Upload
others
View
0
Download
0
Embed Size (px)
Citation preview
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
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
care.diabetesjournals.org Kuhadiya and Associates 1029
http://care.diabetesjournals.org
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.
care.diabetesjournals.org Kuhadiya and Associates 1031
http://care.diabetesjournals.org
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
http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc15-1136/-/DC1http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc15-1136/-/DC1http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc15-1136/-/DC1http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc15-1136/-/DC1http://care.diabetesjournals.org
(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.
References1. Lind M, Svensson AM, Kosiborod M, et al.Glycemic control and excess mortality intype 1 diabetes. N Engl J Med 2014;371:1972–19822. Varanasi A, Bellini N, Rawal D, et al. Liraglu-tide as additional treatment for type 1 diabetes.Eur J Endocrinol 2011;165:77–843. Kuhadiya ND, Malik R, Bellini NJ, et al. Lira-glutide as additional treatment to insulin inobese patients with type 1 diabetes mellitus.Endocr Pract 2013;19:963–9674. Kielgast U, Krarup T, Holst JJ, Madsbad S.Four weeks of treatment with liraglutide re-duces insulin dose without loss of glycemic con-trol in type 1 diabetic patients with and withoutresidual beta-cell function. Diabetes Care 2011;34:1463–14685. Harrison LB, Mora PF, Clark GO, Lingvay I.Type 1 diabetes treatment beyond insulin:role of GLP-1 analogs. J Investig Med 2013;61:40–446. Traina AN, Lull ME, Hui AC, Zahorian TM,Lyons-Patterson J. Once-weekly exenatide asadjunct treatment of type 1 diabetes mellitusin patients receiving continuous subcutaneousinsulin infusion therapy. Can J Diabetes 2014;38:269–2727. Sarkar G, Alattar M, Brown RJ, Quon MJ,Harlan DM, Rother KI. Exenatide treatment for6 months improves insulin sensitivity in adultswith type 1 diabetes. Diabetes Care 2014;37:666–6708. Bode B, Beck RW, Xing D, et al.; Juvenile Di-abetes Research Foundation Continuous GlucoseMonitoring Study Group. Sustained benefit ofcontinuous glucose monitoring on A1C, glu-cose profiles, and hypoglycemia in adultswith type 1 diabetes. Diabetes Care 2009;32:2047–20499. Aljada A,Mohanty P, GhanimH, et al. Increasein intranuclear nuclear factor kappaB and de-crease in inhibitor kappaB in mononuclear cellsafter a mixed meal: evidence for a proinflamma-tory effect. Am J Clin Nutr 2004;79:682–690
10. Ghanim H, Abuaysheh S, Sia CL, et al. In-crease in plasma endotoxin concentrationsand the expression of toll-like receptors andsuppressor of cytokine signaling-3 in mononu-clear cells after a high-fat, high-carbohydratemeal: implications for insulin resistance. Diabe-tes Care 2009;32:2281–228711. Ghanim H, Sia CL, Upadhyay M, et al. Or-ange juice neutralizes the proinflammatory ef-fect of a high-fat, high-carbohydrate meal andprevents endotoxin increase and Toll-like re-ceptor expression. Am J Clin Nutr 2010;91:940–94912. Horowitz M, Flint A, Jones KL, et al. Effectof the once-daily human GLP-1 analogueliraglutide on appetite, energy intake, energyexpenditure and gastric emptying in type 2 di-abetes. Diabetes Res Clin Pract 2012;97:258–26613. Viswanathan P, Chaudhuri A, Bhatia R, Al-Atrash F, Mohanty P, Dandona P. Exenatidetherapy in obese patients with type 2 diabetesmellitus treated with insulin. Endocr Pract 2007;13:444–45014. Frandsen CS, Dejgaard TF, Holst JJ,Andersen HU, Thorsteinsson B, Madsbad S.Twelve-week treatment with liraglutide asadd-on to insulin in normal-weight patientswith poorly controlled type 1 diabetes: a ran-domized, placebo-controlled, double-blindparallel study. Diabetes Care 2015;38:2250–225715. Dejgaard TF, Frandsen CS, Hansen TS,et al. Efficacy and safety of liraglutide for over-weight adult patients with type 1 diabetesand insufficient glycaemic control (Lira-1): arandomised, double-blind, placebo-controlledtrial. Lancet Diabetes Endocrinol 2016;4:221–23216. Novo Nordisk completes second and finalphase 3a trial with liraglutide as adjunct ther-apy to insulin for people with type 1 diabetes(NN9211) [Internet], 2015. Available fromhttp://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.html. Accessed 26March 2016
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