Monotherapy 

Statins are the drugs of choice for lowering LDL-cholesterol, and aggressive treatment with statins should be pursued. Statins also have a modest effect on reducing triglycerides and increasing HDL-cholesterol. Several studies with clinical endpoints support use of statins in primary and secondary prevention. 

If a patient is intolerant to a statin, clinicians are encouraged to have the patient try the other statins before ruling them all out. This is especially important in secondary prevention. In the Heart Protection Study, there was no significant difference between the simvastatin 40 mg and placebo groups, in the number of patients with elevations of serum transaminases or unexplained muscle aches or weakness. 

If patients are unable to take statins, then bile-acid sequestrants, niacin, fibric acids and ezetimibe can be used. 

The secondary-prevention VA-HIT trial – utilizing gemfibrozil 600 mg twice daily in patients with normal LDL-cholesterol, low HDL-cholesterol and triglycerides less than or equal to 300 mg/dL – showed a 22% reduction in the combined incidence of CHD death and non-fatal MI. Almost 50% of this study population had evidence of metabolic syndrome or diabetes, and they showed the greatest benefit. Fibric acids have a variable effect on LDL-cholesterol. Fenofibrate may be more effective at lowering LDL-cholesterol than gemfibrozil. They are usually reserved for hypertriglyceridemia or for an isolated low HDL-cholesterol. 

In the Coronary Drug Project, a large-scale secondary prevention trial, niacin 3 grams/day reduced mortality 11% over placebo. Niacin has a favorable effect on LDL-cholesterol, triglycerides and HDL-cholesterol and is good for mixed hyperlipidemia. Niacin has a greater effect on HDL-cholesterol than other currently available lipid medications. To improve tolerability and compliance, doses of niacin need to be titrated. 

Ezetimibe mainly reduces LDL-cholesterol, with minimal effect on triglycerides or HDL-cholesterol. No clinical outcome studies are currently available, but ezetimibe appears useful for reducing LDL-cholesterol in patients who cannot take a statin and in combination with other LDL-reducing medications. 

In the Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT), participants were to take cholestyramine 12 gm twice daily, but compliance varied. A linear relationship was seen with reduction in CHD risk corresponding to cholestyramine dose and reduction in LDL-cholesterol. A 19% reduction in risk of fatal and non-fatal MI was seen in patients taking cholestyramine 24 gm/day. The bile-acid sequestrants reduce LDL-cholesterol, but they can increase triglycerides so should only be used as monotherapy in patients with baseline triglycerides less than or equal to 200 mg/dL.

Combination therapy 

Although combination therapy is not supported by outcome-based studies, some high-risk patients will require combination therapy. Most likely, these patients will have CHD. Using low doses of two complementary agents can often reduce LDL-cholesterol to a greater extent than a higher dose of either agent, such as when a statin is combined with either ezetimibe or a bile-acid sequestrant, with fewer side effects and possibly less cost. In very resistant cases, triple therapy may be needed. 

In patients with mixed hyperlipidemia (increased LDL-cholesterol and triglycerides), the primary goal is decreasing LDL-cholesterol. A high triglyceride (200-499 mg/dL) with hypercholesterolemia signals a relatively high risk of CHD. These patients often have a low HDL-cholesterol. Combination of a cholesterol-lowering drug with a triglyceride-lowering drug to achieve the non-HDL-cholesterol goal may be most warranted in patients with established coronary artery disease who are at very high risk of recurrent coronary events. Combining nicotinic acid with a statin is favorable for improving LDL-cholesterol, HDL-cholesterol and triglycerides. Use of fibric acids leads to effective decrease in triglycerides and increased HDL-cholesterol, but effect on LDL-cholesterol is varied. 

An increased incidence of severe myopathy has been reported when a statin was combined with nicotinic acid or fibric acids. Most of these cases involved a high dose of the statin in patients with reduced renal function. When these combinations were evaluated in patients with normal renal and liver function in controlled clinical trials, myopathy rarely occurred (incidence of approximately 0.12%). In general, these combinations need not be avoided, but careful patient selection, monitoring and education are required. These combinations should generally be avoided in patients with acute or serious chronic illness (especially chronic renal disease), patients undergoing surgery or in patients who are already receiving cyclosporine, macrolide antibiotics, nefazodone, azole antifungal agents, or protease inhibitors. 

Rosuvastatin dose does not need to be decreased when co-administered with fenofibrate, because co-administration of fenofibrate (67 mg three times daily) with rosuvastatin (10 mg) resulted in no significant changes in plasma concentrations of rosuvastatin or fenofibrate. 

In general, the combination of a statin and a fibrate raises the risk of myopathy and rhabdomyolysis. There may be a lower incidence of myopathy with fenofibrate compared to gemfibrozil. Clinical trials have established that the concurrent use of gemfibrozil and statins results in an increased area under the curve (AUC), elimination half-life and serum peak concentration of the statin. Fenofibrate does not adversely affect either the metabolism or pharmacokinetics of the statins, making it a more appropriate choice. 

There have been several studies with small numbers of carefully selected patients that have shown fibrates (including gemfibrozil) can be used safely with statins (incidence of myopathy was approximately 0.12%). There may be a potential difference in risk of myopathy between gemfibrozil and fenofibrate when combined with statins. Gemfibrozil has been shown to increase plasma levels of simvastatin acid, lovastatin and rosuvastatin, while fenofibrate has no effect on plasma levels of rosuvastatin. Simvastatin, lovastatin and rosuvastatin all have labeled dose restrictions when combined with gemfibrozil, while pravastatin, atorvastatin and fluvastatin do not. 

Renal function should be assessed along with a baseline creatinine kinase (CK). Patients must be asked to report promptly any unexplained muscle aches or weakness, especially if malaise or fever is present, flu-like symptoms (without upper respiratory infection) or brownish urine. If these symptoms occur, repeat the CK and rule out non-drug causes, e.g., recent increased or unusually vigorous exercise. If CK is rapidly rising or 10 times the upper limit of normal, both drugs should be discontinued until the symptoms subside and CK returns to normal. 

Please consult manufacturer's product labeling insert, or PDR for full prescribing information.

(Backman, 2000 [A]; Downs, 1998 [A]; Dujovne, 2002 [C]; Gagne, 2002[C]; Goldberg, 1998[A]; Grundy, 1998 [R]; Heart Protection Study Collaborative Group, 2002 [A]; Jacobson, 2006 [R]; Lipid Research Clinics Program, 1984 [A]; McKenney, 2002 [R]; McKenney, 2001a [R]; Scandinavian Simvastatin Survival Study Group, 1994 [A]; Schrott, 1995 [A]; Shek, 2001 [R])