Resveratrol for protection against statin toxicity in C2C12 and H9c2 cells.

Statins are among the most commonly prescribed drugs for the treatment of high blood cholesterol. Myotoxicity of statins in certain individuals is often a severe side effect leading to withdrawal. Using C2C12 and H9c2 cells, both exhibiting characteristics of skeletal muscle cells, we addressed whether resveratrol (RSV) can prevent statin toxicity. Statins decreased cell viability in a dose and time-dependent manner. Among the five statins tested, atorvastatin, simvastatin, lovastatin, pravastatin, and fluvastatin, simvastatin is the most toxic one. Simvastatin at 10 µM caused about 65% loss of metabolic activity as measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays in C2C12 cells or H9c2 cells. Inhibition of metabolic activity correlates with an increase in caspase activity. RSV was found to protect H9c2 cells from simvastatin-induced activation of caspase-3/7. However, such protection was not found in C2C12 cells. This cell type-dependent effect of RSV adds to the complexity in muscle cell toxicity of statins.

Pravastatin combination with sorafenib does not improve survival in advanced hepatocellular carcinoma.

BACKGROUND & AIMS: Sorafenib is the standard of care for advanced hepatocellular carcinoma (HCC). Combining sorafenib with another treatment, to improve overall survival (OS) within an acceptable safety profile, might be the next step forward in the management of patients with advanced HCC. We aimed to assess whether a combination of sorafenib and a statin improved survival in patients with HCC. METHODS: The objective of the PRODIGE-11 trial was to compare the respective clinical outcomes of the sorafenib-pravastatin combination (arm A) versus sorafenib alone (arm B) in patients with advanced HCC. Child-Pugh A patients with advanced HCC who were naive to systemic treatment (n = 323) were randomly assigned to sorafenib-pravastatin combination (n = 162) or sorafenib alone (n = 161). The primary endpoint was OS; secondary endpoints were progression-free survival, time to tumor progression, time to treatment failure, safety, and quality of life. RESULTS: After randomization, 312 patients received at least 1 dose of study treatment. After a median follow-up of 35 months, 269 patients died (arm A: 135; arm B: 134) with no difference in median OS between treatments arms (10.7 months vs. 10.5 months; hazard ratio = 1.00; p = 0.975); no difference was observed in secondary survival endpoints either. In the univariate analysis, the significant prognostic factors for OS were CLIP score, performance status, and quality of life scores. The multivariate analysis showed that the only prognostic factor for OS was the CLIP score. The main toxicity was diarrhea (which was severe in 11% of patients in arm A, and 8.9% in arm B), while severe nausea-vomiting was rare, and no toxicity-related deaths were reported. CONCLUSION: Adding pravastatin to sorafenib did not improve survival in patients with advanced HCC. LAY SUMMARY: Sorafenib has proven efficacy for the treatment of patients with advanced hepatocellular carcinoma. However, overall survival remains poor in these patients, so we were interested to see if the addition of a statin, pravastatin, improved outcomes in patients with advanced HCC. This randomized-controlled trial demonstrated that the sorafenib-pravastatin combination did not improve overall survival in this study population compared to sorafenib alone. Clinical trial number: NCT01075555.

Coenzyme Q10 protects against ß-cell toxicity induced by pravastatin treatment of hypercholesterolemia.

New onset of diabetes is associated with the use of statins. We have recently demonstrated that pravastatin-treated hypercholesterolemic LDL receptor knockout (LDLr-/- ) mice exhibit reductions in insulin secretion and increased islet cell death and oxidative stress. Here, we hypothesized that these diabetogenic effects of pravastatin could be counteracted by treatment with the antioxidant coenzyme Q 10 (CoQ 10 ), an intermediate generated in the cholesterol synthesis pathway. LDLr -/- mice were treated with pravastatin and/or CoQ 10 for 2 months. Pravastatin treatment resulted in a 75% decrease of liver CoQ 10 content. Dietary CoQ 10 supplementation of pravastatin-treated mice reversed fasting hyperglycemia, improved glucose tolerance (20%) and insulin sensitivity (>2-fold), and fully restored islet glucose-stimulated insulin secretion impaired by pravastatin (40%). Pravastatin had no effect on insulin secretion of wild-type mice. In vitro, insulin-secreting INS1E cells cotreated with CoQ 10 were protected from cell death and oxidative stress induced by pravastatin. Simvastatin and atorvastatin were more potent in inducing dose-dependent INS1E cell death (10-15-fold), which were also attenuated by CoQ 10 cotreatment. Together, these results demonstrate that statins impair ß-cell redox balance, function and viability. However, CoQ 10 supplementation can protect the statins detrimental effects on the endocrine pancreas.

Optimizing Lipid Pattern by Adding a Combined Nutraceutical or Pravastatin to Fenofibrate Treatment in Hypertriglyceridemic Subjects: Single Site, Randomized, Open-Label, Post-Market Clinical Investigation.

INTRODUCTION: Fenofibrate is an effective and safe treatment for hypertriglyceridemia. However, after TG reduction a residual dyslipidemia could appear and require further treatment. AIM: To comparatively evaluate the short-term tolerability and efficacy of a combined lipid-lowering nutraceutical and pravastatin 40 mg in fenofibrate treated patients. METHOD: We prospectively enrolled 40 patients well-tolerating treatment with micronized fenofibrate 145 mg/day and with residual dyslipidemia (LDL-C > 115 mg/dL and TG > 150 mg/dL). Exclusion criteria have been type 2 diabetes, Familial Hypercholesterolemia, previous cardiovascular diseases and severe chronic kidney disease. Then, we have randomly assigned the patients to treatment with pravastatin 40 mg or a combined lipid-lowering nutraceutical (Armolipid Plus®, containing monacolin 3 mg and berberine 500 mg). RESULTS: After 8 weeks of treatment, 80% of pravastatin treated patients (N. 16/20) and 75% of those treated with Armolipid Plus® (N. 15/20) reached the desired LDL-C target, while 50% of pravastatin treated patients (N. 10/20) and 80% of the Armolipid Plus® treated ones reached the desired TG target (N. 16/20). No one adverse event has been registered during Armolipid Plus®, while 1 patient claimed myalgia and 1 reported significant increase of CPK (> 3 ULN) during pravastatin treatment. Both patients were then treated with Armolipid Plus® with resolution of symptoms and CPK increase, respectively. CONCLUSION: In hypertriglyceridemic patients treated with fenofibrate, the association with a combined lipid lowering nutraceutical seem to be more effective in optimizing residual hypertriglyceridemia than pravastatin 40 mg, while being more tolerable and having similar effect on LDL-C plasma level.

Tolerability of red yeast rice (2,400 mg twice daily) versus pravastatin (20 mg twice daily) in patients with previous statin intolerance.

Currently, no consensus has been reached regarding the management of hyperlipidemia in patients who develop statin-associated myalgia (SAM). Many statin-intolerant patients use alternative lipid-lowering therapies, including red yeast rice. The present trial evaluated the tolerability of red yeast rice versus pravastatin in patients unable to tolerate other statins because of myalgia. The study was conducted in a community-based setting in Philadelphia, Pennsylvania. A total of 43 adults with dyslipidemia and a history of statin discontinuation because of myalgia were randomly assigned to red yeast rice 2,400 mg twice daily or pravastatin 20 mg twice daily for 12 weeks. All subjects were concomitantly enrolled in a 12-week therapeutic lifestyle change program. The primary outcomes included the incidence of treatment discontinuation because of myalgia and a daily pain severity score. The secondary outcomes were muscle strength and plasma lipids. The incidence of withdrawal from medication owing to myalgia was 5% (1 of 21) in the red yeast rice group and 9% (2 of 22) in the pravastatin group (p = 0.99). The mean pain severity did not differ significantly between the 2 groups. No difference was found in muscle strength between the 2 groups at week 4 (p = 0.61), week 8 (p = 0.81), or week 12 (p = 0.82). The low-density lipoprotein cholesterol level decreased 30% in the red yeast rice group and 27% in the pravastatin group. In conclusion, red yeast rice was tolerated as well as pravastatin and achieved a comparable reduction of low-density lipoprotein cholesterol in a population previously intolerant to statins.

Rhabdomyolysis in an HIV-infected patient on anti-retroviral therapy precipitated by high-dose pravastatin.

Protease inhibitors (PIs) inhibit the cytochrome P450 CYP3A4. Because the metabolism of pravastatin is independent of the cytochrome P450 CYP3A4, this drug has become the preferred statin for treatment of dyslipidemia associated with human immunodeficiency virus (HIV) infection, with no cases of serious toxicity such as rhabdomyolysis reported to date. We report an HIV-infected patient receiving antiretroviral regimen consisting of atazanavir, ritonavir, emtricitabine and tenofovir who developed severe rhabdomyolysis approximately 4 months after increasing his pravastatin dose from 40 to 80 mg daily. His symptoms resolved within 10 days after the discontinuation of pravastatin and antiretroviral therapy. To our knowledge, this is the first case of rhabdomyolysis possibly caused by pravastatin in an HIV-infected patient.

Effects of intensive versus moderate lipid-lowering therapy on myocardial ischemia in older patients with coronary heart disease: results of the Study Assessing Goals in the Elderly (SAGE).

BACKGROUND: Clinical trials have demonstrated that, compared with placebo, intensive statin therapy reduces ischemia in patients with acute coronary syndromes and in patients with stable coronary artery disease. However, no studies to date have assessed intensive versus moderate statin therapy in older patients with stable coronary syndromes. METHODS AND RESULTS: A total of 893 ambulatory coronary artery disease patients (30% women) 65 to 85 years of age with > or = 1 episode of myocardial ischemia that lasted > or = 3 minutes during 48-hour ambulatory ECG at screening were randomized to atorvastatin 80 mg/d or pravastatin 40 mg/d and followed up for 12 months. The primary efficacy parameter (absolute change from baseline in total duration of ischemia at month 12) was significantly reduced in both groups at month 3 and month 12 (both P<0.001 for each treatment group) with no significant difference between the treatment groups. Atorvastatin-treated patients experienced greater low-density lipoprotein cholesterol reductions than did pravastatin-treated patients, a trend toward fewer major acute cardiovascular events (hazard ratio, 0.71; 95% confidence interval, 0.46, 1.09; P=0.114), and a significantly greater reduction in all-cause death (hazard ratio, 0.33; 95% confidence interval, 0.13, 0.83; P=0.014). CONCLUSIONS: Compared with moderate pravastatin therapy, intensive atorvastatin therapy was associated with reductions in cholesterol, major acute cardiovascular events, and death in addition to the reductions in ischemia observed with both therapies. The contrast between the therapies' differing efficacy for major acute cardiovascular events and death and their nonsignificant difference in efficacy for reduction of ischemia suggests that low-density lipoprotein cholesterol-lowering thresholds for ischemia and major acute cardiovascular events may differ. The Study Assessing Goals in the Elderly (SAGE) demonstrates that older men and women with coronary artery disease benefit from intensive statin therapy.

Intensive versus moderate lipid lowering with statins after acute coronary syndromes.

BACKGROUND: Lipid-lowering therapy with statins reduces the risk of cardiovascular events, but the optimal level of low-density lipoprotein (LDL) cholesterol is unclear. METHODS: We enrolled 4162 patients who had been hospitalized for an acute coronary syndrome within the preceding 10 days and compared 40 mg of pravastatin daily (standard therapy) with 80 mg of atorvastatin daily (intensive therapy). The primary end point was a composite of death from any cause, myocardial infarction, documented unstable angina requiring rehospitalization, revascularization (performed at least 30 days after randomization), and stroke. The study was designed to establish the noninferiority of pravastatin as compared with atorvastatin with respect to the time to an end-point event. Follow-up lasted 18 to 36 months (mean, 24). RESULTS: The median LDL cholesterol level achieved during treatment was 95 mg per deciliter (2.46 mmol per liter) in the standard-dose pravastatin group and 62 mg per deciliter (1.60 mmol per liter) in the high-dose atorvastatin group (P<0.001). Kaplan-Meier estimates of the rates of the primary end point at two years were 26.3 percent in the pravastatin group and 22.4 percent in the atorvastatin group, reflecting a 16 percent reduction in the hazard ratio in favor of atorvastatin (P=0.005; 95 percent confidence interval, 5 to 26 percent). The study did not meet the prespecified criterion for equivalence but did identify the superiority of the more intensive regimen. CONCLUSIONS: Among patients who have recently had an acute coronary syndrome, an intensive lipid-lowering statin regimen provides greater protection against death or major cardiovascular events than does a standard regimen. These findings indicate that such patients benefit from early and continued lowering of LDL cholesterol to levels substantially below current target levels.

Enhanced myopathy following administration of hypolipidemic agents under urethane anesthesia.

The enhanced effect of urethane anesthesia on the serum creatine kinase (CPK) level following administration of hypolipidemic agents was examined to develop a convenient experimental screening method for drug-induced myopathy. After oral administration of a hypolipidemic agent to rats, 25% urethane solution was infused intravenously at a very low rate using a microinfusion pump. Blood samples were collected 7 h after drug administration and the risk of myopathy was evaluated based on the CPK level. When bezafibrate (BF), simvastatin (SV), or pravastatin (PV) (50-500 mg/kg) was orally administered under urethane infusion, enhanced elevation of the serum CPK level was observed dose dependently for BF and SV, but not for PV. The elevation of serum CPK was much higher with BF than with SV or PV. In addition, when SV or PV (50-500 mg/kg) was coadministered with 50 mg/kg of BF, there was a striking increase in the serum CPK level as compared with the drug alone. Without urethane infusion, no significant elevation in serum CPK level was observed even at a high dose of these hypolipidemic agents. These phenomena suggest that the urethane anesthesia enhanced the elevation of the serum CPK level following administration of hypolipidemic agents. We propose that this method is a simple and speedy screening test for drug-induced myopathy.