Background Baricitinib, a novel oral inhibitor of JAK1/2, was evaluated in a Phase 2b study in patients (pts) with moderate to severe RA. The primary ACR20 12-week endpoint was met, and clinical improvements at week 12 were maintained through 24 weeks of treatment1.
Objectives To evaluate changes from baseline in serum LDL, HDL, and total cholesterol over 24 weeks of baricitinib treatment compared with placebo (PB).
Methods Pts were randomized to PB (n=98) or to QD dosing with 1, 2, 4, or 8 mg of baricitinib with ~50 pts per treatment arm. Serum lipids were determined at screening, baseline and at Weeks 2, 4, 8, 12, 14, 16, 20 and 24, and particle size and number were determined by Nuclear Magnetic Resonance (NMR) at baseline and at Weeks 12 and 24.
Results Baricitinib treatment resulted in a dose and time dependent increase relative to PB in LDL, HDL and total cholesterol detectable by Week 2. The mean percent increase in total cholesterol in the combined baricitinib arms was 9.5% (p< 0.001) at Week 12 and 11.3% by Week 24. This increase in total cholesterol reflected an increase in both LDL and HDL cholesterol. LDL cholesterol increased 10.5% (p<0.001) in the combined baricitinib arms at Week 12 and 13.7% by Week 24. Similarly, HDL cholesterol increased 11.8% (p=0.004) in the combined baricitinib arms at Week 12 and 13.4% by Week 24. Neither the magnitude of the increases in LDL nor HDL cholesterol correlated with the reductions in C-reactive protein observed at Week 12. NMR analysis revealed significant changes in the baricitinib-treated groups relative to PB in the size (LDL) and number (HDL and VLDL) of the particles by Week 12 that were sustained at 24 weeks. The increase in LDL cholesterol was associated with an increase primarily in the large LDL particles, which was significant at all baricitinib doses. Large LDL in the combined baricitinib arms (N=203) had a mean value of 486 nmol/L at Week 0 which increased to 539 nmol/L at Week 12 (p=0.001) and to 564 nmol/L at Week 24 (N=154). No significant increases in number of small, medium small, or very small LDL particles, or in the total number of LDL particles in any of the treatment arms were observed. An increase in HDL (10.3%, p=0.006) and VLDL (28.7%, p=0.074) particle numbers was apparent at Week 12 in the combined baricitinib arms which persisted to Week 24 with no significant increases in the mean particle size for HDL or VLDL through 24 weeks. While this analysis reflects pooled doses, the effects on lipids were most marked at 8 mg QD. Furthermore, a subgroup analysis suggests that concomitant use of statins can ameliorate these increases in cholesterol.
Conclusions The increase in LDL cholesterol with baricitinib treatment is attributed to a shift towards larger particles rather than to an overall increase in LDL particle number at Week 12 and persisting through 24 weeks. In contrast, the changes observed in HDL cholesterol were associated with an increase in the total number of HDL particles by Week 12 and persisting through 24 weeks. Literature suggests that larger LDL particles are less atherogenic although this study does not address this correlation.
Genovese et al. Arthritis Rheum 2012; 64(Suppl10):2487
Disclosure of Interest J. Kremer Grant/research support from: Eli Lilly & Company, Consultant for: Eli Lilly & Company, M. Genovese Grant/research support from: Eli Lilly & Company, Consultant for: Eli Lilly & Company, E. Keystone Grant/research support from: Eli Lilly & Company, Consultant for: Eli Lilly & Company, P. Taylor Consultant for: Eli Lilly & Company, S. Zuckerman Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company, D. Schlichting Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company, S. Beattie Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company, W. Macias Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company
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