The n e w e ng l a n d j o u r na l of
Original Article
From St. Vincent’s Institute of Medical
Research (M.W., M.S., S.L., L.S.-V., P.T.,
M.E.D., C.H., B.K., H.E.T., T.W.H.K.), St.
Vincent’s Hospital Melbourne (R.J.M.,
B.K., T.W.H.K.), and the Department of
Medicine at St. Vincent’s Hospital, Uni-
versity of Melbourne (R.J.M., L.S.-V.,
M.E.D., B.K., H.E.T., T.W.H.K.), Fitzroy,
the Walter and Eliza Hall Institute of
Medical Research (J.M.W., P.G.C., L.C.H.),
the Departments of Medical Biology
(J.M.W., L.C.H.) and Medicine (A.G.),
University of Melbourne, the Royal Mel-
bourne Hospital (J.M.W., M.S., C.H., P.G.C.,
L.C.H.), the Royal Children’s Hospital
(F.J.C., G.A.), and the Murdoch Children’s
Research Institute (F.J.C.), Parkville, and
the School of Public Health and Preven-
tive Medicine, Monash University, Mel-
bourne (A.G.), VIC, and Women’s and
Children’s Hospital (J.J.C., J.E.H.) and the
University of Adelaide (J.J.C.), Adelaide,
SA — all in Australia; the New York Stem
Cell Foundation, New York (S.A.); and
Macromoltek, Austin, TX (F.J.M.). Prof.
Kay can be contacted at ­tkay@​­svi​.­edu​.­au
or at St. Vincent’s Institute of Medical Re-
search, 9 Princes St., Fitzroy VIC 3065,
Australia.
*A list of investigators in the BANDIT Study
Group is provided in the Supplementary
Appendix, available at NEJM.org.
Drs. Waibel, Wentworth, and So and Profs.
Thomas and Kay contributed equally to
this article.
This is the New England Journal of Medi-
cine version of record, which includes all
Journal editing and enhancements. The
Author Accepted Manuscript, which is
the author’s version after external peer
review and before publication in the Jour-
nal, is available at PubMed Central.
N Engl J Med 2023;389:2140-50.
DOI: 10.1056/NEJMoa2306691
Copyright © 2023 Massachusetts Medical Society.
CME
at NEJM.org
2140
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m e dic i n e
Baricitinib and β-Cell Function in Patients
with New-Onset Type 1 Diabetes
Michaela Waibel, Ph.D., John M. Wentworth, M.B., B.S., Ph.D.,
Michelle So, M.B., B.S., Ph.D., Jennifer J. Couper, M.D., Fergus J. Cameron, M.D.,
Richard J. MacIsaac, M.B., B.S., Ph.D., Gabby Atlas, M.B., B.S.,
Alexandra Gorelik, M.Sc., Sara Litwak, Ph.D., Laura Sanz‑Villanueva, B.Sc.,
Prerak Trivedi, Ph.D., Simi Ahmed, Ph.D., Francis J. Martin, Ph.D.,
Madeleine E. Doyle, D.M., Jessica E. Harbison, M.B., B.S., Ph.D.,
Candice Hall, B.Sc., Balasubramanian Krishnamurthy, M.D.,
Peter G. Colman, M.D., Leonard C. Harrison, M.D., D.Sc., Helen E. Thomas, Ph.D.,
and Thomas W.H. Kay, M.B., B.S., Ph.D., for the BANDIT Study Group*​​
A BS T R AC T
BACKGROUND
Janus kinase (JAK) inhibitors, including baricitinib, block cytokine signaling and
are effective disease-modifying treatments for several autoimmune diseases.
Whether baricitinib preserves β-cell function in type 1 diabetes is unclear.
METHODS
In this phase 2, double-blind, randomized, placebo-controlled trial, we assigned
patients with type 1 diabetes diagnosed during the previous 100 days to receive
baricitinib (4 mg once per day) or matched placebo orally for 48 weeks. The pri-
mary outcome was the mean C-peptide level, determined from the area under the
concentration–time curve, during a 2-hour mixed-meal tolerance test at week 48.
Secondary outcomes included the change from baseline in the glycated hemoglo-
bin level, the daily insulin dose, and measures of glycemic control assessed with
the use of continuous glucose monitoring.
RESULTS
A total of 91 patients received baricitinib (60 patients) or placebo (31 patients).
The median of the mixed-meal–stimulated mean C-peptide level at week 48 was
0.65 nmol per liter per minute (interquartile range, 0.31 to 0.82) in the baricitinib
group and 0.43 nmol per liter per minute (interquartile range, 0.13 to 0.63) in the
placebo group (P = 0.001). The mean daily insulin dose at 48 weeks was 0.41 U per
kilogram of body weight per day (95% confidence interval [CI], 0.35 to 0.48) in the
baricitinib group and 0.52 U per kilogram per day (95% CI, 0.44 to 0.60) in the
placebo group. The levels of glycated hemoglobin were similar in the two trial
groups. However, the mean coefficient of variation of the glucose level at 48 weeks,
as measured by continuous glucose monitoring, was 29.6% (95% CI, 27.8 to 31.3)
in the baricitinib group and 33.8% (95% CI, 31.5 to 36.2) in the placebo group.
The frequency and severity of adverse events were similar in the two trial groups,
and no serious adverse events were attributed to baricitinib or placebo.
CONCLUSIONS
In patients with type 1 diabetes of recent onset, daily treatment with baricitinib over
48 weeks appeared to preserve β-cell function as estimated by the mixed-meal–
stimulated mean C-peptide level. (Funded by JDRF International and others; BANDIT
Australian New Zealand Clinical Trials Registry number, ACTRN12620000239965.)
n engl j med 389;23 nejm.org December 7, 2023
The New England Journal of Medicine
 Baricitinib and β-Cells in New-Onset Type 1 Diabetes

A
shift from symptom management mittee. The trial was a phase 2, multicenter,
to disease modification has transformed investigator-initiated, double-blind, randomized,
the outcomes of many autoimmune dis- placebo-controlled trial conducted in accordance
A Quick Take
eases. However, autoimmune endocrinopathies, with the principles of the Declaration of Hel- is available at
including type 1 diabetes, continue to be treated sinki and the International Council for Harmoni- NEJM.org
with hormone-replacement therapy after irre- sation Good Clinical Practice guidelines.17 The
versible end-organ damage. In type 1 diabetes, trial was overseen by St. Vincent’s Institute of
insulin replacement has a high treatment burden Medical Research.
and does not fully alleviate the risks of diabetes- The main funder of the trial was JDRF. Bar-
related complications and premature death.1 In- icitinib and identical placebo tablets were pro-
vestigations have provided strong evidence that vided by Eli Lilly through their investigator-initi-
the preservation of residual β-cell function after ated trials program. Neither Eli Lilly nor JDRF
the diagnosis of type 1 diabetes decreases the was involved in the conduct of the trial, the in-
need for exogenous insulin2 and is associated terpretation of the data, or the decision to sub-
with protection from vascular complications and mit the manuscript for publication. The trial
severe hypoglycemia.3,4 protocol, available with the full text of this ar-
Autoreactive CD8+ T cells in type 1 diabetes ticle at NEJM.org, and its publication have been
bind to and are activated by autoantigen peptide approved by JDRF. The last two authors vouch
bound to HLA class I molecules on the surface for the accuracy and completeness of the data
of β-cells, leading to the release of perforin and and the analysis and for the fidelity of the trial
granzymes that effect the death of β-cells.5,6 We to the protocol.
have shown that the interaction between CD8+
T cells and HLA class I molecules requires Janus Patients
kinase (JAK)–associated intracellular signaling All the patients were enrolled from November
molecules.6 Inhibitors of the JAK1 and JAK2 iso- 2020 through February 2022 and provided writ-
forms impair cytokine-induced major histocom- ten informed consent. There were four trial sites,
patibility complex class I expression in cultured all in Australia.
islets and islet cells,7,8 impair CD8+ T-cell activa- Eligibility criteria included an age between 10
tion, and block the formation of immune syn- and 30 years, a diagnosis of type 1 diabetes
apses between β-cells and CD8+ T cells to prevent within 100 days before starting baricitinib or
the death of β-cells.8,9 Furthermore, activating placebo, the presence of at least one islet auto-
mutations in signal transducer and activator of antibody, and either a random C-peptide level of
transcription (STAT) 110 and STAT311 signaling more than 0.3 nmol per liter or a C-peptide level
molecules downstream of JAKs are associated of more than 0.2 nmol per liter during a 2-hour
with the development of autoimmune diabetes. mixed-meal tolerance test. Key exclusion criteria
Baricitinib, a JAK1 and JAK2 inhibitor, is used were treatment with other immunomodulatory
to treat rheumatoid arthritis,12 alopecia areata,13 agents, as well as coexisting conditions includ-
and severe coronavirus disease 2019.14 Other ing cytopenias, known cancer, history of throm-
drugs in this class are used to treat diseases bosis, or a low-density lipoprotein cholesterol
such as juvenile arthritis15 and inflammatory level of more than 155 mg per deciliter. Patients
bowel disease.16 Given the preclinical data from received standard care for diabetes, with a target
analyses of nonobese diabetic mice and the ef- glycated hemoglobin level of less than 7% in
ficacy of JAK inhibitors in other autoimmune adults and less than 7.5% in children.18
diseases, we investigated whether baricitinib
could preserve the function of β-cells and im- Randomization
prove metabolic measures in patients with new- Patients were randomly assigned, in a 2:1 ratio,
onset type 1 diabetes. to receive baricitinib (4 mg per day) or matched
placebo orally for 48 weeks. Randomization was
performed in blocks of 3, 6, or 9 and was strat-
Me thods
ified according to age (≥21 vs. <21 years). Begin-
Trial Design and Oversight ning in January 2022, after 10 cases of coronavi-
Ethics approval was obtained from the Royal Mel- rus disease 2019 (Covid-19) had occurred, the
bourne Hospital human research ethics com- safety committee recommended the suspension

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 The n e w e ng l a n d j o u r na l of m e dic i n e

of baricitinib or placebo for at least 5 days in adjusted for multiplicity. Therefore, these results
patients with Covid-19. should be interpreted as exploratory, and defini-
tive treatment effects should not be inferred.
Outcomes
The primary outcome was the mean C-peptide
level, calculated with the use of the trapezoidal
rule as the area under the concentration–time
curve (AUC) divided by 120 minutes, during a
2-hour mixed-meal tolerance test at week 48.
Secondary outcomes included the glycated hemo-
globin level; the total daily insulin dose; and
measures of glycemic control as assessed with
the use of a continuous glucose monitoring de-
vice (Freestyle Libre 2 [Abbott] or Dexcom G6
[Dexcom]). Safety was assessed by the recording
and grading of adverse events according to the
National Cancer Institute Common Terminology
Criteria for Adverse Events, version 5.0,19 and
through blood counts and biochemical tests of
blood samples throughout the trial. Exploratory
mechanistic outcomes included the degree of
basal and cytokine-stimulated phosphorylation
of STAT proteins and the percentage of effector
memory CD8+ T cells in the CD8+ T-cell popula-
tion (see the Supplementary Appendix, available
at NEJM.org).
Statistical Analysis
All analyses were conducted according to the
intention-to-treat principle. Continuous data are
reported as means with 95% confidence inter-
vals or as medians with interquartile ranges. For
all clinical end points, missing data were im-
puted with the use of multiple imputation.
The mixed-meal–stimulated mean C-peptide
level from the AUC was log-transformed with
the use of the natural logarithm (ln[AUC+1]), and
linear regression was used to estimate the effect
of baricitinib on the ln(AUC+1) at each time
point, with adjustment for body-mass index
(BMI; the weight in kilograms divided by the
square of the height in meters), age, sex, and
ln(AUC+1) at baseline. Multilevel mixed-effects
regression analysis was used to examine the ef-
fect of baricitinib on longitudinal changes in the
ln(AUC+1), with adjustment for BMI, age, sex,
and ln(AUC+1) at baseline.
All the analyses were performed with the use
of Stata software, version 17 (StataCorp), with the
level of significance set at a two-sided P value of
less than 0.05 for all tests. Statistical analyses
of secondary and tertiary end points were not
R e sult s
Patients
Of the 106 children and adults who were
screened, 91 were randomly assigned to receive
baricitinib (60 patients) or placebo (31 patients)
(Fig. S1 in the Supplementary Appendix). The
characteristics of the patients at baseline were
similar in the two trial groups overall and ac-
cording to age (Table 1 and Tables S1 and S2).
One patient from each group withdrew before
the week 48 assessment because they were un-
able to attend scheduled visits during the trial.
Primary Outcome
At the week 48 assessment, the median of the
mixed-meal–stimulated mean C-peptide level
was 0.65 nmol per liter per minute (interquartile
range, 0.31 to 0.82) in the baricitinib group and
0.43 nmol per liter per minute (interquartile
range, 0.13 to 0.63) in the placebo group (ad-
justed mean difference in the ln[AUC+1], 0.13;
95% confidence interval [CI], 0.06 to 0.20;
P = 0.001) (Fig. 1A).
Secondary Outcomes
At week 48, the ln(AUC+1) was 4.2% (95% CI,
−6.3 to 14.9) lower than baseline in the barici-
tinib group and 29.9% (95% CI, 17.1 to 42.7)
lower than baseline in the placebo group. The
adjusted mean difference in the ln(AUC+1) be-
tween the baricitinib group and the placebo group
was 0.07 nmol per liter per minute (95% CI, 0.01
to 0.13) at week 12 and 0.12 nmol per liter per
minute (95% CI, 0.06 to 0.18) at week 24.
The mean daily insulin dose in the baricitinib
group at week 12 and week 24 was less than that
at baseline, whereas the mean daily insulin dose
in the placebo group at week 24 was greater
than that at baseline (Fig. 1B). At week 48, the
mean daily insulin dose was 0.41 U per kilogram
of body weight per day (95% CI, 0.35 to 0.48) in
the baricitinib group and 0.52 U per kilogram
per day (95% CI, 0.44 to 0.60) in the placebo
group. Similar differences between the trial
groups were observed with respect to the basal
and mealtime insulin doses (Table S3). Insulin
pumps were used during part of the trial by 8 of

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 Baricitinib and β-Cells in New-Onset Type 1 Diabetes

Table 1. Characteristics of the Patients at Baseline.*

Baricitinib Placebo
Characteristic (N = 60) (N = 31)
Age
Mean — yr 18.5±5.7 18.7±5.9
Distribution — no. (%)
<18 yr 32 (53) 17 (55)
≥18 yr 28 (47) 14 (45)
Sex — no. (%)
Male 39 (65) 16 (52)
Female 21 (35) 15 (48)
Race — no. (%)†
White 52 (87) 28 (90)
Asian 5 (8) 2 (6)
Black 2 (3) 1 (3)
Other 1 (2) 0
Body-mass index‡ 18.2±8.9 19.3±11.6
Glycated hemoglobin level — % 6.98±1.28 7.47±1.31
Daily insulin dose — U/kg/day 0.43±0.26 0.48±0.28
Median of the mixed-meal–stimulated mean C-peptide 0.6 (0.44–0.82) 0.67 (0.35–0.87)
level at screening (IQR) — nmol/liter/min§
Median time from the diagnosis of type 1 diabetes to 88 (70–95) 72 (59–90)
randomization (IQR) — days
No. of islet autoantibodies at screening — no. (%)
1 1 (2) 2 (6)
2 11 (18) 5 (16)
3 22 (37) 8 (26)
4 26 (43) 16 (52)
Diabetes-associated HLA alleles present — no. (%)
DR3-DQ2 16 (27) 6 (19)
DR4-DQ8 16 (27) 10 (32)
DR3-DQ2 and DR4-DQ8 17 (28) 6 (19)
Other¶ 11 (18) 9 (29)

* Plus–minus values are means ±SD. Percentages may not total 100 because of rounding. IQR denotes interquartile range.
† Race was reported by the patients or their guardians.
‡ The body-mass index is calculated as the weight in kilograms divided by the square of the height in meters.
§ The mixed-meal–stimulated mean C-peptide level was calculated with the use of the trapezoidal rule as the area under
the concentration–time curve divided by 120 minutes.
¶ Other diabetes-associated alleles included DR4-X, DQ2-X, DQ8-X, and X-X.

the patients in the baricitinib group and by 7 of
those in the placebo group. All but three of the
pumps were hybrid closed-loop systems. These
15 patients had a lower daily insulin dose than
the patients who were receiving multiple daily
injections of insulin.
At week 48, the mean glycated hemoglobin
level was 7.0% (95% CI, 6.6 to 7.4), or 53 mmol
per mole (95% CI, 48.6 to 57.4), in the baricitinib
group and 7.5% (95% CI, 6.9 to 8.0), or 58.5 mmol
per mole (95% CI, 51.9 to 63.9), in the placebo
group (Fig. 1C). The coefficient of variation of
the interstitial glucose level, as measured by
continuous glucose monitoring, at week 48 was

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 The n e w e ng l a n d j o u r na l of m e dic i n e

29.6% (95% CI, 27.8 to 31.3) in the baricitinib

A C-Peptide Level
1.0
group and 33.8% (95% CI, 31.5 to 36.2) in the
placebo group and was lower in the baricitinib
P=0.001
0.8 group than in the placebo group at all other as-
Baricitinib sessment times, including baseline (Fig. 2A). At
nmol/liter/min
0.6 weeks 12 and 24 but not at week 48, the daily
mean percentage of time with a glucose level
0.4 Placebo
within the target range of 70 to 180 mg per
0.2 deciliter (3.9 to 10 mmol per liter) was higher in
the baricitinib group than in the placebo group
0.0 (Fig. 2B), and the daily mean percentage of time
0 12 24 36 48
with a glucose level greater than 180 mg per
Weeks since Baseline
deciliter (>10 mmol per liter) was lower in the
B Insulin Dose baricitinib group than in the placebo group
0.8 (Fig. 2C). The mixed-meal–stimulated mean
C-peptide level was associated with measures of
0.6 glycemic control assessed by continuous glucose
Placebo
monitoring and did not differ according to age
(Fig. S2). At weeks 12, 24, and 48, all the pa-
U/kg

0.4
Baricitinib tients had a very low mean percentage of time
with a glucose level less than 70 mg per deciliter
0.2
(<3.9 mmol per liter) (Fig. 2D). The mixed-meal–
stimulated mean C-peptide level was at least
0.0
0 12 24 36 48 95% of the baseline level in 39 of 60 patients
Weeks since Baseline (66%) in the baricitinib group and in 10 of 30
patients (33%) in the placebo group at week 24
C Glycated Hemoglobin Level and in 36 of 58 patients (62%) and 5 of 30 pa-
8.5 tients (17%), respectively, at week 48 (Table S4).
8.0
7.5 Placebo Safety Outcomes
7.0 The frequency and severity of adverse events
Percent

6.5 Baricitinib
6.0
5.5
5.0
0.0
0 12 24 36
Weeks since Baseline
Figure 1. Effect of Baricitinib on the C-Peptide Level,
Daily Insulin Dose, and Glycated Hemoglobin Level.
Panel A shows the median of the mixed-meal–stimu-
lated mean C-peptide level, calculated with the use of
the trapezoidal rule as the area under the concentra-
tion–time curve divided by 120 minutes; Panel B, the
mean daily insulin dose; and Panel C, the mean glycated
hemoglobin level, in the baricitinib and placebo groups
during the trial. I bars indicate 95% confidence intervals.
The widths of confidence intervals in Panels B and C
have not been adjusted for multiplicity and cannot be
used to infer treatment effects.
were similar in the two trial groups (Table 2 and
Table S5). The median number of adverse events
per patient was 2 (interquartile range, 1 to 3) in
the baricitinib group and 3 (interquartile range,
1 to 5) in the placebo group (P = 0.14). Seven
48 serious adverse events were recorded, none of
which were attributed to baricitinib or placebo.
Two serious ketoacidosis events that resulted in
hospitalization occurred in 1 patient in the bar-
icitinib group, who had refrained from taking
insulin against medical advice. Five serious ad-
verse events occurred in 3 patients in the place-
bo group, including three separate serious ad-
verse events — respiratory infection, ketoacidosis,
and hyperglycemia — in 1 patient. The percent-
ages of patients with infection, including upper
respiratory tract infection and skin infection,
were similar in the baricitinib and placebo
groups. Shingles was diagnosed in 1 patient in

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 Baricitinib and β-Cells in New-Onset Type 1 Diabetes

A Coefficient of Variation B Time in Range

40 100

90
35 Placebo

Percentage of Time
80 Baricitinib
30
Percent

70
Baricitinib
25 60 Placebo
50
20
40

0 0
0 12 24 36 48 0 12 24 36 48
Weeks since Baseline Weeks since Baseline

C Time above Range D Time below Range

100 100

50 5
Percentage of Time

Percentage of Time
40 4
Placebo
30 3
Placebo
20 Baricitinib 2

10 1 Baricitinib

0 0
0 12 24 36 48 0 12 24 36 48
Weeks since Baseline Weeks since Baseline

Figure 2. Glycemic Control as Measured by Continuous Glucose Monitoring.

Panel A shows the mean coefficient of variation of the glucose level in the baricitinib and placebo groups during
the trial. Panel B shows the mean daily percentage of time with a glucose level in the target range (70 to 180 mg
per deciliter [3.9 to 10.0 mmol per liter]); Panel C, the mean percentage of time above the target range (>180 mg per
deciliter [>10.0 mmol per liter]); and Panel D, the mean percentage of time below the target range (<70 mg per deci-
liter [<3.9 mmol per liter]). I bars indicate 95% confidence intervals. The widths of confidence intervals have not
been adjusted for multiplicity and cannot be used to infer treatment effects.

the baricitinib group. No differences in lipid
levels, results of liver-function tests, or creati-
nine levels were observed (Table S6).
A total of 22 of 60 patients in the baricitinib
group and 16 of 31 patients in the placebo group
had Covid-19 during the trial. Seventeen patients
stopped taking baricitinib and 10 patients stopped
taking placebo while they had Covid-19; the
duration of cessation was 5 to 7 days in most
of these patients. We did not observe consistent
changes in the mixed-meal–stimulated mean
C-peptide level, measures of glycemic control
assessed by continuous glucose monitoring, or
the daily insulin dose after Covid-19 at the next
routine trial visit, which occurred at a variable
interval after the illness, and we do not have
evidence that Covid-19 could have altered the
median of the mixed-meal–stimulated mean
C-peptide level at week 48.
Mechanistic Outcomes
As a pharmacodynamic measure of JAK inhibi-
tion, interleukin-21–stimulated phosphorylation
of STAT3 was analyzed (see the Methods section
in the Supplementary Appendix).21 The median
geometric mean fluorescence intensity of STAT3
phosphorylation in the baricitinib group was
less than that in the placebo group before
stimulation with interleukin-21 (143 arbitrary
units [AU; interquartile range, 118 to 179] vs.
277 AU [interquartile range, 190 to 301]) and
after stimulation with interleukin-21 (1772 AU

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 2. Adverse Events.*

Baricitinib Placebo
Event (N = 60) (N = 31)

No. of Patients No. of No. of Patients No. of

with Event (%) Events with Event (%) Events
Overall 47 (78) 152 26 (84) 100
Grade 1 46 (77) 118 26 (84) 72
Grade 2 19 (32) 32 13 (42) 23
Grade 3 1 (2) 1 3 (10) 5
Grade 4 1 (2) 1 0   0
Death 0   0 0   0
Serious†
Overall 1 (2) 2 3 (10) 5
Ketoacidosis 1 (2) 2 1 (3) 1
Chronic hyperglycemia 0   0 1 (3) 1
Liver laceration 0   0 1 (3) 1
Severe hypoglycemia 0   0 1 (3) 1
Respiratory infection 0   0 1 (3) 1

* Adverse events were recorded according to the National Cancer Institute Common Terminology Criteria for Adverse
Events, version 5.0.19
† Other serious adverse events — including venous thromboembolism, myocardial infarction, and lung cancer — that
occurred in patients older than 65 years of age in the ORAL surveillance trial of tofacitinib20 were not observed in this
trial.

[interquartile range, 1257 to 2456] vs. 2688 AU
[interquartile range, 1019 to 4135]) (Fig. 3A
and 3B) in the peripheral blood samples col-
lected 2 hours after the last dose. In contrast,
the levels of unstimulated and stimulated phos-
phorylation of STAT3 in the samples collected
24 hours after the receipt of baricitinib or pla-
cebo did not differ between the trial groups.
The effector memory CD8+ T-cell count was
reduced by JAK inhibition in nonobese diabetic
mice.9 The median percentage of effector mem-
ory CD8+ T cells in the baricitinib group at week
24 (17.1% of the CD8+ T-cell population; inter-
quartile range, 14.4 to 22.4) was lower than that
at baseline (23.7% of the CD8+ T-cell popula-
tion; interquartile range, 15.9 to 29.3) (Fig. 3C).
The median percentage of CD8+ T cells in the
CD3+ T-cell population at week 24 did not differ
from that at baseline (Fig. 3D).
Neither the level of phosphorylated STAT3
nor the percentage of CD8+ effector memory T
cells in the CD8+ T-cell population correlated
with changes in the mixed-meal–stimulated
mean C-peptide level. These findings suggest
that both outcomes were pharmacodynamic
measures of JAK inhibition but were not predic-
tors of the median of the mixed-meal–stimulated
mean C-peptide level at week 48.
Discussion
In this trial, 48 weeks of baricitinib treatment
preserved the capacity of β-cells to secrete insu-
lin, as estimated according to the mixed-meal–
stimulated mean C-peptide level, in children and
young adults with type 1 diabetes of recent on-
set. As measured by continuous glucose moni-
toring, variability in the glucose level was lower
and the percentage of time with a glucose level
within the target range was higher in the bar-
icitinib group than in the placebo group over 48
weeks, findings that were coincident with a de-
creased need for exogenous basal and prandial
insulin therapy in the baricitinib group. The
effect size at 48 weeks — a 48% increase in the
median of the mixed-meal–stimulated mean
C-peptide level in the baricitinib group as com-
pared with the placebo group — was similar to
the effect size of interventions such as teplizu­
mab,22 low-dose antithymocyte globulin,23 and

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 Baricitinib and β-Cells in New-Onset Type 1 Diabetes

A Unstimulated pSTAT3 B Interleukin-21–Stimulated pSTAT3

Placebo Baricitinib Placebo Baricitinib
800 8000
pSTAT3 gMFI (AU)

pSTAT3 gMFI (AU)

600 6000

400 4000

200 2000

0 0
2 Hr 24 Hr 2 Hr 24 Hr
Time since Receipt Time since Receipt

C Effector Memory CD8+ T Cells D CD8+ T Cells

60 80
Percentage of CD8+ T Cells

Percentage of CD3+ T Cells

50
60
40

30 40

20
20
10

0 0
Wk 0 Wk 24 Wk 0 Wk 24 Wk 0 Wk 24 Wk 0 Wk 24
Placebo Baricitinib Placebo Baricitinib

Figure 3. Pharmacodynamic and Mechanistic Measures.

The geometric mean fluorescence intensity (gMFI) of unstimulated (Panel A) or interleukin-21–stimulated (Panel B)
phosphorylated signal transducer and activator of transcription 3 (pSTAT3) in peripheral blood CD3+CD8+ T cells
is shown in the baricitinib group (43 patients) and the placebo group (23 patients), as measured by flow cytometry.
Blood samples were obtained during week 24 at 24 hours or 2 hours after the last dose of baricitinib or placebo.
Whole blood was stimulated for 15 minutes with interleukin-21 or left unstimulated before processing for phospho-
flow cytometry. Also shown are the percentage of CD3+CD8+ T cells that were effector memory CD8+ T cells (Panel C)
and the percentage of CD3+ T cells that were CD8+ T cells (Panel D), as determined by flow cytometry of peripheral
blood mononuclear cells at week 0 (baseline) and week 24. Violin plots show median values (dashed lines) with inter-
quartile ranges (dotted lines). AU denotes arbitrary units.

golimumab24 that are currently considered to be
the most effective disease-modifying therapies
in patients with type 1 diabetes.25 In contrast to
these agents, which require intravenous infusion
or subcutaneous injection, the effect of barici-
tinib was achieved with the daily use of a single
tablet that appeared to cause adverse events in a
low percentage of patients in this small trial.
The results of this trial suggest that barici-
tinib improved measures assessed with the use
of continuous glucose monitoring. Continuous
glucose monitoring measures have been shown
to deteriorate progressively from stage 1 to stage
3 type 1 diabetes,26,27 and they have been sug-
gested to be predictive of diabetes complica-
tions28 and to correlate with quality of life29 in
patients with type 1 diabetes of longer duration.
Our findings strengthen the case for the use
of continuous glucose monitoring to assess the
outcomes of immunotherapy in patients with
type 1 diabetes.
Patients in the baricitinib group generally
used lower daily insulin doses, although all but
three of these patients needed exogenous insulin
therapy by the end of the treatment period. We
believe that many patients with stage 3 type 1
diabetes have had too much irreversible damage
to their β-cell mass by the time of diagnosis to
permit the cessation of insulin therapy to be a
realistic goal. The median of the mixed-meal–

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 The n e w e ng l a n d j o u r na l
stimulated mean C-peptide level at the time of
screening was 0.7 nmol per liter in this trial. We
speculate that the initiation of baricitinib earlier,
when the C-peptide level is higher, either im-
mediately after the diagnosis of symptomatic
clinical type 1 diabetes or during presymp-
tomatic stage 2 or stage 3A disease identified
through the screening of relatives of patients
with type 1 diabetes or through the screening of
the general population, may be more effective in
decreasing the need for injected insulin.30
The acceptable safety profile of 1 year of bar-
icitinib therapy in this trial appears to justify
further evaluation of longer treatment durations
in populations with type 1 diabetes, as has been
done in patients with rheumatoid arthritis.12 An
increasing number of trials involving JAK in-
hibitors have been completed in children. The
safety data from a recent trial involving 225
children 2 to 17 years of age with juvenile idio-
pathic arthritis showed no significant difference
in the incidence of adverse events over 44 weeks
between the group that received tofacitinib, a
JAK3 inhibitor, and the group that received pla-
cebo.15 The low incidence of adverse events in
the baricitinib group may be explained in part by
our STAT phosphorylation studies, which showed
partial JAK inhibition at peak baricitinib levels
and no JAK inhibition at trough levels. The short
pharmacokinetic and pharmacodynamic half-
lives of baricitinib suggest that a rapid loss of
efficacy might also be expected if adherence to
taking the drug is poor or after a course of the
drug is finished.
Nonobese diabetic mice that had remission of
type 1 diabetes with JAK inhibitor therapy had
gradual relapse after the treatment was stopped,8
and in patients with autoimmune alopecia and
those with juvenile idiopathic arthritis, recur-
rence on discontinuation of JAK inhibitor treat-
ment has been observed.13,15 Therefore, we spec-
ulate that we will observe loss of β-cell function
in participants as we continue to follow them
after cessation of baricitinib. In future trials,
investigators might consider administering bar-
icitinib to patients for as long as evidence of
β-cell function persists.
The efficacy of baricitinib in patients with
type 1 diabetes may represent a class effect that
should be investigated in trials involving other
JAK inhibitors.31 In preclinical studies of JAK
inhibitors, we have focused on the interactions
2148 n engl j med 389;23
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Copyright © 2023 Massachusetts Medical Society. All rights reserved.
of m e dic i n e
between CD8+ T cells and β-cells.8,9,32 These in-
teractions are dependent on the release of inter­
feron-γ from T cells and the effect of this cyto-
kine on β-cells.33-36 Inhibitors of JAK1 and JAK2
affect both the production of interferon-γ in T cells
and the effect of interferons on the β-cells that
are mediated by the JAK–STAT pathway.37-39 Barici-
tinib has also been identified in bioinformatics
studies as being capable of protecting β-cells
from deleterious effects of interferons.40 Modu-
lation of the inflammatory response of β-cells
may improve the efficacy of targeting the im-
mune system and differentiates JAK1 and JAK2
inhibitors from agents that act solely on the
immune system.
The number of effector memory CD8+ T cells
was lower in blood samples collected from patients
who had been taking baricitinib for 6 months
than in blood samples collected from these pa-
tients before the initiation of baricitinib treat-
ment — a finding consistent with that in our
preclinical studies.9 These cells are dependent
on γc cytokines, such as interleukin-21, and our
trial also showed decreased levels of basal and
interleukin-21–stimulated phosphorylated STAT3
in the baricitinib group. The effects of JAK inhi-
bition on other mechanisms may also be impor-
tant in human type 1 diabetes and may have
contributed to the preservation of β-cell func-
tion that was observed in our trial. These effects
include the homing of lymphocytes to the islets,
owing to the reduced expression of C-X-C motif
chemokine ligand 10 in β-cells and the decreased
expression of adhesion molecules, including vas-
cular adhesion molecule 1, on the islet endothe-
lium — both of which are regulated by inter­
feron-γ.41,42 Effects on other immune cells, such
as B lymphocytes, are also possible.43
The patient population in the present trial
is representative of the global population with
new-onset type 1 diabetes with respect to age
and sex, and it is representative of the Austra-
lian population with new-onset type 1 diabe-
tes with respect to ethnicity (Table S7). How-
ever, our trial had certain limitations. Most of
the patients were White, which limits the gen-
eralizability of our findings to other races.
The relatively small number of patients and
short duration of the trial limited the ability
to identify rare adverse events. No patients
younger than 10 years of age were enrolled in
the trial.
nejm.org December 7, 2023
 Baricitinib and β-Cells in New-Onset Type 1 Diabetes

In this trial, we found that patients treated
with the JAK inhibitor baricitinib had higher
mixed-meal–stimulated mean C-peptide levels at
48 weeks than those treated with placebo, which
suggests that β-cell function was preserved.
Supported by JDRF International and JDRF Australia; a grant
(4-SRA-2020-912-M-B) from the Australian Government Depart-
ment of Health through the Emerging Priorities and Consumer-
Driven Research Initiative, part of the Medical Research Future
Fund; a grant (GNT1150425) from the National Health and
Medical Research Council of Australia; and St. Vincent’s Insti-
tute of Medical Research, Australia. Philanthropic support was
provided by the Romanes, Burgess, and Yencken families. Dr. So
is supported by the Djinda Foundation Rising Star Fellowship.
Infrastructure support has been provided to St. Vincent’s Insti-
tute by the Victorian State Government Operational Infrastruc-
ture Support Program.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
A data sharing statement provided by the authors is available
with the full text of this article at NEJM.org.
We thank the trial patients and their families; the study co-
ordinators, nurses, and support staff at the trial sites; AK Clini-
cal Research for trial monitoring; Resolutum Global for data-
base set up and management; Tara Catterall, Evan Pappas, and
Katherine Woods for logistic activities and processing related to
mechanistic analyses and biobank samples; and Tom Brodnicki
for administrative support.

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