Adherence to statin therapy: why aren't we doing better?

Statins, or HMG-CoA reductase inhibitors, are one of the most remarkable successes of clinical cardiovascular medicine. They lower low-density lipoprotein (LDL) cholesterol levels, the primary target for lipid treatment, by 30% to 40% at starting doses, and by up to 55% at maximal doses. They also lower triglyceride and atherogenic very low-density lipoprotein levels, slightly increase high-density lipoprotein (HDL) cholesterol levels, and decrease vascular inflammation as measured by high-sensitivity C-reactive protein. The evidence supporting their clinical benefits is substantial; statins have been evaluated in placebo-controlled randomized trials lasting 5 or more years that involve more than 50,000 people, comprising diverse populations with or without prior cardiovascular disease (1– 6). The “gold standard” for efficacy— decreased mortality from all causes— has been met by pravastatin (2– 4) and simvastatin (1,6), which also prevent first and recurrent major coronary events and stroke (1– 6). Furthermore, lovastatin has been shown to reduce the incidence of first coronary events in middle-aged people with average LDL and low HDL cholesterol levels, thus extending the benefits to a large proportion of the general population (5). In addition, these statin drugs have excellent tolerability and safety. Why, then, do patients in clinical practice have suboptimal responses in LDL cholesterol levels to statins, and why do they discontinue treatment? In this issue of the Journal, Frolkis et al. (7) report that patients taking statins for 4 to 8 months had less reduction in LDL cholesterol levels than was stated in the package inserts. Although package inserts use results of clinical trials in which there is special attention to high adherence, we can, however, be assured that the LDL cholesterol–lowering effects listed generally represent the actual biological effects of the statins, because large trials conducted following the approval of the inserts showed similar reductions in LDL cholesterol levels. Frolkis et al. also analyzed the distribution of changes in LDL cholesterol level during statin therapy in a clinical practice. These distributions are particularly useful in exploring why a suboptimal response to statins was observed. Although overall study subjects experienced 80% of the expected reduction in LDL cholesterol levels, 25% of patients had less than 50% of the expected response, 16% of patients showed 50% to 74%, and 10% had an increase in LDL cholesterol level. The high overall response is partly due to 38% of patients being hyperresponders. In essence, Frolkis et al. show that in clinical practice there are two distinct groups of patients who undergo statin therapy: poor responders and outstanding responders. Those with a typical LDL cholesterol response (75% to 100% of expected) comprised only 19% of all patients. It is unlikely that patients who had small changes in LDL cholesterol level, about one third of the study group, were biologically hyporesponsive. As the authors point out, LDL cholesterol changes in clinical trials were normally distributed, with few patients showing poor responses. Thus, low compliance is most likely the reason for the suboptimal changes. Consequently, there are several areas for further research. Perhaps certain patient characteristics, such as age, race/ethnicity, or the number of medicines prescribed, were more prevalent among the poor responders. In which case, studies to identify patients who need encouragement regarding adherence would be useful. Patients with poor or outstanding LDL cholesterol responses could be interviewed about factors affecting adherence, such as instruction by the physician or nurse on how to take statins, patient education on the reasons for lowering LDL cholesterol levels, and costs borne by the patient for medication and recommended follow-up visits. Anecdotally, I have heard of patients who shared medications with family or friends who lacked the ability to pay. Patients may also intentionally take a lower dose to reduce costs. Above all, I strongly suspect that fears about safety deter some patients from ever filling a prescription or adhering to a treatment regimen. The safety of statins is best determined by large, placebo-controlled trials of long duration (1– 6). Such trials have not reported an increase in noncardiovascular causes of death. In two studies (4,8), the incidence of cancer, which was similar in patients treated with statins and those given placebo at the end of the 5to 6-year Am J Med. 2002;113:685– 686. From the Nutrition Department, Harvard School of Public Health; and Cardiovascular Division and Channing Laboratory, Brigham & Women’s Hospital, Harvard Medical School, Boston, Massachusetts. Correspondence should be addressed to Frank M. Sacks, MD, Harvard School of Public Health, 665 Huntington Avenue, Boston, Massachusetts 02115, or fsacks@hsph.harvard.edu. Manuscript submitted October 2, 2002.