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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 -
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 -
Current Problems in Cardiology Oct 2023Anthracycline chemotherapy causes cardiotoxicity, and the evidence regarding the benefit of concomitant statin use in reducing it remains uncertain. We conducted a... (Meta-Analysis)
Meta-Analysis Review
Anthracycline chemotherapy causes cardiotoxicity, and the evidence regarding the benefit of concomitant statin use in reducing it remains uncertain. We conducted a meta-analysis of studies using statins and anthracyclines by searching PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov from inception until April 10, 2023. Our analysis included 3 observational studies and 4 RCTs, including the STOP-CA trial released in ACC23. Statin prescription significantly reduced cardiotoxicity in cancer patients receiving anthracycline chemotherapy (OR 0.46, 95% CI: 0.33-0.63; I2: 0%). However, no significant difference was observed in the decline of left ventricular ejection fraction (LVEF) from baseline (MD 4.15, 95% CI: -0.69 to 8.99, I2: 97%). These findings demonstrate the protective effect of concomitant statin prescription.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Cardiotoxicity; Stroke Volume; Ventricular Function, Left; Anthracyclines; Antibiotics, Antineoplastic; Observational Studies as Topic
PubMed: 37336312
DOI: 10.1016/j.cpcardiol.2023.101885 -
Frontiers in Immunology 2023Various immunosuppressive regimens have been developed for the treatment of lupus nephritis (LN). This study aimed to compare the efficacy and safety of... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Various immunosuppressive regimens have been developed for the treatment of lupus nephritis (LN). This study aimed to compare the efficacy and safety of immunosuppressive regimens in adults with LN.
METHODS
We systematically searched the PubMed, Embase, and Cochrane Central Register of Controlled Trials databases, including conference proceedings, trial registries, and reference lists, from inception until July 10, 2022. The effects of treatment were compared and ranked using the surface under the cumulative ranking curve (SUCRA). The primary endpoint was total remission. The secondary endpoints were complete remission, systemic lupus erythematosus disease activity index (SLEDAI), relapse, all-cause mortality, end-stage renal disease (ESRD), infection, herpes zoster, ovarian failure, myelosuppression, and cancer.
RESULTS
Sixty-two trials reported in 172 studies involving 6,936 patients were included in the network meta-analysis. The combination of tacrolimus (TAC), mycophenolate mofetil (MMF), and glucocorticoid (GC) provided the best result for the total remission rate (SUCRA, 86.63%) and SLEDAI (SUCRA, 91.00%), while the combination of voclosporin (VCS) , MMF and GC gave the best improvement in the complete remission rate (SUCRA, 90.71%). The combination of cyclophosphamide (CYC), MMF and GC was associated with the lowest risk of relapse (SUCRA, 85.57%) and cancer (SUCRA, 85.14%), while the combination of obinutuzumab (OTB), MMF and GC was associated with the lowest risk of all-cause mortality (SUCRA, 84.07%). Rituximab (RTX) plus MMF plus GC was associated with the lowest risk of ESRD (SUCRA, 83.11%), while the risk of infection was lowest in patients treated with azathioprine (AZA) plus CYC plus GC (SUCRA, 68.59%). TAC plus GC was associated with the lowest risk of herpes zoster (SUCRA, 87.67%) and ovarian failure (SUCRA, 73.60%). Cyclosporine (CsA) plus GC was associated with the lowest risk of myelosuppression (SUCRA, 79.50%), while AZA plus GC was associated with the highest risk of myelosuppression (SUCRA, 16.25%).
DISCUSSION
This study showed that a combination of TAC, MMF and GC was the best regimen for improving the total remission rate. The optimal regimen for specific outcomes should be highlighted for high-risk patients.
Topics: Humans; Adult; Immunosuppressive Agents; Lupus Nephritis; Network Meta-Analysis; Treatment Outcome; Cyclophosphamide; Tacrolimus; Azathioprine; Mycophenolic Acid; Glucocorticoids; Bone Marrow Diseases; Kidney Failure, Chronic; Recurrence; Herpes Zoster; Neoplasms
PubMed: 37901212
DOI: 10.3389/fimmu.2023.1232244 -
Nutrients Dec 2023Nicotinamide is the active form of vitamin B3 (niacin) obtained through endogenous synthesis, mainly through tryptophan metabolism and dietary supplements, fish, meats,... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Nicotinamide is the active form of vitamin B3 (niacin) obtained through endogenous synthesis, mainly through tryptophan metabolism and dietary supplements, fish, meats, grains, and dairy products. It participates in cellular energy metabolism and modulates multiple cellular survival and death pathways. Nicotinamide has been widely studied as a safe chemopreventive agent that reduces actinic keratosis (AKs) and non-melanoma skin cancers (NMSC).
METHODS
We used the Medline, EMBASE, PubMed, and Cochrane databases to search the concepts "nicotinamide", "chemoprevention", and "skin cancer" up to August 2023. Three independent authors screened titles and abstracts for intervention and study design before searching full texts for eligibility criteria. The primary outcome was the impact of oral nicotinamide on the incidence of NMSC in high-risk patients. We also conducted a systematic search to identify relevant epidemiological studies published evaluating dietary niacin intake and the risk of NMSC.
RESULTS
Two hundred and twenty-five studies were reviewed, and four met the inclusion criteria. There was no association between NAM consumption and risk for squamous cell carcinoma (SCC) (rate ratio (RR) 0.81, 95% CI 0.48-1.37; I = 0%), basal cell carcinoma (BCC) (RR 0.88, 95% CI 0.50-1.55; I = 63%), and NMSC (RR 0.82, 95% CI 0.61-1.12; I = 63%). Adverse events were rare and acceptable, allowing optimal compliance of patients to the treatment. We found only one article evaluating the association between niacin dietary intake and NMSC risk, supporting a potential beneficial role of niacin intake concerning SCC but not BCC or melanoma.
CONCLUSIONS
The present meta-analysis shows, by pooling immunocompetent and immunosuppressed patients, that there is insufficient evidence that oral nicotinamide therapy significantly reduces the number of keratinocyte cancers.
Topics: Animals; Humans; Niacinamide; Niacin; Chemoprevention; Skin Neoplasms; Carcinoma, Basal Cell; Carcinoma, Squamous Cell
PubMed: 38201930
DOI: 10.3390/nu16010100 -
Current Atherosclerosis Reports Nov 2023This review aimed to determine the association between statin use and coronary artery calcification (CAC), as detected by computed tomography in the general population,... (Meta-Analysis)
Meta-Analysis Review
PURPOSE OF REVIEW
This review aimed to determine the association between statin use and coronary artery calcification (CAC), as detected by computed tomography in the general population, in previously published observational studies (OSs) and randomized controlled trials (RCTs).
RECENT FINDINGS
A systematic search until February 2022 identified 41 relevant studies, comprising 29 OSs and 12 RCTs. We employed six meta-analysis models, stratifying studies based on design and effect metrics. For cohort studies, the pooled β of the association with CAC quantified by the Agatston score was 0.11 (95% CI = 0.05; 0.16), with an average follow-up time per person (AFTP) of 3.68 years. Cross-sectional studies indicated a pooled odds ratio of 2.11 (95% CI = 1.61; 2.78) for the presence of CAC. In RCTs, the pooled standardized mean differences (SMDs) for CAC, quantified by Agatston score or volume, over and AFTP of 1.25 years were not statistically significant (SMD = - 0.06, 95% CI = - 0.19; 0.06 and SMD = 0.26, 95% CI = - 0.66; 1.19), but significantly different (p-value = 0.04). Meta-regression and subgroup analyses did not show any significant differences in pooled estimates across covariates. The effect of statins on CAC differs across study designs. OSs demonstrate associations between statin use and higher CAC scores and presence while being prone to confounding by indication. Effects from RCTs do not reach statistical significance and vary depending on the quantification method, hampering drawing conclusions. Further investigations are required to address the limitations inherent in each approach.
Topics: Humans; Coronary Artery Disease; Coronary Vessels; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Risk Factors; Vascular Calcification; Observational Studies as Topic
PubMed: 37796384
DOI: 10.1007/s11883-023-01151-w -
Journal of Stroke and Cerebrovascular... Apr 2024Investigate the efficacy and safety of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) on stroke prevention. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
Investigate the efficacy and safety of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) on stroke prevention.
BACKGROUND
PCSK9i reduce low-density lipoprotein cholesterol (LDL-C) and lipoprotein a (LpA) levels. Their efficacy in reducing the risk of major cardiovascular events has been shown in multiple randomized clinical trials (RCT). However, clinical equipoise remains on the magnitude and mechanisms by which PCSK9i decrease the risk of stroke.
METHODS
We performed a systematic search of biomedical databases from inception to January 15, 2024, to identify RCTs that investigated the efficacy of PCSK9i versus placebo for major cardiovascular event prevention. The primary outcome was total stroke. The safety outcome was the risk of adverse neurological events, as defined by each trial. Effect size was represented by risk ratio (RR), and analysis was done using random-effects meta-analysis. Heterogeneity was assessed by I and Cochrane Q statistics. Meta-regression analyses were performed to assess the association between LDL-C and LpA reduction and stroke risk.
RESULTS
Overall, 20 studies with 93,093 patients were included. The quality of the evidence was moderate and heterogeneity for all comparisons was low (I < 25 %). The mean age was 60.1 years for the PCSK9i group and 59.6 years for the placebo group, with a mean follow-up time of 60.1 weeks. PCSK9i reduced the LDL-C levels by 11 % and LpA levels by 8 %. PCSK9i were associated with a significant reduction in stroke risk (RR 0.75, 95 % CI 0.66-0.86, I = 0 %), without an increase in mortality (RR 0.97, 95 % CI 0.87-1.08, I = 0 %). The risk of adverse neurological events was similar between groups (RR 0.99, 95 % CI 0.84-1.18, I = 11 %). In meta-regression analyses, the stroke risk was not associated with the magnitude of the effect of PCSK9i on LDL-C (LDL C β = -0.01, 95 % CI = -0.03-0.02) and LpA (β = -0.01, 95 % CI = -0.06-0.04) levels.
CONCLUSIONS
PCSK9i significantly reduced the stroke risk, without increasing mortality or the risk of adverse neurological events. Our findings also suggest that the beneficial effect of PCSK9i on stroke risk is mediated by LDL-C- and LpA-independent mechanisms.
Topics: Humans; Middle Aged; PCSK9 Inhibitors; Cholesterol, LDL; Antibodies, Monoclonal, Humanized; Stroke; Anticholesteremic Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Cardiovascular Diseases; Proprotein Convertase 9
PubMed: 38336118
DOI: 10.1016/j.jstrokecerebrovasdis.2024.107633 -
Endocrine Aug 2023This systematic review aimed to evaluate the benefits and harms of fibrate therapy, alone or in combination with statins, in adult patients with type 2 diabetes (T2D). (Meta-Analysis)
Meta-Analysis
PURPOSE
This systematic review aimed to evaluate the benefits and harms of fibrate therapy, alone or in combination with statins, in adult patients with type 2 diabetes (T2D).
METHODS
A comprehensive search was conducted in six databases, from inception to January 27, 2022. Clinical trials that compared fibrate therapy with other lipid-lowering interventions or placebo were included. Outcomes of interest comprised cardiovascular (CV) events, complications of T2D, metabolic profile, and adverse events. Random-effects meta-analyses were performed to estimate mean differences (MD) and risk ratios (RR), alongside 95% confidence intervals (CI).
RESULTS
A total of 25 studies were included, six comparing fibrates against statins, 11 against placebo, and eight evaluating the combination of fibrates with statins. Overall risk of bias was rated as moderate, and most outcomes rendered low confidence per GRADE approach. Fibrates showed reduction of serum triglycerides (TGs) (MD -17.81, CI -33.92 to -1.69) and a marginal increase of high-density lipoprotein cholesterol (HDL-c) (MD: 1.60, CI 0.29 to 2.90) in adults with T2D, but no differences were found in CV events when compared to statin therapy (RR 0.99, CI 0.76 to 1.09). When used in combination with statins, no major differences were exhibited regarding lipid profile and CV outcomes. Adverse events were comparable between fibrate and statin monotherapies (e.g., RR of 1.03 for rhabdomyolysis, and 0.90 for gastrointestinal events).
CONCLUSIONS
Fibrate therapy in patients with T2D results in a marginal improvement of TGs and HDL-c but without reducing the risk of CV events and mortality. Their use should be reserved for very specific scenarios after a deliberative dialogue between patients and clinicians regarding their benefits and harms.
Topics: Adult; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Fibric Acids; Diabetes Mellitus, Type 2; Cholesterol, HDL; Triglycerides; Cardiovascular Diseases
PubMed: 37247046
DOI: 10.1007/s12020-023-03401-y -
BMJ Open Respiratory Research Feb 2024Mycophenolate mofetil (MMF) and azathioprine (AZA) are immunomodulatory treatments in interstitial lung disease (ILD). This systematic review aimed to evaluate the... (Meta-Analysis)
Meta-Analysis
OBJECTIVES
Mycophenolate mofetil (MMF) and azathioprine (AZA) are immunomodulatory treatments in interstitial lung disease (ILD). This systematic review aimed to evaluate the efficacy of MMF or AZA on pulmonary function in ILD.
DESIGN
Population included any ILD diagnosis, intervention included MMF or AZA treatment, outcome was delta change from baseline in per cent predicted forced vital capacity (%FVC) and gas transfer (diffusion lung capacity of carbon monoxide, %DLco). The primary endpoint compared outcomes relative to placebo comparator, the secondary endpoint assessed outcomes in treated groups only.
ELIGIBILITY CRITERIA
Randomised controlled trials (RCTs) and prospective observational studies were included. No language restrictions were applied. Retrospective studies and studies with high-dose concomitant steroids were excluded.
DATA SYNTHESIS
The systematic search was performed on 9 May. Meta-analyses according to drug and outcome were specified with random effects, I evaluated heterogeneity and Grading of Recommendations, Assessment, Development and Evaluation evaluated certainty of evidence. Primary endpoint analysis was restricted to RCT design, secondary endpoint included subgroup analysis according to prospective observational or RCT design.
RESULTS
A total of 2831 publications were screened, 12 were suitable for quantitative synthesis. Three MMF RCTs were included with no significant effect on the primary endpoints (%FVC 2.94, 95% CI -4.00 to 9.88, I=79.3%; %DLco -2.03, 95% CI -4.38 to 0.32, I=0.0%). An overall 2.03% change from baseline in %FVC (95% CI 0.65 to 3.42, I=0.0%) was observed in MMF, and RCT subgroup summary estimated a 4.42% change from baseline in %DL (95% CI 2.05 to 6.79, I=0.0%). AZA studies were limited. All estimates were considered very low certainty evidence.
CONCLUSIONS
There were limited RCTs of MMF or AZA and their benefit in ILD was of very low certainty. MMF may support preservation of pulmonary function, yet confidence in the effect was weak. To support high certainty evidence, RCTs should be designed to directly assess MMF efficacy in ILD.
PROSPERO REGISTRATION NUMBER
CRD42023423223.
Topics: Humans; Azathioprine; Immunosuppressive Agents; Lung Diseases, Interstitial; Lung; Mycophenolic Acid; Enzyme Inhibitors; Observational Studies as Topic
PubMed: 38413120
DOI: 10.1136/bmjresp-2023-002163 -
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