Am Fam Physician. 2000;61(11):3371-3382
Almost 13 million American adults require drug therapy to meet the low-density lipoprotein goals set by the National Cholesterol Education Program. Attempts to achieve these goals through diet and exercise are often unsuccessful. Major studies in recent years have demonstrated that statins decrease low-density lipoprotein levels, coronary events and overall mortality. Statins are the most commonly prescribed lipid-lowering agents because they are effective, well tolerated and easy to administer. Niacin has beneficial effects on all of the main lipid components, and new extended-release tablets have fewer adverse effects. Fibrates remain the most effective agents in lowering triglyceride levels and should be limited to this use. Bile acid sequestrants are seldom prescribed because of their adverse gastrointestinal effects and cumbersome administration.
Coronary heart disease (CHD) is the most common cause of death in the United States. Each year, 500,000 Americans die of this disease, and associated morbidity costs more than $200 billion annually.1 Even though the relationship between CHD and elevated serum cholesterol levels is well established, the medical community has yet to fully embrace this connection as an area of prevention. Results from a 1996 study at a major teaching hospital revealed that only 30 percent of patients with coronary artery disease and hyperlipidemia were receiving lipid-lowering agents from their cardiologists.2 An estimated 52 million adults require dietary changes, and 12.7 million adults need lipid-lowering drugs to meet recommended goals for low-density lipoprotein (LDL) levels.3
Physicians are not the only parties at fault in the fight against CHD. Patient compliance is typically poor. Treatment of lipid abnormalities is a lifelong battle. Approximately one half of the patients taking lipid-lowering drugs discontinue their medication after one year, and 75 percent stop after two years.4 With the advent of new drugs (e.g., “statins”) and modifications of older agents (e.g., niacin), adverse effects are no longer a major obstacle to compliance.
The National Cholesterol Education Program (NCEP) has developed guidelines to establish clear goals for patients with lipid abnormalities (Table 1).5 Pharmacologic treatment goals are based largely on LDL levels.
| Risk-factor score* |
| Age: men > 45 years; women > 55 years or postmenopausal without ERT |
| Current smoker |
| Hypertension |
| Diabetes |
| CHD in first-degree relative (male relative< 55 years; female relative < 65 years) |
| HDL < 35 mg per dL (0.9 mmol per L); subtract 1 risk factor if HDL > 60 mg per dL |
| LDL goal, by risk-factor score† |
| 0 to 1 point: < 160 mg per dL (< 4.15 mmol per L) |
| 2 or more points: < 130 mg per dL (< 3.35 mmol per L) |
| Patients with history of CHD: < 100 mg per dL (< 2.60 mmol per L) |
LDL = low-density lipoprotein; ERT = estrogen replacement therapy; CHD = coronary heart disease; HDL = high-density lipoprotein.
*—Score 1 point for each positive factor.
†—LDL goals established by National Cholesterol Education Program.
Information from Grundy SM, Balady GJ, Criqui MH, Fletcher G, Greenland P, Hiratzka LF, et al. Guide to primary prevention of cardiovascular diseases. A statement for healthcare professionals from the Task Force on Risk Reduction. American Heart Association Science Advisory and Coordinating committee. Circulation 1997;95:2330.
The NCEP guidelines encourage a trial of lifestyle modification (diet and exercise) before initiation of drug treatment. Although dietary measures such as the NCEP step 2 diet succeed in reducing fat intake, they fall short in helping most patients achieve their LDL goals.6 Numerous studies correlate increased exercise with decreased cardiovascular mortality.7 Although aerobic exercise may increase high-density lipoprotein (HDL) levels, its effect in lowering LDL is often minimal (approximately 4 to 6 percent).8 Diet and exercise are helpful in meeting LDL goals, but these steps are seldom successful without the addition of a pharmacologic agent.
HMG-CoA Reductase Inhibitors (Statins)
Statins are the most commonly prescribed lipid-lowering agents in the United States. They are generally effective, are supported by favorable outcome studies and have relatively few adverse effects.9–13 Recent studies have helped establish practice standards for treating patients with elevated LDL levels to reduce the risk of CHD (Table 2).9,10,12–15 Even patients who have had a myocardial infarction but maintain normal total and LDL cholesterol levels have decreased morbidity and mortality from recurrent myocardial infarction and stroke when treated with a statin.11,12 The six statins currently available are atorvastatin (Lipitor), cerivastatin (Baycol), fluvastatin (Lescol), lovastatin (Mevacor), pravastatin (Pravachol) and simvastatin (Zocor).
| Study | Drug | Outcome |
|---|---|---|
| Scandinavian Simvastatin Survival Study (4S)9 | Simvastatin | Decreased cardiac morbidity and mortality in patients with CHD and elevated cholesterol levels |
| “West of Scotland” Study (WOSCOPS)10 | Pravastatin | Decreased coronary morbidity and mortality in hypercholesterolemic men with no clinical evidence of CHD |
| Cholesterol and Recurrent Events (CARE) Study12 | Pravastatin | Significantly reduced incidence of subsequent MI, death from CHD, stroke and need for revascularization procedure in patients with recent MI and normal cholesterol levels |
| Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study13 | Pravastatin | Reduced overall mortality and incidence of MI and stroke in patients with CHD and a broad range of cholesterol levels. |
| Lipoprotein and Coronary Atherosclerosis Study (LCAS)14 | Fluvastatin | Slowed progression of artherosclerotic lesions in patients with CHD |
| Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS)15 | Lovastatin | Significantly reduced incidence of first acute major coronary events in patients without CHD, but with normal to mildly elevated total and LDL cholesterol levels and low HDL cholesterol levels |
CHD = coronary heart disease; MI = myocardial infarction; LDL = low-density lipoprotein; HDL= high-density lipoprotein.
INDICATIONS AND EFFICACY
As a group, statins decrease total and LDL cholesterol levels (Table 3). Although all of the statins decrease triglyceride levels, only cerivastatin, atorvastatin and simvastatin are labeled by the U.S. Food and Drug Administration for this use. All statins have a minimal effect in raising HDL levels; simvastatin and atorvastatin are labeled for this indication. At least two studies comparing the statins (all but cerivastatin) have shown that atorvastatin is the most effective in reducing LDL levels.16,17 However, unlike the more extensively studied agents (e.g., pravastatin, simvastatin), atorvastatin has not been proved to reduce total morbidity and mortality.
| Drug | Changes in lipid components | |||||
|---|---|---|---|---|---|---|
| ↓ T-Chol | ↓ LDL | ↑ HDL | ↓ TG | Cost (generic)* | ||
| HMG-CoA reductase inhibitors (statins) | ||||||
| Atorvastatin (Lipitor) | 29 to 45%† | 39 to 60%† | 6%† | 19 to 37%† | ||
| Starting dosage: 10 mg at bedtime | $ 56 | |||||
| Maximum dosage: 80 mg at bedtime | $210 | |||||
| Cerivastatin (Baycol) | 24%† | 34%† | 7% | 16%† | ||
| Starting dosage: 0.4 mg at bedtime | $ 40 | |||||
| Maximum dosage: 0.4 mg at bedtime | $ 40 | |||||
| Lovastatin (Mevacor) | 17 to 29%† | 24 to 40%† | 6.6 to 9.5% | 10 to 19% | ||
| Starting dosage: 20 mg at bedtime | $ 70 | |||||
| Maximum dosage: 40 mg twice daily | $251 | |||||
| Fluvastatin (Lescol) | NA† | 25 to 34%† | NA | 12 to 23% | ||
| Starting dosage: 20 mg at bedtime | $ 38 | |||||
| Maximum dosage: 40 mg twice daily | $ 75 | |||||
| Pravastatin (Pravachol) | 16 to 25%† | 22 to 34%† | 7 to 12% | 15 to 24% | ||
| Starting dosage: 10 to 20 mg at bedtime | $ 68 | |||||
| Maximum dosage: 40 mg at bedtime | $112 | |||||
| Simvastatin (Zocor) | 28 to 36%† | 38 to 47%† | 8%† | 15 to 24%† | ||
| Starting dosage: 20 mg at bedtime | $114 | |||||
| Maximum dosage: 80 mg at bedtime | $114 | |||||
| Niacin (Nicotinic acid) | ||||||
| Niacin, extended-release (Niaspan) | 3 to 10%† | 5 to 14%† | 18 to 22% | 21 to 28%† | ||
| Starting dosage: 500 mg at bedtime | $ 15 | |||||
| Maximum dosage: 2,000 mg at bedtime‡ | $ 49 | |||||
| Fibric acid derivatives (fibrates) | ||||||
| Gemfibrozil (Lopid) | 10% | 10% | 11% | 35%† | ||
| Starting dosage: 600 mg twice daily | $ 82 (57 to 60) | |||||
| Maximum dosage: 1,600 mg daily in divided doses | $123 (85 to 89)§ | |||||
| Fenofibrate (Tricor) | 17 to 20% | 10 to 20% | 7 to 15% | 25 to 45%† | ||
| Starting dosage: 67 mg daily | $ 21 | |||||
| Maximum dosage: 201 mg daily | $ 62 | |||||
| Bile acid sequestrants | ||||||
| Cholestyramine (LoCholest) | 10 to 15%† | 20%† | 5% | NA | ||
| Starting dosage: 8 g daily | $ 98 (80 to 87) | |||||
| Maximum dosage: 24 g daily | $390 (480 to 525) | |||||
| Colestipol (Colestid) | 10 to 15%† | 20%† | 5% | NA | ||
| Starting dosage: 10 g daily | $100 (199) | |||||
| Maximum dosage: 10 to 30 g daily | $100 (598) | |||||
HMG-CoA = 3-hydroxy-3-methylglutaryl coenzyme A; T-Chol = total cholesterol; LDL = low-density lipoprotein; HDL = high-density lipoprotein; TG = triglycerides; NA = not available in package inserts.
*—Estimated cost to the pharmacist based on average wholesale prices (rounded to the nearest dollar), for one month of therapy at starting and maximum dosages, in Red book. Montvale, N.J.,: Medical Economics Data, 1999. Cost to the patient will be greater, depending on prescription filling fee.
†—Labeled by the U.S. Food and Drug Administration for this indication.
‡—Increase by no more than 500 mg per 4-week period.
§—Cost based on 3 tablets per day.
Information based on data in package inserts.
ADVERSE EFFECTS
The statins have an excellent safety and side effect profile (Table 4).18,19 The most common adverse effects are gastrointestinal disturbances, headache, myalgias and rash. In studies involving simvastatin9 and pravastatin,10 the number of adverse events was similar in both placebo and study groups. These agents were well tolerated, as evidenced by the low dropout rate in the two studies. Despite the statins' favorable side effect profiles, a large percentage of patients given these drugs have discontinued them within a year.
| Drug | Dosage | Adverse effects | Patient information | Monitoring |
|---|---|---|---|---|
| Atorvastatin (Lipitor)* | Initially, 10 mg daily. Bedtime administration is suggested, but dose may be taken any time, without regard to meals. Increase dosage if response is inadequate at 4 weeks. Maximum dosage: 80 mg daily | GI, myalgias, headaches, elevated liver enzymes | Report malaise, fever or any muscle tenderness or weakness. Avoid consumption of alcohol and grapefruit juice while taking this medicine. | Obtain lipid profiles for response at 4 weeks. Perform LFTs before initiating therapy, at 12 weeks and every 6 months thereafter. Repeat LFTs after dosage increase. Discontinue drug if serum transaminase levels exceed 3 times normal level or if myopathy or myositis occurs. |
| Cerivastatin(Baycol)* | Initially, 0.4 mg daily at bedtime without regard to meals. Start at a lower dosage if patient has renal disease: 0.2 mg daily at bedtime if CrCl is < 60 mL per minute (< 1 mL per second). Maximum dosage: 0.4 mg at bedtime | GI, myalgias, peripheral edema, elevated liver enzymes | Report malaise, fever or any muscle tenderness or weakness. Avoid consumption of alcohol and grapefruit juice while taking this medicine. | Obtain lipid profiles for response at 4 weeks. Perform LFTs before initiating therapy, at 6 and 12 weeks and every 6 months thereafter. Repeat LFTs after dosage escalation. Discontinue drug if serum transaminase levels exceed 3 times normal level or if myopathy or myositis occurs. |
| Fluvastatin (Lescol)* | Initially, 20 mg daily at bedtime, without regard to meals. Increase to 40 mg daily if response is inadequate at 4 weeks. Maximum dosage: 80 mg daily, divided into 2 doses. | GI, myalgias, back pain, headaches, dizziness Abdominal pain, insomnia, elevated liver enzymes | Report malaise, fever or any muscle tenderness or weakness. Avoid consumption of alcohol and grapefruit juice while taking this medicine. | Obtain lipid profiles for response at 4 weeks. Perform LFTs before initiating therapy, at 6 and 12 weeks and every 6 months thereafter. Repeat LFTs after dosage escalation. Discontinue drug if serum transaminase levels exceed 3 times normal level or if myopathy or myositis occurs. |
| Lovastatin (Mevacor)* | Initially, 20 mg with evening meal. If serum cholesterol is > 300 mg per dL, start with 40 mg daily. Increase dosage if response is inadequate at 4 weeks. Maximum dosage: 80 mg daily. If CrCl is < 30 mL per minute (< 0.5 mL per second), daily dose should not exceed 20 mg. | GI, myalgias, arthralgias, headaches, dizziness, elevated liver enzymes | Report malaise, fever or any muscle tenderness or weakness. Avoid consumption of alcohol and grapefruit juice while taking this medicine. | Obtain lipid profiles for response at 4 weeks. Perform LFTs before initiating therapy, at 6 and 12 weeks and every 6 months thereafter. Repeat LFTs after dosage escalation. Discontinue drug if serum transaminase levels exceed 3 times normal level or if myopathy or myositis occurs. |
| Pravastatin (Pravachol)* | Initially, 10 mg daily at bedtime, without regard to meals. Increase dosage if response is inadequate at 4 weeks. Maximum dosage: 40 mg daily; 10 mg in patients with hepatic or renal dysfunction. | GI, myalgias, generalized pain, headaches, dizziness, elevated liver enzymes | Report malaise, fever or any muscle tenderness or weakness. Avoid consumption of alcohol and grapefruit juice while taking this medicine. | Obtain lipid profiles for response at 4 weeks. Perform LFTs before initiating therapy and at 12 weeks. Repeat LFTs after dosage escalation. Discontinue drug if serum transaminase levels exceed 3 times normal level or if myopathy or myositis occurs. |
| Simvastatin (Zocor)* | Initially, 20 mg daily at bedtime. Increase dosage if response is inadequate at 4 weeks. Maximum dosage: 40 mg twice daily 5 mg daily at bedtime if patient is elderly or has severe renal insufficiency. | GI, headaches, elevated liver enzymes | Report malaise, fever or any muscle tenderness or weakness. Avoid consumption of alcohol and grapefruit juice while taking this medicine. | Obtain lipid profiles for response at 4 weeks. Perform LFTs before initiating therapy and every 6 months for the first year of therapy. Repeat LFTs every 6 months after dosage escalation for an additional year. Patients taking 80 mg daily should have LFTs every 3 months. Discontinue drug if serum transaminase levels exceed 3 times normal level or if myopathy or myositis occurs. Closely monitor patients with severe renal insufficiency. Do not exceed 10 mg daily if given in combination with fibrates or niacin. |
HMG-CoA = 3-hydroxy-3-methylglutaryl coenzyme A; GI = gastrointestinal; LFTs = liver function tests; CrCl = creatinine clearance; LDL = low-density lipoprotein.
*—Contraindicated in pregnant women and nursing mothers.
Information from Drug facts and comparisons. St. Louis: Wolters Kluwer, 1999, and American Hospital Formulary Service. Drug information 1998. Bethesda, Md.: American Society of Health-System Pharmacists, 1999.
There are no clinically appreciable differences in the safety profiles of the statins.20 However, unlike the other statins, pravastatin is not metabolized by the cytochrome P450 system. Therefore, it is less likely to cause a problem when given concomitantly with drugs that inhibit the cytochrome P450 system (e.g., macrolide antibiotics, azole antifungals).21
Approximately 1 to 2 percent of patients treated with statins are found to have elevated values on liver function tests, (i.e., more than three times the reference range).22 There have even been some reports of statin-induced hepatitis. Elevations in liver enzyme levels (and the rare case of hepatitis) resolve after the statin is discontinued. Liver function tests should be performed before starting therapy with these agents and repeated periodically as therapy continues (Table 4). 18,19 Medications that are hepatotoxic or that inhibit liver enzymes may predispose patients to hepatic dysfunction and myopathy if given concomitantly with a statin. Patients who are taking statins should be counseled to avoid or minimize alcohol consumption.
MONITORING
The patient should take the statin for at least four weeks before repeating lipid level tests. However, because diet and exercise require longer periods to produce meaningful changes, it is acceptable to recheck lipid levels in three months. Patients should be re-examined after each dosage adjustment or therapeutic intervention.
Muscle aches are the statins' most feared adverse effect, because they may herald rhabdomyolysis; however, this complication is rare. In the 4S study,9 only one patient developed rhabdomyolysis. It is more liable to occur when statins are taken in combination with other agents (Table 5).18 Some experts recommend performing a baseline creatine kinase (CK) test before initiating statin therapy.23 Because CK levels will not rise until muscle pain starts, there is no benefit from repeated testing in asymptomatic patients.
| Other medications | Statins | |||||
|---|---|---|---|---|---|---|
| Atorvastatin (Lipitor) | Cerivastatin (Baycol) | Fluvastatin (Lescol) | Lovastatin (Mevacor) | Pravastatin (Pravachol) | Simvastatin (Zocor) | |
| Azole antifungals | A | A | A | A | — | A |
| Cimetidine (Tagamet) | — | — | A | — | — | A |
| Ranitidine (Zantac) | — | — | A | — | — | A |
| Warfarin (Coumadin) | B | B | B | B | B | C |
| Digoxin | D | B | D | B | B | D |
| Erythromycin | A | A | A | A | — | A |
| Gemfibrozil (Lopid) | A | A | A | A | A | A |
| Niacin | A | A | A | A | A | A |
A = May increase serum concentration of statin and therefore increase risk of rhabdomyolysis.
B = Class warning.
C = May potentiate warfarin effect.
D = May increase serum digoxin level.
— = No interaction.
Information from Drug facts and comparisons. St. Louis: Wolters Kluwer, 1999.
COST
The statins are the most expensive lipid-lowering medicines. The cost within the group of statins varies widely, from $42 to more than $200 for a one-month supply of medication (Table 3). Recently, atorvastatin, when compared with simvastatin, lovastatin and fluvastatin, was found to be the most cost-effective choice to achieve NCEP goals.24 However, this study was done before cerivastatin (one of the least expensive statins) became available. In addition, some of the statins have not been tested in clinical outcome studies.
Niacin (Nicotinic Acid)
An extended-release form of niacin (Niaspan) has the same beneficial lipid-altering effects as standard niacin. Although it is less effective than the statins in decreasing LDL levels, extended-release niacin can increase HDL values by 20 percent and decrease triglyceride levels by 25 percent, making it unique among the lipid-lowering agents.
ADVERSE EFFECTS
Until the recent introduction of extended-release tablets, niacin therapy had been plagued by low compliance rates. More than 40 percent of the patients treated with standard niacin discontinued it because of adverse effects, compared with 6 percent of patients taking extended-release tablets.27 Flushing is the most common side effect, affecting more than three quarters of patients. Other adverse effects include abdominal pain, nausea and vomiting (all less than 8 percent).
Flushing can be minimized by starting the patient on a low dosage of niacin and making small increases periodically (Table 6).18,19,28 It is also helpful for the patient to take 162 mg to 325 mg of aspirin 30 minutes before the niacin. Taking the niacin at bedtime and avoiding concomitant ingestion of alcohol or hot beverages will further diminish flushing. Despite these helpful tips, many patients are noncompliant with this regimen and fail to continue the drug beyond the initial stage of flushing. Often there is relief from the flushing if the patient can tolerate it through the first few weeks.
| Drug | Dosage | Adverse effects | Patient information | Monitoring | |
|---|---|---|---|---|---|
| Nonprescription niacin | 50 to 100 mg twice daily for the first week. Double the dosage every week to 1,000 to 1,500 mg daily, in 2 or 3 divided doses. If response is inadequate after 4 to 8 weeks, increase dosage slowly to maximum of 3,000 mg daily. If patient switches brands, restart from low dosage and titrate up to minimize risk of hepatic necrosis. | Flushing, pruritus, abdominal pain, nausea, vomiting, elevated liver enzyme levels, glucose intolerance, rare reversible acanthosis nigricans | To decrease flushing, take in p.m.; take aspirin 30 minutes before, avoid concomitant ingestion of alcohol or hot beverage. To decrease gastrointestinal distress, take daily in 2 or 3 divided doses; take after a low-fat snack. | Check lipid levels before and 4 weeks after reaching desired dosage, and 4 weeks after every dosage increase. Perform LFTs, uric acid determination and fasting glucose test before initiating therapy and 6 weeks after target dose is reached. Repeat LFTs every 12 weeks thereafter for first year, then every 6 to 12 months. Discontinue drug if serum transaminase levels exceed 3 times normal level. | |
| Extended-release niacin tablets (Niaspan)* | Take daily at bedtime: | Flushing, pruritus, abdominal pain, nausea, vomiting, elevated liver enzymes, glucose intolerance | To decrease flushing, take in p.m.; take aspirin 30 minutes before; avoid concomitant ingestion of alcohol or hot beverage. To decrease gastrointestinal distress, take after a low-fat snack. | Check lipid levels 4 weeks after starting and 4 weeks after every dosage increase. Obtain uric acid level and fasting glucose levels before initiating therapy and 6 weeks after target dose is reached. Perform LFTs before initiating therapy and every 12 weeks thereafter for first year, then every 6 to 12 months. Discontinue if serum transaminase levels exceed 3 times normal level. | |
| 500 mg—weeks 1 through 4 1,000 mg—weeks 5 through 8 1,500 mg—after week 8 | |||||
| Maximum dosage: | |||||
| 2,000 mg | |||||
LFTs = liver function tests.
*—Pregnancy category C: adverse effects in animals, no human data.
MONITORING
Less than 1 percent of patients with normal results on liver function tests before taking extended-release niacin tablets have elevated liver enzyme values (more than three times the reference range) after niacin is started. There have been case reports of fulminant liver necrosis with nicacin therapy29,30; therefore, periodic liver function tests are mandatory. The tests should be performed before initiation of therapy, every 12 weeks for the first year and then every six months. The drug should be discontinued if liver enzyme values exceed three times the reference range. Compared with regular niacin, the extended-release tablets have a similar or lesser effect on liver function tests.31
Caution is required in administering a statin concomitantly with extended-release niacin tablets because this combination is associated with an increased incidence of rhabdomyolysis. Niacin may promote glucose intolerance and should be used with caution in patients with diabetes mellitus. Niacin can also increase uric acid levels and precipitate a gout attack. Extended-release niacin tablets are less liable than regular niacin to have these effects on glucose and uric acid.31
Fibric Acid Derivatives (Fibrates)
Fibrates are used to treat hypertriglyceridemia. This class of drugs includes clofibrate (Atromid-S), gemfibrozil (Lopid) and fenofibrate (Tricor). Epidemiologic studies have identified hypertriglyceridemia as a risk factor for CHD.32
The NCEP provides intervention guidelines for patients with elevated serum triglyceride levels (Table 7).33 Drug therapy should be considered when a patient who has hypertriglyceridemia also has established CHD or pancreatitis. Medication is generally not used to treat hypertriglyceridemia unless fasting serum triglyceride levels are greater than 400 mg per dL (4.50 mmol per L). Fibrates decrease triglyceride values by 20 to 45 percent and increase HDL levels by 7 to 15 percent. Although these agents generally lower LDL values by 10 to 20 percent, some patients (i.e., those with type IV hyperlipoproteinemia) show an increased LDL level. Fibrates should not be administered to patients with severe hepatic or renal dysfunction.
| Triglyceride value | Intervention |
|---|---|
| < 200 mg per dL (< 2.25 mmol per L) | Normal value. Some recommend a lower normal value of 150 mg per dL (1.70 mmol per L). |
| 200 to 400 mg per L (2.25 to 4.50 mmol per L) | Primary treatment is lifestyle modification: weight control, low-fat, low-cholesterol diet, regular exercise, smoking cessation and (in selected patients) alcohol restriction. Medication may be considered in patients with established CHD, family history of premature CHD, concomitant total cholesterol level of ≥240 mg per dL (≥6.20 mmol per L) and HDL value of < 35 mg per dL (< 1.0 mmol per L), genetic form of hypertriglyceridemia (e.g., dysbetalipoproteinemia or familial combined hyperlipidemia) or multiple risk factors. |
| 400 to 1,000 mg per dL (4.50 to 11.30 mmol per L) | Treatment as in previous category but with an emphasis on controlling causes of secondary hypertriglyceridemia. Medication is recommended by some authorities and certainly should be used if the patient has a history of acute pancreatitis. |
| > 1,000 mg per dL (> 11.30 mmol per L) | Vigorous triglyceride-lowering efforts are required because of increased risk for pancreatitis. Treat causes of secondary hypertriglyceridemia (e.g., diabetes mellitus). Institute very-low-fat diet, curtail alcohol; if triglyceride level of < 1,000 mg per dL (< 11.30 mmol per L) is not achieved, use medications. |
CHD = coronary heart disease; HDL = high-density lipoprotein.
Information from National Cholesterol Education Program. Second report of the expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel II). Circulation 1994;89:1329–1445.
The Coronary Drug Project evaluated the efficacy of clofibrate in the prevention and treatment of CHD. Although patients exhibited decreases in serum triglycerides (−22.3 percent) and cholesterol (−6.5 percent), the five-year mortality difference between placebo and clofibrate was not significant.25 Because clofibrate is associated with serious adverse effects (cholelithiasis, pancreatitis, malignancy) and has not been proved to affect mortality rates, it is no longer marketed in the United States.34
ADVERSE EFFECTS
Gastrointestinal intolerance (abdominal pain, nausea, vomiting, diarrhea, constipation, dyspepsia) is the most common adverse effect associated with fibrate therapy. Neuromuscular (headache, dizziness, vertigo, arthralgias) and dermatologic reactions have also been reported to occur with these drugs (Table 8).18,19 Monotherapy with a fibrate is rarely associated with myalgias or rhabdomyolysis. The incidence of myalgias and rhabdomyolysis increases with concomitant use of a statin (e.g., gemfibrozil and lovastatin). For this reason, thoughtful consideration should precede prescribing these two drug classes together.
| Drug | Dosage | Adverse effects | Patient information | Monitoring |
|---|---|---|---|---|
| Gemfibrozil (Lopid)* | 600 mg twice daily, 30 minutes before morning and evening meals. Maximum dosage: 600 mg twice daily | Dyspepsia, diarrhea, fatigue, nausea, vomiting, abdominal pain, eczema, rash, vertigo | Take with meals. Report any muscle pain, tenderness or weakness. | Perform LFTs before initiating therapy and repeat periodically during first year of therapy. |
| Micronized fenofibrate (Tricor)* | 67 mg (1 tablet) daily, taken with main meal. Increase dosage at 4-week intervals as tolerated. Maximum dosage: 201 mg daily (may be taken at one time) | Dyspepsia, diarrhea, fatigue, headache, nausea, vomiting, muscle or joint pain, rash, vertigo | Take with meals. Report any muscle pain, tenderness or weakness. | Perform LFTs before initiating therapy and repeat periodically during first year of therapy. Drug contraindicated in patients with severe liver or renal disease. |
LFTs = liver function tests.
*—Pregnancy category C: adverse effects in animals, no human data.
Information from Drug facts and comparisons. St. Louis: Wolters Kluwer, 1999, and American Hospital Formulary Service. Drug information 1998. Bethesda, Md.: American Society of Health-System Pharmacists, 1999.
Gemfibrozil has been associated with cholelithiasis in 1 percent of the patients on long-term therapy.19 Fibrates increase gallbladder and hepatic cholesterol concentrations; therefore, therapy with these drugs should not be started in patients who have gallstones and should be discontinued if gallstones develop. Because the effects of insulin and glyburide may be potentiated by fibrates, patients treated with these medications should be monitored for signs of hypoglycemia.
The standard formulation of fenofibrate has been available for years outside the United States. A micronized formulation that improves absorption (Tricor) was FDA–labeled in 1998, permitting a lower once-daily dose. Absorption is increased by 30 percent when fenofibrate is taken with meals. Renal insufficiency prolongs clearance of the drug.
Fenofibrate is indicated for the treatment of hypertriglyceridemia in persons who are at risk for developing pancreatitis (e.g., serum triglyceride levels greater than 1,000 mg per dL [11.30 mmol per L]). Studies indicate that fenofibrate may inhibit atherogenesis by decreasing platelet aggregation.35 The effects of fenofibrate on CHD have not been evaluated. Fenofibrate is more costly than niacin or gemfibrozil but is an option for patients who cannot tolerate these agents.
Bile Acid Sequestrants
Cholestyramine (LoCholest) and colestipol (Colestid) are the two bile acid sequestrants currently available (Table 9).18,19 These agents lower LDL (20 percent) and raise HDL (5 percent). Rarely, cholestyramine and colestipol increase serum triglyceride values. Maximal therapeutic effect is evident after one month of therapy.
| Drug | Dosage | Adverse effects | Patient information | Monitoring |
|---|---|---|---|---|
| Cholestyramine (LoCholest) powder | Initially, 4 g daily in 2 or 3 divided doses Increase dosage at 4-week intervals as tolerated. Maximum dosage: 24 g daily | Constipation | Take 1 hour before or 4 hours after other medications. Take with meals. Mix with 3 to 6 oz of water, fruit juice or pulpy fruit (applesauce or crushed pineapple). Mixing a dose the night before and refrigerating it will improve palatability. Stir well. Increase fluid intake to avoid constipation. | Check lipid profile at 2 to 4 weeks and monitor for constipation. If constipation occurs, increase fluid and fiber intake, consider stool softener. Some patients require a laxative to prevent constipation. |
| Colestipol (Colestid) granules* | Initially, 5 g daily in 2 or 3 divided doses (granules) or 2 g daily (tablets) Increase dosage at 4-week intervals as tolerated. Maximum dosage: 30 g daily | Constipation Flavored products contain aspartame. Avoid in phenyketonuric patients. | Same as above | Same as above |
*—Pregnancy category B: no adverse effects in animals, no human data.
Information from Drug facts and comparisons. St. Louis: Wolters Kluwer, 1999, and American Hospital Formulary Service. Drug information 1998. Bethesda, Md.: American Society of Health-System Pharmacists, 1999.
ADVERSE EFFECTS
Bile acid sequestrants are seldom used as initial therapy because success is often limited by poor patient tolerance. Gastrointestinal disturbances are common and include constipation, nausea, indigestion, bloating, diarrhea and flatulence. Gradually increasing the dosage, along with increasing fluid intake and taking stool softeners, helps to minimize adverse effects. These agents are not recommended for use in patients with severe chronic constipation or bowel disease.
Bile acid sequestrants interfere with intestinal absorption of various vitamins and minerals (e.g., vitamins A, D, E, K, folic acid, magnesium, iron, zinc). Bile acid sequestrants also decrease the absorption of numerous medications, including levothyroxine, penicillin, propranolol, thiazide diuretics and digoxin.
Combination Therapy and Compliance
Combination regimens should be considered for use in patients who fail to meet target values and are compliant with their current therapy. Patients with moderate to severe hypercholesterolemia generally have more difficulty reaching their goals, although considerable reductions in LDL do occur. If further reductions in LDL are required, and the benefits outweigh the risks, a statin in conjunction with niacin is an effective combination. More patients reach their lipid goals with a statin and niacin than with any other combination regimen.36 When the patent on lovastatin expires in 2001, a one-tablet combination of lovastatin with extended-release niacin is likely. Myopathy and rhabdomyolysis are serious concerns when statins are combined with fibrates or niacin. It is important for physicians to educate their patients about the adverse effects of these medications and instruct them to report muscle pain or tenderness immediately.
Compliance with bile acid sequestrants is a problem. Approximately one third of the patients for whom bile acid sequestrants are prescribed will not take the full dosage because of constipation or poor palatability.37 Combination therapies that include a bile acid sequestrant have lower success rates than other combinations.
The statins have the best compliance or maintenance rates, followed by niacin, gemfibrozil and bile acid sequestrants.37 Despite the use of single or combined drug therapy to treat hypercholesterolemia, only 50 percent of treated patients reach the lipid goals outlined in the NCEP recommendations.37 Combination therapy increases the likelihood of reaching target values, but poor compliance is a variable that can foil even the most aggressive therapeutic interventions.