Statin-induced Adverse Effects Research Articles

Safety Profile of the Concomitant Use of Atorvastatin and Cyclosporine in Renal Transplant Recipients.

Cyclosporine (CyA) and atorvastatin (AT) are often administered concomitantly to treat dyslipidemia in renal transplant recipients. However, CyA greatly increases the plasma concentration of AT; therefore, concomitant use might increase the frequency of statin-induced adverse effects. The aim of this study was to investigate whether concomitant use of CyA and AT increases intolerance of the latter agent in Japanese renal transplantation recipients. We performed a retrospective cohort analysis of renal transplant recipients aged 18 years and older who had concomitantly received AT and CyA, or tacrolimus (Tac) therapy. We defined statin intolerance as a decrease in dose or discontinuation of AT due to adverse effects. We evaluated the incidence of statin intolerance in concomitant therapy with CyA for 100 days after the initial administration of AT in comparison with Tac. A total of 144 renal transplant recipients who received AT and CyA, or Tac between January 2013 and December 2019 were included. There was no statistical difference in the incidence of statin intolerance in both the CyA (1.8%; 1/57 patients) and Tac (3.4%; 3/87 patients) groups. Concomitant use of CyA and AT might not increase the incidence of statin intolerance in Japanese renal transplant recipients.

Efficacy and safety of statins in ethnic differences: alesson for application in Indigenous Australian patient care.

Although statins are effective in treating high cholesterol, adverse effects do occur with their use. Efficacy and tolerability vary among statins in different ethnic groups. Indigenous Australians have a high risk for cardiovascular and kidney diseases. Prescribing statins to Indigenous Australians with multi-morbidity requires different strategies to increase efficacy and reduce their toxicity. Previous studies have reported that Indigenous Australians are more susceptible to severe statin-induced myopathies. However, there is a lack of evidence in the underlying genetic factors in this population. This review aims to identify: inter-ethnic differences in the efficacy and safety of statins; major contributing factors accounting for any identified differences; and provide an overview of statin-induced adverse effects in Indigenous Australians.

Investigating the Incidence, Diagnosis, Prevention and Management of Statin-Induced Adverse Effects

Statin therapy reduces mortality associated with cardiovascular disease by preventing myocardial infarction and ischemic stroke. Despite the proven benefits of statins in this context, there is growing concern among patients and physicians regarding the safety of their short- and long-term use and adverse side effects, particularly muscle toxicity. As a result, nonadherence and withdrawal from treatment occur. This study is aimed to investigate the effectiveness of statin use in the secondary prevention of cardiovascular disease and diabetes in adults and the elderly by examining the incidence, diagnosis, prevention, and management of statin-induced adverse effects. A cross-sectional study of 350 patients using statins was conducted at King Abdulaziz and Hera’a General Hospital in Makkah. Data were retrieved from medical records and analyzed using SPSS software. The mean age of the sample population was 62±12 years old. Nearly 60% of patients had comorbidities, such as diabetes. However, statin treatment significantly decreased the levels of cholesterol, triglycerides, and low-density lipoprotein. Additionally, high-density lipoprotein levels were increased significantly, especially in patients with diabetes, indicating lower cardiovascular risk. The 2019 data showed that a high prevalence of patients used statin therapy. However, more than half of these patients achieved the low density lipoprotein treatment target. These results emphasize effective monitoring by physicians and patient adherence to the medications.

DISTRIBUTION OF POLYMORPHISMS OF GENES OF STATINS METABOLISM AND TRANSPORT IN THE LIVER IN PATIENTS WITH CORONARY ARTERY DISEASE ETHNIC UZBEKS WITH SIMVASTATIN INTOLERANCE

Background. It is well-known that in majority of cases treatment with statins can be safe and well tolerated, but in some patients observed statin-induced adverse liver or muscle symptoms - the main reasons for statin discontinuation. Asian ethnicity - is one of the predisposing factors for statin-associated adverse effects. Objective. To study possible effects of CYP3A5 (6986A>G), CYP2C9 (430C>T), CYP2C9 (1075A>C), SLCO1B1 (521T>C) and BCRP (ABCG2, 421C>A) genetic polymorphism on simvastatin tolerance and safety in ethnic Uzbek patients with Coronary Artery Disease (CAD).Material and methods. The prospective case-control research included 100 patients with CAD. Group "case" were 50 patients who demonstrated statin-induced adverse liver effects (transaminase level increases 3 times and more - in 37 cases) or statin-induced elevations in serum CK (of >3*UNL - in 4 cases) at treatment with simvastatin with the dose of 20 mg/day for 3 months of treatment and 13 with myopathy, associated with increased levels of total creatine phosphokinase (CPK) 3 times or more. In 4 patients with adverse effects on the liver, along with an increase in the enzymes, while there was an increase of CPK levels. Control group contained 50 patient with CAD treated with simvastatin with the dose of 20-40 mg/day for one year without side effects. The both groups of patients were similar in gender, age, original index of kidney function and serum CK level. The comparison group consisted of healthy ethnic Uzbeks (n = 41) of comparable age and sex, with the absence of a family history of coronary artery disease. The research was performed by means of PCR-RFLP method.Results. As a whole, all genotypes (except for CYP2C9 * 2 in patients) were in Hardy-Weinberg equilibrium. Among patients with simvastatin intolerance, compared to the control group, the following genotypes were observed more frequently with high level of confidence: CYP3A5 *3/*3, compared to genotype variants *1/*3 and *1/*1 (OR 9.33; 95% CI 3,37-25,9; P = 0.0001) and BCRP CA (patients with BCRP CC genotype were not observed among those examined) (OR 3.22; 95% CI 1,258,30, P = 0.024).Conclusions. Genotypes CYP3A5 *3/*3 (6986A>G) and BCRP CA (ABCG2, 421C>A) are accompanied with the increase of statin-induced adverse effects in ethnic Uzbek patients with Coronary artery disease.

Efficacy and safety of statins and exercise combination therapy compared to statin monotherapy in patients with dyslipidaemia: A systematic review and meta-analysis.

Background Statin treatment in association with physical exercise can substantially reduce mortality in dyslipidaemic individuals. However, the available data to compare the efficacy and safety of statins and exercise combination therapy with statin monotherapy are limited. Design Systematic review and meta-analysis. Methods We systematically searched PubMed, Embase and the Cochrane Library from database inception until December 2016. We included randomised and non-randomised studies that compared the efficacy and safety of statins and exercise combination therapy with statin monotherapy in patients with dyslipidaemia. Standardised mean differences were calculated and pooled by means of fixed effects models. The risk of bias and heterogeneity among trials was also assessed. Seven articles were assessed in terms of the efficacy of therapy and 13 from the viewpoint of therapeutic safety. Results In terms of efficacy, statins and exercise combination decreased the incidence of diabetes mellitus, improved insulin sensitivity and inflammation, but caused no change in lipid profile compared to statins alone. In terms of safety, statins and exercise combination increased peak oxygen uptake (standardised mean difference 1.01, 95% confidence interval 0.46 to 1.57) compared to statins alone. In contrast to statin-induced myopathy, chronic exercise training prior to statin treatment could counteract statin-induced adverse effects in skeletal muscle. Conclusion Statins and exercise combination therapy is more effective than statin monotherapy in terms of insulin sensitivity, inflammation and exercise capacity. The small number of studies warrants the need for more randomised controlled trials evaluating the efficacy and safety of combination therapy.

Severity of statin-induced adverse effects on muscle and associated conditions: data from the DAMA study

ABSTRACTBackground: Statins are generally well tolerated, but muscular adverse effects appear to be the most common obstacle limiting their use. Our objective was to describe the severity of muscle injury (myalgia, myositis and rhabdomyolysis) and associated conditions related to statin therapy that may be clinically significant.Methods: A cross-sectional one-visit, non-interventional, national multicenter study including patients of both sexes over 18 years of age referred for past or present muscle symptoms associated with statin therapy was conducted. Clinical, biochemical and drug therapy characteristics were obtained at the initial evaluation.Results: 3,845 patients were recruited from a one-day record from 2,001 physicians. Myalgia was present in 78.2% of patients, myositis in 19.3% and rhabdomyolysis in 2.5%. The prevalence of different comorbidities such as diabetes, hypertension, atrial fibrillation, and coronary heart disease increased as the severity of myopathy rose. High-intensity statin therapy was used in 33.4% of patients. Concomitant drugs metabolized by the CYP450 3A4 pathway were taken by 9.3% of patients, and statins with this metabolic route by 75%. Independent variables associated with myositis or rhabdomyolysis compared with myalgia alone in the multivariate model were excessive alcohol consumption and pravastatin therapy.Conclusion: Myalgia was the most common muscle adverse effect associated with statin therapy. Excessive alcohol consumption and pravastatin were independently associated with myositis or rhabdomyolysis.

Effects of Organic Anion Transporting Polypeptide (OATP1B1/SLCO1B1) Genetic Polymorphism on Statin Therapy

The 3-HMG-CoA reductase inhibitors (statins) which are substrates of OATP1B1 transporter protein, is reputed to be effective in reducing morbidity and mortality associated with cardiovascular disease. The OATP1B1 transporter protein is encoded by the SLCO1 genes and almost exclusively expressed in human liver cells. It plays a crucial role in the hepatic uptake and clearance of many drugs including statins. There is a high probability of drug-drug interactions since statins are coadministered with other drugs which may inhibit the OATP1B1 transporter leading to elevated serum levels and statin-induced adverse effects. The OATP1B1 (SLCO1B1) genetic polymorphism is quite invaluable in influencing clinical decisions on the use of statins. Consequently, genotyping for selected SLCO1B1 variants is recommended to identify individuals at increased risk of developing adverse drug effects following statin therapy.

Statin-induced adverse effects – facts and genes

Statin therapy is considered to be safe and rarely associated with serious adverse events. However, a significant proportion of patients on statin therapy show some degree of intolerance which can lead to decreased adherence to statin therapy. The authors summarize the symptoms, signs and frequencies of the most common statin-induced adverse effects and their most important risk factors including some single nucleotide polymorphisms and gene mutations. Also, they review the available approaches to detect and manage the statin-intolerant patients.

Nutritional Status Affects Fluvastatin-Induced Hepatotoxicity and Myopathy in Rats

Rats that consumed a high-fat and high-sucrose diet (HF diet) developed hepatic steatosis. Treatment of HF diet-fed rats with fluvastatin (8 mg/kg) was lethal, followed by an elevation in levels of plasma aspartate aminotransferase and creatine kinase activities and skeletal muscle toxicity. This study was conducted to determine whether nutritional status affects statin-induced adverse effects in rats. Fluvastatin treatment of rats fed the HF diet led to an increase in systemic exposure, suggesting altered metabolism and elimination. In fact, although hepatic multidrug resistance-associated protein (Mrp) 2 and multidrug resistance (Mdr) 1b protein levels were not significantly changed by fluvastatin treatment for 8 days of rats fed a HF diet, the organic anion-transporting protein (Oatp) 1, Mrp3, CYP1A, CYP2C, UDP-glucuronosyltransferase (UGT) 1A1, and UGT1A5 protein levels were moderately decreased and the Oatp2, CYP3A, and UGT2B1 protein levels were markedly suppressed. No significant difference in the baseline level of Oatp1, Oatp2, Mrp2, Mrp3, Mdr1b, CYP1A, CYP2C, CYP3A, UGT1A1, UGT1A5, or UGT2B1 protein was found between the standard diet- and HF diet-fed groups. In addition, the mRNA levels of Oatp2, CYP2C11, and CYP3A1/2 were markedly decreased in HF diet-fed and fluvastatin-treated rats. There was no significant difference in the glucuronidation activities against fluvastatin among the four groups. In liver cell nuclei, levels of constitutive androstane receptor, pregnane X receptor, and hepatocyte nuclear factor 4α proteins were decreased in fluvastatin-treated HF diet-fed rats, which correlated with the decrease in Oatp2, CYP2C, and CYP3A. Taken together, these results indicate that nutritional status may influence adverse effects of fluvastatin by increasing systemic exposure through modulation of hepatic uptake and elimination.

SLCO1B1*5 behind statin-induced adverse effects

SLCO1B1*5 behind statin-induced adverse effects

Pharmacogenetics of the response to statins

Statins (inhibitors of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase) are widely prescribed medications for the prevention of incident and recurrent cardiovascular disease events and death. They are powerful assets in the current arsenal of cardiovascular medications, with high efficacy and minimal toxicity. However, heterogeneity exists with respect to the response to statin medications, and there has been considerable investigation into the genetic determinants of the statin response. In this review, we separate the response to statins into 1) measures of efficacy (low-density lipoprotein cholesterol lowering and protection from cardiovascular events) and 2) effects of toxicity (musculoskeletal adverse effects and nonadherence to statin therapy). The current data suggest that prospective genotyping for certain variants may be of use in tailoring statin therapy to reduce cardiovascular events and to avoid statin-induced adverse effects.