-
Addition of Liraglutide to Insulin inPatients With Type 1
Diabetes: ARandomized Placebo-ControlledClinical Trial of 12
WeeksDiabetes Care 2016;39:1027–1035 | DOI: 10.2337/dc15-1136
OBJECTIVE
To investigate whether addition of three different doses of
liraglutide to insulinin patients with type 1 diabetes (T1D)
results in significant reduction in glycemia,body weight, and
insulin dose.
RESEARCH DESIGN AND METHODS
We randomized 72 patients (placebo = 18, liraglutide = 54) with
T1D to receiveplacebo and 0.6, 1.2, and 1.8 mg liraglutide daily
for 12 weeks.
RESULTS
In the 1.2-mg and 1.8-mg groups, the mean weekly reduction in
average bloodglucose was 20.55 6 0.11 mmol/L (10 6 2 mg/dL) and
20.55 6 0.05 mmol/L(10 6 1 mg/dL), respectively (P < 0.0001),
while it remained unchanged in the0.6-mg andplacebo groups. In the
1.2-mg group,HbA1c fell significantly (20.786 15%,28.5 6 1.6
mmol/mol, P < 0.01), while it did not in the 1.8-mg group (20.42
60.15%,24.66 1.6 mmol/mol, P = 0.39) and 0.6-mg group (20.266
0.17%,22.861.9mmol/mol,P = 0.81) vs. the placebo group (20.36
0.15%,23.36 1.6mmol/mol).Glycemic variability was reduced by 5 6 1%
(P < 0.01) in the 1.2-mg group only.Total daily insulin dose
fell significantly only in the 1.2-mg and 1.8-mg groups(P <
0.05). There was a 56 1 kg weight loss in the two higher-dose
groups (P < 0.05)and by 2.7 6 0.6 kg (P < 0.01) in the 0.6-mg
group vs. none in the placebo group.In the 1.2- and 1.8-mg groups,
postprandial plasma glucagon concentration fellby 726 12% and 476
12%, respectively (P < 0.05). Liraglutide led to higher
gastro-intestinal adverse events (P < 0.05) and £1% increases
(not significant) in percenttime spent in hypoglycemia (
-
self-monitoring of blood glucose (BG)and improved methods of
insulin de-livery like insulin pens and continuoussubcutaneous
insulin infusion (CSII) ofinsulin through insulin pumps.
Recentobservations suggest that the additionof liraglutide to
insulin improves glycemiccontrol significantly (2,3), as reflected
inthe reduction ofmean glucose concentra-tions, glycemic
excursions, and HbA1c. Inthe first study, the patients already
hadwell-controlled diabetes (2), while thesecond included those
whose diabeteswas poorly controlled and who wereobese or overweight
(3). In both studies,the reduction of HbA1c was;0.5% over aperiod
of 6 months. The changes inglycemic control and the reduction in
gly-cemic variability occurred within the firstfew days of the
institution of liraglutidetreatment, as observed with
continuousglucosemonitoring in the first study (2,3).These
retrospective studies also demon-strated the effects of liraglutide
onweightloss (2,3) and the lowering of systolicblood pressure (SBP)
in obese or over-weight (3). The third study was prospec-tively
randomized and demonstrated areduction in BG concentrations
andHbA1c over a period of just 4 weeks (4).Nonrandomized studies
from othergroups have also confirmed similar clin-ical and
metabolic benefits of glucagon-like peptide 1 (GLP-1) receptor
agonistsin T1D (4–7).Based on our previous studies, we
have now conducted a prospectivelyrandomized study in patients
withT1D investigating the effects of threedifferent doses of
liraglutide, using acontinuous glucose-monitoring system(CGMS).
This trial also investigated thecomparative effects of three doses
ofliraglutide and placebo. We hypothe-sized that treatment with
liraglutide inT1D would decrease overall mean glu-cose, fasting and
postprandial glucoseconcentrations, and postprandial gluca-gon and
increase postprandial C-peptideconcentrations. In addition, we also
in-vestigated the effects of liraglutide onSBP, insulin
requirements, carbohydrateintake, body weight, and plasma
CRPconcentrations.
RESEARCH DESIGN AND METHODS
This study is a single-center randomized,placebo-controlled,
parallel-group, anddouble-blind phase IV study conductedfrom
November 2012 to April 2014 at
the Diabetes and Endocrinology CenterofWestern New York at
University at Buf-falo. The local institutional review
boardapproved the study protocol. All patientsprovided written
informed consent.
Patients were eligible for enrollmentin the trial if they were
adults 18–75years of age with T1D, had fastingC-peptide,0.1 nmol/L,
were on insulintherapy (via CSII [also known as insulinpump]) or
multiple (four or more) injec-tions of insulin per day for .12
monthswith or without a history of diabetic ke-toacidosis, had
HbA1c of #8.5% (69mmol/mol), and were well versed withcarbohydrate
counting. Exclusion crite-ria were T1D for ,12 months;
coronaryevent or procedure (myocardial infarc-tion, unstable
angina, coronary arterybypass, surgery, or coronary angio-plasty)
in the previous 3 months; he-patic disease (transaminase .3
timesnormal) or cirrhosis; renal impairment(serum creatinine .1.5
mg/dL); HIV orhepatitis C–positive status; any
otherlife-threatening, noncardiac disease;history of pancreatitis;
history of gas-troparesis; history of medullary thyroidcarcinoma or
multiple endocrine neo-plasia type 2 (MEN 2) syndrome;
familyhistory of MEN 2, medullary thyroidcancer, or familial
medullary thyroidcancer; pregnancy or of childbearingpotential
without use of adequate con-traception; participation in any
otherconcurrent clinical trial; use of an inves-tigational agent or
therapeutic regimenwithin 30 days of study; and inability togive
informed consent.
Subjects who met the inclusion andexclusion criteria were block
random-ized to receive subcutaneous injectiondaily of liraglutide
0.6 mg (18 subjects),1.2 mg (18 subjects), or 1.8 mg (18 sub-jects)
or placebo (18 subjects) for 12weeks. The subjects, study
coordinatorsand investigators who were involved inadjusting insulin
and liraglutide doseswere blinded to the treatment. Liraglu-tide
and placebo administered via a penkit (obtained from Novo Nordisk
Phar-maceuticals) were indistinguishablefrom each other. The
effects of 0.6 mgliraglutide were investigated, as our
firstretrospective study suggested that thisdose when given in 14
patients with T1D(mean BMI 24 kg/m2, HbA1c of 6.6%) for1 week
significantly improved glycemia,with reduced insulin doses within
24and 48 h with reduction in glycemic
variability by ;50% with only 0.5 kgweight loss (2). It thus
suggested thatthis might benefit normal-weight pa-tients with T1D
and those who maynot tolerate higher doses of the drug.
All subjects were instructed by thestudy staff and certified
diabetes educa-tor in the dosing and administration ofthe study
medication. They were seenby a registered dietitian who ensuredthat
they are well versed with their car-bohydrate counting. They were
advisedto monitor their capillary BG by finger-stick before and 2 h
after each meal andto wear their CGMS constantly for 12weeks. Meal
challenge studies were car-ried out at baseline and at the end
ofthe study. All patients were started on0.6mg of study drug per
day tominimizeside effects, with subsequent titrationto 1.2 and 1.8
mg on a weekly basis untilthey reached the maximal tolerated
ortarget dose. Prior to the initiation ofliraglutide, if the HbA1c
was $7.5%(58 mmol/mol), then no reductionswere made in dose of
insulin, whileif the HbA1c ranged from 7 to 7.5%(53 to 58 mmol/mol)
and was #7%(53 mmol/mol) then the basal and pre-prandial insulin
doses were reduced by10%and 25%, respectively. Patientswereseen
every week for the first 4 weeksafter the initiation of study drug
andthen every 2 weeks until the completionof the study. Insulin
doses were titratedduring study visits based on finger-stickBG and
CGMS to attain preprandial BGconcentrations between 4.9 and
6.6mmol/L (90 and 120 mg/dL) and 2-hpostprandial,7.7mmol/L
(140mg/dL).
Medication adherence was evaluatedby counting used pens. All
patients wereblinded to their CGMS (Dexcom SEVENPLUS) including the
patients who werealready using unblinded CGMS, as CGMSuse alone has
been shown to improveglycemic control (8). All patients
wereprovided sufficient training with CGMSuse during the trial
period includingtroubleshooting support. All patientswere allowed
to see the CGMS reportsat the end of their visits.
Average weekly glucose, fasting glu-cose, SD, and percent time
spent in dif-ferent glycemic thresholdswere obtainedfrom CGMS.
Insulin doses, carbohydrateintake (in grams), and carbohydrate
help-ings (frequency of eating) were obtainedfrom insulin pump and
patient food/insulin dose/BG diaries for patients on
1028 Liraglutide Treatment in Type 1 Diabetes Diabetes Care
Volume 39, June 2016
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CSII and multiple daily injections (MDI),respectively. These
parameters weremeasured every week, while bloodpressure (average of
three readings)was measured manually in the fastingstate after 10
min in the sitting positionat study visits. SD in CGMS
representsthe variability of BG concentrations. Allpatients were
instructed to documenttotal carbohydrate intake including
cor-rectional carbohydrates during hypo-glycemia. The carbohydrate
helpingsper day were calculated from numberof carbohydrate entries
from the insulinpump for patients on insulin pump andfrom the
food/insulin dose/BG log forpatients on MDI. The weekly
averagecarbohydrate intake in grams and fre-quency were estimated
every weekover a period of 12 weeks.The primary end point of the
study
was the difference from baseline inmean weekly BG concentrations
beforeand after 12 weeks of treatment in eachof the liraglutide
groups compared withplacebo. The difference in mean weeklyBG
concentrations was calculated everyweek during the 12 weeks of
treatment.The change in HbA1c, insulin doses, per-cent time spent
in different glycemicranges (3.8–8.8, 8.8–13.3,
13.3–22.25,3.05–3.88, and ,3.05 mmol/L), SD(measure of variability
in BG concentra-tions), body weight, SBP, carbohydrateintake, and
postprandial glucagon weresecondary end points.
Meal Challenge Test and PlasmaMeasurements
Meal Challenge Test
In order to assess the postprandialchanges induced by
liraglutide, a mealchallenge was carried out before
startingliraglutide or placebo and at the end ofthe study period on
days 0 and 84. Weused a910-cal; high-fat, high-carbohydratemeal,
which we have used previously (9–11). The ingestion of the meal was
com-pleted in 15min. Insulin boluswas injectedsubcutaneously
immediately before themeal basedon the insulin-to-carbohydrateratio
and correction factor for each indi-vidual subject. Study subjects
continuedto receive their basal insulin (unchangedbasal rates for
patients on CSII or long-acting insulin at their usual time for
pa-tients onMDI). Liraglutidewas omittedonday 0 but was injected on
day 84 (45 minprior to the meal). Sequential blood sam-ples were
obtained at 0, 15, 30, 45, 60, 90,
120, 150, 180, 210, 240, and 300 min.Blood sample was collected
from an in-dwelling intravenous cannula in a superfi-cial forearm
vein.
Plasma Measurements
HbA1c was measured at Quest Diagnos-tics by immunoturbidimetric
assay.ELISAs were used to measure total GLP-1,gastrointestinal
polypeptide (GIP) (EMDMillipore, Billerica, MA), and
glucagon(R&D Systems, Minneapolis, MN). CRPwas measured using
ELISA assay (Amer-ican Diagnostica, Inc., Stamford, CT).Free fatty
acid (FFA) levels were mea-sured by a colorimetric assay
(WakoChemicals, Richmond, VA).
Statistical MethodsThere arenoprevious randomized studiesthat
have examined the effect of liraglu-tide on mean weekly BG
concentrationsin subjects with T1D. With a conservativeestimate of
a difference in mean weeklyBG concentrations of 20 mg/dL beforeand
after treatment with liraglutide (clin-ically significant
difference based on ourpreliminary study [2]), a sample size of
15patients per treatment group should pro-vide adequate power (b =
0.2) to detect asignificant difference (a = 0.05), providedthe SD
of the residuals is not .25. Thus,60 subjects will be needed for
the study.Sample size was increased by 20% to 72to compensate for
potential dropout.
Data are presented as mean 6 SEM.Final analysis was done based
on theintention-to-treat principle. One-wayANOVA was used to
compare baselinecharacteristics (Table 1) of all fourgroups (three
liraglutide groups andone placebo group). Student t test wasused to
compare the change in meanweekly BG concentrations, HbA1c, per-cent
time spent in different glycemicthresholds, insulin doses, body
weight,BMI, carbohydrate intake, and bloodpressure in liraglutide
groups comparedwith placebo. ANOVA was used to com-pare changes in
postprandial glucoseand glucagon between groups. Studentt test was
used to compare changes inarea under the curve (AUC) in
postpran-dial glucose and glucagon in liraglutidegroups compared
with placebo. x2 testwas used to test difference in propor-tions
and frequency of gastrointestinaladverse events and hypoglycemic
epi-sodes. Changes in these end pointswere calculated by averaging
the differ-ences in weekly average values from
baseline. Pearson correlation was usedto test relationships
among variables.All end points were normally distrib-uted. A P
value of,0.05was consideredsignificant. SPSS software (SPSS,
Chi-cago, IL) was used for analysis.
RESULTS
Sixty-three subjects of the 72 random-ized patients completed
the study(12.5% dropout rate) (Fig. 1). These pa-tients were
recruited between 2 No-vember 2012 and 5 January 2014,
withfollow-up until April 2014. Baselinecharacteristics of study
subjects are pre-sented in Table 1. All the groups hadsimilar age,
BMI, and glycemic control.The total and basal insulin doses
werehigher in the 1.2-mg liraglutide group by23–25 units compared
with the placeboand 1.8-mg liraglutide groups (P , 0.05for both).
All patients had a history of atleast one episode of diabetic
ketoacidosis.Approximately 80% and 20% of random-ized patients were
on CSII with insulinpumps and MDI, respectively (Fig. 1).
Effect of Liraglutide on GlycemicControlIn the 1.2-mg and 1.8-mg
groups, themean weekly reduction in average BGconcentrations
(primary end point) was20.5560.11mmol/L (1062mg/dL) and20.55 6 0.05
mmol/L (10 6 1 mg/dL),respectively (P , 0.0001), while it re-mained
unchanged in the 0.6-mg andplacebo groups (Table 2). The change
inaverage glucose was 20.01 6 0.11(P = 0.51) and 0.04 6 0 mmol/L in
the0.6-mg and placebo groups, respectively.
HbA1c fell by 0.78 6 0.15% (28.5 61.6 mmol/mol) in the 1.2-mg
group(from 7.84 6 0.17% [62 6 2 mmol/mol]to 7.06 6 0.15% [54 6 1.6
mmol/mol];P, 0.0001) andby 0.426 15% (4.66 1.6mmol/mol) in the
1.8-mg group (from7.41 6 0.15% [57 6 1.6 mmol/mol]to 6.99 6 0.15%
[53 6 1.6 mmol/mol];P = 0.001). HbA1c fell by 0.26 6 0.17%(2.8 6
1.9 mmol/mol; P = 0.81) in the0.6-mg group and by 0.3 6 0.15%(3.3 6
1.6 mmol/mol) in the placebogroup. Only the decline in the
1.2-mggroup was statistically significant com-pared with placebo
(Table 2). The changein HbA1c was related to baseline HbA1c inthe
1.2-mg and 1.8-mg groups (r = 0.55,P = 0.052, for 1.2 mg, and r =
0.56,P = 0.03, for 1.8 mg) but not to changein BMI (r = 0.26, P =
0.39, for 1.2 mg, and
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Table
1—Base
linech
aracteristicsofpatients
inthestudygro
ups
Placeb
o0.6mg
1.2mg
1.8mg
P
n17
1416
16
Age
(years)
506
345
64
426
342
63
0.27
Age
ofT1Ddiagnosis(years)
196
319
63
216
321
63
0.92
DurationofT1D(years)
306
325
62
216
320
63
0.04
Sex(m
ale/female)
7/10
9/9
8/5
4/11
0.29§
HbA1c,%(m
mol/mol)
7.696
0.17
(616
2)7.466
0.19
(586
2)7.846
0.17(626
2)7.416
0.15(576
1.6)
0.24
Average
glucose
(CGMS),m
mol/L(m
g/dL)
9.376
0.44(169
68)
8.99
60.38(162
67)
9.32
60.33(168
66)
9.436
0.27(170
65)
0.93
Fastingglucose
(CGMS),m
mol/L(m
g/dL)
9.546
0.66(172
612
)8.716
0.66
(157
612
)8.436
0.55
(152
610
)9.216
0.44(166
68)
0.61
SD(CGMS),m
mol/L(m
g/dL)
4.26
0.22(766
4)4.056
0.22
(736
4)4.166
0.16(756
3)3.96
0.16(706
3)0.77
Bodyweight(kg)
806
680
64
96.0
64
836
40.08
BMI(kg/m
2)
286
226
63
336
228
64
0.20
Totalinsulin
dose
(units)
46.1
69.5
52.8
63.7
71.2
65.5¶$
48.1
64.3
0.01
Basalinsulin
dose
(units)
26.0
65.1
30.706
2.9
42.6
64.5¶$
27.0
62.3
0.01
Bolusinsulin
dose
(units)
24.2
65.1
21.9
62.2
28.0
63.2
20.9
62.8
0.46
Dailycarbohydrate
intake
(g)
1606
1516
16
2917
16
1715
36
180.95
Dailycarbohydrate
helpings
(meals/day)
4.16
0.3
3.76
0.4
3.56
0.3
3.36
0.3¶
0.18
SBP(m
mHg)
1226
412
56
412
16
312
06
20.78
Diastolic
bloodpressure
(mmHg)
756
375
63
756
277
62
0.92
Pulserate
766
275
62
756
275
62
0.16
%timespen
tat
BGconcentrations(CGMS)
,3.05
mmol/L(55mg/dL)
46
136
136
126
10.60
3.05–3.88mmol/L(55–
70mg/dL)
56
156
146
146
10.32
3.8–8.8mmol/L(70–16
0mg/dL)
436
349
63
456
244
63
0.74
8.8–13
.3mmol/L(160
–24
0mg/dL)
296
227
62
306
233
62
0.39
13.3–22
.25mmol/L(240
–40
0mg/dL)
186
315
62
186
218
63
0.94
Episodes
ofhypoglycem
ia/totaln
umber
ofSM
BGread
ings
(inciden
ce%)
,3.05
mmol/L(55mg/dL)
1/36(2)
1/37
(2)
1/36
(2)
1/37(2)
0.84
3.05–3.88mmol/L(55–
70mg/dL)
2/36(5)
4/37(10)
3/36
(8)
1/37(2)
0.31
Glucagonlevels(ng/L)
976
1410
66
1211
26
1895
613
0.38
TotalG
LP-1
(pmol/L)
236
921
63
286
520
63
0.24
TotalG
IP(pg/mL)
786
1473
618
916
2073
612
0.41
FFAs(m
mol/L)
0.51
60.08
0.586
0.11
0.496
0.12
0.55
60.07
0.52
CRP(g/L)
3.05
60.57
3.176
1.0
3.016
0.92
3.53
60.67
0.73
Dataaremeans6
SEM
unless
otherwiseindicated
.¶Sign
ificantcompared
withplacebo(P
,0.05
).§x
2test.$Significantcompared
with1.8-m
ggroup(P
,0.05).
1030 Liraglutide Treatment in Type 1 Diabetes Diabetes Care
Volume 39, June 2016
-
r = 0.31, P = 0.27, for 1.8 mg). Basal andbolus insulin doses
fell in both 1.2-mgand 1.8-mg groups. Change in HbA1cwas related to
change in bolus (r =0.50, P = 0.008) and total insulin doses(r =
0.52, P = 0.005). Change in HbA1c wasnot related to sex.The
glycemic variability (SD of CGM
readings) fell by 0.23 6 0.04 mmol/L(4 6 1 mg/dL) (P , 0.01) in
the 1.2-mggroup, while it remained unchanged inother liraglutide
and placebo groups.Percent time spent in hyperglycemia(8.8–13.3
mmol/L, i.e., 160–240 mg/dL)decreased in both the 1.2- and
1.8-mggroups by 3–4% (P , 0.001 for both).Percent time spent in
hyperglycemia(13.3–22.25 mmol/L, i.e., 240–400 mg/dL)decreased by
2% (P , 0.05) and 3%(P , 0.001), respectively, in the 1.2-mgand
1.8-mg liraglutide groups. Percenttime spent in glycemic threshold
(3.8–8.8 mmol/L, i.e., 70–160 mg/dL) in-creased by 1% (P , 0.05) in
the 0.6-mggroup and by;5% (P, 0.001) in the 1.8-mg group. Percent
time spent in differentglycemic thresholds was unchanged inthe
placebo group. All liraglutide groupshad#1% increase in time spent
in hypo-glycemia (,3.8 mmol/L, i.e., 70 mg/dL,and ,3.05 mmol/L,
i.e., 55 mg/dL),
equivalent to 10 min to 2 h per week.The incidence of
hypoglycemia basedon self-monitoring of blood glucose(SMBG)
readings was essentially un-changed. There was no severe
hypogly-cemic episode requiring hospitalizationor urgent medical
attention in the pla-cebo or liraglutide-treated groups. Therewere
no changes in C-peptide concentra-tions in any groups.
Effect of Liraglutide on CarbohydrateIntake and Body WeightThe
total daily carbohydrate intake fellby 30% (;47 g) in the 1.2-mg
and 1.8-mggroups. This effect occurredwithin thefirstweek (decrease
by 34 g in both groups)and continued to the end of the study.The
frequency of carbohydrate helpingswas reduced in the 1.2-mg and
1.8-mggroups from 3.56 0.3 to 2.66 0.3mealsper day, P, 0.001, and
from 3.36 0.3 to2.9 6 0.3, P , 0.01, respectively.
Mean body weight in the 1.2-mg and1.8-mg groups fell by 56 1 kg
(966 4 kgto 916 4 kg and 836 4 kg to 786 5 kg,respectively, P ,
0.001 for both). Thereduction in body weight was most im-pressive
(3.63 kg in the 1.2-mg groupand 2.27 kg in the 1.8-mg group) inthe
first 2 weeks after the initiation of
liraglutide treatment. There was a fur-ther fall of 1.37 kg in
the 1.2-mg and2.53 kg in the 1.8-mg groups thereafterover 10 weeks.
In the 0.6-mg group,there was a reduction in mean bodyweight by 3
kg (80 6 4 to 77 6 4 kg,P = 0.006). Of subjects treated
withliraglutide, 89% lost weight. There wasno weight loss in the
placebo group.
Effect of Liraglutide on BloodPressure, FFAs, and CRPThere was a
fall in SBP by 3 6 1 mmHg(P , 0.05) in the 1.8-mg group only.
Thechange in blood pressure was unrelatedto weight loss (r = 0.247,
P = 0.376). Fast-ing plasma FFA fell significantly in the1.8-mg
group from 0.556 0.07 to 0.4560.05 mmol/L (P, 0.05) (Tables 1 and
2).
CRP concentrations fell significantlyby 15 6 6% (from 3.01 6
0.92 to2.536 0.83 g/L, P, 0.05) in the liraglu-tide 1.2-mg group
and by 196 8% (from3.536 0.67 to 2.576 0.52 g/L, P, 0.05)in the
liraglutide 1.8-mg group (Tables 1and 2), with no changes in other
groups.
Effect of Liraglutide on Glucoseand Glucagon Excursion Aftera
Mixed MealThe increase in plasma glucagon concen-trations after a
high-fat, high-carbohydrate
Figure 1—Trial profile. ITT, intention-to-treat principle.
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Table
2—Effect
ofliraglutidetreatm
entonglyce
mic
control,bodyweight,insu
lindose
,bloodpressure,gluca
gon,FF
A,andCRPco
nce
ntrations
Chan
geover12
weeks
P(vs.placebo)
Placeb
o0.6mg
1.2mg
1.8mg
0.6mg
1.2mg
1.8mg
Average
glucose,mmol/L(m
g/dL)(CGMS)
0.046
0(0.726
0)20.016
0.11
(0.186
1.9)
20.55
60.11(106
2)*
20.55
60.05(106
1)*
0.51
,0.001
,0.001
HbA1c,%(m
mol/mol)
20.36
0.15(2
3.36
1.6)*
20.266
0.17(2
2.86
1.9)
20.786
0.15(2
8.56
1.6)*
20.426
0.15(2
4.66
1.6)*
0.81
,0.01
0.39
Glucose
SD(CGMS),m
mol/L(m
g/dL)
20.026
0.04(0
61)
20.04
60.03(1
60)
20.236
0.04(4
61)
20.126
0.04(2
61)
0.65
,0.01
0.13
Totalinsulin
dose
(units)
21.96
0.7
22.86
0.7
212
.16
0.7*
210
.06
0.5*
0.76
,0.001
,0.001
Basalinsulin
dose
(units)
0.46
0.4
21.46
0.3
26.36
0.4
21.76
0.3
,0.01
,0.001
,0.001
Bolusinsulin
dose
(units)
21.56
0.4
21.46
0.5
26.16
0.6
28.26
0.3*
0.87
,0.001
,0.001
%timespen
tat
BGconcentrations(CGMS)
,3.05
mmol/L(55mg/dL)
20.26
0.2
0.76
0.3
1.06
0.3
1.36
0.2
,0.01
,0.01
,0.001
3.05–3.88mmol/L(55–
70mg/dL)
21.06
0.2
0.16
0.3
1.26
0.4
1.16
0.2
,0.01
,0.001
,0.001
3.8–8.8mmol/L(70–16
0mg/dL)
1.46
0.6
21.16
0.8
2.76
0.7
4.86
0.8
,0.05
0.19
,0.01
8.8–13
.3mmol/L(160
–24
0mg/dL)
20.66
0.5
0.56
0.6
23.56
0.7*
23.86
0.5*
0.13
,0.001
,0.001
13.3–22
.25mmol/L(240
–40
0mg/dL)
0.86
0.7
0.86
0.6
22.16
0.9
23.56
0.5
1.00
,0.05
,0.001
Episodes
ofhypoglycem
ia/totaln
umber
ofSM
BG
read
ings
(inciden
ce%)¶
,3.05
mmol/L(55mg/dL)
14/419
(3)
21/495
(5)
21/426
(4)
14/472
(2)
0.47
0.82
0.65
3.05–3.88mmol/L(55–
70mg/dL)
21/419
(5)
35/495
(7)
24/426
(5)
27/472
(5)
0.61
0.85
0.74
Number
ofpatients
withhypoglycem
ia/totaln
umber
ofpatients¶
,3.05
mmol/L(55mg/dL)
14/17
13/14
16/16
13/16
0.76
0.42
0.85
3.05–3.88mmol/L(55–
70mg/dL)
16/17
14/14
16/16
16/16
0.86
0.89
0.91
Carbohydrate
intake
(g)
213
.46
2.6
223
.76
2.5
247
.66
2.6*
246
.46
1.6*
,0.01
,0.001
,0.001
Dailycarbohydrate
helpings
(mealsper
day)
0.06
0.6
20.36
0.2
20.96
0.3*
20.46
0.1
0.14
,0.001
,0.001
Bodyweight(kg)
20.36
0.5
22.76
0.6*
25.06
1.2*
24.86
0.7*
,0.05
,0.01
,0.001
BMI(kg/m
2)
20.16
0.2
21.16
0.4*
21.76
0.5*
21.56
0.3*
,0.05
,0.01
,0.001
SBP(m
mHg)†
20.56
0.7
23.06
1.1
21.56
1.0
23.36
1.1*
0.07
0.89
,0.05
DBP(m
mHg)
0.96
0.5
0.56
0.70
20.16
0.4
21.06
0.7
0.52
0.34
0.053
Pulserate
06
2216
32.06
126
20.62
0.48
0.43
Glucagon(ng/L)
56
376
4266
996
60.57
0.38
0.66
GLP-1
(pmol/L)
56
756
276
513
64*
0.52
0.44
0.17
GIP
(pg/mL)
210
68
226
2139
613
*38
611
*0.27
,0.05
,0.05
FFA(m
mol/L)
0.036
0.03
0.05
60.04
0.026
0.02
20.16
0.03*
0.54
0.88
,0.05
CRP(g/L)
20.14
60.11
20.216
0.15
20.486
0.15*
20.966
0.19*
0.41
,0.05
,0.05
Dataaremeans6
SEM
unlessotherwiseindicated
.DBP,diastolic
bloodpressure.*P,
0.05
forchan
gecompared
withbaselinewithingroup(pairedttest).¶x2testforcomparison.†Tw
onorm
otensive
subjects
in1.8-m
ggrouptakingACEinhibitorsforrenalprotectionhad
tostoporreduce
thedose
ofthedrugs
because
ofa
fallinSBPto
,10
0mmHg.Tw
oknownhypertensive
subjectsinthisgroupalso
had
thedosesof
ACEinhibitorandb-blocker
reducedbecause
ofa
fallinSBP.Inthe0.6-m
ggroup,inonenorm
otensive
patientthedose
ofvalsartan
was
reducedto
160mgfrom32
0mgatday
56andto
80mgatday
70owingto
fallin
SBPfrom
112to
100mmHg.
1032 Liraglutide Treatment in Type 1 Diabetes Diabetes Care
Volume 39, June 2016
-
meal was reduced in patients taking1.2 mg and 1.8 mg liraglutide
(Fig. 2A andSupplementary Fig. 1A) at 12 weeks: theAUCof
glucagonwas loweredby47612%and 72 6 12% in the 1.2 mg and 1.8
mggroups, respectively, and thus was dosedependent (P , 0.05 for
both comparedwith baseline) (Fig. 2B and SupplementaryFig. 1A).
This was associated with lowerglucose excursion by 216 8% at 12
weeksin the 1.8-mg liraglutide group (AUC from676 5 to 526 5 g * 5
h * dL21, P = 0.017)(Fig. 2C and D and Supplementary Fig. 1B),which
was also significantly lower com-pared with change in the placebo
group(Fig. 2D).
Adverse Effects
The cumulative incidence of nausea was65% (35 of 54) (P = 0.001)
in the liraglu-tide groups vs. 17% (3 of 18) in placebo.Eleven
patients in the 0.6-mg group; 10
in the 1.2-mg group, 9 in the 1.8-mggroup, and 3 in the placebo
group com-plained of transient nausea. Self-reportedmoderate nausea
was reported forthe first 2–5 days after the initiation
ofliraglutide and then for another 2–4days at the time of
escalation of thedose. These patients reported having ei-ther mild
nausea or intermittent nauseaduring the remaining study
duration.The dropout rate resulting from nauseawas 9% (5 of 54) in
all liraglutide groups,and the breakdown in each group isshown in
Fig. 1 (Trial profile). One pa-tient in the 1.2-mg group had to
dropout owing to both nausea and diarrheafor 1 week. One patient
each in the pla-cebo and 0.6-mg groups reported oneepisode of
vomiting, while two patientsin 1.2-mg and 1.8-mg group reportedtwo
episodes of vomiting. Of 16 patients
in the 1.2-mg group, 6 (37.5%) reportedappetite suppression vs.
8 of 16 (50%)patients in the 1.8-mg group and none inthe placebo
group.
CONCLUSIONS
Our data show that after liraglutide, gly-cemic control improved
rapidly, and thisimprovement persisted until the end ofstudy in the
groups given 1.2 and 1.8 mgliraglutide. This improvement was
re-flected in the reduction of mean glucoseconcentration in both
higher-dose lira-glutide groups, with reduction in glyce-mic
variability only in the 1.2-mg groupover the duration of the study.
Percenttime spent in hyperglycemia (.8.8mmol/L, i.e., 160 mg/dL)
decreased sig-nificantly in the 1.2- and 1.8-mg groupsin
association with a reduction in thedose of total and prandial
insulin. Therewas an increase of 1% in hypoglycemia
Figure 2—Change in glucagon concentrations after meal challenge
before and after 12 weeks of liraglutide or placebo treatments (A)
and AUC forglucagon change at 12 weeks compared with 0 weeks in all
groups (B) in patients with T1D. *P , 0.05 compared with 0 weeks.
Change in glucoseconcentrations after meal challenge before and
after 12 weeks of liraglutide or placebo treatments (C) and AUC for
glucose change at 12 weeks (W)compared with 0 weeks in all groups
(D) in patients with T1D. *P , 0.05 compared with 0 weeks. hr,
hours; PP, postprandial.
care.diabetesjournals.org Kuhadiya and Associates 1033
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-
(both ,3.05 mmol/L, i.e., 55 mg/dl, and,3.8 mmol/L, i.e., 70
mg/dL) in the 1.2-and 1.8-mg groups. There was higher in-cidence of
mild gastrointestinal adverseevents. There was no significant
changein any of these indices in patients treatedwith the placebo
or on 0.6 mg liraglutide.Over the period of 12 weeks, HbA1c
fell significantly from baseline in the1.2- and 1.8-mg groups.
However, thedecrease in the group on 1.8 mg wasnot significantly
different from that inthe placebo group. It is not clear whythe
magnitude of the fall in HbA1c wasgreater in the 1.2-mg group than
thatin the 1.8-mg group. It is possiblethat the higher baseline
HbA1c in the1.2-mg group may have contributed tothis, since the
magnitude of change inHbA1c was shown to be related to base-line
HbA1c. This difference is intriguing,since other indices changed
eitherequally or more in the group taking1.8 mg liraglutide. It is
possible that a12-week study is not sufficient to stabilizeHbA1c
levels. Furthermore, the reduc-tion of 0.42% (4.6 mmol/mol) in
HbA1cin the 1.8-mg group was obtained incombination with 5 kg
weight lossand a reduction in the insulin dose by10 units (21%),
while the body weightand insulin dose remain unchanged inthe
placebo group. Although the 1.2-mggroup was heavier than the
1.8-mggroup by 13 kg, the change in HbA1cwas not related to change
in BMI. Largeand longer-duration randomized clinicaltrials in
overweight and obese patientswith T1D with similar baseline
bodyweight, insulin dose, and HbA1c will clar-ify the heterogeneous
HbA1c responsewith two higher-dose liraglutide groups.In addition,
there was a reduction in
body weight of 5 kg in the 1.2- and 1.8-mggroups in 12 weeks.
Protein, fat, and to-tal calorie intake were not measured,and this
is a limitation of our study. Fewpatients may not have documented
cor-rectional carbohydrates consumed dur-ing hypoglycemia, but this
will be truefor all groups, and therefore bias result-ing from this
is likely to be small. How-ever, they were asked to record
theirdaily carbohydrate intake, which fell by47 g in the 1.2-mg and
1.8-mg groups.In the absence of b-cell function,
there are three likely mechanisms thatcontribute to improved
glycemia inthese patients. Firstly, there was a reduc-tion in the
magnitude of postprandial
increase of glucagon by 72% after 1.8 mgliraglutide and 47%
after the 1.2-mgdose, consistent with the effect seen inpatients
with type 2 diabetes (12). Sec-ondly, the reduction in
carbohydrateintake by nearly one-third associatedwith appetite
suppression induced byliraglutide contributed to the
glycemiccontrol. Thirdly, there may be an insulin-sensitizing
effect, which has recently beenshown to occur in patients with T1D
afterthe administration of exenatide, a GLP-1receptor agonist (7),
especially in associa-tion with weight loss.
There was a significant reduction inSBP in spite of an adequate
blood pres-sure control at baseline. A mean reduc-tion of 3 mm in
the 1.8-mg liraglutidegroup occurred in spite of the reductionin
the dose of ACE inhibitors andb-blockers in some patients. The fall
inSBP is consistent with our original obser-vation of such an
effect with exenatidein type 2 diabetes (13) and with our re-cently
published data on liraglutide inobese patients with T1D (3). It is
impor-tant that this effect is not related toweight loss. It is
possible that this effectis due to a direct action on the
vasculature.
A recent 12-week randomized studyin normal-weight patients with
T1Dwith 1.2 mg liraglutide and a 24-weekrandomized study from the
same groupin overweight and obese patients withpoorly controlled
T1D with 1.8 mg lira-glutide demonstrated significant reduc-tion in
body weight and insulin dosewithout any additional effect on
HbA1ccompared with placebo (14,15). The lat-ter study also
demonstrated reductionin hypoglycemic events (15). Novo Nor-disk
has withdrawn their intent to seek aregulatory indication for the
use of lira-glutide in T1D in view of no additionaldifference in
HbA1c in two large phase-3trials despite weight loss and
reducedinsulin doses (16). Considering theabove in light of the
results seen inour study, further research should bedirected toward
overweight and obesepatients with T1D with a composite pri-mary end
point of change in HbA1c,body weight, insulin dose, and
possiblereduction in hypoglycemia and alsoweigh the expense of the
additionaltherapeutic intervention against thesebenefits. Whether
patients newly diag-nosed with T1D and/or patients withT1D with
detectable C-peptide aremore likely to benefit is also of
interest.
Our study has some limitations. Highfrequency of
gastrointestinal adverse ef-fects can easily unmask whowas likely
tobe on liraglutide. But this would be truefor any randomized study
of liraglutidewith placebo or other comparator groupthat does not
have gastrointestinal sideeffects. This is a single-center
studywith a relatively small sample size ofonly 72 patients
randomized to four dif-ferent groups for a short duration of12
weeks, which is not sufficient forHbA1c to stabilize to a new
level. Never-theless, it clearly shows that while thetwo higher
doses have beneficial ef-fects, the lowest dose of 0.6 mg is
notlikely to be effective in in patients withT1D. One of the
strengths of our studyis that we used CGM throughout theentire
duration of the trial for 12 weeks.This allowed us to capture ;1%
in-crease in percent time spent in hypo-glycemia (both ,3.05
mmol/L, i.e.,55 mg/dL, and ,3.8 mmol/L, i.e.,70 mg/dL) in the 1.2-
and 1.8-mgliraglutide groups despite unchangedincidence of
hypoglycemia based onSMBG.
In conclusion, the two higher doses ofliraglutide are effective
in improvingvarious indices of glycemic control, re-ducing
postprandial glucagon increase,total insulin dose, carbohydrate
intake,and body weight. Our study paves theway for larger
multicenter clinical trialsover longer periods in overweight
andobese patients with T1D to establishthe durability and
consistency of effectsof liraglutide in T1D.
Acknowledgments. The authors thank thefollowing for their help
in execution of the study:Howard Lippes, MD (endocrinologist,
CatholicHealth System, State University of New Yorkat Buffalo), and
Manisha Garg, Sargam Kapoor,Abdul Rafeh, Shyam Mohan, and
AishwaryaUtkosh (research volunteers, Department ofEndocrinology,
Diabetes and Metabolism, StateUniversity of New York at Buffalo).
The authorsthank Dexcom for providing 20 Starter kits ofDexcom
SEVEN PLUS Continuous Glucose Mon-itoring System.Funding.N.D.K.
received an Endocrine FellowsFoundation grant. P.D. has received
grantsfrom the National Institutes of Health, theCenters for
Disease Control and Prevention,the John R. Oishei Foundation, the
William G.McGowan Charitable Fund, and the MillardFillmore
Foundation.The Endocrine Fellows Foundation was not
involved in the conduct of the trial, datacollection,
statistical analysis, or preparationof the manuscript.
1034 Liraglutide Treatment in Type 1 Diabetes Diabetes Care
Volume 39, June 2016
-
Duality of Interest. This research was sup-ported by a grant
from Novo Nordisk to P.D.N.D.K. and A.C. have served on the
speakerpanel for Novo Nordisk. S.D. has served onthe speaker panel
for AbbVie. P.D. has receivedresearch support from
GlaxoSmithKline,Novo Nordisk, Bristol-Myers Squibb,
TakedaPharmaceuticals, Allergan, Sanofi, ConjuChem,Dainippon
Pharmaceuticals, Procter & GamblePharmaceuticals, Mitsubishi,
Quigley Pharma,AbbVie, Transition Therapeutics, and Tolerx;has
received honorarium from Eli Lilly, Novartis,GlaxoSmithKline,
Merck, Novo Nordisk, Takeda,and Sanofi; and has received grants
fromGlaxoSmithKline, Bristol-Myers Squibb, NovartisPharmaceuticals,
Abbott Laboratories, Takeda,Sankyo Pharmaceuticals North America,
the citrusindustry of Florida, and Solvay Pharmaceuticals.No other
potential conflicts of interest relevant tothis article were
reported.Novo Nordisk was not involved in the conduct
of the trial, data collection, statistical analysis,
orpreparation of the manuscript.Author Contributions. N.D.K. and
P.D. wrotethe first draft of the manuscript. All of theauthors
participated in subsequent revisionsof the manuscript. N.D.K.,
S.D., H.G., A.Ma.,A.C., and P.D. conceived the study concept
anddesign. N.D.K. spearheaded the conduct of thestudy and
contributed heavily in recruitment ofstudy participants, titration
of insulin doses, andmanagement of patients. N.D.K. and H.G.
per-formed the statistical analysis and interpretationof data.
N.D.K., H.G., and P.D. wrote the man-uscript. S.D., A.Ma., M.B.,
and A.C. reviewedand edited the manuscript and contributed
todiscussion. S.D., A.Me., S.S., J.H., K.G., and N.B.were involved
heavily with the conduct of thestudy and the management of the
patientsincluding the handling of the continuousglucose-monitoring
data on glycemia. M.Y.conducted the quality-of-life aspect of
thestudy. N.D.K. and P.D. are the guarantors ofthis work and, as
such, had full access to all thedata in the study and take
responsibility forthe integrity of the data and the accuracy ofthe
data analysis.Prior Presentation. Parts of this study werepresented
in abstract form at the 74th Scientific
Sessions of the American Diabetes Association,San Francisco, CA,
13–17 June 2014.
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care.diabetesjournals.org Kuhadiya and Associates 1035
http://globenewswire.com/news-release/2015/08/24/762981/0/en/Novo-Nordisk-completes-second-and-final-phase-3a-trial-with-liraglutide-as-adjunct-therapy-to-insulin-for-people-with-type-1-diabetes-NN9211.htmlhttp://globenewswire.com/news-release/2015/08/24/762981/0/en/Novo-Nordisk-completes-second-and-final-phase-3a-trial-with-liraglutide-as-adjunct-therapy-to-insulin-for-people-with-type-1-diabetes-NN9211.htmlhttp://globenewswire.com/news-release/2015/08/24/762981/0/en/Novo-Nordisk-completes-second-and-final-phase-3a-trial-with-liraglutide-as-adjunct-therapy-to-insulin-for-people-with-type-1-diabetes-NN9211.htmlhttp://globenewswire.com/news-release/2015/08/24/762981/0/en/Novo-Nordisk-completes-second-and-final-phase-3a-trial-with-liraglutide-as-adjunct-therapy-to-insulin-for-people-with-type-1-diabetes-NN9211.htmlhttp://globenewswire.com/news-release/2015/08/24/762981/0/en/Novo-Nordisk-completes-second-and-final-phase-3a-trial-with-liraglutide-as-adjunct-therapy-to-insulin-for-people-with-type-1-diabetes-NN9211.htmlhttp://globenewswire.com/news-release/2015/08/24/762981/0/en/Novo-Nordisk-completes-second-and-final-phase-3a-trial-with-liraglutide-as-adjunct-therapy-to-insulin-for-people-with-type-1-diabetes-NN9211.htmlhttp://care.diabetesjournals.org
