Diabetes Care Volume 38, July 2015 1263

Juris J. Meier,1 Julio Rosenstock,2 Contrasting Effects of Agnes` Hincelin-Mery,´ 3 CARE/EDUCATION/NUTRITION/PSYCHOSOCIAL CLIN Christine Roy-Duval,3 Astrid Delfolie,3 and on Postprandial Hans-Veit Coester,4 Bjoern A. Menge,1 Glycemic Control, Gastric Thomas Forst,5 and Christoph Kapitza4 Emptying, and Safety Parameters in Patients With Type 2 on Optimized Glargine With or Without : A Randomized, Open-Label Trial Diabetes Care 2015;38:1263–1273 | DOI: 10.2337/dc14-1984

OBJECTIVE This mechanistic trial compared the pharmacodynamics and safety of lixisenatide and liraglutide in combination with optimized with/without met- formin in (T2D).

RESEARCH DESIGN AND METHODS This was a multicenter, randomized, open-label, three-arm trial comparing lixise- natide 20 mg and liraglutide 1.2 and 1.8 mg once daily for 8 weeks in combination with insulin glargine after optimized titration. The primary end point was change from baseline to week 8 in incremental area under the postprandial plasma curve for 4 h after a standardized solid breakfast (AUC PPG0030–0430 h). Changes from baseline in gastric emptying, 24-h plasma glucose profile, HbA1c, fasting plasma glucose (FPG), 24-h ambulatory heart rate and blood pressure, amylase and lipase levels, and adverse events (AEs) were also assessed.

RESULTS In total, 142 patients were randomized and treated. Lixisenatide 20 mgachieved 1Diabetes Division, St. Josef Hospital, Ruhr- greater reductions of AUC PPG 2 compared with liraglutide (marginal 0030 0430 h University Bochum, Bochum, Germany mean [95% one-sided CI] treatment difference, 26.0 [27.8] h · mmol/L [2108.3 2Dallas Diabetes and Endocrine Center at Medical (2140.0) h · mg/dL] vs. liraglutide 1.2 mg and 24.6 [26.3] h · mmol/L [283.0 City, Dallas, TX (2114.2) h · mg/dL] vs. liraglutide 1.8 mg; P < 0.001 for both), and gastric emptying 3Sanofi R&D, Chilly-Mazarin, France 4 fi was delayed to a greater extent than with liraglutide 1.2 and 1.8 mg (P < 0.001 for Pro l, Neuss, Germany 5Profil, Mainz, Germany treatment comparisons). FPG was unchanged in all treatment arms. At week 8, mean 6 Corresponding author: Juris J. Meier, juris.meier@ 6 6 6 6 SD HbA1c was 6.2 0.4% (44 5 mmol/mol), 6.1 0.3% (44 4 mmol/mol), and rub.de. 6 6 m 6.1 0.3% (44 4 mmol/mol) for lixisenatide 20 g and liraglutide 1.2 and 1.8 mg, Received 18 August 2014 and accepted 16 March respectively. At week 8, both liraglutide doses increased marginal mean 6 SE 24-h heart 2015. rate from baseline by 9 6 1bpmvs.36 1 bpm with lixisenatide (P < 0.001). Occurrence Clinical trial reg. no. NCT01596504, clinicaltrials of symptomatic was higher with lixisenatide; gastrointestinal AEs were .gov. more common with liraglutide. Lipase levels were significantly increased from base- This article contains Supplementary Data online line with liraglutide 1.2 and 1.8 mg (marginal mean 6 SE increase 21 6 7 IU/L for at http://care.diabetesjournals.org/lookup/ suppl/doi:10.2337/dc14-1984/-/DC1. both; P < 0.05). A slide set summarizing this article is available CONCLUSIONS online. Lixisenatide and liraglutide improved glycemic control in optimized insulin © 2015 by the American Diabetes Association. Readers may use this article as long as the work glargine-treated T2D albeit with contrasting mechanisms of action and differing is properly cited, the use is educational and not safety profiles. for profit, and the work is not altered. 1264 Lixisenatide Versus Liraglutide Effect in T2D Diabetes Care Volume 38, July 2015

Basal insulin replacement has become a whereas reductions in FPG were more pro- for at least 3 months at screening (stable well-established treatment approach nounced with liraglutide (21). dose for at least 2 months before screen- when lifestyle measures and oral antidi- The primary objective of this trial was ing) alone or combined with a stable dose abetic agents (OADs) are insufficient to to compare change in AUC PPG0030–0430 h of metformin with/without a dipeptidyl reach individualized glycemic goals after a standardized solid breakfast in peptidase (DPP)-4 inhibitor or a sulfonyl- (1,2). Proper and systematic titration patients with T2D receiving 8 weeks of urea. Use of insulin, other than NPH or of basal insulin allows 50–60% of pa- once-daily lixisenatide 20 mg, liraglutide insulin glargine, was not permitted (in- tients with T2D to reach glycemic goals 1.2 mg, or liraglutide 1.8 mg in combina- cluding rapid-acting ). Exclusion (3–5). Basal insulin improves glycemic tion with insulin glargine with/without criteria included a clinically relevant his- control predominantly by reducing noc- metformin after a period of optimized in- tory of gastrointestinal disease associated turnal and fasting plasma glucose (FPG). sulin glargine titration in a treat-to-target with prolonged nausea or vomiting or a However, many patients experience design. As differences between GLP-1 RAs history of unexplained/chronic pancreati- substantial postprandial glucose (PPG) in terms of effects on gastric emptying tis. Patients were also excluded if they excursions and are unable to achieve and heart rate have previously been re- had alanine aminotransferase, amylase, glycemic targets; even in those who ported (21–23), these parameters were or lipase more than three times the upper do, or get close to target HbA1c,addi- further and more precisely assessed in limit of normal (3 3 ULN) or tional improvements in diabetes control this trial. $20 pg/mL. could be achieved if elevated PPG levels RESEARCH DESIGN AND METHODS were further reduced (6–8). Interventions and Concomitant It has been suggested that, after inten- Trial Design Medications sification of treatment with basal insulin, This was a multicenter, randomized, open- DPP-4 inhibitors or were dis- PPG contributes ;60% of hyperglycemia label, active comparator-controlled, three continued at the start of the run-in period; in patients with a mean HbA1c of 7.0% (9). parallel-arm trial conducted at eight cen- metformin was continued at the same There is therefore a strong rationale for the ters in Germany. Patients were centrally dose throughout the trial. During the run- use of basal insulin in combination with randomized 1:1:1 (by interactive voice re- in period, insulin glargine once daily was fi treatments that can reduce PPG in order sponse system and strati ed by HbA1c introduced (for patients previously on , $ $ to achieve further reductions in HbA1c. [ 8% or 8% and 64 mmol/mol or 64 NPH) and/or titrated individually once Lixisenatide (Lyxumia; Sanofi,Paris, mmol/mol], the use of metformin [yes/ weekly (for a minimum of 4 weeks up to France) is a once-daily prandial GLP-1 no], and study site) to receive lixisenatide 11 weeks) based on FPG levels according receptor agonist (GLP-1 RA) that acts 20 mg s.c. once daily, liraglutide 1.2 mg s.c. to an algorithm (4). After optimal insulin primarily on PPG excursions through de- once daily, or liraglutide 1.8 mg s.c. once glargine titration, patients were random- laying gastric emptying and suppressing daily as add-on therapy to optimized insu- ized to receive lixisenatide or liraglutide if . The efficacy and tolerability of lin glargine for 8 weeks. The trial comprised their mean self-monitored plasma glucose lixisenatide monotherapy or in combi- the following (Supplementary Fig. 1): 1) assessed over 1 week was ,7 mmol/L nation with basal insulin and/or OADs aperiodofupto14weeksthatincludeda (,126 mg/dL) and if they had HbA1c be- for the improvement of glycemic control 2-week screening phase, a run-in period tween6.5and9.0%(48and75mmol/mol). in patients with T2D were established of a minimum of 4 weeks up to 11 weeks After titration, insulin glargine doses in the GetGoal clinical trial program of insulin glargine optimal titration, and were adjusted throughout the remain- (10–14). The longer-acting GLP-1 RA lira- 1 week of baseline pharmacodynamic as- der of the trial to maintain FPG between glutide (Victoza; Novo Nordisk, Bagsvaerd, sessments; 2) an open-label, randomized, 4.4 and 5.6 mmol/L (80 and 100 mg/dL). – Denmark) has also demonstrated efficacy 8-week treatment period (1 2 weeks at If HbA1c was $6.5% and #7.5% ($48 in terms of glycemic control and body the initial liraglutide/lixisenatide dose and #58 mmol/mol) on day –7, insulin weight reductions in patients with T2D and 6–7 weeks of treatment at the main- glargine dose was reduced by 20% in a large phase III clinical trial program tenance dose), with pharmacodynamic on the day before randomization (day –1) (Liraglutide Effect and Action in Diabetes) assessment at the end of treatment; to avoid hypoglycemia when starting (15–20). In these studies, liraglutide signifi- and 3) a follow-up period with an end- treatment with lixisenatide or liraglutide. cantly reduced 24-h hyperglycemia, a finding of-study visit 7 6 2 days after the end Patients randomized to receive lixise- that has been ascribed to its long half-life. of treatment. natide were administered 10 mg once Differences in the pharmacodynamics All patients signed an informed con- daily for 2 weeks, followed by the lixise- of these GLP-1 RAs have been shown sent form. The trial protocol complied natide 20 mg once daily maintenance dose in a 4-week, head-to-head trial of lixisena- with the recommendations of the Dec- for the remainder of the trial. Patients ran- tide 20 mg and liraglutide 1.8 mg as add- laration of Helsinki and was approved by domized to receive liraglutide received 0.6 on to metformin (clinical trial reg. no. independent ethics committees for each mg once daily for 1 week and then were NCT01175473) in patients with T2D of the participating centers. either administered liraglutide 1.2 mg inadequately controlled on metformin Study Population once daily until the trial end or received monotherapy. In this trial, lixisenatide Men and women aged 18–75 years with liraglutide 1.2 mg for 1 week before in- demonstrated significantly greater reduc- T2D for at least 1 year, BMI 20.0–40.0 creasing their dose to 1.8 mg for the re- 2 tions than liraglutide in the area under the kg/m ,andHbA1c $6.5% to #9.5% mainder of the trial. Lixisenatide or plasma glucose curve (AUC PPG0030–0430 h) ($48 to #80 mmol/mol) were included. liraglutide was administered in the morn- during a standardized breakfast meal test, Patients were on NPH or insulin glargine ing ;30 min before breakfast. Timing of care.diabetesjournals.org Meier and Associates 1265

insulin glargine injections throughout 120, 180, and 240 min after breakfast. An Statistical Methods the trial period was kept consistent additional sample was taken 30 min be- A sample size of 117 patients (39 study with the patient’sregimenestablished fore meal test 2 (just before GLP-1 RA dos- completers per treatment arm) was cho- during the run-in period. ing at week 8) for assessment of FPG. sentodetectadifferenceof6.7hz mmol/L Additional blood samples were collected (120 h z mg/dL) in the change from base- Pharmacodynamic Assessments for glucagon, C- (11 samples), and line to week 8 in AUC PPG0030–0430 h End Points the 24-h glucose profile (17 samples). between lixisenatide 20 mgandlira- The trial primary end point was week-8 Blood samples for HbA1c assessment at glutide 1.2 or 1.8 mg, providing a power change from baseline in premeal adjusted screening and day –7werestoredatam- of 90%, assuming the common SD is AUC PPG from the start of a standardized bient temperature for immediate analysis; 8.9 h z mmol/L (160 h z mg/dL), with a breakfast (30 min after injection of the baseline (prior to first GLP-1 RA dosing) one-sided test overall significance level study agent) until 4 h later (AUC andweek4and8sampleswereanalyzed of 0.05 (using the Hochberg procedure PPG0030–0430 h). Secondary end points in- simultaneously from frozen samples (25) to ensure type I error control). cluded week-8 change from baseline in at study end. Plasma glucose, HbA1c,glu- Basedontheresultsofanearlier premeal adjusted glucagon and premeal cagon, and C-peptide were assayed in a study in patients with T2D insufficiently adjusted C-peptide AUC0030–0530 h,HbA1c, central laboratory (MLM Medical Labora- controlledonmetforminwhowere FPG, body weight, and 24-h (17-point) tories, Monchengladbach,¨ Germany). treated with lixisenatide 20 mg once fi plasma glucose pro les. Gastric emptying A total of 15 samples were taken for 13C- daily and liraglutide 1.8 mg once daily – 13 half-life (t1/2 time for retention of Cto octanoic acid breath testing after meal test as add-on to metformin (21), a greater decline to 50%) and lag time (tlag – time at 13 1 (26). Breath samples were centrally an- reduction was expected with lixisenatide which the percentage of C dose ex- 13 alyzed for CO2 by isotope-selective non- 20 mg versus liraglutide 1.2 or 1.8 mg in creted per unit time reaches its peak) dispersive infrared spectrometry (IRIS; the current study in terms of AUC were assessed at baseline and week 8, Analysen Technik, Bremen, Germany). PPG0030–0430h; therefore, a one-sided as were mean 24-h and day- and night- Twenty-four-hour heart rate and DBP approach was chosen for the primary time heart rate and diastolic (DBP) and and SBP were assessed using standard analysis. systolic blood pressure (SBP). ambulatory blood pressure monitoring The modified intent-to-treat (mITT) Assays (model 90207; SpaceLabs, Inc., Redmond, population (all randomized patients Patients were outpatients except for WA). Measurements were recorded ev- who received at least one dose of lixise- two periods of four consecutive days ery 15 min from 0700 to 2300 h (daytime) natide/liraglutide with both a baseline for the baseline and week-8 pharmaco- and every 30 min from 2300 to 0700 h and at least one postbaseline assess- dynamic assessments. During these pe- (nighttime). ment of any primary or secondary vari- riods, patients were asked to refrain able) was used for the primary analysis. from smoking and from drinking alco- Safety Assessments Statistical analyses were performed hol, tea, coffee, chocolate, or caffeine- Adverse events (AEs) were monitored using SAS, version 9.2 (SAS Institute, containing beverages. On days –4and throughout the trial, including symptom- Cary, NC). The primary end point was 55, after an approximate 10-h overnight atic and severe hypoglycemia, increased analyzed considering changes from fast, a standardized 13C-labeled breakfast amylase and lipase levels, and major car- baseline to week 8 and using a linear (meal test 1), consisting of 281 kcal (16% diovascular events. Physical examinations, model with treatment and stratification protein, 62% fat, and 24% carbohydrate) assessment of vital signs, and clinical labo- factors (HbA1c [,8% or $8% and and incorporating 91 mg 13C-octanoic ratory evaluations were also performed. ,64 mmol/mol or $64 mmol/mol], acid (Euriso-Top, Saint-Gobain, France) In the case of amylase and/or lipase the use of metformin, and center) as fixed mixed with egg, was given to patients, levels .2 3 ULN, a retest was performed. effects and the baseline value of the cor- and 13C-octanoic acid breath tests were If the retest confirmed levels .2 3 ULN, responding parameter as a covariate performed for evaluation of gastric emp- this was reported as an AE. Gastroenter- (ANCOVA). Differences between treatment tying (24). In the evening, patients were ological evaluation and imaging were per- arms and CIs were estimated within the given a standardized dinner (50% carbohy- formed to complete the diagnosis if model framework. The Hochberg method drate, 23% protein, 26% fat, and 676 kcal necessary. was used to ensure an overall one-sided in total) and thereafter fasted for at least 8 Documented symptomatic hypogly- level of 5% for the comparisons be- h before eating a standardized solid break- cemia was defined as occurrence of tween lixisenatide 20 mg versus liraglu- fast (meal test 2) consisting of 451 kcal symptoms of hypoglycemia accompa- tide 1.2 mg and lixisenatide 20 mg versus (61% carbohydrate, 12% protein, and nied by plasma glucose #3.9 mmol/L liraglutide 1.8 mg. Secondary outcomes 27% fat) for assessment of postprandial (#70 mg/dL). Probable symptomatic hy- were analyzed using the same model as glycemic end points, glucagon, and C- poglycemia was defined as symptoms of used for the primary outcome with a peptide (days –3 and 56). On days –2and hypoglycemia without plasma glucose two-sided test significance level of 5%. 57 (the last days of the baseline and week- determination, treatable with oral car- Time course data for plasma glucose, 8 inpatient visits), 24-h blood pressure and bohydrate. Severe hypoglycemia was percentage of 13C excreted dose, and heart rate monitoring were performed. defined as a symptomatic event requir- hourly mean heart rate were analyzed Blood samples for analysis of the primary ing assistance of another person to ad- with a repeated-measures mixed model, end point were collected immediately be- minister carbohydrate, glucagon, or and Dunnet adjustment procedure was fore meal test 2 and then 10, 20, 30, 60, 90, other resuscitative actions. used for treatment comparison with 1266 Lixisenatide Versus Liraglutide Effect in T2D Diabetes Care Volume 38, July 2015

control. Safety analyses were performed mmol/L (94–96 mg/dL) in all treatment product); after this period, plasma glu- in the safety population (all randomized arms, indicating that insulin glargine ti- cose levels were comparable versus patients who received at least one dose tration during the run-in period was baseline values (Fig. 1B). Treatment of lixisenatide or liraglutide) and were adequate. with liraglutide (1.2 and 1.8 mg) resulted based on review of descriptive statistics in consistent glucose reductions through- Primary End Point and potentially clinically significant ab- out the day (Fig. 1B). Mean 6 SD AUC PPG0030–0430 h with lix- normalities in laboratory parameters. isenatide 20 mg declined from 15.7 6 6.7 HbA1c decreased from baseline in all , h z mmol/L (282.2 6 120.9 h z mg/dL) at treatment arms (P 0.001), and RESULTS 6 baseline to 3.5 6 6.5 h z mmol/L (63.6 6 mean SD values at trial end were com- Between 22 May 2012 and 25 July 2013, 6 117.9 h z mg/dL) at week 8. Mean 6 SD parable in the three arms: 6.2% 0.4% 236 patients were screened and 142 pa- (44 6 5 mmol/mol), 6.1% 6 0.3% (44 6 tients were randomized and treated in AUC PPG0030–0430 h at baseline in the lir- 6 4 mmol/mol), and 6.1% 6 0.3% (44 6 4 this trial. Patient disposition is shown in aglutide 1.2 and 1.8 mg arms was 15.6 z 6 z mmol/mol) with lixisenatide 20 mg, lira- Supplementary Fig. 2. Treatment dis- 5.6 h mmol/L (280.1 99.9 h mg/dL) 6 z 6 glutide 1.2 mg, and liraglutide 1.8 mg, continuations occurred in two (4.2%), and 17.0 5.7 h mmol/L (307.0 103.2 z respectively. Reductions from baseline three (6.4%), and one subject (2.1%) in h mg/dL), respectively, and treatment re- sulted in reductions to 9.5 6 5.3 h z mmol/L in HbA1c were comparable for lixisenatide the lixisenatide 20 mg, liraglutide 1.2 m (171.7 6 95.2 h z mg/dL) and 8.7 6 3.5 20 g and liraglutide 1.2 mg with a mar- mg, and liraglutide 1.8 mg treatment – h z mmol/L (156.7 6 62.2 h z mg/dL). Mar- ginal mean treatment difference of 0.1% arms, respectively. AE was the reason (95% CI –0.2, 0.03) (–0.9 mmol/mol [–2.1, for discontinuation in four of six sub- ginal mean [95% one-sided CI] difference for m 0.4]) (P = 0.17), while liraglutide 1.8 mg jects. At screening, 77.5% of randomized lixisenatide 20 g versus liraglutide 1.2 mg 2 2 z 2 granted a marginal mean treatment dif- patients were receiving insulin glargine was 6.0 [ 7.8] h mmol/L ( 108.3 2 z ference of –0.2% (–0.3, –0.04) (–1.7 as basal insulin; those who were on NPH [ 140.0] h mg/dL) and versus liraglutide 2 2 z 2 mmol/mol [–3.0, –0.5]) versus lixisena- were switched to insulin glargine at the 1.8 mg was 4.6 [ 6.3] h mmol/L ( 83.0 2 z , tide 20 mg(P =0.007)(Table2). start of the run-in period. Screening [ 114.2] h mg/dL) (P 0.001 for both fi Marginal mean changes from base- demographics and characteristics were comparisons). Plasma glucose pro les and change from baseline to week 8 for AUC line to week 8 in FPG were minimal comparable across the treatment arms and were comparable across the three (Table 1). Mean 6 SD HbA at screening PPG0030–0430 h are shown in Fig. 1A and 1c Supplementary Fig. 3. treatment arms (P =0.91andP =0.90for was 7.8 6 0.8% (62 6 8 mmol/mol). lixisenatide versus liraglutide 1.2 and Median diabetes duration ranged from Secondary Glycemic End Points 1.8 mg, respectively) (Table 2). 10.5 to 12.5 years (minimum 2.1, maxi- Twenty-four-hour plasma glucose pro- mum 32.4 years) with a median duration files were comparable across the three Gastric Emptying of basal insulin treatment of 1.4–2.0 treatment arms at baseline. Greatest re- The percentage of the dose of 13Cex- years (minimum 0.2, maximum 21.7 ductions at week 8 with lixisenatide 20 mg creted over time at baseline and week years). Mean 6 SD baseline FPG at ran- were seen postbreakfast (up to 4 h and 8 for the three treatment arms is pre- domization was approximately 5 6 0.9 30 min after injection of investigational sented in Fig. 1C.Atweek8,tlag was

Table 1—Screening demographic data and patient characteristics: safety population Lixisenatide 20 mg(N = 48) Liraglutide 1.2 mg (N = 47) Liraglutide 1.8 mg (N =47) Age, years 61.6 6 7.4 61.4 6 7.9 62.6 6 9.4 Male sex, n (%) 33 (68.8) 39 (83.0) 33 (70.2) Caucasian patients, n (%) 48 (100.0) 46 (97.9) 47 (100.0) BMI, kg/m2 30.7 6 4.3 30.5 6 4.0 31.2 6 4.3

HbA1c at screening* %7.86 0.7 7.8 6 0.8 7.9 6 0.8 mmol/mol 62 6 8626 9626 9 Current smoker, n (%) 4 (8.3) 11 (23.4) 10 (21.3) Duration of T2D, years 11.4 (2.1, 32.4) 10.5 (3.9, 21.1) 12.5 (4.0, 31.6) Duration of basal insulin treatment, years 2.0 (0.2, 21.7) 1.4 (0.2, 12.0) 1.8 (0.2, 16.7) Patients with evening insulin glargine dosing, n (%) 39 (81.3) 43 (91.5) 41 (87.2) Daily basal insulin dose at screening, units/day NPH 32.1 6 18.9 23.0 6 8.4 24.6 6 7.8 Insulin glargine 26.9 6 10.3 29.7 6 13.9 31.9 6 14.7 OAD use at screening, n (%) Any metformin use† 43 (89.6) 41 (87.2) 41 (87.2) Metformin + DPP-4 inhibitor 9 (18.8) 9 (19.1) 5 (10.6) Metformin + 3 (6.3) 2 (4.3) 4 (8.5) Data are means 6 SD or median (minimum, maximum) unless otherwise indicated. *Stored at ambient temperature; †patients who were taking metformin alone or combined with another medication at screening. care.diabetesjournals.org Meier and Associates 1267

Figure 1—A:Mean6 SEM PPG levels at baseline and week 8 for mITT population. *P , 0.05 for lixisenatide 20 mg vs. liraglutide 1.2 mg; †P , 0.05 for lixisenatide 20 mg vs. liraglutide 1.8 mg. Statistical test compared treatment arms at each time point at week 8. B: Twenty-four-hour plasma glucose profiles (mean 6 SEM) at baseline and week 8 for mITT population. *P , 0.05 for lixisenatide 20 mg vs. liraglutide 1.2 mg; †P , 0.05 for lixisenatide 20 mg vs. liraglutide 1.8 mg; ‡P , 0.05 for liraglutide 1.2 mg and 1.8 mg vs. lixisenatide 20 mg; §P , 0.05 for liraglutide 1.8 mg vs. lixisenatide 20 mg. Hyperglycemia threshold based on International Diabetes Federation 2011 guidelines (50). Statistical tests compared treatment arms at each time point at week 8. C: Percentage of the dose of 13C excreted over time at baseline and week 8. *P # 0.001 vs. liraglutide 1.8 mg; †P , 0.001 vs. liraglutide 1.2 mg; ‡P , 0.05 vs. liraglutide 1.2 mg. Statistical tests compared treatment arms at each time point at week 8. D:Mean6 SEM glucagon concentrations at baseline and week 8 for lixisenatide and liraglutide. Statistical tests compared treatment arms at each time point at week 8. Differences between lixisenatide and liraglutide for glucagon were not significant at any time point. E: Baseline twenty-four-hour heart rate monitoring results (hourly mean 6 SEM) for lixisenatide and liraglutide in the mITT population. F: Change from baseline in hourly mean heart rate (6 SEM) in the mITT population. Baseline was defined as the week-1 time-matched hourly mean. G: Mean change from baseline (6SEM) in lipase levels in the safety population. *P , 0.05 for change from baseline; †P , 0.05 for treatment comparison vs. lixisenatide 20 mg. T0H30, 30 min after injection of the study agent; T0H40, 40 min after injection of the study agent; T0H50, 50 min after injection of the study agent; T1H, 1 h after injection of the study agent; T1H30, 1 h and 30 min after injection of the study agent; T2H, 2 h after injection of the study agent; T2H30, 2 h and 30 min after injection of the study agent; T3H30, 3 h and 30 min after injection of the study agent; T4H30, 4 h and 30 min after injection of the study agent; T5H30, 5 h and 30 min after injection of the study agent; T7H30, 7 h and 30 min after injection of the study agent; T8H30, 8 h and 30 min after injection of the study agent; T10H30, 10 h and 30 min after injection of the study agent; T12H30, 12 h and 30 min after injection of the study agent; T14H30, 14 h and 30 min after injection of the study agent; T24H, 24 h after injection of the study agent. 1268 Lixisenatide Versus Liraglutide Effect in T2D Diabetes Care Volume 38, July 2015

Table 2—Responses to therapy: mITT population Lixisenatide 20 mg Liraglutide 1.2 mg Liraglutide 1.8 mg (N =46) (N =44) (N =46)

Premeal adjusted AUC PPG0030–0430 h, h z mmol/L (h z mg/dL) Baseline, mean 6 SD 15.7 6 6.7 15.6 6 5.6 17.0 6 5.7 (282.2 6 120.9) (280.1 6 99.9) (307.0 6 103.2) Week 8, mean 6 SD 3.5 6 6.5 9.5 6 5.3 8.7 6 3.5 (63.6 6 117.9) (171.7 6 95.2) (156.7 6 62.2) Marginal mean change 6 SE 213.3 6 1.1 27.3 6 1.1 28.7 6 1.2 (–240.2 6 20.0)* (–131.8 6 20.2)* (–157.1 6 21.0)* Marginal mean (95% CI) lixi-lira 26.0 (–7.8) 24.6 (–6.3) difference d (–108.3 [–140.0])‡ (–83.0 [–114.2])‡

HbA1c, % (mmol/mol) Baseline after run-in optimization, mean 6 SD 6.7 6 0.4 (50 6 4) 6.7 6 0.5 (50 6 5) 6.9 6 0.5 (51 6 5) Week 8, mean 6 SD 6.2 6 0.4 (44 6 5) 6.1 6 0.3 (44 6 4) 6.1 6 0.3 (44 6 4) Marginal mean change 6 SE 20.6 6 0.1 (–6 6 1)* 20.7 6 0.1 (–7 6 1)* 20.7 6 0.1 (–8 6 1)* Marginal mean (95% CI) lixi-lira 20.1 (–0.2, 0.03) 20.2 (–0.3, –0.04)¶ difference d (–0.9 [–2.1, 0.4]) (–1.7 [–3.0, –0.5])¶ FPG, mmol/L (mg/dL) Baseline, mean 6 SD 5.3 6 1.0 (96.1 6 18.6) 5.2 6 0.8 (93.8 6 15.1) 5.3 6 1.0 (96.3 6 17.9) Week 8, mean 6 SD 5.4 6 1.0 (96.9 6 17.7) 5.5 6 0.9 (98.2 6 16.7) 5.5 6 1.1 (98.2 6 19.7) Marginal mean change 6 SE 0.1 6 0.2 (1.8 6 3.9) 0.1 6 0.2 (2.3 6 4.0) 0.1 6 0.2 (2.3 6 4.1) Marginal mean (95% CI) lixi-lira 20.02 (–0.4, 0.4) 20.03 (–0.4, 0.4) difference d (–0.4 [–7.8, 7.0]) (–0.5 [–7.8, 6.9])

Gastric emptying tlag,min Baseline, mean 6 SD 113.5 6 26.5 111.2 6 19.7 109.6 6 20.8 Week 8, mean 6 SD 258.9 6 145.7 149.9 6 92.2 125.2 6 63.2 Marginal mean change 6 SE 175.6 6 23.7* 70.1 6 23.8† 48.9 6 24.6† Marginal mean (95% CI) lixi-lira difference d 105.5 (61.1, 149.9)‡ 126.7 (82.8, 170.6)‡

Gastric emptying t1/2,min Baseline, mean 6 SD 169.5 6 41.1 161.7 6 23.4 164.3 6 27.1 Week 8, mean 6 SD 537.4 6 368.7 259.2 6 216.9 206.8 6 138.4 Marginal mean change 6 SE 453.6 6 58.2* 175.3 6 58.5† 130.5 6 60.3† Marginal mean (95% CI) lixi-lira difference d 278.2 (168.7, 387.8)‡ 323.1 (215.3, 430.9)‡ Premeal adjusted C-peptide

AUC0030–0530 h,hz nmol/L (h z ng/mL) Baseline, mean 6 SD 4.4 6 2.6 (13.2 6 7.7) 4.1 6 1.7 (12.3 6 5.2) 4.0 6 1.8 (12.1 6 5.4) Week 8, mean 6 SD 3.0 6 3.4 (9.1 6 10.1) 5.3 6 2.2 (15.8 6 6.6) 4.9 6 2.1 (14.6 6 6.4) Marginal mean change 6 SE 21.2 6 0.4 (–3.5 6 1.1)† 1.2 6 0.4 (3.7 6 1.1)† 0.9 6 0.4 (2.6 6 1.2)† Marginal mean (95% CI) lixi-lira 22.4 (–3.1, –1.7) 22.0 (–2.7, –1.4) difference d (–7.2 [–9.30, –5.1])‡ (–6.1 [–8.2, –4.1])‡ Body weight, kg Baseline, mean 6 SD 90.3 6 13.3 91.4 6 14.0 93.1 6 15.4 Week 8, mean 6 SD 88.4 6 12.9 89.3 6 13.7 90.4 6 15.8 Marginal mean change 6 SE 21.6 6 0.5† 21.8 6 0.5† 22.4 6 0.5* Marginal mean (95% CI) lixi-lira difference d 0.2 (–0.7, 1.1) 0.8 (–0.1, 1.7) Daily insulin glargine dose, units End of run-in, mean 6 SD 42.5 6 19.1 40.7 6 18.4 44.9 6 15.9 Day 1, mean 6 SD 35.4 6 19.0 35.0 6 17.1 39.3 6 15.3 Week 8, mean 6 SD 37.8 6 19.1 36.1 6 17.8 40.9 6 15.8 Mean change 6 SD from end of run-in to week 8 24.7 6 4.8 24.6 6 6.8 24.0 6 6.5 Mean change 6 SD from day 1 to week 8 2.4 6 6.3 1.1 6 3.7 1.6 6 5.0 24-h heart rate, bpm Baseline, mean 6 SD 70.0 6 10.0 68.4 6 9.8 69.8 6 9.0 Baseline, median (min, max) 69.7 (47, 93) 66.5 (52, 92) 69.5 (53, 95) Week 8, mean 6 SD 73.7 6 9.0 78.5 6 9.3 79.3 6 8.8 Week 8, median (min, max) 72.5 (57, 92) 80.7 (58, 92) 78.8 (61, 104) Median (min, max) change at week 8 3.5 (–12, 16) 10.2 (–2, 25) 9.5 (0, 19)

Continued on p. 1269 care.diabetesjournals.org Meier and Associates 1269

Table 2—Continued Lixisenatide 20 mg Liraglutide 1.2 mg Liraglutide 1.8 mg (N =46) (N =44) (N =46)

Marginal mean change 6 SE at week 8 3.3 6 1.3† 9.3 6 1.2* 9.2 6 1.3* Marginal mean (95% CI) lixi-lira difference d 6.0 (3.7, 8.2)§ 5.8 (3.6, 8.0)§ 24-h SBP, mmHg Baseline, mean 6 SD 130.2 6 11.8 130.7 6 13.8 133.9 6 13.9 Week 8, mean 6 SD 130.6 6 11.2 130.2 6 12.7 131.3 6 13.5 Mean change 6 SD at week 8 0.4 6 6.4 20.5 6 7.1 22.5 6 7.7 24-h DBP, mmHg Baseline, mean 6 SD 72.9 6 8.0 74.9 6 8.8 75.6 6 7.1 Week 8, mean 6 SD 73.7 6 7.7 77.3 6 7.9 77.2 6 6.8 Mean change 6 SD at week 8 0.8 6 4.1 2.4 6 4.7 1.6 6 4.7

Premeal adjustment was performed by subtracting premeal value from concentrations. Treatment and stratification factors (HbA1c [,8% or $8% and ,64 mmol/mol or $64 mmol/mol], the use of metformin [yes/no], and study site) were fixed effects in the ANCOVA used for analysis of continuous pharmacodynamic parameters; the baseline value of the corresponding parameter was the model covariate. n = 45 for FPG for lixisenatide 20 mg and liraglutide 1.8 mg and for C-peptide AUC0030–0530 h and for glucagon AUC0030–0530 h for liraglutide 1.8 mg; n = 43 for C-peptide AUC0030–0530 h for liraglutide 1.2 mg. n = 42, 43, and 44 for ambulatory heart rate/blood pressure measurements in the lixisenatide 20 mg and liraglutide 1.2 and 1.8 mg arms, respectively. lixi-lira, lixisenatide-liraglutide. *P , 0.001, †P , 0.05 for change from baseline; ‡P , 0.001 for treatment comparison; §P , 0.001 for treatment comparison; ¶P , 0.01 for treatment comparison.

significantly longer with lixisenatide arms were 90.3 6 13.3, 91.4 6 14.0, and and 9.2 6 1.3 bpm with liraglutide 1.2 20 mg compared with liraglutide 1.2 and 93.1 6 15.4 kg, respectively. At week 8, and 1.8 mg, respectively, compared with 1.8 mg (mean 6 SD 258.9 6 145.7 min, marginal mean 6 SE changes from base- 3.3 6 1.3 bpm with lixisenatide 20 mg 149.9 6 92.2 min, and 125.2 6 63.2 min, line in body weight with lixisenatide and (P , 0.001 for treatment difference) (Table respectively; P , 0.001 for lixisenatide- liraglutide 1.2 mg were –1.6 6 0.5 kg and 2). Median and mean change from baseline liraglutide treatment difference) (Table 2). –1.8 6 0.5 kg, respectively (P , 0.05 for to week-8 heart rate values were compa- At week 8, t1/2 was significantly increased both) and for liraglutide 1.8 mg the rable within each treatment arm, indicat- in lixisenatide-treated patients versus pa- change was –2.4 6 0.5 kg (P , 0.001) ing that heart rate increases were not tients treated with liraglutide 1.2 or 1.8 mg (Table 2). Reductions from baseline in influenced by outlier data (Table 2). (mean 6 SD 537.4 6 368.7 min, 259.2 6 body weight were numerically greater Greater week-8 marginal mean 6 SE 216.9 min, and 206.8 6 138.4 min, re- with liraglutide 1.8 mg compared with lix- increases from baseline in heart rate spectively; P , 0.001 for lixisenatide- isenatide, but this difference did not reach were observed at nighttime versus day- liraglutide treatment difference) (Table 2). statistical significance (P =0.07). time with liraglutide 1.2 mg (10.0 6 1.4 Change in insulin glargine dose was bpm vs. 9.4 6 1.3 bpm) and 1.8 mg Glucagon and C-peptide assessed from the end of the run-in ti- (10.1 6 1.5 bpm vs. 9.1 6 1.4 bpm); this Premeal adjusted glucagon AUC – 0030 0530 h tration period (day –7) and from day 1 of pattern was reversed with lixisenatide was similarly reduced in the three treat- GLP-1 RA treatment (prior to which in- (nighttime increase, 2.2 6 1.5 bpm; day- ment arms during the first hours after sulin dose was decreased by 20% if time increase, 3.7 6 1.4 bpm) (Fig. 1E and meal test 2 (P = 0.13 and P = 0.23 for HbA was #7.5% [58 mmol/mol]). No F and Supplementary Fig. 4). lixisenatide versus liraglutide 1.2 and 1c clinically relevant differences were ob- At week 8, 24-h mean 6 SD DBP was 1.8 mg, respectively); glucagon profiles served between the three treatment slightly increased compared with baseline are presented in Fig. 1D. arms in the change in insulin glargine in patients treated with liraglutide 1.2 and Premeal adjusted C-peptide AUC – 0030 0530 h dose from baseline to week 8 (Table 2). 1.8 mg (2.4 6 4.7 mmHg and 1.6 6 4.7 was reduced with lixisenatide at week mmHg, respectively) (Table 2). SBP was de- 8 (mean 6 SD change from 4.4 6 2.6 creased in patients in the liraglutide 1.8 mg h z nmol/L [13.2 6 7.7 h z ng/mL] to 3.0 6 Heart Rate and Blood Pressure Twenty-four-hour heart rate at baseline arm (–2.5 6 7.7 mmHg) but remained sta- 3.4 h z nmol/L [9.1 6 10.1 h z ng/mL]) and was comparable in all treatment arms (Ta- ble in the other treatment arms (Table 2). increased with liraglutide 1.2 and 1.8 mg ble 2). All treatments resulted in increases (from 4.1 6 1.7 h z nmol/L [12.3 6 5.2 in heart rate from baseline (P , 0.001 for h z ng/mL] to 5.3 6 2.2 h z nmol/L [15.8 6 Safety both liraglutide doses and P , 0.05 for The most commonly reported AEs were 6.6 h z ng/mL] and from 4.0 6 1.8 h z nmol/L lixisenatide). Week-8 mean 6 SD 24-h symptomatic hypoglycemia (see below) [12.1 6 5.4 h z ng/mL] to 4.9 6 2.1 h z nmol/L heart rate was 78.5 6 9.3 bpm and and nausea (Supplementary Table 1). [14.6 6 6.4 h z ng/mL], respectively) (P , 79.3 6 8.8 bpm for liraglutide 1.2 and Gastrointestinal AEs were reported 0.001 for treatment comparison) (Table 2). 1.8 mg, respectively, compared with more frequently with liraglutide than Body Weight and Insulin Dose 73.7 6 9.0 bpm for lixisenatide 20 mg. with lixisenatide. In particular, constipation Mean 6 SD baseline body weights in the Week-8 marginal mean 6 SE heart rate in- was increased with liraglutide 1.2 and 1.8 lixisenatide and liraglutide 1.2 and 1.8 mg creases from baseline were 9.3 6 1.2 bpm mg versus lixisenatide (5 of 47 patients 1270 Lixisenatide Versus Liraglutide Effect in T2D Diabetes Care Volume 38, July 2015

[10.6%], 3 of 47 patients [6.4%], and 0 pa- liraglutide 1.8 mg with elevated lipase however, important to put the percent- tients, respectively). In the lixisenatide (2.2 3 ULN) at day 56, confirmed by re- age of patients experiencing symptom- and liraglutide 1.2 and 1.8 mg groups, test (2.5 3 ULN);atlastretest(aftertrial atic hypoglycemia in this study into nausea rates were 18.8, 17.0, and end on day 69), lipase levels in this patient context. All randomized patients had 23.4%; vomiting rates were 10.4, 4.3, decreased to 1.8 3 ULN. Amylase values been optimally titrated with insulin glar- and 10.6%; and diarrhea rates were were within the normal range throughout gine, and at the start of GLP-1 RA treat- 6.3, 8.5, and 10.6%, respectively. the duration of the study. ment mean FPG in the lixisenatide and No deaths were reported in this study. liraglutide arms ranged from 5.2 to 5.3 Two serious AEs occurred: one event of CONCLUSIONS mmol/L (94 to 96 mg/dL). Moreover, ti- coronary artery disease in the lixisenatide Both lixisenatide and liraglutide in com- tration with insulin glargine was contin- 20 mg arm (patient fully recovered after bination with optimal titration of insulin ual throughout the trial. When patients revascularization, did not discontinue lix- glargine (baseline FPG ;5.3 mmol/L or are tightly titrated in terms of FPG or isenatide, and completed the trial) and 95 mg/dL]) improved glycemic control below an HbA1c of 7%, increased rates myocardial infarction requiring hospitali- to a normal HbA1c of approximately of hypoglycemia are to be expected zation in one patient in the liraglutide 1.2 6.1–6.2% (44 mmol/mol) despite the (29–31). However, despite the low FPG mg arm (patient recovered after revascu- relatively advanced T2D population in levels and HbA1c at randomization, only larization but withdrew from the trial). this study (median duration 10.5–12.5 one case of severe symptomatic hypogly- years). Lixisenatide demonstrated a sig- cemiaoccurredinthecurrentstudy; Symptomatic Hypoglycemia nificantly greater effect than liraglutide moreover, a subanalysis in patients with There were numerical differences in the (1.2 and 1.8 mg) in reducing AUC HbA ,7% vs. $ 7% revealed no differ- number of patients experiencing symp- 1c PPG 2 after a standardized solid ence in hypoglycemia incidence between tomatic hypoglycemia (encompassing 0030 0430 h breakfast, while liraglutide had a less pro- the two groups (data not shown). documented, probable, and severe symp- nounced effect on prandial glucose levels, There are limited published data on the tomatic hypoglycemia) in the lixisenatide- though this was sustained throughout the effects of GLP-1 RAs on pancreatic en- treated arm compared with the liraglutide day. This difference was thought to be zymes, especially during the early phase 1.2 and 1.8 mg treatment arms (14 of 48 mainly attributable to significant delays of treatment when changes would patients [29.2%], 9 of 47 patients [19.1%], in gastric emptying with lixisenatide suggest a direct drug effect. In this trial, and 10 of 47 patients [21.3%], respec- compared with liraglutide, which strongly an increase in mean lipase levels was ob- tively, including one patient experiencing reduced postbreakfast blood glucose ex- served at weeks 4 and 8 in all treatment severe hypoglycemia in the lixisenatide posure. It has been reported previously arms, with substantially greater increases arm) (Supplementary Table 1). that delayed gastric emptying with lixise- in the liraglutide arms. Furthermore, one Monitoring of Pancreatic Enzymes natide prolongs absorption of meal- patient treated with liraglutide 1.8 mg ex- Treatment with liraglutide 1.2 and 1.8 derived glucose, resulting in blunted perienced an asymptomatic episode of mg resulted in significant lipase in- PPG excursions (27). confirmed pancreatitis despite the short creases at week 8 compared with base- In all three treatment arms, HbA1c and term of drug exposure. The mechanisms line (P , 0.05); these increases were body weight were significantly decreased responsible for increases in pancreatic significantly greater than reported for from baseline. Compared with lixisena- enzymes with GLP-1 RAs are currently lixisenatide 20 mg (marginal mean 6 tide 20 mg, liraglutide 1.2 mg did not unknown, and further investigation is SE increases of 21.1 6 7.2 IU/L, 20.8 6 show a statistical difference in terms of warranted. 7.4 IU/L, and 7.0 6 7.1 IU/L, respec- HbA1c and body weight, while liraglutide The results herein confirm earlier tively; P , 0.05 for treatment compari- 1.8 mg demonstrated slightly greater re- findings regarding increased heart rate son). These greater increases from ductions in HbA1c;however,final HbA1c with GLP-1 RAs (32,33), although this is baseline in mean lipase with either levels of 6.1% and 6.2% were basically the first study to compare the effects of dose of liraglutide versus lixisenatide similar between all treatment arms with prandial and nonprandial GLP-1 RAs were observed from week 4 (Fig. 1G properly optimized insulin glargine. objectively assessed by using 24-h am- and Table 2). Marginal mean 6 SE amy- Safety is indeed a major issue with all bulatory monitoring. Treatment with lase levels showed changes from base- new therapies and was carefully moni- liraglutide resulted in a clinically signifi- line at week 8 of 8.0 6 4.0 IU/L, 5.7 6 tored in this trial. Gastrointestinal AEs of cant increase in mean 24-h heart rate by 4.1 IU/L, and 3.0 6 4.0 IU/L in the lira- the lower intestinal tract were slightly approximately 9 bpm (compared with 3 glutide 1.2 and 1.8 mg and lixisenatide 20 more common with liraglutide than bpm with lixisenatide). Median heart mg arms, respectively (P , 0.05 for with lixisenatide. Symptomatic hypogly- rate values at week 8 in the three treat- change from baseline for liraglutide 1.2 cemia occurred in more patients in the ment arms were consistent with their mg, and P =0.17andP = 0.46 for liraglu- lixisenatide plus basal insulin arm in this respective mean values, indicating that tide 1.8 mg and lixisenatide 20 mg, re- study (29%) than in the liraglutide plus reported increases from baseline were spectively) (Fig. 1G and Supplementary basal insulin arms (19–21%). It is possi- not skewed by outlier data, although in- Table 2). No clinical signs or symptoms ble that delay of gastric emptying by creases up to a maximum heart rate of were associated with these pancreatic prandial lixisenatide may decrease glu- 104 bpm were observed for liraglutide enzyme increases. cose absorption to the extent that rapid 1.8 mg. Of note, heart rate increases at MRI showed signs of mild asymptom- recovery from hypoglycemia is pre- week 8 with liraglutide were greater at atic pancreatitis in a patient treated with vented in some patients (28). It is, nighttime, while heart rate increases care.diabetesjournals.org Meier and Associates 1271

with lixisenatide were greatest during for administration of liraglutide, it controlled on basal insulin with/without the day. We postulate that this differ- would not have been possible to source OADs. ence is due to the longer half-life of lir- identical placebo pens to allow blinding. aglutide, which appeared to abolish In addition, this was a phase IIb study circadian rhythms in heart rate (Fig. with three different treatment arms Acknowledgments. The authors thank all of 1F) that were maintained with lixisena- that required two- or three-step uptitra- the study investigators (full author list available in tide treatment. A recent pooled analysis tion of the GLP-1 RAs under investiga- the Supplementary Data), their staff, and the pa- of six 26- to 28-week phase III liraglutide tion and optimization of insulin glargine; tients who participated in the study. The authors studies reported overall heart rate in- the addition of placebo injections to fa- thank their Sanofi R&D colleagues (Christiana creases of 3 bpm and significant de- cilitate blinding would have further Frosio, Frankfurt, Germany, for her contribution to the study management and Natacha Bosc and creases from baseline in SBP (34). As complicated the study regimen. Owing Hel´ ene` Savoye, Chilly-Mazarin, France, and the current study was of 8 weeks’ dura- to the uniformity of the study demo- Sandrine Berne, Montpellier, France, for their tion, it is possible that the heart rate graphics, the data reported herein are contribution to data management and data increases reported herein may have di- only generalizable to Caucasian patients analysis). Editorial assistance was provided to minished if assessed over longer peri- with T2D. the authors by Jane Bryant, PhD, of Caudex Med- ical and was funded by Sanofi. ods. Alternatively, our use of 24-h Combining medications with comple- Duality of Interest. This study was sponsored by ambulatory heart rate and blood pres- mentary effects on FPG and PPG to Sanofi. J.J.M. has received lecture honoraria and sure monitoring may have permitted comprehensively manage glycemia in consulting fees from the AstraZeneca, Berlin- more accurate assessment compared patients with T2D is not a novel concept. Chemie, Bristol-Myers Squibb (BMS), Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme with these phase III trials. As noted by Several prandial agents have been (MSD), Novo Nordisk, Novartis, Roche, and Sanofi; the U.S. Food and Drug Administration shown to help patients with T2D achieve has received reimbursement of congress participa- during evaluation of liraglutide for the HbA1c targets when given in combina- tion fees and travel expenses from MSD, Novo treatment of obesity, a clinical pharma- tion with basal insulin (4,38–43), and Nordisk, and Sanofi; and has initiated projects sup- fi cology study using 24-h continuous treatment intensification with a rapid- ported by MSD, Novo Nordisk, and Sano .J.R.has served on scientific advisory boards and received heart rate monitoring reported in- acting insulin on top of basal insulin is honoraria or consulting fees and has also received creases of 5.7–6.6 bpm in 24-h heart commonly recommended for control of grants/research support from companies involved rate and 7.0–8.9 bpm in 3-h sleeping PPG excursions (2,44). However, more in development of insulins and/or GLP-1 receptor heart rate with liraglutide 1.8 and 3 mg intensive insulin regimens are associ- agonists including Eli Lilly, Sanofi, Novo Nordisk, (35). Treatment with twice-daily pran- ated with hypoglycemia and weight BMS, AstraZeneca, and GlaxoSmithKline. A.H.-M., C.R.-D., and A.D. are full-time employees of dial results in increases from gain, which can result in poor treatment Sanofi. T.F. has participated in speakers bureaus baseline in heart rate (2 bpm at week acceptance and reduced compliance for Berlin-Chemie, Boehringer Ingelheim, BMS, 12), similar to those reported here for (45–48). In a recent study of twice daily Eli Lilly, Novartis, Novo Nordisk, and Sanofi; has once daily prandial lixisenatide, and also exenatide plus insulin glargine, HbA participated in advisory panels for Boehringer 1c fi maintains the natural circadian fluctua- reductions were noninferior and FPG Ingelheim, BMS, Eli Lilly, and Sano ; and has re- ceived research support from Boehringer tions in heart rate (36). The potential and body weight were significantly Ingelheim, Novartis, and Sanofi. C.K. has received mechanism for increased heart rate lower compared with mealtime bolus in- research funds from Boehringer Ingelheim, Dance with GLP-1 RA treatment is currently un- sulin lispro plus insulin glargine. Impor- Pharmaceuticals, Hoffmann-La Roche, Johnson known and does not appear to be nec- tantly, the rate of hypoglycemic events & Johnson, Eli Lilly, Novo Nordisk, Novartis, Noxxon, Sanofi, and Servier and has received essarily related to a drop in blood was reduced with exenatide versus in- speaker and travel grants from Sanofi.Noother pressure. We postulate that heart rate sulin lispro (49). The GLP-1 RA class ef- potential conflicts of interest relevant to this ar- increases could be ascribed to direct ac- fect of weight loss and a low propensity ticle were reported. tion at the sinus node, sympathetic for causing hypoglycemia make GLP-1 Author Contributions. J.J.M. was involved in stimulation, or a parasympathetic blunt- RAs a useful alternative to rapid-acting the clinical conduct of the study and in the fi writing, discussion, and review of the manuscript. ing effect (37), which could be extended insulin for treatment intensi cation of J.R. was involved in the review and interpretation with long-acting liraglutide. The poten- basal insulin. of data and in the writing, discussion, and review tial clinical relevance of increased heart The present trial indicates that lixise- of the manuscript. A.H.-M. was responsible for rate with GLP-1 RAs is also unknown, but natide and liraglutide, when combined medical supervision of the study as the Clinical this issue will hopefully be addressed in with optimized basal insulin glargine, re- Study Director, reviewed the data, and was in- volved in the writing, discussion, and review of the ongoing prospective cardiovascular sult in robust improvements in glycemic the manuscript. C.R.-D. designed and wrote the outcome trials. In the meantime, the control to levels not reached previously, protocol and undertook medical supervision of safety/tolerability profile should be albeit with differing mechanisms of ac- the study, reviewed data, and was involved in the part of the decision-making process in tion and safety/tolerability profiles. writing, discussion, and review of the man- choosing between GLP-1 RAs for treat- These differences should be taken into uscript. A.D. performed the statistical analysis in the study and was involved in the writing, ment of T2D to lower the risk of exacer- account when selecting the most appro- discussion, and review of the manuscript. H.-V.C. bating existing medical conditions (32). priate treatment for a given patient. In was involved in the writing, discussion, and The open-label design was a limita- T2D, reducing FPG with insulin glargine review of the manuscript and was involved in the tion of the current study, and use of and targeting mealtime glucose excur- clinical conduct of the study. B.A.M. was involved in the clinical conduct of the study and in the double blinding would have further sions with lixisenatide is a logical and writing, discussion, and review of the manuscript. strengthened our results. However, as potentially valuable option in the treat- T.F. was involved in the clinical conduct of the we used the approved marketed pens ment of patients with T2D inadequately study and in the writing, discussion, and review 1272 Lixisenatide Versus Liraglutide Effect in T2D Diabetes Care Volume 38, July 2015

of the manuscript. C.K. was the coordinating Investigators. Efficacy and safety of the once- 22. Owens DR, Monnier L, Bolli GB. Differential investigator and was involved in the clinical daily GLP-1 receptor agonist lixisenatide in effects of GLP-1 receptor agonists on compo- conduct of the study and in the writing, discus- monotherapy: a randomized, double-blind, nents of dysglycaemia in individuals with type sion, and review of the manuscript. J.J.M. is the placebo-controlled trial in patients with type 2 2 diabetes mellitus. Diabetes Metab 2013;39: guarantor of this work and, as such, had full diabetes (GetGoal-Mono). Diabetes Care 2012; 485–496 access to all the data in the study and takes 35:1225–1231 23. Robinson LE, Holt TA, Rees K, Randeva HS, responsibility for the integrity of the data and 12. Riddle MC, Aronson R, Home P, et al. Add- O’Hare JP. 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