Briefing Document for Endocrinologic and Metabolic Drugs Advisory Committee Meeting of December 15, 2009

Cardiovascular disease causes substantial disability and continues to be the leading cause of death worldwide despite preventative efforts including statin treatment (Rosamond et al 2008, Waldman and Terzic 2007). Statins are highly effective cholesterol-lowering agents that have been proven to reduce cardiovascular events in numerous clinical studies. The Cholesterol Treatment Trialists’ meta-analysis of over 90000 statin study subjects concluded that statin therapy can safely reduce the incidence of major cardiovascular events largely irrespective of the initial lipid profile or other presenting characteristics such as age, sex, or the presence or absence of diabetes or prevalent coronary heart disease (CHD)(CTT Collaborators 2005). Current cardiovascular disease prevention guidelines recommend statin use, particularly among patients with hypercholesterolemia, cardiovascular disease, or with multiple CHD risk factors (such as older age, cigarette smoking, hypertension, low levels of high density lipoprotein-cholesterol [HDL-C], or a family history of premature CHD) (Expert Panel (NCEP) 2001, Graham et al 2007). However, at least half of all future cardiovascular events occur in individuals with “normal” cholesterol levels who were not recommended for cholesterol-lowering treatment based on current guidelines (Sachdeva et al 2009, Ridker et al 2002). Many of these individuals have elevated levels of the inflammatory biomarker Creactive protein (CRP) when measured with a high sensitivity assay or “hsCRP,” which has been shown to be an independent predictor of cardiovascular risk in numerous epidemiologic studies (Ridker et al 1998, Danesh et al 2000). AstraZeneca conducted the “Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin,” (subsequently referred to as the JUPITER study) to assess the long-term safety and efficacy of rosuvastatin in reducing cardiovascular events. The study was conducted in a population of adults who had an increased cardiovascular risk (identified initially based on age and the presence of an elevated hsCRP level at a screening visit), but who were not recommended for cholesterol-lowering treatment based on current guidelines. This allowed AstraZeneca to ethically conduct a placebo-controlled study and, at the same time, address the need for improved cardiovascular disease prevention. The main results of the JUPITER study were the statistically significant 44% reduction in the risk of sustaining a major cardiovascular event (cardiovascular death, stroke, myocardial infarction, unstable angina, or arterial revascularization) and 20% reduction in total mortality observed in the rosuvastatin compared to the placebo group. AstraZeneca is therefore seeking approval for use of rosuvastatin to reduce the risk of major cardiovascular events in patients at increased cardiovascular risk on the basis of the results of the JUPITER study.