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Controlling Blood Lipids. Part 2: When and How to Use Medication

Tedd L. Mitchell, MD; Larry W. Gibbons, MD, MPH

THE PHYSICIAN AND SPORTSMEDICINE - VOL 26 - NO. 11 - NOVEMBER 2021


This is the second of two articles on controlling blood lipids. The first article, on diet and exercise, appeared in the October issue.

In Brief: Drug treatment for abnormal blood lipids includes bile acid sequestrants, fibric acid derivatives, statins, and niacin. Statins generally offer the best combination of safety and effectiveness. Hormone replacement therapy reduces the risk of coronary artery disease in postmenopausal women. The National Cholesterol Education Program offers clear guidelines as to what levels of low-density lipoprotein cholesterol (LDL-C) should trigger consideration of drug treatment, and the authors suggest what levels of high-density lipoprotein cholesterol should prompt treatment. Measurements of small dense LDL-C and lipoprotein(a) may also be helpful in decisions about drug treatment for selected patients.

Following a carefully planned diet and a program of regular exercise can help many people control blood lipids (see "Controlling Blood Lipids, Part 1: A Practical Role for Diet and Exercise," October, page 41). Unfortunately, a bad genetic profile or lack of motivation can undermine such efforts. In these cases, medication can be important in reducing patients' risk of cardiovascular disease. Knowing what medications are available and when to use them adds significantly to the physician's armamentarium for managing coronary artery disease (CAD).

Indications for Treatment

LDL-C guidelines. The revised National Cholesterol Education Program (NCEP) (1) presents clear guidelines (table 1: not shown) regarding what levels of low-density lipoprotein cholesterol (LDL-C) should prompt consideration of drug treatment, as well as goals for LDL-C management. The aggressiveness of the therapy, of course, depends on the number of risk factors present and the presence or absence of CAD.

HDL-C criteria. The NCEP, however, does not present guidelines for drug treatment of abnormal high-density lipoprotein cholesterol (HDL-C) levels. Such treatment may be appropriate, but only after patients who have low HDL-C have attempted management through lifestyle modification such as smoking cessation, weight loss, and aerobic exercise (see related Highlights items, page 23). For the few patients who are on a very low-fat diet, adding a moderate amount of monounsaturated fat to the diet will often raise HDL-C.

If these lifestyle changes fail to raise HDL-C levels, drug treatment may be considered. Most clinicians hesitate to treat low HDL-C levels with drugs because there is little evidence that such treatment actually decreases CAD incidence. However, logic suggests that raising HDL-C with drugs could lower the risk of coronary disease, and no data suggest that higher HDL-C levels would not decrease the risk. Furthermore, the National Institutes of Health consensus conference report on HDL-C and triglycerides (2) states that drug treatment may be considered when lifestyle approaches fail in such patients.

Cooper Clinic guidelines. At our clinic, we have prescribed drugs for many years for high-risk patients who have low HDL-C levels. On the basis of our clinical experience, we have identified two groups of patients for whom drug therapy should be considered:

  • Patients who have CAD or at least two risk factors and an HDL-C of less than 35 mg/dL for men and 45 mg/dL for women. These HDL-C levels are considered high-risk, and, in our clinic, 20% of men and women fall into this category.

  • Patients who have no risk factors and an HDL-C of less than 28 mg/dL for men and 40 mg/dL for women, which includes 5% of patients in our clinic.

For a discussion of the usefulness of measuring other blood lipids, see "Which Lipids Should Be Measured?" below.

Other diagnostic factors. We also consider several other factors in deciding when and how aggressively to treat abnormal HDL-C or LDL-C levels.

Exercise testing. Many of our patients have had a maximal treadmill test as a part of their evaluation. We test those who are beginning an exercise program if they are men over 40 or women over 50 years old, and anyone who has more than two risk factors for CAD.

Besides considering the standard risk factors, we look at whether the exercise electrocardiogram is normal or abnormal. The degree of fitness is also important, since lack of fitness has been found to be a significant risk factor. For unfit patients—those whose performance in a standardized treadmill test or fitness assessment is in the bottom quintile—we are more likely to prescribe aggressive drug treatment, particularly if their cholesterol level does not improve over time.

Ultrafast CT scans. In any patient who has two or more significant risk factors, an ultrafast computed tomography (CT) scan (also called an electron beam CT scan) is examined for evidence of coronary artery calcium. These scans are particularly helpful in determining how aggressively to treat lipid abnormalities (3). If a patient has two or more risk factors and also has a definite calcium build-up in the coronary tree, aggressive treatment—specified in the NCEP guidelines for patients with CAD—is warranted. If a patient has fewer than two risk factors but has a high calcium score on the ultrafast CT scan, diet and/or drugs may be used to reduce the LDL-C below 100 mg/dL, even in the absence of symptomatic coronary disease.

Benefits and risks. Any consideration of drug treatment should include an assessment of the benefits and risks. Medications should be used sparingly in young adult men and premenopausal women, since their CAD risk is usually low. The medications that help lower LDL-C have only a temporary effect, so if treatment is stopped, LDL-C will return to its previous level. Patients must understand that they will need to take the medication for a long time, though not necessarily for the rest of their lives. Some patients may need to be reassured that stopping medication will not put them at greater risk than they faced before starting.

Comparing Medications

Medications for treating elevated LDL-C include four major categories: bile acid sequestrants, fibric acid derivatives, statins, and niacin. Knowing a patient's HDL-C level is important since it is often a good guide to which medication is most appropriate in managing abnormal LDL-C levels. For example, patients who have an HDL-C level of less than 35 mg/dL may receive the most benefit from niacin, especially if this is their most significant lipid abnormality. (For a discussion of the role of estrogen in controlling cholesterol, see "Estrogen and Cholesterol," below.)

Bile acid sequestrants. Bile acid sequestrants (cholestyramine resin and colestipol hydrochloride) bind bile acids and promote conversion of cholesterol to bile acids. The processes involved increase the number of LDL-C receptors in the liver and help pull cholesterol out of the serum.

Bile acid sequestrants are very safe but are expensive, can cause constipation and bloating, and are unpleasant to take because they are in powder or granular form. They may also increase triglycerides and may interfere with the absorption of other drugs.

Fibric acid derivatives. Medications such as gemfibrozil, probucol, and clofibrate are reasonably safe, and they lower triglycerides while modestly elevating HDL-C. However, they are not very effective in lowering LDL-C, they are expensive, and they must be taken twice daily. In addition, they may cause gallstones.

Statins. Medications such as pravastatin, lovastatin, simvastatin, atorvastatin, and fluvastatin block cholesterol synthesis in the cell, which increases LDL receptors in the liver and the clearance of LDL-C from the blood. These medications are safe, effective, and easy to take—one pill daily—and currently form the foundation of drug treatment for abnormal LDL-C.

Statins have several disadvantages, however, including expense and ineffectiveness in raising HDL-C significantly. They may also cause elevations of liver enzymes, but this is uncommon and is reversible when the medication is stopped. Given this potential, however, liver function tests should be done after 3 to 6 months of treatment and then perhaps a year later and annually thereafter.

Statins may also cause myositis, but the incidence is extremely low. For example, only one case of myositis occurred in 2,220 patients who took 20 or 40 mg/day of simvastatin for an average of 5.4 years (4).

The comparative advantages and disadvantages of the statins are as follows:

  • Simvastatin and atorvastatin may elevate HDL-C more than the others do, and they appear to be the most cost-effective in producing the maximum decrease in LDL-C.
  • Simvastatin yields greater benefits as the daily dosage increases (up to 80 mg/day), while the effect of lovastatin levels off at 40 mg.
  • Fluvastatin has not been as effective as the others in lowering LDL-C.

All of the statins except atorvastatin should be taken in the evening (see table 2 for normal dosages: not shown). Split doses taken in the morning and evening do not improve results and may, in fact, be less effective than a single dose in the evening. Patients rarely report sleep difficulty from these medications.

Niacin. Niacin is an attractive drug because it is inexpensive and significantly lowers LDL-C and triglycerides and raises HDL-C, though the mechanism of action is unclear.

Unfortunately, niacin has negative side effects, such as flushing, nausea, and heartburn. Though most of these are mild and not significant threats to health, they can interfere with treatment. In a study (5) of 133 patients who were taking long- or short-acting niacin, 42% eventually discontinued the medication because of side effects. Some of these did not occur until patients had been taking niacin for 2 to 3 years.

We recommend that patients start treatment with a very low dose—about 50 mg with each meal for 2 weeks—and then increase the dose by 50 mg/day every 2 weeks. We rarely treat a patient with more than 1,000 mg three times per day (a total of 3,000 mg/day). Niacin should be taken with meals but not with hot drinks. Missed doses can increase flushing. If flushing is a problem, taking an aspirin with each dose may help.

We usually do not recommend the use of long-acting niacin because of an increased risk of more serious side effects (hepatotoxicity). If long-acting niacin is used, patients should take half the dose of regular niacin—a maximum of 1,500 mg/day. Taking 3,000 mg/day will almost inevitably produce significant side effects.

Liver function must be monitored in any patient who takes niacin. Tests should be done every 3 months for 1 to 2 years and every 6 months thereafter. The onset of nausea and malaise in a patient who is taking niacin almost always indicates abnormal liver function.

A new form of niacin, Niaspan (Kos Pharmaceuticals Inc, Miami), has the advantage of being taken only once a day in the evening with a low-fat snack. It is currently being promoted as a form of niacin that causes fewer side effects, including less flushing and a low risk of liver abnormalities. Experience is limited, but at this point, the medication looks promising. If the claims prove true, this form of niacin will be a valuable addition to the lipid-lowering arsenal.

Combining medications. Bile acid sequestrants may be combined with statins and fibric acid with niacin, but these combinations may not improve the results. In theory, using statins with niacin is not recommended because of the risk of liver damage, but in practice, this combination has effected a significant reduction of LDL-C and an increase in HDL-C in patients who have no history of liver problems and a high risk for CAD. This combination usually allows a lower dose of niacin, reducing the risk of side effects. Patients who take this combination, however, must be monitored every 3 months with liver function and muscle enzyme tests. Combining statins and fibric acid is not recommended because of a risk of liver function abnormalities.

Basic Principles

Controlling blood lipids can be a complex process. To facilitate that process and maximize the effectiveness of drug treatment in patients who have lipid abnormalities, we recommend that physicians follow some basic principles:

  • Don't undertreat. If you use medication, use enough to do the job.
  • Appropriate diet is important and significantly increases the effectiveness of the medications discussed above.
  • Follow-up is crucial. Patients are likely to stop taking medications, not because of side effects, but for nonmedical reasons or just because they wonder if they still need to take a drug. Measuring lipid profiles after 2 to 3 months of treatment is important for determining if more aggressive treatment is needed and for encouraging patients who are making good progress.
  • Use the NCEP guidelines. They provide reliable, authoritative criteria for deciding who needs drug treatment.
  • Patients who are older than 65 years still benefit from lowering cholesterol (6). The older the patient, the more likely is the need for medication to reduce elevated LDL-C.
  • Women who have elevated LDL-C should be treated. Remember that just as many women as men die of CAD, and women are much more likely to die of this disease than of breast cancer.

Controlling blood lipids is essential in primary and secondary prevention of cardiovascular disease. With the appropriate use of diet, exercise, and, if needed, medication, nearly all patients who have abnormal lipid profiles can achieve normal or nearly normal cholesterol levels and reduce their risk of significant disease and premature death.

References

  1. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults: Summary of the Second Report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel II). JAMA 1993;269(23):3015-3023
  2. NIH Consensus Conference: Triglyceride, high-density lipoprotein and coronary heart disease. JAMA 1993;269(4):505-510
  3. Baumgart D, Schmermund A, George G, et al: Comparison of electron beam computed tomography with ultrasound and coronary angiography for detection of coronary atherosclerosis. J Am Coll Cardiol 1997;30(1):57-64
  4. The Scandinavian Simvastatin Survival Study Group: Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344(8934):1383-1389
  5. Gibbons LW, Gonzalez B, Gordon N, et al: The prevalence of side-effects with regular and sustained release nicotinic acid. Am J Med 1995;99(4):378-385
  6. Carlson LA, Rosenhamer G: Reduction of mortality in the Stockholm Ischemic Heart Disease Secondary Prevention Study by combined treatment with clofibrate and nicotinic acid. Acta Med Scand 120218;223(5):405-418


Which Lipids Should Be Measured?

Small Dense LDL Cholesterol

Numerous clinical studies have shown that lowering low-density lipoprotein cholesterol (LDL-C) reduces the risk of coronary events. However, some patients' coronary artery disease (CAD) continues to worsen despite significant decreases in LDL-C. These patients may have other risk factors, but they may also have a high level of small dense LDL-C (SDLDL-C).

Some studies show that individuals who develop CAD are more likely to have more SDLDL-C than larger LDL-C particles.(1 )Whether SDLDL-C is the culprit or an innocent bystander in these cases is unclear. Careful studies have come down on both sides of the issue.

SDLDL-C could increase coronary risk through two plausible means: (1) The smaller particles might filter into the vessel wall more readily than larger particles, or (2) they may be oxidized more easily, facilitating entry into the vessel wall.

SDLDL-C is more likely than larger LDL-C to be associated with low high-density lipoprotein cholesterol (HDL-C) and high triglycerides. Further, patients who have a high level of SDLDL-C appear to have a low level of HDL-C even after significant weight loss.

Though measuring SDLDL-C is relatively expensive, physicians should consider testing patients who have

  • a strong family history of early CAD, particularly if there are no other risk factors;
  • normal or nearly normal LDL-C levels and a strong family history of early CAD, particularly if the affected family member(s) had similar LDL-C levels; or
  • progression of heart disease despite a normal LDL-C level and control of other risk factors.

Patients who have a high level of SDLDL-C usually do not respond well to statins. However, they may respond to treatment with niacin and to following a carefully planned low-cholesterol, low-fat diet (2).

Lipoprotein(a)

Lipoprotein(a) (Lp[a]) is a type of LDL-C modified by the addition of an apolipoprotein in the liver. There is a significant association between high levels of Lp(a) and an increased risk of CAD (3), but no study shows that a decrease in Lp(a) will decrease CAD incidence.

About 20% of the population appears to have increased levels of Lp(a), a purely genetic characteristic. Elevated Lp(a) is more common in African Americans but does not appear to be as atherogenic in them as in other groups.

Though measuring Lp(a) is relatively expensive, we suggest testing patients who have a strong family history of premature CAD and those whose CAD is progressing despite control of risk factors (4).

The median level of Lp(a) in the general population is 4 mg/dL, and those in the 90th percentile have an average of 18 mg/dL. Lowering a high level of Lp(a), is difficult. Niacin and estrogen may be effective, but definitive studies are lacking. The best means of reduction is to decrease LDL-C as much as possible, since lowering LDL-C substantially decreases the risk associated with elevated Lp(a).

HDL Subfractions and Apolipoproteins

Special laboratory procedures allow the measurement of two subclasses of HDL-C: HDL2 and HDL3. Findings regarding these subfractions vary. Some indicate that HDL2 is a more effective protection against CAD than HDL3. Others suggest that exercise affects the level of HDL2 more than that of HDL3. Alcohol appears to influence primarily HDL3.

The largest study (5) concluded that the level of these subfractions did not predict the risk of CAD any more effectively than total HDL-C did. We agree and do not currently recommend measuring these subfractions to evaluate heart disease risk in most patients.

Measurement of apolipoprotein subfractions has also been advocated as a useful tool in heart disease management. Although some evidence (6) suggests that reliable apolipoprotein measurements might improve lipid management, we believe that most evidence does not support the routine clinical measurement of apolipoprotein levels.

References

  1. Grundy SM: Cholesterol and coronary heart disease. JAMA 1990;264(23):3053-3059
  2. Superko HR: Current and future trends in therapy for dyslipidemias. Endocrine Practice 1997;3(4):255-260
  3. Bostom AG, Cupples LA, Jenner JL, et al: Elevated plasma lipoprotein(a) and coronary heart disease in men aged 55 years and younger. JAMA 1996;276(7):544-548
  4. Kinlay S, Dobson AJ, Heller RF, et al: Risk of primary and recurrent actute myocardial infarction from lipoprotein(a) in men and women. J Am Coll Cardiol 1996;28(4):870-875
  5. Sweetnam PM, Bolton CH, Yarnell JW, et al: Associations of the HDL2 and HDL3 cholesterol subfractions with the development of ischemic heart disease in British men. Circulation 1994;90(2):769-774
  6. Grundy SM: Cholesterol and coronary heart disease. JAMA 1990;264(23):3053-3059


Estrogen and Cholesterol

Postmenopausal women have a much greater risk of heart disease than of breast cancer. Since the use of estrogen in hormone replacement therapy raises HDL-C and lowers LDL-C and also substantially decreases the risk of coronary artery disease (CAD) (1), we recommend this therapy in postmenopausal women. Hormone replacement is even more important in postmenopausal women who have abnormal lipid profiles and other risk factors.

Estrogen treatment for men is impractical, for obvious reasons, and, to our knowledge, no large-scale studies have examined treating high-risk men or men who have CAD with estrogen.

Some research indicates that estrogen lowers Lp(a) levels, but the evidence is not sufficient for us to recommend treating elevated Lp(a) with estrogen.

Reference

  1. Grodstein F, Stampfer MJ, Colditz GA, et al: Postmenopausal hormone therapy and mortality. N Engl J Med 1997;336(25):1769-1775


Dr Mitchell is the medical director of the Cooper Wellness Program, and Dr Gibbons is the medical director of Cooper Clinic, both in Dallas. Address correspondence to Tedd L. Mitchell, MD, Cooper Clinic, 12200 Preston Rd, Dallas, TX 75230.


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