Statins, a class of drugs that prevent the synthesis of cholesterol in the liver, have been a mainstay of pharmacologic treatment for elevated lipid levels since lovastatin (Mevacor) was first marketed in 1987. The Food and Drug Administration (FDA) recently made several changes to statin labeling, which have created some confusion about statin safety. But statins remain important in combating cardiovascular disease and preventing life-threatening events such as myocardial infarction and stroke. These label changes shouldn't be interpreted as a recommendation to discontinue all statin therapy. Nurses need to be aware of these revisions in order to assess and reassure their patients appropriately and to provide necessary patient education. To understand these changes and put them in perspective, a brief history and overview of statin development and actions may be helpful.
Cholesterol is created by the body and used in the creation of hormones, such as estrogen and testosterone, and to help build cell walls. It is transported throughout the body in the form of lipoproteins, some of which contribute to the blockage of arteries. Low-density lipoproteins (LDLs) comprise a mixture of triglycerides, cholesteryl ester, and free cholesterol. LDLs are responsible for transporting cholesterol to the tissues. They come in various sizes and densities. Larger LDL particles are thought to be more buoyant than smaller, denser LDL particles, but smaller particles may form more atherosclerotic deposits and, consequently, create greater cardiovascular risk. Although the National Cholesterol Education Program Adult Treatment Panel III guidelines recognized that elevations in levels of small, dense LDLs are an important cardiovascular risk factor (see http://1.usa.gov/11YuWk), LDL size hasn't been universally recognized as the most important aspect of LDL monitoring; the quantity of LDLs may be as important or even more important than particle size.
High-density lipoproteins (HDLs) are very small lipoproteins that are responsible for bringing cholesterol back from the tissues and circulation to the liver for metabolism. HDL cholesterol is generally considered to be “good” cholesterol because of its role in decreasing circulating cholesterol levels.
A brief history of statins. Statins were originally developed by a Japanese scientist named Akira Endo. (These historical notes come from The Little Book of Medical Breakthroughs by Naomi Craft [New York City: New Holland, 2008].) Other scientists had already determined that the liver was the primary source of cholesterol in the body and that the liver used an enzyme called HMG-CoA reductase in the first phase of cholesterol production. Endo suspected that fungi most likely produced a chemical for protection from parasitic bacteria that worked by preventing the synthesis of cholesterol needed to make cell walls as the parasite attempted to reproduce. Endo hypothesized that this particular chemical might also prevent cholesterol synthesis in humans. In 1973, after studying 6,000 molds, he identified mevastatin, produced by the fungus Penicillium citrinum, which blocked HMG-CoA reductase. It effectively reduced cholesterol levels but wasn't deemed marketable because of its adverse effects profile. Building on Endo's research, Merck isolated a similar chemical from Aspergillus terreus mold called lovastatin, which became the first commercially marketed statin.
The new class of antilipid drugs, originally called HMG-CoA reductase inhibitors, has become known as statins. As Endo discovered, they inhibit the effect of HMG-CoA reductase; consequently the liver isn't able to synthesize cholesterol and circulating levels decrease. In addition, statins cause the upregulation of LDL receptors, which increases LDL clearance from plasma. Because cholesterol synthesis is believed to occur mostly at night, statins with short half-lives (such as simvastatin [Zocor]) are usually most effective if given at bedtime. (See Table 1 for a list of FDA-approved statins.)
MONITORING FOR PERMANENT LIVER TOXICITY
It's well known that all statins increase liver enzyme levels (which are determined by measuring serum alanine aminotransferase and aspartate aminotransferase levels). Most times these elevations are mild and not indicative of a serious problem. Significant elevations in liver enzyme levels can occur, leading to a temporary state of liver toxicity, but these resolve after statin therapy is discontinued. In fact, many cases will resolve even if statin therapy is continued.
There has been a concern that severe elevations in liver enzymes could induce permanent liver toxicity, and statin labels have, therefore, always recommended monitoring liver enzyme levels closely and repeatedly throughout drug therapy. However, permanent liver toxicity and damage have now been determined to be extremely rare. After extensive review, the positions of the National Lipid Association's Liver Expert Panel and Statin Safety Assessment Task Force, both of which were published in the April 17, 2006, American Journal of Cardiology (by Cohen and colleagues and McKenney and colleagues, respectively), were that the cause of these rare events, although not currently known, doesn't appear to be statins specifically. In fact, such events may not occur any more frequently in people who take statins than they do in people who have lipid elevations and other risk factors for liver damage but who don't take statins. If, however, there is a connection between statin therapy and cases of permanent liver toxicity, it most likely represents an idiosyncratic response within the patient and is unpredictable and not preventable. The 2006 panels recommended that, given the absence of evidence that ongoing periodic monitoring of liver enzymes provides any data that would prevent permanent liver toxicity, monitoring isn't necessary. The panels further concluded that periodic monitoring could lead some practitioners to discontinue statin therapy because of nonserious enzyme elevations, placing patients at risk for complications from hyperlipidemia. Additionally, the Liver Expert Panel concluded that patients with “chronic liver disease, nonalcoholic fatty liver disease, or nonalcoholic steatohepatitis may safely receive statin therapy” because even this at-risk group didn't have a higher rate of permanent liver toxicity when receiving statins. When the panels made their recommendation in 2006, they encouraged the FDA to reconsider the labeling instructions for statins. The FDA reviewed these recommendations, as well as adverse events reported to the FDA and data from the Acute Liver Failure Study Group (Reuben and colleagues, Hepatology, December 2010), and agreed, removing that direction from statin labels. (For more on this decision, go to 1.usa.gov/wkr5BO.)
Health care providers should obtain a baseline liver enzyme reading to rule out any preexisting liver problems before a patient starts statin therapy (practitioners may also assess liver function prior to each dosage change). Patients receiving statins who develop symptoms of liver toxicity (jaundice, nausea, and abdominal pain) should undergo an evaluation of their fractionated bilirubin level, which is a more specific indicator of liver damage than liver enzymes. There may be times when an asymptomatic patient receiving a statin requires an evaluation of liver enzymes. If the findings indicate a level between one and three times the upper limit of normal, there's no reason to discontinue the statin. If the asymptomatic patient has a liver enzyme level greater than three times the upper limit of normal, the physician or NP should rule out a nonstatin cause of the elevation; after doing so, the provider can either continue the statin as prescribed, decrease the dosage of the statin, or discontinue the drug, based on her or his clinical judgment, according to the 2006 National Lipid Association Statin Safety Assessment Task Force.
LABEL CHANGES RELATED TO ADVERSE EFFECTS
Neurocognitive deficits. Statins have been implicated for a number of years in cases of neurocognitive deficits. It has been hypothesized that these effects arise because statins cross the blood–brain barrier. Roth and colleagues first reported daytime impairment from lovastatin in 1992, when subjects demonstrated increased psychomotor reaction times in response to visual cues on a screen. Sleep deprivation hadn't occurred and couldn't have been the source of the daytime impairment. This deficit appears to be temporary, rather than a chronic, progressive dementia, and disappears on discontinuation of the drug.
There doesn't seem to be any evidence from randomized controlled clinical trials that memory loss occurs more frequently with statin therapy. Still, over the years there have been several case reports of memory loss during statin therapy, which dissipates after the drug is discontinued. Based on these case reports, the FDA has added more information about this rare adverse effect to the label of all statins.
Glucose levels. Several clinical trials examined by the FDA have indicated that significant increases in glucose levels occur with statin therapy, specifically with atorvastatin in a Pravastatin or Atorvastatin Evaluation and Infection Therapy—Thrombolysis in Myocardial Infarction 22 substudy and rosuvastatin in the Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin. In these trials, some previously nondiabetic patients' glucose level was elevated enough to result in a diagnosis of diabetes. The FDA also closely examined data from several meta-analyses and, in light of the evidence, has revised statin labels to indicate that statins have the potential to cause hyperglycemia. Because diabetes is a risk factor for cardiovascular events, glucose monitoring and control are important while patients are on statin therapy. The FDA still supports the use of statins to decrease the risk of cardiovascular disease, however, concluding that the benefits outweigh the risks.
DRUG–DRUG INTERACTIONS WITH LOVASTATIN
The FDA revised the label for simvastatin in June 2011, based on a review of findings of the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine. In that revision, several drug–drug interactions were described, and some dose limitations on simvastatin were initiated (see Drug Watch, October 2011). After that time, the FDA began to review data regarding drug–drug interactions with lovastatin because simvastatin is a lovastatin prodrug (the simvastatin molecule is converted within the body into a lovastatin molecule), and lovastatin is metabolized by the cytochrome P-450 (CYP) system isoenzyme CYP3A4. Itraconazole, a strong inhibitor of CYP3A4, has been found to increase lovastatin levels by as much as 20 times, which can result in rhabdomyolysis. It has been assumed that other strong CYP3A4 inhibitors have this same effect. Lovastatin's label has been revised to reflect this information (see Table 2).
Nurses need to teach patients the signs and symptoms of liver disease, and instruct them to report any that develop. Symptomatic patients should be assessed for elevations in fractionated bilirubin. Nurses should ask patients whether they have experienced memory loss and assess patients for elevations in glucose levels; elevations may warrant treatment with antidiabetic drug therapy.
A complete drug assessment should be done to check for drug interactions if the patient is prescribed lovastatin; avoid drugs that are strong CYP3A4 inhibitors. Encourage patients to be active and lose weight, which will greatly assist in the control of cholesterol and triglyceride levels and decrease the risks of cardiovascular events and diabetes.