The UCSD Statin Study: a randomized controlled trial assessing the impact of statins on selected noncardiac outcomes

Abstract

There has been persistent controversy regarding possible favorable or adverse effects of statins or of cholesterol reduction on cognition, mood and behavior (including aggressive or violent behavior), muscle function, and quality of life. The UCSD Statin Study seeks to ascertain the beneficial or adverse effects of statin cholesterol-lowering drugs on a set of noncardiac endpoints, including cognition, behavior, and serotonin biochemistry. The study will enroll 1000 subjects (minimum 20% female) of mixed ethnicity from San Diego. Subjects must be age 20 and older, postmenopausal if female, without known cardiovascular disease or diabetes, and with LDLcholesterol between 115 and 190 mg/dl. Subjects will be randomized to a double-blind, placebocontrolled trial with assignment 1/3, 1/3, 1/3 to placebo, simvastatin 20 mg, or pravastatin 40 mg (equipotent LDL-cholesterol-lowering doses for drug arms with simvastatin and pravastatin chosen to represent the extremes of the lipophilicity spectrum) for 6 months of treatment followed by 2 months postcessation follow-up. Primary outcomes are cognition (cognitive battery), irritability/aggression (behavior measure), and serotonin (gauged by whole blood serotonin), assessed as the difference between baseline and 6 months, judging combined statin groups vs. placebo. Secondary outcomes include mood (CES-D and Wakefield depression inventory), quality of life (SF-12V), sleep (Leeds sleep scale, modified), and secondary aggression measures (Conflict Tactics Scale; Overt Aggression Scale, Modified). Cardiovascular reactivity will be examined in a 10% subset. As additional secondary endpoints, primary and selected secondary outcomes will be assessed by statin assignment (lipophilic simvastatin vs. hydrophilic pravastatin). "Reversibility" of changes, if any, at 2 months postcessation will be determined. If effects (favorable or unfavorable) are identified, we will seek to ascertain whether there are baseline variables that predict who will be most susceptible to these favorable or adverse noncardiac effects (i.e., effect modification). NIH Public Access BackgroundStatins are important and widely prescribed drugs, with well-documented and incontrovertible cardiac benefits. However, controversy remains regarding the existence and impact of noncardiac effects, including central nervous system (CNS) effects. The University of California-San Diego (UCSD) Statin Study, a National Institutes of Health/ National Heart Lung and Blood Institute-funded double-blind, placebo-controlled study, seeks to address these issues through a complex battery of tests assessing noncardiac outcomes pertaining to cognition, behavior, quality of life, and biochemistry, among other endpoints. This paper provides the general methodology employed and addresses certain theoretical issues in study design.Statin cholesterol-lowering drugs (HMG-CoA reductase inhibitors) are the most prescribed drugs in the United States and the world and contributed substantially to prescription drug cost increases in 200...

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