COVER STORY

TAMING A KILLER

New guidelines and new drugs are changing the management of hyperlipidemia

When it comes to managing hyperlipidemia, it's a numbers game. Use the National Cholesterol Education Program (NCEP) Adult Treatment Panel III guidelines to figure the risk factors, determine the LDL target for primary or secondary prevention, and set the intervention plan in motion to reduce the LDL, increase the HDL, and reduce triglyceride levels to the given targets. Looks simple enough, doesn't it? In reality, it isn't.

Statistics tell us that more than 100 million American adults have total cholesterol levels greater than 200 mg/dl with more than 41 million higher than 240 mg/dl. Guidelines for lipid lowering have been in place since 1987; yet, as many as 52 million adults need additional dietary guidance and change to meet target goals. Thirteen to 15 million require lipid-lowering therapy to reach target goals.

And, as Gerald Fletcher, M.D., a cardiologist at Mayo Clinic, Jacksonville, Fla., pointed out, although "there are some data showing that we are achieving these goals very slowly, we are setting new lipid goals as we go along. Total cholesterol goals used to be anything less than 220. Now it's less than 200."

Increasingly, guidelines for treatment of hyperlipidemia differentiate primary prevention from secondary prevention. The goal of primary prevention is to prevent atherosclerosis. The goal of secondary prevention is to prevent cardiac events in an individual likely to already have established coronary heart disease.

In the most recent iteration of guidelines, the standard for secondary prevention for the LDL-C target dropped to less than 100 mg/dl in individuals with coronary heart disease or coronary heart disease risk equivalents (noncoronary atherosclerosis, diabetes, or 10-year risk of coronary heart disease greater than 20%). In individuals who have no heart disease and fewer than two risk factors, the target is less than 160 mg/dl. In individuals who have no heart disease but more than two risk factors, the target is less than 130 mg/dl. But this is probably about to change.

Several recent studies have led some experts to believe all patients with acute coronary syndromes should be treated with statins, regardless of their LDL level. Trials currently under way looking at this issue include the Treating to New Targets (TNT) trial, the Incremental Decrease in Endpoints through Aggressive Lipid Lowering (IDEAL), the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine with Simvastatin and Folate/B₁₂ (SEARCH) trial, and the Heart Protection II trial.

Gregory G. Schwartz, M.D., Ph.D., chief, cardiology section, Denver VA Medical Center, and professor of medicine, University of Colorado, commented, "In patients with chronic atherosclerotic vascular disease or diabetes, current [NCEP-III] guidelines state that LDL-lowering therapy is not required when baseline LDL cholesterol is < 100 mg/dl. Recent evidence, primarily from the Heart Protection Study, suggests that this guideline may be unfounded and that such patients benefit from statin treatment irrespective of baseline LDL-C. Similarly, in the setting of acute coronary syndrome, the MIRACL [Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering] study [of which Schwartz was the first author] also found no significant interaction between baseline LDL-C and the benefit of short-term treatment with atorvastatin."

The recent study by Christopher Heeschen, M.D., and colleagues lends further support to the benefit of statin therapy in acute coronary syndromes. In this study, clinicians found that patients in whom chronic statin therapy was discontinued following an acute coronary syndrome had a higher incidence of cardiac events in the following 30 days than did the patients who continued statin therapy. In addition, patients beginning statin therapy showed some measure of protection from cardiac events as early as 14 days after implementation (which is far too soon to attribute to a lipid-lowering effect). Authors of the study suggested that discontinuing chronic statin treatment during acute coronary syndromes might impair vascular function—independent of lipid-lowering effects associated with statins.

So what will it take to tame American's No. 1 killer? The most obvious answer comes from the guidelines: reducing cholesterol levels. This can be accomplished in two ways, by therapeutic lifestyle changes and drug therapy. Therapeutic lifestyle changes include the following: reduce saturated fats to less than 7% of calories, reduce cholesterol intake to less than 200 mg/day, add dietary adjuncts such as plant stanols/sterols, reduce weight, and increase physical exercise. The potential reduction in the LDL-C level by lifestyle modification varies from 20%-35%.

When lifestyle modification cannot adequately reduce the LDL-C level, the approach becomes drug therapy, and more than 90% of prescriptions currently written are for statins. For some patients, statin therapy is effective in achieving target goal. For others, it isn't. W. Virgil Brown, M.D., director, division of arteriosclerosis and lipid metabolism at Emory University, Atlanta, explained, "I think that patients respond differently to different drugs because everyone brings a different set of genes to the table. There are many patients who don't get adequate reduction, certainly many who don't have adequate triglyceride reduction and HDL elevation."

Brown alluded to the fact that prescribers base their choice of lipid drug therapy on the likelihood it will successfully reduce lipid levels to target (see chart). He stated, "The feasibility issue will drive the habits of the doctors. Doctors tend not to try to do things they feel are very difficult to do." Pharmaceutical manufacturers, recognizing the need for even more effective cholesterol-lowering medications, have several drugs in trials to meet the demand.

Drugs in development

AstraZeneca recently received an "approvable letter" from the Food & Drug Administration for its rosuvastatin (Crestor). It will probably be released this summer, though there is some concern about an increased incidence of rhabdomyolysis reported with the 80-mg strength. This might be of particular concern since Baycol (cerivastatin, Bayer), a rather potent statin, was withdrawn from the market last year due to rhabdomyolysis. Published clinical trials suggest rosuvastatin will be the most potent statin drug marketed. Doses usually cited for comparison are rosuvastatin 10 mg, and, at least initially, the drug is expected to be marketed in the 5-mg strength.

Trials comparing the efficacy of rosuvastatin with that of other statins found that 10 mg had a greater effect in lowering LDL-C than atorvastatin 10 mg (43%-51% versus 35%-44%) and a greater effect than pravastatin 20 mg and simvastatin 20 mg (rosuvastatin 49% versus pravastatin 28% and simvastatin 37%). In addition to lowering LDL-C, rosuvastatin has demonstrated greater increases in HDL (rosuvastatin 12%-14% versus atorvastatin 10 mg 7%-8%; rosuvastatin 7% versus pravastatin 20 mg 4% and simvastatin 20 mg 4%).

A second statin, pitavastatin (Sankyo Pharma and Novartis) is in phase II trials in Europe and the United States and phase III trials in Japan. A recently published comparative trial of 240 patients showed pitavastatin 2 mg significantly lowered LDL-C cholesterol by 37.6% from baseline in comparison with pravastatin 10 mg's 18.4%. Pitavastatin also significantly lowered total cholesterol, triglycerides, apo B, C-II, and C-III and increased HDL-C.

In addition to new statins, another approach to reducing lipids levels will more effectively inhibit cholesterol absorption. Brown explained that a drug that blocks cholesterol absorption in the intestine actually blocks both endogenous cholesterol that has been generated by synthesis in the body and dietary cholesterol. This is the mechanism of the stanol esters and phytosterol esters; for example, Take Control or Benecol margarine.

More effective than these dietary products is ezetimibe 10 mg (Zetia, Merck/Schering-Plough). Phase III trials currently under FDA review demonstrate ezetimibe plus pravastatin (pooled across pravastatin doses from 10-40 mg) significantly decreased LDL-C over pravastatin (37.3% versus 24.3%), significantly decreased triglycerides (17.6% versus 7.6%), and increased HDL, though not significantly. Ezetimibe used in combination with lovastatin (pooled across lovastatin doses from 10-40 mg) demonstrated significantly greater decreases in LDL-C than lovastatin alone (39% versus 24.7%), significantly greater decreases in triglycerides (21.7% versus 11.2%), and significantly greater increases in HDL-C (8.6% versus 4.0%). Brown predicted, "It will probably be used, for the most part, in conjunction with statin treatment."

Although triglyceride reduction is not the primary target of the NCEP ATP III guidelines, hypertriglyceridemia is a significant problem with limited answers, particularly in those individuals with morbidly high values. Brown noted that groups of drugs in development to address hypertri- glyceridemia include peroxisome proliferator- activated receptor (PPAR) alpha agonists and PPAR-gamma agonists. Gemfibrozil and fenofibrate work in part as PPAR-alpha agonists, enhancing the liver clearance of triglycerides. PPAR-gamma agonists, antidiabetic drugs such as pioglitazone (Actos, Lilly) or rosiglitazone (Avandia, GlaxoSmithKline), turn on a series of genes that tend to promote insulin sensitivity and reduce the mobilization of fatty acids from adipose tissue.

Brown also sees promise in drugs that are acyl cholesterol acyl transferase (ACAT) inhibitors. ACAT is required to generate macrophages full of fat in the arterial walls, and those cells are the driving force in atherosclerosis. Some drug companies are developing drugs that (when taken orally) will get into the macrophage and block cholesterol ester formation and macrophage formation, actually lowering them inside the artery walls. "At least one, avasimibe, which is a Pfizer drug in phase II trials, has been shown to prevent atherosclerosis in a couple of different animal models."

Another group of drugs in development inhibit the transfer of cholesterol from one lipoprotein to another. HDL, for example, gives up cholesterol to VLDL (very low density lipoprotein) through the actions of a protein called cholesterol ester transfer protein. By inhibiting that protein, cholesterol remains in HDL form, and HDL levels go up. But, Brown explained, there are pros and cons to this approach. If the drug raises HDL (HDL will deliver cholesterol to the liver to get rid of it), and the drug prevents it from going into the atherogenic particles, VLDL and LDL (that would also be delivered to the liver to clear), will this actually prevent atherosclerosis? There is concern that without one of the pathways for dealing with cholesterol, cholesterol (in the form of HDL) remains in the plasma—which is not ideal.

Avant Immunotherapeutics has a vaccine against endogenous cholesteryl ester transfer protein (CTEP) in phase II trials. If successful, the twice-a-year injection could prove a means of reducing risk factors for atherosclerosis without the need for daily medication(s).

To more effectively reduce lipid levels, multiple lipid-lowering therapies are used in combination. Though niacin is often used in combination with statin therapy, the first dual component therapy—Advicor (extended-release nicotinic acid and lovastatin)—was launched at the end of January 2002 by Kos Pharmaceuticals. Clinical trial data have shown that, at the maximum recommended dose, the combination causes average reductions in LDL cholesterol of up to 42% from baseline and for triglycerides of up to 44%, while increasing HDL cholesterol by up to 30%.

Statins have also been used in combination with bile acid sequestrants, including the more effective gram-for-gram bile acid sequestrant, colesevelam (Welchol, Sankyo). Because some evidence suggests that doubling a statin dose only results in an additional 6% decrease in LDL-C, adding a bile acid sequestrant or other type of therapy to statin therapy may prove beneficial.

In a slightly different approach (not strict- ly targeting LDL-C), Bristol-Myers Squibb is considering submission of a supplemental New Drug Application for the combination of pravastatin 40 mg and buffered acetylsalicylic acid 81 or 325 mg. Both drugs have been approved for reduction of cardiac events in individuals who are candidates for secondary prevention strategies; combination therapy would make treatment simpler for the patients.

Perhaps to alter the competitive environment expected with the approval of rosuvastatin, Pfizer has recently obtained FDA approval for dosing of atorvastatin to individualize drug therapy. Recommended starting doses are 10 mg, 20 mg, or 40 mg, with dose adjustment up to 80 mg.

Role of natural products

A smattering of studies have begun to demonstrate that some natural products have some efficacy in lowering cholesterol. One product, policosanol 10 mg, was compared with simvastatin 10 mg in elderly patients who had followed a standard cholesterol-lowering diet for six weeks. After eight weeks, 28 patients treated with policosa- nol showed significantly reduced total cholesterol, LDL-C, and triglycerides (14.7%, 17.9%, and 13.8%, respectively). Simvastatin was similarly effective in reducing total cholesterol, LDL-C, and triglycerides in 25 patients (15.2%,19.8%, and 8.7%, respectively). Another study demonstrated policosanol efficacy in comparison with probucol in 30 patients.

Other natural products that have been evaluated in clinical trials include garlic, flaxseed, oat bran, red yeast, psyllium, and soy. Preliminary animal studies suggest sap from the guggul tree, used for more than 2,000 years in India, may also successfully reduce cholesterol levels. In addition, clinical studies have shown consuming fish oils can reduce triglycerides—in addition to their other beneficial effects.

Even with the best possible drug therapy for lowering lipid levels, successful therapy is determined by appropriate prescribing practices and adherence to therapy by the patients themselves. Marcia Brackbill, Pharm.D., assistant professor of pharmacy, Bernard J. Dunn School of Pharmacy, Shenandoah University, sees part of her role at the Heart Center as one of education. "I have cardiology patients and also cardiac surgery patients. So for all of our people at discharge, I try my best to do patient education on how important [adherence to drug therapy] is and what their goals would be for their cholesterol, especially now that the newer guidelines are out."

Brackbill said she also watches lipid levels in patients coming through the center and, when necessary, calls them to the attention of the surgeon or nurse practitioner, though she is quick to admit that her team is very cognizant of cholesterol levels and the need for therapy.

In working with patients, Brackbill has been surprised by the number of patients who report muscle aches and blame them on their statin agent. "It's not the majority by any means, but myopathies are definitely an issue in some of the patients. I can tell from talking to them." Myopathies and rhabdomyolysis can cause patients to discontinue therapy, though the incidence of these side effects is small (see table). As noted previously, cerivastatin was withdrawn from the market in 2001 because of adverse effects that appear to be much less common with other statins. Interestingly, a letter that appeared in Lancet (Feb. 23) suggests that statins lower endogenous coenzyme Q-10, which might lead to myopathies.

Adverse effects associated with statins

Earlier this year, concerns surfaced that statins might contribute to memory problems, especially in the elderly, and some patients wondered whether they should discontinue therapy. Drug manufacturers flatly denied any association between statins and cognitive impairment. One study published this spring found that women who used statins scored higher on cognitive tests than did those with high LDL-C levels, even after scores were adjusted for age, education, and hormone replacement therapy. The authors contended that uncontrolled hyperlipidemia is detrimental to cognitive function.

Cost is a factor

Another reason patients discontinue cholesterol-lowering therapy is cost. Brackbill stated, "I hear from my patients that if they didn't continue taking [drug therapy], it's because of the tremendous cost. We have a fairly large indigent population." Brackbill works with indigent programs and case managers to try to identify those patients in need of assistance.

The cost of cholesterol-lowering therapy has also caught the attention of third-party payers. From the perspective of managed care, Robert Lipsky, Pharm.D., FASHP, manager of clinical pharmacy services, HealthNet of Arizona, finds cholesterol therapy is not cost-effective for all populations. "We know that just based on data from Framingham, if you lower cholesterol, you're going to lower the risk of heart disease. There's just no question about it." Based on the pharmacoeconomic data currently available, he can readily make the case for treating individuals who have high cholesterol levels. But as an individual's cholesterol level trends toward normal, it becomes increasingly less cost-effective to push it to normal.

Thus, even though the current guidelines have increased the number of people who should take drug therapy to reduce cholesterol levels, Lipsky does not foresee cholesterol management as a cost-effective service for payers to underwrite. He is hopeful, however, that federal legislation will allow pharmacists to be reimbursed for treating the Medicare population. Then, perhaps based on studies showing cost-effectiveness of interventions for cardiovascular problems such as congestive heart failure, cholesterol management could be included in the mix.

In summary, it's tough to do battle with the nation's No. 1 killer. Current research has provided a wealth of tactics and will soon offer clinicians "bigger guns." The trade-off is, fighting cardiovascular disease is a costly undertaking. Nevertheless, pharmacists are involved in cholesterol management at multiple levels and continue to press forward to neutralize the morbidity and mortality of cardiovascular disease.

Kathy Hitchens, Pharm.D.

The author is a clinical writer based in the Indianapolis area.

Kathy Hitchens. TAMING A KILLER.

Drug Topics

2002;12:33.