oVERVIEW

HMG-CoA 3-hydroxy-3-methylglutaryl coenzyme A—reductase inhibitors (statins) inhibit the rate-limiting step of cholesterol synthesis in the liver. HMG-CoA reductase inhibitors are effective in raising the serum high-density lipid cholesterol (HDL-C) levels and lowering the serum total cholesterol, low-density lipoprotein cholesterol (LDL-C), and triglyceride levels. Also, they have a low prevalence of adverse effects, the most common of which are hepatotoxicity and myopathy.

The hepatotoxicity in most cases is very mild, produces no symptoms, and is signified by mild liver inflammation with elevated liver transaminase levels. This liver inflammation resolves fairly quickly after cessation of the medication. Although those who take statins must have their liver transaminase levels monitored for at least a year, the risk of significant injury is extremely low. Multiple large, 5-year, double-blind statin trials have shown no difference in liver function test results or liver toxicity rates in the treatment groups compared with those of the placebo groups. Moreover, until transaminase levels increase to greater than 3 times the upper limit of the reference range, statins should be continued.

In extremely rare cases, hepatic injury is more serious and leads to jaundice and mild liver dysfunction. Several instances of severe liver dysfunction and failure with cerivastatin sodium (Baycol), particularly when administered with gemfibrozil (Lopid), have been reported. These cases led to Baycol being removed from the market by the FDA.

If myopathy occurs, it is in the form of myositis. This myositis is usually mild, but in extremely rare instances, it can lead to massive muscle inflammation and muscle breakdown, resulting in rhabdomyolysis. The resulting massive muscle breakdown and extreme nitrogen buildup in the kidneys can lead to renal failure, requiring dialysis. In most cases, the myositis resolves quickly after cessation of the medication. Concurrent administration of medications, such as gemfibrozil, cyclosporine (Neoral, Gengraf), niacin (Niaspan, Nicobid), fenofibrate (Tricor), and others in various combinations, can increase the risk of myositis. The adverse effects of statin medications may be the result of these agents substantially reducing the blood levels of CoQ10. (These findings were presented by investigators in a study published in the Archives of Neurology in June 2004.) If a patient develops muscle symptoms, his or her creatine kinase level should be checked immediately. In many large, 5-year, double-blind statin trials, the incidence of muscle complaints and increases in creatine kinase levels in the treatment groups matched those of the placebo groups.

SELECT Clinical TRIALS

A considerable body of literature from large, well-controlled, randomized, landmark clinical trials, such as the Scandinavian Simvastatin Survival Study, supports the clinical utility of treatment with HMG-CoA reductase inhibitors (statins) for coronary heart disease (CHD) prevention, as well as for vascular disease prevention (eg, strokes, aortic and lower limb atherosclerosis).

A low HDL-C level is thought to accelerate the development of atherosclerosis because of impaired reverse cholesterol transport and, possibly, the absence of other protective effects of HDL-C, such as decreased oxidation of other lipoproteins. Statins reduce coronary morbidity and prolong life in persons who have had an MI and in those who have an increased risk of having a first MI, even if the risk is moderate.

Longitudinal population studies have confirmed that HDL-C is an independent, inverse coronary risk factor.

In the Framingham study, the inverse association of a high HDL-C level and low coronary risk was as statistically significant as the direct association of high LDL-C levels, low HDL-C levels, and high coronary risk. Statins are generally known for eliciting marked decreases in LDL-C levels and mild-to-moderate increases in HDL-C levels. Statins are known to raise HDL-C values by 5-15%. Randomized controlled trials have demonstrated that an HDL-C increase of 6% significantly reduces the risk of both fatal and nonfatal coronary events, particularly in those with initially low HDL-C values. In the Prospective Cardiovascular Münster (PROCAM) study, individuals with an HDL-C level less than 35 mg/dL had a 4-fold increase in fatal and nonfatal coronary events compared to those who had HDL-C levels greater than 35 mg/dL. This study confirmed that a 1-mg/dL increase in HDL-C concentration decreases cardiovascular risk by 2-3%.

CLINICAL GUIDELINES

The importance of the metabolic effects of HDL-C has been reflected in consensus guidelines for nearly a decade. In the second National Cholesterol Education Program (NCEP) Adult Treatment Panel II (NCEP ATP II) consensus guidelines, a high HDL-C level (> 60 mg/dL) was classified as a "negative" or "inverse" risk factor, and hence protective against future cardiovascular events.1 The third NCEP consensus guidelines (ATP III) increased the number of patients eligible for treatment by raising the upper limit of low HDL-C levels from 35 mg/dL to 40 mg/dL. For the metabolic syndrome in which multiple mild abnormalities in lipids, waist size (abnormal waist circumference), blood pressure, and blood sugar increase the risk of coronary artery disease (CAD), the designated HDL-C levels that contribute to the syndrome are sex-specific. For men, a high-risk HDL-C level is still less than 40 mg/dL, but for women, the high-risk HDL-C level is less than 50 mg/dL.

Current guidelines regarding acceptable lipid levels, per the Third Report of the National Cholesterol Education Program (NCEP III), are as follows:

• For those with known atherosclerosis (clinical CHD, symptomatic carotid artery disease, peripheral arterial disease, or abdominal aortic aneurysm), the LDL-C goal is less than 100 mg/dL.
  
  
• For those with 2 or more risk factors, the LDL-C goal is less than 130 mg/dL, with recommendations for drug therapy if their estimated 10-year risk of developing hard CAD is greater than 10%.
  
  
• For those at low risk (0-1 risk factors), the LDL-C goal is less than 160 mg/dL, with drug therapy recommended for persons with LDL-C values greater than 190 mg/dL.
  
  
• For those with diabetes mellitus or CHD- equivalent risk, the LDL-C goal is less than 100 mg/dL. (Recent data suggest that the goal should be less than 70 mg/dL.)

During a follow-up period of 12 years, Framingham study participants who had high HDL-C levels were at 50% lower risk of cardiovascular events compared to participants who had low HDL-C levels.

In the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT), which involved 2531 men with CAD and low HDL-C values (mean, 32 mg/dL), treatment with gemfibrozil (a fibrate, not a statin) at 1200 mg per day raised HDL-C by 6% compared to the placebo, with no observed differences in LDL-C. However, continuation of this fibrate therapy for approximately 5 years reduced coronary events, including nonfatal MI, fatal MI, and sudden cardiac death, by 34% when compared with the placebo.

CLINICAL BENEFITS OF STATINS

HMG-CoA reductase inhibitors (statins) modestly raise HDL-C levels. Statins lower LDL-C levels by inhibiting the rate-limiting enzyme in cholesterol biosynthesis and up-regulating hepatic receptor-mediated LDL-C clearance.

In randomized, controlled, head-to-head comparative studies, rosuvastatin (Crestor) elevated HDL-C levels by approximately 6-12% over its dose range compared with about 2-8% for atorvastatin (Lipitor), 5-7% for simvastatin (Zocor), and 3-6% for pravastatin (Pravachol).

Statins may confer the strongest cardioprotective effects on those whose baseline HDL-C values are low. A low HDL-C value was a major CAD risk factor among the 6515 individuals evaluated in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) (Downs, 1998). The baseline mean HDL-C level was 36 mg/dL for men and 40 mg/dL for women; 35% of participants in both the lovastatin and placebo groups had HDL-C levels of less than 35 mg/dL. If NCEP ATP II guidelines had been applied, most participants in AFCAPS/TexCAPS would not have been eligible for pharmacotherapy.

Treatment with lovastatin at 20-40 mg per day (titrated to achieve an LDL-C level < 110 mg/dL) increased HDL-C by 6% while lowering LDL-C by 25%, whereas increases in both parameters were modest with the placebo. Over a median follow-up period of 5.2 years, lovastatin treatment lowered coronary events (ie, fatal or nonfatal MI, sudden death, unstable angina) by 37% when compared to the placebo (P < .001). The clinical benefits of the statin in preventing coronary events were most marked in patients in the lower tertile of baseline HDL-C levels (=34 mg/dL) (Downs, 1998).

This finding of a primary prevention study was echoed by data from a subgroup analysis of an angiographic trial. In the Lipid and Coronary Atherosclerosis Study (LCAS) of CAD patients with mild-to-moderate elevations of LDL-C, those with low HDL-C levels (ie, < 35 mg/dL; n = 68) at baseline had the greatest degree of CAD progression (Rader, 2003). Thus, although their HDL-C–raising effects are modest, statins reduce cardiovascular risk in those with low HDL-C concentrations.

Results of epidemiological studies and many recent trials have established that lowering HDL levels significantly increases the risk of cardiovascular disease, even with very low LDL levels.

This has led to great interest in both LDL-C and HDL-C; however, the data on HDL-C have been much more limited than with LDL-C, and predicting what effects will ensue if HDL-C levels are changed is much more difficult than if LDL-C levels are changed. For a decade, well-designed clinical trials have investigated the effects of lowering LDL-C levels, but few data are related to specific changes in HDL-C.

Clearly, even at very low LDL-C levels, HDL-C persists as a major risk factor, which has led investigators to conclude that a 1-mg decrease in the LDL-C level reduces CHD risk by 1%. Based primarily on epidemiological data and some clinical trial data, a 1-mg increase in HDL-C concentration reduces CHD risk by approximately 3%.

References

Cannon CP, Braunwald E, McCabe CH, et al. Comparison of Intensive and Moderate Lipid Lowering with Statins after Acute Coronary Syndromes. N Engl J Med. 2004 Apr 8;350(15):1495-504.

Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA. 1998 May 27;279(20):1615-22.

Grundy SM. Can statins cause chronic low-grade myopathy? Ann Intern Med. 2002 Oct 1;137(7):617-8.

Haffner SM, Alexander CM, Cook TJ, et al. Reduced coronary events in simvastatin-treated patients with coronary heart disease and diabetes or impaired fasting glucose levels: subgroup analyses in the Scandinavian Simvastatin Survival Study. Arch Intern Med. 1999 Dec 13-27;159(22):2661-7.

Mingpeng S, Zongli W. The protective role of high-density lipoproteins in atherosclerosis. Exp Gerontol. 1999;34(4):539-48.

National Cholesterol Education Program: Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP). Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA. 2001 May 16;285(19):2486-97.

Phillips PS, Haas RH, Bannykh S, et al. Statin-associated myopathy with normal creatine kinase levels. Ann Intern Med. 2002 Oct 1;137 (7):581-5.

Rader DJ. High-density lipoproteins as an emerging therapeutic target for atherosclerosis. JAMA. 2003 Nov 5;290(17):2322-4.

Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med. 1999 Aug 5;341(6):410-8.