Are Add-on Agents to Statin Therapy Necessary in Hypercholesterolemia?

Linda Dayer-Berenson; Mary Finckenor; Michelle Tuzzolino


Clin Lipidology. 2014;9(6):695-707. 

In This Article

Abstract and Introduction


Elevated cholesterol is a major risk factor for atherosclerosis and coronary heart disease, and its control remains poor. Diet and exercise may not achieve LDL-C goals, particularly in high-risk patients. Statins are first-line treatment for lowering LDL-C. Recent ACC/AHA guidelines focus on groups benefiting the most from a statin, as well as using higher dose statins rather than a low-dose statin in combination with other cholesterol-lowering agents. Statin monotherapy will be inadequate to get half of treated patients to LDL-C goal, necessitating add-on therapy. Combining a statin with a bile acid sequestrant, fibrate or ezetimibe can help achieve lipid goals, and a bile acid sequestrant has the unique ability to reduce LDL-C, while improving glycemic control in patients with diabetes.


Cholesterol plays a vital role in the biochemistry of the body. It is a necessary component in the synthesis of cell membranes, bile acids, steroid hormones (including estrogen, progesterone, testosterone and cortisol) and vitamin D. Cholesterol is synthesized by the body and also acquired through dietary sources. Homeostasis is normally achieved by the elimination of cholesterol via bile acid synthesis and fecal excretion, which balances cholesterol produced by de novo synthesis and dietary intake. Despite these compensatory mechanisms, cholesterol can become elevated and when increased above recommended levels cholesterol is an important threat to public health.[1] Globally, raised cholesterol results in approximately 2.6 million deaths (4.5% of total mortality) and 29.7 million disability adjusted life years.[2] The WHO estimated that in 2008 the prevalence of raised total cholesterol (≥190 mg/dl) was 39% worldwide (highest in the WHO region of Europe (54%) and lowest in Africa (22.6%), with only a <3.9 mg/dl decrease per decade between 1980 and 2008.[2] It is noteworthy that >50% of adults in high-income countries had raised total cholesterol, which was more than twice the level observed in low-income countries.[2] Ford et al. examined NHANE surveys from 1999–2006 and found that the unadjusted prevalence of hypercholesterolemia remained relatively steady over the study period, ranging from 53.2 to 56.1% in the USA. Although the control rate among all participants increased from 7.2 to 17.1%, overall, control remains poor and increasing the control rate remains a major public health challenge.[1] This study also found important disparities in control based on gender, race or ethnicity that also need to be addressed by the healthcare community, i.e., reduced rates of control in women compared with men, and reduced rates of cholesterol checks in both African and Mexican Americans.[1]

Elevated cholesterol is a well-documented major risk factor for atherosclerosis and coronary heart disease (CHD).[3] It is estimated that more than 1 in 3 (83.6 million) adults in the USA have at least one type of cardiovascular disease, with 15.4 million having CHD.[4] Moreover, the lifetime risk of developing cardiovascular disease in individuals cardiovascular disease-free at age 50 is 51.7% in men/39.2% in women, and the prevalence of cardiovascular disease adults aged 60–79 years is >70%.[4] Mortality data reported for 2009 showed that cardiovascular disease (including congenital cardiovascular defects) was the underlying cause in 32.3% of deaths in the USA.[4] Although mortality due to cardiovascular disease (mainly CHD and stroke) has been declining in most European countries, it is still responsible for greater than 4 million deaths in Europe, as well as 1.9 million deaths in the EU.[5] Importantly, it has been shown that cardiovascular disease is the primary cause of death in women in all European countries and in men in all except six countries.[5] Slightly less than 50% of all cardiovascular disease-related deaths in Europe are attributable to CHD.[5] Moreover, the overall cost of cardiovascular disease in the EU is estimated to be €196 billion/year.[5]

Numerous clinical trials have shown that LDL-cholesterol (LDL-C) is the primary target of lipid-lowering therapy to reduce cardiovascular disease risk, and aggressively reducing LDL-C reduces both morbidity and mortality.[6–12] Current ATP III guidelines typically define LDL-C goals as <130 mg/dl for those with ≥2 risk factors, and <100 mg/dl for those with CHD or CHD risk equivalents (i.e., high risk), with an optional goal of <70 mg/dl for those with CHD and additional risk factors.[6,13]

The American Association of Clinical Endocrinologists guidelines recommend that all adults achieve an LDL-C level <100 mg/dl (Table 1); however, it is estimated that 69% of adults in the USA have an LDL-C level >100 mg/dl.[14] Equally concerning, the American Heart Association Heart Disease and Stroke Statistics – 2013 Update reported that the prevalence of LDL-C level ≥130 mg/dl was 31.1% in adults aged ≥20 years in the USA (Table 2). Moreover, 5.6% of all adults in the USA had undiagnosed hypercholesterolemia so they are thus unaware of their medical condition.[4]

It is important to note that the American College of Cardiology and the American Heart Association recently published revised guidelines for reducing cholesterol that place the emphasis on reducing risk in patient groups at high risk for cardiovascular disease rather than focusing on specific LDL-C targets.[15] The guidelines are discussed in more detail below. However, these new guidelines are still being reviewed and evaluated by the medical community and have not yet been universally endorsed, either in the USA or globally.

Encouragingly, clinical study data suggest that each 1% reduction in LDL-C levels is associated with approximately a 1% reduction in relative risk for major CHD events, CHD death and nonfatal myocardial infarction.[10,13] In addition, results reported from the Heart Protection Study suggest this relationship even applies to LDL-C levels <100 mg/dl.[9] Clinical studies have shown that if sufficiently low LDL-C levels are achieved, not only is the risk of CHD reduced, but the progression of atherosclerosis can be prevented, or even regress.[16–18] One such study demonstrated that intensive LDL-C lowering resulted in the regression of coronary atherosclerosis in patients with coronary disease in whom LDL-C was reduced to <70 mg/dl (mean of 61.1 mg/dl; HDL-cholesterol [HDL-C] was also increased [mean HDL-C = 48.3 mg/dl]).[16]

The purpose of this review is to summarize the current pharmacological treatment options for the treatment of hypercholesterolemia. Although dietary modifications and exercise are recommended to reduce elevated levels of LDL-C, pharmacological intervention is often necessary to achieve lipid goals, especially in high-risk patients. Cholesterol-lowering drugs include the statins, bile acid sequestrants (BASs), fibrates and ezetimibe. Statins are the agent of choice to lower LDL-C due to their proven efficacy and safety. However, as discussed below, statin monotherapy cannot always achieve cholesterol goal, and may not be an appropriate option for some patients. This review discusses the role of statins in treating hypercholesterolemia and the efficacy and safety of BASs, fibrates and ezetimibe as monotherapy, and in combination with a statin.