Statin-related Side Effects Research Articles

Gender-Related Factors in Medication Adherence for Metabolic and Cardiovascular Health.

This review explores the impact of gender on medication adherence in the context of metabolic and cardiovascular diseases. Optimal adherence to medication is crucial for achieving treatment goals and preventing adverse outcomes in chronic diseases. The review examines specific conditions such as type 2 diabetes, hypercholesterolemia, arterial hypertension, cardiovascular diseases, and heart failure. In type 2 diabetes, female sex, younger age, new drug prescription, non-white ethnicity, low education level, and low income were identified as predictors of non-adherence. Depressive disorders were also found to influence adherence. In hypercholesterolemia, women exhibited poorer adherence to statin therapy compared to men, with statin-related side effects and patient perception being significant factors. Adherence to anti-hypertensive therapy showed conflicting results, with studies reporting both higher and lower adherence in women. Limited evidence suggests that women may have poorer adherence after acute myocardial infarction and stroke. Regarding heart failure, adherence studies have shown inconsistent findings. The reasons for gender differences in medication adherence are multifactorial and include sociodemographic, disease-related, treatment-related, and psychological factors. This review emphasizes the need for further research to better understand these differences and develop gender-customized interventions that can improve medication adherence and reduce the burden of metabolic and cardiovascular diseases.

Muscle pain and muscle weakness in COVID19 patients: Cross-talk with statins – Preliminary results

BackgroundMuscle pain and muscle weakness, common symptoms among statin-treated patients, may worsen with COVID-19 infection. AimsThe aim of the paper was to find out if concomitant COVID-19 infections increase the frequency of specific side effects of statins such as muscle pain and muscle weakness. MethodA total of 66 patients diagnosed with COVID-19 without comorbidities participated in the study. The patients were divided into two groups: statin-users who had not experienced adverse effects of statins in the past (statin group (SG)) and patients who had not used any drugs in the past six months (control group (CG)). The severity of muscle pain and creatinine kinase (CK) activity was evaluated in each patient, and muscle weakness was confirmed by a dynamometer test (grip strength on both hands). ResultsIn SG, muscle pain was more common and it was characterized by a high level of intensity. Muscle weakness occurred more frequently in the SG and it was more frequent compared to CG. The CK parameter was observed to be higher in the SG compared to the CG and was often associated with the severity of muscle pain in the range of moderate to severe. ConclusionsOur study indicates that COVID-19 is associated with the higher risk of occurrence of typical statin-related side effects, especially with more advanced age, which should be considered in future trials and treatments.

Advances in the management of statin myopathy.

Statins are highly effective therapies for reducing low-density lipoprotein cholesterol and preventing cardiovascular events. However, many patients taking statins experience statin-associated muscle symptoms. In the current manuscript, we review algorithms to define statin intolerance and approaches to optimize cardiovascular risk reduction and reduce the nocebo effect among individuals reporting statin-associated muscle pain. Patients with statin intolerance have a higher cardiovascular event risk. These data underscore the need to apply clinical strategies that improve treatment utilization and adherence of patients experiencing statin-related side effects. Recent data have shown that the nocebo effect is frequent with statin therapy. This may be explained by the high frequency of muscle symptoms in the general population and media misinformation. When statins even at a low dosage are not tolerated other therapies can be used such as fibrate, ezetimibe nutraceuticals and antiPCSK9 antibodies. Recent data have identified other alternative therapeutic strategies such as bempedoic acid. There are multiple strategies for the management of statin-intolerance, both pharmacological and nonpharmacological. Patient involvement in the justification of statin treatment indication and therapeutic choice is the first step to overcome misbelief and reduce nocebo effect.

Statin-induced myopathic changes in primary human muscle cells and reversal by a prostaglandin F2 alpha analogue

Statin-related muscle side effects are a constant healthcare problem since patient compliance is dependent on side effects. Statins reduce plasma cholesterol levels and can prevent secondary cardiovascular diseases. Although statin-induced muscle damage has been studied, preventive or curative therapies are yet to be reported. We exposed primary human muscle cell populations (n = 22) to a lipophilic (simvastatin) and a hydrophilic (rosuvastatin) statin and analyzed their expressome. Data and pathway analyses included GOrilla, Reactome and DAVID. We measured mevalonate intracellularly and analyzed eicosanoid profiles secreted by human muscle cells. Functional assays included proliferation and differentiation quantification. More than 1800 transcripts and 900 proteins were differentially expressed after exposure to statins. Simvastatin had a stronger effect on the expressome than rosuvastatin, but both statins influenced cholesterol biosynthesis, fatty acid metabolism, eicosanoid synthesis, proliferation, and differentiation of human muscle cells. Cultured human muscle cells secreted ω-3 and ω-6 derived eicosanoids and prostaglandins. The ω-6 derived metabolites were found at higher levels secreted from simvastatin-treated primary human muscle cells. Eicosanoids rescued muscle cell differentiation. Our data suggest a new aspect on the role of skeletal muscle in cholesterol metabolism. For clinical practice, the addition of omega-n fatty acids might be suitable to prevent or treat statin-myopathy.

Patient Characteristics and General Practitioners\u2019 Advice to Stop Statins in Oldest-Old Patients: a Survey Study Across 30 Countries

BackgroundStatins are widely used to prevent cardiovascular disease (CVD). With advancing age, the risks of statins might outweigh the potential benefits. It is unclear which factors influence general practitioners’ (GPs) advice to stop statins in oldest-old patients.ObjectiveTo investigate the influence of a history of CVD, statin-related side effects, frailty and short life expectancy, on GPs’ advice to stop statins in oldest-old patients.DesignWe invited GPs to participate in this case-based survey. GPs were presented with 8 case vignettes describing patients > 80 years using a statin, and asked whether they would advise stopping statin treatment.Main MeasuresCases varied in history of CVD, statin-related side effects and frailty, with and without shortened life expectancy (< 1 year) in the context of metastatic, non-curable cancer. Odds ratios adjusted for GP characteristics (ORadj) were calculated for GPs’ advice to stop.Key ResultsTwo thousand two hundred fifty GPs from 30 countries participated (median response rate 36%). Overall, GPs advised stopping statin treatment in 46% (95%CI 45–47) of the case vignettes; with shortened life expectancy, this proportion increased to 90% (95CI% 89–90). Advice to stop was more frequent in case vignettes without CVD compared to those with CVD (ORadj 13.8, 95%CI 12.6–15.1), with side effects compared to without ORadj 1.62 (95%CI 1.5–1.7) and with frailty (ORadj 4.1, 95%CI 3.8–4.4) compared to without. Shortened life expectancy increased advice to stop (ORadj 50.7, 95%CI 45.5–56.4) and was the strongest predictor for GP advice to stop, ranging across countries from 30% (95%CI 19–42) to 98% (95% CI 96–99).ConclusionsThe absence of CVD, the presence of statin-related side effects, and frailty were all independently associated with GPs’ advice to stop statins in patients aged > 80 years. Overall, and within all countries, cancer-related short life expectancy was the strongest independent predictor of GPs’ advice to stop statins.

Lipids: a personal view of the past decade.

The past decade has witnessed considerable progress in the field of lipids. New drugs have been "rapidly" developed and some of these drugs have already been evaluated in event-based large trials. This evidence has led to the guidelines recommending new, more aggressive treatment goals for low-density lipoprotein cholesterol (LDL-C) levels. Although LDL-C remains the principal goal for cardiovascular disease (CVD) risk reduction, there has also been considerable interest in other lipid variables, such as high-density lipoprotein cholesterol, triglycerides, and lipoprotein(a). Statin intolerance is now considered a very important topic in daily clinical practice. This has resulted in more attention focusing on non-statin drugs [e.g., ezetimibe and proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors] and statin-related side effects. The latter mainly involve muscles, but there is also a need to consider other adverse effects associated with statin use (e.g., new onset diabetes). New specific areas of statin use have attracted interest. For example, statin-loading before procedures (e.g., coronary stenting), the prevention of stroke, and the treatment of non-alcoholic fatty liver disease (NAFLD). Statins will remain the most widely used drugs to treat dyslipidaemia and decrease CVD risk. However, we also need to briefly consider some other lipid-lowering drugs, including those that may become available in the future.

Study could curb exaggerated claims of statin side effects.

A new study could help counter adverse effects on public health of exaggerated claims about statin-related side effects, its authors say.

Adverse events associated with unblinded, but not with blinded, statin therapy in the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid-Lowering Arm (ASCOT-LLA): a randomised double-blind placebo-controlled trial and its non-randomised non-blind extension phase

In blinded randomised controlled trials, statin therapy has been associated with few adverse events (AEs). By contrast, in observational studies, larger increases in many different AEs have been reported than in blinded trials. In the Lipid-Lowering Arm of the Anglo-Scandinavian Cardiac Outcomes Trial, patients aged 40-79 years with hypertension, at least three other cardiovascular risk factors, and fasting total cholesterol concentrations of 6·5 mmol/L or lower, and who were not taking a statin or fibrate, had no history of myocardial infarction, and were not being treated for angina were randomly assigned to atorvastatin 10 mg daily or matching placebo in a randomised double-blind placebo-controlled phase. In a subsequent non-randomised non-blind extension phase (initiated because of early termination of the trial because efficacy of atorvastatin was shown), all patients were offered atorvastatin 10 mg daily open label. We classified AEs using the Medical Dictionary for Regulatory Activities. We blindly adjudicated all reports of four prespecified AEs of interest-muscle-related, erectile dysfunction, sleep disturbance, and cognitive impairment-and analysed all remaining AEs grouped by system organ class. Rates of AEs are given as percentages per annum. The blinded randomised phase was done between February, 1998, and December, 2002; we included 101 80 patients in this analysis (5101 [50%] in the atorvastatin group and 5079 [50%] in the placebo group), with a median follow-up of 3·3 years (IQR 2·7-3·7). The non-blinded non-randomised phase was done between December, 2002, and June, 2005; we included 9899 patients in this analysis (6409 [65%] atorvastatin users and 3490 [35%] non-users), with a median follow-up of 2·3 years (2·2-2·4). During the blinded phase, muscle-related AEs (298 [2·03% per annum] vs 283 [2·00% per annum]; hazard ratio 1·03 [95% CI 0·88-1·21]; p=0·72) and erectile dysfunction (272 [1·86% per annum] vs 302 [2·14% per annum]; 0·88 [0·75-1·04]; p=0·13) were reported at a similar rate by participants randomly assigned to atorvastatin or placebo. The rate of reports of sleep disturbance was significantly lower among participants assigned atorvastatin than assigned placebo (149 [1·00% per annum] vs 210 [1·46% per annum]; 0·69 [0·56-0·85]; p=0·0005). Too few cases of cognitive impairment were reported for a statistically reliable analysis (31 [0·20% per annum] vs 32 [0·22% per annum]; 0·94 [0·57-1·54]; p=0·81). We observed no significant differences in the rates of all other reported AEs, with the exception of an excess of renal and urinary AEs among patients assigned atorvastatin (481 [1·87%] per annum vs 392 [1·51%] per annum; 1·23 [1·08-1·41]; p=0·002). By contrast, during the non-blinded non-randomised phase, muscle-related AEs were reported at a significantly higher rate by participants taking statins than by those who were not (161 [1·26% per annum] vs 124 [1·00% per annum]; 1·41 [1·10-1·79]; p=0·006). We noted no significant differences between statin users and non-users in the rates of other AEs, with the exception of musculoskeletal and connective tissue disorders (992 [8·69% per annum] vs 831 [7·45% per annum]; 1·17 [1·06-1·29]; p=0·001) and blood and lymphatic system disorders (114 [0·88% per annum] vs 80 [0·64% per annum]; 1·40 [1·04-1·88]; p=0·03), which were reported more commonly by statin users than by non-users. These analyses illustrate the so-called nocebo effect, with an excess rate of muscle-related AE reports only when patients and their doctors were aware that statin therapy was being used and not when its use was blinded. These results will help assure both physicians and patients that most AEs associated with statins are not causally related to use of the drug and should help counter the adverse effect on public health of exaggerated claims about statin-related side-effects. Pfizer, Servier Research Group, and Leo Laboratories.

Statin associated myopathy in clinical practice. Results of DAMA study

Background and objectiveMuscle symptoms, with or without elevation of creatine kinase are one of the main adverse effects of statin therapy, a fact that sometimes limits their use. The aim of this study was to evaluate the clinical characteristics of patients treated with statins who have complained muscle symptoms and to identify possible predictive factors. Patients and methodsA 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. 3845 patients were recruited from a one-day record from 2001 physicians. ResultsMyalgia was present in 78.2% of patients included in the study, myositis in 19.3%, and rhabdomyolysis in 2.5%. Patients reported muscle pain in 77.5% of statin-treated individuals, general weakness 42.7%, and cramps 28.1%. Kidney failure, intense physical exercise, alcohol consumption (>30g/d in men and 20g/d in women) and abdominal obesity were the clinical situations associated with statin myopathy. ConclusionsMyalgia followed by myositis are the most frequent statin-related side effects. It should be recommended control environmental factors such as intense exercise and alcohol intake as well as abdominal obesity and renal function of the patient treated with statins.

Miopatía asociada al uso de estatinas en la práctica clínica. Resultados del estudio DAMA

Background and objectiveMuscle symptoms, with or without elevation of creatin kinase are one of the main adverse effects of statin therapy, a fact that sometimes limits their use. The aim of this study was to evaluate the clinical characteristics of patients treated with statins who have complained muscle symptoms and to identify possible predictive factors. Patients and methodsA 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. 3,845 patients were recruited from a one-day record from 2,001 physicians. ResultsMyalgia was present in 78.2% of patients included in the study, myositis in 19.3%, and rhabdomyolysis in 2.5%. Patients reported muscle pain in 77.5% of statin-treated individuals, general weakness 42.7%, and cramps 28.1%. Kidney failure, intense physical exercise, alcohol consumption (>30g/d in men and 20g/d in women) and abdominal obesity were the clinical situations associated with statin myopathy. ConclusionsMyalgia followed by myositis are the most frequent statin-related side effects. It should be recommended control environmental factors such as intense exercise and alcohol intake as well as abdominal obesity and renal function of the patient treated with statins.

Ticagrelor

Ticagrelor

Niemann-Pick C1-Like 1 (NPC1L1) Inhibition and Cardiovascular Diseases

Circulating levels of cholesterol are derived from either endogenous production or intestinal absorption of dietary and biliary cholesterol. Niemann-Pick C1-Like 1 (NPC1L1) is a transmembrane protein that plays a key role in the intestinal absorption of cholesterol by facilitating its uptake through vesicular endocytosis. NPC1L1 is the molecular target of ezetimibe which binds its extracellular loop and inhibits sterol absorption without affecting the absorption of other molecules. Ezetimibe significantly reduces plasma levels of total and low density lipoprotein cholesterol (LDL-C) as monotherapy or when added to statins, the association with a low dose of statin is of particular interest for patients experiencing statin-related side effects. The recent results of the IMPROVE-IT study, which evaluated the cardiovascular effect of ezetimibe added to simvastatin therapy in subjects who had had an acute coronary syndrome and with LDL-C levels within the recommended range, showed that a further LDL-C lowering reduced the incidence of cardiovascular events. To date, ezetimibe represents the only inhibitor of NPC1L1 available for clinical use, however, novel aminoß- lactam ezetimibe derivatives have been synthesized and their efficacy to inhibit NPC1L1 protein and decrease plasma cholesterol levels is under evaluation.

Molecular mechanisms of statin intolerance

Statins reduce cardiovascular morbidity and mortality in primary and secondary prevention. Despite their efficacy, many persons are unable to tolerate statins due to adverse events such as hepatotoxicity and myalgia/myopathy. In the case of most patients, it seems that mild-to-moderate abnormalities in liver and muscle enzymes are not serious adverse effects and do not outweigh the benefits of coronary heart disease risk reduction. The risk for mortality or permanent organ damage ascribed to statin use is very small and limited to cases of myopathy and rhabdomyolysis. Statin-induced muscle-related adverse events comprise a highly heterogeneous clinical disorder with numerous, complex etiologies and a variety of genetic backgrounds. Every patient who presents with statin-related side effects cannot undergo the type of exhaustive molecular characterization that would include all of these mechanisms. Frequently the only solution is to either discontinue statin therapy/reduce the dose or attempt intermittent dosing strategies at a low dose.

When compliance is an issue-how to enhance statin adherence and address adverse effects.

Cardiovascular disease is prevalent and costly. Interventions and therapies that reduce morbidity and mortality associated with cardiovascular disease could have an enormous impact on clinical and economic outcomes. Statins reduce atherosclerotic cardiovascular disease-related morbidity and mortality; however, adherence to statins is less than optimal. It is important for clinicians as well as health plan managers to be aware of the patient- and insurance plan-specific factors that have been shown to influence adherence. Perceived statin-related side effects may also decrease adherence. Statin-related myalgia may be difficult to distinguish from myalgia caused by other conditions, and statin therapy may be discontinued unnecessarily in patients who would otherwise benefit. It is imperative that clinicians work closely with patients to improve adherence to statin therapy and be knowledgable in managing potential statin-related side effects.

Reducing Residual Risk in Secondary Prevention of Cardiovascular Disease

Prevention of cardiovascular disease (CVD) spans the human lifespan, including primordial, primary, and secondary prevention efforts. Extensive evidence from epidemiological, genetic, and animal studies confirms the central importance of elevated low-density lipoprotein (LDL) cholesterol (LDL-C) in atherosclerotic CVD events.1 The Cholesterol Treatment Trialists Collaboration provides per-person documentation from large-scale randomized clinical trials of the striking reduction in CVD events per 1 mmol (38.8 mg/dL) of LDL-C lowering with statins over a wide range of baseline LDL-C values.2,3 It is worth recalling that the major statin trials were not designed to determine the effectiveness of titration to LDL-C or even to non–high-density lipoprotein cholesterol goals by statins but were fixed-dose comparisons of various statins against placebo and then, more recently, large-dose statin therapy versus moderate-dose statin therapy. What is not so clear is whether we can intervene to reduce so-called residual risk further in secondary prevention patients optimally treated with statin therapy. A promising short list of proposed potential targets other than LDL includes efforts to promote smoking cessation and therapies to improve the prothrombotic and inflammatory state of the metabolic syndrome and to control elevated blood pressure.4 Article see p 1979 The article by Mora et al5 in this issue of Circulation is helpful in shedding light on this unresolved but important clinical problem. The investigators used data from a large-scale clinical trial of secondary prevention patients called Treating to New Targets (TNT). They evaluated risk factors for recurrent CVD events in those treated with intensive statin therapy (atorvastatin 80 mg/d) to address the challenges inherent in further risk reduction for those who had major cardiovascular events despite high-dose (atorvastatin 80 mg/d) statin therapy. The trial design of TNT included enrollment of participants with chronic coronary artery …

Balancing Efficacy and Tolerability Issues with Statin Therapy— Considerations for the Use of Pitavastatin in Special Patient Populations

One of the main objectives of cardiovascular care is to control elevated low-density lipoprotein cholesterol (LDL-C). Statins are the mainstay for managing LDL-C with proven high efficacy and satisfactory safety profiles. However, the most known side effects are muscle symptoms, which are particularly common in individuals who often have co-existing conditions and are taking multiple medications. The latest statin that has become available, pitavastatin, is not known to cause cytochrome P450-mediated drug–drug interactions, making it an ideal statin for individuals at a high risk for side effects. Pitavastatin will be particularly beneficial in treating patients with mixed dyslipidemia, as it is effective in reducing triglycerides and increasing high-density lipoprotein cholesterol (HDL-C). Pitavastatin has an established history of use, and has a safety and adverse event profile similar to that of other existing statins. Individuals at high risk from side effects with statins include older people (&gt;65 years), individuals with diabetes, kidney disease, or metabolic syndrome and individuals taking multiple medications. South Asian populations that have migrated to Western countries are at particularly high risk for cardiovascular disease, and this population also has an increased risk for statin-related side effects. This article will summarize the factors that place individuals at high risk for dyslipidemia, treatment of high risk populations with statins, and the issues associated with treating high risk populations with statins. The benefits of treating these individuals with pitavastatin will be reviewed, as well as alternative forms of therapy.

Correction: Another Side to Statin-Related Side Effects

Correction: Another Side to Statin-Related Side Effects

Another Side to Statin-Related Side Effects

Another Side to Statin-Related Side Effects

Statin Side Effects — Targets of Ongoing Research

Although statins generally are well tolerated, many clinicians believe that, in practice, statin-related side effects occur more commonly than was

Questioning the “beatification” of statins

Statins have been described as miracle drugs, but such “beatification" is not justified. Changes in lifestyle should be considered the cornerstone in cardiovascular prevention. However, trends in mortality from coronary heart disease have not effectively changed since statins were approved in the United States, while obesity has risen significantly. Have these drugs contributed to a deterioration in lifestyle among those who believe a pill will protect them? Adherence to healthful lifestyle has been shown to be associated with reductions in the rates of coronary disease, diabetes in women, and mortality in elderly. Patients with major lifestyle problems enrolled in recent statin trials were given only drugs, and no statin has ever been compared with a nonatherogenic lifestyle and shown to be superior or additive. Furthermore, there is no evidence for a total mortality benefit in women and elderly persons from dyslipidemia therapy. Side effects are often presented as relative, not absolute risk, and are suggested to be low. However, there is reason to believe that their numbers are much larger in clinical practice where the drugs may be given to most patients usually excluded in randomised trials. Statin-related side effects may be considered as a complication to the primary disease. However, these complaints may be statin therapy related. Finally, the relationship between long-standing statin therapy and cancerogenesis is not fully understood. Investigators should carefully resist the natural tendency to highlight the most positive findings in their studies while minimising harm, especially when commercially sponsored.