonly accepted, there is no evidence for what the therapeutic raised target should be.15

Without evidence that treating low HDL itself is beneficial, we are forced to look at a series of different studies to develop a treatment strategy. The most applicable is a trial of American men and women without previous coronary disease but with moderate LDL elevation and low HDL. Compared with placebo, lovastatin alone (20-40 mg) significantly reduced initial coronary events in the study population.16 Those who had a baseline HDL <40 had a nearly 50% reduction in events.17 These dramatic results showed that statin therapy alone produced reduction of initial heart attack and other events in low HDL syndrome without resorting to combination therapy. Evidence from other trials is less clear.

Much attention has focused on the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT), which studied gemfibrozil (a fibrate agent) vs. placebo in patients with known heart disease and moderate LDL. Gemfibrozil alone reduced subsequent cardiac events by 22%.18 This appears related to a modest increase in HDL of about 6% (or slightly >2 mg/dL), since LDL did not change and the triglyceride reduction was not correlated with events reduction.19 However, since VA-HIT was conducted long before such projects as the Heart Protection Study (which indicated all patients with known heart disease should be on statin therapy), its relevance is unclear in the current practice situation.

Do not assume studies like VA-HIT support the addition of gemfibrozil to a statin. In fact, gemfibrozil interferes with the metabolism of all statins; therefore the combination is risky. Some authors recommend the two never be used together.12

Gemfibrozil therapy alone was used in the Helsinki Heart Study. In both the five-year placebo-controlled initial study and the long-term follow-up, gemfibrozil reduced cardiac events but not total mortality.20 Also, the benefits appear to be confined to the subset of patients with metabolic syndrome.21

Benzafibrate was studied in a population with known CHD and HDL <45. Despite an increase in HDL of 18% and lowering of triglycerides by 21%, there was no reduction in recurrent cardiac events.22 In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial, fenofibrate (Tricor) was compared with placebo in diabetic patients not on statin therapy. Fenofibrate showed no significant reduction in cardiac events in these patients.23

When taken in their entirety, these trials do not present a clear picture of how and when use of fibrates is clearly beneficial. Niacin is also widely used to raise HDL and treat other lipid disorders. Supporters point to the Coronary Drug Project to defend its use. However, a careful examination of the study shows the results were less than dramatic.24

Published in 1975, the study looked at patients with known CHD who were given 3,000 mg of niacin.25 After five years, the niacin group had a reduction in nonfatal MI, but there was no effect on cardiac or total mortality. Almost nine years after the project was completed, a follow-up study showed a reduction in total and cardiac mortality in the patients who had been in the niacin arm.25 The significance of this information is unclear given the time lapse between the two studies.

Niacin has been studied in combination with several statins to examine their benefit and safety on the lipid parameters.26,27 In general, a 2-g dose was fairly well tolerated. It produced an increase in HDL and lowered triglycerides but did not affect LDL.26

While adding fenofibrate or niacin can increase HDL, no data show combination with statins further reduces cardiac events. The Air Force/Texas Coronary Atherosclerosis Prevention Study showed statin therapy reduced cardiac events by almost 50%.17 Without evidence that adding a second lipid agent (which will increase patient costs and potential side effects) will add benefit, I use aggressive statin therapy alone to dramatically lower LDL. In a recent study, aggressive lowering of the LDL to <70 in high-risk patients reduced the impact of low HDL to borderline significance.28

Lowering triglycerides

A number of studies have shown an association between elevated triglycerides and coronary events.29 However, it remains unclear whether the elevated triglycerides caused the increased events. Since most patients with triglyceride elevations have elevated LDL and reduced HDL (usually along with metabolic syndrome, insulin resistance, or frank diabetes), teasing the triglyceride impact out of that mass of cardiac risk factors is very difficult.30

The NCEP guidelines recommend possibly adding a fibrate or niacin in patients with persistent low HDL or elevated triglycerides.7 Note that this therapy is not mandated.

Since statin therapy is necessary in these patients, the question of triglycerides in patients already on statins must be examined. Two interesting papers have evaluated the impact of elevated triglycerides in patients treated with statins (the Scandinavian Simvastatin Survival Study and West of Scotland Study). Both were from placebo-controlled trials early in the history of statin research.31,32 These showed that elevated triglycerides increased the risk of cardiac events in patients randomized to placebo. However, elevated triglycerides did not increase risk in patients who had received statin therapy.

In the VA-HIT trial, there was no evidence that lowering triglycerides with gemfibrozil was associated with the reduction seen in events.18 These studies, combined with the failure of the other fibrate trials to reduce cardiac events in spite of significant reduction in triglycerides, raises serious doubts about treating triglycerides. Again, aggressive statin therapy to drive down LDL may remain the proper treatment.

There is growing interest in omega-3 supplements as triglyceride-reducing agents. The support for their effectiveness comes predominantly from an open-label study in which omega-3 supplements were given to post-MI patients.33 This study, which was not placebo-controlled or randomized and showed a short-term reduction (12 months) in cardiac mortality in post-MI patients, strongly suggests an anti-arrhythmic benefit.33 The modest triglyceride reduction (seven points) also supports the anti-arrhythmic hypothesis.

Two subsequent studies looked at this hypothesis. These were double-blind, placebo-controlled trials of omega-3 supplements in patients who had implantable defibrillators. In the first study, patients receiving omega-3 supplements had an increased rate of serious arrhythmias.34 The second study showed no difference in the serious arrhythmias between the omega-3 and placebo patients.35 Agents that reduce cardiac arrhythmias can also induce arrhythmias. These agents cannot be recommended until this issue is resolved.

Conclusions

Statins remain the cornerstone of therapy for hyperlipidemia.36,37 When considering whether to institute combination therapy for further reduction of one or more of the lipid fractions, carefully study the information about the benefits (or lack thereof) to guide your decision making. Remember, aggressive LDL reduction with statin therapy alone is shown to reduce cardiac events in patients.

Dr. Guthrie is professor of emergency medicine, internal medicine, and pharmacology at The Ohio State University in Columbus.

References

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2. Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med. 1995;333:1301-1307.

3. 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.

4. Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350:1495-1504.

5. deLemos JA, Blazing MA, Wiviott SD, et al. Early intensive vs. a delayed conservative simvastatin strategy in patients with acute coronary syndromes. Phase Z of the A to Z trial. JAMA. 2004;292:1307-1316.

6. LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352: 1425-1435.

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

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

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

11. Tall AR. CETP inhibitors to increase HDL cholesterol levels. N Engl J Med. 2007;356:1364-1366.

12. Guthrie RM. How safe is aggressive statin therapy? Prog Cardiovasc Nurs. 2006;21:140-145.

13. Theheart.org. ENHANCE results yield disappointment for ezetimibe. Available at www.theheart.org/article/837243. Accessed January 23, 2008.

14. Ballantyne CM, Blazing MA, King TR, et al. Efficacy and safety of ezetimibe co-administered with simvastatin compared with atorvastatin in adults with hypercholesterolemia. Am J Cardiol. 2004;93:1487-1494.

15. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). 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.

16. Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels. JAMA. 1998;279:1615-1622.

17. 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. 2000;101:477-484.

18. 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;341:410-418.

19. Robins SJ, Collins D, Wittes JT. Relation of gemfibrozil treatment and lipid levels with major coronary events. JAMA. 2001;285:1585-1591.

20. Frick MH, Elo O, Haapa K, et al. Helsinki Heart Study: primary- prevention trial with gemfibrozil in middle-aged men with dyslipidemia. N Engl J Med. 1987;317:1237-1245.

21. Tenkanen L, Manttari M, Kovanen PT, et al. Gemfibrozil in the treatment of dyslipidemia: An 18-year mortality follow-up of the Helsinki Heart Study. Arch Intern Med. 2006;166:743-748.

22. Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease. Circulation. 2000;102:21-27.

23. Keech A, Simes RJ, Barter P, et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet. 2005;366:1849-1861.

24. Clofibrate and niacin in coronary heart disease. JAMA. 1975;231:360-381.

25. Canner PL, Berge KG, Wenger NK, et al. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol. 1986;8:1245-1255.

26. Capuzzi DM, Morgan JM, Weiss RJ, et al. Beneficial effects of rosuvastatin alone and in combination with extended-release niacin in patients with a combined hyperlipidemia and low HDL-density lipoprotein cholesterol levels. Am J Cardiol. 2003; 91:1304-1310.

27. Zhao XQ, Morse JS, Dowdy AA, et al. Safety and tolerability of simvastatin plus niacin in patients with coronary artery disease and low high- density lipoprotein cholesterol. Am J Cardiol. 2004;93:307-312.

28. Barter P, Gotto AM, LaRosa JC, et al. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular risk. N Engl J Med. 2007;357:1301-1310.

29. Nordestgaard BG, Benn M, Schnohr P, Tybjaerg-Hansen A. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA. 2007;298:299-308.

30. Brunzell JD. Hypertriglyceridemia. N Engl J Med. 2007;357:1009-1017.

31. Pedersen TR, Olsson AG, Faergeman O, et al. Lipoprotein changes and reduction in the incidence of major coronary heart disease events in the Scandinavian Simvastatin Survival Study (4S). Circulation. 1998;97:1453-1460.

32. Influence of pravastatin and plasma lipids on clinical events in the West of Scotland Coronary Prevention Study (WOSCOPS). Circulation. 1998;97:1440-1445.

33. Marchioli R, Barzi F, Bomba E, et al. Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: time-course analysis of the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI)-Prevenzione. Circulation. 2002;105:1897-1903.

34. Raitt MH, Connor WE, Morris C, et al. Fish oil supplementation and risk of ventricular tachycardia and ventricular fibrillation in patients with implantable defibrillators. JAMA. 2005;293:2884-2891.

35. Brouwer IA, Zock PL, Camm J, et al. Effect of fish oil on ventricular tachycardia and death in patients with implantable cardioverter defibrillators. JAMA. 2006;295:2613-2619.

36. Jones P. Statins as the cornerstone of drug therapy for dyslipidemia: monotherapy and combination therapy options. Am Heart J. 2004;148:S9-S13.

37. Streja D. Combination therapy for the treatment of dyslipidemia. Curr Opin Invest Drugs. 2004;5:306-312.

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