OBJECT: The favorable effect of statin treatment after traumatic brain injury (TBI) has been shown in animal studies and is probably true in humans as well. The objective of this study was to determine whether acute statin treatment following TBI could reduce inflammatory cytokines and improve functional outcomes in humans.
METHODS: The authors performed a double-blind randomized clinical trial in patients with moderate to severe TBI. Exclusion criteria were as follows: prior severe disability; use of modifiers of statin metabolism; multisystem trauma; prior use of mannitol, barbiturates, corticosteroids, or calcium channel blockers; isolated brainstem lesions; allergy to statins; previous hepatopathy or myopathy; previous treatment at another clinic; and pregnancy. Patients were randomly selected to receive 20 mg of rosuvastatin or placebo for 10 days. The main goal was to determine the effect of rosuvastatin on plasma levels of tumor necrosis factor-α, interleukin (IL)-1β, IL-6, and IL-10 after 72 hours of TBI. Amnesia, disorientation, and disability were assessed 3 and 6 months after TBI.
RESULTS: Thirty-six patients were analyzed according to intention-to-treat analysis; 19 patients received rosuvastatin and 17 received placebo. The best-fit mixed model showed a significant effect of rosuvastatin on the reduction of tumor necrosis factor-α levels (p = 0.004). Rosuvastatin treatment did not appear to affect the levels of IL-1β, IL-6, and IL-10. The treatment was associated with a reduction in disability scores (p = 0.03), indicating a favorable functional outcome. Life-threatening adverse effects were not observed.
CONCLUSIONS: The authors' data suggest that statins may induce an antiinflammatory effect and may promote recovery after TBI. The role of statins in TBI therapy should be confirmed in larger clinical trials.
OBJECTIVES: The purpose of this study was to assess the impact on cardiovascular and adverse events of attaining low-density lipoprotein cholesterol (LDL-C) levels <50 mg/dl with rosuvastatin in apparently healthy adults in the JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) trial.
BACKGROUND: The safety and magnitude of cardiovascular risk reduction conferred by treatment to LDL-C levels below current recommended targets remain uncertain.
METHODS: A cohort of 17,802 apparently healthy men and women with high-sensitivity C-reactive protein ≥2 mg/l and LDL-C <130 mg/dl were randomly allocated to rosuvastatin 20 mg daily or placebo, and followed up for all-cause mortality, major cardiovascular events, and adverse events. In a post-hoc analysis, participants allocated to rosuvastatin were categorized as to whether or not they had a follow-up LDL-C level <50 mg/dl.
RESULTS: During a median follow-up of 2 years (range up to 5 years), rates of the primary trial endpoint were 1.18, 0.86, and 0.44 per 100 person-years in the placebo group (n = 8,150) and rosuvastatin groups without LDL-C <50 mg/dl (n = 4,000) or with LDL-C <50 mg/dl (n = 4,154), respectively (fully-adjusted hazard ratio: 0.76; 95% confidence interval: 0.57 to 1.00 for subjects with no LDL-C <50 mg/dl vs. placebo and 0.35, 95% confidence interval: 0.25 to 0.49 for subjects attaining LDL-C <50 mg/dl; p for trend <0.0001). For all-cause mortality, corresponding event rates were 0.67, 0.65, and 0.39 (p for trend = 0.004). Rates of myalgia, muscle weakness, neuropsychiatric conditions, cancer, and diabetes mellitus were not significantly different among rosuvastatin-allocated participants with and without LDL-C <50 mg/dl.
CONCLUSIONS: Among adults with LDL-C <130 mg/dl and high-sensitivity C-reactive protein ≥2 mg/l, rosuvastatin-allocated participants attaining LDL-C <50 mg/dl had a lower risk of cardiovascular events without a systematic increase in reported adverse events.
BACKGROUND: Lowering cholesterol is associated with reduced CNS amyloid deposition and increased dietary cholesterol increases amyloid accumulation in animal studies. Epidemiologic data suggest that use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) may decrease the risk of Alzheimer disease (AD) and a single-site trial suggested possible benefit in cognition with statin treatment in AD, supporting the hypothesis that statin therapy is useful in the treatment of AD. OBJECTIVE: To determine if the lipid-lowering agent simvastatin slows the progression of symptoms in AD. METHODS: This randomized, double-blind, placebo-controlled trial of simvastatin was conducted in individuals with mild to moderate AD and normal lipid levels. Participants were randomly assigned to receive simvastatin, 20 mg/day, for 6 weeks then 40 mg per day for the remainder of 18 months or identical placebo. The primary outcome was the rate of change in the Alzheimer’s Disease Assessment Scale–cognitive portion (ADAS-Cog). Secondary outcomes measured clinical global change, cognition, function, and behavior. RESULTS: A total of 406 individuals were randomized: 204 to simvastatin and 202 to placebo. Simvastatin lowered lipid levels but had no effect on change in ADAS-Cog score or the secondary outcome measures. There was no evidence of increased adverse events with simvastatin treatment. CONCLUSION: Simvastatin had no benefit on the progression of symptoms in individuals with mild to moderate AD despite significant lowering of cholesterol. Classification of evidence: This study provides Class I evidence that simvastatin 40 mg/day does not slow decline on the ADAS-Cog. (PsycInfo Database Record (c) 2024 APA, all rights reserved)
BACKGROUND: There is some evidence that statins may have a protective and symptomatic benefit in Alzheimer disease (AD). The LEADe study is a randomized controlled trial (RCT) evaluating the efficacy and safety of atorvastatin in patients with mild to moderate AD. METHODS: This was an international, multicenter, double-blind, randomized, parallel-group study. Subjects had mild to moderate probable AD (Mini-Mental State Examination score 13–25), were aged 50–90 years, and were taking donepezil 10 mg daily for ≥3 months prior to screening. Entry low-density lipoprotein cholesterol levels (LDL-C) were >95 and <195 mg/dL. Patients were randomized to atorvastatin 80 mg/day or placebo for 72 weeks followed by a double-blind, 8-week atorvastatin withdrawal phase. Coprimary endpoints were changes in cognition (Alzheimer's Disease Assessment Scale-Cognitive Subscale [ADAS-Cog]) and global function (Alzheimer's Disease Cooperative Study Clinical Global Impression of Change [ADCS-CGIC]) at 72 weeks. RESULTS: A total of 640 patients were randomized in the study. There were no significant differences in the coprimary endpoints of ADAS-cog or ADCS-CGIC or the secondary endpoints. Atorvastatin was generally well-tolerated. CONCLUSIONS: In this large-scale randomized controlled trial evaluating statin therapy as a treatment for mild to moderate Alzheimer disease, atorvastatin was not associated with significant clinical benefit over 72 weeks. This treatment was generally well-tolerated without unexpected adverse events. (PsycInfo Database Record (c) 2024 APA, all rights reserved)
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.
Amnesia is a common sequela following traumatic brain injury (TBI), for which there is no current treatment. Pleiotropic effects of statins have demonstrated faster recovery of spatial memory after TBI in animals. We conducted a double-blind randomized clinical trial add-on of patients with TBI (16–50 years of age), with Glasgow Coma Scale (GCS) scores of 9-13, and intracranial lesions as demonstrated by computed tomography (CT) scan. We excluded those patients with recent head injury or severe disability; administration of known drugs as modifiers of statin metabolism; multisystemic trauma; prior use of mannitol, barbiturate, corticosteroids, indomethacin or calcium antagonists; surgical or isolated lesion in brainstem; allergy to statins; previous hepatopathy or myopathy; previous management in another clinic; or pregnancy. Each patient received the same treatment and was randomly allocated to receive either rosuvastatin (RVS) or placebo over a period of 10 days. The primary outcome measures assessed were amnesia and disorientation times using Galveston Orientation Amnesia Test. Additionally, we evaluated plasma levels of interleukin (IL)1β , tumor necrosis factor (TNF) α, and IL-6, as well as disability at 3 months. We analyzed eight patients with RVS and 13 controls with similar basal characteristics. Using Cox regression analysis, administration of RVS showed a reduction of amnesia time with a hazard ratio of 53.76 (95% confidence interval [CI], 1.58–1824.64). This was adjusted for early intubation, basal leukocytes, basal Marshall and Fisher score, change of IL-1β levels, and lesion side. IL-6 values at day 3 were increased in the RVS group (p = 0.04). No difference was detected in disability at 3 months. While statins may reduce amnesia time after TBI, possibly by immunomodulation, further trials are needed in order to confirm this positive association. (PsycInfo Database Record (c) 2021 APA, all rights reserved)
<b>BACKGROUND: </b>Increased levels of the inflammatory biomarker high-sensitivity C-reactive protein predict cardiovascular events. Since statins lower levels of high-sensitivity C-reactive protein as well as cholesterol, we hypothesized that people with elevated high-sensitivity C-reactive protein levels but without hyperlipidemia might benefit from statin treatment.<b>METHODS: </b>We randomly assigned 17,802 apparently healthy men and women with low-density lipoprotein (LDL) cholesterol levels of less than 130 mg per deciliter (3.4 mmol per liter) and high-sensitivity C-reactive protein levels of 2.0 mg per liter or higher to rosuvastatin, 20 mg daily, or placebo and followed them for the occurrence of the combined primary end point of myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes.<b>RESULTS: </b>The trial was stopped after a median follow-up of 1.9 years (maximum, 5.0). Rosuvastatin reduced LDL cholesterol levels by 50% and high-sensitivity C-reactive protein levels by 37%. The rates of the primary end point were 0.77 and 1.36 per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively (hazard ratio for rosuvastatin, 0.56; 95% confidence interval [CI], 0.46 to 0.69; P<0.00001), with corresponding rates of 0.17 and 0.37 for myocardial infarction (hazard ratio, 0.46; 95% CI, 0.30 to 0.70; P=0.0002), 0.18 and 0.34 for stroke (hazard ratio, 0.52; 95% CI, 0.34 to 0.79; P=0.002), 0.41 and 0.77 for revascularization or unstable angina (hazard ratio, 0.53; 95% CI, 0.40 to 0.70; P<0.00001), 0.45 and 0.85 for the combined end point of myocardial infarction, stroke, or death from cardiovascular causes (hazard ratio, 0.53; 95% CI, 0.40 to 0.69; P<0.00001), and 1.00 and 1.25 for death from any cause (hazard ratio, 0.80; 95% CI, 0.67 to 0.97; P=0.02). Consistent effects were observed in all subgroups evaluated. The rosuvastatin group did not have a significant increase in myopathy or cancer but did have a higher incidence of physician-reported diabetes.<b>CONCLUSIONS: </b>In this trial of apparently healthy persons without hyperlipidemia but with elevated high-sensitivity C-reactive protein levels, rosuvastatin significantly reduced the incidence of major cardiovascular events. (ClinicalTrials.gov number, NCT00239681.)
CONTEXT: Neurofibromatosis type 1 (NF1) is among the most common genetic disorders that cause learning disabilities. Recently, it was shown that statin-mediated inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase restores the cognitive deficits in an NF1 mouse model. OBJECTIVE: To determine the effect of simvastatin on neuropsychological, neurophysiological, and neuroradiological outcome measures in children with NF1. Design, Setting, and Participants: Sixty-two of 114 eligible children (54%) with NF1 participated in a randomized, double-blind, placebo-controlled trial conducted between January 20, 2006, and February 8, 2007, at an NF1 referral center at a Dutch university hospital. Intervention: Simvastatin or placebo treatment once daily for 12 weeks. MAIN OUTCOME MEASURES: Primary outcomes were scores on a Rey complex figure test (delayed recall), cancellation test (speed), prism adaptation, and the mean brain apparent diffusion coefficient based on magnetic resonance imaging. Secondary outcome measures were scores on the cancellation test (standard deviation), Stroop color word test, block design, object assembly, Rey complex figure test (copy), Beery developmental test of visual-motor integration, and judgment of line orientation. Scores were corrected for baseline performance, age, and sex. RESULTS: No significant differences were observed between the simvastatin and placebo groups on any primary outcome measure: Rey complex figure test (β = 0.10; 95% confidence interval [CI], -0.36 to 0.56); cancellation test (β = -0.19; 95% CI, -0.67 to 0.29); prism adaptation (odds ratio = 2.0; 95% CI, 0.55 to 7.37); and mean brain apparent diffusion coefficient (β = 0.06; 95% CI, -0.07 to 0.20). In the secondary outcome measures, we found a significant improvement in the simvastatin group in object assembly scores (β = 0.54; 95% CI, 0.08 to 1.01), which was specifically observed in children with poor baseline performance (β = 0.80; 95% CI, 0.29 to 1.30). Other secondary outcome measures revealed no significant effect of simvastatin treatment. CONCLUSION: In this 12-week trial, simvastatin did not improve cognitive function in children with NF1. (PsycInfo Database Record (c) 2021 APA, all rights reserved)
The favorable effect of statin treatment after traumatic brain injury (TBI) has been shown in animal studies and is probably true in humans as well. The objective of this study was to determine whether acute statin treatment following TBI could reduce inflammatory cytokines and improve functional outcomes in humans.
METHODS:
The authors performed a double-blind randomized clinical trial in patients with moderate to severe TBI. Exclusion criteria were as follows: prior severe disability; use of modifiers of statin metabolism; multisystem trauma; prior use of mannitol, barbiturates, corticosteroids, or calcium channel blockers; isolated brainstem lesions; allergy to statins; previous hepatopathy or myopathy; previous treatment at another clinic; and pregnancy. Patients were randomly selected to receive 20 mg of rosuvastatin or placebo for 10 days. The main goal was to determine the effect of rosuvastatin on plasma levels of tumor necrosis factor-α, interleukin (IL)-1β, IL-6, and IL-10 after 72 hours of TBI. Amnesia, disorientation, and disability were assessed 3 and 6 months after TBI.
RESULTS:
Thirty-six patients were analyzed according to intention-to-treat analysis; 19 patients received rosuvastatin and 17 received placebo. The best-fit mixed model showed a significant effect of rosuvastatin on the reduction of tumor necrosis factor-α levels (p = 0.004). Rosuvastatin treatment did not appear to affect the levels of IL-1β, IL-6, and IL-10. The treatment was associated with a reduction in disability scores (p = 0.03), indicating a favorable functional outcome. Life-threatening adverse effects were not observed.
CONCLUSIONS:
The authors' data suggest that statins may induce an antiinflammatory effect and may promote recovery after TBI. The role of statins in TBI therapy should be confirmed in larger clinical trials.
