The Controversies of Statin Therapy: Weighing the Evidence


Statin therapy is associated with a 25%-45% reduction in risk for cardiovascular events. However, concerns regarding adverse effects potentially associated with statin use have continued to be debated. Recently, the US Food and Drug Administration (FDA) expanded the warning label for all statins; the changes included a removal of the need for routine periodic monitoring of liver enzymes, along with warnings regarding potential for increased risk for cognitive impairment, cancer, and diabetes associated with statin use. The authors of this thoughtful state-of-the-art paper have reviewed the current evidence related to these adverse events, grouping findings by level of evidence from case reports to randomized control trials. With regard to cognitive impairment, several case reports suggest statin therapy is associated with short-term memory loss, which is reversible upon discontinuation of the statin. Among observational studies, the authors identified nine studies, of which four found benefits of statins related to cognition, three studies observed no effects of statins, and two studies found increased risk of cognitive impairment. Randomized controlled trials including Prospective Study of Pravastatin in the Elderly at Risk for Vascular Disease (PROSPER) observed no difference in cognitive decline between subjects randomized to pravastatin compared to those randomized to placebo. Two other large-scale trials, Heart Protection Study (HPS) and Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER), also did not observe an association between cognitive impairment and statin use. Vascular risk is associated with statin therapy and cognitive decline. Thus, confounding by indication was cited by the authors of this commentary.

The authors also reviewed evidence for cancer risk associated with statins. Current data suggest an association between low low-density lipoprotein (LDL) cholesterol and increased risk for cancer, independent of statin therapy. Confounding by risk factors for cancer, which has also been associated with recommendations for statins such as smoking, may explain the association between cancer and statins, which were observed in some studies. It should be noted that PROSPER and Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) did observed an increased risk for cancer associated with statins; however, an analysis of pooled data observed a nonsignificant odds ratio (OR) of risk (OR, 1.07; 95% confidence interval [CI], 0.97-1.18). Risk ratios did increase with increasing age. Extended follow-up in the PROSPER cohort observed no increased cancer risk related to statin therapy.

Lastly, risk of diabetes associated with statins was discussed. Observational data have suggested an association between statin therapy and diabetes, which has also been observed in data from randomized controlled trials. However these trial results have not been consistent; JUPITER investigators observed an increased incidence of diabetes among those randomized to rosuvastatin, whereas West of Scotland Coronary Prevention Study (WOSCOPS) found a decreased risk for diabetes among those participants randomized to pravastatin. A larger meta-analysis including 13 trials suggests an increased risk of diabetes associated with statins (OR, 1.09; 95% CI, 1.02-1.17).

In summary, the authors suggest there is currently no convincing evidence for changes in cognition or cancer risk associated with statins; however, a small increased risk for diabetes has been observed. They suggest no change in current practice patterns in regards to the use of statin therapy among patients at high risk for cardiovascular disease or with existing cardiovascular disease.

Clinical Topics: Dyslipidemia, Nonstatins, Novel Agents, Statins

Keywords: Scotland, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Cardiovascular Diseases, Risk Factors, Diabetes Mellitus

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