Trial Outcomes & Findings for GLP-1 Receptor Agonist Lixisenatide Versus Exenatide in Patients With Type 2 Diabetes for Glycemic Control and Safety Evaluation, on Top of Metformin (NCT NCT00707031)

Last Updated: 2016-12-02

Results Overview

Absolute Change = HbA1c value at Week 24 minus HbA1c value at baseline. The on-treatment period for this efficacy variable is time from the first dose of study drug and up to 3 days after the last dose of study drug, on or before Visit 11 (Week 24) or Day 169 if Visit 11 is not available, and before the introduction of rescue therapy. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

639 participants

Primary outcome timeframe

Baseline, Week 24

Results posted on

2016-12-02

Participant Flow

The study was conducted at 122 centers in 18 countries between June 23, 2008 and November 18, 2010. The overall duration of treatment was at least 76 weeks (24 weeks main open-label treatment; variable open-label extension treatment).

A total of 1243 patients were screened of which 604 were screen failures; main reason for screen failure was glycosylated hemoglobin (HbA1c) values being out of the defined protocol range (greater than or equal to 7% and less than or equal to 10%). A total of 639 patients were randomized.

Participant milestones

Participant milestones
Measure	Lixisenatide 2-step initiation regimen of lixisenatide: 10 microgram (mcg) once daily (QD) subcutaneously for 1 week, followed by 15 mcg QD for 1 week, then 20 mcg QD up to the end of treatment.	Exenatide 1-step initiation regimen of exenatide: 5 mcg twice daily (BID) subcutaneously for 4 weeks, followed by 10 mcg BID up to the end of treatment.
Overall Study STARTED	320	319
Overall Study Treated/Safety Population	318	316
Overall Study Modified Intent-to-Treat Population	315	315
Overall Study COMPLETED	216	220
Overall Study NOT COMPLETED	104	99

Reasons for withdrawal

Reasons for withdrawal
Measure	Lixisenatide 2-step initiation regimen of lixisenatide: 10 microgram (mcg) once daily (QD) subcutaneously for 1 week, followed by 15 mcg QD for 1 week, then 20 mcg QD up to the end of treatment.	Exenatide 1-step initiation regimen of exenatide: 5 mcg twice daily (BID) subcutaneously for 4 weeks, followed by 10 mcg BID up to the end of treatment.
Overall Study Adverse Event	45	45
Overall Study Lack of Efficacy	19	6
Overall Study Lost to Follow-up	2	1
Overall Study Protocol Violation	1	0
Overall Study Withdrawal by Subject	7	8
Overall Study Poor Compliance to Protocol	7	13
Overall Study Familial or Personal Reasons	12	15
Overall Study Serious Noncompliance	2	3
Overall Study Sponsor Decision	9	8

Baseline Characteristics

GLP-1 Receptor Agonist Lixisenatide Versus Exenatide in Patients With Type 2 Diabetes for Glycemic Control and Safety Evaluation, on Top of Metformin

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Lixisenatide n=318 Participants 2-step initiation regimen of lixisenatide: 10 mcg QD subcutaneously for 1 week, followed by 15 mcg QD for 1 week, then 20 mcg QD up to the end of treatment.	Exenatide n=316 Participants 1-step initiation regimen of exenatide: 5 mcg BID subcutaneously for 4 weeks, followed by 10 mcg BID up to the end of treatment.	Total n=634 Participants Total of all reporting groups
Age, Continuous	57.3 years STANDARD_DEVIATION 9.2 • n=5 Participants	57.6 years STANDARD_DEVIATION 10.7 • n=7 Participants	57.4 years STANDARD_DEVIATION 9.9 • n=5 Participants
Sex: Female, Male Female	167 Participants n=5 Participants	129 Participants n=7 Participants	296 Participants n=5 Participants
Sex: Female, Male Male	151 Participants n=5 Participants	187 Participants n=7 Participants	338 Participants n=5 Participants
Race/Ethnicity, Customized Race: Caucasian/White	296 participants n=5 Participants	292 participants n=7 Participants	588 participants n=5 Participants
Race/Ethnicity, Customized Race: Black	8 participants n=5 Participants	10 participants n=7 Participants	18 participants n=5 Participants
Race/Ethnicity, Customized Race: Asian/Oriental	3 participants n=5 Participants	4 participants n=7 Participants	7 participants n=5 Participants
Race/Ethnicity, Customized Race: Other	11 participants n=5 Participants	10 participants n=7 Participants	21 participants n=5 Participants
Race/Ethnicity, Customized Ethnicity: Hispanic	87 participants n=5 Participants	83 participants n=7 Participants	170 participants n=5 Participants
Race/Ethnicity, Customized Ethnicity: Non Hispanic	231 participants n=5 Participants	233 participants n=7 Participants	464 participants n=5 Participants
Glycosylated Hemoglobin (HbA1c)	7.95 percentage of hemoglobin STANDARD_DEVIATION 0.81 • n=5 Participants	7.97 percentage of hemoglobin STANDARD_DEVIATION 0.78 • n=7 Participants	7.96 percentage of hemoglobin STANDARD_DEVIATION 0.80 • n=5 Participants
Fasting Plasma Glucose (FPG)	9.7 millimole per liter (mmol/L) STANDARD_DEVIATION 2.0 • n=5 Participants	9.7 millimole per liter (mmol/L) STANDARD_DEVIATION 2.3 • n=7 Participants	9.7 millimole per liter (mmol/L) STANDARD_DEVIATION 2.1 • n=5 Participants
Body Weight	94.0 kilogram (kg) STANDARD_DEVIATION 19.6 • n=5 Participants	96.1 kilogram (kg) STANDARD_DEVIATION 22.5 • n=7 Participants	95.0 kilogram (kg) STANDARD_DEVIATION 21.13 • n=5 Participants
Patient Assessment of Upper Gastrointestinal Disorders-Quality of Life (PAGI-QOL) Total Score	0.59 units on a scale STANDARD_DEVIATION 0.7 • n=5 Participants	0.56 units on a scale STANDARD_DEVIATION 0.7 • n=7 Participants	0.58 units on a scale STANDARD_DEVIATION 0.7 • n=5 Participants
Body Mass Index (BMI)	33.68 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 6.27 • n=5 Participants	33.51 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 6.54 • n=7 Participants	33.60 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 6.40 • n=5 Participants
Duration of Diabetes	6.78 years STANDARD_DEVIATION 5.54 • n=5 Participants	6.75 years STANDARD_DEVIATION 4.87 • n=7 Participants	6.76 years STANDARD_DEVIATION 5.21 • n=5 Participants
Daily Metformin Dose	2020.20 milligram (mg) STANDARD_DEVIATION 459.41 • n=5 Participants	2058.39 milligram (mg) STANDARD_DEVIATION 453.23 • n=7 Participants	2039.24 milligram (mg) STANDARD_DEVIATION 456.38 • n=5 Participants

PRIMARY outcome

Timeframe: Baseline, Week 24

Population: mITT population:all randomized patients who received at least 1 dose;had baseline,at least 1 post-baseline efficacy assessment, irrespective of compliance with study protocol/procedures. Last observation carried forward used. Number of patients analyzed=patients with baseline and at least 1 post-baseline HbA1c assessment during on-treatment period.

Outcome measures

Outcome measures
Measure	Lixisenatide n=295 Participants 2-step initiation regimen of lixisenatide.	Exenatide n=297 Participants 1-step initiation regimen of exenatide.
Absolute Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 24	-0.79 percentage of hemoglobin Standard Error 0.053	-0.96 percentage of hemoglobin Standard Error 0.054

SECONDARY outcome

Timeframe: Baseline, Week 24

Population: mITT population. Missing data was imputed using last observation carried forward (LOCF). Here, number of patients analyzed = patients with baseline and at least 1 post-baseline FPG assessment during on-treatment period.

Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is time from the first dose of study drug and up to 1 day after the last dose of study drug, on or before Visit 11 (Week 24) or Day 169 if Visit 11 is not available, and before the introduction of rescue therapy. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required.

Outcome measures

Outcome measures
Measure	Lixisenatide n=310 Participants 2-step initiation regimen of lixisenatide.	Exenatide n=301 Participants 1-step initiation regimen of exenatide.
Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24	-1.22 mmol/L Standard Error 0.116	-1.45 mmol/L Standard Error 0.119

SECONDARY outcome

Timeframe: Baseline, Week 24

Population: mITT population. Missing data was imputed using LOCF. Here, number of patients analyzed = patients with baseline and at least 1 post-baseline body weight assessment during on-treatment period.

Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is time from the first dose of study drug and up to 3 days after the last dose of study drug, on or before Visit 11 (Week 24) or Day 169 if Visit 11 is not available, and before the introduction of rescue therapy. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required.

Outcome measures

Outcome measures
Measure	Lixisenatide n=295 Participants 2-step initiation regimen of lixisenatide.	Exenatide n=296 Participants 1-step initiation regimen of exenatide.
Change From Baseline in Body Weight at Week 24	-2.96 kilogram Standard Error 0.231	-3.98 kilogram Standard Error 0.232

SECONDARY outcome

Timeframe: Week 24

Population: mITT population. Here, number of patients analyzed = patients with baseline and at least 1 post-baseline HbA1c assessment during on-treatment period.

The on-treatment period for this efficacy variable is time from the first dose of study drug and up to 3 days after the last dose of study drug, on or before Visit 11 (Week 24) or Day 169 if Visit 11 is not available, and before the introduction of rescue therapy. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required.

Outcome measures

Outcome measures
Measure	Lixisenatide n=295 Participants 2-step initiation regimen of lixisenatide.	Exenatide n=297 Participants 1-step initiation regimen of exenatide.
Percentage of Patients With Glycosylated Hemoglobin (HbA1c) Level Less Than 7% at Week 24	48.5 percentage of participants	49.8 percentage of participants

SECONDARY outcome

Timeframe: Week 24

Population: mITT population. Here, number of patients analyzed = patients with baseline and at least 1 post-baseline HbA1c assessment during on-treatment period.

Outcome measures

Outcome measures
Measure	Lixisenatide n=295 Participants 2-step initiation regimen of lixisenatide.	Exenatide n=297 Participants 1-step initiation regimen of exenatide.
Percentage of Patients With Glycosylated Hemoglobin (HbA1c) Level Less Than or Equal to 6.5% at Week 24	28.5 percentage of participants	35.4 percentage of participants

SECONDARY outcome

Timeframe: Baseline up to Week 24

Population: mITT population.

Routine fasting self-monitored plasma glucose (SMPG) and central laboratory FPG (and HbA1c after week 12) values were used to determine the requirement of rescue medication. If fasting SMPG value exceeded the specified limit for 3 consecutive days, the central laboratory FPG (and HbA1c after week 12) were performed. Threshold values - from baseline to Week 8: fasting SMPG/FPG \>270 milligram/deciliter (mg/dL) (15.0 mmol/L), from Week 8 to Week 12: fasting SMPG/FPG \>240 mg/dL (13.3 mmol/L), and from Week 12 to Week 24: fasting SMPG/FPG \>200 mg/dL (11.1 mmol/L) or HbA1c \> 8.5%. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required.

Outcome measures

Outcome measures
Measure	Lixisenatide n=315 Participants 2-step initiation regimen of lixisenatide.	Exenatide n=315 Participants 1-step initiation regimen of exenatide.
Percentage of Patients Requiring Rescue Therapy During Main 24-Week Period	2.2 percentage of participants	3.8 percentage of participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline, Week 24

Population: mITT population. Here, number of patients analyzed = patients with baseline and at least 1 post-baseline body weight assessment during on-treatment period.

Outcome measures

Outcome measures
Measure	Lixisenatide n=295 Participants 2-step initiation regimen of lixisenatide.	Exenatide n=296 Participants 1-step initiation regimen of exenatide.
Percentage of Patients With at Least 5% Weight Loss From Baseline at Week 24	25.1 percentage of participants	31.4 percentage of participants

OTHER_PRE_SPECIFIED outcome

Timeframe: First dose of study drug up to 3 days after the last dose administration, for up to 116 weeks

Population: Safety population included all randomized patients who received at least 1 dose of study drug, regardless of the amount of treatment administered.

Symptomatic hypoglycemia was an event with clinical symptoms that were considered to result from a hypoglycemic episode with an accompanying plasma glucose less than 60 mg/dL (3.3 mmol/L) or associated with prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration if no plasma glucose measurement was available. Severe symptomatic hypoglycemia was an event with clinical symptoms that were considered to result from hypoglycemia in which the patient required the assistance of another person and was associated with either a plasma glucose level below 36 mg/dL (2.0 mmol/L) or prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration, if no plasma glucose measurement was available.

Outcome measures

Outcome measures
Measure	Lixisenatide n=318 Participants 2-step initiation regimen of lixisenatide.	Exenatide n=316 Participants 1-step initiation regimen of exenatide.
Number of Patients With Symptomatic Hypoglycemia and Severe Symptomatic Hypoglycemia Symptomatic Hypoglycemia	16 participants	46 participants
Number of Patients With Symptomatic Hypoglycemia and Severe Symptomatic Hypoglycemia Severe Symptomatic Hypoglycemia	0 participants	0 participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline, Week 24

Population: mITT population. Missing data was imputed using LOCF. Here, number of patients analyzed = patients with baseline and at least 1 post-baseline PAGI-QOL assessment during on-treatment period.

PAGI-QOL: a 30-item self-administered questionnaire to measure health related QOL of patients with upper gastrointestinal disorders during past 2 weeks. Consists of 5 sub-scales. Each item rated on a 0-5 point Likert scale (0 \[none of the time\] to 5 \[all the time\]). Sub-scale score calculated by dividing sum of all items of subscale by number of items in the sub-scale. Total score calculated by taking mean of sub-scale scores. Sub-scale score and total score ranges from 0=none of the time (lowest score) to 5=all of the time (highest score) with lower scores indicating better QOL. The on-treatment period for this variable is time from the first dose of study drug and up to 3 days after the last dose of study drug, on or before Visit 11 (Week 24) or Day 169 if Visit 11 is not available, and before the introduction of rescue therapy. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required.

Outcome measures

Outcome measures
Measure	Lixisenatide n=302 Participants 2-step initiation regimen of lixisenatide.	Exenatide n=292 Participants 1-step initiation regimen of exenatide.
Quality of Life: Change From Baseline in Patient's Satisfaction to Treatment (PAGI-QOL) at Week 24	-0.09 units on a scale Standard Error 0.031	-0.06 units on a scale Standard Error 0.032

Adverse Events

Lixisenatide

Serious events: 26 serious events

Other events: 204 other events

Deaths: 0 deaths

Exenatide

Serious events: 22 serious events

Other events: 218 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Trial Transparency Team

Sanofi

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee If no publication has occurred within 12 months of the completion of the study, the Investigator shall have the right to publish/present independently the results of the study. The Investigator shall provide the Sponsor with a copy of any such presentation/publication for comment at least 30 days before any presentation/submission for publication. If requested by the Sponsor, any presentation/submission shall be delayed up to 90 days, to allow the Sponsor to preserve its proprietary rights.
Publication restrictions are in place

Restriction type: OTHER

Measure	Lixisenatide n=318 participants at risk 2-step initiation regimen of lixisenatide.	Exenatide n=316 participants at risk 1-step initiation regimen of exenatide.
Infections and infestations Bronchitis	6.0% 19/318 • First dose of study drug up to 3 days after the last dose administration, for up to 116 weeks Median exposure to study treatment was 562 and 560 days in lixisenatide and exenatide treatment arms, respectively. The analysis was performed on safety population, defined as all randomized patients who were exposed to at least 1 dose of study drug, regardless of the amount of treatment administered.	6.0% 19/316 • First dose of study drug up to 3 days after the last dose administration, for up to 116 weeks Median exposure to study treatment was 562 and 560 days in lixisenatide and exenatide treatment arms, respectively. The analysis was performed on safety population, defined as all randomized patients who were exposed to at least 1 dose of study drug, regardless of the amount of treatment administered.
Infections and infestations Influenza	9.1% 29/318 • First dose of study drug up to 3 days after the last dose administration, for up to 116 weeks Median exposure to study treatment was 562 and 560 days in lixisenatide and exenatide treatment arms, respectively. The analysis was performed on safety population, defined as all randomized patients who were exposed to at least 1 dose of study drug, regardless of the amount of treatment administered.	10.1% 32/316 • First dose of study drug up to 3 days after the last dose administration, for up to 116 weeks Median exposure to study treatment was 562 and 560 days in lixisenatide and exenatide treatment arms, respectively. The analysis was performed on safety population, defined as all randomized patients who were exposed to at least 1 dose of study drug, regardless of the amount of treatment administered.
Infections and infestations Nasopharyngitis	15.4% 49/318 • First dose of study drug up to 3 days after the last dose administration, for up to 116 weeks Median exposure to study treatment was 562 and 560 days in lixisenatide and exenatide treatment arms, respectively. The analysis was performed on safety population, defined as all randomized patients who were exposed to at least 1 dose of study drug, regardless of the amount of treatment administered.	11.1% 35/316 • First dose of study drug up to 3 days after the last dose administration, for up to 116 weeks Median exposure to study treatment was 562 and 560 days in lixisenatide and exenatide treatment arms, respectively. The analysis was performed on safety population, defined as all randomized patients who were exposed to at least 1 dose of study drug, regardless of the amount of treatment administered.
Infections and infestations Upper respiratory tract infection	5.7% 18/318 • First dose of study drug up to 3 days after the last dose administration, for up to 116 weeks Median exposure to study treatment was 562 and 560 days in lixisenatide and exenatide treatment arms, respectively. The analysis was performed on safety population, defined as all randomized patients who were exposed to at least 1 dose of study drug, regardless of the amount of treatment administered.	4.1% 13/316 • First dose of study drug up to 3 days after the last dose administration, for up to 116 weeks Median exposure to study treatment was 562 and 560 days in lixisenatide and exenatide treatment arms, respectively. The analysis was performed on safety population, defined as all randomized patients who were exposed to at least 1 dose of study drug, regardless of the amount of treatment administered.
Metabolism and nutrition disorders Hypoglycaemia	5.7% 18/318 • First dose of study drug up to 3 days after the last dose administration, for up to 116 weeks Median exposure to study treatment was 562 and 560 days in lixisenatide and exenatide treatment arms, respectively. The analysis was performed on safety population, defined as all randomized patients who were exposed to at least 1 dose of study drug, regardless of the amount of treatment administered.	15.2% 48/316 • First dose of study drug up to 3 days after the last dose administration, for up to 116 weeks Median exposure to study treatment was 562 and 560 days in lixisenatide and exenatide treatment arms, respectively. The analysis was performed on safety population, defined as all randomized patients who were exposed to at least 1 dose of study drug, regardless of the amount of treatment administered.
Nervous system disorders Dizziness	6.6% 21/318 • First dose of study drug up to 3 days after the last dose administration, for up to 116 weeks Median exposure to study treatment was 562 and 560 days in lixisenatide and exenatide treatment arms, respectively. The analysis was performed on safety population, defined as all randomized patients who were exposed to at least 1 dose of study drug, regardless of the amount of treatment administered.	9.8% 31/316 • First dose of study drug up to 3 days after the last dose administration, for up to 116 weeks Median exposure to study treatment was 562 and 560 days in lixisenatide and exenatide treatment arms, respectively. The analysis was performed on safety population, defined as all randomized patients who were exposed to at least 1 dose of study drug, regardless of the amount of treatment administered.
Nervous system disorders Headache	14.5% 46/318 • First dose of study drug up to 3 days after the last dose administration, for up to 116 weeks Median exposure to study treatment was 562 and 560 days in lixisenatide and exenatide treatment arms, respectively. The analysis was performed on safety population, defined as all randomized patients who were exposed to at least 1 dose of study drug, regardless of the amount of treatment administered.	9.8% 31/316 • First dose of study drug up to 3 days after the last dose administration, for up to 116 weeks Median exposure to study treatment was 562 and 560 days in lixisenatide and exenatide treatment arms, respectively. The analysis was performed on safety population, defined as all randomized patients who were exposed to at least 1 dose of study drug, regardless of the amount of treatment administered.
Vascular disorders Hypertension	6.0% 19/318 • First dose of study drug up to 3 days after the last dose administration, for up to 116 weeks Median exposure to study treatment was 562 and 560 days in lixisenatide and exenatide treatment arms, respectively. The analysis was performed on safety population, defined as all randomized patients who were exposed to at least 1 dose of study drug, regardless of the amount of treatment administered.	3.2% 10/316 • First dose of study drug up to 3 days after the last dose administration, for up to 116 weeks Median exposure to study treatment was 562 and 560 days in lixisenatide and exenatide treatment arms, respectively. The analysis was performed on safety population, defined as all randomized patients who were exposed to at least 1 dose of study drug, regardless of the amount of treatment administered.
Gastrointestinal disorders Abdominal pain upper	5.0% 16/318 • First dose of study drug up to 3 days after the last dose administration, for up to 116 weeks Median exposure to study treatment was 562 and 560 days in lixisenatide and exenatide treatment arms, respectively. The analysis was performed on safety population, defined as all randomized patients who were exposed to at least 1 dose of study drug, regardless of the amount of treatment administered.	4.4% 14/316 • First dose of study drug up to 3 days after the last dose administration, for up to 116 weeks Median exposure to study treatment was 562 and 560 days in lixisenatide and exenatide treatment arms, respectively. The analysis was performed on safety population, defined as all randomized patients who were exposed to at least 1 dose of study drug, regardless of the amount of treatment administered.
Gastrointestinal disorders Constipation	4.4% 14/318 • First dose of study drug up to 3 days after the last dose administration, for up to 116 weeks Median exposure to study treatment was 562 and 560 days in lixisenatide and exenatide treatment arms, respectively. The analysis was performed on safety population, defined as all randomized patients who were exposed to at least 1 dose of study drug, regardless of the amount of treatment administered.	5.4% 17/316 • First dose of study drug up to 3 days after the last dose administration, for up to 116 weeks Median exposure to study treatment was 562 and 560 days in lixisenatide and exenatide treatment arms, respectively. The analysis was performed on safety population, defined as all randomized patients who were exposed to at least 1 dose of study drug, regardless of the amount of treatment administered.
Gastrointestinal disorders Diarrhoea	15.1% 48/318 • First dose of study drug up to 3 days after the last dose administration, for up to 116 weeks Median exposure to study treatment was 562 and 560 days in lixisenatide and exenatide treatment arms, respectively. The analysis was performed on safety population, defined as all randomized patients who were exposed to at least 1 dose of study drug, regardless of the amount of treatment administered.	17.1% 54/316 • First dose of study drug up to 3 days after the last dose administration, for up to 116 weeks Median exposure to study treatment was 562 and 560 days in lixisenatide and exenatide treatment arms, respectively. The analysis was performed on safety population, defined as all randomized patients who were exposed to at least 1 dose of study drug, regardless of the amount of treatment administered.
Gastrointestinal disorders Dyspepsia	6.0% 19/318 • First dose of study drug up to 3 days after the last dose administration, for up to 116 weeks Median exposure to study treatment was 562 and 560 days in lixisenatide and exenatide treatment arms, respectively. The analysis was performed on safety population, defined as all randomized patients who were exposed to at least 1 dose of study drug, regardless of the amount of treatment administered.	6.6% 21/316 • First dose of study drug up to 3 days after the last dose administration, for up to 116 weeks Median exposure to study treatment was 562 and 560 days in lixisenatide and exenatide treatment arms, respectively. The analysis was performed on safety population, defined as all randomized patients who were exposed to at least 1 dose of study drug, regardless of the amount of treatment administered.
Gastrointestinal disorders Nausea	28.6% 91/318 • First dose of study drug up to 3 days after the last dose administration, for up to 116 weeks Median exposure to study treatment was 562 and 560 days in lixisenatide and exenatide treatment arms, respectively. The analysis was performed on safety population, defined as all randomized patients who were exposed to at least 1 dose of study drug, regardless of the amount of treatment administered.	37.7% 119/316 • First dose of study drug up to 3 days after the last dose administration, for up to 116 weeks Median exposure to study treatment was 562 and 560 days in lixisenatide and exenatide treatment arms, respectively. The analysis was performed on safety population, defined as all randomized patients who were exposed to at least 1 dose of study drug, regardless of the amount of treatment administered.
Gastrointestinal disorders Vomiting	12.9% 41/318 • First dose of study drug up to 3 days after the last dose administration, for up to 116 weeks Median exposure to study treatment was 562 and 560 days in lixisenatide and exenatide treatment arms, respectively. The analysis was performed on safety population, defined as all randomized patients who were exposed to at least 1 dose of study drug, regardless of the amount of treatment administered.	15.5% 49/316 • First dose of study drug up to 3 days after the last dose administration, for up to 116 weeks Median exposure to study treatment was 562 and 560 days in lixisenatide and exenatide treatment arms, respectively. The analysis was performed on safety population, defined as all randomized patients who were exposed to at least 1 dose of study drug, regardless of the amount of treatment administered.
Musculoskeletal and connective tissue disorders Arthralgia	6.0% 19/318 • First dose of study drug up to 3 days after the last dose administration, for up to 116 weeks Median exposure to study treatment was 562 and 560 days in lixisenatide and exenatide treatment arms, respectively. The analysis was performed on safety population, defined as all randomized patients who were exposed to at least 1 dose of study drug, regardless of the amount of treatment administered.	4.1% 13/316 • First dose of study drug up to 3 days after the last dose administration, for up to 116 weeks Median exposure to study treatment was 562 and 560 days in lixisenatide and exenatide treatment arms, respectively. The analysis was performed on safety population, defined as all randomized patients who were exposed to at least 1 dose of study drug, regardless of the amount of treatment administered.
Musculoskeletal and connective tissue disorders Back pain	6.0% 19/318 • First dose of study drug up to 3 days after the last dose administration, for up to 116 weeks Median exposure to study treatment was 562 and 560 days in lixisenatide and exenatide treatment arms, respectively. The analysis was performed on safety population, defined as all randomized patients who were exposed to at least 1 dose of study drug, regardless of the amount of treatment administered.	5.1% 16/316 • First dose of study drug up to 3 days after the last dose administration, for up to 116 weeks Median exposure to study treatment was 562 and 560 days in lixisenatide and exenatide treatment arms, respectively. The analysis was performed on safety population, defined as all randomized patients who were exposed to at least 1 dose of study drug, regardless of the amount of treatment administered.
General disorders Fatigue	5.0% 16/318 • First dose of study drug up to 3 days after the last dose administration, for up to 116 weeks Median exposure to study treatment was 562 and 560 days in lixisenatide and exenatide treatment arms, respectively. The analysis was performed on safety population, defined as all randomized patients who were exposed to at least 1 dose of study drug, regardless of the amount of treatment administered.	2.8% 9/316 • First dose of study drug up to 3 days after the last dose administration, for up to 116 weeks Median exposure to study treatment was 562 and 560 days in lixisenatide and exenatide treatment arms, respectively. The analysis was performed on safety population, defined as all randomized patients who were exposed to at least 1 dose of study drug, regardless of the amount of treatment administered.