An Association of Prior Statin Use with Decreased Perihematomal Edema

Objective  To investigate the impact of statins on perihematomal edema following spontaneous supratentorial intracerebral hemorrhage (ICH). Background  Hematoma expansion and evolution of perihematomal edema are most commonly responsible for neurological deterioration following ICH. A possible role of statins in reducing perihematomal edema has been suggested based on studies in animal models. Methods  Records of consecutive ICH patients admitted to The Johns Hopkins Hospital from 1999 to 2006 were reviewed. Patients with ICH related to trauma or underlying lesions (e.g., brain tumors, aneurysms, and arterio-venous malformations) and of infratentorial location were excluded. Absolute and relative perihematomal edema were assessed on initial head CT. Using regression analysis, the impact of prior statin use on absolute and relative edema at presentation was assessed correcting for other factors possibly impacting perihematomal edema, such as age, coagulopathy, aspirin use, admission mean arterial pressure (MAP), and blood glucose. Results  A total of 125 consecutive ICH patients were studied. Patients with prior statin exposure had a mean edema volume of 13.2 ± 9.2 cc compared to 22.3 ± 18.3 cc in patients who were not using statins at the time of ICH. Following multiple linear regression analysis, we have identified a statistically significant association between prior statin use with reduced early absolute perihematomal edema (P = 0.035). Mean relative perihematomal edema was significantly lower in patients on statins at presentation (0.44) as opposed to 0.81 in patients with no prior statin use. This difference remained statistically significant (P = 0.021) after correcting for other variables. Conclusions  We report the association between statin use prior to ICH and decreased absolute and relative perihematomal edema. A prospective study analyzing the role of statins in perihematomal edema reduction and the resultant effect on mortality and functional outcomes following ICH is warranted.     

On the factors modulating the effect of statins on malignant cell proliferation

HuCC, EHEB, K562, and Raji cells were incubated with 3 hydrophobic statins (atorvastatin, lovastatin, and simvastatin) and one hydrophilic statin (pravastatin). The 4 statins inhibited HuCC cell proliferation; however, none of them affected their apoptosis. EHEB and K562 cell proliferation was inhibited by the hydrophobic statins, but not by pravastatin. Raji cell proliferation was not affected by any of the 4 statins. The hydrophobic statins solely enhanced early apoptosis of the hematological cell lines. The results point out that the antiproliferative effect of statins on tumor cells and their effect on the apoptotic rate depends on their dosage, physiochemical property, and the type of the malignant cells.     

Statin therapy may protect against acute kidney injury in patients hospitalized for interstitial SARS-CoV2 pneumonia

Background and aimsCOVID-19-associated acute kidney injury (AKI) represents an independent risk factor for all-cause in-hospital death in patients with COVID-19. Chronic statin therapy use is highly prevalent in individuals at risk for severe COVID-19. Our aim is to assess whether patients under treatment with statins have a lower risk of AKI and in-hospital mortality during hospitalization for interstitial SARS-CoV2 pneumonia.Methods and resultsOur study is a prospective observational study on 269 consecutive patients admitted for COVID-19 pneumonia at the Internal Medicine Unit of IRCCS Sant'Orsola Hospital in Bologna, Italy. We compared the clinical characteristics between patients receiving statin therapy (n = 65) and patients not treated with statins and we assessed if chronic statin use was associated with a reduced risk for AKI, all-cause mortality, admission to ICU, and disease severity. Statin use was associated with a significant reduction in the risk of developing AKI (OR 0.47, IC 0.23 to 0.95, p 0.036) after adjustment for age, sex, BMI, hypertension, diabetes, and chronic kidney disease (CKD). Additionally, statin use was associated with reduced C-reactive protein (CRP) levels (p 0.048) at hospital admission. No significant impact in risk of all-cause mortality (HR 1.98, IC 0.71 to 5.50, p 0.191) and ICU admission (HR 0.93, IC 0.52 to 1.65, p 0.801) was observed with statin use, after adjustment for age, sex, BMI, hypertension, diabetes, and CKD.ConclusionThe present study shows a potential beneficial effect of statins in COVID-19-associated AKI. Furthermore, patients treated with statins before hospital admission for COVID-19 may have lower systemic inflammation levels.     

Central nervous system effects of current and emerging multiple sclerosis-directed immuno-therapies

Objective

To review the direct and indirect effects on the central nervous system (CNS) of systemically administered immuno-modulatory therapies in use or under evaluation for the relapsing forms of multiple sclerosis (MS).

Methods

We summarize data published by our own lab and by others that delineate the effects of such therapies on in vitro neural cell cultures and in animal model-based systems.

Results

The long-approved therapies, interferon β (IFNβ) and glatiramer acetate (GA), do not readily access the CNS. These agents can still indirectly have an effect on disease-related immune regulatory and effector functions within the CNS by modulating the properties of systemic immune cells that migrate to this compartment. Such immune cells could interact with perivascular and innate immune cells that are involved in immune regulation and with cells that are either targets of the disease process (oligodendrocytes, neurons) and/or are involved with repair (progenitor cells). Newer agents reported to favorably impact on relapse frequency in MS include the sphingosine-1-phosphate agonist, fingolimod, and the lipophilic statin, simvastatin. Both agents access the CNS and thus represent examples of agents that could directly impact on disease-relevant injury and repair process within the CNS.

Conclusions

The observations reviewed in this report regarding indirect and direct effects of immuno-modulatory agents on the CNS indicate the need to understand and monitor the neurobiologic effects of such therapies.     

Statins decrease TNF-alpha-induced osteoprotegerin production by endothelial cells and smooth muscle cells in vitro

Recent reports have implicated osteoprotegerin (OPG) in cardiovascular disease processes. Endothelial and smooth muscle cells produce OPG and its expression in these cells is upregulated by inflammatory mediators. Statins, which besides their lipid lowering properties have various vasculoprotective effects, have been shown to regulate OPG expression in osteoblasts. We investigated whether statins affect the expression of OPG in human endothelial and smooth muscle cells. Using an ELISA we could demonstrate that statins reduce tumor necrosis factor-alpha (TNF-alpha)-induced OPG production in cultured human endothelial cells and smooth muscle cells. Atorvastatin also downregulated interleukin-1alpha (IL-1alpha)-induced OPG production in endothelial cells. A significant reduction of TNF-alpha-induced OPG was seen when statins were used in the nanomolar range. These results were confirmed at the level of specific mRNA expression by real-time-PCR. Using LDH leakage as a marker of cell damage we show that cell viability was not affected by statins at concentrations used in our study. The effect of statins on TNF-alpha-induced OPG production was reversed by mevalonate and geranyl-geranyl pyrophosphate at the level of protein production and at the level of mRNA expression, suggesting that it was brought about by inhibition of the mevalonic acid pathway and protein prenylation. Through our results we have added OPG to the list of molecules whose TNF-alpha-induced upregulation is counteracted by statins. If such an effect is also operative in the in vivo setting, one could postulate a role for statins in the modulation of cardiovascular disease processes possibly regulated by OPG.     

Statin-induced new onset of diabetes in dyslipidemic patients: a retrospective study

Background: Previously conducted studies with statins shows an increased risk of developing new onset of diabetes. This study helps in analyzing the risk of statins to cause new onset of diabetes.

Objective: To assess the prevalence, causality, severity, preventability and risk factors of statin-induced new onset of diabetes in dyslipidemic patients.

Methods: The study was conducted in a tertiary care hospital. A 6-month retrospective study was carried out in the cardiology department and analyzed between year 2013-2017medical records of dyslipidemic patients treated with statins of age >18 years. Patients with congenital diabetes, previous history of diabetes, patients using antipsychotics and steroids, and patients with incomplete data were excluded. Patients were reported as diabetic according to the American Diabetes Association’s classification. Patients who developed statin-induced new onset of diabetes were assessed by the WHO probability scale, Naranjo’s causality assessment scale, Hartwig’s severity assessment scale, and Modified Schumock and Thornton preventability scale.

Results: Out of 270 dyslipidemic patients, 19 patients developed statin-induced new onset of diabetes and 69 were classified as pre-diabetic. The major risk factors were: dose, gender, age, geriatric patients, and duration of the therapy. Patients who developed statin-induced new onset of diabetes were managed by dose reduction and treatment with anti-diabetic medications.

Conclusion The prevalence of statin-induced new onset of diabetes is 7.03%. The main risk factors identified in the study were in older patients (≥60 years), rosuvastatin therapy, high dose and longer duration of statin therapy.     

Effect of statins use on the prevention of venous thromboembolism： a meta-analysis

ObjectiveTo estimate the effect of statins use on the prevention of venous thromboembolism (VTE).MethodsWe systematically searched MEDLINE (1980-June 2012), EMBASE (1980-June 2012), Google Scholar, Cochrane Library, and ISI Web of Science, manually reviewed references, and contacted experts. Case-control studies and cohort studies that compared any dose of statin with no statin or placebo are included. Data extraction and study quality evaluation were independently conducted in duplicate.Results12 studies including four cohort studies and eight case-control studies were identified and eligible for meta-analysis. Upon meta-analysis, statin use was associated with a statistically significant reduction in the odds of developing VTE (OR 0.91, 95% CI 0.86–0.96).ConclusionThis meta-analysis of current and available literature suggests that statins can reduce patient's risk of developing VTE. Due to the limitations of observational study, this conclusion should be considered with caution, and additionally, specifical well-designed trials are needed.     

Do Statins have a Role in Reduction/Prevention of Post‐PCI Restenosis?

The pathophysiology of post‐PCI restenosis involves neointimal formation that consists of three phases: thrombosis (within 24 h), recruitment (3–8 days), and proliferation, which starts on day 8 of PCI. Various factors suggested to be predictors/risks for restenosis include C‐reactive protein (CRP), inflammatory mediators (cytokines and adhesion molecules), oxygen radicals, advanced glycation end products (AGEs) and their receptors (RAGE), and soluble RAGE (sRAGE). The earlier noted factors produce thrombogenesis, vascular smooth muscle cell proliferation, and extracellular matrix formation. Statins have pleiotropic effects. Besides lowering serum cholesterol, they have various other biological effects including antiinflammatory, antithrombotic, CRP‐lowering, antioxidant, antimitotic, and inhibition of smooth muscle cell proliferation. They inhibit matrix metalloproteinase and cyclooxygenase‐2, lower AGEs, decrease expression of RAGE and increase levels of serum sRAGE. They also increase the synthesis of nitric oxide (NO) by increasing endothelial NO synthase expression and activity. Preprocedural statin therapy is known to reduce peri‐ and post‐PCI myonecrosis and reduce the need for repeat revascularization. There is evidence that statin‐eluting stents inhibit in‐stent restenosis in animal models. It is concluded that because of the above attributes of statins, they are suitable candidates for reduction of post‐PCI restenosis and post‐PCI myonecrosis. The future directions for the use of statins in reduction of post‐PCI restenosis and myonecrosis have been discussed.     

Lipid-altering efficacy of the ezetimibe/simvastatin single tablet versus rosuvastatin in hypercholesterolemic patients

ABSTRACT

Objective: To assess the lipid-altering efficacy and safety of ezetimibe/simvastatin single tablet product compared with rosuvastatin at the approved usual starting, next highest, and maximum doses.

Research design and methods: Double-blind, multicenter, 6‐week, parallel-group study in hypercholesterolemic patients (n = 2959). Patients were randomized based on stratification by low-density lipoprotein cholesterol (LDL-C) levels to ezetimibe/simvastatin or rosuvastatin, respectively, at the usual starting (10/20 or 10?mg/day), the next highest (10/40 or 20?mg/day), and maximum doses (10/80 or 40?mg/day).

Results: At all doses and across doses, ezetimibe/simvastatin reduced LDL‐C levels significantly more (52–61%) than rosuvastatin (46–57%; p ≤ 0.001). Significantly greater percentages of all patients (p < 0.001) and high risk patients (p ≤ 0.005) attained LDL‐C levels < 70?mg/dL (1.8?mmol/L) following ezetimibe/simvastatin treatment compared with rosuvastatin at the prespecified doses and across doses. Ezetimibe/simvastatin also produced significantly greater reductions in total cholesterol (?p < 0.001), non-high-density lipoprotein cholesterol (?p < 0.001), lipid ratios (?p ≤ 0.003), and apolipoprotein B (?p < 0.05). Reductions in triglycerides were significantly greater with ezetimibe/simvastatin than rosuvastatin at the usual starting (?p = 0.004) and next highest (?p = 0.006) doses, and across all doses (?p < 0.001). Increases in high-density lipoprotein cholesterol, and decreases in high sensitivity C reactive protein (hsCRP) were similar between treatment groups. Safety profiles were comparable for both treatments; however, the percent of patients with proteinuria was significantly higher following rosuvastatin treatment than ezetimibe/simvastatin, respectively at 10?mg versus 10/20?mg/day (?p = 0.004) and 40?mg versus 10/80?mg/day (?p < 0.001).

Conclusion: Ezetimibe/simvastatin was more effective than rosuvastatin in LDL‐C lowering, and provided greater or comparable improvements in other lipid measures and hsCRP at the approved usual starting, next highest, and maximum doses in hypercholesterolemic patients. Although the doses compared in this study were not equivalent on a milligram basis, the results provide clinically relevant information regarding the use of these drugs for initial therapy and for subsequent use at higher doses when appropriate. Both treatments were generally well-tolerated; however, this study was not powered nor of sufficient duration to assess the prevalence of rare clinical adverse effects. Overall, ezetimibe/simvastatin offers an effective and tolerable treatment option for lipid management. An assessment of its full clinical benefit awaits evaluation in longer-term clinical studies.     

Statins and renal function in patients with diabetes mellitus

SUMMARY

Lipids may adversely affect renal function. The recently published MRC/BHF Heart Protection Study (HPS) subgroup analysis showed that simvastatin significantly reduced the fall in glomerular filtration rate in high-risk patients with and without diabetes mellitus. These findings are in line with those of

smaller earlier studies, including the GREek Atorvastatin and Coronary heart disease Evaluation (GREACE) Study. Lipid lowering trials need to consider that changes in renal function may occur. Renal and ischaemic heart disease may progress in parallel and statins may be beneficial to both organs.