Update on the Controversies of Statin Therapy

Abstract & Commentary

By Harold L. Karpman, MD, FACC, FACP. Clinical Professor of Medicine, UCLA School of Medicine. Dr. Karpman reports no financial relationships relevant to this field of study.

Synopsis: After careful evaluation of all the published studies regarding the possible adverse effects of statin therapy, Jukema et al have concluded that there is no proven increased risk of cognitive decline or cancer development. However, there is a possible small increased risk for the development of type 2 diabetes mellitus.

Source: Jukema JW, et al. The controversies of statin therapy: Weighing the evidence. J Am Coll Cardiol 2012;60:875-881.

As is well known, cardiovascular disease is the leading cause of death in industrialized nations.1 The prevention and avoidance of the progression of cardiovascular disease is critically dependent on lipid-lowering therapy, which has been most often and reliably achieved with 3-hydroxymethyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, also known as statin drugs. Statins are now the most widely prescribed class of drugs worldwide, and their widespread use is a major reason for the 25-45% reduction of cardiovascular events in the modern era. They are extremely well tolerated with only minimal adverse side effects, such as transient myopathies and/or elevations of liver enzymes, and on rare occasions, serious rhabdomyolysis may occur with their use.

Earlier this year, the FDA expanded the warning section of all statin drug labels to include the serious risk of liver damage. Although the occurrence of serious liver damage with statin therapy is rare and unpredictable, periodic liver-monitoring tests do not appear to be effective for detecting or preventing liver injury and therefore should not be performed on a frequent basis. However, an increased number of observations have surfaced suggesting that statin use may increase cognitive decline2 manifested by memory loss, forgetfulness, and confusion. These events have rarely been reported, have occurred with the use of all statin products and in all age groups, and have occurred in individuals whether they had been taking the medication for only a day or two or for many years. The reported symptoms were generally not serious and were usually reversible within a few weeks of the patient stopping the statin drug.


Since the introduction of statins in 1987, the association between statin drug use and possible adverse cognitive effects has been carefully studied.3 Cognitive symptoms reported have included short- and long-term memory loss, behavioral changes, impaired concentration and attention, paranoia, and anxiety. Some scientists have suggested that since cholesterol synthesis is essential for neurons to function normally, the metabolic effects of inhibition of cholesterol synthetic pathways may, in some individuals, result in adverse neurocognitive effects. Jukema and his colleagues4 identified nine observational studies related to statin use and cognitive function.5-13 Four studies observed beneficial effects of statins on cognitive performance,5-8 three studies found no cognitive side effects,9-11 and two studies found an increased risk of cognitive impairment associated with statin use.12,13 Of course, it must be clearly recognized that the possible adverse effects of statin drugs noted in these observational studies may be compounded by the fact that the patient population receiving statin drug therapy is usually already at risk for cerebral vascular disease because they are usually older than those not receiving statin therapy and frequently are afflicted with multiple cardiac risk factors. Therefore, by definition, these subjects are more prone to developing cognitive impairment whether they are taking a statin drug or not.14 Furthermore, statistical correction for imbalances between treatment groups in observational studies has proven to be unreliable.15

After careful evaluation of two large, randomized, controlled clinical trials16,17 on the effects of statin drugs on cognitive function, Jukema et al4 concluded that there was no solid evidence that statins had a detrimental (or beneficial) effect on cognitive function. Furthermore, after evaluating systematic reviews and large meta-analyses they found that there was no increased risk of incident cancer associated with statin therapy. However, they did note that a recent meta-analysis revealed that those subjects receiving intensive-dose statin therapy compared with those receiving only moderate-dose statins were found to have a higher incidence of new-onset diabetes. They conclude that more research is needed to find the possible underlying mechanism of the observed small statin-related diabetes risk. They also state that the proven large benefit of statin therapy in the primary and secondary prevention of cardiovascular events — especially in diabetic patients — far outweighs the small absolute risk for the development of new-onset diabetes.

In conclusion, after careful evaluation of all of the published studies regarding the possible adverse effects of statin therapy, Jukema et al4 have concluded that there is no proven increased risk of cognitive decline or cancer development. However, a small increased risk for development of type 2 diabetes mellitus does exist. Because of the overwhelming benefit of statins in the reduction of cardiovascular events, they concluded that the small absolute risk for developing type 2 diabetes is far outweighed by the cardiovascular benefits in patients for whom statin therapy is recommended.


1. McGovern PG, et al. N Engl J Med 1996;334:884-890.

2. FDA Drug Safety Communication: Important safety label changes to cholesterol-lowering statin drugs. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm293101.htm. Accessed November 9, 2012.

3. Rojas-Fernandez CH, et al. Ann Pharmacother 2003; 23:871-880.

4. Jukema JW, et al. J Am Coll Cardiol 2012;60:875-881.

5. Jick H, et al. Lancet 2000;356:1627-1631.

6. Hajjar I, et al. J Gerontol A Biol Sci Med Sci 2002;57: M414-418 .

7. Rockwood K, et al. Arch Neurol 2002;59:223-227.

8. Yaffe K, et al. Arch Neurol 2002;59:378-384.

9. Starr JM, et al. Int J Geriatr Psychiatry 2004;19:327-332.

10. Agostini JV, et al. J Am Geriatr Soc 2007;55:420-425.

11. Redelmeier DA, et al. CMAJ 2008;179:645-652.

12. Glasser SP, et al. Clin Cardiol 2010;33:280-288.

13. Benito-Leon J, et al. J Alzheimers Dis 2010;21:95-102.

14. Danaei G, et al. Am J Epidemiol 2012;175:250-262.

15. Vandenbroucke JP. Lancet 2009;373:1233-1235.

16. Shepherd J, et al. Lancet 2002;360:1623-1630.

17. Collins R, et al. Lancet 2004;363:757-767.