Over 28 million Americans have some form of cardiovascular disease (CVD), which causes more deaths than cancer, diabetes, accidents, and chronic lung diseases combined. A large amount of observational data, as well as clinical trials, support a significant, modifiable role of blood lipids in the production of disease. Cholesterol is transported in the blood in the form of particles containing lipids and proteins, called lipoproteins. Levels of low density lipoprotein cholesterol (LDL-c) correlate with the development of CVD, while levels of high-density lipoprotein cholesterol (HDL-c) are associated with a lower risk of disease. Cholesterol is a normal part of cell membranes, hormones, and bile acids that are involved in the absorption of some vitamins. Levels of cholesterol are influenced by its production in the liver and the ingestion of dietary fats. Bile acids are released into the intestine, aid in digestion, and then are mostly reabsorbed. Evidence suggests that lowering LDL-c reduces coronary heart disease (CHD) and ischemic stroke, making LDL-c a primary target of therapy. The National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) recommendations provide guidance on the initiation of treatment aimed at lowering lipid levels based on individual patient characteristics. Medications available for lipid-lowering therapy have various mechanisms of action and pharmacokinetic properties. The most widely prescribed are the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors. Known as statins, these agents reduce the production of cholesterol in the liver by binding with the enzyme responsible for its production. In contrast, fibrates do not influence lipid synthesis but rather reduce the levels of fatty acids in the blood. Ezetimibe is an agent that inhibits intestinal absorption by acting on the sterol transporter NPC1L1. Niacin (nicotinic acid) reduces LDL-c and increases HDL-c via a mechanism yet to be fully elucidated, although it is suspected to be involved in the synthesis and metabolism of apolipoproteins. Bile acid sequestrants (BAS) bind bile acids in the bowel, thereby preventing reabsorption of bile from the intestine. Omega-3 fatty acids have been postulated to lower postprandial triglycerides and have antithrombotic and blood-pressure reducing effects. Statins are the most studied and prescribed group of lipid-lowering medications and may be used alone or in combination with a medication of another type. Treatment options for individuals requiring intensive lipid-modifying therapy include increasing the dose of a statin or using a statin in combination with a lipid-modifying agent of another class. It is unclear which of these strategies is superior with respect to clinical outcomes or the attainment of treatment targets. Combining different types of medications may appear attractive but could result in more harms, be less tolerable, or be less effective than statin therapy alone. This systematic review compares the benefits and risks of these two options in terms of clinical events (e.g., myocardial infarction, stroke, or death), surrogate measures (e.g., levels of LDL-c), tolerability, and adherence. This evidence report was commissioned by the Agency for Healthcare Research and Quality (AHRQ) to address the following key questions: KQ 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? KQ 2. Do these regimens differ in reaching LDL targets (or other surrogate markers), short-term side effects, tolerability, and/or adherence? KQ 3. Compared with higher dose statins and to one another, do combination regimens differ in benefits and harms within subgroups of patients?