Hyperlipidemia: Part 2. Pharmacologic management

Pharmacologic therapy for lipid disorders is now dominated by hydroxymethyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins). They have been conclusively proved to prevent coronary events and save lives in a wide variety of situations and are acceptably safe.

Alternatives to statins include resins (eg, cholestyramine), fibric acid derivatives (eg, gemfibrozil), and nicotinic acid (table 1, see p 400). They all have a place in lipid management but should be considered second-line agents.

STATINS (HMG-COA REDUCTASE INHIBITORS)

• Competitively inhibit HMG-CoA reductase, which catalyzes the rate-limiting step in cholesterol synthesis, leading to greater uptake of low-density-lipoprotein cholesterol (LDL-C) in hepatocytes

• Decrease LDL-C levels by a greater amount (30%-60%) and have shown a clearer reduction in overall mortality (as many as 3.3 lives saved per 100 patients over 5 years) than the other lipid-lowering agents

• Better tolerated than the other 3 major classes¹

• Roughly 1% of patients who take statin drugs have reversible, asymptomatic, dose-dependent elevations in aminotransferase levels to more than 3 times normal

• Myopathy, defined as creatine kinase elevations to more than 10 times normal, occurs in less than 0.2% of patients. Combination therapy with niacin or gemfibrozil increases the risk

• Coronary outcomes have been studied in 5 major randomized placebo-controlled trials (table 2, see p 401)

Table 2.

Summary of major trials of statin drugs

Study name	Type of prevention	Baseline LDL-C (avg), mg/dL*	Active treatment	Effect on LDL-C%	Mortality		CHD events†
					RRR, %	ARR, %	RRR, %	ARR, %
4S	Secondary	188	Simvastatin	-38	30	3.2	34	8.2
LIPID	Secondary	150	Pravastatin	-25	22	3.1	24	3.6
CARE	Secondary	139	Pravastatin	-28	20	0.8	24	3.0
WOSCOP	Primary	192	Pravastatin	-26	28	0.9	31	2.4
AFCAPS	Primary	150	Lovastatin	25	NS	NS	40	2.3
NS=not significant.

^*To convert to SI units (mmol/L), multiply by 0.02586.

^†CHD events = CHD deaths plus nonfatal MIs

SCANDINAVIAN SIMVASTATIN SURVIVAL STUDY (₄S)²

Statins are thought to stabilize coronary plaques by mechanisms other than lowering LDL-C levels alone: depletion of the plaques' lipid core, strengthening of the fibrous cap, normalization of the endothelium, anti-inflammatory effects, and inhibition of thrombus formation.

• In patients with known coronary artery disease (CAD) and high LDL-C levels (mean, 4.91 mmol/L [190 mg/dL]), simvastatin lowered LDL-C levels by 38% and increased high-density-lipoprotein cholesterol (HDL-C) levels by 8%

• For every 100 patients treated for 5 years, simvastatin saved 3.3 lives overall (the greatest benefit ever reported for cholesterol treatment). Coronary events decreased by 42%

LONG-TERM INTERVENTION WITH PRAVASTATIN IN ISCHAEMIC DISEASE (LIPID) STUDY³

• In patients with known CAD and moderately elevated LDL-C levels (mean, 3.88 mmol/L [150 mg/dL]), pravastatin prevented about 2 coronary deaths and 4 coronary events for every 100 patients treated for 6 years

CHOLESTEROL AND RECURRENT EVENTS (CARE) STUDY⁴

• In patients with a history of myocardial infarction (MI) and normal LDL-C levels (mean, 3.59 mmol/L [139 mg/dL]), pravastatin prevented about 1 coronary death, 2 nonfatal MIs, 1 stroke, and 4 revascularization procedures for every 100 men treated for 5 years

WEST OF SCOTLAND CORONARY PREVENTION STUDY (WOSCOPS)⁵

• In mostly healthy men with high LDL levels, pravastatin lowered LDL-C levels by 26%

• For every 100 men treated for 5 years, pravastatin prevented 2 nonfatal MIs, 3 revascularizations, and 0.5 coronary death

AIR FORCE/TEXAS CORONARY ATHEROSCLEROSIS PREVENTION STUDY (AFCAPS/TEXCAPS)⁶

• In healthy patients with average total cholesterol levels (mean, 572 mmol/L [221 mg/dL]) and below-average HDL-C levels (mean, 0.93 mmol/L [36 mg/dL]), the use of lovastatin, 20 to 40 mg per day, was associated with a 37% reduction in the incidence of first acute major coronary events over 5 years

• All-cause mortality was not affected

SUMMARY OF CLINICAL EVIDENCE OF STATINS

Statin trials demonstrate an important axiom of clinical epidemiology: the same RRR may produce markedly different ARRs across different patient populations. For example, pravastatin's 25% RRR in subjects with heart disease (LIPID) saved more than 2 lives per 100 treated, but its equal 24% RRR in healthy subjects (WOSCOPS) saved less than 1 life per 100.

• Many trials across a broad spectrum of risk demonstrate that aggressive treatment of cholesterol can prevent adverse coronary events and save lives

• The statin drugs have the most impressive effect on mortality of any lipid-lowering agents

• Although sample sizes were smaller for women in the statin trials, they appeared to have similar benefits to those for men

• The relative risk reduction (RRR) in coronary events is consistently about 25% to 35%, regardless of the baseline cholesterol level or type of statin. The absolute risk reduction (ARR) varies with the subjects

• The greatest absolute benefits are seen in patients with the highest baseline risk (with CAD and high LDL-C levels). Absolute risk reductions in overall mortality range from 0% to 3% over 5 years, depending on the baseline risk

• A meta-analysis of 28 trials concluded that statin drugs reduce the incidence of stroke; diet, fibrates, and resins do not⁷

NICOTINIC ACID (NIACIN)

• Decreases LDL-C levels 10% to 25% and decreases triglyceride levels 20% to 50%

• Increases HDL-C levels 15% to 35%

• Limited by patients' ability to tolerate the bothersome side effect of cutaneous flushing. The administration of aspirin 30 minutes before niacin can reduce flushing

• Nicotinic acid can cause asymptomatic increases in aminotransferase levels, especially at doses about 3 g per day. These levels should be monitored every 6 to 12 weeks in the first year, then every 6 months thereafter

• Niacin may also cause glucose intolerance, hyperuricemia, and exacerbation of peptic ulcer

• In the Coronary Drug Project, a secondary prevention study, niacin prevented about 4 coronary events per 100 men over 6 years.⁸ Coronary mortality was not affected

• The best-tolerated nicotinic acid preparations are once-per-day agents that may be taken at bedtime. In a randomized trial to assess side effects, a once-per-day preparation of 2 g taken at bedtime decreased LDL-C levels by 16% and triglyceride levels by 35% and increased HDL-C levels by 26%⁹

BILE ACID SEQUESTRANTS (RESINS)

Resins should be administered before the evening meal, when bile acid secretion is greatest. Preprandial dosing also decreases the major adverse side effects, which include bloating, abdominal pain, and distension. Little additional benefit is gained with more than 4 scoops (16 g) per day.

• Decrease LDL-C levels 15% to 30% and increase HDL-C levels 3% to 5%

• May increase triglyceride levels. Contraindicated when triglyceride level is greater than 5.65 mmol/L (500 mg/dL)

• Block enterohepatic recirculation of bile acids by binding them in the gut. They do not act systemically

• Can interfere with absorption; other medications should be taken 1 hour before or 3 to 4 hours after the resin

• May be started with 1 or 2 scoops (4-8 g) dissolved in juice 30 minutes before supper, and may be increased as tolerated

• In healthy men with high LDL-C levels, cholestyramine resin prevented 2 CAD events for every 100 patients treated for 7 years. There was no effect on overall mortality¹⁰

FIBRATES (GEMFIBROZIL, FENOFIBRATE, CLOFIBRATE)

• Increase HDL-C levels 10% to 15% and decrease triglyceride levels 20% to 50%

• Have only a modest effect on LDL-C levels

• Are generally used in patients with low HDL-C levels or high triglyceride levels

• Their use is contraindicated in patients with active peptic ulcer or cholelithiasis

• Should be carefully monitored if used in combination with statin drugs due to the risk of myopathy and rhabdomyolysis

• In the Helsinki Heart Study, gemfibrozil prevented 1.5 coronary events in 100 patients over 5 years (RRR=34%) in healthy men with high total cholesterol levels.¹¹ The greatest reduction in the incidence of coronary events was in patients with the highest triglyceride and lowest HDL-C levels. Total mortality was higher in the gemfibrozil group, mostly due to excess cancer deaths

• In a more recent trial, treatment with gemfibrozil prevented 3 nonfatal MIs and 2 coronary deaths over a 5-year period for every 100 men with CAD (average baseline HDL-C and LDL-C levels, 0.83 and 2.90 mmol/L [32 and 112 mg/dL], respectively). There was no effect on cancer mortality.¹² Interestingly, gemfibrozil's effect on HDL-C levels (increased 10%) was no better than that achieved by simvastatin at a dose of 40 mg per day (table 3, see p 401)

Table 3.

Lipid-lowering effects (%) of selected statin drugs^*

Agent (dose in mg)	Total cholesterol, mg/dL	LDL-C, mg/dL	HDL-C, mg/dL	Triglycerides, mg/dL
Atorvastatin calcium (80)	-42	-54	+0	-25
Atorvastatin calcium (40)	-40	-51	+5	-32
Simvastatin (80)†	-35	-47	+8	-23
Simvastatin (40)	-30	-41	+10	-15
Pravastatin (40)	-24	-34	+6	-10
Lovastatin (40)	-23	-31	+5	-2
Fluvastatin (40)	-19	-23	-3	-13

^*Adapted from Jones P, Kafonek S, Laurora I, Humminghake D. Comparative dose efficacy study of atorvastatin, simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES Study). Am J Cardiol 1998;81;582-587. This study was funded by the makers of atorvastatin calcium.

^†The 80-mg dose was not studied in the CURVES study. The 80-mg figures were taken from Davidson MH, Stein EA, Dujovne CA, et al. The efficacy and six-week tolerability of simvastatin 80 and 160 mg/day. Am J Cardiol 1997;79:38-42. This study was funded by the makers of simvastatin.

COMBINATION REGIMENS

A small randomized crossover trial comparing 3 regimens (nicotinic acid [NIC] at 400 mg 3 times a day, lovastatin [LOV] at 20 mg a day, or both) showed the following effects compared with no treatment, with TC representing total cholesterol level:

	TC, %	LDL, %	HDL
NIC	-6	-11	—
LOV	-17	-25	—
NIC + LOV	-27	-37	—

• Two or even 3 drugs may be used together

• In patients with hypercholesterolemia on a maximal-dose statin regimen, niacin or a bile acid sequestrant drug may be added

• In patients with hypertriglyceridemia receiving a fibrate, niacin or a statin drug may be added

• The risk of hepatitis, statin-induced myopathy, and rhabdomyolysis is increased when niacin and, especially, gemfibrozil are added. Patients taking combinations must be monitored closely

ESTROGEN

No adverse events were reported in this small trial. Vacek JL, Dittmeier G, Chiarelli T, White J, Bell HH. Comparison of lovastatin (20 mg) and nicotinic acid (1.2 g) with either drug alone for type II hyperlipoproteinemia. Am J Cardiol1995;76:182-184.

• Decreases LDL-C levels 15% and increases HDL-C levels 20% to 30%

• Can increase triglyceride levels; they should be monitored if initially high

• Case-control studies suggest a 40% to 50% reduction in cardiovascular events

• In postmenopausal women with a history of CAD, however, treatment with a combination of estrogen and progesterone (Pempro) did not lower the overall rates of MI or death from CAD over an average follow-up of 4.1 years.¹³ This occurred despite 10% lowering of LDL-C levels and 11% raising of HDL-C levels in the estrogen group compared with the placebo group

OTHER DYSLIPIDEMIAS

Hypertriglyceridemia

Associated risk factors

• The role of triglycerides as an independent risk factor for coronary artery disease remains unclear¹⁴

• Triglyceride levels higher than 5.65 mmol/L (500 mg/dL) are associated with acute pancreatitis

• Gemfibrozil, nicotinic acid, and statins are the most effective agents at decreasing triglyceride levels

ATP III Classification of serum triglyceride levels (mmol/L [mg/dL])

Triglyceride conversion factor: 1 mmol/L=88.6 mg/dL

The effect of statins on triglyceride levels is roughly proportional to the effect on LDL-C levels (see table 3).

<1.70 (<150): normal

1.70-2.25 (150-199): borderline high

2.26-5.64 (200-499): high

≥5.65 (≥500): very high

Treatment of Hypertriglyceridemia

Non-HDL cholesterol = total cholesterol — HDL

• If triglyceride levels are higher than 5.65 mmol/L (>500 mg/dL), the level should first be lowered to prevent pancreatitis. This should be done with a triglyceride-lowering drug (fibrate or niacin) and weight loss through a very-low-fat diet and exercise

• When triglyceride levels are below 5.65 mmol/L (<500 mg/dL), LDL-C level-lowering therapy becomes the priority

• In patients with triglyceride levels higher than 2.26 mmol/L (>200 mg/dL) after the LDL-C goal is reached, the sum of LDL plus very-low-density-lipoprotein (VLDL) cholesterol (a non-HDL cholesterol) is a secondary target. A goal of a level of non-HDL cholesterol 30 mg/dL higher than the LDL-C goal should be sought

Non-HDL cholesterol targets for patients with triglyceride levels higher than 2.26 mmol/L (>200 mg/dL) after attaining LDL-C goal

	LDL-C Goal, mg/dL	Non-HDL-C Goal
CAD or equivalent	<100	<130
≥2 risk factors	<130	<160
0 or 1 risk factor	<100	<130

Low HDL-C Level (<1.03 mmol/L [<40 mg/dL])

Associated risk factors

• Independently associated with coronary events. Low HDL-C level increases risk even when total cholesterol level is less than 2.26 mmol/L (<200 mg/dL)

• Every 1 mg/dL decrease in HDL-C levels is associated with a 2% to 3% increased risk of coronary events

• Levels are decreased by cigarette smoking, sedentary lifestyle, obesity, and use of β-blockers and anabolic steroids

• Levels are increased by moderate alcohol use, exercise, and weight reduction

• Statins, fibric acid derivatives, and niacin all increase HDL-C levels, with the greatest effects (20%-30% increase) produced by niacin

Treatment

• First reach LDL-C goal

• Weight loss through diet and exercise

• If triglyceride levels are 2.26 to 5.64 mmol/L (200-499 mg/dL), achieve non-HDL-C goal

• If triglyceride levels are below 2.26 mmol/L (<200 mg/dL) (isolated low HDL-C level) in a patient with CAD or equivalent, consider administering nicotinic acid or a fibrate

Table 1.

Agents for treating hyperlipidemia

Drug (trade name)*	Dosage form	Dosage range
Statins†
Atorvastatin calcium (Lipitor)	10, 20, 40 mg	10-40 mg PO per day (any time of day)
Lovastatin (Mevacor)	10, 20, 40 mg	10-80 mg PO each evening
Fluvastatin (Lescol)	20, 40 mg	20-40 mg PO each evening
Pravastatin (Pravachol)	10, 20, 40 mg	10-40 mg PO each evening
Simvastatin (Zocor)	5, 10, 20, 40, 80 mg	5-80 mg PO each evening
Fibrates
Gemfibrozil (Lopid)	600 mg	600 mg PO twice a day before meals
Fenofibrate (Tricor)	67 mg	201 mg per day
Colestipol hydrochloride (Colestid)	1 packet = 5 g	5 mg PO per day-15 mg twice a day
Bile acid sequestrants
Cholestyramine resin (Questran)	4-g packets	4-12 g in 8 oz of water PO twice a day
Niacin
Niacin (nicotinic acid)	500 mg	1-2 PO 3 times a day with food
Female hormones
Conjugated estrogens (Premarin)	0.625 mg	0.625 mg PO per day
PO = by mouth.

^*The trade name is given for information purposes only and should not be interpreted as endorsement by either the authors of this article or wjm's editors.

^†Cerivastatin sodium (Baycol) was taken off the market because of its association with an excessive incidence of fatal rhabdomyolis.