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Statins and Potentially Interacting Medications: A Managed Care Perspective
Lida Etemad, PharmD, MS
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Safety and Statins: Pharmacologic and Clinical Perspectives
Michael B. Bottorff, PharmD

Safety and Statins: Pharmacologic and Clinical Perspectives

Michael B. Bottorff, PharmD

Among the 20 leading prescription drugs in the United States, 3 agents-atorvastatin (Lipitor), simvastatin (Zocor), and pravastatin (Pravachol)-are of the class known formally as 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors and informally as statins.

Statins are a primary form of therapy for patients with unhealthy lipid profiles, especially elevations in low-density lipoprotein (LDL) cholesterol.

Collectively, statins represent the number 1 category of prescribed drug in the United States in terms of dollar volume (more than $14 billion annually) and the number 3 category in terms of new prescription volume (more than 120 million annually). 1,2

With approximately 15 million people in the United States taking a statin at any given time, even infrequent adverse events can affect tens of thousands of patients. Overall, the record of safety with statins has been good. The main adverse effects are myotoxicity and hepatotoxicity, both of which appear to be dose related.

Statin-induced Myotoxicity

Myotoxicity, the most common form of statin-induced toxicity, has traditionally been defined by 2 criteria: the presence of muscle symptoms and elevations in creatine kinase (CK) levels. In general, the incidence is much higher for the milder forms of statin-induced myotoxicity than for the more severe forms. 3

Definitions

Myalgia refers to muscle aches, soreness, or weakness, with minimal or no elevation in CK. These symptoms may be specific in terms of discomfort at certain locations or general in terms of overall weakness.The onset of myalgia does not automatically dictate a change in therapy if CK levels remain normal, but close monitoring of CK levels is advisable.

Myopathy refers to muscle symptoms associated with elevations in CK at least 10 times the upper limit of normal (ULN). Statin dose reduction, switching to a different statin, or discontinuation of statin therapy is indicated in such cases to allow resolution of symptoms and recovery of normal laboratory values.

Rhabdomyolysis refers to myopathy extensive enough to cause spillage of myoglobin into the urine; this nephrotoxic substance can induce acute renal failure. Rhabdomyolysis is typically associated with extreme elevations in CK, to values exceeding 10,000 U/L, which is more than 50 times ULN. This condition is potentially fatal, but the incidence is low ( < 0.1%).

These traditional definitions are not absolute. A normal CK level does not rule out muscle pathology, and muscle symptoms associated with CK elevations less than 10 times ULN are also clinically relevant and may warrant a revision in therapy.

Risk Factors

A variety of factors may contribute to the risk of statin-induced myotoxicity (Table 1). 4 Two types of drugódrug interaction are associated with increased risk. Pharmacokinetic interactions result from concomitant use of a drug whose binding affinity for an isoenzyme of the cytochrome P450 (CYP) system is stronger than that of a statin whose metabolism depends on the same isoenzyme. With the metabolism of the statin blocked because it cannot bind to its enzyme, the amount of active statin present in the body is greater than would otherwise be expected at the given dosage, resulting in an increased risk of toxicity. Pharmacodynamic interactions result from concomitant use of other drugs that also have the capacity to induce myotoxicity (such as fibrates and niacin, which are often used in combination with statins to correct adverse lipid profiles).The result is an additive adverse effect.

Table 1
Table 1

Other risk factors that may contribute to a higher risk of myotoxicity include the type of statin used (specifically, its degree of lipid solubility) and the doses given. Female sex and older age may be associated with statin levels that are higher than expected for the given dose. Hypothyroidism (which by itself may cause myalgia and mild elevation in CK) and renal insufficiency may also predispose patients to statin myopathy.

Statin-induced Hepatotoxicity

Several factors may place patients at increased risk for hepatotoxicity, starting with high doses of statins (Table 2). 5 Asymptomatic baseline elevations in transaminase values pose an increased risk, and statins should not be used at all in patients with preexisting hepatitis. More typically, baseline liver function tests are normal when patients start taking a statin, but show minor elevations (to < 3 times ULN) on retesting after the start of treatment. According to some postmarketing surveillance studies, approximately 70% of these statininduced elevations will spontaneously fall back into the normal range even as treatment continues. 5 In cases in which the transaminase elevation persists, the physician must decide whether to reduce the dose of the statin, switch to a different statin, or discontinue statin therapy entirely.

Table 2
Table 2

As with myotoxicity, the risk of hepatotoxicity is also increased by pharmacodynamic interactions with other potentially hepatotoxic compounds, including fibrates, niacin, acetaminophen, and alcohol. Pharmacodynamic interactions between drugs that act as CYP450 inhibitors and statins that depend on CYP450 isoenzymes for metabolism also increase risk. Although pharmacokinetic interactions are more commonly associated with myotoxicity, published case reports of myotoxicity caused by this mechanism frequently mention marked elevations in transaminase values.

Statin Lipophilicity and the Risk of CYP450 Interactions

The metabolic properties of the statins differ and this affects the risk of drugódrug interactions. Atorvastatin, pravastatin, fluvastatin (Lescol), and rosuvastatin (Crestor) are given in the active acid form. Active acid refers to the pharmacophore, the component of the chemical structure responsible for the activity that defines the statins as a class-binding to the HMG-CoA reductase enzyme to produce lowering of LDL cholesterol. In contrast, lovastatin (Mevacor,Altocor) and simvastatin are administered in inactive form as lactones, some portion of which is then hydrolyzed into the active acid form to produce their clinical effects. In terms of elimination from the body, the lactone forms are highly lipid soluble and require CYP450-mediated conversion to a water-soluble form, whereas the active acid forms undergo glucuronidation in the liver. Additional groups on the molecular structure of the drugs define other specific characteristics that distinguish the various statins from each other. These characteristics include lipophilicity, binding affinity to HMG-CoA reductase, and relative selectivity for the liver as the site of clinical action versus muscle tissue as the site of adverse effects (Figure 1).

Figure 1. Several statins are administered in active acid form that can bind to HMG-CoA reductase. Simvastatin and lovastatin are administered in lactone form and must first undergo conversion to active acid form to produce their clinical effects.
				 HMG-CoA indicates 3-hydroxy-3-methylglutaryl coenzyme A
				.
Figure 1. Several statins are administered in active acid form that can bind to HMG-CoA reductase. Simvastatin and lovastatin are administered in lactone form and must first undergo conversion to active acid form to produce their clinical effects.
HMG-CoA indicates 3-hydroxy-3-methylglutaryl coenzyme A.

Lipophilicity is especially important in terms of the likelihood of pharmacokinetic interactions that can lead to statin toxicity. Statins that are highly lipophilic must be metabolized to a water-soluble form for renal excretion. Because that process depends on CYP450 isoenzymes, a lipophilic statin is subject to metabolic inhibition by concomitantly-administered drugs with stronger affinity for the same isoenzyme. In contrast, a water-soluble statin depends less or not at all on the CYP450 system and is therefore less subject to pharmacokinetic interactions.

Figure 2. Increase in simvastatin exposure when used in conjunction with verapamil, itraconazole, and erythromycin versus placebo.
				
				Sources: Kantola T, et al.
				Clin Pharmacol Ther.
				1998; 64:177-182; Neuvonen PJ, et al.
				Clin Pharmacol Ther.
				1998; 63:322-341.
Figure 2. Increase in simvastatin exposure when used in conjunction with verapamil, itraconazole, and erythromycin versus placebo.
Sources: Kantola T, et al. Clin Pharmacol Ther. 1998; 64:177-182; Neuvonen PJ, et al. Clin Pharmacol Ther. 1998; 63:322-341.

The CYP450 isoenzyme involved in the metabolism of the greatest number of different drugs is labeled CYP3A4. CYP3A4 accounts for the majority of CYP450 isoenzymes in the liver and also in the gut wall. Most pharmacokinetic interactions occur when 2 or more drugs that are metabolized by the same CYP450 isoenzyme (whether it is CYP3A4 or a different isoenzyme) are given concurrently. The drug with the stronger binding affinity for the isoenzyme will effectively block the metabolism of the drug with weaker binding affinity, resulting in increased concentrations of active (nonmetabolized) drug and an increased risk of toxicity. 6

The lipid-soluble statins that depend on CYP3A4-mediated metabolism tend to bind relatively weakly to the isoenzyme. Therefore, many drugs with stronger binding affinity for CYP3A4 will act as metabolic inhibitors when used concurrently with those statins. In contrast, statins that do not depend on CYP3A4 have a low propensity for causing toxicity as a result of pharmacokinetic interactions. 7

Figure 3. Increase in lovastatin exposure when used in conjunction with diltiazem, erythromycin, itraconazole, or cyclosporine versus placebo.
				
				Sources: Olbricht C, et al.
				Clin Pharmacol Ther
				. 1997; 62:311-321; Neuvonen PJ, et al.
				Clin Pharmacol Ther
				. 1996; 60:54-61; Azie NE, et al.
				Clin Pharmacol Ther
				. 1998; 64:369-377; Bottorff MB, et al.
				Pharmacotherapy
				. 1997; 17:184-185.
Figure 3. Increase in lovastatin exposure when used in conjunction with diltiazem, erythromycin, itraconazole, or cyclosporine versus placebo.
Sources: Olbricht C, et al. Clin Pharmacol Ther . 1997; 62:311-321; Neuvonen PJ, et al. Clin Pharmacol Ther . 1996; 60:54-61; Azie NE, et al. Clin Pharmacol Ther . 1998; 64:369-377; Bottorff MB, et al. Pharmacotherapy . 1997; 17:184-185.

 
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