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BMC Gastroenterology Mar 2021There is increased interest in the therapeutic use of statins in cirrhosis, but preferred statin and safety outcomes are still not well known. In this systematic review...
BACKGROUND/AIMS
There is increased interest in the therapeutic use of statins in cirrhosis, but preferred statin and safety outcomes are still not well known. In this systematic review we aimed to address pharmacokinetics (PK), safety, and effects on cardiovascular (CV) outcomes of statins in cirrhosis.
METHODS
Our systematic search in several electronic databases and repositories of two regulatory bodies up to 2020-06-11 yielded 22 articles and 2 drug monographs with relevant data.
RESULTS
Rosuvastatin and pitavastatin showed minimal PK changes in Child-Pugh A cirrhosis. Only rosuvastatin was assessed in a repeated dosing PK study. Atorvastatin showed pronounced PK changes in cirrhosis. No PK data was found for simvastatin, the most commonly used statin in cirrhosis trials. There was insufficient data to assess CV effects of statins in cirrhosis. Clinical trials in cirrhosis were limited to simvastatin, atorvastatin, and pravastatin. In patients taking simvastatin 40 mg, pooled frequency of rhabdomyolysis was 2%, an incidence 40-fold higher than that reported in non-cirrhosis patients, while this was no rhabdomyolysis observed in patients on simvastatin 20 mg, atorvastatin 20 mg, or pravastatin 40 mg. Drug-induced liver injury was of difficult interpretation due to co-existence of muscle damage. No overt liver failure was reported.
CONCLUSIONS
Simvastatin 40 mg should be avoided in decompensated cirrhosis. Safety data on simvastatin 20 mg or other statins are based on small study sample size. This rarity of evidence combined with lack of data in dose adjustment methods in cirrhosis is a barrier for using statins for CV indications or for investigational use for liver indications.
Topics: Atorvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Liver Cirrhosis; Pravastatin; Simvastatin
PubMed: 33726685
DOI: 10.1186/s12876-021-01704-w -
Nutrients Jul 2020Statins and omega-3 supplementation have been recommended for cardiovascular disease prevention, but comparative effects have not been investigated. This study aimed to... (Comparative Study)
Comparative Study Meta-Analysis
Comparative Effect of Statins and Omega-3 Supplementation on Cardiovascular Events: Meta-Analysis and Network Meta-Analysis of 63 Randomized Controlled Trials Including 264,516 Participants.
Statins and omega-3 supplementation have been recommended for cardiovascular disease prevention, but comparative effects have not been investigated. This study aimed to summarize current evidence of the effect of statins and omega-3 supplementation on cardiovascular events. A meta-analysis and a network meta-analysis of 63 randomized controlled trials were used to calculate pooled relative risks (RRs) and 95% confidence intervals (CIs) for the effects of specific statins and omega-3 supplementation compared with controls. Overall, the statin group showed significant risk reductions in total cardiovascular disease, coronary heart disease, myocardial infarction, and stroke; however, omega-3 supplementation significantly decreased the risks of coronary heart disease and myocardial infarction only, in the comparison with the control group. In comparison with omega-3 supplementation, pravastatin significantly reduced the risks of total cardiovascular disease (RR = 0.81, 95% CI = 0.72-0.91), coronary heart disease (RR = 0.75, 95% CI = 0.60-0.94), and myocardial infarction (RR = 0.71, 95% CI = 0.55-0.94). Risks of total cardiovascular disease, coronary heart disease, myocardial infarction, and stroke in the atorvastatin group were statistically lower than those in the omega-3 group, with RRs (95% CIs) of 0.80 (0.73-0.88), 0.64 (0.50-0.82), 0.75 (0.60-0.93), and 0.81 (0.66-0.99), respectively. The findings of this study suggest that pravastatin and atorvastatin may be more beneficial than omega-3 supplementation in reducing the risk of total cardiovascular disease, coronary heart disease, and myocardial infarction.
Topics: Aged; Atorvastatin; Cardiovascular Diseases; Coronary Disease; Dietary Supplements; Fatty Acids, Omega-3; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Middle Aged; Myocardial Infarction; Network Meta-Analysis; Pravastatin; Randomized Controlled Trials as Topic; Stroke; Treatment Outcome
PubMed: 32722395
DOI: 10.3390/nu12082218 -
European Journal of Clinical... Dec 2020A growing body of preclinical and observational research suggests that statins have potential as a therapeutic strategy in patients with cancer. This systematic review...
PURPOSE
A growing body of preclinical and observational research suggests that statins have potential as a therapeutic strategy in patients with cancer. This systematic review of randomised controlled trials (RCTs) in patients with solid tumours aimed to determine the efficacy of statin therapy on mortality outcomes, their safety profile and the risk of bias of included studies.
METHODS
Full-text articles comparing statin therapy versus control in solid tumours and reporting mortality outcomes were identified from Medline and Embase from conception to February 2020. A systematic review with qualitative (primarily) and quantitative synthesis was conducted. This systematic review was prospectively registered (Prospero registration CRD42018116364).
RESULTS
Eleven trials of 2165 patients were included. Primary tumour sites investigated included lung, colorectal, gastro-oesophageal, pancreatic and liver. Most trials recruited patients with advanced malignancy and used sub-maximal statin doses for relatively short durations. Aside from one trial which demonstrated benefit with allocation to pravastatin 40 mg in hepatocellular carcinoma, the remaining ten trials did not demonstrate efficacy with statins. The pooled hazard ratio for all-cause mortality with allocation to pravastatin in patients with hepatocellular carcinoma in two trials was 0.69 (95% confidence interval CI 0.30-1.61). Study estimates were imprecise. There were no clinically important differences in statin-related adverse events between groups. Overall, included trials were deemed low risk of bias.
CONCLUSION
The trial evidence is not sufficiently robust to confirm or refute the efficacy and safety of statins in patients with solid malignant tumours. Study and patient characteristics may explain this uncertainty. The potential role of high-dose statins in adjuvant settings deserves further research.
Topics: Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Neoplasms; Pravastatin; Progression-Free Survival; Randomized Controlled Trials as Topic; Time Factors
PubMed: 32719919
DOI: 10.1007/s00228-020-02967-0 -
Cancer Causes & Control : CCC Oct 2020The link between lipid-stabilizing medications and epithelial ovarian carcinogenesis is incompletely understood. Statins may reduce ovarian cancer risk, but results are... (Meta-Analysis)
Meta-Analysis
PURPOSE
The link between lipid-stabilizing medications and epithelial ovarian carcinogenesis is incompletely understood. Statins may reduce ovarian cancer risk, but results are inconclusive.
METHODS
We conducted a systematic review and meta-analysis of studies reporting associations between statin use and ovarian cancer risk in PubMed. Summary risk ratios (RRs) and confidence intervals (CIs) were calculated. Subgroup analyses by cancer histotype, statin class (lipo- or hydrophilic) and duration of statin use were conducted. Use of individual statins in populations was assessed to determine population-specific differences in statin types.
RESULTS
Nine studies with 435,237 total women were included (1 randomized controlled trial (RCT); 4 prospective; 4 case-control). Statin use was associated with a reduced risk of ovarian cancer (RR 0.87, 95% CI 0.74-1.03) and risk was significantly reduced in populations with low pravastatin use (RR 0.83, 95% CI 0.70-0.99). Risk estimates varied by statin class (3 studies; lipophilic: RR 0.88, 95% CI 0.69-1.12; hydrophilic: RR 1.06, 95% CI 0.72-1.57) and cancer histotype (3 studies; serous: RR 0.95, 95% CI 0.69-1.30; clear cell: RR 1.17, 95% CI 0.74-1.86). Long-term use was associated with a reduced risk of ovarian cancer (RR 0.77, 95% CI 0.54-1.10) that further reduced when pravastatin use was low (RR 0.68, 95% CI 0.46-1.01). Between-study heterogeneity was high overall and in subgroups (I > 60%).
CONCLUSION
Statins may be associated with a reduced risk of ovarian cancer, but the effect likely differs by individual statin, duration of use and cancer histotype. Additional well-powered studies are needed to elucidate important subgroup effects.
Topics: Case-Control Studies; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Ovarian Neoplasms; Prospective Studies; Randomized Controlled Trials as Topic; Risk
PubMed: 32685996
DOI: 10.1007/s10552-020-01327-8 -
Cardiovascular Therapeutics 2020The drug efficacy may differ among different statins, and evidence from head-to-head comparisons is sparse and inconsistent. The study is aimed at comparing the... (Meta-Analysis)
Meta-Analysis
Comparative Lipid-Lowering/Increasing Efficacy of 7 Statins in Patients with Dyslipidemia, Cardiovascular Diseases, or Diabetes Mellitus: Systematic Review and Network Meta-Analyses of 50 Randomized Controlled Trials.
OBJECTIVE
The drug efficacy may differ among different statins, and evidence from head-to-head comparisons is sparse and inconsistent. The study is aimed at comparing the lipid-lowering/increasing effects of 7 different statins in patients with dyslipidemia, cardiovascular diseases, or diabetes mellitus by conducting systematic review and network meta-analyses (NMA) of the lipid changes after certain statins' use.
METHODS
In this study, we searched four electronic databases for randomized controlled trials (RCTs) published through February 25, 2020, comparing the lipid-lowering efficacy of no less than two of the included statins (or statin vs. placebo). Three reviewers independently extracted data in duplicate. Firstly, mixed treatment overall comparison analyses, in the form of frequentist NMAs, were conducted using STATA 15.0 software. Then, subgroup analyses were conducted according to different baseline diseases. At last, sensitivity analyses were conducted according to age and follow-up duration. The trial was registered with PROSPERO (number CRD42018108799).
RESULTS
As a result, seven statin monotherapy treatments in 50 studies (51956 participants) were used for the analyses. The statins included simvastatin (SIM), fluvastatin (FLU), atorvastatin (ATO), rosuvastatin (ROS), lovastatin (LOV), pravastatin (PRA), and pitavastatin (PIT). In terms of LDL-C lowering, rosuvastatin ranked 1 with a surface under cumulated ranking (SUCRA) value of 93.1%. The comparative treatment efficacy for LDL-C lowering was ROS>ATO>PIT>SIM>PRA>FLU>LOV>PLA. All of the other ranking and NMA results were reported in SUCRA plots and league tables.
CONCLUSIONS
According to the NMAs, it can be concluded that rosuvastatin ranked 1 in LDL-C, ApoB-lowering efficacy and ApoA1-increasing efficacy. Lovastatin ranked 1 in TC- and TG-lowering efficacy, and fluvastatin ranked 1 in HDL-C-increasing efficacy. The results should be interpreted with caution due to some limitations in our review. However, they can provide references and evidence-based foundation for drug selection in both statin monotherapies and statin combination therapies.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers; Cardiovascular Diseases; Diabetes Mellitus; Down-Regulation; Dyslipidemias; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipids; Male; Middle Aged; Network Meta-Analysis; Randomized Controlled Trials as Topic; Treatment Outcome; Young Adult
PubMed: 32411300
DOI: 10.1155/2020/3987065 -
Turk Kardiyoloji Dernegi Arsivi : Turk... Mar 2020The aim of this study was to examine and present the effect of statin treatment on the low-density lipoprotein (LDL) cholesterol level of patients in Turkey by...
OBJECTIVE
The aim of this study was to examine and present the effect of statin treatment on the low-density lipoprotein (LDL) cholesterol level of patients in Turkey by evaluating the data of studies conducted in the country.
METHODS
Manuscripts published between January 1, 2008 and December 31, 2017 with terms 'LDL' and 'TURK' in the title or abstract and reporting LDL cholesterol data of patients treated with statins were evaluated for inclusion in the study. From the initial search result a total of 1795 papers, 39 manuscripts with 63 study arms were selected for analysis and the data of 3486 patients were included. Descriptive analysis was used to assess the data. Weighted averages of the data were also calculated.
RESULTS
The female/male ratio was 42/58. The mean age was 52.9±10.1 years. The proportion of patients with the recommended LDL cholesterol level of <70 mg/dL after treatment with statins was 15.3%;. In all, 10.2% of the patients who were prescribed a low-dose statin and 28.0% of those who were prescribed a high-dose statin had an LDL cholesterol of <70 mg/dL after treatment. Among patients who were being treated with statins for ≤2 months, 25.7% achieved an LDL cholesterol level of <70 mg/dL. Among those who were being treated with statins for 2-4 months and >4 months the proportion was 11.4% and 9.7%, respectively. The percentage of patients at the target level was 21.8%, 21.7%, 17.9%;, 8.6%, and 0.8% among those using atorvastatin, simvastatin, rosuvastatin, fluvastatin, and pravastatin, respectively.
CONCLUSION
In Turkey, only 15% of the patients who had received statin therapy had a LDL cholesterol level of <70 mg/dL. Revision of the current treatment should be considered to reach the target levels recommended in the guidelines, especially for patients with high cardiovascular risk.
Topics: Cholesterol, LDL; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Turkey
PubMed: 32147651
DOI: 10.5543/tkda.2019.45156 -
Annals of Translational Medicine Dec 2019Pulmonary hypertension (PH) is a multi-causal disease and no satisfactory therapeutic strategies for it. Statins have been suggested as potential drugs in PH, whose...
BACKGROUND
Pulmonary hypertension (PH) is a multi-causal disease and no satisfactory therapeutic strategies for it. Statins have been suggested as potential drugs in PH, whose effects in different clinic types of PH have not been conclusive. In this study, we included randomized controlled clinical trials (RCTs) evaluating the efficacy and safety of statins therapy in PH.
METHODS
We searched databases including Medline, Embase, Cochrane, PubMed and Web of science, with time up to January 1, 2019. With 95% confidence interval (CI), weighted mean difference (WMD) or standardized mean difference (SMD) was pooled and calculated in a random or fixed effect model according to I2 statistic.
RESULTS
A total of nine RCTs with 657 patients were included. Four types of statins (atorvastatin, pravastatin, rosuvastatin and simvastatin) were used at different doses (10-80 mg daily) for up to 6 months. In the pooled-data analysis, compared with placebo, there were significant improvements in pulmonary arterial pressure (PAP), in addition to low-density lipoprotein (LDL) in patients treated with statins, but not in 6-minute walking distance (6MWD), cardiac index (CDI). No more adverse events and all-cause mortality were revealed. Subgroup analysis indicated that statins could decrease PAP in the subtype of PH due to chronic obstructive pulmonary disease (COPD), but not pulmonary arterial hypertension (PAH).
CONCLUSIONS
This study indicates that statins can efficiently and safely reduce PAP in PH, especially in the subtype due to COPD. Further RCTs are needed to focus on the efficacy and safety of statin therapy in different subtypes of PH.
PubMed: 32042802
DOI: 10.21037/atm.2019.11.19 -
Scientific Reports Nov 2019Previous studies showed that statins reduce the progression of kidney function decline and proteinuria, but whether specific types of statins are more beneficial than... (Meta-Analysis)
Meta-Analysis
Previous studies showed that statins reduce the progression of kidney function decline and proteinuria, but whether specific types of statins are more beneficial than others remains unclear. We performed a network meta-analysis of randomized controlled trials (RCT) to investigate which statin most effectively reduces kidney function decline and proteinuria. We searched MEDLINE, Embase, Web of Science, and the Cochrane database until July 13, 2018, and included 43 RCTs (>110,000 patients). We performed a pairwise random-effects meta-analysis and a network meta-analysis according to a frequentist approach. We assessed network inconsistency, publication bias, and estimated for each statin the probability of being the best treatment. Considerable heterogeneity was present among the included studies. In pairwise meta-analyses, 1-year use of statins versus control reduced kidney function decline by 0.61 (95%-CI: 0.27; 0.95) mL/min/1.73 m and proteinuria with a standardized mean difference of -0.58 (95%-CI:-0.88; -0.29). The network meta-analysis for the separate endpoints showed broad confidence intervals due to the small number available RCTs for each individual comparison. In conclusion, 1-year statin use versus control attenuated the progression of kidney function decline and proteinuria. Due to the imprecision of individual comparisons, results were inconclusive as to which statin performs best with regard to renal outcome.
Topics: Atorvastatin; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Kidney; Kidney Diseases; Lovastatin; Network Meta-Analysis; Pravastatin; Proteinuria; Rosuvastatin Calcium; Simvastatin; Treatment Outcome
PubMed: 31719617
DOI: 10.1038/s41598-019-53064-x -
The Cochrane Database of Systematic... Nov 2019Familial hypercholesterolemia is one of the most common inherited metabolic diseases and is an autosomal dominant disorder meaning heterozygotes, or carriers, are... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Familial hypercholesterolemia is one of the most common inherited metabolic diseases and is an autosomal dominant disorder meaning heterozygotes, or carriers, are affected. Those who are homozygous have severe disease. The average worldwide prevalence of heterozygous familial hypercholesterolemia is at least 1 in 500, although recent genetic epidemiological data from Denmark and next generation sequencing data suggest the frequency may be closer to 1 in 250. Diagnosis of familial hypercholesterolemia in children is based on elevated total cholesterol and low-density lipoprotein cholesterol levels or DNA-based analysis, or both. Coronary atherosclerosis has been detected in men with heterozygous familial hypercholesterolemia as young as 17 years old and in women with heterozygous familial hypercholesterolemia at 25 years old. Since the clinical complications of atherosclerosis occur prematurely, especially in men, lifelong treatment, started in childhood, is needed to reduce the risk of cardiovascular disease. In children with the disease, diet was the cornerstone of treatment but the addition of lipid-lowering medications has resulted in a significant improvement in treatment. Anion exchange resins, such as cholestyramine and colestipol, were found to be effective, but they are poorly tolerated. Since the 1990s studies carried out on children aged 6 to 17 years with heterozygous familial hypercholesterolemia have demonstrated significant reductions in their serum total and low-density lipoprotein cholesterol levels. While statins seem to be safe and well-tolerated in children, their long-term safety in this age group is not firmly established. This is an update of a previously published version of this Cochane Review.
OBJECTIVES
To assess the effectiveness and safety of statins in children with heterozygous familial hypercholesterolemia.
SEARCH METHODS
Relevant studies were identified from the Group's Inborn Errors and Metabolism Trials Register and Medline. Date of most recent search: 04 November 2019.
SELECTION CRITERIA
Randomized and controlled clinical studies including participants up to 18 years old, comparing a statin to placebo or to diet alone.
DATA COLLECTION AND ANALYSIS
Two authors independently assessed studies for inclusion and extracted data.
MAIN RESULTS
We found 26 potentially eligible studies, of which we included nine randomized placebo-controlled studies (1177 participants). In general, the intervention and follow-up time was short (median 24 weeks; range from six weeks to two years). Statins reduced the mean low-density lipoprotein cholesterol concentration at all time points (high-quality evidence). There may be little or no difference in liver function (serum aspartate and alanine aminotransferase, as well as creatinine kinase concentrations) between treated and placebo groups at any time point (low-quality evidence). There may be little or no difference in myopathy (as measured in change in creatinine levels) (low-quality evidence) or clinical adverse events (moderate-quality evidence) with statins compared to placebo. One study on simvastatin showed that this may slightly improve flow-mediated dilatation of the brachial artery (low-quality evidence), and on pravastatin for two years may have induced a regression in carotid intima media thickness (low-quality evidence). No studies reported rhabdomyolysis (degeneration of skeletal muscle tissue) or death due to rhabdomyolysis, quality of life or compliance to study medication.
AUTHORS' CONCLUSIONS
Statin treatment is an effective lipid-lowering therapy in children with familial hypercholesterolemia. Few or no safety issues were identified. Statin treatment seems to be safe in the short term, but long-term safety remains unknown. Children treated with statins should be carefully monitored and followed up by their pediatricians and their care transferred to an adult lipidologist once they reach 18 years of age. Large long-term randomized controlled trials are needed to establish the long-term safety issues of statins.
Topics: Adolescent; Adult; Child; Cholesterol, LDL; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipoproteinemia Type II; Male; Randomized Controlled Trials as Topic; Young Adult
PubMed: 31696945
DOI: 10.1002/14651858.CD006401.pub5 -
Basic & Clinical Pharmacology &... Apr 2020The high prevalence of statin and clarithromycin utilization creates potential for overlapping use. The objectives of this MiniReview were to investigate the evidence... (Comparative Study)
Comparative Study
The high prevalence of statin and clarithromycin utilization creates potential for overlapping use. The objectives of this MiniReview were to investigate the evidence base for drug-drug interactions between clarithromycin and currently marketed statins and to present management strategies for these drug combinations. We conducted a systematic literature review following PRISMA guidelines with English language studies retrieved from PubMed and EMBASE (from inception through March 2019). We included 29 articles (16 case reports, 5 observational, 5 clinical pharmacokinetic and 3 in vitro studies). Based on mechanistic/clinical studies involving clarithromycin or the related macrolide erythromycin (both strong inhibitors of CYP3A4 and of hepatic statin uptake transporters OATP1B1 and OATP1B3), clarithromycin is expected to substantially increase systemic exposure to simvastatin and lovastatin (>5-fold increase in area under the plasma concentration-time curve (AUC)), moderately increase AUCs of atorvastatin and pitavastatin (2- to 4-fold AUC increase) and slightly increase pravastatin exposure (≈2-fold AUC increase) while having little effect on fluvastatin or rosuvastatin. The 16 cases of statin-clarithromycin adverse drug reactions (rhabdomyolysis (n = 14) or less severe clinical myopathy) involved a CYP3A4-metabolized statin (simvastatin, lovastatin or atorvastatin). In line, a cohort study found concurrent use of clarithromycin and CYP3A4-metabolized statins to be associated with a doubled risk of hospitalization with rhabdomyolysis or other statin-related adverse events as compared with azithromycin-statin co-administration. If clarithromycin is necessary, we recommend (a) avoiding co-administration with simvastatin, lovastatin or atorvastatin; (b) withholding or dose-reducing pitavastatin; (c) continuing pravastatin therapy with caution, limiting pravastatin dose to 40 mg daily; and (d) continuing fluvastatin or rosuvastatin with caution.
Topics: Area Under Curve; Clarithromycin; Drug Interactions; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Rhabdomyolysis
PubMed: 31628882
DOI: 10.1111/bcpt.13343