Which Statin Is Right for My Patient?

Darrell Hulisz, PharmD

Disclosures

August 28, 2007

Question

For the dyslipidemic patient, how do we differentiate between the statins; ie, when should one be used preferentially over the other? Are there significant clinical differences among them?

Response From Expert

 

Darrell Hulisz, PharmD
Associate Professor, Department of Family Medicine, Case Western Reserve University School of Medicine, University Hospitals, Case Medical Center, Cleveland, Ohio

Statins are widely prescribed for the treatment of dyslipidemia. These drugs are hydroxymethylglutaryl-coenzyme A reductase inhibitors, also known as HMG-CoA reductase inhibitors. They work by reversibly and competitively inhibiting the enzyme necessary for conversion of HMG-CoA to mevalonate, the rate-limiting step in hepatic cholesterol synthesis. This leads to increased low density lipoprotein (LDL)-receptor expression on the hepatocyte surface, increased uptake of LDL, and decreased circulating LDL.1,2 Statins also decrease triglycerides and modestly increase high density lipoprotein (HDL) levels.

While all statins have the same mechanism of action, they differ in terms of chemistry, pharmacokinetics, potency, cost, and approved indications. The following is a summary of some of the more important distinguishing characteristics.

Chemistry

Lovastatin, pravastatin, and simvastatin are derived from fungi, whereas atorvastatin, fluvastatin, and rosuvastatin are synthetic. Atorvastatin, lovastatin, and simvastatin are lipophilic, whereas pravastatin, rosuvastatin, and fluvastatin are more hydrophilic.

Lipophilic statins cross the blood-brain barrier more readily, which may lead to central nervous system complaints such as insomnia, although this is rare. Hydrophilic statins exhibit greater hepatoselectivity and less influence on smooth muscle proliferation.[1,2]

Pharmacokinetics

Lovastatin's absorption increases when taken with food, whereas absorption of atorvastatin, fluvastatin, and pravastatin decreases when taken with food. Simvastatin and rosuvastatin are not affected by food intake.[1]

All statins are extensively bound to plasma proteins with the exception of pravastatin, which is about 50% bound to plasma proteins, making it less likely to displace albumin-bound drugs, such as warfarin.[1,2]

Lovastatin and simvastatin are prodrugs and must be hydrolyzed to the active hydroxy acid, while other statins are administered in the active hydroxy acid form.

All statins are subject to extensive first-pass metabolism with the exception of pravastatin.[1,2] Neither pravastatin nor rosuvastatin undergo extensive CYP450 metabolism, which can increase a drug's likelihood of producing muscle toxicity due to drug interactions. Atorvastatin, lovastatin, and simvastatin are metabolized by the 3A4 isoform, while fluvastatin is metabolized by 2C9. Possible drug interactions include 3A4 inhibitors (azole antifungals, macrolides, calcium channel blockers, cyclosporine, cimetidine, and grapefruit juice); 2C9 inhibitors (omeprazole, ritonavir, azole antifungals); and inducers of both 3A4 and 2C9, such as phenobarbital, rifampin, phenytoin, and carbamazepine.[1,2]

Rosuvastatin, fluvastatin, simvastatin, and pravastatin are eliminated primarily in the feces, whereas atorvastatin and lovastatin are eliminated primarily in the bile. The dosage of pravastatin should be modified in patients with moderate-to-severe renal impairment, and dosages of lovastatin, rosuvastatin, and simvastatin should be modified in cases of severe renal impairment. No change in dose is needed for atorvastatin or fluvastatin in these patients.[2]

Due to their longer half-lives, rosuvastatin and atorvastatin can be administered at any time of day. Other statins have shorter half-lives and should be administered in the evening, when synthesis of endogenous cholesterol occurs.

Potency

Rosuvastatin and atorvastain are the most potent statins with respect to lowering LDL, followed by simvastatin and pravastatin. Differences in increasing HDL or decreasing triglycerides are less clear. Doubling a statin dose produces only about a 5% decrease in total cholesterol and a 7% decrease in LDL concentration, so a more potent statin may be necessary in the case of subtherapeutic response.[3]

Safety

Rare adverse events include liver or skeletal muscle toxicity, and they occur most often when a statin is given in combination with an interacting drug or with another medication that is also hepatotoxic or myotoxic. More common events include gastrointestinal disturbances, headache, insomnia, myalgia, and rash.[4] Statins are generally well-tolerated, with low dropout rates from clinical trials.[1]

All statins are in pregnancy category X, defined by the US Food and Drug Administration as contraindicated in pregnancy.

For patients with renal failure, atorvastatin or fluvastatin may be preferred over the others because they are less affected by renal impairment. In clinical situations where patients must receive multiple medications (eg, patients with HIV/AIDS), pravastatin is least likely to interact because it is not metabolized by CYP450.

Cost

Another important distinguishing feature of statins is their cost to the patient. Brand-only statins (atorvastatin, rosuvastatin, fluvastatin) may be too expensive for some patients, may not be in a patient's insurance formulary, or may require a higher co-payment, compared with statins that are available generically (lovastatin, pravastatin, and simvastatin).

Pleiotropic Effects

Statins appear to confer clinical benefits that are independent of their lipid lowering activity; these are known as pleiotropic effects.[6] Statins inhibit synthesis of nonsteroidal isoprenoid compounds, resulting in improvement of endothelial cell function, modification of inflammatory responses, antioxidant effects, antithrombotic effects, and reduction of smooth muscle proliferation and cholesterol accumulation.[1,2] While there may be subtle differences among the statins in this regard, the exact clinical relevance of this is uncertain.

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