Determining the role of statins in Parkinson's disease risk reduction and disease modification: A comprehensive meta-analysis of 4 million participants' data.

BACKGROUND: Many observational studies have examined the association between statins and the incidence of Parkinson's disease (PD) in high-risk populations. On the other hand, clinical trials as well as other observational studies investigated the safety and efficacy of statins in slowing disease progression in PD patients. However, the evidence has been inconclusive in both questions. To that end, we conducted this systematic review and meta-analysis to synthesize evidence on the role of statins in decreasing the risk of PD among high-risk populations and as a possible disease-modifying agent for patients with PD. METHODS: A comprehensive literature search of electronic databases including PubMed, Scopus, Cochrane, and Web of Science has been performed. Relevant studies were chosen and data were extracted and analyzed using RevMan software version 5.4.1. RESULTS: Twenty-five studies (14 cohort, 9 case-control, and 2 randomized controlled trials) have been included in the present systematic review. Of them, 21 studies reported the association between statins and PD risk. Statins were found to significantly reduce the risk of developing PD (pooled RR 0.86, 95% CI [0.77-0.95], p < 0.005). Four studies investigated statins as a disease-modifying agent. The pooled mean difference (MD) in the UPDRS-III from baseline to endpoint did not differ significantly between the statin and control groups (MD -1.34 points, 95% CI [-3.81 to 1.14], p = 0.29). CONCLUSION: Although epidemiological observational studies showed that statin use was associated with a reduced risk of PD, current evidence is insufficient to support the role of statins in slowing the progression of PD. These findings are limited by the fact that most of the included studies are observational studies which carry a high risk of confounding bias which highlights the need for future well-designed RCTs.

Statin Use and Reduced Risk of Pneumonia in Patients with Melioidosis: A Lung-Specific Statin Association.

Rationale: 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) use is associated with a lower risk of incident pneumonia and, less robustly, with nonpulmonary infections. Whether statin use is associated with a lower risk of pneumonia than other clinical presentations of infection with the same pathogen is unknown. Objectives: To assess whether preadmission statin use is associated with a lower risk of pneumonia than nonpneumonia presentations among patients hospitalized with Burkholderia pseudomallei infection (melioidosis). Methods: We performed a secondary analysis of a prospective multicenter cohort study of patients hospitalized with culture-confirmed B. pseudomallei infection (melioidosis). We used Poisson regression with robust standard errors to test for an association between statin use and pneumonia. We then performed several sensitivity analyses that addressed healthy user effect and indication bias. Results: Of 1,372 patients with melioidosis enrolled in the parent cohort, 1,121 were analyzed. Nine hundred eighty (87%) of 1,121 were statin nonusers, and 141 (13%) of 1,121 were statin users. Forty-six (33%) of 141 statin users presented with pneumonia compared with 432 (44%) of 980 statin nonusers. Statin use was associated with a lower risk of pneumonia in unadjusted analysis (relative risk, 0.74; 95% confidence interval, 0.58-0.95; P = 0.02) and, after adjustment for demographic variables, comorbidities, environmental exposures, and symptom duration (relative risk, 0.73; 95% confidence interval, 0.57-0.94; P = 0.02). The results of sensitivity analyses, including active comparator analysis and inverse probability of treatment weighting, were consistent with the primary analysis. Conclusions: In hospitalized patients with melioidosis, preadmission statin use was associated with a lower risk of pneumonia than other clinical presentations of melioidosis, suggesting a lung-specific protective effect of statins.

The N-Acetylgalactosamine-conjugated small interfering RNA inclisiran can be coadministered safely with atorvastatin in cynomolgus monkeys resulting in additive low-density lipoprotein cholesterol reductions.

Inclisiran, a small interfering RNA, selectively inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9) synthesis in the liver and has been shown to reduce low-density lipoprotein cholesterol (LDL-C) by ≥50% in patients with hypercholesterolemia receiving maximally tolerated statins. The toxicokinetic, pharmacodynamic, and safety profiles of inclisiran when coadministered with a statin were characterized in cynomolgus monkeys. Six cohorts of monkeys were administered either atorvastatin (40 mg/kg, reduced to 25 mg/kg during the study, daily, oral gavage), inclisiran (300 mg/kg every 28 days, subcutaneous administration), atorvastatin (40/25 mg/kg) and inclisiran combinations (30, 100, or 300 mg/kg), or control vehicles over 85 days followed by 90 days' recovery. Inclisiran and atorvastatin toxicokinetic parameters were similar in cohorts administered either agent alone or in combination. Inclisiran exposure increased in a dose-proportional manner. At Day 86, atorvastatin increased plasma PCSK9 levels four-fold from pretreatment levels but did not significantly lower serum LDL-C levels. Inclisiran (alone or in combination) reduced PCSK9 (mean decrease 66-85%) and LDL-C (mean decrease 65-92%) from pretreatment levels at Day 86; levels were significantly lower than the control group (p ≤ .05) and remained decreased during the 90-day recovery. Coadministration of inclisiran with atorvastatin resulted in greater reductions in LDL-C and total cholesterol compared with either drug alone. No toxicities or adverse effects were observed in any cohort receiving inclisiran, either alone or in combination. In summary, inclisiran significantly inhibited PCSK9 synthesis and decreased LDL-C in cynomolgus monkeys without increasing the risk of adverse effects when coadministered with atorvastatin.

Evaluating the role of statins in prevention of preeclampsia: deeper insights into maternal cardiometabolic changes.

Pregnant women with gestational hypertension and/or preeclampsia, have derangements of atherogenic lipids in early pregnancy. Changes in maternal lipids can promote atherogenesis through endothelial injury. These alterations in serum lipid levels have been linked to adverse pregnancy outcomes and maternal morbidity and mortality. Several recent studies have examined maternal atherogenic profiles in early pregnancy, and their relationships to preeclampsia and other adverse pregnancy outcomes. Given their effects on reduction of endothelial dysfunction, inflammation, and plaque stabilization, statin therapies may have utility in prevention and treatment of preeclampsia. We sought to investigate this further by examining the association between dyslipidemia and preeclampsia, as well as the potential role of statins in the prevention of preeclampsia. We discuss the pathophysiology of placental dysfunction in preeclampsia, the safety profile of statins in pregnancy, and evaluate the potential utility of statins in pregnancy, based on recent studies, specifically for women at high risk of developing preeclampsia. The lipid-lowering, immunomodulatory, anti-inflammatory, and pleiotropic effects of statins may make them promising candidates for the prevention and treatment of preeclampsia. However, it is important to note that the clinical use of statin therapy to prevent preeclampsia has no support from current research and is not justified. A reasonably large trial of pravastatin reported no effect on preeclampsia but used limited dosing with the intervention performed only in women at high-risk of term preeclampsia. Further research in randomized controlled trials extending the parameters of statin dosing is needed to help determine if preeclampsia can be effectively prevented.

The role of statins in the prevention of preeclampsia.

Preeclampsia is a common hypertensive disorder of pregnancy associated with considerable neonatal and maternal morbidities and mortalities. However, the exact cause of preeclampsia remains unknown; it is generally accepted that abnormal placentation resulting in the release of soluble antiangiogenic factors, coupled with increased oxidative stress and inflammation, leads to systemic endothelial dysfunction and the clinical manifestations of the disease. Statins have been found to correct similar pathophysiological pathways that underlie the development of preeclampsia. Pravastatin, specifically, has been reported in various preclinical and clinical studies to reverse the pregnancy-specific angiogenic imbalance associated with preeclampsia, to restore global endothelial health, and to prevent oxidative and inflammatory injury. Human studies have found a favorable safety profile for pravastatin, and more recent evidence does not support the previous teratogenic concerns surrounding statins in pregnancy. With reassuring and positive findings from pilot studies and strong biological plausibility, statins should be investigated in large clinical randomized-controlled trials for the prevention of preeclampsia.

Effects of Statins on Memory, Cognition, and Brain Volume in the Elderly.

BACKGROUND: There is widespread consumer concern that statin use may be associated with impaired memory and cognitive decline. OBJECTIVES: This study sought to examine the association between statin use and changes in memory and global cognition in the elderly population over 6 years and brain volumes over 2 years. Interactions between statin use and known dementia risk factors were examined. METHODS: Prospective observational study of community-dwelling elderly Australians age 70 to 90 years (the MAS [Sydney Memory and Ageing Study], n = 1,037). Outcome measures were memory and global cognition (by neuropsychological testing every 2 years) and total brain, hippocampal and parahippocampal volumes (by magnetic resonance) in a subgroup (n = 526). Analyses applied linear mixed modeling, including the covariates of age, sex, education, body mass index, heart disease, diabetes, hypertension, stroke, smoking, and apolipoprotein Eε4 carriage. Interactions were sought between statin use and dementia risk factors. RESULTS: Over 6 years there was no difference in the rate of decline in memory or global cognition between statin users and never users. Statin initiation during the observation period was associated with blunting the rate of memory decline. Exploratory analyses found statin use was associated with attenuated decline in specific memory test performance in participants with heart disease and apolipoprotein Eε4 carriage. There was no difference in brain volume changes between statin users and never users. CONCLUSIONS: In community-dwelling elderly Australians, statin therapy was not associated with any greater decline in memory or cognition over 6 years. These data are reassuring for consumers concerned about statin use and risk of memory decline.

Prevalence and Predictors of Statin Treatment Among Patients With Chronic Heart Failure at a Tertiary-Care Center in Thailand.

BACKGROUND: Statins play important roles in the prevention of atherosclerotic vascular diseases; however, their beneficial effects in patients with chronic heart failure (CHF) are uncertain. This study aimed to investigate the prevalence and predictors of treatment with statins to better understand their prescribing patterns in CHF patients. METHODS: We conducted a cross-sectional study in patients with first-time diagnoses of CHF receiving care in the outpatient clinics affiliated with a tertiary-care teaching hospital in Thailand. Data were retrieved from electronic claims database. Multivariable logistic regression was used to identify independent predictors of treatment with statins. RESULTS: A total of 3445 patients were included in this study. Among them, 1908 (55.4%) were prescribed statins, with most of them (89.7%) receiving simvastatin 20 mg daily. Factors independently associated with the statin treatment include the following: being male (odds ratio [OR] = 1.21, 95% confidence interval [CI] = 1.02-1.44, P = .03); diagnoses of dyslipidemia (OR = 4.88, 95% CI = 3.88-6.14, P < .001), ischemic heart disease (OR = 2.71, 95% CI = 2.18-3.36, P < .001), diabetes (OR = 1.95, 95% CI = 1.55-2.46, P < .001), or cerebrovascular disease (OR = 1.64, 95% CI = 1.12-2.40, P = .01); and receipt of angiotensin-converting enzyme inhibitors (OR = 3.44, 95% CI = 2.87-4.13, P < .001), aspirin (OR = 2.79, 95% CI = 2.30-3.40, P < .001), non-dihydropyridine calcium channel blockers (OR = 2.35, 95% CI = 1.30-4.24, P = .004), organic nitrates (OR = 2.04, 95% CI = 1.16-3.58, P = .01), beta-blockers (OR = 1.51, 95% CI = 1.23-1.84, P < .001), and digoxin (OR = 0.65, 95% CI = 0.50-0.86, P = .002). CONCLUSIONS: Statins were prescribed to more than half of the newly diagnosed CHF patients. Independent predictors of statin treatments include hypercholesterolemia and comorbidities indicative of high atherosclerotic vascular risk as well as drugs recommended as cardiovascular protective therapy for CHF patients.

The Role of Perioperative Statin Use in the Prevention of Delirium After Total Knee Replacement Under Spinal Anesthesia.

BACKGROUND: The relationship between statin use and incidence of postoperative delirium (POD) is controversial. We investigated the association between perioperative statin use and occurrence of delirium after total knee arthroplasty (TKA) under spinal anesthesia. METHODS: We retrospectively reviewed the electronic medical records of patients who underwent TKA under spinal anesthesia at a single tertiary care hospital between January 2005 and October 2017. POD incidence was recorded for patients who received statins continuously from 1 month before surgery until discharge and for patients who did not receive any statins. Univariable and multivariable logistic regression analyses were conducted to investigate an association between occurrence of POD and perioperative statin use. RESULTS: In total, 6020 procedures were included, and 992 (16.4%) were associated with perioperative statin use. POD was confirmed for 304 (5.0%) procedures. The statin group showed a 1.7% significant lower incidence (P = .017) of POD (35/992, 3.5%) than the no statin group (1420/5,028, 5.4%). In multivariable logistic regression analysis, the POD incidence in the statin group was 34% lower than that in the no statin group (odds ratio [OR] 0.66, 95% confidence interval [CI] 0.45-0.97, P = .036]. Moreover, the POD incidence was decreased by 37% (OR 0.63, 95% CI 0.40-0.99, P = .047) and 79% (OR 0.21, 95% CI 0.05-0.88, P = .033) respectively, when atorvastatin and simvastatin were administered. CONCLUSION: Continuous perioperative statin use may be associated with a significantly lower risk of delirium after TKA under spinal anesthesia; simvastatin was the most effective statin for POD prevention.

Effect of hyperlipidemia on response to nonsurgical periodontal therapy: Statin users versus nonusers.

OBJECTIVE: To evaluate the response to nonsurgical periodontal therapy among hyperlipidemic subjects and whether statin use by hyperlipidemic subjects influences the response. MATERIALS AND METHODS: This study was conducted on 107 chronic periodontitis subjects (35 normolipidemic [NL] controls, 36 hyperlipidemics on nonpharmacological therapy and 36 hyperlipidemics on statins). Periodontal (plaque index, gingival index [GI], probing depth [PD], and clinical attachment level [CAL]) and biochemical (plasma triglyceride [TG], total cholesterol [TC], low-density lipoprotein cholesterol [LDL-C], and high-DL-C [HDL-C] levels) examination was done at baseline and 3 months after nonsurgical periodontal treatment. RESULTS: Both the NL and statin groups exhibited significantly greater improvement in GI as compared to the hyperlipidemic group on nonpharmacological therapy (P = 0.004 and 0.006, respectively). Mean change in PD correlated negatively with baseline TC (r = -0.306) and LDL-C (r = -0.360) while mean change in GI positively correlated with baseline HDL-C (r = 0.219). Regression analyses revealed that mean change in PD was negatively associated with LDL-C (ß = -0.358, P < 0.001) while mean change in GI was positively associated with HDL-C (ß = 0.219, P = 0.023). CONCLUSIONS: While higher baseline lipid levels were somewhat detrimental to the resolution of inflammation postperiodontal treatment, the inclusion of statin therapy among hyperlipidemic subjects seemed to improve clinical response as compared to those devoid of the drug. The findings of the study are suggestive of a possible adjunctive role of statins in periodontal treatment that warrants future studies.

Effect of previous statin therapy in patients with acute coronary syndrome and percutaneous coronary intervention.

BACKGROUND AND OBJECTIVES: Statin therapy after percutaneous coronary intervention (PCI) has been associated with reduced major adverse cardiovascular events (MACE). However, it has been less clear as to whether statin therapy before acute coronary syndrome (ACS) is beneficial. We studied the effect of previous statin therapy, initiated ≥1 month before PCI, on the outcome of patients with ACS who had undergone early invasive strategies. SUBJECTS AND METHODS: We stratified 479 consecutive patients with ACS who had undergone PCI, according to preprocedural statin administration as follows: previous statin-treated patients (statin group, n=237) and statin-naive patients (control group, n=242). The incidence of periprocedural myocardial infarction (MI) and in-hospital MACE was assessed. RESULTS: The incidence of Braunwald class III angina and MI presentation were significantly lower in the statin group than in the control group. Angiographic and procedural characteristics were similar between the two groups; however, slow/no reflow phenomenon occurred more frequently in the control group. After PCI, the incidence of periprocedural MI was higher in the control group than in the statin group (6.6% vs. 2.1%, p=0.016). Multivariate analysis revealed that no prior use of statin {odds ratio (OR)=2.8; 95% confidence interval (CI)=1.1-7.2; p=0.038), procedural complication (OR=4.0; 95% CI=1.5-10.5; p=0.004), stent overlap (OR=4.7; 95% CI=1.3-16.4; p=0.015), and old age (OR=3.2; 95% CI=1.2-8.0; p=0.016) were independent predictors for in-hospital MACE. CONCLUSION: Previous statin therapy before ACS was associated with milder clinical presentation and lower incidence of in-hospital MACE after early invasive strategies. The beneficial outcome is attributable to a significant reduction in periprocedural MI after PCI.