Sustained effects of interleukin-1 receptor antagonist treatment in type 2 diabetes.

Abstract

Interleukin (IL)-1 impairs insulin secretion and induces beta-cell apoptosis. Pancreatic beta-cell IL-1 expression is increased and interleukin-1 receptor antagonist (IL-1Ra) expression reduced in patients with type 2 diabetes. Treatment with recombinant IL-1Ra improves glycemia and beta-cell function and reduces inflammatory markers in patients with type 2 diabetes. Here we investigated the durability of these responses.
Among 70 ambulatory patients who had type 2 diabetes, A1C >7.5%, and BMI >27 kg/m(2) and were randomly assigned to receive 13 weeks of anakinra, a recombinant human IL-1Ra, or placebo, 67 completed treatment and were included in this double-blind 39-week follow-up study. Primary outcome was change in beta-cell function after anakinra withdrawal. Analysis was done by intention to treat.
Thirty-nine weeks after anakinra withdrawal, the proinsulin-to-insulin (PI/I) ratio but not stimulated C-peptide remained improved (by -0.07 [95% CI -0.14 to -0.02], P = 0.011) compared with values in placebo-treated patients. Interestingly, a subgroup characterized by genetically determined low baseline IL-1Ra serum levels maintained the improved stimulated C-peptide obtained by 13 weeks of IL-1Ra treatment. Reductions in C-reactive protein (-3.2 mg/l [-6.2 to -1.1], P = 0.014) and in IL-6 (-1.4 ng/l [-2.6 to -0.3], P = 0.036) were maintained until the end of study.
IL-1 blockade with anakinra induces improvement of the PI/I ratio and markers of systemic inflammation lasting 39 weeks after treatment withdrawal.

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Sustained Effects of Interleukin-1 Receptor
Antagonist Treatment in Type 2 Diabetes
CLAUS M. LARSEN, MD1
MIRJAM FAULENBACH, MD2
ALLAN VAAG, MD, PHD1,3
JAN A. EHSES, PHD2
MARC Y. DONATH, MD2
THOMAS MANDRUP-POULSEN, MD, PHD1,4,5
OBJECTIVE — Interleukin (IL)-1 impairs insulin secretion and induces ?-cell apoptosis.
Pancreatic ?-cell IL-1 expression is increased and interleukin-1 receptor antagonist (IL-1Ra)
expression reduced in patients with type 2 diabetes. Treatment with recombinant IL-1Ra im-
proves glycemia and ?-cell function and reduces inflammatory markers in patients with type 2
diabetes. Here we investigated the durability of these responses.
RESEARCH DESIGN AND METHODS — Among 70 ambulatory patients who had
type 2 diabetes, A1C ?7.5%, and BMI ?27 kg/m2and were randomly assigned to receive 13
weeks of anakinra, a recombinant human IL-1Ra, or placebo, 67 completed treatment and were
included in this double-blind 39-week follow-up study. Primary outcome was change in ?-cell
function after anakinra withdrawal. Analysis was done by intention to treat.
RESULTS — Thirty-nine weeks after anakinra withdrawal, the proinsulin-to-insulin (PI/I)
ratio but not stimulated C-peptide remained improved (by ?0.07 [95% CI ?0.14 to ?0.02],
P ? 0.011) compared with values in placebo-treated patients. Interestingly, a subgroup char-
acterized by genetically determined low baseline IL-1Ra serum levels maintained the improved
stimulated C-peptide obtained by 13 weeks of IL-1Ra treatment. Reductions in C-reactive pro-
tein (?3.2 mg/l [?6.2 to ?1.1], P ? 0.014) and in IL-6 (?1.4 ng/l [?2.6 to ?0.3], P ? 0.036)
were maintained until the end of study.
CONCLUSIONS — IL-1 blockade with anakinra induces improvement of the PI/I ratio and
markers of systemic inflammation lasting 39 weeks after treatment withdrawal.
Diabetes Care 32:1663–1668, 2009
T
due to insulin resistance (1). During the
course of the disease, ?-cell function pro-
gressively declines irrespective of treat-
ment with glucose-lowering drugs (2–4).
?-Cell mass is reduced through apoptosis
(5) and type 2 diabetes is associated with
a low-grade systemic inflammation (6),
but the mechanisms underlying ?-cell
failure and destruction in type 2 diabetes
remain elusive.
In vitro, long-term exposure to high
glucose and the peptide hormone leptin
ype 2 diabetes is caused by inability
ofthefunctional?-cellmasstocom-
pensate for increased insulin needs
secreted by adipose tissue induce ?-cell
apoptosis and production of the proin-
flammatory cytokine interleukin (IL)-1 in
?-cells and pancreatic islets, respectively
(7,8). IL-1 inhibits the function and in-
duces apoptosis of ?-cells (9) and has
been implicated as a mediator of the
?-celldestructionleadingtotype1diabe-
tes (10). Exogenous addition of interleu-
kin-1 receptor antagonist (IL-1Ra), a
naturally occurring competitive inhibitor
ofIL-1signaling,protectsthe?-cellsfrom
the deleterious effects of high glucose and
leptin exposure (7,8).
Both?-cellexpressionandserumlev-
els of IL-1Ra are reduced in patients with
type 2 diabetes (8,11). This inadequate
IL-1 antagonism seems to be a genetic
trait because genetic polymorphisms in
the gene encoding IL-1Ra are associated
with altered serum levels of IL-1Ra
(12–15).
We showed previously that 13 weeks
of IL-1Ra treatment improved ?-cell
functionandreducedA1Candmarkersof
systemic inflammation in patients with
type 2 diabetes (16). The aim of this 39-
week follow-up study was to investigate
the durability of these effects.
RESEARCH DESIGN AND
METHODS— This study was a 52-
week investigator-initiated, placebo-
controlled, double-blind, parallel-group,
randomized proof-of-concept clinical
trial conducted in Switzerland (Univer-
sityHospitalZurich)andDenmark(Steno
Diabetes Center) between January 2004
and March 2006. The protocol for the
study was in accordance with the Decla-
ration of Helsinki and was approved by
the local ethics committees. Written in-
formed consent was provided by all pa-
tients before entering the study.
The study was designed a priori in
two parts (Fig. 1). The first part was a
13-week intervention study to test the
efficacy and safety of recombinant
human IL-1Ra (anakinra, [Kineret]) in
patients with type 2 diabetes, with
metabolic control as the primary out-
come and ?-cell function, insulin sensi-
tivity, and inflammatory markers as
secondary outcomes, as reported previ-
ously (16). The second part of the study
reported here (supplementary consort
information, available in an online ap-
pendix http://care.diabetesjournals.org/
cgi/content/full/dc09-0533/DC1) was a
39-week follow-up study commencing at
the time of withdrawal of study drug to
test the durability of the intervention on
?-cell function, inflammatory markers,
insulin requirement, and insulin sensitiv-
ity. In the follow-up study, glucose-low-
ering therapy was intensified if indicated,
andinsulintreatmentwasinitiatedifA1C
was ?8.0% or fasting plasma glucose ex-
ceeded8mmol/l.Othermedicationswere
added or increased in dose at the discre-
tionoftheinvestigator.Thestudywasun-
● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●
From the1Hagedorn Research Institute and Steno Diabetes Center, Gentofte, Denmark; the2Clinic for
Endocrinology and Diabetes, University Hospital Zurich, Zurich, Switzerland; the3University of Lund,
Lund, Sweden; the4Core Unit for Medical Research Methodology, Department of Biomedical Sciences,
University of Copenhagen, Copenhagen, Denmark; and the5Karolinska Institutet, Stockholm, Sweden.
Corresponding author: Thomas Mandrup-Poulsen, tmpo@hagedorn.dk.
Received 18 March 2009 and accepted 8 June 2009.
Published ahead of print at http://care.diabetesjournals.org on 19 June 2009. DOI: 10.2337/dc09-0533.
Clinical trial reg. no. NCT00303394, clinicaltrials.gov.
C.M.L., M.F., M.Y.D., and T.M.-P. contributed equally to this study.
© 2009 by the American Diabetes Association. Readers may use this article as long as the work is properly
cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.
org/licenses/by-nc-nd/3.0/ for details.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby
marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
E m e r g i n g T r e a t m e n t s a n d T e c h n o l o g i e s
O R I G I N A LA R T I C L E
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blinded after the last patient’s final visit
(week 52).
Inclusion and exclusion criteria have
beendescribedpreviously(16).Inclusion
criteria were age ?20 years, type 2 diabe-
tes according to criteria from the Ameri-
can Diabetes Association (17) for ?3
months, BMI ?27 kg/m2, A1C ?7.5%,
and no change in either type or doses of
medications in 3 months preceding the
study. In brief, exclusion criteria were au-
toantibodies to GAD65 or islet cell anti-
body 512, A1C ?12%, fasting C-peptide
?400 pmol/l, and current treatment with
anti-inflammatory drugs (low-dose aspi-
rin was allowed).
Study outcomes
The primary outcome of the follow-up
study was change between baseline and
52 weeks in ?-cell secretory function
measured by the fasting ratio of proinsu-
lin to insulin (PI/I) and the area under the
concentration-timecurve(AUC)forstim-
ulated C-peptide during an oral glucose
tolerance test; an intravenous stimulation
test with glucose, glucagon, and arginine;
and the two tests combined. Secondary
outcomes included change between base-
line and 52 weeks in IL-6, C-reactive pro-
tein (CRP), insulin requirements, A1C,
and the homeostasis model assessment–
insulin sensitivity index (HOMA-Si) (18).
In addition, IL-1Ra genotypes were
determined.
Study procedures
In the follow-up study patients were seen
at week 13 on the last day of anakinra or
placebo treatment and at weeks 26, 39,
and 52. A1C was measured at every visit,
and glucose-lowering therapy was inten-
sified if indicated. At baseline and at 13
and 52 weeks, ?-cell secretory function
was assessed by the fasting PI/I ratio and
by a 2-h oral glucose tolerance test di-
rectly followed by a 12-min intravenous
glucose, glucagon, and arginine stimula-
tion test as described previously (16).
Physical examination, funduscopy, rou-
tine safety blood tests, and analysis of uri-
nary albumin excretion were performed
at baseline and after 13 and 52 weeks. At
baseline whole blood was sampled for
DNA analysis of the IL-1Ra gene (IL1RN).
Laboratory values
C-peptide, insulin, and proinsulin were
determined at the Steno Diabetes Center.
Insulin and proinsulin were assessed by
enzyme-linked immunosorbent assays,
and C-peptide levels were determined by
a time-resolved fluoroimmunoassay. IL-
Figure1—Enrollmentandoutcome.Ofthe70patientswhounderwentrandomization,67completed13weeksofanakinraorplacebotreatmentand
were included in the present 39-week follow-up study. Of the former anakinra- and placebo-treated patients, 33 and 31, respectively, completed the
study.
IL-1Ra and sustained ?-cell function
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1Ra, IL-6, and CRP were measured at the
University Hospital Zurich by enzyme-
linked immunosorbent assays. Measure-
ments of A1C levels and routine clinical
laboratory tests were performed locally in
thecentrallaboratoryunitsofthetwopar-
ticipating centers. DNA was extracted
fromwhole-bloodbuffycoatsbytheMax-
well16System(Promega).Genotypingof
the variable number tandem repeat
(VNTR) polymorphism in intron 2 of
IL1RN was analyzed as described previ-
ously (19) with use of (forward) 5?-CTC
AGC AAC ACT CCTAT-3? and (reverse)
5?-TCC TGG TCT GCA GGTAA-3? prim-
ersandseparationofthePCRproductson
2% agarose gel. Genotyping of the single
nucleotide polymorphism (SNP) tagged
by rs4251961 near 5? of IL1RN (13) was
performedwithTaqManSNPGenotyping
Assays (c-32060323-10; Applied Biosys-
tems) according to the manufacturer’s
description.
Statistical analysis
All end points were analyzed in the inten-
tion-to-treat population, defined as pa-
tientscompleting13weeksofanakinraor
placebo treatment. Missing data were im-
putedbylastobservationcarriedforward.
Differences in continuous variables were
compared by a two-sample t test. The
Mann-WhitneyUtestwasusedinthecase
of nonnormal distribution. For categori-
cal variables, Fisher’s exact test was used.
Correlations were analyzed by regression
analysis. P ? 0.05 was considered to in-
dicate statistical significance.
RESULTS— Thirty-three of 34 pa-
tients who finished anakinra treatment
and 31 of 33 patients who finished pla-
cebo treatment completed the study (Fig.
1). At the end of the study, 39 weeks after
withdrawal of anakinra or placebo treat-
ment, the PI/I ratio was lower in the
former anakinra-treated patients than in
theformerplacebo-treatedpatientswitha
baseline adjusted between-group differ-
ence of ?0.07 (95% CI ?0.14 to ?0.02,
P ? 0.011) (Fig. 2A). No differences in
AUC for C-peptide during the oral glu-
cose tolerance test, the intravenous stim-
ulation test, and the combined test at
study end between former anakinra- and
placebo-treated patients were observed
with baseline adjusted between-group
differences of 11.0 (?13.4 to 35.3, P ?
0.224),2.9(?3.1to9.0,P?0.333),and
11.1 (?18.3 to 40.6, P ? 0.282) nmol/
l ? min for the oral, intravenous, and
combined test, respectively.
After 39 weeks of anakinra with-
drawal,CRP(?3.2mg/l[95%CI?6.2to
?1.1, P ? 0.014]) (Fig. 2C) and IL-6
(?1.4 ng/l [?2.6 to ?0.3, P ? 0.036])
(Fig. 2D) were reduced compared with
values in placebo group patients. No cor-
relation between the reduction in PI/I ra-
tio and the reductions in CRP (r2?
0.007, P ? 0.670) or IL-6 (r2? 0.012,
P ? 0.556) was observed in the anakinra-
treated patients.
At52weekstheadjustedmeandiffer-
ence in A1C from baseline between the
former anakinra- and placebo-treated pa-
tients was ?0.05% (95% CI ?0.62 to
0.52, P ? 0.867) (Fig. 2B). The absolute
means ? SEM reductions in A1C were
from 8.7 ? 0.2 to 7.8 ? 0.2% and from
8.2 ? 0.2 to 7.4 ? 0.1% in the anakinra
and placebo groups, respectively. Insulin
sensitivity at study end assessed by
HOMA-Siwas unchanged with a baseline
adjusted between-group difference
(anakinra vs. placebo) of ?0.04 l2/mM ?
mU (?0.20 to 0.13, P ? 0.485). The av-
erage daily insulin dose from withdrawal
of anakinra or placebo treatment until
week 52 increased by 18.9 ? 4.0 and
28.5?7.9IU(P?0.670)intheanakinra
and placebo groups, respectively. The
daily metformin dose was increased by
69 ? 50 and 308 ? 115 mg (P ? 0.257)
in the anakinra and placebo groups, re-
spectively. Other oral glucose–lowering
medications were unchanged during the
study.
Statin therapy was initiated in seven
andeightpatientsduringthefollow-upof
anakinra- and placebo-treated patients,
respectively.Threeanakinraandfourpla-
cebogrouppatientsstartedaspirinduring
the follow-up. The average weight gains
during the study for anakinra- and place-
bo-treated patients were 1.3 ? 0.6 and
1.7 ? 0.8 kg (P ? 0.678), respectively.
Three symptomatic self-reported hypo-
glycemic episodes were noted: two in the
placebo group and one in the anakinra
group. No change in blood pressure, lip-
ids, 24-h urinary albumin excretion, or
retinal fundus photographs was observed
during the study.
As reported previously (16) 21 of 34
patients responded to treatment defined
as any reduction in A1C after 13 weeks of
anakinra treatment (responders to anak-
inra), whereas 10 of 33 patients receiving
placebo treatment experienced reduc-
tions in A1C (P ? 0.0001). To character-
ize the responders to anakinra treatment,
a subgroup analysis was performed. At
baseline patients responding to anakinra
(n ? 21) were older (P ? 0.015) and had
a higher rate of cardiovascular disease
Figure 2—Change in glycemic and inflammatory markers at study end. Data for PI/I ratio (A),
A1C (B), C-reactive protein (C), and IL-6 (D) at baseline and end of study (week 52) in patients
treated with anakinra (f) or placebo (?) from baseline until week 13. Data are means ? SEM.
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(P ? 0.009) compared with nonre-
sponders to anakinra (n ? 13) (supple-
mentary Table A1, available in an online
appendix).
Furthermore, the baseline IL-1Ra se-
rum level was lower in responders to
anakinra than in nonresponders (519 ?
104vs.1,299?314ng/l,P?0.009)and
remained unchanged at the end of the
study (Fig. 3A). Because polymorphisms
of the IL1RN gene encoding IL-1Ra have
beenassociatedtoserumlevelsofthepro-
tein, two IL1RN gene polymorphisms
were investigated. Allele 2 of the VNTR
polymorphism in intron 2 of the gene has
been associated with an increased serum
IL-1Ra level (12,15). An overall correla-
tion between allele 2 carrier status and
baseline serum IL-1Ra levels was found
(r2? 0.18, P ? 0.021); however, there
was no difference between responders
and nonresponders with respect to allele
2 frequency (P ? 1.0) (Fig. 3B). Allele C
of the SNP rs4251961 tagging near 5? of
IL1RN has been associated with a lower
serumIL-1RalevelandhigherserumCRP
and IL-6 levels (13,14). In this study the
correlation between allele C carrier status
andbaselineserumIL-1Ralevelswascon-
firmed (r2? 0.46, P ? 0.001); however,
nocorrelationtobaselineCRP(r2?0.11,
P?0.124)orIL-6(r2?0.06,P?0.254)
was found. Allele C frequency was higher
(58%)intheresponderstoanakinratreat-
ment than in the nonresponders (21%,
P ? 0.007) (Fig. 3B).
Identical target A1C at 52 weeks (Fig.
3C) was reached with lower increases in
insulin dose (10.8 ? 2.6 IU/day) in the
patients responding to anakinra com-
pared with anakinra-unresponsive pa-
tients (31.4 ? 6.0 IU/day, P ? 0.006)
(Fig. 3D).
At the end of anakinra treatment
(week13)responderstoanakinrashowed
improved ?-cell function as assessed by
the PI/I ratio (P ? 0.041) and AUC for
C-peptide during the stimulation tests
(oral test P ? 0.006, intravenous test P ?
0.048, and combined tests P ? 0.025)
compared with that in patients not re-
sponding to anakinra treatment (Fig. 4).
Theimproved?-cellfunctioninrespond-
ers to anakinra treatment was maintained
39 weeks after anakinra withdrawal,
whereas a reduction in ?-cell function in
nonresponderstoanakinratreatmentwas
seen 39 weeks after anakinra withdrawal
(Fig.4),withtheexceptionoftheAUCfor
C-peptide of the intravenous stimulation
test, which was unchanged (P ? 0.793)
(Fig.4C).TheinflammatorymarkersCRP
and IL-6 were reduced compared with
baselinebothatthetimeofanakinrawith-
drawal and at the end of the study irre-
spective of whether the patients were
responsive (reduction in A1C) or unre-
sponsivetoanakinratreatment.Nocorre-
lation between the changes in CRP and
IL-6 and any measurement of?-cell func-
tion in either of the two subgroups was
found(datanotshown).Nosubgroupdif-
ferences in insulin sensitivity measured
by HOMA-Siwere observed.
CONCLUSIONS — Inthefirstpartof
this clinical trial, we reported that 13
weeks of IL-1Ra treatment with anakinra
reduced A1C, improved ?-cell function,
and reduced inflammatory markers (16).
In the present protocolled follow-up
study,weshowthatthereducedPI/Iratio
and CRP and IL-6 serum levels were
maintained 39 weeks after anakinra with-
drawal, indicating that at least 39 weeks
of remission of these parameters were
caused by 13 weeks of anakinra
treatment.
Furthermore, a subgroup analysis
showed that the 21 (62%) patients who
experienced any reduction in A1C after
13 weeks of IL-1Ra treatment with anak-
inra (responders) maintained their anak-
inra-induced improved ?-cell function
assessed by both the PI/I ratio and stimu-
latory testing 39 weeks after anakinra
withdrawal, whereas the ?-cell function
of the patients treated with placebo and
those unresponsive to anakinra treatment
further deteriorated after cessation of pla-
cebo and anakinra therapy, respectively.
The superior ?-cell function of the anak-
inra-responsive patients was reflected by
a lower insulin requirement to obtain tar-
get glycemia in this group.
The preserved ?-cell function 39
weeksafteranakinrawithdrawalindicates
that modulation of ?-cell function or in-
creased ?-cell mass occurred during IL-
1Ra therapy. Apart from one study using
short-term intensive insulin treatment
(20), in which the 45–51% who re-
sponded had maintained an acute insulin
response to intravenous glucose testing,
noothertherapyhasbeenshowntomain-
Figure 3—IL-1Ra serum levels and genotypes; A1C and insulin requirements. A: Serum IL-1Ra
levels at baseline and end of study (week 52) in patients with (?, responders) or without (f,
nonresponders) any reduction in A1C after 13 weeks of anakinra treatment. B: Allele frequencies
of allele 2 and C of the VNTR tandem repeat polymorphism in intron 2 and the SNP tagged by
rs4251961,respectively,oftheIL1-Rageneinresponders(?)andnonresponders(f)toanakinra
treatment. C: A1C at baseline (week 0), and 13, 26, 39, and 52 weeks in responders (?) and
nonresponders(Œ)toanakinratreatment.D:Dailyinsulindoseatbaselineandendofstudy(week
52) in responders (?) and nonresponders (f) to anakinra treatment. Data are means ? SEM or
frequencies where indicated.
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tain ?-cell function in type 2 diabetes af-
ter treatment withdrawal.
Both leptin and hyperglycemia in-
duce IL-1 production in the pancreatic
islets (7,8). Reduction of hyperglycemia
improves ?-cell function (20). How-
ever, the improvement in ?-cell func-
tion observed in this study does not
seem to be a consequence of improved
glycemia per se, because declining
?-cell function was observed in patients
not responsive to anakinra and placebo
group patients, irrespective of the im-
proved glycemic control obtained dur-
ing the follow-up phase. This finding
suggests that the inhibition of IL-1 sig-
naling was the mechanism behind the
improved ?-cell function.
Elevated IL-1Ra serum levels are
foundinnondiabeticindividualsproneto
develop type 2 diabetes (21), whereas pa-
tients with overt type 2 diabetes have re-
duced ?-cell expression and serum levels
of IL-1Ra (8,11), indicating that a down-
regulation of IL-1Ra expression is a con-
sequence of the diabetic state. In this
study, low baseline IL-1Ra serum levels
predicted the glycemic and ?-cell secre-
toryresponsestoanakinratreatment.The
increased frequency of the C allele of SNP
rs4251961, associated with lower IL-1Ra
and higher IL-1 serum levels (13,14) in
the responders to anakinra treatment, in-
dicates that the observed 62% response
rate to anakinra treatment may be genet-
icallydetermined.Inaccordancewiththis
notion, we have previously shown that
?-cells from 6 of 10 patients with type 2
diabetes expressed IL-1 mRNA (22). The
observed frequencies of the T and C al-
leles of SNP rs4251961 in this study did
not differ from the frequencies in popula-
tions without type 2 diabetes (13,14), in-
dicating that the C allele is not
predisposingtodiabetesdevelopmentper
se but is a pharmacogenetic biomarker
for a glycemic response to anakinra
treatment.
The lack of association between
changesinCRPandIL-6,surrogatemark-
ers of systemic IL-1 activity, and the PI/I
ratio or any reduction in A1C after anak-
inra therapy indicates that systemic in-
flammation is not likely to affect ?-cell
function and that the improved ?-cell
function caused by anakinra treatment is
due to inhibition of IL-1 produced in the
vicinity of the ?-cell. IL-1 production
couldthusoriginatefromthe?-cell(7)or
from macrophages infiltrating the islets
(23) as the IL1B gene is overexpressed in
blood monocytes from patients with type
2 diabetes (24).
The sustained reduction of CRP and
IL-6 levels at 39 weeks after anakinra
withdrawal is notable and indicates that
transient IL-1 blockade is capable of in-
ducing not only a metabolic but also a
39-week-longinflammatoryremission.In
this study, the inflammatory remission
was not related to insulin sensitivity. This
findingisinlinewithrecentfindingsfrom
the Whitehall II study (25).
There are some limitations to this fol-
low-up study. First, multiple hypotheses
were tested; second, a subgroup analysis
was performed.
In summary, this study suggests that
13weeksofanakinratreatmentiscapable
of inducing a 39-week-long preservation
of?-cellfunctionandasimilarinflamma-
tory remission in patients with type 2 di-
abetes. Low baseline serum IL-1Ra levels
predicted the metabolic response, and
this phenotypic trait was associated with
theCalleleofanIL1RNSNP.Futurestud-
ies will have to be conducted to confirm
these results and to test higher doses and
longertreatmentandfollow-upperiodsin
patients with type 2 diabetes selected on
the basis of their IL1RN SNP genotype. If
the results are confirmed, the perspective
of these findings is that anakinra treat-
ment could be used as substitution ther-
apy in patients with type 2 diabetes with
genetically determined IL-1Ra deficiency
and as induction therapy during flares of
hyperglycemia in the course of the
disease.
Acknowledgments— M.Y.D. is listed as the
inventor of a patent filed in 2003 for the use of
an interleukin-1 receptor antagonist for the
Figure 4—?-Cell function after anakinra withdrawal. ?-Cell function assessed by PI/I (A); and
AUC for C-peptide during an oral glucose-tolerance test (B); an intravenous stimulation with
glucose, glucagon, and arginine (C); and the oral and intravenous test combined (D) at baseline,
anakinra withdrawal (week 13), and end of study (week 52) in patients with (?, responders) or
without (f, nonresponders) any reduction in A1C after 13 weeks of anakinra treatment. A: *P ?
0.041 vs. nonresponders at week 13, †P ? 0.435 vs. responders week 52, ‡P ? 0.016 vs. nonre-
sponders week 52, and §P ? 0.005 vs. nonresponders week 52. B: *P ? 0.006 vs. nonresponders
atweek13,†P?0.750vs.respondersweek52,‡P?0.021vs.nonrespondersweek52,and§P?
0.008 vs. nonresponders week 52. C: *P ? 0.048 vs. nonresponders at week 13, †P ? 0.039 vs.
responders week 52, ‡P ? 0.793 vs. nonresponders week 52, and §P ? 0.092 vs. nonresponders
week 52. D: *P ? 0.025 vs. nonresponders at week 13, †P ? 0.947 vs. responders week 52,
‡P ? 0.021 vs. nonresponders week 52, and §P ? 0.001 vs. nonresponders week 52. Data are
means ? SEM.
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treatment or prophylaxis against type 2 diabe-
tes. No other potential conflicts of interest rel-
evant to this article were reported.
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