Twenty-five Years of Statins: Where Do We Go From Here?

Antonio M Gotto Jr; Jennifer E Moon


Clin Lipidology. 2015;10(1):33-45. 

In This Article

Abstract and Introduction


More than 25 years of clinical trial data have established statins as first-line therapy for the prevention and treatment of atherosclerotic cardiovascular disease. With regard to low-density lipoprotein cholesterol, a wealth of evidence indicates that 'lower is better,' although recent guidelines from the American College of Cardiology and the American Heart Association take a different approach. A variety of approved and experimental lipid-lowering agents may be used as supplements or alternatives to statin therapy in patient subgroups, including those with familial hypercholesterolemia, mixed dyslipidemia or statin intolerance. Strategies to achieve further reductions in low-density lipoprotein cholesterol, target high-density lipoprotein cholesterol and triglycerides or reduce inflammation may help address residual cardiovascular risk, although early lifestyle interventions are crucial to prevention strategies.


After more than 25 years in clinical use, statins have transformed the field of lipid management and cardiovascular risk reduction. Due to their proven efficacy and safety, they have become first-line therapy for individuals who are unable to manage their dyslipidemia through lifestyle changes alone. Between 1988 and 2010, average LDL-cholesterol levels fell from 129 to 116 mg/dl in the USA, and HDL-cholesterol increased from 50.7 to 52.5 mg/dl.[1] It is likely that an increase in the number of people taking lipid-lowering medications – from 3.4 to 15.5% over the same time period – contributed substantially to these favorable trends. The introduction of statins has also played an important role in the decline in cardiovascular mortality rates observed in the USA since 1970. By helping to prevent the development of atherosclerotic cardiovascular disease before it occurs and by reducing the risk of a future event in those with a clinical diagnosis, statins have had an enormous public health impact.

Still, ischemic heart disease and stroke remain leading causes of death worldwide. The release of new recommendations for cholesterol management from the American College of Cardiology (ACC) and the American Heart Association (AHA) generated considerable controversy among lipid experts and indicates that there are widely divergent views on the optimum strategy for treatment with statins. In addition, there is a pressing need for alternative therapies, particularly for patients with familial hypercholesterolemia (FH), mixed dyslipidemia or statin intolerance. Several nonstatin drugs, including ezetimibe, nicotinic acid and fibrates, have been challenged in recent years due to negative results from clinical trials. It is important that we clearly identify the patient subgroups that can achieve the greatest benefit from these medications.

This Perspective highlights some of the key issues and the most exciting new therapies in development within clinical lipidology. It begins by placing the statins in historical perspective and briefly summarizes the clinical trial data that provide robust support for the 'lower is better' approach to treating LDL-cholesterol. Although the ACC/AHA guidelines recommend a different strategy, 'lower is better' remains an important principle in the field. This Perspective also reviews existing and experimental agents designed to achieve further LDL-cholesterol reduction, as well as drugs that target HDL-cholesterol, triglycerides and inflammation. When targeted to the appropriate patient, these therapies have the potential to lower cardiovascular risk beyond the effects of statin treatment.