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The risk of respiratory tract infections and interstitial lung disease with interleukin 12/23 and interleukin 23 antagonists in patients with autoimmune diseases: A systematic review and meta-analysis.
Akiyama, S, Yamada, A, Micic, D, Sakuraba, A
Journal of the American Academy of Dermatology. 2021;(3):676-690
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BACKGROUND Respiratory tract infections (RTIs) and interstitial lung disease (ILD) secondary to interleukin (IL) 12/23 or IL-23 antagonists have been reported in autoimmune diseases. OBJECTIVE To assess the risk of RTIs and noninfectious ILD with these drugs. METHODS We conducted a systematic review and meta-analysis of randomized controlled trials. Risk of RTIs and noninfectious ILD was compared to placebo by Mantel-Haenszel risk difference. We divided RTIs into upper RTIs (URTI), viral URTIs, and lower RTIs (LRTIs) including infectious pneumonia. Noninfectious ILD included ILD, eosinophilic pneumonia, and pneumonitis. RESULTS We identified 54 randomized controlled trials including 10,907 patients with 6 IL-12/23 or IL-23 antagonists and 5175 patients with placebo. These drugs significantly increased the risk of RTIs (Mantel-Haenszel risk difference, 0.019; 95% confidence interval, 0.005-0.033; P = .007), which was attributed to URTIs, but not viral URTIs or LRTIs. There was no significant difference in infectious pneumonia and noninfectious ILD between 2 groups. LIMITATIONS Because of the rarity of infectious pneumonia and ILD, sensitivity analysis was required. CONCLUSIONS The use of IL-12/23 or IL-23 antagonists for autoimmune diseases increased the risk of URTIs, but not viral URTIs, LRTIs, and noninfectious ILD.
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Comparison of First-Line Treatments for Patients With Extensive-Stage Small Cell Lung Cancer: A Systematic Review and Network Meta-analysis.
Zhou, T, Zhang, Z, Luo, F, Zhao, Y, Hou, X, Liu, T, Wang, K, Zhao, H, Huang, Y, Zhang, L
JAMA network open. 2020;(10):e2015748
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IMPORTANCE Combinations of chemotherapy with immunotherapy or bevacizumab in first-line treatments of extensive-stage small cell lung cancer (ES-SCLC) have been evaluated in various clinical trials. However, it remains unclear what the optimal combination regimen is. OBJECTIVE To clarify which first-line combination regimen is associated with the best tumor response among patients with ES-SCLC. DATA SOURCES Electronic databases (PubMed, Embase, Cochrane Central Register of Controlled Trials, and Web of Science) were systematically searched to extract eligible literature from database inception to December 2019. STUDY SELECTION Head-to-head randomized clinical trials on first-line treatments for patients with ES-SCLC were included with outcomes and toxic effects reported, including objective response rate (ORR, involving complete response and partial response), disease control rate (DCR, involving complete response, partial response, and stable disease), progression-free survival (PFS), overall survival (OS), and treatment related adverse events (TRAEs) of grades 3 to 5. Of 199 eligible articles, 14 were included. DATA EXTRACTION AND SYNTHESIS Data were independently extracted and collected by 2 reviewers based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. Data were pooled using a random-effects model. MAIN OUTCOMES AND MEASURES Main outcomes were OS, PFS, DCR, ORR, and TRAEs of grades 3 to 5. RESULTS A total of 3 phase 2 and 11 phase 3 randomized clinical trials involving 4838 patients were included. Programmed cell death ligand 1 (PD-L1) inhibitor (durvalumab and atezolizumab) plus etoposide-based chemotherapy, compared with etoposide-based chemotherapy alone, showed the most favorable OS (hazard ratio, 1.40; 95% CI, 1.09-1.80) and the best DCR (odds ratio [OR], 0.42; 95% CI, 0.21-0.81). Bevacizumab plus etoposide-based chemotherapy provided the best PFS compared with etoposide-based chemotherapy alone (hazard ratio, 1.54; 95% CI, 1.09-2.27), although this was not translated into OS benefit. The addition of PD-L1 inhibitors to etoposide-platinum chemotherapy caused no more toxic effects in general (compared with etoposide-based chemotherapy alone: OR, 1.14; 95% CI, 0.36-2.31), while bevacizumab plus etoposide-platinum regimen induced the most TRAEs grades 3 to 5 among all first-line treatments (eg, compared with irinotecan-platinum regimen: OR, 4.24; 95% CI, 1.26-14.57). Based on the surface under the cumulative ranking curve value, PD-L1 inhibitor plus etoposide-platinum had the highest probability of being ranked first for OS (0.87) and DCR (0.97). CONCLUSIONS AND RELEVANCE The findings of this systematic review and network meta-analysis suggest that the combination of a PD-L1 inhibitor (durvalumab and atezolizumab) and etoposide-based chemotherapy may be an optimal first-line treatment option for patients with ES-SCLC patients.
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Efficacy and Safety of PCSK9 Monoclonal Antibodies in Patients at High Cardiovascular Risk: An Updated Systematic Review and Meta-Analysis of 32 Randomized Controlled Trials.
Mu, G, Xiang, Q, Zhou, S, Liu, Z, Qi, L, Jiang, J, Gong, Y, Xie, Q, Wang, Z, Zhang, H, et al
Advances in therapy. 2020;(4):1496-1521
Abstract
INTRODUCTION Proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies are powerful lipid-lowering drugs which have been shown to improve clinical endpoints in patients with hypercholesterolemia. However, it is not clear how effective PCSK9 monoclonal antibodies are for patients at high cardiovascular risk. Also, whether the effectiveness of PCSK9 monoclonal antibodies varies between different drug types, dosages, race, and indications for PCSK9 monoclonal antibodies remains unclear. Therefore, we used recently published studies to systematically evaluate the efficacy and safety of PCSK9 monoclonal antibodies by analyzing the lipid profiles, adverse events, and clinical endpoints in patients at high cardiovascular risk. METHODS Randomized controlled trials (RCTs) comparing PCSK9 monoclonal antibodies with placebos or active drugs in patients at high cardiovascular risk were retrieved from electronic databases from their inception until November 2019. Efficacy and safety outcomes included low-density lipoprotein cholesterol (LDL-C) and other lipid profiles, treatment-emergent adverse events (TEAEs) and adverse events of interests, and clinical endpoints. Subgroup analyses based on drug types, dosing, and race were conducted. Statistical analysis was performed using STATA 15.1 and RevMan 5.0. RESULTS Thirty-two RCTs were included in the systematic review, and 25 of them (57,090 individuals) were included in the meta-analysis. PCSK9 monoclonal antibodies significantly improved LDL-C and other lipid profiles (P < 0.05), and no racial differences were found. A recommended dose of 140 mg of evolocumab every 2 weeks was likely to produce a relatively stronger effect than 150 mg of alirocumab every 2 weeks in terms of the absolute change (weighted mean differences (WMD) - 0.36; 95% confidence interval (CI) - 0.71 to - 0.01; P = 0.041) and percent change (WMD - 19.53; 95% CI - 32.02 to - 7.04; P = 0.002) in LDL-C levels. Overall, PCSK9 monoclonal antibodies were safe, except for the significantly increased risk of injection site reactions (relative risks (RR) 1.54; 95% CI 1.38-1.71; P < 0.001). Both alirocumab (RR 0.89; 95% CI 0.83-0.95; P < 0.001) and evolocumab (RR 0.86; 95% CI 0.80-0.92; P < 0.001) were associated with a lower risk of major cardiovascular events (MACEs), especially in secondary preventive patients (alirocumab group: RR 0.88; 95% CI 0.82-0.95; P < 0.001; evolocumab group: RR 0.86; 95% CI 0.80-0.92; P < 0.001). The reduction in MACEs was observed in White but not in Asian subjects. No significant reduction of all-cause mortality was found (RR 0.88; 95% CI 0.72-1.07; P = 0.182). CONCLUSION Both alirocumab and evolocumab are well tolerated and can greatly improve lipid profiles for patients at high cardiovascular risk. Both PCSK9 monoclonal antibodies significantly reduce the risk of nonfatal MACEs in patients with previous cardiovascular events, but the effect on all-cause mortality remains uncertain.
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Effect of proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies on new-onset diabetes mellitus and glucose metabolism: A systematic review and meta-analysis.
Cao, YX, Liu, HH, Dong, QT, Li, S, Li, JJ
Diabetes, obesity & metabolism. 2018;(6):1391-1398
Abstract
AIMS: To investigate the effect of two clinically applied proprotein convertase subtilisin/kexin type 9 monoclonal antibodies (PCSK9-mAbs) on glycaemia and new-onset diabetes mellitus (NODM). MATERIALS AND METHODS PubMed, MEDLINE, Embase, Cochrane databases and ClinicalTrials.gov websites were systematically searched for randomized controlled trials that reported data on fasting plasma glucose (FPG), glycated haemoglobin (HbA1c) or NODM incidence. Risk ratios (RRs) for NODM and mean difference (MD) for FPG and HbA1c with 95% confidence intervals (CIs) were calculated using a fixed-effect model. Heterogeneity was examined using the I2 statistic and potential publication bias was assessed using funnel plots and Egger's test. RESULTS A total of 18 studies including 26 123 participants without diabetes were identified. No significant difference was observed in the PCSK9-mAb treatment groups in terms of NODM (RR 1.05, 95% CI 0.95-1.16), FPG (MD 0.00 mmol/L, 95% CI -0.02 to 0.02) or HbA1c (MD 0.00% [0 mmol/L], 95% CI -0.01 to 0.01) compared with control groups. Subgroup (PCSK9-mAb type, participant characteristics, treatment duration, treatment method and differences in control treatment) and sensitivity analyses did not significantly alter the results. Meta-regression analyses showed that risk of NODM was not associated with baseline age, baseline body mass index (BMI), proportion of men, treatment duration or percent LDL cholesterol reduction. CONCLUSIONS Alirocumab and evolocumab, two types of PCSK9-mAb approved by the US Food and Drug Administration and the European Medicines Agency, had no significant impact on NODM and glucose homeostasis, regardless of PCSK9-mAb type, participant characteristics, treatment duration, treatment method and differences in control treatment. Baseline age, BMI, proportion of men, treatment duration, and percent change of LDL cholesterol did not influence diabetes risk.
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Comparisons of three different doses of alirocumab application in patients with hypercholesterolemia: a meta-analysis.
Zhang, YS, Hao, YH, Luo, HL, Xie, BC, Fu, JY, Zhou, ZK
Minerva medica. 2018;(3):229-238
Abstract
INTRODUCTION Low high-density lipoprotein cholesterol (HDL-C) and high low-density lipoprotein cholesterol (LDL-C) levels are associated with incidence of cardiovascular disease (CVD). Alirocumab has been considered as an efficacious, safe and promising therapeutic modality for hypercholesterolemia. The purpose of this study is to compare the differences of the three different doses of alirocumab in patients with hypercholesterolemia. EVIDENCE ACQUISITION Randomized controlled trials were identified from PubMed, EMBASE, PMC and Cochrane-library databases. The inter-comparison of different doses were performed by subgroups analysis. Meta-analyses were performed by the Review Manager 5.3 and STATA 13.0 software. EVIDENCE SYNTHESIS A total of nine studies involving 3870 patients were included in this meta-analysis. Alirocumab administered at 75-150 mg every 2 weeks (Q2W) resulted in a greater percent change from baseline in LDL-C concentrations (MD, -55.17; 95% CI: -64.35 to -45.99; P<0.05), and HDL-C levels (MD, 7.70; 95% CI 5.94 to 9.46; P<0.05) than other two doses (300 mg every 4 weeks [Q4W], 150 mg every 2 weeks [Q2W]). There was no difference in achieving the treatment goal of LDL-C (≤1.8 mmol/L), in other serum lipid parameters (total cholesterol [TC], triglyceride [TG]), and in the incidence of adverse events. CONCLUSIONS The results demonstrate that alirocumab at a dose of 75-150 mg Q2W should be preferred in patients with hypercholesterolemia.
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Efficacy and safety of alirocumab among individuals with diabetes mellitus and atherosclerotic cardiovascular disease in the ODYSSEY phase 3 trials.
Ganda, OP, Plutzky, J, Sanganalmath, SK, Bujas-Bobanovic, M, Koren, A, Mandel, J, Letierce, A, Leiter, LA
Diabetes, obesity & metabolism. 2018;(10):2389-2398
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AIMS: Individuals with both diabetes mellitus (DM) and atherosclerotic cardiovascular disease (ASCVD) are at very high risk of cardiovascular events. This post-hoc analysis evaluated efficacy and safety of the PCSK9 inhibitor alirocumab among 984 individuals with DM and ASCVD pooled from 9 ODYSSEY Phase 3 trials. MATERIALS AND METHODS Changes in low-density lipoprotein cholesterol (LDL-C) and other lipids from baseline to Week 24 were analysed (intention-to-treat) in four pools by alirocumab dosage (150 mg every 2 weeks [150] or 75 mg with possible increase to 150 mg every 2 weeks [75/150]), control (placebo/ezetimibe) and background statin usage (yes/no). RESULTS At Week 24, LDL-C changes from baseline in pools with background statins were -61.5% with alirocumab 150 (vs -1.0% with placebo), -46.4% with alirocumab 75/150 (vs +6.3% with placebo) and -48.7% with alirocumab 75/150 (vs -20.6% with ezetimibe), and -54.9% with alirocumab 75/150 (vs +4.0% with ezetimibe) without background statins. A greater proportion of alirocumab recipients achieved LDL-C < 70 and < 55 mg/dL at Week 24 vs controls. Alirocumab also resulted in significant reductions in non-high-density lipoprotein cholesterol, apolipoprotein B and lipoprotein(a) vs controls. Alirocumab did not appear to affect glycaemia over 78-104 weeks. Overall safety was similar between treatment groups, with a higher injection-site reaction frequency (mostly mild) with alirocumab. CONCLUSION Alirocumab significantly reduced LDL-C and other atherogenic lipid parameters, and was generally well tolerated in individuals with DM and ASCVD.