Olumiant ® ▼ (baricitinib)

This information is intended for UK registered healthcare professionals only as a scientific exchange in response to your search for information. Please refer to the link for full prescribing information: Olumiant Summary of Product Characteristics (SmPC)

Olumiant® ▼ (baricitinib): Lipid Effects in the Atopic Dermatitis Clinical Trial Program

Baricitinib was associated with increased lipid parameters in the atopic dermatitis clinical trial program. It is recommended to assess lipid parameters approximately 12 weeks after baricitinib initiation.

Baricitinib Label Information Related to Lipids

Warnings and Precautions

Dose dependent increases in blood lipid parameters were reported in patients treated with baricitinib compared to placebo.1

  • Elevations in LDL cholesterol decreased to pre- treatment levels in response to statin therapy.1

  • Lipid parameters should be assessed approximately 12 weeks following initiation of baricitinib therapy and thereafter patients should be managed according to international clinical guidelines for hyperlipidaemia.1

  • The effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined.1

Adverse Drug Reactions

In atopic dermatitis clinical studies, baricitinib treatment was associated with increases in lipid parameters including total cholesterol, LDL cholesterol, and HDL cholesterol. Elevations were observed at 12 weeks and mean total and LDL cholesterol increased through week 52. There was no increase in the LDL/HDL ratio. No dose-relationships were observed in controlled studies, for up to 16 weeks for total cholesterol, LDL cholesterol, or HDL cholesterol. There was no increase in triglycerides levels.1

In controlled studies, for up to 16 weeks, the following frequencies were observed for baricitinib 4 mg vs. placebo:

  • Increased total cholesterol ≥ 5.17 mmol/L:

    • Rheumatoid Arthritis: 49.1 % vs.15.8 %, respectively

    • Atopic Dermatitis: 20.7 % vs. 10.0 %, respectively

  • Increased LDL cholesterol ≥ 3.36 mmol/L:

    • Rheumatoid Arthritis: 33.6 % vs. 10.3 %, respectively

    • Atopic Dermatitis: 13.2 % vs. 6.3 %, respectively

  • Increased HDL cholesterol ≥ 1.55 mmol/L:

    • Rheumatoid Arthritis: 42.7 % vs. 13.8 %, respectively

    • Atopic Dermatitis: 25.3 % vs. 14.7 %, respectively

  • Increased triglycerides ≥ 5.65 mmol/L:

    • Rheumatoid Arthritis: 0.4 % vs. 0.5 %, respectively

    • Atopic Dermatitis: 0.7 % vs. 0.8 %, respectively.1

Lipid Changes in the Baricitinib Atopic Dermatitis Development Program

The effects of BARI on lipid analytes are consistent with a pharmacologic effect of JAK inhibition, which may be explained, in part, by the inhibition of IL-6 signaling.2,3 Data from the BARI RA clinical development program demonstrated that patients with significant increases in LDL-C responded to statin treatment.4

Dataset Descriptions Used to Assess Lipids in the BREEZE-AD Clinical Program

The assessment of lipids was based on analyses performed using

  • mean changes from baseline

  • shifts in analytes according to NCEP criteria, and

  • review of TEAEs potentially related to hyperlipidemia.2,5

The integrated datasets used to evaluate lipid analytes are described in Table 3.

Mean Change From Baseline in Lipid Analytes

In patients in the BREEZE-AD program, mean total cholesterol, mean LDL and HDL were elevated for baricitinib treated patients in the placebo-controlled period and continued to be elevated during the extended period  (see mean plots in Figure 1).2,6

Figure 1. Plots of Mean Total Cholesterol, Mean HDL-C, and Mean LDL-C in Patients Treated With BARI 4 mg and BARI 2 mg in the Placebo Controlled and Extended Periods in the Atopic Dermatitis Clinical Trials2,6

Abbreviations: AD = atopic dermatitis; BARI = baricitinib; ext = extended; HDL-C = high density lipoprotein cholesterol; LDL-C = low density lipoprotein cholesterol; LLN = lower limit of normal.

 Note: grey = placebo, blue = BARI 2 mg, and red is BARI 4 mg.

Treatment-Emergent Shifts From Baseline

The proportion of patients who had a categorical increase (according to NCEP criteria) was higher in the BARI treatment groups compared to the placebo group for total cholesterol, LDL-C, and HDL-C.

Categorical increases for triglycerides were similar between the BARI treatment groups and placebo groups (see Table 1).2,6

Table 1. Treatment-Emergent Shifts in Total Cholesterol, LDL-C, HDL-C, and Triglycerides2,6


Total Cholesterol ≥200 mg/dL (5.2 mmol/L)

LDL-C ≥130 mg/dL (3.4 mmol/L)

HDL-C ≥60 mg/dL (1.6 mmol/L)

Triglycerides ≥500 mg/dL (5.65 mmol/L)

BARI 2 mg Placebo-Controlleda, n/NAR (%)b

Placebo, n=889

60/557 (10.8)

41/643 (6.4)

73/524 (13.9)

8/789 (1.0)

BARI 2 mg, n=721

95/472 (20.1)c

64/540 (11.9)d

92/438 (21.0)c

4/632 (0.6)

BARI 4 mg Placebo-Controlleda, n/NAR (%)b

Placebo, n=743

47/469 (10.0)

34/542 (6.3)

65/442 (14.7)

5/662 (0.8)

BARI 4 mg, n=489

66/319 (20.7)e

48/363 (13.2)f

75/297 (25.3)e

3/437 (0.7)

BARI 2 vs 4 mga, n/NAR (%)b

BARI 2 mg, n=576

77/386 (19.9)

52/435 (12.0)

70/360 (19.4)

3/510 (0.6)

BARI 4 mg, n=489

66/319 (20.7)

48/363 (13.2)

75/297 (25.3)

3/437 (0.7)

BARI 2 mg vs 4 mg extended, n/NAR (%)b

BARI 2 mg, n=576

113/388 (29.1)

85/437 (19.5)

91/362 (25.1)

6/514 (1.2)

BARI 4 mg, n=489

117/322 (36.3)g

93/366 (25.4)g

102/300 (34.0)g

5/440 (1.1)

All BARI AD, n/NAR (%)b

All doses, N=2531

508/1614 (31.5)

408/1868 (21.8)

443/1500 (29.5)

22/2269 (1.0)

Abbreviations: AD = atopic dermatitis; adj = adjusted; BARI = baricitinib; HDL-C = high-density lipoprotein-cholesterol; IR = incidence rate; LDL-C = low-density lipoprotein-cholesterol; NAR = number at risk.

a Data through 16-week placebo-controlled period.

b % based on number of patients at risk.

c p<.001 BARI 2 mg vs placebo.

d p<.01 BARI 2 mg vs placebo.

e p<.001 BARI 4 mg vs placebo.

f p<.01 BARI 4 mg vs placebo.

g p<.05 BARI 2 mg vs BARI 4 mg.

Treatment Emergent Adverse Events Related to Hyperlipidemia

There were no clinically meaningful differences in the integrated safety datasets for lipid-related TEAEs (see Table 2).2


Table 2. Treatment Emergent Adverse Events Related to Hyperlipidemia2

 

 

 

 

 

 

 

 

 

 

 

BARI 2 mg Placebo-Controlleda
n (adj %)
b

BARI 4 mg Placebo-Controlleda
n (adj %)
c

BARI 2 mg vs 4 mg
n (adj %)
d

BARI 2 mg vs 4 mg ext
n (adj %)
e [adj IR]

All BARI AD
n (%) [IR]


Placebo
n=889

BARI 2 mg
n=721

Placebo
n=743

BARI 4 mg
n=489

BARI 2 mg
n=576

BARI 4 mg
n=489

BARI 2 mg
n=576

BARI 4 mg
n=489

All doses
N=2531

>1 lipid-related TEAE

11 (1.2)

16 (2.1)

9 (1.0)

7 (1.3)

14 (1.9)

7 (1.3)

15 (2.1) [3.3]

20 (3.8) [4.1]

67 (2.6) [3.0]

Increased Blood Cholesterol

2 (0.2)

5 (0.5)

1 (0.1)

2 (0.3)

5 (0.5)

2 (0.3)

6 (0.7) [1.2]

4 (0.7) [0.9]

13 (0.5) [0.6]

Hypercholesterolaemia

3 (0.3)

5 (0.7)

3 (0.3)

1 (0.2)

4 (0.6)

1 (0.2)

4 (0.6) [0.9]

2 (0.4) [0.4]

16 (0.6) [0.7]

Hypertriglyceridaemia

4 (0.4)

5 (0.8)

4 (0.4)

2 (0.4)

5 (0.8)

2 (0.4)

6 (0.9) [1.3]

4 (0.8) [0.8]

14 (0.6) [0.6]

Increased Blood TGs

3 (0.4)

3 (0.3)

2 (0.3)

2 (0.4)

2 (0.2)

2 (0.4)

2 (0.2) [0.4]

3 (0.6) [0.7]

9 (0.4) [0.4]

LDL-C Increased

1 (0.1)

3 (0.3)

1 (0.1)

2 (0.3)

3 (0.3)

2 (0.3)

3 (0.3) [0.5]

2 (0.3) [0.5]

5 (0.2) [0.2]

Dyslipidaemia

0

2 (0.3)

0

0

2 (0.3)

0

2 (0.3) [0.4]

1 (0.2) [0.2]

7 (0.3) [0.3]

Hyperlipidemia

0

0

0

1 (0.2)

0

1 (0.2)

0

7 (1.3) [1.3]f

14 (0.6) [0.6]

Lipids Increased

1 (0.1)

0

1 (0.1)

0

0

0

0

0

1 (0.0) [0]

Lipids Abnormal

NA

NA

NA

NA

NA

NA

0

1 (0.2) [0.2]

1 (0.0) [0]

Abbreviations: AD = atopic dermatitis; adj = adjusted; BARI = baricitinib; ext = extended; IR = incidence rate; LDL-C = low-density lipoprotein-cholesterol; TEAE = treatment emergent adverse event; TGs = Triglycerides.

a Data through 16-week placebo-controlled period.

b For the integrated controlled analysis sets where the randomized ratio of patients receiving BARI to placebo or BARI to active control is not the same across all the integrated studies (example 2:1:1:1 vs 1:1:1:1), the study-size adjusted percentages were calculated for the adverse events to provide appropriate direct comparisons between treatment groups. 

c For the integrated controlled analysis sets where the randomized ratio of patients receiving BARI to placebo or BARI to active control is not the same across all the integrated studies (example 2:1:1:1 vs 1:1:1:1), the study-size adjusted percentages were calculated for the adverse events to provide appropriate direct comparisons between treatment groups. 

d For the integrated controlled analysis sets where the randomized ratio of patients receiving BARI to placebo or BARI to active control is not the same across all the integrated studies (example 2:1:1:1 vs 1:1:1:1), the study-size adjusted percentages were calculated for the adverse events to provide appropriate direct comparisons between treatment groups. 

e For the integrated controlled analysis sets where the randomized ratio of patients receiving BARI to placebo or BARI to active control is not the same across all the integrated studies (example 2:1:1:1 vs 1:1:1:1), the study-size adjusted percentages were calculated for the adverse events to provide appropriate direct comparisons between treatment groups. 

f p<.01.

Integrated Safety Datasets Table

Table 3. Integrated Analysis Datasets Used to Evaluate Safety in Atopic Dermatitis Clinical Trials2,6

Analysis Set

Description

BARI 2 mg Placebo-Controlled

Studies: JAHG, BREEZE-AD1, BREEZE-AD2, BREEZE- AD4, BREEZE- AD5, and BREEZE-AD7

Compares BARI 2 mg vs placebo

Includes patients with AD from 1 phase 2 and 5 phase 3 studies who were randomized to

  • BARI 2 mg (n=721, PYE=210.6), or

  • placebo (n=889, PYE=252.7).

Treatment period was 0 to 16 weeks.

BARI 4 mg Placebo-Controlled

Studies: JAHG, BREEZE-AD1, BREEZE-AD2, BREEZE- AD4, and BREEZE-AD7

Compares BARI 4 mg vs placebo

Includes patients with AD from 1 phase 2 and 4 phase 3 studies who were randomized to

  • BARI 4 mg (n=489, PYE=147.1), or

  • placebo (n=743, PYE=211.8).

Treatment period was 0 to 16 weeks.

BARI 2 mg vs 4 mg

Studies: JAHG, BREEZE-AD1, BREEZE-AD2, BREEZE-AD4, and BREEZE-AD7

Compares BARI 2 mg vs BARI 4 mg through 16 weeks

Includes patients with AD from 1 phase 2 and 4 phase 3 studies who were randomized to

  • BARI 2 mg (n=576, PYE=169.1), or

  • BARI 4 mg (n=489, PYE=147.1).

Treated for 0 to 16 weeks during the placebo-controlled period.

BARI 2 mg vs 4 mg Extended

Studies: JAHG, BREEZE-AD1, BREEZE-AD2, BREEZE-AD4, BREEZE-AD7, and extension study BREEZE-AD3

Compares BARI 2 mg vs BARI 4 mg including extended evaluations

Includes patients with AD from 1 phase 2 and 4 phase 3 studies and any further exposure for those patients in the phase 3 extension study, BREEZE-AD3, who were randomized to

  • BARI 2 mg (n=576, PYE=425.5), or

  • BARI 4 mg (n=489, PYE=459.3).

Data censored at dose or treatment change (rescue, dose switch, or re-randomization to a different BARI dose or placebo) for BREEZE-AD4 and BREEZE-AD3.

All BARI AD

Studies: JAHG, BREEZE-AD1, BREEZE-AD2, BREEZE-AD4, BREEZE-AD5, BREEZE-AD7, and extension studies BREEZE-AD3, BREEZE-AD6

No between-group comparisons

Includes 2531 (total PYE=2247.4) patients with AD from 1 phase 2, 5 phase 3, and 2 phase 3 extension studies who received BARI at a variety of doses, including

  • BARI 1 mg (n=538, PYE=245.9)

  • BARI 2 mg (n=1580, PYE=1129.5), and

  • BARI 4 mg (n=914, PYE=872.8).

Includes all patients who were exposed to any BARI dose at any time during the studies, either from randomization or from switch or rescue from placebo.

 No censoring of data at dose change.

Abbreviations: AD = atopic dermatitis; BARI = baricitinib; PYE = patient-years of exposure.

Note: BARI 1 mg was studied in pivotal trials, however it is not approved. Please refer to section 4.2 of the Olumiant Summary of Product Characteristics for approved dosage.

References

1. Olumiant [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.

2. Data on file, Eli Lilly and Company and/or one of its subsidiaries.

3. Charles-Schoeman C, Gonzalez-Gay MA, Kaplan I, et al. Effects of tofacitinib and other DMARDs on lipid profiles in rheumatoid arthritis: implications for the rheumatologist. Semin Arthritis Rheum. 2016;46(1):71-80. https://doi.org/10.1016/j.semarthrit.2016.03.004

4. Taylor PC, Kremer JM, Emery P, et al. Lipid profile and effect of statin treatment in pooled phase II and phase III baricitinib studies. Ann Rheum Dis. 2018;77(7):988-995. http://dx.doi.org/10.1136/annrheumdis-2017-212461

5. National Cholesterol Education Program (NCEP). Third report of the NCEP expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III) final report. National Heart, Lung, and Blood Institute, National Institutes of Health, NIH Publication No. 02-5215. September 2002. https://www.nhlbi.nih.gov/files/docs/resources/heart/atp-3-cholesterol-full-report.pdf

6. Bieber T, Thyssen JP, Reich K, et al. Pooled safety analysis of baricitinib in adult patients with atopic dermatitis from 8 randomized clinical trials. J Eur Acad Dermatol Venereol. 2021;35(2):476-485. https://doi.org/10.1111/jdv.16948

Glossary

AD = atopic dermatitis

BARI = baricitinib

HDL-C = high-density lipoprotein cholesterol

IL = interleukin

JAK = Janus kinase

LDL-C = low-density lipoprotein cholesterol

NCEP = National Cholesterol Education Program

RA = rheumatoid arthritis

TEAE = treatment-emergent adverse event

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.

Date of Last Review: February 02, 2021


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