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European Heart Journal Jun 2020Lipoprotein(a) [Lp(a)] is elevated in 20-30% of people. This study aimed to assess the effect of statins on Lp(a) levels. (Meta-Analysis)
Meta-Analysis
AIMS
Lipoprotein(a) [Lp(a)] is elevated in 20-30% of people. This study aimed to assess the effect of statins on Lp(a) levels.
METHODS AND RESULTS
This subject-level meta-analysis includes 5256 patients (1371 on placebo and 3885 on statin) from six randomized trials, three statin-vs.-placebo trials, and three statin-vs.-statin trials, with pre- and on-treatment (4-104 weeks) Lp(a) levels. Statins included atorvastatin 10 mg/day and 80 mg/day, pravastatin 40 mg/day, rosuvastatin 40 mg/day, and pitavastatin 2 mg/day. Lipoprotein(a) levels were measured with the same validated assay. The primary analysis of Lp(a) is based on the log-transformed data. In the statin-vs.-placebo pooled analysis, the ratio of geometric means [95% confidence interval (CI)] for statin to placebo is 1.11 (1.07-1.14) (P < 0.0001), with ratio >1 indicating a higher increase in Lp(a) from baseline in statin vs. placebo. The mean percent change from baseline ranged from 8.5% to 19.6% in the statin groups and -0.4% to -2.3% in the placebo groups. In the statin-vs.-statin pooled analysis, the ratio of geometric means (95% CI) for atorvastatin to pravastatin is 1.09 (1.05-1.14) (P < 0.0001). The mean percent change from baseline ranged from 11.6% to 20.4% in the pravastatin group and 18.7% to 24.2% in the atorvastatin group. Incubation of HepG2 hepatocytes with atorvastatin showed an increase in expression of LPA mRNA and apolipoprotein(a) protein.
CONCLUSION
This meta-analysis reveals that statins significantly increase plasma Lp(a) levels. Elevations of Lp(a) post-statin therapy should be studied for effects on residual cardiovascular risk.
Topics: Atorvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipoprotein(a); Pravastatin; Randomized Controlled Trials as Topic; Rosuvastatin Calcium
PubMed: 31111151
DOI: 10.1093/eurheartj/ehz310 -
Circulation Aug 2021Effective screening for term preeclampsia is provided by a combination of maternal factors with measurements of mean arterial pressure, serum placental growth factor,... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Effective screening for term preeclampsia is provided by a combination of maternal factors with measurements of mean arterial pressure, serum placental growth factor, and serum soluble fms-like tyrosine kinase-1 at 35 to 37 weeks of gestation, with a detection rate of ≈75% at a screen-positive rate of 10%. However, there is no known intervention to reduce the incidence of the disease.
METHODS
In this multicenter, double-blind, placebo-controlled trial, we randomly assigned 1120 women with singleton pregnancies at high risk of term preeclampsia to receive pravastatin at a dose of 20 mg/d or placebo from 35 to 37 weeks of gestation until delivery or 41 weeks. The primary outcome was delivery with preeclampsia at any time after randomization. The analysis was performed according to intention to treat.
RESULTS
A total of 29 women withdrew consent during the trial. Preeclampsia occurred in 14.6% (80 of 548) of participants in the pravastatin group and in 13.6% (74 of 543) in the placebo group. Allowing for the effect of risk at the time of screening and participating center, the mixed-effects Cox regression showed no evidence of an effect of pravastatin (hazard ratio for statin/placebo, 1.08 [95% CI, 0.78-1.49]; =0.65). There was no evidence of interaction between the effect of pravastatin, estimated risk of preeclampsia, pregnancy history, adherence, and aspirin treatment. There was no significant between-group difference in the incidence of any secondary outcomes, including gestational hypertension, stillbirth, abruption, delivery of small for gestational age neonates, neonatal death, or neonatal morbidity. There was no significant between-group difference in the treatment effects on serum placental growth factor and soluble fms-like tyrosine kinase-1 concentrations 1 and 3 weeks after randomization. Adherence was good, with reported intake of ≥80% of the required number of tablets in 89% of participants. There were no significant between-group differences in neonatal adverse outcomes or other adverse events.
CONCLUSIONS
Pravastatin in women at high risk of term preeclampsia did not reduce the incidence of delivery with preeclampsia. Registration: URL: https://www.isrctn.com; Unique identifier ISRCTN16123934.
Topics: Adult; Biomarkers; Comorbidity; Female; Gestational Age; Humans; Incidence; Kaplan-Meier Estimate; Mass Screening; Medication Adherence; Placebos; Pravastatin; Pre-Eclampsia; Pregnancy; Pregnancy Outcome; Prognosis; Risk Assessment; Risk Factors; Treatment Outcome; Young Adult
PubMed: 34162218
DOI: 10.1161/CIRCULATIONAHA.121.053963 -
Circulation Research Oct 2021[Figure: see text].
[Figure: see text].
Topics: Animals; Antineoplastic Agents; Autophagy; Autophagy-Related Protein 7; Cardiotoxicity; Doxorubicin; Myocarditis; Pravastatin; Spironolactone; Zebrafish; Zebrafish Proteins
PubMed: 34384247
DOI: 10.1161/CIRCRESAHA.121.319104 -
The Cochrane Database of Systematic... Sep 2023A detailed summary and meta-analysis of the dose-related effect of pravastatin on lipids is not available. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
A detailed summary and meta-analysis of the dose-related effect of pravastatin on lipids is not available.
OBJECTIVES
Primary objective To assess the pharmacology of pravastatin by characterizing the dose-related effect and variability of the effect of pravastatin on the surrogate marker: low-density lipoprotein (LDL cholesterol). The effect of pravastatin on morbidity and mortality is not the objective of this systematic review. Secondary objectives • To assess the dose-related effect and variability of effect of pravastatin on the following surrogate markers: total cholesterol; high-density lipoprotein (HDL cholesterol); and triglycerides. • To assess the effect of pravastatin on withdrawals due to adverse effects.
SEARCH METHODS
The Cochrane Hypertension Information Specialist searched the following databases for randomized controlled trials (RCTs) up to September 2021: CENTRAL (2021, Issue 8), Ovid MEDLINE, Ovid Embase, Bireme LILACS, the WHO International Clinical Trials Registry Platform, and ClinicalTrials.gov. We also contacted authors of relevant papers regarding further published and unpublished work. The searches had no language restrictions.
SELECTION CRITERIA
Randomized placebo-controlled trials evaluating the dose response of different fixed doses of pravastatin on blood lipids over a duration of three to 12 weeks in participants of any age with and without evidence of cardiovascular disease.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed eligibility criteria for studies to be included, and extracted data. We entered lipid data from placebo-controlled trials into Review Manager 5 as continuous data and withdrawal due to adverse effects (WDAEs) data as dichotomous data. We searched for WDAEs information from all trials. We assessed all trials using Cochrane's risk of bias tool under the categories of sequence generation, allocation concealment, blinding, incomplete outcome data, selective reporting, and other potential biases.
MAIN RESULTS
Sixty-four RCTs evaluated the dose-related efficacy of pravastatin in 9771 participants. The participants were of any age, with and without evidence of cardiovascular disease, and pravastatin effects were studied within a treatment period of three to 12 weeks. Log dose-response data over the doses of 5 mg to 160 mg revealed strong linear dose-related effects on blood total cholesterol and LDL cholesterol, and a weak linear dose-related effect on blood triglycerides. There was no dose-related effect of pravastatin on blood HDL cholesterol. Pravastatin 10 mg/day to 80 mg/day reduced LDL cholesterol by 21.7% to 31.9%, total cholesterol by 16.1% to 23.3%,and triglycerides by 5.8% to 20.0%. The certainty of evidence for these effects was judged to be moderate to high. For every two-fold dose increase there was a 3.4% (95% confidence interval (CI) 2.2 to 4.6) decrease in blood LDL cholesterol. This represented a dose-response slope that was less than the other studied statins: atorvastatin, rosuvastatin, fluvastatin, pitavastatin and cerivastatin. From other systematic reviews we conducted on statins for its effect to reduce LDL cholesterol, pravastatin is similar to fluvastatin, but has a decreased effect compared to atorvastatin, rosuvastatin, pitavastatin and cerivastatin. The effect of pravastatin compared to placebo on WADES has a risk ratio (RR) of 0.81 (95% CI 0.63 to 1.03). The certainty of evidence was judged to be very low.
AUTHORS' CONCLUSIONS
Pravastatin lowers blood total cholesterol, LDL cholesterol and triglyceride in a dose-dependent linear fashion. This review did not provide a good estimate of the incidence of harms associated with pravastatin because of the lack of reporting of adverse effects in 48.4% of the randomized placebo-controlled trials.
Topics: Humans; Infant, Newborn; Infant; Pravastatin; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Atorvastatin; Cardiovascular Diseases; Cholesterol, HDL; Cholesterol, LDL; Fluvastatin; Rosuvastatin Calcium; Drug-Related Side Effects and Adverse Reactions
PubMed: 37721222
DOI: 10.1002/14651858.CD013673.pub2 -
American Heart Journal Apr 2019The current guidelines of statins for primary cardiovascular disease (CVD) prevention were based on results from systematic reviews and meta-analyses that suffer from... (Comparative Study)
Comparative Study Meta-Analysis
Comparative effectiveness and safety of statins as a class and of specific statins for primary prevention of cardiovascular disease: A systematic review, meta-analysis, and network meta-analysis of randomized trials with 94,283 participants.
UNLABELLED
The current guidelines of statins for primary cardiovascular disease (CVD) prevention were based on results from systematic reviews and meta-analyses that suffer from limitations.
METHODS
We searched in PubMed for existing systematic reviews and individual open-label or double-blinded randomized controlled trials that compared a statin with a placebo or another, which were published in English until January 01, 2018. We performed a random-effect pairwise meta-analysis of all statins as a class and network meta-analysis for the specific statins on different benefit and harm outcomes.
RESULTS
In the pairwise meta-analyses, statins as a class showed statistically significant risk reductions on non-fatal MI (risk ratio [RR] 0.62, 95% CI 0.53-0.72), CVD mortality (RR 0.80, 0.71-0.91), all-cause mortality (RR 0.89, 0.85-0.93), non-fatal stroke (RR 0.83, 0.75-0.92), unstable angina (RR 0.75, 0.63-0.91), and composite major cardiovascular events (RR 0.74, 0.67-0.81). Statins increased statistically significantly relative and absolute risks of myopathy (RR 1.08, 1.01-1.15; Risk difference [RD] 13, 2-24 per 10,000 person-years); renal dysfunction (RR 1.12, 1.00-1.26; RD 16, 0-36 per 10,000 person-years); and hepatic dysfunction (RR 1.16, 1.02-1.31; RD 8, 1-16 per 10,000 person-years). The drug-level network meta-analyses showed that atorvastatin and rosuvastatin were most effective in reducing CVD events while atorvastatin appeared to have the best safety profile.
CONCLUSIONS
All statins showed statistically significant risk reduction of CVD and all-cause mortality in primary prevention populations while increasing the risk for some harm risks. However, the benefit-harm profile differed by statin type. A quantitative assessment of the benefit-harm balance is thus needed since meta-analyses alone are insufficient to inform whether statins provide net benefit.
Topics: Atorvastatin; Cardiovascular Diseases; Cause of Death; Chemical and Drug Induced Liver Injury; Double-Blind Method; Fluvastatin; Headache; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Kidney Diseases; Lovastatin; Middle Aged; Muscular Diseases; Nausea; Neoplasms; Network Meta-Analysis; Placebos; Pravastatin; Randomized Controlled Trials as Topic; Risk Assessment; Rosuvastatin Calcium; Simvastatin; Withholding Treatment
PubMed: 30716508
DOI: 10.1016/j.ahj.2018.12.007 -
The Cochrane Database of Systematic... Jan 2016This is an update of a Cochrane review first published in 2001 and then updated in 2009. Vascular risk factors including high cholesterol levels increase the risk of... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
This is an update of a Cochrane review first published in 2001 and then updated in 2009. Vascular risk factors including high cholesterol levels increase the risk of dementia due to Alzheimer's disease and of vascular dementia. Some observational studies have suggested an association between statin use and lowered incidence of dementia.
OBJECTIVES
To evaluate the efficacy and safety of statins for the prevention of dementia in people at risk of dementia due to their age and to determine whether the efficacy and safety of statins for this purpose depends on cholesterol level, apolipoprotein E (ApoE) genotype or cognitive level.
SEARCH METHODS
We searched ALOIS (the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group), The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS, ClinicalTrials.gov and the World Health Organization (WHO) Portal on 11 November 2015.
SELECTION CRITERIA
We included double-blind, randomised, placebo-controlled trials in which statins were administered for at least 12 months to people at risk of dementia.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures expected by Cochrane.
MAIN RESULTS
We included two trials with 26,340 participants aged 40 to 82 years of whom 11,610 were aged 70 or older. All participants had a history of, or risk factors for, vascular disease. The studies used different statins (simvastatin and pravastatin). Mean follow-up was 3.2 years in one study and five years in one study. The risk of bias was low. Only one study reported on the incidence of dementia (20,536 participants, 31 cases in each group; odds ratio (OR) 1.00, 95% confidence interval (CI) 0.61 to 1.65, moderate quality evidence, downgraded due to imprecision). Both studies assessed cognitive function, but at different times using different scales, so we judged the results unsuitable for a meta-analysis. There were no differences between statin and placebo groups on five different cognitive tests (high quality evidence). Rates of treatment discontinuation due to non-fatal adverse events were less than 5% in both studies and there was no difference between statin and placebo groups in the risk of withdrawal due to adverse events (26,340 participants, 2 studies, OR 0.94, 95% CI 0.83 to 1.05).
AUTHORS' CONCLUSIONS
There is good evidence that statins given in late life to people at risk of vascular disease do not prevent cognitive decline or dementia. Biologically, it seems feasible that statins could prevent dementia due to their role in cholesterol reduction and initial evidence from observational studies was very promising. However, indication bias may have been a factor in these studies and the evidence from subsequent RCTs has been negative. There were limitations in the included studies involving the cognitive assessments used and the inclusion of participants at moderate to high vascular risk only.
Topics: Adult; Aged; Aged, 80 and over; Alzheimer Disease; Anticholesteremic Agents; Cognition; Dementia; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Middle Aged; Pravastatin; Randomized Controlled Trials as Topic; Simvastatin
PubMed: 26727124
DOI: 10.1002/14651858.CD003160.pub3 -
Current Atherosclerosis Reports Apr 2019Observational studies and meta-analyses of randomized clinical trials data have revealed a 10-12% increased risk of new-onset diabetes (NOD) associated with statin... (Review)
Review
PURPOSE OF REVIEW
Observational studies and meta-analyses of randomized clinical trials data have revealed a 10-12% increased risk of new-onset diabetes (NOD) associated with statin therapy; the risk is increased with intensive treatment regimens and in people with features of the metabolic syndrome or prediabetes. The purpose of this review is to provide an updated summary of what is known about the potential mechanisms for the diabetogenic effect of statins.
RECENT FINDINGS
Hydroxyl methyl glutaryl coenzyme A reductase (HMGCoAR) is the target of statin therapy and the activity of this key enzyme in cholesterol synthesis is reduced by statins in a partial and reversible way. Mendelian randomization studies suggest that the effect of statins on glucose homeostasis reflect reduced activity of HMGCoAR. In vitro and in vivo data indicate that statins reduce synthesis of mevalonate pathway products and increase cholesterol loading, leading to impaired β-cell function and decreased insulin sensitivity and insulin release. While this effect has been thought to be a drug class effect, recent insights suggest that pravastatin and pitavastatin could exhibit neutral effects on glycaemic parameters in patients with and without diabetes mellitus. The mechanisms by which statins might lead to the development of NOD are unclear. The inhibition of HMGCoAR activity by statins appears to be a key mechanism. It is difficult to offer a comprehensive view regarding the diabetogenic effect of statins because our understanding of the most widely recognized potential mechanisms, i.e. underlying statin-induced reduction of insulin sensitivity and/or insulin secretion, is still far from complete. The existence of this dual mechanism is supported by the results of a study in a large group of non-diabetic men, showing that a 46% higher risk of NOD in statin users compared to non-users was accompanied by a significant 12% reduction in insulin secretion and a 24.3% increase in insulin resistance. Although statin therapy is associated with a modest increase in the risk of NOD (about one per thousand patient-years), patients should be reassured that the benefits of statins in preventing cardiovascular disease (CVD) events far outweigh the potential risk from elevation in plasma glucose.
Topics: Aged; Animals; Blood Glucose; Cardiovascular Diseases; Cholesterol; Diabetes Mellitus, Type 2; Humans; Hydroxymethylglutaryl CoA Reductases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Incidence; Insulin; Male; Metabolic Syndrome; Mice; Middle Aged; Pravastatin; Quinolines; Risk Factors
PubMed: 31037345
DOI: 10.1007/s11883-019-0780-z -
The Medical Letter on Drugs and... Sep 2019
Review
Topics: Anticholesteremic Agents; Delayed-Action Preparations; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Pravastatin; Statistics as Topic
PubMed: 31599870
DOI: No ID Found -
Medicina Clinica Jun 2018
Topics: Abdomen, Acute; Adenocarcinoma; Aged; Antimetabolites, Antineoplastic; Capecitabine; Combined Modality Therapy; Fenofibrate; Humans; Hypertriglyceridemia; Hypolipidemic Agents; Male; Oxaliplatin; Pancreatitis; Pravastatin; Sigmoid Neoplasms
PubMed: 29150119
DOI: 10.1016/j.medcli.2017.10.004