Contribution of Liraglutide in theFixed-Ratio Combination ofInsulin Degludec and Liraglutide(IDegLira)Diabetes Care 2014;37:2926–2933 | DOI: 10.2337/dc14-0785

OBJECTIVE

Insulin degludec/liraglutide (IDegLira) is a novel combination of insulin degludec(IDeg) and liraglutide. This trial investigated the contribution of the liraglutidecomponent of IDegLira versus IDeg alone on efficacy and safety in patients withtype 2 diabetes.

RESEARCH DESIGN AND METHODS

In a 26-week, double-blind trial, patients with type 2 diabetes (A1C 7.5–10.0% [58–86 mmol/mol]) on basal insulin (20–40 units) and metformin with or withoutsulfonylurea/glinides were randomized (1:1) to once-daily IDegLira + metforminor IDeg + metformin with titration aiming for fasting plasma glucose between 4and 5mmol/L.Maximumallowed doseswere 50 dose steps (equal to 50 units IDegplus 1.8 mg liraglutide) and 50 units for IDeg. The primary end point was change inA1C from baseline.

RESULTS

A total of 413 patients were randomized (mean A1C 8.8% [73 mmol/mol]; BMI33.7 kg/m2). IDeg dose, alone or as part of IDegLira, was equivalent (45 units). A1Cdecreased by 1.9% (21 mmol/mol) with IDegLira and by 0.9% (10 mmol/mol) withIDeg (estimated treatment difference21.1% [95% CI21.3,20.8],212mmol/mol[95% CI214,29; P < 0.0001). Mean weight reduction with IDegLira was 2.7 kg vs.no weight change with IDeg, P < 0.0001. Hypoglycemia incidence was comparable(24% for IDegLira vs. 25% for IDeg). Overall adverse events were similar, andincidence of nausea was low in both groups (IDegLira 6.5% vs. IDeg 3.5%).

CONCLUSIONS

IDegLira achieved glycemic control superior to that of IDeg at equivalent insulindoses without higher risk of hypoglycemia and with the benefit of weight loss.These findings establish the efficacy and safety of IDegLira and the distinct con-tribution of the liraglutide component.

Basal insulin therapy, often in combination with oral agents, including metformin, iswell established for the treatment of patients with type 2 diabetes. Once initiated,basal insulin is usually continued even when control is not achieved (1,2). Indeed,more than half of patients with type 2 diabetes treated with basal insulin do notachieve glycemic control (A1C #7.0% [53 mmol/mol]) (1,3,4) and are therefore atincreased risk of developing diabetes complications. Delayed or suboptimal

1University of North Carolina School of Medicine,Endocrinology & Metabolism, Chapel Hill, NC2University of Copenhagen, Gentofte Hospital,Center for Diabetes Research, Copenhagen,Denmark3Endocrinology, SSM Medical Group, St. Louis,MO4Texas Diabetes and Endocrinology, Austin, TX5Novo Nordisk A/S, Søborg, Denmark6Endocrine and Metabolic Consultants, ClinicalResearch, Rockville, MD

Corresponding author: John B. Buse, john_buse@med.unc.edu.

Received 28 March 2014 and accepted 8 July2014.

Clinical trial reg. no. NCT01392573, clinicaltrials.gov.

This article contains Supplementary Data onlineat http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc14-0785/-/DC1.

© 2014 by the American Diabetes Association.Readers may use this article as long as the workis properly cited, the use is educational and notfor profit, and the work is not altered.

John B. Buse,1 Tina Vilsbøll,2

Jerry Thurman,3 Thomas C. Blevins,4

Irene H. Langbakke,5

Susanne G. Bøttcher,5 and

Helena W. Rodbard,6 on behalf of the

NN9068-3912 (DUAL-II) Trial Investigators

2926 Diabetes Care Volume 37, November 2014

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treatment intensification is often causedby common associated barriers, bothfrom a patient perspective (fear of hypo-glycemia and weight gain, increased reg-imen complexity) and from a physicianperspective (lack of patient adherence,increased need for resources, reluctanceto titrate insulin and add to additionalinsulin injections). Further treatment op-tions for optimizing glycemic control aretherefore needed, ideally without in-creasing complexity, the risk of hypogly-cemia, or weight gain (5–8).The American Diabetes Association

and European Association for the Studyof Diabetes have recommended thecombination of basal insulin and aGLP-1 receptor agonist (9). In linewith this, insulin degludec/liraglutide(IDegLira), a novel combination of basalinsulin degludec (IDeg) and GLP-1 ana-log liraglutide, is being developed forthe treatment of patients with type 2diabetes as a once-daily, single subcuta-neous injection. IDegLira combines thecomplementary effects of IDeg and lira-glutide on glycemic control (10–12). Themain pharmacologic effect of IDeg is tolower fasting plasma glucose (FPG) lev-els (13), while liraglutide targets FPG aswell as modestly reducing postprandialglucose excursions (14). The effects ofthe liraglutide component of IDegLiraon b-cell and a-cell function are glucosedependent and may counterbalancethe risk of hypoglycemia seen with in-creasing doses of insulin. Furthermore,by reducing hunger and food intake,IDegLira has the potential to mitigatethe weight gain associated with insulintherapy.The aim of this trial was to determine

the relative contribution of the liraglu-tide component of the combinationproduct while examining the efficacyand safety of IDegLira, as recommendedby regulatory authorities. This goal wasachieved by conducting a comparison ofIDegLira with IDeg in a double-blindfashion and with identical exposure toIDeg in both arms of the study. Forachievement of this latter target, a pa-tient population was recruited that waslikely to require near-maximal doses ofIDegLira (patients inadequately con-trolled on prior insulin therapy), andIDeg titration was limited to the maxi-mal amount provided in full doses ofIDegLira (50 units). A companion study,which will be reported separately,

allowed for unlimited IDeg titration incomparison with IDegLira.

RESEARCH DESIGN AND METHODS

Trial Design and ParticipantsDUAL II was a phase 3, 26-week, ran-domized, parallel, two-arm, double-blind trial comparing the efficacy andsafety of IDegLira + metformin withIDeg + metformin in patients with type2 diabetes inadequately controlled onbasal insulin + metformin with or with-out sulfonylurea/glinides.

Patients were screened at 75 trialsites across seven countries (Supple-mentary Table 1). The trial protocol,consent form, and information sheetwere approved by appropriate healthauthorities and independent ethicscommittee/institutional review boards.Written informed consent was obtainedfrom participants before enrollment.The trial was performed in accordancewith the Declaration of Helsinki (15) andInternational Conference on Harmoni-sation of Technical Requirements forRegistration of Pharmaceuticals for Hu-man Use Good Clinical Practice (16).

Eligible participants were $18 yearsof age, with inadequately controlledtype 2 diabetes (A1C of 7.5210.0%[58286 mmol/mol], inclusive) and aBMI $27 kg/m2 and treated for $90days with basal insulin at a stable dose(20240 units/day [610%]) in combina-tion withmetforminwith or without sul-fonylurea or glinides. SupplementaryTables 2 and 3 provide full lists of eligi-bility criteria. Race/ethnicity was iden-tified by the investigator, choosingbetween the following: race, white,black or African American, Asian Indian,Asian non-Indian, American Indian orAlaska Native, Native Hawaiian or otherPacific Islander, other, or not applicable,and ethnicity, Hispanic or Latino, non-Hispanic, or Latino.

Randomization and MaskingVia a central interactive voice/websystem, participants were randomlyallocated 1:1 to receive once-daily, sub-cutaneous injections of either IDegLira(100 units/mL IDeg and 3.6 mg/mL lira-glutide in a 3-mL prefilled FlexPen; NovoNordisk, Bagsvaerd, Denmark) or IDeg(100 units/mL in a 3-mL prefilledFlexPen). Allocation was stratified withrespect to pretrial treatment with orwithout sulfonylurea/glinide.

Novo Nordisk ensured continuoussafety surveillance and monitoring oftitration. An external independentevent adjudication committee (EAC)performed ongoing adjudication ofcardiovascular events, pancreatitis, neo-plasms, and thyroid disease requiringthyroidectomy (Supplementary Table4). An independent committee of thy-roid experts regularly monitored plasmacalcitonin levels.

Treatment was blinded for investi-gators and participants via use of visu-ally identical trial drugs. Blinding wasmaintained for all involved in the trial(including titration, event adjudication,and calcitonin monitoring) until thedatabase was released for statisticalanalyses.

ProceduresAt randomization, participants discon-tinued all glucose-lowering drugs exceptfor metformin (kept at pretrial dose andfrequency) and transferred from currentbasal insulin to IDegLira or IDeg. Initia-tion dose was 16 units IDeg or 16 dosesteps IDegLira (16 units IDeg plus 0.6 mgliraglutide). One dose step of IDegLiracontains 1 unit IDeg plus 0.036 mgliraglutide.

Doses of IDeg and IDegLira wereadjusted biweekly according to a prede-fined titration algorithm, based on self-measured prebreakfast FPG (mean of 3consecutive days), striving for a meanprebreakfast glucose concentration of4.0–5.0 mmol/L (72–90 mg/dL) (Supple-mentary Table 5). IDegLira and IDegwere to be dosed once daily, indepen-dent of meals but preferably at the sametime every day. Maximum dose was 50units IDeg or 50 dose steps IDegLira(50 units IDeg plus 1.8 mg liraglutide).

Participants performed blood glucosemonitoring with a glucose meter (AbbottDiabetes Care, Abbott Park, IL), calibratedto plasma values.

Outcome MeasuresThe primary end point was change frombaseline in A1C after 26 weeks of treat-ment. Secondary efficacy end points in-cluded doses of IDegLira and IDeg after26 weeks, achievement of A1C levels of,7.0% (53 mmol/mol) and #6.5% (48mmol/mol), and achievement of theseA1C levels with or without confirmedhypoglycemia or weight gain, changesin laboratory-measured FPG, 9-point

care.diabetesjournals.org Buse and Associates 2927

plasma glucose (PG) profiles, and bodyweight.Safety assessments included adverse

events (AEs), hypoglycemic episodes,laboratory analyses, physical examina-tion, and electrocardiogram. Confirmedhypoglycemia consisted of episodesconfirmed by a PG value ,3.1 mmol/L(56 mg/dL) (regardless of symptoms)and severe episodes (requiring assis-tance of another person). Confirmed hy-poglycemia with onset between 0001and 0559 h (inclusive) was classified asnocturnal.A central laboratory (Quintiles Lim-

ited, Livingston, U.K.) performed labora-tory analyses.

Statistical AnalysesThe primary objective was to confirmthe superiority of IDegLira versus IDegwith respect to change from baselinein A1C after 26 weeks of treatment.Sample size was calculated using a two-sided t test of size 5%, assuming a meantreatmentdifferenceof 0.4% (4mmol/mol)and SD of 1.2% (13 mmol/mol) for A1C.To obtain at least 90% power ofmeetingthe primary objective, we required 382participants. The primary end point wasanalyzed using an ANCOVA model withtreatment, previous glucose-loweringdrugs, and country as fixed factors andbaseline value as covariate. Superioritywas confirmed if the 95% CI for thetreatment difference was entirely be-low 0%. All analyses of efficacy andsafety end points, as well as summa-rized baseline values, were based onthe full analysis set (subjects contributedto the analysis “as randomized”). The fullanalysis set comprised all randomizedparticipants except for 15 (8 IDegLiraand 7 IDeg) who were excluded fromanalysis before unmasking of trial resultsowing to a breach in Good Clinical Prac-tice at a trial site. Sensitivity analyseswere performed for the primary endpoint (Supplementary Table 6).Mean daily insulin dose and change

from baseline in FPG, body weight,mean 9-point PG profile, and meanprandial increment across meals wereanalyzed using the same model as usedfor the primary end point; for dose,baseline A1C was also included as covar-iate. Analysis of responder end pointswas based on a logistic regressionmodelwith treatment, region, and previousglucose-lowering drugs as fixed factors

and baseline value(s) as covariate(s).Mean of the 9-point PG profile wasdefined as the area under the pro-file (calculated using the trapezoidalmethod) divided by the measurementtime. The mean increment across meals(calculated as change from premeal to90 min postmeal) was derived as themean of all available meal increments.A mixed-effect model for repeatedmeasures was fitted to the 9-pointprofile data. The model included treat-ment, time point, previous antidiabetestreatment, country, and treatment bytime-point interaction as fixed factorsand baseline 9-point profile value as co-variate. The number of confirmed andnocturnal confirmed hypoglycemic epi-sodes was analyzed using a negative bi-nomial regression model with a log-linkfunction and the logarithm of the timeperiod in which a hypoglycemic episodewas considered treatment emergent asoffset. The model included treatment,previous antidiabetes treatment, and re-gion as fixed factors.

RESULTS

Of 831 patients screened, 413 wererandomized and treated between 28November 2011 and 4 October 2012.Of ineligible patients, 90% failed tomeet the requirement for A1C. Comple-tion rates were 85% for IDegLira and83% for IDeg. Withdrawal patternswere comparable between treatment

groups; none withdrew owing to gastro-intestinal AEs (Supplementary Fig. 1).

Baseline characteristics were similarbetween treatment groups and repre-sentative of a population with type 2diabetes inadequately controlled ontheir current treatment (Table 1).

While doses were uptitrated, meanA1C concentration decreased overtime with both treatments (Fig. 1A, B,and E). The decrease was observed ear-lier with IDegLira than with IDeg. At 26weeks, mean A1C was reduced by 1.9%(21 mmol/mol) with IDegLira and by0.9% (10 mmol/mol) with IDeg to 6.9%(52 mmol/mol) and 8.0% (64 mmol/mol),respectively (Fig. 1A and B). The esti-mated treatment difference (ETD)(IDegLira – IDeg) was 21.1% (95% CI21.3, 20.8) (212 mmol/mol [95% CI214, 29]), P , 0.0001, confirming su-periority of IDegLira over IDeg; again,note that IDeg titration in this protocolwas limited to a maximal dose of 50units per day. All sensitivity analysesconfirmed this result (SupplementaryTable 6).

After 26 weeks, the mean daily dosesof IDeg, either alone or as part ofIDegLira, were equivalent (45 units, P =NS) (Fig. 1E), thus allowing for a validassessment of the contribution of theliraglutide component in IDegLira.

At trial end, 60% of participants in theIDegLira group had achieved A1C ,7.0%(53 mmol/mol), compared with 23% in

Table 1—Baseline characteristics

Characteristic IDegLira IDeg

FAS, n 199 199

Female/male, % 44/56 47/53

Race: white/black/Asian/other#, % 79/5/17/0 76/5/18/1

Ethnicity: Hispanic or Latino/non-Hispanicor Latino, % 8/92 12/88

Age, years 57 6 9 58 6 11

Weight, kg 95.4 6 19 93.5 6 20

BMI, kg/m2 33.6 6 6 33.8 6 6

Duration of diabetes, years 10 6 6 11 6 7

A1C, % (mmol/mol) 8.7 6 0.7 (72 6 8) 8.8 6 0.7 (73 6 8)

FPG, mg/dL 175 6 52 173 6 56

FPG, mmol/L 9.7 6 2.9 9.6 6 3.1

Basal insulin dose (units) 29 6 8 29 6 8

Treatment at screeningBasal insulin + metformin, n (%) 95 (48) 98 (49)Basal insulin + metformin + SU/glinides, n (%) 104 (52) 101 (51)

Data are mean 6 SD unless otherwise stated. SU, sulfonylurea. #“Other” comprises“American Indian/Alaska Native” (n = 0), “Native Hawaiian/other Pacific Islander” (n = 1), and“Other” (n = 1).

2928 Insulin Degludec/Liraglutide in T2D Diabetes Care Volume 37, November 2014

the IDeg group. The estimated oddsof achieving A1C ,7.0% (53 mmol/mol)after 26 weeks were statistically signifi-cantly higher for participants treatedwith IDegLira compared with IDeg (P ,0.0001).With IDegLira, 40%of participants

achieved A1C ,7.0% (53 mmol/mol)without any confirmed hypoglycemicepisodes during the last 12 weeks oftreatment and without weight gain(change in body weight from baseline#0kg), comparedwith8.5%ofparticipants

treated with IDeg (P , 0.0001) (Supple-mentary Table 7). FPG decreased overtime with both treatments, most pro-nouncedly with IDegLira. The greatestchange in FPG was observed during thefirst 8weeks, reaching a plateau at 12–16

Figure 1—Glycemic efficacy, insulin dose, bodyweight, and AEs. Data aremeans (SE).A: A1C. B: Change in A1C. C: FPG.D: Change in FPG. E: Daily doseof IDeg alone or as part of IDegLira. F: Change in body weight. G: Proportion of subjects with nausea. H: Overall confirmed hypoglycemic episodes.

care.diabetesjournals.org Buse and Associates 2929

weeks (Fig. 1C andD). At 26weeks, mean(SD) FPG had decreased by 3.5 (2.9)mmol/L [62 (53) mg/dL] with IDegLiraand 2.6 (3.3) mmol/L [46 (60) mg/dL]with IDeg to 6.2 mmol/L (112 mg/dL)and 7.0 mmol/L (126 mg/dL), respec-tively. ETD was 20.73 mmol/L (95% CI21.19, 20.27) (213 mg/dL [95% CI221, 25]), P = 0.0019, demonstratingstatistically significantly greater reduc-tion in FPG for IDegLira compared withIDeg.The 9-point profiles were similar at

baseline (Fig. 2). After 26 weeks, PG con-centrations had decreased with bothtreatments, and the 9-point profile forIDegLira revealed statistically signifi-cantly lower glucose concentrationscompared with IDeg at all 9 time points(P value ranged from ,0.0001 to0.0290). The mean of the 9-point pro-files decreased by 3.2 mmol/L (58 mg/dL)with IDegLira and by 2.0 mmol/L (36mg/dL) with IDeg to end-of-trial valuesof 7.5 mmol/L (135 mg/dL) and 8.7mmol/L (157 mg/dL), respectively. ETDwas 21.1 mmol/L (95% CI 1.4, 0.7) (219mg/dL [95% CI 226, 213]), P , 0.0001,demonstrating statistically significantlygreater reduction in mean glucose con-centration with IDegLira compared withIDeg. At trial end, the mean prandial in-crement across meals was smaller withIDegLira (2.2 mmol/L [40 mg/dL]) thanwith IDeg (2.4 mmol/L [43 mg/dL]); ETD

20.4 mmol/L (95% CI 20.7, 20.0) (27mg/dL [95% CI 212, 21]), P = 0.0260.

After initiation of IDegLira at 16 dosesteps, an immediate decline in meanprebreakfast glucose concentrationwas observed. In contrast, a transientincrease occurred upon initiation ofIDeg at 16 units (Supplementary Fig.2A–C). A fraction of participants had aprebreakfast glucose increase .5.0mmol/L (91 mg/dL) 3 days after transfer(IDegLira 2.6%, IDeg 5.2%), while agreater proportion had an increase.2.0 mmol/L (36 mg/dL) (IDegLira19%, IDeg 29%). Notably, there wereno withdrawals due to ineffective ther-apy during the first 2 weeks of treat-ment (Supplementary Table 8).

Mean body weight decreased frombaseline by 2.7 kg in the IDegLira armcompared with no weight change withIDeg (Fig. 1F), resulting in an ETD be-tween IDegLira and IDeg of 2.5 kg (95%CI 23.2, 21.8), P , 0.0001.

At lowermean A1C level with IDegLiraat trial end, the incidence of confirmedhypoglycemia was comparable (IDegLira24% vs. IDeg 25%). The rate of confirmedhypoglycemic episodes with IDegLirawas numerically, though not statisticallysignificantly, lower at trial end (Fig. 1H).One case of severe hypoglycemia wasreported in the IDegLira treatmentgroup: the event occurred during ex-ercise (mountain climbing), and the

participant recovered fully after admin-istration of a sweet beverage. Rates ofconfirmed nocturnal hypoglycemia werelow and similar for IDegLira and IDeg(Supplementary Table 9).

Rates of AEs were similar for IDegLiraand IDeg (4.0 vs. 3.6 events per patient-years of exposure). The rate and fre-quency of serious AEs was also similarbetween treatments, and there were notreatment-specific patterns or cluster-ing (Supplementary Table 10). One ma-jor adverse cardiovascular event in theIDegLira group (myocardial infarction)and two in the IDeg group (myocardialinfarction and stroke) were confirmedby the EAC. One event of metastaticpancreatic carcinoma was reported inthe IDeg group. No AEs related to med-ullary thyroid carcinomas, thyroid neo-plasms, or pancreatitis were confirmed.

Mean lipase increased during the trialin the IDegLira group; mean changefrom baseline to week 26 was 14.4units/L for IDegLira (range 2124 to405) and 23.6 units/L for IDeg (range2536 to 133). During the trial, 19 par-ticipants had plasma lipase levels threeor more times above the upper-normalrange (12 IDegLira, 7 IDeg). Of these,only one (IDegLira) presented withsymptoms (nausea, abdominal pain)qualifying for event adjudication owingto suspicion of pancreatitis. The EAC didnot confirm the event to be related to

Figure 2—Mean 9-point self-monitored blood glucose profiles at baseline (dotted line) and after 26 weeks (full line). Mean values based on fullanalysis set and with missing profiles imputed from baseline; dotted line and gray area indicate the glycemic range of IDegLira. *At all 9 time points,self-monitored blood glucose values were statistically significantly lower with IDegLira compared with IDeg (P values ranged from ,0.0001 to0.0290). BF, breakfast.

2930 Insulin Degludec/Liraglutide in T2D Diabetes Care Volume 37, November 2014

pancreatitis. Similarly to lipase, but lesspronounced, a mean increase in amy-lase was observed for IDegLira (meanchange at week 26: 9.3 units/L [range251 to 164]). Mean amylase remainedunchanged for IDeg (20.2 units/L [range2147 to 90]). Seven participants hadplasmaamylase threeormore times abovethe upper-normal range (five IDegLira,two IDeg). None of these reportedsymptoms of pancreatitis. Overall, theincidences of gastrointestinal AEs (nau-sea, vomiting, and diarrhea) were lowbut slightly higher with IDegLira com-pared with IDeg (Table 2). With IDegLira,nausea was more frequent during thefirst 12 weeks of the treatment periodcompared with the last 12 weeks (Fig.1G). Vomiting and diarrhea were less fre-quent (Supplementary Fig. 3). No partic-ipants discontinued the study owing togastrointestinal AEs.

CONCLUSIONS

This 26-week, randomized, controlled,parallel, two-arm double-blind trial ininsulin-treated patients with type 2 di-abetes was designed to determine therelative contribution of the liraglutidecomponent of the IDegLira combinationproduct to glycemic control while exam-ining the efficacy and safety of IDegLira.The study achieved insulin dose equiva-lence between the two arms allowingassessment of the added effects of lira-glutide to those of IDeg in this setting.As the dose of IDeg was limited to 50units, this study does not fully reflectthe glucose lowering or other effectsof fully titrated basal insulin.Superiority of IDegLira over IDeg (lim-

ited to 50 units) in terms of change inA1C was confirmed with an observedreduction of 1.9% (21 mmol/mol) forIDegLira and a difference between the twotreatments of 21.1% (212 mmol/mol).

In addition, from a baseline value of8.7% (72 mmol/mol), IDegLira brought60% of participants to A1C ,7.0% (53mmol/mol), and 40% achieved A1C,7.0% (53 mmol/mol) without con-firmed hypoglycemic episodes duringthe last 12 weeks and without weightgain. The secondary glycemic end pointssupported the results of the primary endpoint: IDegLira was associated with sig-nificantly greater reductions in FPG andmean 9-point PG profiles comparedwith IDeg. Remarkably, at an A1C level1.1% (12 mmol/mol) lower with IDegLira,the rate of confirmed hypoglycemiatrended lower with IDegLira than IDeg(Fig. 1H).

In line with results of previous trialswith liraglutide alone (17–20), a signifi-cant reduction in mean body weight af-ter 26 weeks was seen when liraglutidewas combined with IDeg in the IDegLiragroup compared with IDeg alone. Thereduced insulin dose (from pretrialmean insulin doses of ;30 units to astarting trial insulin dose of 16 dosesteps/16 units), combined with the factthat;50% of subjects discontinued sul-fonylureas at randomization, may tosome extent explain the initial bodyweight reduction in both treatmentgroups. In the IDegLira arm, furtherweight reduction was attributed to theeffect of the liraglutide component.

A 50-unit limit to the maximum dosein the IDeg arm was implemented inthis trial in order to balance insulin ex-posure between arms to allow isolationof the contribution of the liraglutidecomponent of IDegLira. The dose re-strictions stipulated for IDeg in this trialdesign limit the conclusions that can bedrawn in terms of direct comparisonswith real-life treatment with IDeg. An-other study comparing IDegLira withIDeg in patients with type 2 diabetes

inadequately controlled on metforminwith or without pioglitazone supportsthe benefits of IDegLira compared withIDeg as well as liraglutide (21).

At trial drug initiation, participantstransferred from their pretrial basal in-sulin to IDegLira or IDeg. The start doseof 16 dose steps for IDegLira ensuredthat patients discontinuing their pretrialbasal insulin (20–40 units) were trans-ferred to the highest possible insulindose while taking into account the rec-ommended starting dose of liraglutidein GLP-1–naı̈ve patients (0.6 mg). A con-siderable reduction in basal insulincould potentially lead to transientlyworsened glucose control in botharms. In the IDegLira group, mean pre-breakfast glucose declined after the firsttreatment week in the majority of indi-viduals, indicating early onset of the ef-fect of the liraglutide component. Nowithdrawals due to ineffective therapyoccurred during the first 2 weeks oftreatment, thus indicating a safe trans-fer of patients from basal insulin toIDegLira. As would be expected, a largerproportion of the individuals whoswitched from their baseline doseof basal insulin to 16 units IDegdemonstrated a transient increase inprebreakfast PG levels. Nevertheless,glycemic escape was not a clinical prob-lem in this trial.

In this double-blinded study, IDegLirawas generally well tolerated and thetypes of AEs reported for IDegLirawere not different from what was ex-pected from the components IDeg andliraglutide (22–25). No events of pancre-atitis or thyroid disease were observed.Notably, while incidences of nausea,vomiting, and diarrhea were slightlyhigher in the IDegLira group than inthe IDeg group, the percentage of par-ticipants experiencing gastrointestinalAEs during titration was markedly lowerwith IDegLira compared with what wasseen in previous trials with liraglutidealone (24). We speculate that this is re-lated to slower titration and smallerdose increments in this protocol thanin prior studies with liraglutide.

While insulin therapy is still one of themost effective ways to reduce A1C, sig-nificant barriers to therapy intensifica-tion, including hypoglycemia, weightgain, and regimen complexity, reducethe likelihood of patients achieving tar-get levels of glycemic control.

Table 2—Treatment-emergent AEs occurring with a frequency of ‡5%

AE

IDegLira (N = 199) IDeg (N = 199)

% R % R

Nausea 6.5 21.8 3.5 7.8

Diarrhea 6.5 22.8 3.5 8.9

Headache 6.0 25.0 2.0 6.7

Nasopharyngitis 2.5 5.4 6.0 15.6

Lipase increased 6.0 13.1 3.5 7.8

%, percentage of subjects; N, number of subjects in the safety analysis set; R, event rate per 100exposure-years.

care.diabetesjournals.org Buse and Associates 2931

The current Position Statement byAmerican Diabetes Association andEuropean Association for the Study ofDiabetes is more patient-centered andless prescriptive than previous versionsand emphasizes that the recommenda-tions should be considered within thecontext of the needs, preferences, andtolerance of each patient; individualiza-tion of treatment is the cornerstone ofsuccess (9). For patients inadequatelycontrolled on OADs and basal insulintreatment, intensification with IDegLiracould be considered as a future treat-ment option in the context of individualtreatment goals and patient character-istics. The benefits of improved glycemiccontrol and weight loss when transfer-ring from basal insulin to IDegLirashould therefore be balanced againstthe risk profile associated with GLP-1 re-ceptor agonist treatment, including (pri-marily transient) moderately increasedrisk of gastrointestinal AEs such asnausea associated with the liraglutidecomponent of IDegLira.This trial demonstrates that, at equiv-

alent doses of IDeg, the liraglutide com-ponent of IDegLira provides additionalglycemic control by reducing both FPGand, to a lesser extent, postprandial ex-cursions in addition to promotingweight loss and a low rate of hypoglyce-mia. Indeed, the substantial reductionin A1C with a single daily injection ofIDegLira in patients inadequately con-trolled on basal insulin therapy demon-strates the potential role of thiscombination in the treatment of type 2diabetes. Furthermore, IDegLira has alow rate of gastrointestinal AEs. IDegLiramay therefore offer clinical advantagesin patients with type 2 diabetes in-adequately controlled with basal insulinand in need of further treatmentoptimization.

Acknowledgments. The authors thank theinvestigators, trial staff, and participants fortheir participation (see Supplementary Table 11for principal investigators).Duality of Interest. This study was sponsoredby Novo Nordisk (Bagsværd, Denmark). Employ-ees of Novo Nordisk (the sponsor) were respon-sible for designing and conducting the trial;collection, management, analysis, and interpre-tation of the data; preparation and review of themanuscript; and decision to submit the manu-script for publication. The authors thank HeidiSørensen, PhD, employee of Novo Nordisk, forproviding medical writing assistance and Izabel

James at Watermeadow Medical (sponsored byNovo Nordisk) for production and submissionassistance. J.B.B. is a consultant for PhaseBioPharmaceuticals, Inc., and will receive pay-ments, reimbursement for travel, and stockoptions for that effort. J.B.B. is an investiga-tor and/or consultant for the following com-panies without any direct financial benefitunder contracts between his employer andthe companies: Amylin Pharmaceuticals,Inc.; Andromeda; AstraZeneca; BoehringerIngelheim GmbH & Co. KG; Bristol-MyersSquibb Company; Elcelyx Therapeutics, Inc.; EliLilly and Company; GI Dynamics; GlaxoSmithKline;Halozyme Therapeutics; F. Hoffmann-La Roche,Ltd.; Intarcia Therapeutics; Johnson & Johnson;Lexicon; LipoScience; Medtronic; Merck; Meta-vention; Novo Nordisk A/S; Orexigen Therapeu-tics, Inc.; Osiris Therapeutics, Inc.; Pfizer,Inc.; Quest Diagnostics; Sanofi; Santarus; ScionNeuroStim; Takeda; Tolerx; and TransTechPharma. T.V. has received lecture fees fromAstraZeneca, Boehringer Ingelheim Pharmaceuti-cals, Bristol-Myers Squibb, Eli Lilly and Company,Merck Sharp & Dohme, Novo Nordisk, Novartis,Sanofi, and Zealand Pharma and is a member ofthe advisory boards of Novo Nordisk, MerckSharp & Dohme, Takeda, and Bristol-MyersSquibb/AstraZeneca. J.T. is a consultant forNovo Nordisk and Sanofi and has received hon-oraria (speaking) from Novo Nordisk, Sanofi,GlaxoSmithKline, Janssen, Bristol-Myers Squibb,and AbbVie. T.C.B. has received clinical researchsupport from Novo Nordisk, Lilly, Sanofi, andHalozyme and is on the speaker’s bureau ofNovo Nordisk, Lilly, and Sanofi. I.H.L. and S.G.B.are full-time employees of and own stock atNovo Nordisk A/S. H.W.R. has received grants orresearch support fromAmylin, AstraZeneca, Biodel,Bristol-Myers Squibb, Lilly, Halozyme, Merck,Novartis, Novo Nordisk, and Sanofi; has servedon advisory panels for Amylin Pharmaceuticals,Roche Diagnostics, AstraZeneca, Biodel, Janssen,Novartis, Novo Nordisk, Sanofi, and Takeda; andhas served on the speaker’s bureau for Amylin,Merck, AstraZeneca, Bristol-Myers Squibb, BoehringerIngelheim, Janssen, Lilly, and Novo Nordisk. Noother potential conflicts of interest relevant tothis article were reported.Author Contributions. J.B.B. developed thestudy concept and design; acquired, analyzed,and interpreted data; drafted the manuscript;critically revised the manuscript for importantintellectual content; provided administrative,technical, or material support; and supervisedthe study. T.V. acquired, analyzed, and inter-preted data; critically revised the manuscriptfor important intellectual content; providedadministrative, technical, or material support;and supervised the study. J.T. acquired data;critically revised the manuscript for importantintellectual content; and provided admini-strative, technical, or material support. T.C.B.acquired, analyzed, and interpreted data; criti-cally revised the manuscript for importantintellectual content; and provided administra-tive, technical, or material support. I.H.L. ac-quired, analyzed, and interpreted data; draftedthe manuscript; critically revised the manuscriptfor important intellectual content; and providedadministrative, technical, or material support.S.G.B. acquired, analyzed, and interpreted data;

drafted the manuscript; critically revised themanuscript for important intellectual content;provided administrative, technical, or materialsupport; and performed statistical analysis.H.W.R. acquired, analyzed, and interpreted data;critically revised the manuscript for importantintellectual content; and provided administrative,technical, or material support. J.B.B. is the guar-antor of this work and, as such, had full access toall the data in the study and takes responsibilityfor the integrity of the data and the accuracy ofthe data analysis.Prior Presentation. Parts of this study werepresented in abstract form at the InternationalDiabetes Federation World Diabetes Congress,Melbourne, Australia, 2–6 December 2013, andas oral presentations at the 74th ScientificSessions of the American Diabetes Association,San Francisco, CA, 13–17 June 2014.

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