Combination Therapy Versus Intensification of Statin Monotherapy

Cardiovascular disease (CVD) includes conditions such as coronary heart disease, stroke, heart failure, arrhythmia, heart valve disease, congenital heart disease, and hypertension. The American Heart Association has estimated that CVD affects 83.6 million individuals in the U.S., contributes to 32.3% of deaths, and is a leading cause of disability. Atherosclerosis causes coronary heart disease (CHD), cerebrovascular disease, and peripheral artery disease. Abnormal lipoprotein metabolism predisposes individuals to atherosclerosis. Due to the consistent and robust association of higher LDL-c levels with atherosclerotic CVD across experimental and epidemiologic studies, therapeutic strategies to decrease risk have focused on LDL-c reduction as a primary goal. In contrast to LDL-c, high-density lipoprotein (HDL-c) has a protective role against atherosclerotic CVD. Questions remain as to how best to modify lipid levels with the goal of preventing CHD. The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are the most widely prescribed lipid-lowering agents and are often used as monotherapy. However, some patients do not reach their treatment goals on statin monotherapy or are troubled by side effects, prompting interest in combination therapy as a way to improve lipid levels without having to increase statin dosage or as a way to reduce side effects. Statins can be combined with an additional lipid-modifying medication such as a bile acid sequestrant, cholesterol absorption inhibitor, fibric acid, nicotinic acid, or omega-3 fatty acid. There are potential benefits to treating with multiple agents, as the different mechanisms of action of the other lipid-modifying agents may produce benefits unlikely to be achieved with a statin alone. For example, a fibrate or niacin in combination with a statin may increase HDL-c and decrease triglycerides above what is achieved with statin treatment alone. Combination therapy could potentially result in fewer statin-related side effects, as lower doses of statin could be used. Conversely, a combination of agents could result in an increase in side effects, as patients may experience the side effects common to both drugs. Two contextual factors need to be kept in mind while considering the evidence comparing statin intensification to combination therapy. First, guideline recommendations about intensifying statin therapy or adding an additional nonstatin agent to achieve a specific lipid target level have recently changed. Second, several large trials have compared statin monotherapy to combination therapy with the same statin dose plus another lipid-lowering drug. These trials have demonstrated that "add-on" combination therapy can lead to superior lipid outcomes but fails to reduce atherosclerosis or lead to decreased rates of cardiovascular death, MI, revascularization, or stroke. This evidence calls into question previous assumptions that lowering LDL-c or raising HDL-c are always reliable predictors of improved clinical outcomes, as well as increasing the importance of patient-centered clinical outcomes for evaluating the effectiveness of lipid-modifying therapies. We aimed to assess the effectiveness, safety, and tolerability of the combination of statin and other lipid-modifying medication compared to intensification of statin monotherapy. The specific Key Questions addressed are: 1) For patients who require intensive lipid-modifying therapy, what are the comparative long-term benefits and rates of serious adverse events of coadministration of different lipid-modifying agents (i.e., a statin plus another lipid-modifying agent) compared with higher dose statin monotherapy? 2) Do these regimens differ in reaching LDL targets (or other surrogate markers), short-term side effects, tolerability, and/or adherence? 3) Compared with higher dose statins and with one another, do combination regimens differ in benefits and harms within subgroups of patients?