- Six statins are available: atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin.
Efficacy
- Substantial reductions in LDL-cholesterol of 25%-60%. This is dose-dependent, with the greatest effect seen at the starting dose, and an additional 6%-7% reduction with each doubling of the dose.
- Reductions in triglycerides are possible with all statins but are dependent on the baseline triglyceride level, the LDL-cholesterol-lowering potency of the statin, and the dose utilized.
The Scandinavian Simvastatin Survival Study (4S) trial reported reductions of 30%-45% in deaths due to CHD, cardiovascular disease and all causes after 4.5 years treatment with simvastatin in patients with CHD. This was shown in men, women and elderly (Scandinavian Simvastatin Survival Study Group, 1994 [A])
- The Heart Protection Study, utilizing 40 mg of simvastatin, reported a 24% reduction in first occurrence of major vascular events (non-fatal MI or coronary death, non-fatal or fatal stroke, coronary or non-coronary revascularization) in a wide range of high-risk individuals, 40-80 years of age, regardless of baseline cholesterol levels (Heart Protection Study Collaborative Group, 2002 [A]).
- The West of Scotland trial reported a 31% reduction in risk of non-fatal MI or death from CHD in men with hypercholesterolemia and no history of MI who were treated using 40 mg of pravastatin daily (West of Scotland Coronary Prevention Group, 1998 [A]).
- The CARE study, using 40 mg of pravastatin daily, showed a 24% reduction in major coronary events in men and women with a mean LDL-cholesterol of 139 mg/dL who had survived a myocardial infarction (Goldberg, 1998 [A]).
- In AFCAPS/TexCAPS, treatment with lovastatin 20-40 mg daily resulted in a 37% reduction in the risk of first major coronary events. This reduction occurred in men and women without clinically evident atherosclerotic cardiovascular disease, with average LDL-cholesterol (mean 150 mg/dL) and below-average HDL-cholesterol (mean 36 mg/dL in men and 40 mg/dL in women) (Downs, 1998 [A]).
- The PROVE-IT trial, comparing pravastatin 40 mg (mean LDL-chol 95 mg/dL) versus atorvastatin 80 mg (mean LDL-cholesterol 62 mg/dL) in patients following acute coronary syndrome, reported a 25% reduction in the risk of death, MI or urgent revascularization in the atorvastatin group (Cannon, 2004 [A]).
- Asymptomatic increases in serum transaminases to greater than three times the upper limit of normal (ULN) on two consecutive lab tests is estimated to occur in 0.1 to 2 percent of patients (incidence is similar to patients treated with placebo). Elevations are usually transient and may normalize even with continued therapy or may not reoccur even with reintroduction of the same statin and dose. Nonetheless, patients should be closely monitored until the transaminases have normalized. The FDA contraindicated statin use in patients with cholestasis and active liver disease. It is not known whether statins worsen the outcome in patients with chronic transaminase elevations due to Hepatitis B or C. There is no evidence that they are harmful in patients with fatty liver due to obesity. The use of statins in patients with chronic liver disease depends on the clinical judgment of risk versus benefit. Use with caution at reduced dosages in patients with primary biliary cirrhosis.
- Dipstick-positive proteinuria and microscopic hematuria have been seen in rosuvastatin-treated patients. The incidence appears to increase with dose escalation. These increases were generally transient and not associated with worsening renal function. The clinical significance of this is unknown, but a dose reduction should be considered in patients on 40 mg/day with unexplained persistent proteinuria on routine urinalysis testing.
- Characterized by muscle aches, soreness, weakness and significant elevation in creatinine kinase (CK) or a CK level generally 10 times the upper limit of normal (ULN), myopathy appears dose dependent and is rare with monotherapy (0.1 percent). The percentage of patients in placebo-controlled trials with non-specific muscle aches or joint pains without significant increases in CK was similar in both statin and placebo groups. Nonetheless, patients can develop clinically significant myopathy, and failure to recognize it and discontinue the statin can lead to rhabdomyolysis, myoglobinuria and renal necrosis.
Risk of myopathy appears increased in patients with impaired renal insufficiency. Older patients may be more susceptible, and it is most likely to occur in patients with complex medical problems and/or on multiple medications. Risk appears increased in patients who are receiving a fibric acid, niacin or drugs that inhibit the cytochrome P450 enzyme, particularly 3A4, which is the major metabolizing enzyme of lovastatin, simvastatin and atorvastatin. Expression of this enzyme varies among individuals 10- to 40-fold, and the affinity of substrates to inhibit this enzyme also varies. Thus it is difficult to predict when a significant interaction will occur, but providers need to be aware of the potential. Some inhibitors of 3A4 include (list is not all-inclusive) macrolide antibiotics*, azole antifungals**, protease inhibitors, cyclosporine, tacrolimus, dexamethasone, danazol, testosterone, propoxyphene, quinidine, nefazodone, pimozide, fluoxetine, fluvoxamine, verapamil, diltiazem, nifedipine, nicardipine, sildenafil, amiodarone, zafirlukast, and grapefruit juice.
Fluvastatin and to a small extent rosuvastatin are metabolized by the 2C9 isoenzyme. Potential interactions may occur when they are given along with medications that are also metabolized by the 2C9 isoenzyme (e.g., oral anticoagulants, phenytoin, oral sulfonylureas, NSAIDs) or those that inhibit the 2C9 isoenzyme (e.g., fluconazole**, oral miconazole, gemfibrozil). Controlled clinical trials with fibric acids have failed to document a substantial risk of myopathy in patients with normal renal function. Some key points for combination with a fibric acid include:
- Establish that the patient has normal renal and thyroid function.
- Establish that there is no other potential drug interaction that could increase the blood level of the statin or fibric acid.
- Limit the initial statin dose to the starting or intermediate dose. The dose of statin can then be increased cautiously if needed.
- Teach the patient to recognize and report promptly symptoms of muscle soreness, tenderness, pain or brownish urine.
- Obtain a baseline CK blood level prior to initiating combination therapy. The CK should be repeated if a patient reports symptoms suggestive of myopathy.
- If a patient experiences these muscle symptoms, with or without CK elevations, rule out common causes such as exercise or strenuous work. Advise moderation in activity for patients who experience this finding during combination therapy.
- Discontinue combination therapy if a CK of five times the upper limit of normal or greater occurs in a patient with muscle symptoms. Wait for the symptoms to resolve and CK to return to normal before reinstituting therapy with either drug and use a lower dose of the drug(s).
- If a patient experiences muscle symptoms with either no elevation in CK level or a moderate elevation (i.e., three to less than five times the upper limit of normal), monitor the patient's symptoms and CK levels until symptoms resolve and CK level returns to normal or until the clinical situation worsens to the point described above and discontinue both drugs.
When combined with cyclosporine, only low doses of statins should be used. FDA-labeled dosing for combination with cyclosporine is 10-20 mg of lovastatin and pravastatin***, 5 mg of rosuvastatin and 5 to 10 mg of simvastatin.
In two reported cases, possibly associated with macrolide antibiotics, rhabdomyolysis occurred after completion of a course of clarithromycin and azithromycin in patients who had been taking lovastatin 40 mg/day for 5 years. Both patients had been receiving diltiazem and low-dose prednisone and one had renal insufficiency. If at all possible, macrolide antibiotics should be avoided in patients on a statin, especially if the patient has renal insufficiency or is already on another drug known to increase the risk of myopathy. If a macrolide antibiotic cannot be avoided, consideration should be given to temporarily discontinuing the statin, reducing the dose of the statin, or if long-term therapy with the macrolide is needed, change to pravastatin or fluvastatin.
If treatment with systemic azole antifungals** (ketoconazole, itraconazole, miconazole, fluconazole greater than or equal to 200 mg/day) is necessary, then the statin should be temporarily discontinued during treatment or changed to pravastatin.
Grapefruit juice is a known inhibitor of the 3A4 isoenzyme in the gut wall. Consumption of more than 1 quart of juice per day has caused dramatic increases of 12- to 15-fold of the AUC and Cmax of lovastatin, whereas consumption of 8 ounces of juice per day has caused a twofold increase in the AUC and Cmax of lovastatin. Patients taking statins that are metabolized by the 3A 4 isoenzyme should be advised to limit consumption of grapefruit to no more than 8 ounces of juice or one-half fruit per day.
Studies of verapamil combined with simvastatin and diltiazem combined with lovastatin have shown a four- to fivefold increase in mean AUC and three- to fourfold increase in mean Cmax of the parent drug. If a patient is on diltiazem or verapamil, then the statin should be initiated with the recommended starting dose, and increased only if warranted. Alternatively, pravastatin and fluvastatin could be used.
Major surgery is a known risk factor for rhabdomyolysis. Consider temporarily stopping the statin until the patient is home and ambulatory.
Regardless of statin used, patients must be told to report promptly any unexplained muscle aches or weakness, especially if malaise or fever is present, or flu-like symptoms (without upper respiratory infection) or brown urine. If these symptoms occur and myopathy is suspected, the lipid-lowering medication(s) should be temporarily discontinued, and a medical evaluation including CK is recommended.
*Azithromycin, dirithromycin do not inhibit CYP450 3A4. Azithromycin has been implicated in a case of lovastatin-induced rhabdomyolysis.
** Fluconazole in doses greater than or equal to 200 mg/day may inhibit clearance of statins metabolized by CYP450 3A4. Fluconazole and miconazole are potent inhibitors of CYP450 2C9 and may affect clearance of fluvastatin. Fluconazole has been shown to have a clinically insignificant effect on rosuvastatin clearance.
*** Pravastatin and rosuvastatin are not significantly metabolized by CYP450 3A4, but a study in heart transplant (HT) patients on cyclosporine showed their respective AUCs were 20-fold higher and 7-fold higher vs. the control group.
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Legend Cost Legend
(B) = Brand name only available $ = $0-$25
(G) = Generic available (cost of generic listed) $$ = $25.01-$50
$$$ = $50.01-$75
$$$$ = $75.01-$100
$$$$$ = > $100
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Please consult manufacturer's product label
insert, PDR, etc., for full prescribing information (Azie, 1998 [A];
Ballantyne, 2003 [R]; Blum, 1994 [R]; Evans, 2002 [R]; Grunden, 1997 [R];
Grundy, 1998 [R]; Kantola, 1998 [A]; Lovastatin-Erythromycin, 1997 [R];
McKenney, 2001a[R]; McKenney, 2003[R]; Murdock, 1999 [D]; National Cholesterol
Education Program, 2001[R]; Prueksaritanont, 2002 [C]; Shek, 2001[R]; Shepherd,
1995 [A]; Venkatakrishnan, 2000 [R]; Wierzbicki, 2003 [R]).
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