More Similarities ThanDifferences Testing InsulinGlargine 300 Units/mL VersusInsulin Degludec 100 Units/mL inInsulin-Naive Type 2 Diabetes:The Randomized Head-to-HeadBRIGHT TrialDiabetes Care 2018;41:2147–2154 | https://doi.org/10.2337/dc18-0559

OBJECTIVE

To compare insulin glargine 300 units/mL (Gla-300) versus insulin degludec100 units/mL (IDeg-100) in this first head-to-head randomized controlled trial.

RESEARCH DESIGN AND METHODS

BRIGHT (NCT02738151) was a multicenter, open-label, active-controlled, two-arm,parallel-group, 24-week, noninferiority study in insulin-naive patients with un-controlled type2diabetes. Participantswere randomized1:1 toeveningdosingwithGla-300 (N = 466) or IDeg-100 (N = 463), titrated to fasting self-monitored plasmaglucose of 80–100mg/dL. The primary endpointwasHbA1c change frombaseline toweek 24. Safety end points included incidence and event rates of hypoglycemia.

RESULTS

At week 24, HbA1c improved similarly from baseline values of 8.7% (72 mmol/mol)in the Gla-300 group and 8.6% (70 mmol/mol) in the IDeg-100 group to 7.0%(53 mmol/mol)dleast squares mean difference 20.05% (95% CI 20.15 to 0.05)(20.6 mmol/mol [21.7 to 0.6])ddemonstrating noninferiority of Gla-300 ver-sus IDeg-100 (P < 0.0001). Hypoglycemia incidence and event rates over 24 weekswere comparable with both insulins, whereas during the active titration period(0–12 weeks) the incidence and rate of anytime (24-h) confirmed hypoglycemia(£70 and <54 mg/dL) were lower with Gla-300. Both insulins were properlytitrated and exhibited no specific safety concerns.

CONCLUSIONS

Gla-300 and IDeg-100 provided similar glycemic control improvements withrelatively low hypoglycemia risk. Hypoglycemia incidence and rates were com-parable with both insulins during the full study period but lower in favor of Gla-300during the titration period. The choice between these longer-acting basal insu-lins may be determined by factors such as access and cost, alongside clinicalconsiderations.

1DallasDiabetesResearchCenter atMedical City,Dallas, TX2Division of Endocrinology andMetabolism, Uni-versity of Toronto, Toronto, Canada3Klinikum Schwabing and Klinikum Bogenhau-sen, Stadtisches Klinikum Munchen GmbH, Mu-nich, Germany4Sanofi, Paris, France5AIXIAL, Boulogne-Billancourt, France6Sanofi, Tokyo, Japan7Sanofi, Frankfurt, Germany8Sanofi, Budapest, Hungary9Sanofi, Beijing, China10National Research Institute, Los Angeles, CA11Diabetology Endocrinology Nutrition, HopitalBichat, DHU FIRE, Assistance Publique Hopitauxde Paris, Paris, France12INSERM U-1138, Centre de Recherche desCordeliers, Paris, France13UFR de Medecine, Universite Paris Diderot,Sorbonne Paris Cite, Paris, France14Perugia University Medical School, Perugia,Italy

Corresponding author: Julio Rosenstock,juliorosenstock@dallasdiabetes.com.

Received 13 March 2018 and accepted 13 July2018.

Clinical trial reg. no. NCT02738151, clinicaltrials.gov.

This article contains Supplementary Data onlineat http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc18-0559/-/DC1.

This article is featured in a podcast availableat http://www.diabetesjournals.org/content/diabetes-core-update-podcasts.

© 2018 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. More infor-mation is available at http://www.diabetesjournals.org/content/license.

Julio Rosenstock,1 Alice Cheng,2

Robert Ritzel,3 Zsolt Bosnyak,4

Christine Devisme,5 Anna M.G. Cali,6

Jochen Sieber,7 Peter Stella,8

Xiangling Wang,9 Juan P. Frıas,10

Ronan Roussel,11,12,13 and

Geremia B. Bolli14

Diabetes Care Volume 41, October 2018 2147

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GINGTH

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DRUGSANDREG

IMEN

S

Long-acting basal insulin analogs repre-sented a significant advance in the man-agement of diabetes, providing longerduration of action, flatter action profiles(1), and less day-to-day variability thanNPH insulin, with lower risk for hypo-glycemia (1). Basal insulin analogs con-tributed to an important translationalclinical advancement in the treatmentof patients with type 2 diabetes, allow-ing for the development of the treat-to-target concept (2) that could be facilitatedmore easily with these longer-actingbasal insulin analogs with less hypo-glycemia. Currently, basal insulin ana-logs are increasingly used not only byendocrinologists but also by generalpractitioners.Further pharmacokinetic/pharmaco-

dynamic (PK/PD) improvements havebeen made with the even longer-actingsecond-generation basal insulin analogsinsulin degludec 100 units/mL (IDeg-100)and insulin glargine 300 units/mL(Gla-300) (3–5), which have smootherPK/PD profiles than insulin glargine100 units/mL (Gla-100) with lower var-iability (3,5). The BEGIN and EDITIONclinical trial development programs forIDeg-100 and Gla-300, respectively,demonstrated similar HbA1c reductionsto Gla-100 but with less hypoglycemia inpeople with type 2 diabetes (6,7). How-ever, direct clinical comparisons be-tween these two second-generationbasal insulin analogs are unavailable,except for two head-to-head PK/PD in-sulin clamp comparisons in type 1 di-abetes (8,9) that showed conflictingresults.Here we report on the BRIGHT study,

the first head-to-head randomized clin-ical trial designed to compare the efficacyand safety of Gla-300 with IDeg-100 inparticipants with type 2 diabetes inad-equately controlled with oral agents withor without glucagon-like peptide 1 recep-tor agonists (GLP-1 RAs).

RESEARCH DESIGN AND METHODS

Study Design and ParticipantsBRIGHT (reg. no. NCT02738151, Clinical-Trials.gov) was a multicenter (158 sites,16 countries), open-label, randomized,active-controlled, two-arm, parallel-group, 24-week noninferiority study inadult participants with uncontrolled type 2diabetes (HbA1c $7.5% [$58 mmol/mol]and#10.5% [#91mmol/mol] at screen-ing) on oral agents, including sodium–

glucose cotransporter 2 (SGLT2) inhibi-tors, with or without GLP-1 RAs. Exclu-sion criteria included current or previoususe of insulin, initiation of new glucose-lowering medications and/or weight-loss drug in the last 3 months beforescreening; BMI,25 kg/m2or.40kg/m2,end-stage renal disease, any contraindi-cation to IDeg-100 orGla-300, andhistoryof hypersensitivity to the active sub-stance or to any of the excipients ofIDeg-100 or Gla-300. A full list of inclu-sion and exclusion criteria are presentedin Supplementary Table 1.

All participants provided written in-formed consent and the study wasconducted in accordance with the Dec-laration of Helsinki and the InternationalConference on Harmonization of Tech-nical Requirements for Pharmaceuticalsfor Human Use Guideline for Good Clin-ical Practice.

Randomization and TreatmentThe randomization scheme was providedby the study statistician to an interac-tive response technology (IRT) system,which then generated the patient ran-domization list and allocated treatmentarms to the patients accordingly. At thescreening visit the investigator contactedthe IRT center to receive the patientnumber. Treatment kits were allocatedusing the centralized IRT system, requiringthe investigator to contact the central-ized IRT system and provide patient-specific details.

Eligible participants were randomized1:1 to receive Gla-300 or IDeg-100 andwere stratified by HbA1c level (,8.0%,$8.0% [,64mmol/mol,$64mmol/mol])and sulfonylurea (SU) or glinide use(yes, no) at screening. Gla-300 andIDeg-100 were self-administered bysubcutaneous injection once daily be-tween 1800 h and 2000 h throughoutthe study period. Starting doses, as perlabeling, were 0.2 units/kg for Gla-300and 10 units for IDeg-100 and weretitrated to achieve glycemic targets ac-cording to the same titration algorithm(Supplementary Table 2). Doses wereadjusted at least weekly, but not moreoften than every 3 days, targeting afasting self-monitored plasma glucose(SMPG) of 80–100 mg/dL while avoidinghypoglycemia. The “active” titration pe-riod was 0–12 weeks, during which timeachievement of the fasting SMPG targetwas aimed for. During weeks 13–24, dose

titrations were still allowed. Dose adjust-ments (22, 0, +2, +4, or +6 units) werebased on median fasting SMPG valuesfrom the last three measurements, in-cluding the day of titration. Backgroundtherapies were not changed during thestudy unless safety concerns necessi-tated dose reduction or discontinuation.

End PointsThe primary end point was the changein HbA1c from baseline to week 24.Secondary efficacy end points includedchange in fasting plasma glucose (FPG),fasting SMPG, and eight-point SMPGprofiles from baseline to week 24; changein variability of 24-h SMPG, based oneight-point profiles; percentage of par-ticipants reaching target HbA1c ,7.0%(,53 mmol/mol) at week 24; and per-centage of participants reaching targetHbA1c ,7.0% (,53 mmol/mol) at week24 without confirmed hypoglycemia(#70 mg/dL and ,54 mg/dL) during the24-week treatment period.

Safety end points included the inci-dence and event rates of hypoglycemiaduring the 24-week on-treatment period,the active titration period (weeks 0–12),and the maintenance period (weeks 13–24). Documented symptomatic hypogly-cemia was defined as an event that wassymptomatic with a confirmatory bloodglucose reading (#70 mg/dL or ,54mg/dL). Severe hypoglycemia was de-fined as an event requiring assistancefrom another person to administer car-bohydrate, glucagon, or other resuscita-tive actions. Confirmed hypoglycemiaincluded documented symptomatic orasymptomatic hypoglycemia (#70 mg/dLor,54mg/dL) and severe events, if any.Hypoglycemia that occurred between0000 h and 0559 h was defined as noc-turnal. Other safety outcomes includedbody weight and adverse events (AEs).Change in basal insulin dose was alsoassessed, although this was not a pre-specified end point.

Data Analysis and StatisticsSample size calculations were made us-ing nQuery Advisor software version 7.0(Cork, Ireland). Analyseswere performedusing SAS version 9.4 (Cary, NC).

A sample size of 920 randomized par-ticipants was chosen to ensure with atleast 90% power that the upper bound ofthe two-sided 95% CI of the adjustedmean difference in HbA1c change from

2148 Gla-300 Versus IDeg-100: Efficacy and Safety Diabetes Care Volume 41, October 2018

baseline between Gla-300 and IDeg-100would not exceed a noninferiority mar-gin of 0.3%, assuming a common SD of1.4% with a one-sided test at the 2.5%significance level and a true differenceof 0.0%. If noninferiority was achieved,superiority was tested according to ahierarchical procedure.All efficacy end points were assessed

in the intention-to-treat (ITT) population(all randomized participants who re-ceived at least one dose of study insu-lin, analyzed according to the treatmentgroup allocated by randomization).Safety end points were analyzed in thesafety population (all randomized pa-tients who received at least one doseof study insulin, according to the treat-ment actually received). The primaryend point, change in HbA1c during the24-week on-treatment period, was ana-lyzed by a mixed-effect model with re-peated measures (MMRM), using themissing at random framework, with fixedcategorical effects of treatment, visit,treatment-by-visit interaction, randomi-zation strata of SU or glinide use atscreening (yes, no), and the continuousfixed covariates of baseline efficacyparameter value and baseline efficacyparameter value-by-visit interaction.Sensitivity analyses were conductedfor the primary end point using all avail-able postbaseline HbA1c values, regard-less of study treatment discontinuationand rescue therapy initiation (devia-tions); the per-protocol population (asubset of the ITT population withoutdeviations); and multiple imputation(missing at random, penalized) and tip-ping point analyses in order to assessthe robustness of primary efficacy analy-sis results with regard to missing HbA1cat week 24.All continuous secondary efficacy end

points were analyzed using the sameMMRM approach, with the additionalrandomization strata of HbA1c at screen-ing. Binary efficacy end points wereassessed during the 24-week on-treat-ment period and before any rescuetreatment, analyzed using a logisticregression model adjusted on random-ization strata. For participants who dis-continued study treatment prematurelyor for those who received rescue ther-apy during the 24-week on-treatmentperiod, time windows were applied toretrieve assessments performed at pre-mature end-of-treatment and prerescue

visits for the MMRM analyses. No multi-plicity adjustments were made on sec-ondary efficacy variables; only 95% CIswere reported.

For safety end points, proportion ofparticipants experiencing $1 hypogly-cemic event was analyzed using logis-tic regression, including randomizationstrata as covariates. Hypoglycemic eventrates were analyzed using an overdis-persed Poisson regression model adjustedon randomization strata. AEs were codedusing MedDRA.

RESULTS

Baseline CharacteristicsParticipants (N = 929) were randomizedinto the Gla-300 (N = 466) and IDeg-100(N = 463) treatment arms, and the ITTpopulation included 462 participantsin each treatment arm (SupplementaryFig. 1). Overall, 99.5% of the random-ized population received treatment, with94.2% completing the 24-week treat-ment period.

At baseline, the most commonly usednoninsulin antihyperglycemic drugswere metformin (91.5%) and SU (65.7%)and, overall, characteristics were similarin both treatment arms (Table 1).

Glycemic ControlMean (6 SD) HbA1c at baseline was 8.760.8% (726 9 mmol/mol) and 8.66 0.8%(70 6 9 mmol/mol) in the Gla-300 andIDeg-100 groups, respectively, decreas-ing to 7.06 0.8% (536 9 mmol/mol) and7.0 6 0.8% (53 6 8 mmol/mol) by week24 (Fig. 1A and Table 2). Least squares (LS)mean change (6 SE) in HbA1c frombaseline to week 24 was 21.64 60.04% (218.0 6 0.4 mmol/mol) forGla-300 and 21.59 6 0.04% (217.4 60.4 mmol/mol) for IDeg-100, with a LSmean difference for Gla-300 versusIDeg-100 of 20.05% (95% CI 20.15 to0.05) (20.6 mmol/mol [21.7 to 0.6]),demonstrating noninferiority of Gla-300versus IDeg-100 (P , 0.0001) for theprimary end point. Superiority of Gla-300

Table 1—Baseline characteristics (randomized population)

Baseline characteristicsGla-300(N = 466)

IDeg-100(N = 463)

Total(N = 929)

Age, years 60.6 6 9.6 60.5 6 9.8 60.5 6 9.7

Sex (% male/female) 53/47 54/46 54/46

BMI, kg/m2 31.7 6 4.3 31.3 6 4.4 31.5 6 4.4

Known type 2 diabetes duration, years 10.5 6 6.1 10.7 6 6.5 10.6 6 6.3

HbA1c% 8.71 6 0.83 8.57 6 0.80 8.64 6 0.82mmol/mol 71.7 6 9.1 70.2 6 8.7 70.9 6 9.0

HbA1c randomization strata,8.0% (,64 mmol/mol) 86 (18.5) 85 (18.4) 171 (18.4)$8.0% ($ 64 mmol/mol) 380 (81.5) 378 (81.6) 758 (81.6)

FPG, mg/dL 191 6 49 182 6 51 186 6 51

Fasting SMPG, mg/dL 178 6 40 172 6 38 175 6 39

eGFR, mL/min/1.73 m2 92.4 6 26.8 90.8 6 26.0 91.6 6 26.4

Number of prior noninsulinantihyperglycemic agents used

0 0 (0.0) 1 (0.2) 1 (0.1)1 70 (15.0) 65 (14.0) 135 (14.5)2 179 (38.4) 187 (40.4) 366 (39.4).2 217 (46.6) 210 (45.4) 427 (46.0)

Prior noninsulin antihyperglycemictreatment (%)

Metformin 91.8 91.1 91.5SUs 64.6 66.7 65.7Glinides 2.6 1.9 2.3Thiazolidinediones 4.5 5.2 4.8DPP-4 inhibitors 26.0 22.9 24.4SGLT2 inhibitors 13.3 13.4 13.3GLP-1 RAs 9.9 14.0 11.9a-Glucosidase inhibitors 1.9 1.5 1.7Other 0.2 0.2 0.2

Data are presented asmean6 SD or n (%) unless otherwise stated. DPP-4, dipeptidyl peptidase 4;eGFR, estimated glomerular filtration rate.

care.diabetesjournals.org Rosenstock and Associates 2149

versus IDeg-100 was not demonstrated.Robustness of the primary analysis wassupported by the results of sensitivityanalyses to assess the impact of missingdata, including a per-protocol analysis(not shown). Furthermore, no evidenceof heterogeneity of treatment effectaccording to randomization strata of SUor glinide use (yes, no) was observed(P = 0.626, data not shown).The proportions of participants who

reached HbA1c target ,7.0% (,53mmol/mol), or HbA1c target ,7.0%(,53 mmol/mol) without confirmed hy-poglycemia (#70 mg/dL or ,54 mg/dL)at any time of day (24 h), at week 24 werecomparable between treatment arms(Table 2).Mean FPG and fasting SMPG at base-

line and week 24 are presented in Table 2and Fig. 1C and D. The LS mean differencein FPG change from baseline to week24 was 7.7 mg/dL (95% CI 2.7–12.7) forGla-300 versus IDeg-100. The LS meandifference in fasting SMPG change frombaseline to week 24 was 1.1 mg/dL[95% CI 21.9 to 4.1] for Gla-300 versusIDeg-100. The eight-point fasting SMPGprofiles appeared similar with Gla-300

and IDeg-100 by week 24 (Fig. 1B). Meancoefficient of variation for eight-pointprofiles (24-h SMPG), expressing within-day plasma glucose variability, wascomparable for Gla-300 and IDeg-100at baseline (22.5% and 23.4%, respec-tively) and at week 24 (27.6% and 28.0%,respectively).

Hypoglycemia

Anytime (24-h) Hypoglycemia

The incidence of confirmed hypoglyce-mia (#70mg/dL) at any timeofday (24h)during the 24-week on-treatment pe-riod was comparable with Gla-300 andIDeg-100, being 66.5% and 69.0% (oddsratio [OR] 0.88 [95% CI 0.66–1.17]. Therewas also no difference between treat-ments in the incidence of confirmedhypoglycemia at the,54 mg/dL thresh-old over 24 weeks (Fig. 2). Patients usingSUs or glinides at screening were morelikely to experience hypoglycemia thanthose who were not, but no evidence ofheterogeneity of treatment effect ac-cording to randomization strata of SUor glinide use (yes, no) was observed forthe incidence of confirmed hypogly-cemia (#70 mg/dL and ,54 mg/dL)

(P . 0.05, data not shown). The event rateof confirmed hypoglycemia (#70 mg/dL)at any time of day during the 24-weekon-treatment period was comparablewith Gla-300 and IDeg-100, with 9.3and 10.8 events per patient-year, respec-tively (rate ratio [RR] 0.86 [95% CI 0.71–1.04]) (Fig. 2). A comparable rate ofconfirmed hypoglycemia (,54 mg/dL)was also observed with Gla-300 andIDeg-100 (0.6 versus 0.9 events perpatient-year, RR 0.69 [95% CI 0.45–1.08]) (Fig. 2).However, for both incidenceand rates, the direction of effect was infavor of Gla-300 for confirmed hypo-glycemia (defined by either glycemicthreshold) over 24 weeks (Fig. 2).

During the first 12 weeks, incidence andevent rates of confirmed hypoglycemia(#70mg/dL and,54 mg/dL) were lowerwith Gla-300 versus IDeg-100 (Fig. 2).Incidence and event rates of confirmedhypoglycemia (#70mg/dLand,54mg/dL)were comparable in both treatmentgroups during weeks 13–24 (Fig. 2).

The results for anytime (24-h) docu-mented symptomatic hypoglycemia weresimilar to those for confirmed hypogly-cemia (data not shown).

Figure 1—HbA1c levels (A), eight-point SMPG profiles (B), FPG levels (C), and fasting SMPG levels (D) over 24 weeks of treatment, ITT population.BL, baseline; FSMPG, fasting SMPG; W, week. (A high-quality color representation of this figure is available in the online issue.)

2150 Gla-300 Versus IDeg-100: Efficacy and Safety Diabetes Care Volume 41, October 2018

Nocturnal (0000–0559 h) Hypoglycemia

The incidence of nocturnal (0000–0559h) confirmed hypoglycemia (#70mg/dL)during the 24-week on-treatment periodwas comparable with both treatments:28.6% with Gla-300 and 28.8% withIDeg-100 (OR 0.99 [95% CI 0.74–1.32]).No difference between treatments over24 weeks was seen in the incidenceof confirmed hypoglycemia at the ,54mg/dL threshold (Fig. 2). The event ratesof nocturnal confirmed hypoglycemia(#70 mg/dL) during the 24-week pe-riod were comparable with Gla-300 andIDeg-100, being 1.8 and 2.3 events perpatient-year, respectively (RR 0.81 [95%CI 0.58–1.12]) (Fig. 2). Event rates ofnocturnal confirmed hypoglycemia (,54mg/dL) during the 24-week period werealso comparable with Gla-300 and IDeg(Fig. 2).When analyzing hypoglycemia by

study period (Fig. 2), the incidence of noc-turnal confirmed hypoglycemia (#70and,54 mg/dL) was comparable across

treatment groups during the first12 weeks. During this period, the rateof confirmed nocturnal hypoglycemia(#70 mg/dL) was lower with Gla-300than with IDeg, at 1.4 and 2.2 eventsper patient-year, respectively (RR 0.65[95% CI 0.43–0.98]), whereas the rateof confirmed nocturnal hypoglycemia(,54 mg/dL) was comparable with bothtreatments.

For nocturnal (0000–0559 h) docu-mented symptomatic hypoglycemia,similar results as for confirmed hypogly-cemia were observed (data not shown).

Severe HypoglycemiaOverall, during the 24-week study, only1 participant (female, 49 years old, treatedwith metformin) experienced severehypoglycemia. This single event was re-ported in the Gla-300 group during the13–24-week period and was due to thepatient skipping her evening meal andnot reducing her insulin dose after anonsevere event 2 days earlier.

Insulin DoseThe mean daily insulin dose (6 SD) onday 1 was 16.9 6 4.4 units (0.196 0.04units/kg) for Gla-300 and 10.26 1.9 units(0.12 6 0.04 units/kg) for IDeg-100. Atweek 24, the mean daily dose was 50.5625.6 units (0.54 6 0.26 units/kg) forGla-300 and 39.2 6 23.3 units (0.43 60.24 units/kg) for IDeg-100 (Supplemen-tary Fig. 2A). The mean dose increasesfrom baseline to week 24 were 33.6 624.4 units (0.36 6 0.25 units/kg) and29.16 23.3 units (0.316 0.24 units/kg)for Gla-300 and IDeg-100, respectively(Supplementary Fig. 2B).

Body WeightMean (6 SD) body weight increased frombaseline (90.6 6 16.1 kg and 88.7 615.9 kg in the Gla-300 and IDeg-100groups, respectively) to week 24 (92.5616.6 and 91.4 6 16.7 kg), an absolutemean increase of 2.0 6 3.8 kg withGla-300 and 2.3 6 3.6 kg with IDeg-100(Supplementary Fig. 3). LS mean differ-ence in body weight change for Gla-300versus IDeg-100 was 20.33 kg (95% CI20.81 to 0.15).

AEsOverall, 202 (43.7%) and 221 (47.8%)participants in the Gla-300 and IDeg-100groups, respectively, reported AEs dur-ing the 24-week study period. SeriousAEs were reported in 21 (4.5%) and20 (4.3%) participants, respectively.Four (0.9%) participants in the Gla-300group and 5 (1.1%) in the IDeg-100 groupreported an AE that led to permanentdiscontinuation of the investigationaldrug. One death occurred in the Gla-300group, due to adenocarcinoma of thecolon. Injection site reactions occurredin 1.7% (n = 8) and 1.3% (n = 6) partic-ipants in the Gla-300 and IDeg-100groups, respectively.

CONCLUSIONS

To date, head-to-head comparisons be-tween Gla-300 and IDeg-100 have re-lied on PK/PD studies in type 1 diabetesand indirect trial-level meta-analyses(3,4,10,11). The BRIGHT study is the firsthead-to-head trial investigating the clin-ical efficacy and safety of these twosecond-generation, longer-acting basalinsulin analogs. In this population ofinsulin-naive patients with uncontrolledlong-standing type 2 diabetes on multi-ple oral antihyperglycemic drugs with orwithout GLP-1 RAs, Gla-300 was similar

Table 2—Glycemic control (ITT population)

Efficacy parameters Gla-300 (N = 462) IDeg-100 (N = 462)

HbA1cBaseline% 8.72 6 0.83 8.57 6 0.80mmol/mol 71.8 6 9.1 70.2 6 8.8

Week 24% 7.03 6 0.79 7.03 6 0.77mmol/mol 53.3 6 8.6 53.3 6 8.4

LSmean change frombaseline toweek 246 SE% 21.64 6 0.04 21.59 6 0.04mmol/mol 218.0 6 0.4 217.4 6 0.4

LS mean difference (95% CI)% 20.05 (20.15 to 0.05)a

mmol/mol 20.6 (21.7 to 0.6)a

Patients who reached HbA1c target ,7.0%(,53 mmol/mol), n (%) 225 (48.7) 206 (44.6)

OR (95% CI) 1.19 (0.91–1.54)

Patients who reached HbA1c target withoutconfirmed (#70mg/dL) hypoglycemia, n (%) 62 (13.4) 60 (13.0)

OR (95% CI) 1.05 (0.71–1.55)

Patients who reached HbA1c target withoutconfirmed (,54mg/dL) hypoglycemia, n (%) 194 (42.0) 175 (37.9)

OR (95% CI) 1.20 (0.92–1.57)

FPG, mg/dLBaseline 190.60 6 49.36 182.12 6 51.68Week 24 123.76 6 40.60 114.54 6 33.23LSmean change frombaseline toweek 246 SE 263.47 6 1.956 271.16 6 1.977LS mean difference (95% CI) 7.68 (2.71–12.65)

Fasting SMPG, mg/dLBaseline 177.85 6 40.49 171.65 6 38.16Week 24 115.21 6 23.66 113.29 6 20.65LSmean change frombaseline toweek 246 SE 258.11 6 1.21 259.18 6 1.22LS mean difference (95% CI) 1.08 (21.94 to 4.10)

Baseline and week 24 values are mean 6 SD. aPrimary end point; P , 0.0001 for noninferiority(noninferiority margin 0.3%).

care.diabetesjournals.org Rosenstock and Associates 2151

to IDeg-100 in terms of HbA1c reduc-tion (from an overall mean 8.6% [71mmol/mol] at baseline to 7.0% [53mmol/mol] at week 24). Furthermore,similar proportions of participants in theGla-300 and IDeg-100 groups achievedHbA1c target ,7.0% (,53 mmol/mol)without confirmed hypoglycemia (#70mg/dL and ,54 mg/dL). Hypoglycemiaincidence and rates were generally low,although slightly higher than in theinsulin-naive population in the EDITION3 study comparing Gla-300 versus Gla-100(where, in contrast with the BRIGHTstudy, SUs and glinides were discontin-ued) (12). Most notably, only one severehypoglycemic event occurred during theentire 24-week trial, attesting to thesafety of both these longer-acting basalinsulins, which can allow stricter glyce-mic goals when properly initiated andtitrated.At study end, FPG values were fairly

similar with IDeg-100 and Gla-300, al-though there was a greater reductionfrom baseline with IDeg-100 than Gla-300(Fig. 1C). In contrast, fasting SMPGwas higher at baseline with Gla-300but decreased similarly compared with

IDeg-100 and was no different at studyend (Fig. 1D). The reasons for the smalldiscrepancy between FPG and fastingSMPG are not clear but may reflectdifferences in how and when samplesfor FPG and fasting SMPG were taken;FPG sampling and analysis was per-formed during on-site visits, while fastingSMPG was usually sampled and testedwhen participants awoke and prior tobreakfast, with mean values from theprevious 7 days used in the analysis foreach relevant time point. Furthermore,the fasting SMPG results may be ofmore clinical relevance, given that thesevalues guided insulin titration (as perprotocol) during the study. Neverthe-less, these findings are consistent withresults from trial-level meta-analysesindirectly comparing the EDITION andBEGIN clinical trial programs, whichshowed a discrepancy between the FPGand fasting SMPG change for Gla-300and IDeg-100 versus Gla-100 (13).

Of note, within-day variability of 24-hSMPG (based on the eight-point SMPGprofiles) in BRIGHT was comparablewithin the Gla-300 and IDeg-100 groupsat baseline and week 24, indicating no

difference in within-day intrasubjectvariability between these two second-generation basal insulins. The increase inintrasubject variability from baseline toweek 24 was minimal, suggesting thatboth longer-acting basal insulins reduceblood glucose levels smoothly in type 2diabetes. Further analyses will be con-ducted to assess whether day-to-daydifferences in glucose variability, if any,exist between Gla-300 and IDeg-100 inpatients with type 2 diabetes in clinicalpractice.

Hypoglycemia incidence and rateswere comparable between the insulinsover the entire 24-week treatmentperiod. However, lower incidence andannualized rates of anytime (24-h) con-firmed hypoglycemia (#70 and ,54mg/dL) were observed with Gla-300versus IDeg-100 during the initial titra-tion period (0–12 weeks), despite thistime also being the period with thehighest increase in insulin doses andgreatest drop in fasting SMPG andHbA1c. During the 13–24-week period,when there were smaller changes ininsulin dose, the incidence and rates ofconfirmed hypoglycemia were comparable

Figure 2—Hypoglycemia at any time of day (24 h) (A) or during the nocturnal period (0000–0559 h) (B), safety population. Nominal P values areprovided.

2152 Gla-300 Versus IDeg-100: Efficacy and Safety Diabetes Care Volume 41, October 2018

in both treatment groups. The finding ofless hypoglycemia with Gla-300 versusIDeg-100 during the time of more in-tensive insulin titration could help tobuild patient confidence to initiate andproperly titrate their basal insulin withless fear of hypoglycemia. Similar HbA1cimprovement accompanied by less hy-poglycemia is consistent with studies ofbasal insulin analogs versus the “stan-dard comparator” in insulin-naive type2 diabetes (2,14). Additional studies(real-world evidence and/or random-ized controlled) comparing Gla-300and IDeg-100 in more advanced type2 diabetes are needed to determinewhether the difference between thetwo insulins observed in the currentstudy also applies to patients at higherrisk of hypoglycemia (such as those onlong-term basal or basal-bolus insulintreatment).The reduced rates of certain categories

of hypoglycemia with Gla-300 com-pared with IDeg-100 may reflect PK/PDdifferences. Despite the limitations ofavailable PK/PD studies in type 1 diabe-tes (8,9), it appears from steady-statePD profiles (8,9) that IDeg-100 has a ten-dency for greater glucose-lowering ac-tivity between 8 and 12 h postdosingcompared with Gla-300. Given the even-ing injection time, this might explain, atleast in part, the slightly higher rates ofnocturnal hypoglycemia (#70 mg/dL)with IDeg-100 observed during thisstudy. However, PK/PD studies in type 2diabetes are needed to more specificallycharacterize similarities and differencesbetween Gla-300 and IDeg-100, notonly with evening but also with morn-ing dosing.The mean starting dose of Gla-300 was

higher by 0.07 units/kg than the dose ofIDeg-100, as per label instructions (0.2units/kg for Gla-300 and 10 units forIDeg-100), and remained higher through-out the study. At week 24 the Gla-300insulin dose was higher by 0.11 units/kgthan the IDeg-100 dose, an increase inthe mean dose difference by 0.04 units/kg compared with baseline. This differ-ence was to be expected, given the sim-ilar doses observed between IDeg-100and Gla-100 in the BEGIN trials (15)and the higher doses of Gla-300 versusGla-100 in theEDITIONtrials (7). Thedosedifference is not due to a lower potencyof Gla-300, since the mechanism of ac-tion and metabolism (generation of the

active metabolite M1) is the same asthat of Gla-100 (16), and Gla-300 has thesame potency as both regular human in-sulin and Gla-100 after intravenous ad-ministration (17,18). The greater dose ofGla-300 after subcutaneous injection isneeded to compensate for its lower bio-availability owing to the longer residencetime of its microprecipitates in the sub-cutaneous space and subsequent localdegradation by tissue proteases. This in-terpretation is indirectly favored by thefact that the slightly higher Gla-300dose in BRIGHT did not translate into in-creased hypoglycemia risk nor greaterweight gain; in fact, the trends, if any,were in the opposite direction, in linewith the EDITION studies in people withtype 2 diabetes (7).

The strengths of this study include thehead-to-head, randomized trial design,which was powered to assess the pri-mary HbA1c end point. The study wasconducted effectively, with systematic,proper insulin titration, and with mostparticipants (who had similar baselinecharacteristics) completing the treat-ment period. The open-label designwas a limitation, but it was unavoidableowing to the difficulty in blinding trialparticipants to the identity of the twobasal insulin analog pens. This may haveintroduced a bias if users or investigatorsperceived either insulin as “more effec-tive” or “safer” than the other. Further-more, the study may be limited by therelatively short 24-week duration, andassessing outcomes over a longer follow-up period would be of interest.

This head-to-head study of Gla-300versus IDeg-100 in insulin-naive individ-uals with type 2 diabetes demonstratedthat both second-generation longer-acting basal insulin analogs were asso-ciatedwith comparable reductions in HbA1c,glucose profiles, and fasting SMPG. Com-parable glycemic control was achievedalongside similarly low overall incidenceand rates of hypoglycemia in both insulingroups throughout the treatment pe-riod. However, Gla-300 was associatedwith lower incidence and rates of any-time (24-h) confirmed hypoglycemia (#70and ,54 mg/dL) than IDeg-100 duringthe 0–12-week period when most of theinsulin dose titration and plasma glucosereduction occurred. Gla-300 was also as-sociated with a lower rate of nocturnal(0000–0559 h) confirmed hypoglycemia(#70 mg/dL) during the initial titration

period. The overall safety profiles forGla-300 and IDeg-100 were similar, andboth insulins were well tolerated withno specific safety concerns. This trial isthe first to identify hypoglycemia riskreduction for Gla-300 versus IDeg-100.Notably, there was only one episode ofsevere hypoglycemia, suggesting thatreducing severe hypoglycemia riskneed not necessarily be a factor in thedecision-making process for selectingthese longer-acting basal insulins intreatment of insulin-naive patientswith type 2 diabetes. Moreover, giventhat there are more similarities thandifferences in efficacy and safety be-tween these two second-generationbasal insulin analogs, it is suggestedthat selection of which to use in clini-cal practice should be determined notjust by the evaluation of clinical factorsbut mainly by practical factors such asaccess and cost.

Acknowledgments. The authors thank thestudy participants, trial staff, and investigatorsfor their participation (a full list of participat-ing physicians is presented in the APPENDIX). Theauthors also thank Emmanuelle Boelle-Le Corfec(Sanofi) for review. Editorial and writing assis-tance was provided by Simon Rees of FishawackCommunications Ltd. and was funded by Sanofi.Sanofi sponsored, designed, and coordinated theclinical trial presented in this article.Duality of Interest. J.R. has served on scientificadvisory boards and received honoraria orconsulting fees from Eli Lilly, Novo Nordisk,Sanofi, Janssen, Boehringer Ingelheim, and In-tarcia and has received grants/research sup-port from Merck, Pfizer, Sanofi, Novo Nordisk,Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline,AstraZeneca, Janssen, Genentech, BoehringerIngelheim, Intarcia, and Lexicon. A.C. has servedon advisory panels for Abbott, AstraZeneca,Boehringer Ingelheim, Eli Lilly, Janssen, Merck,Novo Nordisk, Sanofi, Servier, and Takeda and isa speaker for Abbott, AstraZeneca, BoehringerIngelheim, Eli Lilly, Janssen, Merck, Novo Nor-disk, and Sanofi. R.Ri. has received honorariaor consulting fees from Sanofi, Novo Nor-disk, Merck Sharp & Dohme, and Servier andspeakers’ bureau fees from Sanofi, NovoNordisk, Novartis, Eli Lilly, Berlin-Chemie, MerckSharp & Dohme, and AstraZeneca. Z.B. is anemployee/shareholder of Sanofi. C.D. is an em-ployee of AIXIAL, providing consultancy to Sanofi.A.M.G.C., J.S., P.S., and X.W. are employees/shareholders of Sanofi. J.P.F. has received researchfunding from AbbVie, Allergan, AstraZeneca,Boehringer Ingelheim, Bristol-Myers Squibb,Elcelyx, Eli Lilly, Genentech, Ionis, Janssen, Johnson& Johnson, Lexicon, Ligand, Madrigal, Merck,Mylan,Myovant, Novartis, NovoNordisk, Ogeda,Pfizer, Sanofi, TaiwanJ, Theracos, and VikingTherapeutics and has received honoraria for ad-visory boards and consulting from AstraZeneca,

care.diabetesjournals.org Rosenstock and Associates 2153

Bristol-Myers Squibb, Elcelyx, Johnson & Johnson,Novo Nordisk, and Sanofi. R.Ro. is an advisorypanel member for AstraZeneca, AbbVie, Sanofi,Merck Sharp & Dohme, Eli Lilly, Janssen, NovoNordisk, and Physiogenex; is a speaker forBayer and Servier; and has received researchfunding and provided research support toDanone Research, Amgen, Sanofi, and NovoNordisk. G.B.B. has received honoraria or con-sulting fees from Sanofi and Menarini and re-search funding and speakers’ bureau fees fromSanofi. No other potential conflicts of interestrelevant to this article were reported.AuthorContributions. J.R.,A.C.,R.Ri.,A.M.G.C.,J.S., P.S., X.W., R.Ro., and G.B.B. were involvedin the study concept and design. C.D. performedthe statistical analyses of the data. All authorsparticipated in the interpretation of data andthe writing, reviewing, and editing of the man-uscript and had final responsibility for approvingthe published version of the manuscript. J.R. isthe guarantor of this work and, as such, had fullaccess to all the data in the study and takesresponsibility for the integrity of thedata and theaccuracy of the data analysis.Prior Presentation. Parts of this study werepresented in abstract form at the 11th Interna-tional Conference on Advanced Technologies &Treatments for Diabetes, Vienna, Austria, 14–17February2018, and inposterandabstract formatthe 78th Scientific Sessions of the AmericanDiabetes Association, Orlando, FL, 22–26 June2018.

Appendix

Participating Physicians. Bulgaria: ZdravkoKamenov, Malina Petkova, and NataliyaDzhermanova-Temelkova. Croatia: DubravkaJurisic Erzen, Sanja Klobucar Majanovic, andLea Smircic Duvnjak. Czech Republic: Juraj Di-vinec, Milan Kvapil, Renata Golanova, RenataVodickova, Sabina Palova, Dagmar Bartaskova,Martin Prazny, and Marek Honka. Denmark:Hans Perrild, Ulrik Pedersen-Bjergaard, SoerenGregersen, and Knud Yderstraede. France:Bertrand Cariou, Gerard Fradet, Didier Gouet,Samy Hadjaj, Anne-Marie Guedj, and PierreSerusclat. Greece: Ioannis Doupis, NikolaosTentolouris, Andreas Melidonis, and NikolaosPapanas. Hungary: Gyorgy Jermendy, AdamTabak, Judit Rapi, and Albert Szocs. Israel: NaimShehadeh, Jacob Ilani, Muhammad Sabbah,Rosane Abramof-Ness, Julio Wainstein, MuhammadSheikh Ahmad, and Victor Vishlitzky. Italy: CarloGiorda, Fabio Broglio, Francesco Giorgino, PaolaD’Angelo, Giorgio Sesti, Agostino Consoli, Raf-faele Napoli, Enzo Bonora, Stefano Genovese,Piermarco Piatti, Paolo Pozzilli, and MatteoBonomo. Romania: Eduard Adamescu, AncaCerghizan, Adriana Cif, Dana Cosma, CarmenCrisan, Brindusa Cofaru, Ioana Ferariu, Ana-Maria Mateescu, Annamaria Bodo, AdrianaOnaca, Mihai Pena, Delia Reurean-Pintilei, andCristian Serafinceanu. Serbia: Nebojsa Lalic,Radivoj Kocic, and Milica Pesic. Slovakia: ZbynekSchroner, Emil Martinka, Martina Merciakova,Dasa Skripova, and Edita Fedurcova. Sweden:Margareta Hellgren and Magnus Londahl. Swit-zerland: Bernd Schultes and Gottfried Rudofsky.

U.K.: Ahmed Yousseif, Jeffrey Stephens, AndrewGough, Stonny Joseph, Chinnusamy Ravikumar,and Ajith George. U.S.: Michael Dempsey,George Dailey, Dama Alexander Ziworitin, MarkBenson, Michael Reeves, Julio Rosenstock, DeirdreMcMullen, Carl Meisner, Azazuddin Ahmed,Vanita Aroda, Ronald Brazg, Juan Pablo Frıas,SumanaGangi, LenitaHanson, Richard Jackson,Michael Jardula, Wynter Kipgen, Milton Wong,Charles Lovell, Charles Lunn, Jose Mandry, Car-oline Mbogua, Michael Oliver, Marina Raikhel,Preet Randhawa, Jackson Rhudy, Jay Sandberg,Luis Soruco, Faizullah Syed, Ronald Watts, MichelleZaniewski-Singh, Ahmed Arif, Brian Webster,Darron Molter, Samer Nakhle, Rakesh Patel,Normam Fishman, Peter Winkle, Aron Schlau,Dale Allison, Robert Strzinek, Lawrence Alwine,Jamal Hammoud, Michael Robinson, John Earl,Jeffrey Green, Isam Marar, Stephen Smith, DanStreja, Ernie Riffer, Ronald Mayfield, AdeniyiOlabiyi Odugbesan, Thad Riley, Louis Chaykin,Lisa Cohen, Charles Debusk, Bernard Grunstra,Sanford Plevin, Jeffrey Unger, Jonathan Wilson,Randall Huling Jr., John Reed, Richard Sachson,Alan Schwartz, Paul Wakefield, Salil Nadkarni,C. Wilson Sofley, Douglas Denham, JackWhalen,Kathleen Jones, Sandra Weber, Udaya Kabadi,and Anuj Bhargava.

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2154 Gla-300 Versus IDeg-100: Efficacy and Safety Diabetes Care Volume 41, October 2018