Parkinson’s Disease Progression and Statins: Hydrophobicity Matters

Background: Recent randomized clinical trials using hydrophobic statins reported no influence on Parkinson’s disease (PD) clinical progression. Hydrophobicity is a key determinant for blood-brain barrier penetrance. Objective: Investigate a potential effect of statins on PD progression. Methods: Statin use was determined at baseline and subtyped according to hydrophobicity in 125 PD patients participated PD Biomarker Program (PDBP, 2012–2015) at our site. Clinical (N = 125) and susceptibility MRI (N = 86) data were obtained at baseline and 18-months. Movement Disorders Society-Unified PD Rating Scales were used to track progression of non-motor (MDS-UPDRS-I) and motor (MDS-UPDRS-II) symptoms, and rater-based scores (MDS-UPDRS-III) of patients in the “on” drug state. R2 * values were used to capture pathological progression in the substantia nigra. Associations between statin use, its subtypes, and PD progression were evaluated with linear mixed effect regressions. Results: Compared to statin non-users, overall statin or lipophilic statin use did not significantly influence PD clinical or imaging progression. Hydrophilic statin users, however, demonstrated faster clinical progression of non-motor symptoms [MDS-UPDRS-I (β= 4.8, p = 0.010)] and nigral R2 * (β= 3.7, p = 0.043). A similar trend was found for MDS-UPDRS-II (β= 3.9, p = 0.10), but an opposite trend was observed for rater-based MDS-UPDRS-III (β= –7.3, p = 0.10). Compared to lipophilic statin users, hydrophilic statin users also showed significantly faster clinical progression of non-motor symptoms [MDS-UPDRS-I (β= 5.0, p = 0.020)], but R2 * did not reach statistical significance (β= 2.5, p = 0.24). Conclusion: This study suggests that hydrophilic, but not lipophilic, statins may be associated with faster PD progression. Future studies may have clinical and scientific implications.

Association between CYP3A5 Polymorphism and Statin-Induced Adverse Events: A Systemic Review and Meta-Analysis

Purpose: Cytochrome P450 (CYP) is involved in the metabolism of statins; CYP3A5 is the main enzyme responsible for lipophilic statin metabolism. However, the evidence of the association between CYP3A5*3 polymorphism and the risk of statin-induced adverse events remains unclear. Therefore, this study aimed to perform a systematic review and meta-analysis to investigate the relationship between the CYP3A5*3 polymorphism and the risk of statin-induced adverse events. Methods: The PubMed, Web of Science, and EMBASE databases were searched for qualified studies published until August 2020. Observational studies that included the association between statin-induced adverse events and the CYP3A5*3 polymorphism were reviewed. The odds ratios (ORs) and 95% confidence intervals (CIs) were evaluated to assess the strength of the relationship. The Mantel–Haenszel method was used to provide the pooled ORs. Heterogeneity was estimated with I2 statistics and publication bias was determined by Begg’s and Egger’s test of the funnel plot. Data analysis was performed using Review Manager (version 5.4) and R Studio (version 3.6). Results: In total, data from 8 studies involving 1614 patients were included in this meta-analysis. The CYP3A5*3 polymorphism was found to be associated with the risk of statin-induced adverse events (*3/*3 vs. *1/*1 + *1/*3: OR = 1.40, 95% CI = 1.08–1.82). For myopathy, the pooled OR was 1.30 (95% CI: 0.96–1.75). The subgroup analysis of statin-induced myopathy revealed a trend, which did not achieve statistical significance. Conclusions: This meta-analysis demonstrated that the CYP3A5*3 polymorphism affected statin-induced adverse event risk. Therefore, CYP3A5 genotyping may be useful to predict statin toxicity.

Abstract P228: Mineralocorticoid Receptor Antagonist And Lipophilic Statin Reduce Urinary Kidney Injury Marker 1 (Kim-1) In Female Rats Receiving L-NAME And Angiotensin II

Statins have beneficial cardiovascular effects some of which appear to be cholesterol-independent and the mechanisms for these latter effects are still unclear. Urinary kidney injury molecule-1 (Kim-1) is a sensitive biomarker of acute renal injury and in clinical studies predicts cardiovascular disease. Aldosterone causes both cardiac and renal injury and a few studies suggest that aldosterone is associated with increased Kim-1. Therefore, in this study we used the N omega-nitro-L-arginine methyl ester (L-NAME)/Angiotensin II (AngII) model of cardiorenal injury to determine whether urinary Kim-1 correlates with the degree of cardiac injury/stroke and whether blockade of the mineralocorticoid receptor prevents increases in urinary Kim-1. Further, since our group reported previously that lipophilic statins, but not hydrophilic statins reduce aldosterone levels, we also asked whether administration of either a lipophilic or a hydrophilic statin affects Kim-1 levels. To test the hypothesis, 8-10 week-old, female Wistar rats consuming liberal salt diet (1.6% Na + ) were randomized to the following conditions for 14 days: control; L-NAME (0.2 mg/ml in drinking water)/AngII (225ug/kg/day for days 12-14 only); L-NAME/AngII + eplerenone (100 mg/kg/day p.o.); L-NAME/Ang II + pravastatin (hydrophilic statin-20 mg/kg/day p.o.); L-NAME/Ang II + simvastatin (lipophilic statin-20 mg/kg/day p.o.) groups. Groups treated with L-NAME/AngII had significantly higher blood pressure, urine aldosterone and plasma aldosterone levels compared to control. L-NAME/AngII treatment increased cardiac injury/stroke composite score, including cardiac histopathology evaluation and stroke status, and 24 hour-urinary Kim-1 compared to control. Eplerenone reduced cardiac injury/stroke composite score (p=0.04) and both eplerenone and simvastatin reduced urinary Kim-1 (p=0.0046, p=0.031, respectively). Pravastatin had no effect on these damage markers. Urinary Kim-1 correlated with cardiac injury/stroke composite score (p<0.0001, spearman ranked correlation=0.67). In conclusion, in a rat model of L-NAME/AngII induced cardiovascular injury, urinary Kim-1 predicts cardiac/stroke injury; eplerenone and simvastatin reduced urinary Kim-1.

Acute Statin Administration Reduces Levels of Steroid Hormone Precursors

Cholesterol-lowering statin drugs are used by approximately 25% of US adults 45 years of age and older and frequency of use is even higher among the elderly. Cholesterol provides the substrate for steroid hormone synthesis and its intracellular concentrations are tightly regulated. Our aim was to evaluate whether statin use acutely changes the circulating levels of cortisol, other glucocorticoid precursor molecules and their metabolites. Fourteen subjects not taking statins were administered a single oral dose (2 mg) of pitavastatin. Blood samples collected at baseline and 24 h post-treatment were analyzed for plasma cholesterol and steroid hormone profile. A parallel study in mice entailed the administration of atorvastatin (10 mg/kg) via orogastric delivery for three consecutive days. Cholesterol and corticosterone levels were quantified at baseline and at 1-day and 1-week post-treatment. Several precursor molecules in the steroidogenic pathway (corticosterone, cortisone, and 11-deoxycortisol) were significantly decreased 24 h after administration of a single dose of pitavastatin in human study subjects. Their circulating cholesterol concentrations were unchanged. In mice, there were no significant differences in serum cholesterol or corticosterone at 1-day or 1-week post-treatment compared to both pre-treatment baseline levels and control group levels. We conclude that acute dysregulation of the production of certain glucocorticoid precursor molecules was observed after a single treatment with a lipophilic statin drug. This may be of clinical relevance for individuals with underlying or subclinical adrenal insufficiency.

The Different Cardiovascular Outcomes Between Long-Term Efficacy of Hydrophilic and Lipophilic Statin Therapy in Both Asian Diabetic Sexes

Purpose: To evaluate the long-term efficacy of hydrophilic and lipophilic statin therapy for cardiovascular outcomes in Asian diabetic patients. Method: Newly diagnosed cases of type 2 diabetes during the period from January 2000 to December 2011 were divided into 2 cohorts on the basis of their statin use, namely hydrophilic statin and lipophilic statin. We used Cox proportional hazard regression models to analyze the risks of cardiovascular outcomes. Result: In this study, 12 896 patients used statin, including 4259 patients using hydrophilic statin and 8637 patients using lipophilic statin. With 12-year follow-up, higher incidence rate of coronary artery disease and stroke was noted in the lipophilic statin use instead of hydrophilic statin use. Conclusion: According to our long-term cohort study, hydrophilic statin use may be a better choice than lipophilic statin to reduce cardiovascular events in Asian diabetic patients.

Would Lipophilic Statin Therapy as a Prognostic Factor Improve Survival in Patients With Uterine Cervical Cancer?

ObjectivesIn vitro studies showed that lipophilic statins inhibit cell growth, adhesion, and invasion and induce apoptosis in cancer cell lines. In uterine cervical cancer, several important factors including age, stage, anemia, lymphovascular invasion, lymph node metastases, and parametrial spread were known to significantly predict survival. We investigated whether statin therapy as a prognostic factor would significantly predict survival in cervical cancer.MethodsPatients with stages IB to IV cervical cancer who received radical hysterectomy and/or para-aortic lymph node dissection were included. The statin-use group was identified as patients who were continuously prescribed with lipophilic statins from prediagnostic period of the cancer.ResultsThe baseline characteristics of both statin-use group and control group were comparable. During a median follow-up of 36.6 months, progression-free survival and overall survival of the statin-use group were significantly higher than the control group (P< 0.001 andP= 0.004, respectively). In multivariate analysis, the statin-use group had an independent prognostic significance compared with other prognostic factors (progression-free survival: hazards ratio = 0.062, 95% confidence interval = 0.008–0.517,P= 0.010; overall survival: hazards ratio = 0.098, 95% confidence interval = 0.041–0.459,P= 0.032).ConclusionsIn the present study, continuous lipophilic statin therapy from the prediagnostic period of uterine cervical cancer could reflect favorable outcome, independently.