LIRA-LIXI™: Efficacy and Safety of Liraglutide Versus Lixisenatide as add-on to Metformin in Subjects With Type 2 Diabetes

• Sponsor: Novo Nordisk A/S (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01973231
• Collaborator: (none)
• Enrollment: 404
• Locations: 61
• Arms: 2
• Duration (Months): 13
• Patients Per Site: 6.6
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

This trial is conducted in Europe. The aim of the trial is to investigate the efficacy and safety of liraglutide versus lixisenatide as add-on to metformin in subjects with type 2 diabetes (T2DM).

Condition or Disease	Intervention/Treatment	Phase
Diabetes; Diabetes Mellitus, Type 2	Drug: liraglutide; Drug: lixisenatide	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 404 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Efficacy and Safety of Liraglutide Versus Lixisenatide as add-on to Metformin in Subjects With Type 2 Diabetes
• Study Start Date: Oct 1, 2013
• Actual Primary Completion Date: Nov 1, 2014
• Actual Study Completion Date: Nov 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Metformin + liraglutide 1.8 mg	Drug: liraglutide; Starting dose of 0.6 mg/day, with weekly dose escalations of 0.6 mg/day until the maintenance dose of 1.8 mg/day is reached. Administered s.c. (subcutaneously, under the skin) once daily in addition to the subject's stable pre-trial metformin (equal to or above 1000 mg/day and up to 3000 mg/day).
Active Comparator: Metformin + lixisenatide 20 microg	Drug: lixisenatide; Starting dose of 10 microg to be administered s.c. once daily, within the hour prior to the first meal of the day or the evening meal in addition to subject's stable pre-trial metformin (equal to or above 1000mg/day and up to 3000mg/day). Dose escalation to 20 microg s.c. once daily from day 15 after randomization.

Outcome Measures

Primary Outcome Measures

1. Change in Glycosylated Haemoglobin (HbA1c) From Baseline [Week 0, week 26]

   Change from baseline in HbA1c after 26 weeks of treatment.

Secondary Outcome Measures

1. Change in Fasting Plasma Glucose (FPG) From Baseline [Week 0, week 26]

   Change from baseline in FPG after 26 weeks of treatment.

2. Change in Body Weight From Baseline [Week 0, week 26]

   Change from baseline in body weight after 26 weeks of treatment.

3. Subjects Who Achieve HbA1c Below 7.0% (53 mmol/Mol) (American Diabetes Association (ADA) Target) (Yes/no) [After 26 weeks of treatment]

   Subjects who achieved HbA1c below 7.0% (53 mmol/mol) after 26 weeks of treatment (yes/no).

4. Subjects Who Achieve HbA1c Equal to or Below 6.5% (48 mmol/Mol) (American Association of Clinical Endocrinologists [AACE] Target) (Yes/no) [After 26 weeks of treatment]

   Subjects who achieved HbA1c below equal to or below 6.5% (48 mmol/mol) after 26 weeks of treatment (yes/no).

5. Subjects Who Achieve HbA1c Below 7.0% (53 mmol/Mol) and no Weight Gain (Yes/no) [After 26 weeks of treatment]

   Subjects who achieved HbA1c below 7.0% (53 mmol/mol) and no weight gain after 26 weeks of treatment (yes/no).

6. Number of Treatment Emergent Adverse Events (TEAEs) [Weeks 0-26]

   A Treatment Emergent Adverse Event (TEAE) was defined as an event that had onset date on or after the first day of exposure to randomised treatment and no later than 7 days after the last day of randomised treatment. Severity was assessed by investigator.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Informed consent obtained before any trial-related activities. Trial-related activities are any procedures that are carried out as part of the trial, including activities to determine suitability for the trial

• Subjects diagnosed with T2DM and on unchanged metformin treatment at the maximum tolerated dose (at least 1000 mg/day and up to 3000 mg/day) for at least 90 days prior to screening

• HbA1c 7.5 - 10.5% (53 mmol/mol - 91 mmol/mol) (both inclusive)

• Body Mass Index (BMI) equal to or above 20 kg/m^2

Exclusion Criteria:

• Female of child-bearing potential who is pregnant, breast-feeding or intend to become pregnant or is not using adequate contraceptive methods. (Adequate contraceptive measures as required by local law or practice)

• Treatment with glucose lowering agent(s) other than stated in the inclusion criteria in a period of 90 days prior to screening. Exception is short-term treatment (equal to or below 7 days in total) with insulin in connection with intercurrent illness

• History of chronic pancreatitis or idiopathic acute pancreatitis

• Screening calcitonin value equal to or above 50 ng/L

• Personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome type 2 (MEN 2)

• Impaired liver function, defined as alanine aminotransferase (ALAT) equal to or above 2.5 times upper normal limit (UNL)

• Impaired renal function defined as estimated glomerular filtration rate (eGFR) below 60 mL/min/1.73 m^2 per Modification of Diet in Renal Disease (MDRD) formula

• Any episode of unstable angina, acute coronary event, cerebral stroke/transient ischemic attack (TIA) or other significant cardiovascular event as judged by the investigator within 90 days prior to screening

• Heart failure, New York Heart Association (NYHA) class IV

• Uncontrolled hypertension (defined as systolic blood pressure equal to or above 180 mmHg and/or diastolic blood pressure equal to or above 100 mmHg)

• Diagnosis of malignant neoplasm in the previous 5 years (except basal cell skin cancer or squamous cell skin cancer)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novo Nordisk Investigational Site	Hradec Kralove		Czech Republic	50005
2	Novo Nordisk Investigational Site	Mlada Boleslav		Czech Republic	293 50
3	Novo Nordisk Investigational Site	Olomouc		Czech Republic	77900
4	Novo Nordisk Investigational Site	Plzen		Czech Republic	32600
5	Novo Nordisk Investigational Site	Prostejov		Czech Republic	79601
6	Novo Nordisk Investigational Site	Helsinki		Finland	00260
7	Novo Nordisk Investigational Site	Jyväskylä		Finland	40100
8	Novo Nordisk Investigational Site	Oulu		Finland	FI-90220
9	Novo Nordisk Investigational Site	Pori		Finland	FI-28120
10	Novo Nordisk Investigational Site	Rovaniemi		Finland	96400
11	Novo Nordisk Investigational Site	Boulogne Billancourt		France	92100
12	Novo Nordisk Investigational Site	Corbeil Essonnes		France	91106
13	Novo Nordisk Investigational Site	Hinx		France	40180
14	Novo Nordisk Investigational Site	LA ROCHELLE cedex		France	17019
15	Novo Nordisk Investigational Site	Saint Herblain		France	44800
16	Novo Nordisk Investigational Site	Strasbourg		France	67000
17	Novo Nordisk Investigational Site	Venissieux		France	69200
18	Novo Nordisk Investigational Site	Bad Lauterberg		Germany	37431
19	Novo Nordisk Investigational Site	Berlin		Germany	13055
20	Novo Nordisk Investigational Site	Bochum		Germany	44869
21	Novo Nordisk Investigational Site	Dresden		Germany	01219
22	Novo Nordisk Investigational Site	Duisburg		Germany	47051
23	Novo Nordisk Investigational Site	Friedrichsthal		Germany	66299
24	Novo Nordisk Investigational Site	Lampertheim		Germany	68623
25	Novo Nordisk Investigational Site	Ludwigshafen		Germany	67059
26	Novo Nordisk Investigational Site	St. Ingbert		Germany	66386
27	Novo Nordisk Investigational Site	Baja		Hungary	6500
28	Novo Nordisk Investigational Site	Budapest		Hungary	1042
29	Novo Nordisk Investigational Site	Budapest		Hungary	1089
30	Novo Nordisk Investigational Site	Budapest		Hungary	1125
31	Novo Nordisk Investigational Site	Gyula		Hungary	5700
32	Novo Nordisk Investigational Site	Pécs		Hungary	7623
33	Novo Nordisk Investigational Site	Salgótarján		Hungary	3100
34	Novo Nordisk Investigational Site	Szeged		Hungary	H-6720
35	Novo Nordisk Investigational Site	Catania		Italy	95122
36	Novo Nordisk Investigational Site	Cittadella (PD)		Italy	35013
37	Novo Nordisk Investigational Site	Padova		Italy	35143
38	Novo Nordisk Investigational Site	Palermo		Italy	90129
39	Novo Nordisk Investigational Site	Terni		Italy	05100
40	Novo Nordisk Investigational Site	Ogre		Latvia	LV-5001
41	Novo Nordisk Investigational Site	Riga		Latvia	LV-1002
42	Novo Nordisk Investigational Site	Riga		Latvia	LV-1012
43	Novo Nordisk Investigational Site	Riga		Latvia	LV-1024
44	Novo Nordisk Investigational Site	Riga		Latvia	LV-1038
45	Novo Nordisk Investigational Site	Kaunas		Lithuania	48259
46	Novo Nordisk Investigational Site	Kaunas		Lithuania	50009
47	Novo Nordisk Investigational Site	Klaipeda		Lithuania	94198
48	Novo Nordisk Investigational Site	Siauliai		Lithuania	76231
49	Novo Nordisk Investigational Site	Vilnius		Lithuania	08661
50	Novo Nordisk Investigational Site	Basingstoke		United Kingdom	RG24 9GT
51	Novo Nordisk Investigational Site	Bristol		United Kingdom	BS10 5NB
52	Novo Nordisk Investigational Site	Chester		United Kingdom	CH2 1UL
53	Novo Nordisk Investigational Site	Chiswick		United Kingdom	W4 3JL
54	Novo Nordisk Investigational Site	Coventry		United Kingdom	CV2 2DX
55	Novo Nordisk Investigational Site	Derby		United Kingdom	DE22 3NE
56	Novo Nordisk Investigational Site	Devon		United Kingdom	EX2 5DW
57	Novo Nordisk Investigational Site	Great Yarmouth		United Kingdom	NR31 6LA
58	Novo Nordisk Investigational Site	Lancaster		United Kingdom	LA1 1RP
59	Novo Nordisk Investigational Site	Plymouth		United Kingdom	PL6 8BQ
60	Novo Nordisk Investigational Site	Sandbach		United Kingdom	CW11 1EQ
61	Novo Nordisk Investigational Site	Taunton		United Kingdom	TA1 5DA

Sponsors and Collaborators

• Novo Nordisk A/S

Investigators

• Study Director: Global Clinical Registry (GCR, 1452), Novo Nordisk A/S

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Clinical Trials at Novo Nordisk

Publications

None provided.

• Responsible Party: Novo Nordisk A/S
• ClinicalTrials.gov Identifier: NCT01973231
• Other Study ID Numbers: NN2211-3867; 2012-004984-27; U1111-1136-3644
• First Posted: Oct 31, 2013
• Last Update Posted: Feb 9, 2017
• Last Verified: Dec 1, 2016

• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2; Liraglutide; Lixisenatide

Study Results

Participant Flow

Recruitment Details	The trial was conducted at 56 sites in 9 countries; Czech Republic (5), Finland (4), France (6), Germany (8), Hungary (6), Italy (5), Latvia (6), Lithuania (5) and UK (11).

Arm/Group Title	Liraglutide	Lixisenatide
Arm/Group Description	Liraglutide was administered subcutaneously (s.c.; under the skin) once daily in addition to the subject's stable pre-trial metformin (maximum tolerated dose, equal to or above 1000 mg/day and up to 3000 mg/day) for a total duration of 26 weeks. Starting dose of liraglutide was 0.6 mg/day, with weekly dose escalations of 0.6 mg/day until the maintenance dose of 1.8 mg/day was reached.	Lixisenatide was administered s.c. once daily, within the hour prior to the first meal of the day or the evening meal in addition to subject's stable pre-trial metformin (maximum tolerated dose, equal to or above 1000mg/day and up to 3000mg/day) for a total duration of 26 weeks. Starting dose of lixisenatide was 10 µg once daily, the dose was escalated to 20 µg once daily from day 15 after randomisation.
Period Title: Overall Study
STARTED	202	202
COMPLETED	191	190
NOT COMPLETED	11	12

Baseline Characteristics

Arm/Group Title	Liraglutide	Lixisenatide	Total
Arm/Group Description	Liraglutide was administered subcutaneously (s.c.; under the skin) once daily in addition to the subject's stable pre-trial metformin (maximum tolerated dose, equal to or above 1000 mg/day and up to 3000 mg/day) for a total duration of 26 weeks. Starting dose of liraglutide was 0.6 mg/day, with weekly dose escalations of 0.6 mg/day until the maintenance dose of 1.8 mg/day was reached.	Lixisenatide was administered s.c. once daily, within the hour prior to the first meal of the day or the evening meal in addition to subject's stable pre-trial metformin (maximum tolerated dose, equal to or above 1000mg/day and up to 3000mg/day) for a total duration of 26 weeks. Starting dose of lixisenatide was 10 µg once daily, the dose was escalated to 20 µg once daily from day 15 after randomisation.	Total of all reporting groups
Overall Participants	202	202	404
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	56.3 (10.6)	56.1 (10.0)	56.2 (10.3)
Gender (Count of Participants)
Female	70 34.7%	90 44.6%	160 39.6%
Male	132 65.3%	112 55.4%	244 60.4%
Glycosylated Haemoglobin (HbA1c) (Percent (%) glycosylated haemoglobin) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Percent (%) glycosylated haemoglobin]	8.40 (0.723)	8.43 (0.785)	8.41 (0.754)
Fasting plasma glucose (FPG) (mmol/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmol/L]	10.47 (2.368)	10.25 (2.254)	10.36 (2.312)
Body Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	101.89 (23.344)	100.58 (19.949)	101.24 (21.696)

Outcome Measures

1. Primary Outcome

Title	Change in Glycosylated Haemoglobin (HbA1c) From Baseline
Description	Change from baseline in HbA1c after 26 weeks of treatment.
Time Frame	Week 0, week 26

Outcome Measure Data

Analysis Population Description

The full analysis set (FAS) included all randomised subjects. Missing values were imputed using predicted values from the mixed model for repeated measurements (MMRM) model. Due to missing HbA1c post baseline data, 194 and 191 subjects in liraglutide and lixisenatide treatment group, respectively were included in the HbA1c analysis.

Arm/Group Title	Liraglutide	Lixisenatide
Arm/Group Description	Liraglutide was administered subcutaneously (s.c.; under the skin) once daily in addition to the subject's stable pre-trial metformin (maximum tolerated dose, equal to or above 1000 mg/day and up to 3000 mg/day) for a total duration of 26 weeks. Starting dose of liraglutide was 0.6 mg/day, with weekly dose escalations of 0.6 mg/day until the maintenance dose of 1.8 mg/day was reached.	Lixisenatide was administered s.c. once daily, within the hour prior to the first meal of the day or the evening meal in addition to subject's stable pre-trial metformin (maximum tolerated dose, equal to or above 1000mg/day and up to 3000mg/day) for a total duration of 26 weeks. Starting dose of lixisenatide was 10 µg once daily, the dose was escalated to 20 µg once daily from day 15 after randomisation.
Measure Participants	194	191
Mean (Standard Deviation) [Percent (%) glycosylated haemoglobin]	-1.809 (0.9159)	-1.238 (1.0085)

2. Secondary Outcome

Title	Change in Fasting Plasma Glucose (FPG) From Baseline
Description	Change from baseline in FPG after 26 weeks of treatment.
Time Frame	Week 0, week 26

Outcome Measure Data

Analysis Population Description

The FAS included all randomised subjects. Missing values were imputed using predicted values from the MMRM model. Due to missing FPG post baseline data, 194 and 189 subjects in liraglutide and lixisenatide treatment group, respectively were included in the FPG analysis.

Arm/Group Title	Liraglutide	Lixisenatide
Arm/Group Description	Liraglutide was administered subcutaneously (s.c.; under the skin) once daily in addition to the subject's stable pre-trial metformin (maximum tolerated dose, equal to or above 1000 mg/day and up to 3000 mg/day) for a total duration of 26 weeks. Starting dose of liraglutide was 0.6 mg/day, with weekly dose escalations of 0.6 mg/day until the maintenance dose of 1.8 mg/day was reached.	Lixisenatide was administered s.c. once daily, within the hour prior to the first meal of the day or the evening meal in addition to subject's stable pre-trial metformin (maximum tolerated dose, equal to or above 1000mg/day and up to 3000mg/day) for a total duration of 26 weeks. Starting dose of lixisenatide was 10 µg once daily, the dose was escalated to 20 µg once daily from day 15 after randomisation.
Measure Participants	194	189
Mean (Standard Deviation) [mmol/L]	-2.904 (2.2309)	-1.644 (2.1511)

3. Secondary Outcome

Title	Change in Body Weight From Baseline
Description	Change from baseline in body weight after 26 weeks of treatment.
Time Frame	Week 0, week 26

Outcome Measure Data

Analysis Population Description

The FAS included all randomised subjects. Missing values were imputed using predicted values from the MMRM model. Due to missing body weight post baseline data, 194 and 191 subjects in liraglutide and lixisenatide treatment group, respectively were included in the body weight analysis.

Arm/Group Title	Liraglutide	Lixisenatide
Arm/Group Description	Liraglutide was administered subcutaneously (s.c.; under the skin) once daily in addition to the subject's stable pre-trial metformin (maximum tolerated dose, equal to or above 1000 mg/day and up to 3000 mg/day) for a total duration of 26 weeks. Starting dose of liraglutide was 0.6 mg/day, with weekly dose escalations of 0.6 mg/day until the maintenance dose of 1.8 mg/day was reached.	Lixisenatide was administered s.c. once daily, within the hour prior to the first meal of the day or the evening meal in addition to subject's stable pre-trial metformin (maximum tolerated dose, equal to or above 1000mg/day and up to 3000mg/day) for a total duration of 26 weeks. Starting dose of lixisenatide was 10 µg once daily, the dose was escalated to 20 µg once daily from day 15 after randomisation.
Measure Participants	194	191
Mean (Standard Deviation) [kg]	-4.24 (4.273)	-3.69 (4.746)

4. Secondary Outcome

Title	Subjects Who Achieve HbA1c Below 7.0% (53 mmol/Mol) (American Diabetes Association (ADA) Target) (Yes/no)
Description	Subjects who achieved HbA1c below 7.0% (53 mmol/mol) after 26 weeks of treatment (yes/no).
Time Frame	After 26 weeks of treatment

Outcome Measure Data

Analysis Population Description

The FAS included all randomised subjects. Missing values were imputed using predicted values from the MMRM model. Due to missing HbA1c post baseline data, 194 and 191 subjects in liraglutide and lixisenatide treatment group, respectively were included in the HbA1c analysis.

Arm/Group Title	Liraglutide	Lixisenatide
Arm/Group Description	Liraglutide was administered subcutaneously (s.c.; under the skin) once daily in addition to the subject's stable pre-trial metformin (maximum tolerated dose, equal to or above 1000 mg/day and up to 3000 mg/day) for a total duration of 26 weeks. Starting dose of liraglutide was 0.6 mg/day, with weekly dose escalations of 0.6 mg/day until the maintenance dose of 1.8 mg/day was reached.	Lixisenatide was administered s.c. once daily, within the hour prior to the first meal of the day or the evening meal in addition to subject's stable pre-trial metformin (maximum tolerated dose, equal to or above 1000mg/day and up to 3000mg/day) for a total duration of 26 weeks. Starting dose of lixisenatide was 10 µg once daily, the dose was escalated to 20 µg once daily from day 15 after randomisation.
Measure Participants	194	191
Yes	74.2	45.5
No	25.8	54.5

5. Secondary Outcome

Title	Subjects Who Achieve HbA1c Equal to or Below 6.5% (48 mmol/Mol) (American Association of Clinical Endocrinologists [AACE] Target) (Yes/no)
Description	Subjects who achieved HbA1c below equal to or below 6.5% (48 mmol/mol) after 26 weeks of treatment (yes/no).
Time Frame	After 26 weeks of treatment

Outcome Measure Data

Analysis Population Description

The FAS included all randomised subjects. Missing values were imputed using predicted values from the MMRM model. Due to missing HbA1c post baseline data, 194 and 191 subjects in liraglutide and lixisenatide treatment group, respectively were included in the HbA1c analysis.

Arm/Group Title	Liraglutide	Lixisenatide
Arm/Group Description	Liraglutide was administered subcutaneously (s.c.; under the skin) once daily in addition to the subject's stable pre-trial metformin (maximum tolerated dose, equal to or above 1000 mg/day and up to 3000 mg/day) for a total duration of 26 weeks. Starting dose of liraglutide was 0.6 mg/day, with weekly dose escalations of 0.6 mg/day until the maintenance dose of 1.8 mg/day was reached.	Lixisenatide was administered s.c. once daily, within the hour prior to the first meal of the day or the evening meal in addition to subject's stable pre-trial metformin (maximum tolerated dose, equal to or above 1000mg/day and up to 3000mg/day) for a total duration of 26 weeks. Starting dose of lixisenatide was 10 µg once daily, the dose was escalated to 20 µg once daily from day 15 after randomisation.
Measure Participants	194	191
Yes	54.6	26.2
No	45.4	73.8

6. Secondary Outcome

Title	Subjects Who Achieve HbA1c Below 7.0% (53 mmol/Mol) and no Weight Gain (Yes/no)
Description	Subjects who achieved HbA1c below 7.0% (53 mmol/mol) and no weight gain after 26 weeks of treatment (yes/no).
Time Frame	After 26 weeks of treatment

Outcome Measure Data

Analysis Population Description

The FAS included all randomised subjects. Missing values were imputed using predicted values from the MMRM model. Due to missing HbA1c post-baseline data, 194 and 191 subjects in liraglutide and lixisenatide treatment group, respectively were included in the HbA1c analysis.

Arm/Group Title	Liraglutide	Lixisenatide
Arm/Group Description	Liraglutide was administered subcutaneously (s.c.; under the skin) once daily in addition to the subject's stable pre-trial metformin (maximum tolerated dose, equal to or above 1000 mg/day and up to 3000 mg/day) for a total duration of 26 weeks. Starting dose of liraglutide was 0.6 mg/day, with weekly dose escalations of 0.6 mg/day until the maintenance dose of 1.8 mg/day was reached.	Lixisenatide was administered s.c. once daily, within the hour prior to the first meal of the day or the evening meal in addition to subject's stable pre-trial metformin (maximum tolerated dose, equal to or above 1000mg/day and up to 3000mg/day) for a total duration of 26 weeks. Starting dose of lixisenatide was 10 µg once daily, the dose was escalated to 20 µg once daily from day 15 after randomisation.
Measure Participants	194	191
Yes	66.5	41.9
No	33.5	58.1

7. Secondary Outcome

Title	Number of Treatment Emergent Adverse Events (TEAEs)
Description	A Treatment Emergent Adverse Event (TEAE) was defined as an event that had onset date on or after the first day of exposure to randomised treatment and no later than 7 days after the last day of randomised treatment. Severity was assessed by investigator.
Time Frame	Weeks 0-26

Outcome Measure Data

Analysis Population Description

The safety analysis set (SAS) included all subjects who received at least one dose of any of the trial products.

Arm/Group Title	Liraglutide	Lixisenatide
Arm/Group Description	Liraglutide was administered subcutaneously (s.c.; under the skin) once daily in addition to the subject's stable pre-trial metformin (maximum tolerated dose, equal to or above 1000 mg/day and up to 3000 mg/day) for a total duration of 26 weeks. Starting dose of liraglutide was 0.6 mg/day, with weekly dose escalations of 0.6 mg/day until the maintenance dose of 1.8 mg/day was reached.	Lixisenatide was administered s.c. once daily, within the hour prior to the first meal of the day or the evening meal in addition to subject's stable pre-trial metformin (maximum tolerated dose, equal to or above 1000mg/day and up to 3000mg/day) for a total duration of 26 weeks. Starting dose of lixisenatide was 10 µg once daily, the dose was escalated to 20 µg once daily from day 15 after randomisation.
Measure Participants	202	202
Events	540	435
Serious	13	7
Severe	10	3
Moderate	109	84
Mild	421	348

Adverse Events

Time Frame	Weeks 0-26
Adverse Event Reporting Description	The SAS included all subjects who received at least one dose of any of the trial products.
Arm/Group Title	Liraglutide		Lixisenatide
Arm/Group Description	Liraglutide was administered subcutaneously (s.c.; under the skin) once daily in addition to the subject's stable pre-trial metformin (maximum tolerated dose, equal to or above 1000 mg/day and up to 3000 mg/day) for a total duration of 26 weeks. Starting dose of liraglutide was 0.6 mg/day, with weekly dose escalations of 0.6 mg/day until the maintenance dose of 1.8 mg/day was reached.		Lixisenatide was administered s.c. once daily, within the hour prior to the first meal of the day or the evening meal in addition to subject's stable pre-trial metformin (maximum tolerated dose, equal to or above 1000mg/day and up to 3000mg/day) for a total duration of 26 weeks. Starting dose of lixisenatide was 10 µg once daily, the dose was escalated to 20 µg once daily from day 15 after randomisation.
All Cause Mortality
	Liraglutide		Lixisenatide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Liraglutide		Lixisenatide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/202 (5.9%)		7/202 (3.5%)
Cardiac disorders
Atrial fibrillation	0/202 (0%)	0	1/202 (0.5%)	1
Cardiac failure	0/202 (0%)	0	1/202 (0.5%)	1
Coronary artery disease	0/202 (0%)	0	1/202 (0.5%)	1
Myocardial ischaemia	1/202 (0.5%)	1	0/202 (0%)	0
Gastrointestinal disorders
Abdominal hernia	1/202 (0.5%)	1	0/202 (0%)	0
Gastric ulcer haemorrhage	1/202 (0.5%)	1	0/202 (0%)	0
Oesophageal ulcer haemorrhage	1/202 (0.5%)	1	0/202 (0%)	0
General disorders
Pyrexia	1/202 (0.5%)	1	0/202 (0%)	0
Hepatobiliary disorders
Cholecystitis acute	1/202 (0.5%)	1	0/202 (0%)	0
Infections and infestations
Diabetic foot infection	1/202 (0.5%)	1	0/202 (0%)	0
Influenza	1/202 (0.5%)	1	0/202 (0%)	0
Lobar pneumonia	0/202 (0%)	0	1/202 (0.5%)	1
Injury, poisoning and procedural complications
Thermal burn	0/202 (0%)	0	1/202 (0.5%)	1
Musculoskeletal and connective tissue disorders
Rotator cuff syndrome	1/202 (0.5%)	1	0/202 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia	1/202 (0.5%)	1	0/202 (0%)	0
Nervous system disorders
Ischaemic stroke	1/202 (0.5%)	1	0/202 (0%)	0
Syncope	1/202 (0.5%)	1	0/202 (0%)	0
Psychiatric disorders
Anxiety disorder	0/202 (0%)	0	1/202 (0.5%)	1
Reproductive system and breast disorders
Prostatic dysplasia	0/202 (0%)	0	1/202 (0.5%)	1
Skin and subcutaneous tissue disorders
Skin ulcer	1/202 (0.5%)	1	0/202 (0%)	0
Other (Not Including Serious) Adverse Events
	Liraglutide		Lixisenatide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	90/202 (44.6%)		83/202 (41.1%)
Gastrointestinal disorders
Diarrhoea	25/202 (12.4%)	39	20/202 (9.9%)	22
Dyspepsia	11/202 (5.4%)	11	6/202 (3%)	9
Nausea	44/202 (21.8%)	67	44/202 (21.8%)	60
Vomiting	14/202 (6.9%)	18	18/202 (8.9%)	22
Infections and infestations
Nasopharyngitis	13/202 (6.4%)	13	20/202 (9.9%)	22
Investigations
Lipase increased	17/202 (8.4%)	17	5/202 (2.5%)	5
Metabolism and nutrition disorders
Decreased appetite	13/202 (6.4%)	13	5/202 (2.5%)	5
Nervous system disorders
Headache	15/202 (7.4%)	31	17/202 (8.4%)	35

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Novo Nordisk maintains the right to be informed of plans by any investigator to publish and to review any scientific paper, presentation, communication or other information concerning the investigation described in this protocol. Any such communication must be submitted in writing to the Novo Nordisk trial manager before submission for comments. Comments will be given within four weeks from receipt of the planned communication.