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Expert Opinion on Drug Safety Feb 2024Dyslipidaemia is a crucial risk factor for cardiovascular morbidity and mortality. A short interfering RNA called inclisiran diminishes circulating levels of PCSK9 and... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Dyslipidaemia is a crucial risk factor for cardiovascular morbidity and mortality. A short interfering RNA called inclisiran diminishes circulating levels of PCSK9 and LDL-C by hindering PCSK9 translation in the liver.
METHODS
RCTs were electronically searched on PubMed, Cochrane Central, and Clinicaltrials.gov to assess the safety and efficacy of inclisiran. Cochrane Review Manager 5 was used to conduct the pooled analysis. Risk of bias was assessed and GRADE pro-GDT was utilized, respectively, to estimate the methodological quality and overall quality of evidence.
RESULTS
Of 218 records screened, four studies were included with 2203 participants in inclisiran and 1949 participants in the placebo group. Inclisiran was related to non-significant elevated risk of total adverse events[RR = 1.05(0.98,1.12), = 0.16; I = 53%], non-serious adverse events[RR = 1.09(0.97,1.22), = 0.15;I = 61%] and all-cause mortality[RR = 1.01(0.60,1.70), = 0.97;I = 0%] whereas a lower risk of serious adverse events[RR = 0.94(0.70,1.25), = 0.67;I = 73%], cardiac disorders [RR = 0.87(0.66,1.15), = 0.33;I = 42%] and Major adverse cardiovascular events(MACE)[RR = 0.79(0.62,1.00), = 0.05; I = 0%] as compared to placebo. Inclisiran was also linked to a substantial decline in the percentage of LDL-C, PCSK9, total cholesterol, and Apo B.
CONCLUSION
The pooled analysis of the existing evidence shows that inclisiran showed reduced risk of MACE along with excellent efficacy in managing dyslipidemia.
CLINICAL TRIAL REGISTRATION
www.clinicaltrials.gov identifiers are NCT03399370, NCT03397121, NCT03400800, and NCT02597127.
Topics: Humans; Anticholesteremic Agents; Cardiovascular Diseases; Cholesterol, LDL; Dyslipidemias; Hyperlipidemias; Proprotein Convertase 9; RNA, Small Interfering
PubMed: 38063346
DOI: 10.1080/14740338.2023.2293201 -
Canadian Family Physician Medecin de... Oct 2023To assess the benefits and harms of lipid-lowering therapies used to prevent or manage cardiovascular disease including bile acid sequestrants (BAS), ezetimibe,...
OBJECTIVE
To assess the benefits and harms of lipid-lowering therapies used to prevent or manage cardiovascular disease including bile acid sequestrants (BAS), ezetimibe, fibrates, niacin, omega-3 supplements, proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors, and statins.
DATA SOURCES
MEDLINE, the Cochrane Database of Systematic Reviews, and a grey literature search.
STUDY SELECTION
Systematic reviews of randomized controlled trials published between January 2017 and March 2022 looking at statins, ezetimibe, PCSK9 inhibitors, fibrates, BAS, niacin, and omega-3 supplements for preventing cardiovascular outcomes were selected. Outcomes of interest included major adverse cardiovascular events (MACE), cardiovascular mortality, all-cause mortality, and adverse events.
SYNTHESIS
A total of 76 systematic reviews were included. Four randomized controlled trials were also included for BAS because no efficacy systematic review was identified. Statins significantly reduced MACE (6 systematic reviews; median risk ratio [RR]=0.74; interquartile range [IQR]=0.71 to 0.76), cardiovascular mortality (7 systematic reviews; median RR=0.85, IQR=0.83 to 0.86), and all-cause mortality (8 systematic reviews; median RR=0.91, IQR=0.88 to 0.92). Major adverse cardiovascular events were also significantly reduced by ezetimibe (3 systematic reviews; median RR=0.93, IQR=0.93 to 0.94), PCSK9 inhibitors (14 systematic reviews; median RR=0.84, IQR=0.83 to 0.87), and fibrates (2 systematic reviews; mean RR=0.86), but these interventions had no effect on cardiovascular or all-cause mortality. Fibrates had no effect on any cardiovascular outcomes when added to a statin. Omega-3 combination supplements had no effect on MACE or all-cause mortality but significantly reduced cardiovascular mortality (5 systematic reviews; median RR=0.93, IQR=0.93 to 0.94). Eicosapentaenoic acid ethyl ester alone significantly reduced MACE (1 systematic review, RR=0.78) and cardiovascular mortality (2 systematic reviews; RRs of 0.82 and 0.82). In primary cardiovascular prevention, only statins showed consistent benefits on MACE (6 systematic reviews; median RR=0.75, IQR=0.73 to 0.78), cardiovascularall-cause mortality (7 systematic reviews, median RR=0.83, IQR=0.81 to 0.90), and all-cause mortality (8 systematic reviews; median RR=0.91, IQR=0.87 to 0.91).
CONCLUSION
Statins have the most consistent evidence for the prevention of cardiovascular complications with a relative risk reduction of about 25% for MACE and 10% to 15% for mortality. The addition of ezetimibe, a PCSK9 inhibitor, or eicosapentaenoic acid ethyl ester to a statin provides additional MACE risk reduction but has no effect on all-cause mortality.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Proprotein Convertase 9; Cardiovascular Diseases; PCSK9 Inhibitors; Niacin; Systematic Reviews as Topic; Ezetimibe; Lipids; Fibric Acids; Primary Health Care; Anticholesteremic Agents
PubMed: 37833094
DOI: 10.46747/cfp.6910701 -
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 -
World Neurosurgery May 2017Aneurysmal hemorrhage induced cerebral vasospasm; delayed ischemic neurologic deficit (DIND), poor neurologic outcome, and mortality are major causes of mortality and... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Aneurysmal hemorrhage induced cerebral vasospasm; delayed ischemic neurologic deficit (DIND), poor neurologic outcome, and mortality are major causes of mortality and morbidity. The effects of cholesterol-lowering agents in these patients remain controversial. This up-to-date systematic review and meta-analysis aimed to evaluate the efficacy of statin use in patients with aneurysmal subarachnoid hemorrhage.
METHODS
A systematic review of the literature conducted using electronic database searched up to September 2016 included Cochrane Central Register of Controlled Trials in the Cochrane Library, Medline, Embase, and Science Citation Index Expanded database to identify relevant studies. Data were extracted and critically appraised by 3 independent authors. In addition, fixed or random-effects model were applied to calculated pooled results based on degree of heterogeneity.
RESULTS
Ten randomized controlled trials were identified with 1214 patients; 587 patients received statins and there were 627 patients in the placebo group. Statins were found to significantly reduce cerebral vasospasm (odds ratio [OR], 0.46; 95% confidence interval [CI], 0.28-0.78, P = 0.002) and DIND (OR, 0.72; 95% CI, 0.54-0.97; P = 0.03). However, there was no significant decrease in mortality (OR, 0.77; 95% CI, 0.54-1.11; P = 0.16) and poor neurologic outcome (OR, 0.96; 95% CI, 0.75-1.23; P = 0.74).
CONCLUSIONS
The outcome of this meta-analysis showed that use of statins in aneurysmal subarachnoid hemorrhage might have the potential to decrease occurrence of vasospasm and DIND. However, there was no benefit in the reduction of mortality and poor neurologic outcome. This is a call for further research.
Topics: Anticholesteremic Agents; Cholesterol; Humans; Randomized Controlled Trials as Topic; Subarachnoid Hemorrhage; Treatment Outcome; Vasospasm, Intracranial
PubMed: 28192263
DOI: 10.1016/j.wneu.2017.01.125 -
JAMA Jul 2023Lipid screening in childhood and adolescence can lead to early dyslipidemia diagnosis. The long-term benefits of lipid screening and subsequent treatment in this... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Lipid screening in childhood and adolescence can lead to early dyslipidemia diagnosis. The long-term benefits of lipid screening and subsequent treatment in this population are uncertain.
OBJECTIVE
To review benefits and harms of screening and treatment of pediatric dyslipidemia due to familial hypercholesterolemia (FH) and multifactorial dyslipidemia.
DATA SOURCES
MEDLINE and the Cochrane Central Register of Controlled Trials through May 16, 2022; literature surveillance through March 24, 2023.
STUDY SELECTION
English-language randomized clinical trials (RCTs) of lipid screening; recent, large US cohort studies reporting diagnostic yield or screen positivity; and RCTs of lipid-lowering interventions.
DATA EXTRACTION AND SYNTHESIS
Single extraction, verified by a second reviewer. Quantitative synthesis using random-effects meta-analysis.
MAIN OUTCOMES AND MEASURES
Health outcomes, diagnostic yield, intermediate outcomes, behavioral outcomes, and harms.
RESULTS
Forty-three studies were included (n = 491 516). No RCTs directly addressed screening effectiveness and harms. Three US studies (n = 395 465) reported prevalence of phenotypically defined FH of 0.2% to 0.4% (1:250 to 1:500). Five studies (n = 142 257) reported multifactorial dyslipidemia prevalence; the prevalence of elevated total cholesterol level (≥200 mg/dL) was 7.1% to 9.4% and of any lipid abnormality was 19.2%. Ten RCTs in children and adolescents with FH (n = 1230) demonstrated that statins were associated with an 81- to 82-mg/dL greater mean reduction in levels of total cholesterol and LDL-C compared with placebo at up to 2 years. Nonstatin-drug trials showed statistically significant lowering of lipid levels in FH populations, but few studies were available for any single drug. Observational studies suggest that statin treatment for FH starting in childhood or adolescence reduces long-term cardiovascular disease risk. Two multifactorial dyslipidemia behavioral counseling trials (n = 934) demonstrated 3- to 6-mg/dL greater reductions in total cholesterol levels compared with the control group, but findings did not persist at longest follow-up. Harms reported in the short-term drug trials were similar in the intervention and control groups.
CONCLUSIONS AND RELEVANCE
No direct evidence on the benefits or harms of pediatric lipid screening was identified. While multifactorial dyslipidemia is common, no evidence was found that treatment is effective for this condition. In contrast, FH is relatively rare; evidence shows that statins reduce lipid levels in children with FH, and observational studies suggest that such treatment has long-term benefit for this condition.
Topics: Adolescent; Child; Humans; Cholesterol; Dyslipidemias; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipids; Mass Screening; Hypercholesterolemia
PubMed: 37462700
DOI: 10.1001/jama.2023.8867 -
Journal of Gastrointestinal and Liver... Dec 2020The use of statins has been shown to be associated with a decreased risk of cholangiocarcinoma (CCA) in many studies although the results have been inconsistent. We... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND AIMS
The use of statins has been shown to be associated with a decreased risk of cholangiocarcinoma (CCA) in many studies although the results have been inconsistent. We conducted this systematic review and meta-analysis to further investigate this possible association by identifying all relevant studies and combining their results together.
METHODS
A comprehensive literature review was conducted utilizing the MEDLINE and EMBASE databases through March 2020 to identify all studies that compared the risk of CCA among individuals who use statins with individuals who do not use statins. Effect estimates from each study were extracted and combined using the random-effect, generic inverse variance method of DerSimonian and Laird.
RESULTS
A total of seven studies with 6,251,187 participants fulfilled the eligibility criteria and were included in this meta-analysis. The pooled analysis found a significantly decreased risk of CCA among individuals who use statins compared with individuals who do not use statins with the pooled odds ratio of 0.68 (95% CI: 0.52-0.89; I 2 96%).
CONCLUSIONS
The current systematic review and meta-analysis found a significant association between the use of statins and a decreased risk of CCA.
Topics: Bile Duct Neoplasms; Cholangiocarcinoma; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors
PubMed: 33331334
DOI: 10.15403/jgld-2990 -
Archives of Internal Medicine Apr 2005Guidelines for the prevention and treatment of hyperlipidemia are often based on trials using combined clinical end points. Mortality data are the most reliable data to... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Guidelines for the prevention and treatment of hyperlipidemia are often based on trials using combined clinical end points. Mortality data are the most reliable data to assess efficacy of interventions. We aimed to assess efficacy and safety of different lipid-lowering interventions based on mortality data.
METHODS
We conducted a systematic search of randomized controlled trials published up to June 2003, comparing any lipid-lowering intervention with placebo or usual diet with respect to mortality. Outcome measures were mortality from all, cardiac, and noncardiovascular causes.
RESULTS
A total of 97 studies met eligibility criteria, with 137,140 individuals in intervention and 138,976 individuals in control groups. Compared with control groups, risk ratios for overall mortality were 0.87 for statins (95% confidence interval [CI], 0.81-0.94), 1.00 for fibrates (95% CI, 0.91-1.11), 0.84 for resins (95% CI, 0.66-1.08), 0.96 for niacin (95% CI, 0.86-1.08), 0.77 for n-3 fatty acids (95% CI, 0.63-0.94), and 0.97 for diet (95% CI, 0.91-1.04). Compared with control groups, risk ratios for cardiac mortality indicated benefit from statins (0.78; 95% CI, 0.72-0.84), resins (0.70; 95% CI, 0.50-0.99) and n-3 fatty acids (0.68; 95% CI, 0.52-0.90). Risk ratios for noncardiovascular mortality of any intervention indicated no association when compared with control groups, with the exception of fibrates (risk ratio, 1.13; 95% CI, 1.01-1.27).
CONCLUSIONS
Statins and n-3 fatty acids are the most favorable lipid-lowering interventions with reduced risks of overall and cardiac mortality. Any potential reduction in cardiac mortality from fibrates is offset by an increased risk of death from noncardiovascular causes.
Topics: Cardiovascular Diseases; Clofibric Acid; Diet, Fat-Restricted; Fatty Acids, Omega-3; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Niacin
PubMed: 15824290
DOI: 10.1001/archinte.165.7.725 -
Postgraduate Medicine Jan 2018Cardiovascular disease (CVD) is the major cause of morbidity and mortality worldwide. Anacetrapib may be a new treatment option that has a cardiovascular benefit for the... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Cardiovascular disease (CVD) is the major cause of morbidity and mortality worldwide. Anacetrapib may be a new treatment option that has a cardiovascular benefit for the management of dyslipidemia.
OBJECTIVE
The aim of our current study was to perform a systematic review and meta-analysis of all randomized controlled trials (RCTs) assessing the effect and safety of anacetrapib in the treatment of dyslipidemia.
METHODS
We systematically searched PubMed, Embase, and Cochrane Library database from their inception to 5 October 2017, with the terms: 'anacetrapib' and 'placebo'. From 287 initial citations, 10 studies including 34781 patients with dyslipidemia were included in the final systematic review and meta-analysis.
RESULTS
Pooled results showed that anacetrapib significantly increased high density lipoprotein cholesterol (HDL-C) [weighted mean differences (WMD) 53.07, 95% confidence interval (95% CI) 46.79 to 59.36] and apolipoprotein AI (ApoAI) (WMD 53.44, 95% CI 45.72 to 61.16). Our study also showed that anacetrapib significantly reduced low density lipoprotein cholesterol (LDL-C) (WMD -32.99; 95% CI -37.13 to -28.86), Non-HDL-C (WMD -39.19; 95% CI -52.22 to -26.16), triglycerides (TG) (WMD -9.97; 95% CI -10.54 to -9.41), apolipoprotein B (ApoB) (WMD -22.55; 95% CI -28.56 to -16.54) and lipoprotein a [LP(a)] (WMD -13.35; 95% CI -18.31 to -8.39). Our results demonstrated that there was no significant difference in all the following adverse events between the anacetrapib group and placebo group: [hepato-toxicity (OR 0.90, 95% CI: 0.75 to 1.07); musculoskeletal injury (OR 1.01, 95% CI: 0.88 to 1.15); drug-related adverse event (OR 1.00, 95% CI: 0.96 to 1.05); drug-related withdrawn (OR 1.01, 95% CI: 0.95 to 1.08)].
CONCLUSIONS
Although further studies are needed, our findings clearly offer support to the use of anacetrapib in the clinical management of patients with dyslipidemia.
Topics: Anticholesteremic Agents; Dyslipidemias; Humans; Oxazolidinones
PubMed: 29135318
DOI: 10.1080/00325481.2018.1401421 -
The Lancet. Haematology Feb 2017Statins have been suggested to have a protective effect on venous thromboembolism (which includes deep vein thrombosis and pulmonary embolism), but the evidence is... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Statins have been suggested to have a protective effect on venous thromboembolism (which includes deep vein thrombosis and pulmonary embolism), but the evidence is uncertain. We sought to evaluate the extent to which statins are associated with first venous thromboembolism events.
METHODS
We did a systematic review and meta-analysis of observational cohort studies and randomised controlled trials (RCTs). Relevant studies that reported associations between statins and first venous thromboembolism outcomes were identified from MEDLINE, Embase, Web of Science, Cochrane Library, and a manual search of bibliographies for studies published up until July 18, 2016, and from email correspondence with investigators. Observational cohorts that assessed the association of statin use with venous thromboembolism, deep vein thrombosis, or pulmonary embolism in adults were included, as were intervention studies that assessed the effects of statin therapy compared with a placebo or no treatment and collected data on venous thromboembolism, deep vein thrombosis, or pulmonary embolism outcomes. Studies that compared statins with another statin or lipid-lowering agent were excluded. Study specific relative risks (RRs) were aggregated using random-effects models and were grouped by study-level characteristics. The review has been registered with PROSPERO, number CRD42016035622.
FINDINGS
36 eligible studies (13 cohort studies comprising 3 148 259 participants and 23 RCTs of statins vs placebo or no treatment comprising 118 464 participants) were included. In observational studies, the pooled RR for venous thromboembolism was 0·75 (95% CI 0·65-0·87; p<0·0001) when statin use was compared with no statin use. This association remained consistent when grouped by various study-level characteristics. In RCTs, the RR for venous thromboembolism was 0·85 (0·73-0·99; p=0·038) when statin therapy was compared with placebo or no treatment. Subgroup analyses suggested significant differences in the effect of statins by type of statin, with rosuvastatin having the lowest risk on venous thromboembolism compared with other statins 0·57 (0·42-0·75; p=0·015). There was no evidence of an effect of statin use on pulmonary embolism. Statin use was associated with a significant reduction in risk of the specific endpoint of deep vein thrombosis compared with no statin use (RR 0·77, 95% CI 0·69-0·86; p<0·0001).
INTERPRETATION
Available evidence from observational and intervention studies suggest a beneficial effect of statin use on venous thromboembolism. In intervention studies, therapy with rosuvastatin significantly reduced venous thromboembolism compared with other statins. Further evidence is however needed to validate these findings.
FUNDING
None.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Primary Prevention; Venous Thromboembolism
PubMed: 28089655
DOI: 10.1016/S2352-3026(16)30184-3 -
Cardiovascular Drugs and Therapy Dec 2016
Meta-Analysis Review
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Anticholesteremic Agents; Cholesterol, LDL; Humans; Hypercholesterolemia; PCSK9 Inhibitors
PubMed: 27830381
DOI: 10.1007/s10557-016-6703-0