Randomized Clinical TrialComparing Basal Insulin Peglisproand Insulin Glargine in PatientsWith Type 2 Diabetes PreviouslyTreated With Basal Insulin:IMAGINE 5Diabetes Care 2016;39:92–100 | DOI: 10.2337/dc15-1531
OBJECTIVE
To evaluate the efficacy and safety of basal insulin peglispro (BIL) versus insulinglargine inpatientswith type2diabetes (hemoglobinA1c [HbA1c]£9% [75mmol/mol])treated with basal insulin alone or with three or fewer oral antihyperglycemicmedications.
RESEARCH DESIGN AND METHODS
This 52-week, open-label, treat-to-target study randomized patients (mean HbA1c
7.42% [57.6 mmol/mol]) to BIL (n = 307) or glargine (n = 159). The primary endpoint was change from baseline HbA1c to 26 weeks (0.4% [4.4 mmol/mol] non-inferiority margin).
RESULTS
At 26 weeks, reduction in HbA1c was superior with BIL versus glargine (20.82%[28.9 mmol/mol] vs. 20.29% [23.2 mmol/mol]; least squares mean difference20.52%, 95%CI20.67 to20.38 [25.7mmol/mol, 95%CI27.3 to24.2; P< 0.001);greater reduction in HbA1cwith BIL wasmaintained at 52weeks.More BIL patientsachieved HbA1c <7% (53 mmol/mol) at weeks 26 and 52 (P < 0.001). With BILversus glargine, nocturnal hypoglycemia rate was 60% lower, more patientsachieved HbA1c <7% (53 mmol/mol) without nocturnal hypoglycemia at 26 and52 weeks (P < 0.001), and total hypoglycemia rates were lower at 52 weeks (P =0.03). At weeks 26 and 52, glucose variability was lower (P < 0.01), basal insulindose was higher (P < 0.001), and triglycerides and aminotransferases were higherwith BIL versus glargine (P < 0.05). Liver fat content (LFC), assessed in a subset ofpatients (n = 162), increased from baseline with BIL versus glargine (P < 0.001),with stable levels between 26 and 52 weeks.
CONCLUSIONS
BIL provided superior glycemic control versus glargine, with reduced nocturnaland total hypoglycemia, lower glucose variability, and increased triglycerides,aminotransferases, and LFC.
1University of North Carolina School of Medicine,Chapel Hill, NC2Endocrine andMetabolic Consultants, Rockville,MD3Hospital de la Ribera, Valencia, Spain4Eli Lilly and Company, Indianapolis, IN5inVentiv Health Clinical, Blue Bell, PA
Many patients with type 2 diabetes failto achieve glycemic control with basalinsulin plus oral antihyperglycemicmed-ications (OAMs) (1). Barriers to achiev-ing optimal glycemic control includefear of hypoglycemia and weight gain(2). Hypoglycemia is a limiting factor intitration of basal insulin to achieveglycemic targets (3,4).Basal insulin peglispro (BIL) is PEGylated
insulin lispro with a half-life of 2–3days in patients with type 2 diabetes andduration of action related to delayed in-sulin absorption and reduced clearance(5). In patients with type 1 diabetesand healthy subjects, BIL has hepato-preferential action compared withinsulin glargine, resulting from lesserperipheral action rather than an accen-tuated or enhanced effect on the liver(6–8). This liver-to-peripheral tissueactivity distribution is more consis-tent with the physiological action ofendogenous insulin secretion (9,10).In a 12-week phase 2 study comparing
BIL with glargine in patients with type 2diabetes previously treated with basalinsulin, BIL was associated with similarglycemic control, reductions in nocturnalhypoglycemia and weight, and higher tri-glycerides and aminotransferases (11).This 52-week phase 3 open-label studycompares the efficacy and safety ofswitching to BIL in patients with type 2diabetes previously treated with basal in-sulin alone or in combination with up tothree OAMs.
RESEARCH DESIGN AND METHODS
This phase 3, open-label, multicenter,multinational, randomized, controlled,parallel-design trial (SupplementaryFig. 1) was approved by local ethics re-view boards and conducted in accor-dance with Good Clinical Practice ofthe International Conference on Harmo-nisation guideline. All patients providedwritten informed consent. An un-blinded, independent data monitoringcommitteemonitored patient safety. En-rollment started in May 2012, and thelast patient completed in December2013.Data were analyzed according to the
predefined statistical analysis plan. Tominimize potential bias in this open-label study, the sponsor study team, in-cluding the physician overseeing globalconduct of the study and statistician,remained blinded prior to primary
database lock at 26weeks. Investigatorsand patients were aware of treatmentassignment.
ParticipantsAdults with type 2 diabetes (12) wereeligible if treated with basal insulin(insulin glargine, insulin detemir, orNPH insulin) alone or with three orfewer OAMs for $90 days and had he-moglobin A1c (HbA1c) #9% (75 mmol/mol)(additional inclusion/exclusion criteriain Supplementary Table 1). Investiga-tors at 65 study centers in eight countriesparticipated (Supplementary Table 2).
Study Design and TreatmentAfter a 1-week prerandomization pe-riod, including collection of baseline hy-poglycemia data, randomization to BILor glargine (Lantus, Sanofi) occurred bycountry with block size of six (2:1 ran-domization), stratified on baseline HbA1c(# or .8.0% [64 mmol/mol]), LDL cho-lesterol (LDL-C) (, or $100 mg/dL),and sulfonylurea/meglitinide use.OAM doses were to remain stable ex-cept in emergency situations or ifcontraindications developed.
Bedtime dosing of study basal insulinwas initiated (Supplementary Table 3)and adjusted according to a treat-to-target algorithm (goal fasting bloodglucose [FBG] by self-monitoredblood glucose [SMBG] #100 mg/dL)(Supplementary Table 3). Algorithm ad-herence was mandatory up to week 26.After week 26, basal insulin dosing wasdetermined by the investigator, and res-cue therapy (prandial rapid-acting insu-lin) was permitted for HbA1c $8.0%(64 mmol/mol) or FBG $250 mg/dL for3 days over 2 weeks. Lipid and hepaticcriteria for study insulin discontinuationare listed in Supplementary Table 4.
Patients performed SMBG eachmorning fasting, with two 6-pointSMBG profiles (fasting, prior to mid-day/evening meals, bedtime, 0300 h,and next day fasting) prior to prespeci-fied visits, and whenever hypoglycemiawas suspected. Hypoglycemia was de-fined as signs/symptoms of hypoglyce-mia or measured SMBG #70 mg/dL.Nocturnal hypoglycemia was an eventoccurring between bedtime and waking.Documented symptomatic hypoglyce-mia was an event associated with signs/symptoms of hypoglycemia andmeasuredSMBG #70 mg/dL. Severe hypoglycemia
was determined by the investigator as anepisode with a medical need for assis-tance of another person to administercarbohydrates, glucagon, or other resus-citative actions.
Deaths and nonfatal cardiovascularevents (myocardial infarction, stroke,and hospitalization for unstable angina)were adjudicated by an independentclinical end point committee. Adjust-ments in lipid-lowering therapy wereprohibited from randomization toweek 12. In a patient subgroup, MRIwas performed to assess liver fat con-tent (LFC) and abdominal visceral-to-subcutaneous fat ratio (13). MRI sitesin the U.S., Puerto Rico, Germany, andGreece underwent qualification pro-cedures, including phantom scan-ning. Study images were centrallyread by a vendor with MRI expertise inmulticenter trials (VirtualScopics, Inc.,Rochester, NY).
Statistical AnalysesAnalyses (SAS 9.1 or higher, Cary, NC)were based on all randomized patientswho took at least one dose of study in-sulin. The primary efficacy measure inthis 52-week study was noninferiority ofBIL to glargine for HbA1c change from 0 to26 weeks (margin 0.4% [4.4 mmol/mol]).For control of the overall type 1 errorat a = 0.05, a sequential gatekeepingstrategy (14) was used to adjust formultiplicity for the primary and sixkey secondary objectives. The six keysecondary objectives (in order) wereto demonstrate superiority of BIL ver-sus glargine at/during 26 weeks oftreatment for nocturnal hypoglycemiarate, percent patients with HbA1c ,7%(53 mmol/mol) without experiencingnocturnal hypoglycemia, change inHbA1c, percent patients with HbA1c
,7% (53 mmol/mol), total hypoglyce-mia rate, and laboratory fasting serumglucose (FSG). The gated objective wasmet if all preceding objectives weremet, and the gated objective reachedstatistical significance at a = 0.05.
A total of 426 randomized patientsprovided 90% statistical power to dem-onstrate noninferiority of BIL to glargine(margin 0.4% [4.4 mmol/mol]) forchange in HbA1c from 0 to 26 weekswith assumptions of no difference be-tween treatment, SD of 1.1%, at two-sided a-level 0.05, and 15% dropoutrate in 26 weeks.
A mixed-model repeated-measuresmodel was used to analyze HbA1c, con-tinuous glycemic variables, and weight.HbA1c ,7.0% (53 mmol/mol) and HbA1c,7% (53 mmol/mol) without nocturnalhypoglycemia (last observation carriedforward) were analyzed using logisticregression. Hypoglycemia rates werecompared using negative binomial re-gression with adjustment for treatment,baseline sulfonylurea/meglitinide use,and baseline hypoglycemia rate (15).Between-group differences are pre-sented as least squares mean (LSM) dif-ference (BIL 2 glargine) and baselineand end point values as LSM6 SE unlessotherwise indicated.
RESULTS
Patients (N = 466) were randomized toBIL (n = 307) or glargine (n = 159). Pa-tient disposition was similar betweengroups (Supplementary Fig. 2). There
were no significant differences in inci-dence of discontinuations at 26 or 52weeks. Baseline characteristics, includ-ing OAM use, were similar betweengroups (Table 1). OAM treatment over-all remained stable throughout thestudy; 1.5% of patients had protocolviolations for OAM changes other thansafety reasons as allowed per protocol.
The primary objective, noninferiorityof BIL compared with glargine for HbA1cchange from 0 to 26 weeks, was achievedwith LSM difference of20.52% (95% CI20.67 to 20.38) (25.7 mmol/mol[95% CI 27.3 to 24.2]) indicatingstatistical superiority of BIL comparedwith glargine with multiplicity adjust-ment (P, 0.001) (Fig. 1A). At 52 weeks,change from baseline HbA1c (LSM)for BIL- and glargine-treated pa-tients was 20.67% (27.3 mmol/mol)and 20.22% (22.5 mmol/mol), re-spectively (P , 0.001) (Fig. 1A). More
BIL-treated patients achieved HbA1c
,7% (53 mmol/mol) at week 26 (72.5vs. 52.2%, P , 0.001) and week 52(63.9 vs. 45.9%, P , 0.001) (Fig. 1B). Atweek 26, more BIL-treated patientsachieved HbA1c #6.5% (48 mmol/mol)(50.3 vs. 28.7%, P , 0.001), HbA1c
,7% (53 mmol/mol) without experienc-ing nocturnal hypoglycemia from 0–26weeks (40.1 vs. 18.5%, P , 0.001), andHbA1c #6.5% (48 mmol/mol) withoutexperiencing nocturnal hypoglycemiafrom 0 to 26 weeks (28.1 vs. 8.9%, P ,0.001); at week 52, more BIL-treated pa-tients also achieved these HbA1c targets(P , 0.001). Laboratory FSG was lowerfor BIL versus glargine at weeks 26 and52 (Table 2).
FBG from SMBG was similar betweenBIL and glargine at weeks 26 (106.3 61.1 vs. 104.5 6 1.5 mg/dL) and 52(110.6 6 1.2 vs. 107.5 6 1.7 mg/dL).At weeks 26 and 52, six-point SMBG pro-file daily mean glucose and midday pre-meal, evening premeal, and bedtimeSMBG levels were lower with BIL(Fig. 2A and Supplementary Fig. 3).
Between-day FBG variability (SD ofFBG in preceding 7 days) was lowerwith BIL at weeks 26 (24.19 mg/dL,P , 0.001) and 52 (23.20 mg/dL, P =0.004), as was within-day variability(SD of six-point SMBG) at weeks 26(26.30 mg/dL, P , 0.001) and 52(24.81 mg/dL, P = 0.001). Bedtime topremorning meal excursion was re-duced with BIL versus glargine at weeks26 (218.22 mg/dL; P , 0.001) and 52(219.16 mg/dL; P, 0.001), as was bed-time to 0300 h excursion at weeks 26(212.27 mg/dL, P = 0.003) and 52(215.67 mg/dL, P , 0.001).
Total hypoglycemia relative rate forBIL/glargine was 0.79 from 0 to 26weeks (P = 0.05) and 0.77 from 0 to 52weeks (P = 0.03) (Table 2). Total hypo-glycemia incidence from 0 to 26 and 0 to52 weeks was similar between treat-ments. There were no differences inrate or incidence of documented symp-tomatic hypoglycemia (Table 2). Noctur-nal hypoglycemia rate and incidenceand documented symptomatic noctur-nal hypoglycemia rate and incidencewere lower for BIL than glargine fromweeks 0–26 and 0–52 (Table 2). The per-centage of symptomatic hypoglycemiaepisodes (BIL, 52%; glargine, 51%)and the LSM glucose value associatedwith symptomatic hypoglycemia events
Table 1—Baseline demographics and disease characteristics
Glargine BIL
n 159 307
Age (years), mean 6 SD 60.4 6 10.1 61.8 6 8.5
Men, n (%) 93 (58.5) 175 (57.0)
Race/ethnicity, n (%)American Indian or Alaskan Native 0 (0.0) 2 (0.7)Asian 2 (1.3) 4 (1.3)Black or African American 9 (5.7) 17 (5.6)Multiple 0 (0.0) 1 (0.3)Native Hawaiian or other Pacific Islander 0 (0.0) 1 (0.3)White 148 (93.1) 280 (91.8)Hispanic or Latino 25 (15.7) 57 (18.6)
Weight (kg), mean 6 SD 91.8 6 18.5 92.2 6 17.1
BMI (kg/m2), mean 6 SD 31.9 6 5.0 32.1 6 5.0
Duration of diabetes (years), mean 6 SD 12.1 6 6.8 12.4 6 6.9
(BIL, 62.4 mg/dL; glargine, 61.3 mg/dL)were not statistically significant betweengroups (P = 0.071).Cumulative total and nocturnal hypo-
glycemia events/100 patients over 52weeks were lower for BIL than for glar-gine (Fig. 2). Total hypoglycemia rate by2-h intervals over 24 h from 0 to 52weeks is displayed in Fig. 2D. BIL pa-tients had overall stable total hypogly-cemia rates over 24 h. In contrast,glargine patients had higher rates from0000 to 1000 h, with lower rates duringthe day and the largest difference be-tween groups occurring from 0400 to0600 h. Through week 52, there weretwo cases of severe hypoglycemia inglargine-treated patients (Table 2).Basal insulin dose (units/day and
units/kg/day) was higher for BIL pa-tients beginning at week 2 throughweek 52 (P , 0.001) (Fig. 1C). At week26, basal insulin dose was higher with BIL(53.2 units/day [0.57 units/kg/day]) vs.glargine (47.0units/day [0.49units/kg/day];
P , 0.001). At week 52, basal dosewas essentially unchanged from week26 for the BIL and glargine groups(54.5 units/day [0.58 units/kg/day] vs.47.0 units/day [0.49 units/kg/day], re-spectively; P , 0.001). Investigatoradherence to the dosing algorithmpostbaseline up to week 26, when algo-rithm compliance was required, was notstatistically significantly different be-tween groups. Fromweek 26 to 52, eightpatients (BIL, n = 3 [1.1%]; glargine, n = 5[3.5%]; P = 0.13) received bolus insulinwhen rescue therapy was allowed perthe protocol based on glycemic parame-ters. Weight increased with bothtreatments and was not statistically sig-nificantly different in BIL versus glargine-treated patients at 26 or 52 weeks(Fig. 1D).
With the prespecified gate-keepingstrategy for the primary and six key sec-ondary objectives, superiority of BIL ver-sus glargine at or during 26 weeks inchange in HbA1c, nocturnal hypoglycemia
rate, proportion of patients with HbA1c,7% (53 mmol/mol), and proportionachieving HbA1c ,7% (53 mmol/mol)without nocturnal hypoglycemia was sta-tistically significant with multiplicity ad-justment. The fifth gated objective forsuperiority of BIL versus glargine for totalhypoglycemia rate from baseline to 26weeks did not meet the gate-keepingtest for multiplicity. The FSG for BIL waslower versus glargine but did not meetthe gate-keeping test for multiplicity.
Treatment-emergent adverse eventswere comparable between groups exceptfor more skin and subcutaneous tissuedisorders with BIL (Supplementary Table5). Six (2.0%) BIL- and no glargine-treatedpatients experienced prospectivelydefined treatment-emergent adverseevents of injection site reactions of spe-cial interest, including injection sitehypertrophy (n = 2), lipohypertrophy(n = 2), injection site edema (n = 1), andlipodystrophy (n = 1). Serious adverseevents were similar between treatments
Figure 1—HbA1c, percent of patients with HbA1c ,7%, basal insulin dose, and change in body weight over 52 weeks of treatment for BIL- andglargine-treated patients. A: HbA1c (LSM 6 SE) over time. B: Percent of patients with HbA1c ,7.0% (53 mmol/mol) at baseline, 26 weeks, and 52weeks. C: Basal insulin dose over time (LSM6 SE).D: Change in bodyweight over time (LSM6 SE). Closed circleswith solid line or black bar, BIL; opencircles with dashed line or white bar, insulin glargine. *P , 0.05 for between-treatment group comparisons.
except that cardiac disorders and metab-olism and nutrition disorders (hypoglyce-mia and hypovolemia) occurred lesscommonly with BIL (SupplementaryTable 5). Treatment-emergent anti-BILantibody responseswere similar betweengroups (Table 2).Adjudicated major adverse cardiac
events (MACE), including nonfatalmyocardial infarction, nonfatal stroke,and cardiovascular death, were similarbetween BIL and glargine: 2.3% vs.4.4%, hazard ratio 0.5 (95% CI 0.18–1.43),
P = 0.20. There were no cases ofunstable angina with hospitalization;thus, MACE+ results were equivalent toMACE. Six deaths, three (1.0%) with BIL(cardiac death, cardiac arrest, and pul-monary hypertension) and three (1.9%)with glargine (multiorgan failure,myocardial infarction, and cardiac ar-rhythmia) occurred. There were no dif-ferences in heart rate or systolic ordiastolic blood pressure (Table 2).
Triglycerides increased from 0 to 4weeks and remained overall stable
thereafter during BIL treatment, withtreatment differences through week52 (LSM difference [BIL 2 glargine]15 mg/dL, P = 0.026) (Table 2 andSupplementary Fig. 4A). At study endpoint, after transition off BIL, triglycer-ides returned to baseline levels in the BILgroup and were lower than with glargine(Supplementary Fig. 4A). One patient ineach treatment groupmetdiscontinuationcriteria of triglyceride level.600 mg/dL.
HDL cholesterol (HDL-C) decreasedfrom 0 to 4weeks with BIL and remained
Table 2—Treatment outcomes at baseline and after 26 and 52 weeks of treatment
Outcome
Baseline* 26 weeks 52 weeks
Glargine(n = 159)
BIL(n = 307)
Glargine(n = 159)
BIL(n = 307) P**
Glargine(n = 159)
BIL(n = 307) P**
HbA1c, %† 7.41 6 0.06 7.43 6 0.05 7.13 6 0.06 6.60 6 0.04 ,0.001 7.20 6 0.06 6.75 6 0.05 ,0.001Change from baseline d d 20.29 6 0.06 20.82 6 0.04 20.22 6 0.06 20.67 6 0.05LSM difference (95% CI) d d 20.52 (20.67 to 20.38) 20.44 (20.60 to 20.29)
HbA1c, mmol/mol† 57.5 6 0.7 57.7 6 0.5 54.4 6 0.7 48.7 6 0.5 ,0.001 55.1 6 0.7 50.3 6 0.5 ,0.001Change from baseline d d 23.2 6 0.7 28.9 6 0.5 22.5 6 0.7 27.3 6 0.5LSM difference (95% CI) d d 25.7 (27.3 to 24.2) 24.9 (26.5 to 23.2)
n reflects maximal sample size. *No between-treatment differences (P. 0.05) in any baseline parameter. †LSM6 SE. ‡Group mean6 SE. §Numberof patients (%). |For hypoglycemia rate data, values shown are events/patients/30 days for baseline to week 26 and baseline to week 52.¶Treatment-emergent anti-BIL antibody response is defined as change from baseline to postbaseline in the anti-BIL antibody level either 1) fromundetectable to detectable and the postbaseline value $1% + cut point or 2) from detectable to the value with a relative change([postbaseline2 baseline]/baseline) $30% and absolute change$1%. #N = 52 for glargine; N = 110 for BIL. **Between-treatment differences.††LSM.
96 Basal Insulin Peglispro in Type 2 Diabetes Diabetes Care Volume 39, January 2016
lower than baseline through week 52, re-sulting in lower HDL-C (,2 mg/dL) withBIL versus glargine at week 52 (Table 2,Supplementary Fig. 4B). At study endpoint, after transition off treatment,HDL-Cwas higher with BIL versus glargine(Supplementary Fig. 4B). There were notreatment differences in LDL-C at week26, and LDL-Cwas lowerwithBIL atweeks4 and 52 (Table 2 and Supplementary Fig.4C). There were no differences in totalcholesterol between groups during treat-ment (Supplementary Fig. 4D) or non-HDL-C (Table 2). Therewere no significantdifferences in the use of lipid-loweringmedication or changes to lipid-loweringmedications between the treatmentgroups.Alanine aminotransferase (ALT) and
aspartate aminotransferase (AST) in-creased from baseline with BIL and de-creased toward baseline after transitionoff BIL, with treatment differences at all
time points (Table 2, Supplementary Fig.5). Mean ALT and AST remained within/slightly above reference ranges at alltimes. Seven (2.3%) BIL- and no glargine-treated patients experienced ALT threeor more times the upper limit of normal(ULN). All seven patients had a reduc-tion in ALT less than three times ULNduring the study, with four patients con-tinuing treatment and three patients dis-continuing BIL and completing studyvisits. No patients in either grouphad bilirubin two or more times ULNpostbaseline.
A patient subset participated in theMRI addendum (n = 110 BIL, n = 52 glar-gine). Baseline characteristics, change inHbA1c, and liver/lipid laboratory resultsin MRI addendum patients were consis-tent with overall study results. BaselineLFC (10%) was similar between groups(Table 2). With BIL, LFC increased from0 to 26 weeks and remained stable at
week 52. LFC did not change signifi-cantly from baseline with glargine (Ta-ble 2). LFC change from baseline washigher with BIL versus glargine at weeks26 and 52 (LSM difference 6.0% and5.3%, respectively; P , 0.001). At 52weeks, 10 (10.9%) BIL patients versus 1(2.3%) glargine patient had an absoluteincrease from baseline of $10% in LFC(P = 0.103). Change from baseline of theabdominal visceral-to-subcutaneous fatratio was higher with BIL versus glargineat weeks 26 and 52 (LSM difference 0.04and 0.06, respectively; P , 0.001)(Table 2).
CONCLUSIONS
This is one of the first direct compari-sons of two basal insulins in whichsuperiority in glycemic control was dem-onstrated in a treat-to-target trial. In pa-tients with type 2 diabetes previouslytreated with basal insulin, switching to
Figure 2—SMBG and hypoglycemia for BIL- and glargine-treated patients. A: Six-point SMBG profile at baseline and 52 weeks. Premorning, fasting(premorning meal); Pre-midday, pre-midday meal; Pre-evening, pre-evening meal. Data are LSM 6 SE. *P , 0.05 for between-treatment groupcomparisons. B: Cumulative total hypoglycemia events/100 patients over time during 52 weeks of treatment. C: Cumulative nocturnal hypoglycemiaevents/100 patients over time during 52 weeks of treatment. For both B and C, “lines” are continuous data points indicating rates of hypoglycemiathroughout 52 weeks of treatment.D: Total hypoglycemia by 2-h intervals (0–52 weeks). Data are group mean. GL, insulin glargine. The P value is forbetween-treatment group comparisons.
BIL compared with glargine resulted in aclinically significant 0.5% (5.7 mmol/mol)greater HbA1c reduction at 26 weeks(6.6 vs. 7.1% [48.7 vs. 54.4 mmol/mol]).Greater HbA1c reduction with BIL wasmaintained at 52 weeks. In addition,more BIL-treated patients reachedtarget HbA1c ,7.0% (53 mmol/mol)and #6.5% (48 mmol/mol). Despitegreater HbA1c reduction, BIL-treatedpatients experienced statistically andclinically significant reductions innocturnal hypoglycemia.The superior HbA1c reduction achieved
with BIL is noteworthy, since noninferior-ity has usually been observed in basal in-sulin treat-to-target trials (16–18). TheFSG levels in glargine-treated patientswere well within ranges reported inmany treat-to-target trials, whereas BIL-treated patients had greater reduction inFSG compared with glargine (19–21). Notonly was HbA1c efficacy in BIL-treated pa-tients superior to glargine-treated pa-tients, but the levels achieved were wellbelow those reported in many major in-sulin clinical trials (16,18,21,22). TheHbA1c levels with BIL treatment wereslightly higher than those achievedin the intensive arm of Action to Con-trol Cardiovascular Risk in Diabetes(ACCORD), in which multiple thera-pies, including bolus insulin, were al-lowed and the median HbA1c was 6.4%(46 mmol/mol) (23).Improved glycemic control was
achieved without increased rates of to-tal or nocturnal hypoglycemia, impor-tant limiting factors in titrating basalinsulin to achieve glycemic targets. Noc-turnal hypoglycemia was consistentlylower in BIL-treated patients, with a clin-ically relevant 60% rate reduction versusglargine. Total hypoglycemia was alsoreduced over 52 weeks, and more pa-tients reached HbA1c ,7% (53 mmol/mol)without experiencing nocturnal hy-poglycemia over 26 and 52 weeks. Re-duced nocturnal hypoglycemia with BILwas also seen in insulin-naıve patientswith type 2 diabetes (24) and in phase2 BIL studies (11,25) and may reflect itslonger duration of action and lowerpeak-to-trough ratio, as well as reducedglucose variability versus glargine, withpotentially more stable and predictablemetabolic control (26).Basal insulin dose was higher in BIL-
versus glargine-treated patients (;13%and ;16% higher at weeks 26 and 52,
respectively). With modeling of HbA1cand basal insulin dose, HbA1c reductionper 10 units of basal insulin from 0 to 26weeks was 0.36% (3.9mmol/mol) for BILand 0.30% (3.3 mmol/mol) for glargine,suggesting that BIL was at least as po-tent as glargine on a per unit basis.These results suggest that BIL may betitrated effectively to reach glycemictargets due to lower nocturnal hypogly-cemia rates with less glucose variabilityand smaller overnight glucose excur-sions. In addition, potential basalinsulin coverage throughout the daywith greater reduction in afternoon/evening SMBG levels, when the effectsof glargine may be waning, could havealso contributed to the greater improve-ment in glycemic control with BIL com-pared with glargine in a treat-to-targetsetting. Although BIL had greater effectson HbA1c and other glycemic measuresand patients had higher basal insulindoses, weight was not statistically signif-icantly different with BIL versus glargineat 26 or 52 weeks. This contrasts with aphase 2 BIL study in patients with type 2diabetes in which weight loss and similarHbA1c was seen, possibly reflectingsmaller sample size and 12-week dura-tion, which may have limited titrationto optimal basal insulin dose.
Increased mean aminotransferases,within or slightly above referenceranges, were seen with BIL. ALT at orabove three times ULN occurred in2.3% of BIL-treated patients, but nocases were associated with increases inbilirubin at or above two times ULN.Hence, no patients met criteria for Hy’slaw, a predictor of future risk of severedrug-induced liver injury (27), consistentwith other BIL studies (11,24,25).
In theMRI subset, LFC and visceral-to-subcutaneous fat ratio increased in BIL-but not glargine-treated patients at 26weeks and remained stable in bothgroups at 52 weeks. This contrasts withthe IMAGINE 2 study findings in insulin-na ıve patients with type 2 diabetes,where BIL-treated patients had no sig-nificant change in LFC, but glargine-treated patients had a reduction in LFCfrom 13% at baseline to 10% at 52weeks(24). In the insulin-naıve study, the visceral-to-subcutaneous fat ratio was similarwith BIL and glargine over 52 weeks.Prior studies in insulin-naıve patientswith type 2 diabetes have shown de-creases in hepatic steatosis with 3–7
months of treatment with currentlyavailable basal and premixed insulins(28,29).
Conventional insulins may decreaseLFC in insulin-na ıve patients withtype 2 diabetes by decreasing surplusfatty acid delivery to the liver by increas-ing fat delivery to the peripheral tissuesthrough increased lipoprotein lipase ac-tivity and suppression of lipolysis in theadipose tissue. An animal model hasrecently demonstrated that hepatictriglyceride synthesis is primarily depen-dent on fatty acid delivery and indepen-dent of hepatic insulin action or changesin hepatic insulin signaling (30).
Baseline LFC (10%) in the currentstudy of patients previously treatedwith basal insulin was similar to the re-duced LFC level seen after 26 and 52weeks in the glargine armof the IMAGINE2 insulin-naıve type 2 diabetes study(24). In the current study, baseline LFCmay have already been decreased due toprior treatment with conventional basalinsulins, primarily glargine; thus, glarginetreatment during the study had no fur-ther effect on LFC. In contrast, switchingfrom a conventional basal insulin to BIL,with limited peripheral access, may haveled to reduced suppression of peripherallipolysis and relatively higher fatty aciddelivery to the liver and increased LFC,which remained stable through 52weeks. Further research will help to un-derstand the underlying mechanismsand clinical consequences of these LFCdifferences with BIL in patients previ-ously treated with conventional basalinsulins.
Increased triglycerides with BIL re-mained stable through 52weeks and de-creased after stopping BIL, consistentwith other BIL studies in patients withtype 1 diabetes or type 2 diabetes pre-viously treated with insulin (11,25). Ininsulin-naıve patients with type 2 diabe-tes, triglyceride levels were essentiallyunchanged with BIL and decreasedwith glargine over 26 weeks of treat-ment (24). Insulin glargine and otherconventional insulins have been associ-ated with a reduction in triglyceride lev-els (31–33). Increased triglycerides inthe current study were accompaniedby a ,2 mg/dL decrease in HDL, a de-crease in LDL-C at week 52, and no dif-ferences in non-HDL-C with BIL versusglargine. As discussed above, we hy-pothesize that the reduced peripheral
98 Basal Insulin Peglispro in Type 2 Diabetes Diabetes Care Volume 39, January 2016
action of BIL may increase relative fattyacid delivery to the liver and, hence, in-crease hepatic triglyceride reesterifica-tion and VLDL secretion. Nonalcoholicfatty liver disease and visceral adiposityhave been associated with cardiovascu-lar risk factors (34). In BIL phase 3 type 2diabetes studies, including IMAGINE 5,there were no significant differences inblood pressure between BIL and glar-gine (24,35). In the BIL phase 2 and 3program, there were no significant dif-ferences in incidence rates of MACE+,MACE, or all-cause death between BILand comparator (36).Potential study limitations include
the open-label design, which may in-crease risk of bias. Of note, the treat-to-target SMBG FBG levels and dosingalgorithm adherence were not signifi-cantly different in the BIL and glarginegroups. The BIL phase 3 program in-cludes three double-blind studies in-cluding IMAGINE 2 (24). Although thisglobal study involved eight countries,the study population was primarilywhite. The study patients overall hadreasonably controlled diabetes at base-line given the eligibility criteria of HbA1c#9% for safety reasons, as these pa-tients were to continue a basal insulinregimen with glargine or switch to newtherapy with BIL. The BIL phase 3 clinicalprogram includes patients with higherbaseline HbA1c levels (such as theIMAGINE 2 study) as well as patients beingtreated with other diabetes regimens.This 52-week, treat-to-target study in
patients with type 2 diabetes previouslytreated with basal insulin demonstratesthat switching to BIL provides superiorglycemic efficacy with clinically signifi-cant reductions in HbA1c with lowerrisk of nocturnal and total hypoglycemiaand lower glucose variability. Increaseswere seen in aminotransferases, triglyc-erides, and LFC in comparison withglargine. The conversion from a conven-tionally acting basal insulin to BIL, ahepatopreferential insulin with reducedperipheral action, may account forthese findings.
NOTE ADDED IN PROOF
Since this article was accepted for publica-tion, Eli Lilly and Company has announcedplans to cease development of basal insu-lin peglispro (https://investor.lilly.com/releasedetail.cfm?ReleaseID=945541).This decision is based on unresolved
questions regarding changes in liver fatthat developed during the late stages ofdrug testing.
Acknowledgments.Theauthors thankthestudyparticipantsandtheinvestigators,nurses,andstudycoordinatorswho cared for them. The authors alsothank Drs. Byron Hoogwerf and Melvin Prince(Eli Lilly and Company, Indianapolis, IN) forcritically reviewing the manuscript.Dualityof Interest. This studywas fundedby EliLilly and Company. J.B.B. is a consultant for and ashareholder of PhaseBio Pharmaceuticals andis a consultant/investigator for Andromeda,AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb (BMS), Elcelyx Therapeutics, Eli Lillyand Company, GI Dynamics, GlaxoSmithKline,Halozyme Therapeutics, F. Hoffmann-La Roche,Intarcia Therapeutics, Johnson & Johnson, Lexicon,LipoScience, Medtronic, Merck, Metabolon,Metavention, Novo Nordisk A/S, Orexigen Ther-apeutics, Osiris Therapeutics, Pfizer, PhaseBioPharmaceuticals, Quest Diagnostics, RhythmPharmaceuticals, Sanofi, Spherix, Takeda,ToleRx, and TransTech Pharma. H.W.R. serves onan advisory panel for AstraZeneca, BoehringerIngelheim, Janssen, Lilly, Merck, Novo Nordisk,and Sanofi; is a consultant for AstraZeneca, BMS,Biodel, Boehringer Ingelheim, Lilly, Merck, NovoNordisk, and Sanofi; received research supportfromAstraZeneca, Boehringer Ingelheim, Halozyme,Hamni, Janssen, Lilly, Merck, Novo Nordisk,and Sanofi; and has been on the speakers’ bu-reau for AstraZeneca, Boehringer Ingelheim,Janssen, Lilly, Merck,MSD, Novo Nordisk, Sanofi,and Takeda. J.L., T.I., J.B.-V., M.L.H., and A.M.C.are employees and shareholders of Eli Lilly andCompany. No other potential conflicts of inter-est relevant to this article were reported.AuthorContributions. J.B.B.,H.W.R., andC.T.S.participated as trial investigators and reviewedand edited the manuscript. J.L. contributed tothe study design, the statistical analyses, theinterpretation of the research, and writing thestatistical methods. T.I. and J.B.-V. participatedin the conduct of the study and reviewed andedited the manuscript. M.L.H. participated inthe discussion of the research and reviewed andedited the manuscript. M.A.C. contributed tothe discussion of the research and writing themanuscript. A.M.C. was responsible formedicaloversight during the trial and contributed to thestudy design, the data analysis and interpreta-tionof the research, andwriting themanuscript.All authors approved the final manuscript to bepublished. A.M.C. is the guarantor of this workand, as such, had full access to all the data in thestudyand takes responsibility for the integrityofthe data and the accuracy of the data analysis.Prior Presentation. Parts of this study werepresented in abstract form at the 75th ScientificSessions of the American Diabetes Association,Boston, MA, 5–9 June 2015, and at the 51stEuropean Association for the Study of DiabetesAnnual Meeting, Stockholm, Sweden, 14–18September 2015.
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