Pharmacogenomics of statins: lipid response and other outcomes in Brazilian cohorts.

Statins are inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase, a key enzyme in cholesterol biosynthesis, that are highly effective in reducing plasma low-density lipoprotein (LDL) cholesterol and decreasing the risk of cardiovascular events. In recent years, a multitude of variants in genes involved in pharmacokinetics (PK) and pharmacodynamics (PD) have been suggested to influence the cholesterol-lowering response. However, the vast majority of studies have analyzed the pharmacogenetic associations in populations in Europe and the USA, whereas data in other populations, including Brazil, are mostly lacking. This narrative review provides an update of clinical studies on statin pharmacogenomics in Brazilian cohorts exploring lipid-lowering response, adverse events and pleiotropic effects. We find that variants in drug transporter genes (SLCO1B1 and ABCB1) positively impacted atorvastatin and simvastatin response, whereas variants in genes of drug metabolizing enzymes (CYP3A5) decreased response. Furthermore, multiple associations of variants in PD genes (HMGCR, LDLR and APOB) with statin response were identified. Few studies have explored statin-related adverse events, and only ABCB1 but not SLCO1B1 variants were robustly associated with increased risk in Brazil. Statin-related pleiotropic effects were shown to be influenced by variants in PD (LDLR, NR1H2) and antioxidant enzyme (NOS3, SOD2, MTHFR, SELENOP) genes. The findings of these studies indicate that statin pharmacogenomic associations are distinctly different in Brazil compared to other populations. This review also discusses the clinical implications of pharmacogenetic studies and the rising importance of investigating rare variants to explore their association with statin response.

Statin Therapy and Intensity: Prognosis in Patients with Myocardial Injury.

BACKGROUND: No guideline-directed pharmacological therapy has been established for patients with myocardial injury without type 1 myocardial infarction. We investigated the impact of statin treatment in patients with myocardial injury. METHODS: Patients with myocardial injury (nonischemic acute and chronic myocardial injury), type 2 myocardial infarction, and type 1 myocardial infarction with at least 1 emergency department visit for chest pain from 2011 to 2014 were included. Dispensed prescriptions of all types of statins with dosage within 180 days from the index visit were collected. In total, 2054 patients were divided into 3 groups: 1) acute myocardial injury (type 2 myocardial infarction, acute nonischemic myocardial injury), 2) chronic myocardial injury, and 3) type 1 myocardial infarction. We estimated the adjusted hazard ratio with 95% confidence interval for death with low- (reference), moderate-, and high-intensity statin therapy. RESULTS: The mean follow-up was 4.2 ± 1.8 years. Only 13% of patients with acute and chronic myocardial injury and 30% with type 1 myocardial infarction were treated with high-intensity statins. Adjusted mortality rates were higher in patients with acute and chronic myocardial injury than in those with type 1 myocardial infarction across all statin intensity categories. In patients with type 1 myocardial infarction, the adjusted mortality risk was 20% (hazard ratio, 0.80; 95% confidence interval, 0.36-1.77) lower in patients with high-intensity therapy. Point estimates in the adjusted models indicated similar associations between statin intensity and mortality risk in patients with acute and chronic myocardial injury. CONCLUSION: Patients with myocardial injury may benefit from high-intensity statin treatment, but the associations were not statistically significant when adjusting for confounders.

Comparative Hepatic and Intestinal Efflux Transport of Statins.

Previous studies have shown that lipid-lowering statins are transported by various ATP-binding cassette (ABC) transporters. However, because of varying methods, it is difficult to compare the transport profiles of statins. Therefore, we investigated the transport of 10 statins or statin metabolites by six ABC transporters using human embryonic kidney cell-derived membrane vesicles. The transporter protein expression levels in the vesicles were quantified with liquid chromatography-tandem mass spectrometry and used to scale the measured clearances to tissue levels. In our study, apically expressed breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp) transported atorvastatin, fluvastatin, pitavastatin, and rosuvastatin. Multidrug resistance-associated protein 3 (MRP3) transported atorvastatin, fluvastatin, pitavastatin, and, to a smaller extent, pravastatin. MRP4 transported fluvastatin and rosuvastatin. The scaled clearances suggest that BCRP contributes to 87%-91% and 84% of the total active efflux of rosuvastatin in the small intestine and the liver, respectively. For atorvastatin, the corresponding values for P-gp-mediated efflux were 43%-79% and 66%, respectively. MRP3, on the other hand, may contribute to 23%-26% and 25%-37% of total active efflux of atorvastatin, fluvastatin, and pitavastatin in jejunal enterocytes and liver hepatocytes, respectively. These data indicate that BCRP may play an important role in limiting the intestinal absorption and facilitating the biliary excretion of rosuvastatin and that P-gp may restrict the intestinal absorption and mediate the biliary excretion of atorvastatin. Moreover, the basolateral MRP3 may enhance the intestinal absorption and sinusoidal hepatic efflux of several statins. Taken together, the data show that statins differ considerably in their efflux transport profiles. SIGNIFICANCE STATEMENT: This study characterized and compared the transport of atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin acid and four atorvastatin metabolites by six ABC transporters (BCRP, MRP2, MRP3, MRP4, MRP8, P-gp). Based on in vitro findings and protein abundance data, the study concludes that BCRP, MRP3, and P-gp have a major impact in the efflux of various statins. Together with in vitro metabolism, uptake transport, and clinical data, our findings are applicable for use in comparative systems pharmacology modeling of statins.

Comparative Hepatic and Intestinal Metabolism and Pharmacodynamics of Statins.

This study aimed to comprehensively investigate the in vitro metabolism of statins. The metabolism of clinically relevant concentrations of atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, and their metabolites were investigated using human liver microsomes (HLMs), human intestine microsomes (HIMs), liver cytosol, and recombinant cytochrome P450 enzymes. We also determined the inhibitory effects of statin acids on their pharmacological target, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. In HLMs, statin lactones were metabolized to a much higher extent than their acid forms. Atorvastatin lactone and simvastatin (lactone) showed extensive metabolism [intrinsic clearance (CLint) values of 3700 and 7400 µl/min per milligram], whereas the metabolism of the lactones of 2-hydroxyatorvastatin, 4-hydroxyatorvastatin, and pitavastatin was slower (CLint 20-840 µl/min per milligram). The acids had CLint values in the range <0.1-80 µl/min per milligram. In HIMs, only atorvastatin lactone and simvastatin (lactone) exhibited notable metabolism, with CLint values corresponding to 20% of those observed in HLMs. CYP3A4/5 and CYP2C9 were the main statin-metabolizing enzymes. The majority of the acids inhibited HMG-CoA reductase, with 50% inhibitory concentrations of 4-20 nM. The present comparison of the metabolism and pharmacodynamics of the various statins using identical methods provides a strong basis for further application, e.g., comparative systems pharmacology modeling. SIGNIFICANCE STATEMENT: The present comparison of the in vitro metabolic and pharmacodynamic properties of atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin and their metabolites using unified methodology provides a strong basis for further application. Together with in vitro drug transporter and clinical data, the present findings are applicable for use in comparative systems pharmacology modeling to predict the pharmacokinetics and pharmacological effects of statins at different dosages.

Statin Use in Older Adults with Stable Atherosclerotic Cardiovascular Disease.

BACKGROUND/OBJECTIVES: Older adults (>75 years of age) represent two-thirds of atherosclerotic cardiovascular disease (ASCVD) deaths. The 2013 and 2018 American multi-society cholesterol guidelines recommend using at least moderate intensity statins for older adults with ASCVD. We examined annual trends and statin prescribing patterns in a multiethnic population of older adults with ASCVD. DESIGN: Retrospective longitudinal study using electronic health record (EHR) data from 2007 to 2018. SETTING: A large multi-specialty health system in Northern California. PARTICIPANTS: A total of 24,651 adults older than 75 years with ASCVD. MEASUREMENTS: Statin prescriptions for older adults with known ASCVD were trended over time. Multivariable regression models were used to identify predictors of statin prescription (logistic) after controlling for relevant demographic and clinical factors. RESULTS: The study cohort included 24,651 patients older than 75 years; 48% were women. Although prescriptions for moderate/high intensity statins increased over time for adults over 75, fewer than half of the patients (45%) received moderate/high intensity statins in 2018. Women (odds ratio (OR) = 0.77; 95% confidence interval (CI) = 0.74, 0.80), patients who had heart failure (OR = 0.69; 95% CI = 0.65, 0.74), those with dementia (OR = 0.88; 95% CI = 0.82, 0.95) and patients who were underweight (OR = 0.64; 95% CI = 0.57, 0.73) were less likely to receive moderate/high intensity statins. CONCLUSIONS: Despite increasing prescription rates between 2007 and 2018, guideline-recommended statins remained underused in older adults with ASCVD, with more pronounced disparities among women and those with certain comorbidities. Future studies are warranted to examine reasons for statin underuse in older adults with ASCVD.

Comparison between high and low potency statins in the incidence of open-angle glaucoma: A retrospective cohort study in Japanese working-age population.

Some findings on the association between glaucoma and statins in the Asian population have been reported. We conducted a retrospective cohort study using health insurance claims data maintained by the JMDC Inc., which comprises data on about three million individuals representing 2.4% of the Japanese population. The association between the potency of statins and open-angle glaucoma in Japanese working-age population was examined using a commercially available health insurance claims and enrollment database. We identified 117,036 patients with a prescription of statins between January 1, 2005 and March 31, 2014; 59,535 patients were selected as new statin users. Of these, 49,671 (83%) patients without glaucoma who were prescribed statins for the first time were part of the primary analysis. New users of statin were defined as those with a prescription of statin at the beginning of the study, but without a prescription six months earlier. The cohort comprised 29,435 (59%) and 20,236 (41%) patients with a prescription of high-potency statin (atorvastatin and rosuvastatin) and low-potency statin (pravastatin, fluvastatin, pitavastatin, and simvastatin), respectively. Using Cox proportional hazards regression analysis, hazard ratios (HRs) were estimated for glaucoma adjusted for baseline characteristics. Although some baseline characteristics were not similar between the high-potency and low-potency statin groups, the standardized difference for all covariates was less than 0.1. No associations were found between high-potency statin use and glaucoma (adjusted HR = 1.08; 95% confidence interval, 0.93-1.24) in the primary analyses, using the risk for glaucoma in the low-potency statin group as reference. The risk of glaucoma with individual statin use was not significantly different from that with pravastatin. No significant association was found between high-potency statins and the increased risk of glaucoma in Japanese working-age population. Further studies are needed to examine the association between statins and glaucoma in the elderly population.

Statin Use and the Risk of Prostate Cancer in Ischemic Heart Disease Patients in Taiwan.

Patients with ischemic heart disease (IHD) are more likely to be diagnosed with prostate cancer. Statins, which are widely used in such patients, are shown to modify the risk of prostate cancer. To clarify the association between statin use and the risk of prostate cancer among patients with higher risk of developing prostate cancer in Taiwan, a cohort of 26,628 men with IHD and aged between 55 and 100 were acquired from the National Health Insurance Research Database and followed over a period of 8 years. The risk of prostate cancer was calculated by time-dependent Cox regression model. Statin use was associated with significantly lower risk of both total and advanced prostate cancer (adjusted hazard ratio (HR): 0.719, 95% confidence interval (CI): 0.570-0.908; adjusted HR: 0.718, 95% CI: 0.530-0.972 respectively). In Taiwan IHD population, the reduction in risk of prostate cancer was observed in statin users as compared with nonusers.

Comparative risk of lipophilic and hydrophilic statins on incident depression: A retrospective cohort study.

OBJECTIVES: To evaluate the risk of new-onset depression in a cohort of US adult patients initiating lipophilic statin therapy compared to hydrophilic statin therapy. DESIGN: Retrospective cohort study. SETTING: Large US commercial claims database PARTICIPANTS: 1:1 propensity score matched cohort of lipophilic (atorvastatin, lovastatin and simvastatin) and hydrophilic (pravastatin and rosuvastatin) statin initiators between January 2009 to June 2015. OUTCOME: New onset of depression. RESULTS: In a propensity-score matched cohort of 299,298 statin initiators, the crude incidence of depression in the hydrophilic and lipophilic group was 136.6 and 142.8 per 10,000 person-years respectively. Compared to hydrophilic statin use, lipophilic statin use was not associated with a statistically significant increase in the risk of depression, adjusted HR 1.05 (95% CI, 1.00-1.10, p = 0.078) and excess incidence of 6.3 (95% CI, -0.7-13.7) per 10,000 person-years. Findings were consistent across the subgroups of patients with history of psychiatric conditions HR 1.05 (95% CI, 0.94-1.16, p = 0.41), and those initiating statins for primary or secondary prevention, HR 1.03 (95% CI, 0.97-1.10, p = 0.33) and 1.07 (95% CI, 0.99-1.16, p = 0.10) respectively. Within individual lipophilic statins, only simvastatin was associated with a moderate increase in the risk of depression HR 1.09 (95% CI, 1.02-1.16, p = 0.003), followed by lovastatin HR 1.07 (95% CI, 0.93-1.24, p = 0.34) and atorvastatin HR 1.05 (95% CI, 0.97-1.13, p = 0.27). LIMITATIONS: Findings are generalizable to patients with commercial insurance. CONCLUSIONS: Lipophilic statin use was not associated with a significant increase in the risk of incident depression.

A Brief Drug Class Review: Considerations for Statin Use, Toxicity, and Drug Interactions.

For approximately 30 years, statins have been effectively used to control cholesterol, thereby reducing the morbidity and mortality associated with cardiovascular disease. Evidence-based recommendations regarding how these drugs are dosed and used have changed significantly through the years. There are seven statins approved for use in the United States, and although the mechanism of action pertaining to cholesterol reduction is the same for all statins, each has its own specific pharmacologic profile. One unique aspect of statin dosing is understanding the potential drug interactions associated with statin use; interactions can occur with all statins, but the mechanism and type of interaction can vary significantly among drugs. These interactions can result in significant elevations in statin blood concentrations, thereby increasing the risk of the adverse effects of statins, the most significant of which is muscle toxicity. Practitioners who care for patients receiving statins should understand the pharmacologic differences among these drugs, as well as the varied drug interaction potential that all statins possess.

Impact of Different Types of Statins on Clinical Outcomes in Patients Hospitalized for Ischemic Heart Failure.

INTRODUCTION: The effect of statins on risk of heart failure (HF) hospitalization and lethal outcome remains dubious. AIM: To investigate whether statin therapy improves clinical outcomes in patients hospitalized for ischemic heart failure (HF), to compare the efficacy of lipophilic and hydrophilic statins and to investigate which statin subtype provides better survival and other outcome benefits. MATERIAL AND METHODS: Total amount of 155 patients in the study were admitted to the Clinic for Cardiology, Rheumatology and Vascular diseases in Clinical Center University of Sarajevo in the period from January 2014- December 2017. Inclusion criteria was HF caused by ischemic coronary artery disease upon admission. For each patient the following data were obtained: gender, age, comorbidities and medications on discharge. New York Heart Association (NYHA) class for heart failure was determined by physician evaluation and left ventricle ejection fraction (LVEF) was determined by echocardiography. The patients were followed for a period of two years. Outcome points were: rehospitalization, in-hospital death, mortality after 6 months, 1 year and 2 years. All-cause mortality included cardiovascular events or worsening heart failure. RESULTS: Overall, 58.9% of HF patients received statin therapy, with 33.9% patients receiving atorvastatin and 25.0% rosuvastatin therapy. The most frequent rehospitalization was in patients without statin therapy (66.7%), followed by patients on rosuvastatin (64.1%), and atorvastatin (13.2%), with statistically significant difference p = 0.001 between the groups. Mortality after 6 months, 1 year and 2 years was the most frequent in patients without statin therapy with a statistically significant difference (p = 0.001). Progression of HF accounted for 31.7% of mortality in patients without statin therapy, 12.8% in patients on rosuvastatin therapy and 3.8% in patients on atorvastatin therapy (p = 0.004). CONCLUSION: Lipophilic statin therapy is associated with substantially better long-term outcomes in patients with HF.

Statins may facilitate Parkinson's disease: Insight gained from a large, national claims database.

OBJECTIVE: Using a large U.S. claims database (MarketScan), we investigated the controversy surrounding the role of statins in Parkinson's disease (PD). METHODS: We performed a retrospective case-control analysis. First, we identified 2322 incident PD cases having a minimum of 2.5 years of continuous enrollment prior to earliest diagnosis code or prescription of antiparkinson medication. A total of 2322 controls were then matched individually by age, gender, and a follow-up window to explore the relationship of statin use with incident PD. RESULTS: Statin usage was significantly associated with PD risk, with the strongest associations being for lipophilic (odds ratio = 1.58, P < .0001) versus hydrophilic (odds ratio = 1.19, P = .25) statins, statins plus nonstatins (odds ratio = 1.95, P < .0001), and for the initial period after starting statins (<1 year odds ratio = 1.82, 1-2.5 years odds ratio = 1.75, and ≥2.5 years odds ratio = 1.37; Ptrend < .0001). CONCLUSION: The use of statin (especially lipophilics) was associated with higher risk of PD, and the stronger association in initial use suggests a facilitating effect. © 2017 International Parkinson and Movement Disorder Society.

Comparison of Effects of Different Statins on Contrast-Induced Acute Kidney Injury in Rats: Histopathological and Biochemical Findings.

Statins are a promising new strategy to prevent contrast-induced acute kidney injury (CI-AKI). In this study we compared the ameliorative effect of different statins in a rat model of CI-AKI. Sprague-Dawley rats were divided into five groups: control group; CI-AKI group; CI-AKI + rosuvastatin group (10 mg/kg/day); CI-AKI + simvastatin group (80 mg/kg/day); and CI-AKI + atorvastatin group (20 mg/kg/day). CI-AKI was induced by dehydration for 72 hours, followed by furosemide intramuscular injection 20 minutes before low-osmolar contrast media (CM) intravenous injection. Statins were administered by oral gavage once daily for 3 consecutive days before CM injection and once 4 hours after CM injection. Rats were sacrificed 24 hours after CM injection, and renal function, kidney histopathology, nitric oxide (NO) metabolites, and markers of oxidative stress, inflammation, and apoptosis were evaluated. The results showed that atorvastatin and rosuvastatin but not simvastatin ameliorated CM-induced serum creatinine elevation and histopathological alterations. Atorvastatin and rosuvastatin showed similar effectiveness against CM-induced oxidative stress, but simvastatin was less effective. Atorvastatin was most effective against NO system dysfunction and cell apoptosis, whereas rosuvastatin was most effective against inflammation. Our findings indicate that statins exhibit differential effects in preventing CI-AKI when given at equivalent lipid-lowering doses.

Statins and risk for new-onset diabetes mellitus: A real-world cohort study using a clinical research database.

Although concern regarding the increased risk for new-onset diabetes mellitus (NODM) after statin treatment has been raised, there has been a lack of evidence in real-world clinical practice, particularly in East Asians. We investigated whether statin use is associated with risk for NODM in Koreans. We conducted a retrospective cohort study using the clinical research database from electronic health records. The study cohort consisted of 8265 statin-exposed and 33,060 matched nonexposed patients between January 1996 and August 2013. Matching at a 1:4 ratio was performed using a propensity score based on age, gender, baseline glucose levels (mg/dL), and hypertension. The comparative risks for NODM with various statins (atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin) were estimated by both statin exposure versus matched nonexposed and within-class comparisons. The incidence of NODM among the statin-exposed group (6.000 per 1000 patient-years [PY]) was higher than that of the nonexposed group (3.244 per 1000 PY). The hazard ratio (HR) of NODM after statin exposure was 1.872 (95% confidence interval [CI], 1.432-2.445). Male gender (HR, 1.944; 95% CI, 1.497-2.523), baseline glucose per mg/dL (HR, 1.014; 95% CI, 1.013-1.016), hypertension (HR, 2.232; 95% CI, 1.515-3.288), and thiazide use (HR, 1.337; 95% CI, 1.081-1.655) showed an increased risk for NODM, while angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker showed a decreased risk (HR, 0.774; 95% CI, 0.668-0.897). Atorvastatin-exposed patients showed a higher risk for NODM than their matched nonexposed counterparts (HR, 1.939; 95% CI, 1.278-2.943). However, the risk for NODM was not significantly different among statins in within-class comparisons. In conclusion, an increased risk for NODM was observed among statin users in a practical healthcare setting in Korea.

The Risk of Hepatotoxicity, New Onset Diabetes and Rhabdomyolysis in the Era of High-Intensity Statin Therapy: Does Statin Type Matter?

The 2013 American College of Cardiology/American Heart Association guidelines on cholesterol management have placed greater emphasis on high-intensity statin dosing for those with known cardiovascular disease or diabetes mellitus. Differences in risk of hepatotoxicity, new onset diabetes and rhabdomyolysis specifically between the high-intensity statins and the most common moderate-intensity statin, simvastatin, were not found to a significant degree in this review. Rather, baseline characteristics and drug-drug interactions (DDIs) appear to be more important regarding the risk of these adverse effects. Pharmacogenetic differences in statin metabolism may explain individual susceptibility, however genetic testing is not felt to be cost effective at this time. More importantly, statin choice should consider concomitant use of the many prevalent CYP3A4 inhibitors or inducers, and when present, rosuvastatin selection is recommended to reduce DDIs and risk of statin-induced adverse effects.

Systematic review with network meta-analysis: statins and risk of hepatocellular carcinoma.

OBJECTIVES: Usage of statins is suggested to decrease the incidence of HCC. When it comes to different statin subtypes, the chemopreventive action remains controversial. We aim to compare the usage of different statins and reduction of HCC risk. METHODS: We searched PubMed, Embase.com and Cochrane Library database up to August 10, 2015. Duplicated or overlapping reports were eliminated. We performed a traditional pair-wise meta-analysis and a Bayesian network meta-analysis to compare different treatments with a random-effects model. RESULTS: We reviewed five observational studies enrolling a total of 87127 patients who received at least two different treatment strategies including rosuvastatin, atorvastatin, simvastatin, pravastatin, fluvastatin, cerivastatin, and lovastatin or observation alone. Direct comparisons showed that usage of atorvastatin (OR 0.63, 95%CI 0.45-0.89) and fluvastatin (OR 0.58, 95%CI 0.40-0.85) could significantly cut the risk of liver cancer. The difference of indirect comparisons between the included regimens is not statistically significant. However, usage of all types of statins, such as fluvastatin (RR 0.55, 95%CI 0.26-1.11), atorvastatin (RR 0.59, 95%CI 0.30-1.16), simvastatin (RR 0.69, 95%CI 0.38-1.25), cerivastatin (RR 0.71, 95%CI 0.19-2.70), pravastatin (RR 0.72, 95%CI 0.37-1.45), lovastatin (RR 0.81, 95%CI 0.34-1.96) and rosuvastatin (RR 0.92, 95%CI 0.44-1.80), appeared to be superior to observation alone. Notably, fluvastatin was hierarchically the best when compared with the six other statins. CONCLUSIONS: Our analyses indicate the superiority of usage of statins in reduction of liver cancer. Available evidence supports that fluvastatin is the most effective strategy for reducing HCC risk compared with other statin interventions.

Does the use of statins improve outcomes in coronary artery bypass graft surgery?

Statins (3-hydroxy-3-methylglutaryl CoA reductase inhibitors) are one of the most frequently prescribed medications throughout the world with beneficial effects that extend beyond their lipid-lowering activity. It has been suggested that statins may offer a simple and cost-effective strategy to reduce some of the complications that occur in association with coronary artery bypass graft (CABG) surgery. Limited existing randomized trial evidence in the setting of cardiac surgery suggests that statins may reduce the incidence of postoperative atrial fibrillation. However, any effect of statins on other outcomes is less clear. The clinical significance of specific statin agent and dose, acute statin withdrawal and the potential benefits associated with statin reloading remain important yet currently unresolved issues. Despite limited high-quality evidence, class I recommendations have been made that all patients undergoing coronary artery bypass graft surgery should receive statin therapy unless contraindicated.

Comparative Effects of Statins on the Kidney Function in Patients with Type 2 Diabetes.

AIM: Whether there are differences among statins in their effect on the kidney function in diabetic patients remains controversial. In this report, we aimed to examine the comparative effects of statins on the kidney function in a long-term follow-up study. METHODS: This was a single-center longitudinal observational historical cohort study. We enrolled 326 Japanese adult ambulatory patients with type 2 diabetes who were newly prescribed one of four statins (pravastatin, rosuvastatin, atorvastatin and pitavastatin) and who had an estimated glomerular filtration rate (eGFR) of ≥30 mL/min/1.73m(2). The outcome measurement was the annual rate of change in eGFR. We used the standardized inverse probability of treatment weighted (IPTW) method based on the propensity score to adjust for the effects of confounding factors. Furthermore, in order to take into account the variety in the number and spacing of eGFR measurements and the duration of the follow-up period for each individual, we conducted a linear mixed-effects model regression analysis. RESULTS: The median follow-up period was 4.3years (range, 3.0-7.1years). In an analysis using the IPTW method, the mean (±standard error) annual rate of change in eGFR among the patients treated with pravastatin (-0.86±0.28 mL/min/1.73m(2)/year) was significantly lower than that observed among the patients treated with rosuvastatin (-1.80±0.27, p=0.02), atorvastatin (-1.99± 0.28, p=0.004) and pitavastatin (-2.23±0.49, p=0.02). Similar results were obtained in the linear mixed-effects model regression analysis. CONCLUSIONS: Pravastatin may be superior to rosuvastatin, atorvastatin and pitavastatin in preserving the kidney function in patients with type 2 diabetes.

Do statins reduce the risk of aneurysm development? A case-control study.

OBJECT: Recent studies in rats have demonstrated that statins may have an inhibitory effect on intracranial aneurysm (IA) development. The purpose of this study was to assess whether long-term statin use is associated with a reduced risk of IA formation in humans. METHODS: This was a single-center case-control study that included consecutive patients admitted to the authors' institution between January 1, 2005, and December 31, 2008. A case was defined as a patient with a cerebral angiography-confirmed diagnosis of IA. Three controls were matched to each case based on age, sex, and index year of hospital admission. The primary exposure of interest was cumulative statin use. Conditional logistic regression was used to assess the relationship between statin intake and incidence of IA. RESULTS: In total, 1200 patients were included in the study. No overall association was found between statin use and incidence of IA formation (OR 1.08, 95% CI 0.69-1.69), nor when dichotomized into hydrophilic and lipophilic user, or between short (≤ 12-month) and long (≥ 36-month) duration of intake. Hypertension and smoking significantly increased the risk of IA development (OR 4.02, 95% CI 2.49-6.45, and OR 1.67, 95% CI 1.02-2.72, respectively). CONCLUSIONS: In contrast to recent experimental reports of the association between statins and a reduction of IA formation, the authors' findings suggest that in humans statins may have no significant beneficial effect on IA suppression.