Effects of Baricitinib on Lipid, Apolipoprotein, and Lipoprotein Particle Profiles in a Phase IIb Study of Patients With Active Rheumatoid Arthritis

Kremer, Joel M.; Genovese, Mark C.; Keystone, Edward; Taylor, Peter; Zuckerman, Steven H.; Ruotolo, Giacomo; Schlichting, D.; Crotzer, Victoria L.; Nantz, Eric; Beattie, Scott; Macias, William L.

doi:10.1002/art.40036

Cited by 43 publications

(31 citation statements)

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“…The study by Fleischmann et al (19) was ignored due to the combined use of baricitinib and methotrexate (MTX). A total of 4 studies were eliminated due to the lack of available data for analysis (20–23). Finally, 7 RCTs were selected, including 2 phase-II (24,25) trials and 5 phase-III trials (3,26–29).…”

Section: Resultsmentioning

confidence: 99%

Efficacy and safety of baricitinib for active rheumatoid arthritis in patients with an inadequate response to conventional synthetic or biological disease‑modifying anti‑rheumatic drugs: A meta‑analysis of randomized controlled trials

Zhang

Bai

et al. 2018

Exp Ther Med

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The purpose of the present meta-analysis was to assess the efficacy and safety of baricitinib for active rheumatoid arthritis (RA) in patients with an inadequate response or intolerance to conventional synthetic or biological disease-modifying anti-rheumatic drugs (DMARDs). A total of 7 randomized controlled trials (RCTs) were included. The primary effective outcome was the RA improvement to reach an American College of Rheumatology 20% (ACR20) response rate. The safety outcomes were composed of clinical laboratory parameters. All patients included received 4 mg baricitinib once daily to treat RA for 12 or 24 weeks. The ACR20 response rate in the baricitinib group was significantly higher compared with that in the control group at 12 weeks [relative risk (RR), 1.77; 95% confidence interval (CI), 1.62–1.94; P<0.00001] and 24 weeks (RR, 1.76; 95% CI, 1.48–2.10; P<0.00001). Similarly, other effective outcome measures also exhibited significant improvements in the baricitinib group compared with those in the placebo group. Regarding the safety outcomes, no significant difference in adverse events (AEs) was identified at 12 weeks (P=0.14), but AEs were significantly higher in the baricitinib group compared with those in the control group at 24 weeks (P=0.03). Most laboratory values were significantly different between the baricitinib and placebo groups; however, the clinical significance of these changes remains to be determined. In summary, the present meta-analysis demonstrated that 4 mg baricitinib once daily was beneficial in patients with active RA with an inadequate response or intolerance to conventional synthetic or biological DMARDs. More high-quality RCTs are required to determine the sustained efficacy and the safety of baricitinib.

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Section: Resultsmentioning

confidence: 99%

Efficacy and safety of baricitinib for active rheumatoid arthritis in patients with an inadequate response to conventional synthetic or biological disease‑modifying anti‑rheumatic drugs: A meta‑analysis of randomized controlled trials

Zhang

Bai

et al. 2018

Exp Ther Med

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“… 7–11 Increases in lipids persisted in a phase II study of baricitinib. 12 The increase in LDL-C was associated with an increase in large and a decrease in small LDL, without any increase in LDL particle number. The increase in HDL-C was associated with an increase in HDL particle number across all particle sizes.…”

Section: Introductionmentioning

confidence: 92%

“…The increase in HDL-C was associated with an increase in HDL particle number across all particle sizes. 12 This LDL and HDL particle profile has been associated with reduced atherogenic risk. 13 …”

Section: Introductionmentioning

confidence: 99%

Lipid profile and effect of statin treatment in pooled phase II and phase III baricitinib studies

et al. 2018

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ObjectivesLipid profiles are altered by active disease in patients with rheumatoid arthritis (RA) and may be further modified by treatment with Janus kinase inhibitors and other disease-modifying antirheumatic drugs.MethodsLipid data were analysed from phase II and III studies of 4 mg (n=997) and 2 mg (n=479) oral baricitinib administered once daily in patients with moderate-to-severe active RA. Lipoprotein particle size and number and GlycA were evaluated with nuclear magnetic resonance in one phase III study. The effect of statin therapy on lipid levels was evaluated in patients on statins at baseline and in patients who initiated statins during the study.ResultsTreatment with baricitinib was associated with increased levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides, but no significant change in LDL-C:HDL-C ratio. Lipid levels plateaued after 12 weeks of treatment. Baricitinib treatment increased large LDL and decreased small, dense LDL particle numbers and GlycA. Lipid changes from baseline were not significantly different between baseline statin users and non-users. In patients who initiated statin therapy during the study, LDL-C, triglycerides (baricitinib 4 mg only) and apolipoprotein B decreased to pre-baricitinib levels; HDL-C and apolipoprotein A-I levels remained elevated.ConclusionsBaricitinib was associated with increased LDL-C, HDL-C and triglyceride levels, but did not alter the LDL-C:HDL-C ratio. Evaluation of cardiovascular event rates during long-term treatment is warranted to further characterise these findings and their possible clinical implications.Trial registration numberNCT00902486, NCT01469013, NCT01185353, NCT01721044, NCT01721057, NCT01711359, NCT01710358, NCT01885078.

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“…However, the role of these agents in the modulation of cardiovascular risk remains undetermined 15 16. Limited evidence suggested that tofacitinib-based therapy positively modifies the risk of cardiovascular disease,17 18 while a growing body of literature indicated that Jakinibs adversely affect several cardiovascular risk factors (such as serum lipid profile and platelet count) and potentially increase thrombotic risk which directly leads the US Food and Drug Administration (FDA) to restrict approval to only 2 mg baricitinib 19–22. Additionally, in upadacitinib premarketing trials, major adverse cardiovascular events (MACEs) continuously reported in patients with RA receiving upadacitinib has further generated cardiovascular concerns 23…”

Section: Introductionmentioning

confidence: 99%

Impact of Janus kinase inhibitors on risk of cardiovascular events in patients with rheumatoid arthritis: systematic review and meta-analysis of randomised controlled trials

et al. 2019

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ObjectivesTo investigate the effect of Janus kinase inhibitors (Jakinibs) on cardiovascular risk in adult patients with rheumatoid arthritis (RA) via a meta-analysis of randomised controlled trials (RCTs).MethodsPubMed, Embase and Cochrane library were thoroughly searched for RCTs reporting safety issues in patients with RA receiving Jakinibs, from inception to October 2018. The primary and secondary outcomes were all cardiovascular events (CVEs) and major adverse cardiovascular events (MACEs)/venous thromboembolism events (VTEs). OR and 95% CI were calculated using the Mantel-Haenszel fixed-effect method.Results26 RCTs randomising 11 799 patients were included. No significant difference was observed regarding all CVEs risk following Jakinibs usage in general (OR 1.04 (0.61 to 1.76), p = 0.89), tofacitinib (OR 0.63 (0.26 to 1.54), p = 0.31), baricitinib (OR 1.21 (0.51 to 2.83), p = 0.66), upadacitinib (OR 3.29 (0.59 to 18.44), p = 0.18), peficitinib (OR 0.43 (0.07 to 2.54), p = 0.35) or decernotinib (OR 1.12 (0.13 to 10.11), p = 0.92). Likewise, there was no significant difference for Jakinibs treatment overall regarding occurrence of MACEs (OR 0.80 (0.36 to 1.75), p = 0.57) or VTEs (OR 1.16 (0.48 to 2.81), p = 0.74). Dose-dependent impact of Jakinibs on the risks of all CVEs, MACEs and VTEs was not observed in tofacitinib (5 mg vs 10 mg), upadacitinib (15 mg vs 30 mg), whereas baricitinib at 2 mg was found to be safer than 4 mg in all CVEs incidence (OR 0.19 (0.04 to 0.88), p = 0.03).ConclusionThe existing evidence from RCTs indicated no significant change in cardiovascular risk for Jakinib-treated patients with RA in a short-term perspective, but postmarketing data are sorely needed to ascertain their cardiovascular safety, especially at the higher dose, due to increased risk of thromboembolism events for both tofacitinib and baricitinib at higher dosage.

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Effects of Baricitinib on Lipid, Apolipoprotein, and Lipoprotein Particle Profiles in a Phase IIb Study of Patients With Active Rheumatoid Arthritis

Abstract: Baricitinib-associated increases in serum lipid levels were observed in this study. Increases in levels of HDL cholesterol correlated with improved clinical outcomes.

Cited by 43 publications

References 26 publications

Efficacy and safety of baricitinib for active rheumatoid arthritis in patients with an inadequate response to conventional synthetic or biological disease‑modifying anti‑rheumatic drugs: A meta‑analysis of randomized controlled trials

Efficacy and safety of baricitinib for active rheumatoid arthritis in patients with an inadequate response to conventional synthetic or biological disease‑modifying anti‑rheumatic drugs: A meta‑analysis of randomized controlled trials

Lipid profile and effect of statin treatment in pooled phase II and phase III baricitinib studies

Impact of Janus kinase inhibitors on risk of cardiovascular events in patients with rheumatoid arthritis: systematic review and meta-analysis of randomised controlled trials

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