Lipid Management: Tools for Getting to the Goal

Transcription

1 ... PRESENTATIONS... Lipid Management: Tools for Getting to the Goal Based on a presentation by James M. McKenney, PharmD Presentation Summary The treatment of hypercholesterolemia in the United States begins with the recognition of elevated low-density lipoprotein cholesterol (LDL-C) as the primary target. An optimal LDL-C level has been defined as < 100 mg/dl. The first step in lowering LDL-C continues to be lifestyle modification, which includes a restriction of saturated fat and cholesterol, increased physical activity, and weight loss, if applicable. Approximately half of all patients with elevated LDL-C levels will ultimately need treatment with a lipid-lowering drug to achieve treatment goals. The preferred drug for first-line treatment in most patients is a statin; a bile acid resin or niacin can be used in patients who cannot tolerate statins or who are not candidates for statin therapy. Combination therapy is an option, with several combinations showing efficacy in lowering LDL-C (statin plus bile acid resin, niacin plus bile acid resin) and in lowering both LDL-C and triglycerides (statin plus fibrate, statin plus niacin, bile acid resin plus niacin). Successful lipid management includes treating to reach the LDL-C goal level, treating to reach the non highdensity lipoprotein cholesterol goal level if applicable, and managing other risk factors for coronary heart disease. The treatment of hypercholesterolemia in the United States, according to new guidelines released in May 2001 from the National Cholesterol Education Program (NCEP), begins with the recognition of an elevated low-density lipoprotein cholesterol (LDL- C) level. 1,2 The new guidelines have provided a new definition of LDL-C levels, including the definition of an LDL-C level of < 100 mg/dl as optimal (Table 1). 2 Initial treatment of lipid disorders is aimed at matching the aggressiveness of LDL-C lowering to the patient s risk of experiencing a coronary event. The greater the coronary heart disease (CHD) risk, the lower the LDL-C goal, and the greater the need for drugs to treat the patient (Table 2). 2 High-density lipoprotein cholesterol (HDL-C) is recognized as a strong marker of CHD risk and is useful in identifying patients who require risk-reduction therapy with LDL-C lowering regimens. However, clinical trials have not demonstrated that raising only HDL-C without affecting any other lipid or lipoprotein particle will prevent CHD, so the new guidelines do not recommend a treatment target for HDL-C. On the other hand, there is growing evidence that triglycerides are directly linked to CHD and that lowering high triglyceride levels will reduce the risk of coronary events. 3-5 For this reason, the new NCEP guidelines have set new treatment targets, defined by non HDL-C, which become a second treatment goal after the LDL-C goal is obtained. 1,2 Lifestyle Modification The first step in lowering LDL-C is, has been, and will continue to be lifestyle modification. Lifestyle modification, although an effective treatment for most patients with elevated LDL-C, is difficult to maintain. For physicians and other VOL. 7, NO. 9, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S299

2 PRESENTATIONS Table 1. Classification of LDL-C and HDL-C Lipoprotein Level (mg/dl) Comment LDL-C <100 Optimal Near optimal Borderline high High 190 Very high HDL-C <40 Low >60 High HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol. Source: Reference 2. Table 2. LDL-C Goals of Therapy Risk Category LDL-C Goal (mg/dl) <2 risk factors* <160 2 or more risk factors* <130 CHD or CHD equivalents <100 Noncoronary atherosclerosis Diabetes 10-year risk >20% CHD = coronary heart disease; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol. *Current cigarette smoking, hypertension (blood pressure >140/90 or on antihypertensive therapy), HDL-C <40 mg/dl, family history of premature CHD, male >45 years, or female >55 years. Peripheral arterial disease, strokes, transient ischemic attacks, abdominal aortic aneurysm. Source: Reference 2. healthcare professionals, advocating lifestyle modification is labor intensive because it involves continually educating patients to eat healthfully, exercise, and reduce or maintain weight. For those who practice in managed care organizations, lifestyle modification education also involves concerns about resources and resource allocation. Providing a registered dietitian or other nutritional specialist to teach patients a complicated diet that will lower LDL-C and triglyceride levels is recommended by the new guidelines. 1,2 The new guidelines also encourage all healthcare professionals, including pharmacists, to teach and encourage patients to follow these recommendations. Lifestyle modification is a legitimate and effective treatment modality for lowering LDL-C, and should be part of the treatment plan for all patients with dyslipidemia. An effective low-fat diet could lower LDL-C by 20% to 30%. 6-8 Moreover, data have demonstrated improvement in outcomes with lifestyle modification. Several large studies have shown that diets rich in fresh fruits and vegetables and monounsaturated fatty acids, particularly omega-3 fatty acids, are associated with favorable outcomes. 9,10 The new guidelines have called the lifestyle modification approach the therapeutic lifestyle change (TLC) and advocate it as the first step in lowering elevated LDL-C levels. 2 TLC restricts meats and dairy products to keep saturated fat intake below 7% of total daily calories and cholesterol intake below 200 mg/day. 2 TLC also encourages weight loss in overweight and obese patients and regular physical exercise for everyone. At least 3 large studies have demonstrated that it is possible to reduce saturated fat intake to this level for a year or more and reduce LDL-C by a respectable amount (Table 3). 6-8 Furthermore, the TLC diet is flexible; adjustments can be made to include additional fiber from vegetables, omega-3 fatty acids from fish, and to augment the diet with dietary adjuncts such as fiber and stanol/sterol esters, to further lower LDL-C. Drug Therapy For patients who are not able to reach their LDL-C goal on the TLC program, drug therapy is the next step. 2 Approximately half of all patients with elevated LDL-C levels will ultimately need treatment with a lipid-lowering drug. As recommended in the new guide- S300 THE AMERICAN JOURNAL OF MANAGED CARE AUGUST 2001

3 Lipid Management: Tools for Getting to the Goal lines, the preferred drug for most patients is a statin; a bile acid resin or niacin is recommended for patients who cannot tolerate statins or who are not candidates for statin therapy. 2 Statins. Statins are effective in lowering LDL-C levels by reducing the synthesis of cholesterol in all cells throughout the body, but most importantly in the hepatocyte. 2 When cholesterol synthesis is reduced in the hepatocytes, these cells upregulate LDL-C receptors, which are also known as apolipoprotein B or E receptors because they recognize both apolipoproteins. These cell-surface receptors combine with proteins on the surface of circulating LDL-C particles, bind with them, and bring them from the circulation into the hepatocyte. The net result is a lower LDL-C blood level. 2 During this process, very-low-density lipoprotein cholesterol (VLDL-C) remnants, which also contain apolipoproteins B and E and also carry cholesterol that can lead to atherosclerosis, are taken up by the hepatocyte and the blood level of these particles is reduced as well. 2 Traditionally, statins are started at an initial dose and then titrated upward. Alternatively, the new guidelines suggest that clinicians may consider starting the statin at a higher dose if it is more likely to lower LDL-C to goal levels and then adjusting this dose up or down as needed during a follow-up visit. 2 An appropriate starting dose can be selected depending on a patient s required reduction (Table 4) Additional reductions in LDL-C of 6% to 7% are achieved by doubling the dose. Thus, if a patient needs to reduce his or her LDL-C by 50%, for example, it makes sense to start atorvastatin at 40 mg/day rather than the usual starting dose of 10 mg/day. As a class, the statins are remarkably free of side effects, although dose-related changes in liver function are seen, especially at the highest doses (where the incidence of significant liver function change increases from about 1% to 2.5%) Myositis is seen as well, most commonly at the higher doses (where an incidence of 0.2% is reported). Thus, side effects are a consideration when prescribing higher doses as part of a more aggressive lipid management strategy. In addition to their proven efficacy in lowering LDL-C, statins also reduce triglyceride and apolipoprotein B levels and modestly increase HDL-C levels. Moreover, 5 large-scale primary- and secondary-prevention trials have demonstrated that statins reduce the risk of coronary events by 25% to 45% over 5 years in a broad range of patients In fact, these trials have shown that statins reduce every clinical manifestation of atherosclerosis Statin therapy is not appropriate for all patients with elevated LDL-C levels. For example, statins may not be appropriate for those who are intolerant to statins, who are best treated with nonsystemic therapy (eg, young adults, women of childbearing potential), who require only a modest reduction in LDL-C, those with active liver disease or increased liver function test (LFT) values, and who predominantly have hypertriglyceridemia. Bile Acid Resins. Bile acid resins, which reduce LDL-C by a mechanism of action different from that of the statins, may be appropriate first-line therapy for some patients. After the liver converts cholesterol into bile acids, the bile acids circulate through the gallbladder to the intestines, where they participate in a Table 3. Therapeutic Lifestyle Change Diet Component of Diet Source: Reference 2. % of Total Daily Calories Total fat 25% to 35% Saturated fat <7% Polyunsaturated fat Up to 10% Monounsaturated fat Up to 20% Carbohydrates 50% to 60% Protein Approximately 15% Cholesterol <200 mg/dl VOL. 7, NO. 9, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S301

4 PRESENTATIONS variety of processes, including the absorption of nutrients and bowel function. Bile acids are then reabsorbed in the ileum through a bile acid transport system that returns them to the liver, where they are converted into cholesterol, thus continuing the cycle. Bile acids are bound in the intestines by bile acid resin, increasing their excretion from the intestine. The liver responds by upregulating cholesterol 7-alpha hydroxylase, which increases the conversion of cholesterol to bile acids in the liver, thereby reducing the cholesterol concentration in the hepatocyte. This upregulates the LDL-C receptors, as the statins do, and increases the removal of LDL-C particles from the circulation. The net result is an efficient reduction in the LDL-C blood level. Also, bile acid resins have been shown in the Lipid Research Table 4. Efficacy of Statins in Reducing LDL-C Average LDL-C Drug Daily Dose (mg) Reduction (%) Atorvastatin Cerivastatin Fluvastatin Lovastatin Pravastatin Simvastatin LDL-C = low-density lipoprotein cholesterol. Sources: References Clinics Coronary Primary Prevention Trial (LRC-CPPT) to reduce coronary events. 22 Older bile acid resins, cholestyramine and colestipol, are associated with constipation and flatulence, which do not appear to be a problem with colesevelam, a recently approved bile acid resin that appears to be tolerated much better and is associated with a far lower incidence of gastrointestinal disturbances. 23 The older agents are also associated with drug interactions because they bind with other negatively charged drugs, impede absorption of drugs and/or fat-soluble vitamins, and must be taken 1 hour after or 4 to 6 hours before other drugs. This requirement complicates dosing and adversely affects compliance with therapy. As with the gastrointestinal side effects, drug interactions do not appear to be a problem with colesevelam. Moreover, unlike the older bile acid resins, which are grainy powders that have to be mixed with water or juice, colesevelam is administered as a tablet. Bile acid resins lower LDL-C approximately 10% to 25%. Colesevelam, for example, at a dose of 3.8 g/day produces a 15% reduction in LDL-C and at 4.5 g/day produces an 18% reduction in LDL-C, an appropriate decrease in patients who need only moderate LDL-C lowering. 23 Niacin. Niacin, or nicotinic acid, reduces the secretion of VLDL-C particles from the liver; therefore, there are fewer of these triglyceride-carrying particles that can be converted into LDL-C. Thus, niacin reduces both LDL-C and triglyceride blood levels effectively. Through mechanisms that are not yet entirely clear, niacin is also the most effective agent for raising HDL-C levels. 24 In addition, niacin has been shown, in the Coronary Drug Project, to reduce coronary events and all-cause mortality. 25 Niacin, which is available in immediate-release, sustained-release, and extended-release formulations, is associated with a number of adverse effects, including flushing, itching, headaches (with immediate-release formulations), and hepatotoxicity (with sustained-release S302 THE AMERICAN JOURNAL OF MANAGED CARE AUGUST 2001

5 Lipid Management: Tools for Getting to the Goal formulations). 24 It is contraindicated in patients with active liver disease or unexplained elevations in LFT values, and requires frequent monitoring of liver function: at baseline, every 6 to 12 weeks for the first year, and approximately every 6 months thereafter. 24 The preferred agents in managing patients are the immediate- and extended-release formulations because they are generally more effective and much less apt to cause liver toxicity. However, they can cause bothersome flushing in up to 50% of patients. Flushing may be reduced by administering doses at bedtime and having the patient take an adult aspirin 30 minutes prior to the daily dose. 24 Combination Therapy. If the LDL-C goal is not achieved with any one of the above therapies, the options provided by the new guidelines are to escalate the statin dose or begin combination therapy by adding a bile acid resin or niacin to the statin. 2 The new guidelines suggest that combination therapy may be a more effective strategy, allowing the physician to skip several dose-titration steps to achieve the same LDL-C reduction. 2 For example, a recent study reported LDL-C reductions of 26% and 34% with daily simvastatin doses of 10 and 20 mg, respectively. 26 When colesevelam at a standard dose of 3.8 g/day was added to the 10-mg simvastatin dose, a 42% reduction in LDL-C was achieved. Similarly, the addition of colesevelam at a dose of 2.3 g/day to 20 mg of simvastatin also resulted in a 42% reduction in LDL-C. 26 This finding is particularly important because it indicates that the reduction in LDL-C that results from the addition of a bile acid resin to a statin is superior to the reduction in LDL-C that results from a single doubling of the statin dose. Thus, for the patient who requires a considerable reduction in LDL-C, combination therapy with a bile acid resin and a statin may represent a good alternative. A recent study evaluating combination therapy with extended-release niacin in patients taking a stable dose of a variety of statins for at least 3 months also reports additive LDL-C reduction. The statin and 1 g/day of extended-release niacin produced an additional 8% reduction in LDL-C whereas 2 g of niacin daily when added to a statin produced a surprising 31% additional LDL-C reduction. 27 For patients who are able to tolerate niacin therapy, this combination also offers a good alternative to achieve LDL-C goals. 27 Non HDL-C Targets. After the LDL-C goal has been achieved, the next step is to determine whether the patient has a triglyceride abnormality. Patients with high triglycerides often have increased levels of triglyceride-rich and cholesterolrich remnant particles, which may be just as atherogenic as the LDL-C particle. 28 Thus, if the patient is found to have a triglyceride level above 200 mg/dl after the LDL-C goal is achieved, the new guidelines recommend that he or she be treated to a second goal defined by non HDL-C (Table 5). Non HDL-C is determined by subtracting HDL-C from the total cholesterol and represents the sum of LDL-C and VLDL-C. Statins alone or in combination with bile acid resins effectively remove LDL-C particles as well as VLDL-C remnant particles. Thus, one way to treat patients to the non HDL-C goal is to intensify the statin dose or add a resin to it. Another way to manage these patients is to add a triglyceride-lowering drug to Table 5. Targets for Therapy After LDL-C Goal Has Been Met and Triglyceride Levels Remain Above 200 mg/dl LDL-C Target Non HDL-C Target Risk Category (mg/dl) (mg/dl) No CHD, <2 risk factors <160 <190 No CHD, 2+ risk factors <130 <160 CHD or CHD risk equivalent <100 <130 CHD = coronary heart disease; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol. Source: Reference 2. VOL. 7, NO. 9, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S303

6 PRESENTATIONS the LDL-C lowering regimen. Thus, a statin-fibrate or statin-niacin combination is recommended. 2 The combination of a fibrate and a statin has been reported to increase the risk of producing myopathy, a condition that includes muscle weakness or soreness and an elevation in creatine phosphokinase blood level to more than 10 times the upper limit of normal. 2 These problems can be minimized by not using this combination in patients with compromised liver or renal function, by using the lowest effective doses of the statin and fibrate, and by assuring that drugs that interact with either the statin or fibrate to increase their blood levels are not taken concurrently. Examples of potentially interacting drugs are macrolide antibiotics and azole antifungal agents. Conclusion The pathway to successful management of dyslipidemia is to: Treat to reach the LDL-C goal with statin monotherapy or with combination therapy that includes a statin Treat to reach the non HDL-C goal, if applicable (after the LDL-C goal is achieved), by further reducing LDL-C or by combining therapy that lowers both LDL-C and triglyceride levels Manage other CHD risk factors... DISCUSSION HIGHLIGHTS... Very Low LDL-C Level Member of the Audience: You mentioned reducing LDL-C to the range of about 50 to 70 mg/dl. Do safety and efficacy data exist to support having an LDL-C that low? Dr. McKenney: Yes. If you look at all the trials that have been done worldwide in recent years, there are thousands of patients who have been treated to an LDL-C level of 60 to 80 mg/dl with a statin. For example, atorvastatin trials alone have included more than 40,000 patients, and almost all of the trials are studying doses of 80 mg, which we would expect to reduce LDL-C levels well below 100 mg/dl. The safety profile coming out of this experience is exactly what you would predict. For example, the incidence of LFT changes greater than 3 times the upper limit of normal in the Atorvastatin Versus Revascularization Trial which evaluated atorvastatin 80 mg versus placebo was around 2.5%, exactly what the package insert predicted it would be. Further, we are not sure just how to interpret LFT changes. Patients receiving statins are not dying of hepatic failure, requiring liver transplants, or having hepatic dysfunction. Transaminase levels are simply going up in a few patients. When the statin is withdrawn, these levels return to normal. The other part of the answer to that question is how much LDL-C do you need. At birth, LDL-C levels are roughly 20 to 30 mg/dl. As people age, LDL-C levels begin to rise. Not all countries have levels as high as those in the United States. There are populations with levels that are lower, in the 70s and 80s, and they do well. And then there is abetalipoproteinemia, in which patients do not make apolipoprotein B at all, and their LDL-C levels are zero without apparent problems. Clinical trial data and epidemiologic observations suggest that LDL-C levels of 50 to 70 mg/dl are safe. Would our other speakers like to comment on that? Ms. Mason: From years of clinical practice, working with patients individually, and measuring their risk of having future events against small rises in LFTs, we are far more comfortable with small rises than we used to be. We have not seen any problems. We see so much benefit from therapy that we have more or less accepted LFT levels that are 2 to 3 times normal. Dr. Jones: The biggest concern is whether very low LDL-C levels might increase noncardiovascular disease mortality. Observational data show that a low LDL- S304 THE AMERICAN JOURNAL OF MANAGED CARE AUGUST 2001

7 Lipid Management: Tools for Getting to the Goal C level does not cause noncardiovascular disease but is the result of disease. For example, patients with cirrhosis have particularly low levels of LDL-C. Raising HDL-C Member of the Audience: You seemed to be implying that raising HDL-C or modestly increasing HDL-C has not been sufficiently proven to be of benefit in decreasing cardiovascular risk. Could you clarify that? Also, did the Veterans Affairs High-Density Cholesterol Lipoprotein Intervention Trial (VA-HIT) clarify anything? Or is there just not enough evidence? Dr. McKenney: This is a complicated question. Undoubtedly, HDL-C is a strong risk factor for CHD and helps us identify patients who need intervention to reduce this risk. But should we be raising HDL-C, and should we be treating everybody with a low HDL-C with drugs? That is the question. There are no drugs that uniquely raise HDL-C without altering other lipid levels. So we have never had the opportunity to look at what happens when you raise HDL-C alone. Statins lower LDL-C substantially and raise HDL-C a little. Bile acid resins do the same. Actually, a subanalysis of the LRC-CPPT showed us that raising HDL-C with bile acid resins was an important contributing factor to the reduction of CHD risk. Therefore, we know that even these modest changes, in combination with other changes, appear to be beneficial. Another problem is that HDL-C particles are heterogeneous. Therefore, simply knowing the HDL-C level, or knowing that a drug has raised the HDL-C level, does not necessarily tell us a lot about how the HDL-C particle is functioning. What you really want to know is whether the drug removes cholesterol from the system. HDL-C particles are involved in reverse cholesterol transport. In addition to the HDL-C level, we need to understand if HDL-C is effectively removing cholesterol, or if it is passing the cholesterol to another particle that could potentially deposit it in coronary arteries. As you know, HDL-C exchanges cholesterol and triglycerides with LDL-C. That is one way HDL-C gets rid of its cholesterol, by giving it to LDL-C and taking on triglycerides in exchange. If this were to happen to an appreciable extent, cholesterol esters could be deposited in the arteries by LDL-C. We are now working with a drug, in the research setting, that inhibits cholesterol ester transfer protein. This protein allows cholesterol to be transferred from these remnant particles to HDL-C, thus increasing HDL-C levels substantially. But whether this effect leads to a net removal of cholesterol from the circulation needs to be studied. We can raise HDL-C levels pharmacologically. But where is that going? Is that good? Is HDL-C actually being fluxed out of the system or not? We have to understand more about reverse cholesterol transport, the removal of cholesterol from the body, the role of HDL-C in cholesterol removal, and how we define HDL-C functionally before we can understand how to treat it properly. Dr. Jones: I think Dr. McKenney is trying to tell us that we are way behind in HDL- C research. Increased HDL-C is usually a marker of improvement in other lipid fractions and other areas of the CHD risk profile. For example, many of the patients in the VA-HIT trial had diabetes or metabolic syndrome, and low HDL-C is a marker for that condition. Raising HDL-C appears to benefit these patients. Why is that? Because they have small, dense, LDL-C particles that increase to larger, more buoyant LDL-C particles as triglycerides are reduced. Investigators compared patients in The Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) study who met the VA-HIT criteria with patients in the VA-HIT. The investigators found that the LIPID subgroup, treated with a statin, had lower event rates than did the VA-HIT patients, who were treated with a fibrate. 29 VOL. 7, NO. 9, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S305

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