LIRA-SWITCH™: Efficacy and Safety of Switching From Sitagliptin to Liraglutide in Subjects With Type 2 Diabetes Not Achieving Adequate Glycaemic Control on Sitagliptin and Metformin

• Sponsor: Novo Nordisk A/S (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01907854
• Collaborator: (none)
• Enrollment: 407
• Locations: 106
• Arms: 2
• Actual Duration (Months): 18.4
• Patients Per Site: 3.8
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This trial is conducted in Asia, Europe and North America. The aim of the trial is to investigate the efficacy and safety of switching from sitagliptin to liraglutide in subjects with type 2 diabetes not achieving adequate glycaemic control on sitagliptin and metformin.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 407 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Efficacy and Safety of Switching From Sitagliptin to Liraglutide in Subjects With Type 2 Diabetes Not Achieving Adequate Glycaemic Control on Sitagliptin and Metformin
• Actual Study Start Date: Dec 2, 2013
• Actual Primary Completion Date: Jun 15, 2015
• Actual Study Completion Date: Jun 15, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Liraglutide + metformin + sitagliptin placebo	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 subcutaneously (s.c., under the skin) once daily + metformin tablets (at least 1000 mg/day); Drug: placebo; Sitagliptin placebo tablets once-daily
Experimental: Sitagliptin + metformin + liraglutide placebo	Drug: sitagliptin; 100 mg/day sitagliptin tablets once-daily + metformin (at least 1000 mg/day); Drug: placebo; Sitagliptin placebo tablets once-daily

Outcome Measures

Primary Outcome Measures

1. Change in HbA1c (Glycosylated Haemoglobin) [From baseline to week 26]

   Change from baseline in HbA1c was analysed after 26 weeks of treatment. Analysis population set: full analysis set (FAS); all randomised subjects receiving at least one dose of any of the trial products. Missing values were imputed using mixed model for repeated measurements (MMRM).

Secondary Outcome Measures

1. Change in Body Weight [From baseline to week 26]

   Change from baseline in body weight was analysed after 26 weeks of treatment. Analysis population set: FAS: all randomised subjects receiving at least one dose of any of the trial products. Missing values were imputed using MMRM.

2. Change in Fasting Plasma Glucose [From baseline to week 26]

   Change from baseline in fasting plasma glucose was analysed after 26 weeks of treatment. Missing values were imputed using MMRM.

3. Change in Fasting Blood Lipids [From baseline to week 26]

   Ratio to baseline in fasting blood lipids (total cholesterol, low density lipoprotein [LDL], very low density lipoprotein [VLDL], high density lipoprotein [HDL], triglycerides, and free fatty acids) were analysed after 26 weeks treatment. Missing values were imputed using MMRM. Here we are presenting ratio to baseline data.

4. Change in Systolic Blood Pressure and Diastolic Blood Pressure [From baseline to week 26]

   Change from baseline in systolic and diastolic blood pressure were analysed after 26 weeks of treatment. Missing values were imputed using MMRM.

5. Subjects Who Achieve HbA1c Below 7.0% (53 mmol/Mol) (American Diabetes Association Target) (y/n) [After 26 weeks of treatment]

   Number of subjects who achieve HbA1c <7.0% were analysed after 26 weeks of treatment. Missing values were imputed using MMRM.

6. Number of Treatment Emergent Adverse Events (TEAEs) [During 26 weeks of treatment plus one week follow-up period.]

   A treatment emergent adverse event (TEAE) was defined as an event that had an onset date (or increase in severity) on or after the first day of exposure to randomised treatment and no later than seven days after the last day of randomised treatment. The number of TEAEs was recorded during 26 weeks of treatment plus one week follow-up period.

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 type 2 diabetes and treated with metformin equal to or above 1500 mg/day (or maximum tolerated dose equal to or above 1000 mg/day) and sitagliptin 100 mg/day, both at a stable dose for at least 90 days prior to screening. Stable is defined as unchanged medication and dose
• • HbA1c 7.5% - 9.5% (58 mmol/mol - 80 mmol/mol) (both inclusive)
• • Body mass index equal to or above 20 kg/m^2

Exclusion Criteria:

• • Any chronic disorder or severe disease which at the discretion of the investigator might jeopardise subject's safety or compliance with the protocol
• • Treatment with glucose lowering agent(s) other than stated in the inclusion criteria in a period of 90 days prior to screening. An exception is short-term treatment (equal to or less than 7 days in total) with insulin in connection with intercurrent illness
• • Female who is pregnant, breast-feeding, intends to become pregnant or of child-bearing potential not using adequate contraceptive methods (adequate contraceptive measures as required by local regulations or practice)
• • 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 or multiple endocrine neoplasia syndrome type 2
• • Diagnosis of malignant neoplasm in the previous 5 years (except basal cell skin cancer or squamous cell skin cancer)
• • Impaired liver function, defined as alanine aminotransferase equal to or above 2.5 times upper normal limit
• • Impaired renal function defined as estimated glomerular filtration rate 60 mL/min/1.73 m^2 per modification of diet in renal disease formula
• • Any episode of unstable angina, acute coronary event, cerebral stroke/transient ischemic attack or other significant cardiovascular event as judged by the investigator within 90 days prior to screening
• • Heart failure, New York Heart Association class IV
• • Uncontrolled treated or untreated hypertension (systolic blood pressure equal to or above 180 mmHg and/or diastolic blood pressure equal to or above 100 mmHg)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novo Nordisk Investigational Site	Phoenix	Arizona	United States	85018
2	Novo Nordisk Investigational Site	Phoenix	Arizona	United States	85027
3	Novo Nordisk Investigational Site	Tucson	Arizona	United States	85704
4	Novo Nordisk Investigational Site	Tucson	Arizona	United States	85724
5	Novo Nordisk Investigational Site	Escondido	California	United States	92025
6	Novo Nordisk Investigational Site	Mission Viejo	California	United States	92691
7	Novo Nordisk Investigational Site	Roseville	California	United States	95661
8	Novo Nordisk Investigational Site	Colorado Springs	Colorado	United States	80909
9	Novo Nordisk Investigational Site	Colorado Springs	Colorado	United States	80922
10	Novo Nordisk Investigational Site	Chiefland	Florida	United States	32626
11	Novo Nordisk Investigational Site	Fort Lauderdale	Florida	United States	33308
12	Novo Nordisk Investigational Site	Hialeah	Florida	United States	33012
13	Novo Nordisk Investigational Site	Jacksonville	Florida	United States	32207
14	Novo Nordisk Investigational Site	Jacksonville	Florida	United States	32216
15	Novo Nordisk Investigational Site	Jacksonville	Florida	United States	32258
16	Novo Nordisk Investigational Site	Miami	Florida	United States	33183
17	Novo Nordisk Investigational Site	North Miami	Florida	United States	33181
18	Novo Nordisk Investigational Site	Port Charlotte	Florida	United States	33952
19	Novo Nordisk Investigational Site	Johns Creek	Georgia	United States	30097
20	Novo Nordisk Investigational Site	Honolulu	Hawaii	United States	96814
21	Novo Nordisk Investigational Site	Blackfoot	Idaho	United States	83221
22	Novo Nordisk Investigational Site	Arlington Heights	Illinois	United States	60005-4144
23	Novo Nordisk Investigational Site	Chicago	Illinois	United States	60604
24	Novo Nordisk Investigational Site	Peoria	Illinois	United States	61602
25	Novo Nordisk Investigational Site	Skokie	Illinois	United States	60077
26	Novo Nordisk Investigational Site	Avon	Indiana	United States	46123
27	Novo Nordisk Investigational Site	Evansville	Indiana	United States	47714
28	Novo Nordisk Investigational Site	Evansville	Indiana	United States	47725
29	Novo Nordisk Investigational Site	Council Bluffs	Iowa	United States	51501
30	Novo Nordisk Investigational Site	Bangor	Maine	United States	04401
31	Novo Nordisk Investigational Site	Fall River	Massachusetts	United States	02720
32	Novo Nordisk Investigational Site	Troy	Michigan	United States	48085-5524
33	Novo Nordisk Investigational Site	Saint Peters	Missouri	United States	63376
34	Novo Nordisk Investigational Site	Las Vegas	Nevada	United States	89119
35	Novo Nordisk Investigational Site	Nashua	New Hampshire	United States	03063
36	Novo Nordisk Investigational Site	Berlin	New Jersey	United States	08009
37	Novo Nordisk Investigational Site	Elizabeth	New Jersey	United States	07202
38	Novo Nordisk Investigational Site	Albany	New York	United States	12206
39	Novo Nordisk Investigational Site	Charlotte	North Carolina	United States	28210
40	Novo Nordisk Investigational Site	Salisbury	North Carolina	United States	28144
41	Novo Nordisk Investigational Site	Akron	Ohio	United States	44311
42	Novo Nordisk Investigational Site	Reading	Pennsylvania	United States	19606
43	Novo Nordisk Investigational Site	Moncks Corner	South Carolina	United States	29461
44	Novo Nordisk Investigational Site	Orangeburg	South Carolina	United States	29118
45	Novo Nordisk Investigational Site	Memphis	Tennessee	United States	38119
46	Novo Nordisk Investigational Site	Edinburg	Texas	United States	78539
47	Novo Nordisk Investigational Site	Fort Worth	Texas	United States	76104
48	Novo Nordisk Investigational Site	Houston	Texas	United States	77024
49	Novo Nordisk Investigational Site	Houston	Texas	United States	77030
50	Novo Nordisk Investigational Site	Houston	Texas	United States	77036
51	Novo Nordisk Investigational Site	Houston	Texas	United States	77079
52	Novo Nordisk Investigational Site	Midland	Texas	United States	79707
53	Novo Nordisk Investigational Site	New Braunfels	Texas	United States	78130
54	Novo Nordisk Investigational Site	North Richland Hills	Texas	United States	76180
55	Novo Nordisk Investigational Site	San Antonio	Texas	United States	78245
56	Novo Nordisk Investigational Site	Sugar Land	Texas	United States	77478
57	Novo Nordisk Investigational Site	Virginia Beach	Virginia	United States	23454
58	Novo Nordisk Investigational Site	Spokane	Washington	United States	99202-3649
59	Novo Nordisk Investigational Site	Surrey	British Columbia	Canada	V3S 2N6
60	Novo Nordisk Investigational Site	Brampton	Ontario	Canada	L6S 0C6
61	Novo Nordisk Investigational Site	Burlington	Ontario	Canada	L7M 4Y1
62	Novo Nordisk Investigational Site	Concord	Ontario	Canada	L4K 4M2
63	Novo Nordisk Investigational Site	Etobicoke	Ontario	Canada	M9R 4E1
64	Novo Nordisk Investigational Site	Grimsby	Ontario	Canada	L3M 1P3
65	Novo Nordisk Investigational Site	Ottawa	Ontario	Canada	K1K 4L2
66	Novo Nordisk Investigational Site	Sarnia	Ontario	Canada	N7T 4X3
67	Novo Nordisk Investigational Site	Strathroy	Ontario	Canada	N7G 1Y7
68	Novo Nordisk Investigational Site	Toronto	Ontario	Canada	M3J 1N2
69	Novo Nordisk Investigational Site	Toronto	Ontario	Canada	M4G 3E8
70	Novo Nordisk Investigational Site	Toronto	Ontario	Canada	M9V 4B4
71	Novo Nordisk Investigational Site	Drummondville	Quebec	Canada	J2B 7T1
72	Novo Nordisk Investigational Site	Montreal	Quebec	Canada	H4A 3T2
73	Novo Nordisk Investigational Site	St. Romuald	Quebec	Canada	G6W 5M6
74	Novo Nordisk Investigational Site	Trois Rivières	Quebec	Canada	G8T 7A1
75	Novo Nordisk Investigational Site	Quebec		Canada	G3K 2P8
76	Novo Nordisk Investigational Site	Budapest		Hungary	1042
77	Novo Nordisk Investigational Site	Debrecen		Hungary	4043
78	Novo Nordisk Investigational Site	Eger		Hungary	3300
79	Novo Nordisk Investigational Site	Gyula		Hungary	H-5700
80	Novo Nordisk Investigational Site	Salgótarján		Hungary	3100
81	Novo Nordisk Investigational Site	Sopron		Hungary	9400
82	Novo Nordisk Investigational Site	Szeged		Hungary	H-6720
83	Novo Nordisk Investigational Site	Tatabánya		Hungary	2800
84	Novo Nordisk Investigational Site	Hyderabad	Andhra Pradesh	India	500082
85	Novo Nordisk Investigational Site	Visakhapatnam	Andhra Pradesh	India	530002
86	Novo Nordisk Investigational Site	Ahmedabad	Gujarat	India	380008
87	Novo Nordisk Investigational Site	Gandhinagar	Gujarat	India	382428
88	Novo Nordisk Investigational Site	Bangalore	Karnataka	India	560002
89	Novo Nordisk Investigational Site	Mumbai	Maharashtra	India	400007
90	Novo Nordisk Investigational Site	Pune	Maharashtra	India	411040
91	Novo Nordisk Investigational Site	New Delhi		India	110060
92	Novo Nordisk Investigational Site	Haifa		Israel	3339419
93	Novo Nordisk Investigational Site	Haifa		Israel	35152
94	Novo Nordisk Investigational Site	Herzliya		Israel	46851
95	Novo Nordisk Investigational Site	Kfar Saba		Israel	44281
96	Novo Nordisk Investigational Site	Nahariya		Israel	22100
97	Novo Nordisk Investigational Site	Ofakim		Israel	87520
98	Novo Nordisk Investigational Site	Tel Aviv		Israel	6937947
99	Novo Nordisk Investigational Site	Tel-Aviv		Israel	62038
100	Novo Nordisk Investigational Site	San Juan		Puerto Rico	00921
101	Novo Nordisk Investigational Site	Badalona		Spain	08916
102	Novo Nordisk Investigational Site	El Ferrol		Spain	15405
103	Novo Nordisk Investigational Site	Granada		Spain	18003
104	Novo Nordisk Investigational Site	Málaga		Spain	29006
105	Novo Nordisk Investigational Site	Sanlúcar de Barrameda		Spain	11540
106	Novo Nordisk Investigational Site	Sevilla		Spain	41009

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: NCT01907854
• Other Study ID Numbers: NN2211-4059; 2012-004931-22; U1111-1136-2073; CTRI/2014/05/004623
• First Posted: Jul 25, 2013
• Last Update Posted: Oct 2, 2018
• Last Verified: Sep 1, 2018

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

Study Results

Participant Flow

Recruitment Details	The trial was conducted at 86 sites in 6 countries: Canada (14); Hungary (8); India (7); Israel (8); Spain (6); and United States (43).
Pre-assignment Detail	Screening details: Subjects were adult males or females with type 2 diabetes mellitus (T2DM) who had inadequate glycaemic control with stable doses of sitagliptin and metformin for 90 days prior to screening.

Arm/Group Title	Liraglutide	Sitagliptin
Arm/Group Description	Subjects in this arm received treatments for a duration of 26 weeks; once-daily (OD) liraglutide (s.c., [under the skin] injection 0.6 mg/day, with weekly dose escalations of 0.6 mg/day up to a maintenance dose of 1.8 mg/day) + metformin tablets (≥1500 mg/day [or documented maximum tolerated dose ≥1000 mg/day]) + OD sitagliptin placebo tablets.	Subjects in this arm received treatments for a duration of 26 weeks; OD sitagliptin tablets (100 mg) + metformin tablets (≥1500 mg/day [or documented maximum tolerated dose ≥1000 mg/day]) + OD s.c., injection of liraglutide placebo.
Period Title: Overall Study
STARTED	203	204
Exposed	202	204
COMPLETED	187	191
NOT COMPLETED	16	13

Baseline Characteristics

Arm/Group Title	Liraglutide	Sitagliptin	Total
Arm/Group Description	Subjects in this arm received treatments for a duration of 26 weeks; once-daily (OD) liraglutide (s.c., [under the skin] injection 0.6 mg/day, with weekly dose escalations of 0.6 mg/day up to a maintenance dose of 1.8 mg/day) + metformin tablets (≥1500 mg/day [or documented maximum tolerated dose ≥1000 mg/day]) + OD sitagliptin placebo tablets.	Subjects in this arm received treatments for a duration of 26 weeks; OD sitagliptin tablets (100 mg) + metformin tablets (≥1500 mg/day [or documented maximum tolerated dose ≥1000 mg/day]) + OD s.c., injection of liraglutide placebo.	Total of all reporting groups
Overall Participants	202	204	406
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	56.3 (10.6)	56.5 (9.7)	56.4 (10.2)
Sex: Female, Male (Count of Participants)
Female	85 42.1%	79 38.7%	164 40.4%
Male	117 57.9%	125 61.3%	242 59.6%
HbA1c (percentage of glycosylated haemoglobin) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percentage of glycosylated haemoglobin]	8.3 (0.6)	8.2 (0.6)	8.3 (0.6)
Body Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	88.9 (19.8)	91.2 (19.6)	90.1 (19.7)
Fasting Plasma Glucose (mmol/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmol/L]	10.0 (2.7)	9.7 (2.5)	9.9 (2.6)

Outcome Measures

1. Primary Outcome

Title	Change in HbA1c (Glycosylated Haemoglobin)
Description	Change from baseline in HbA1c was analysed after 26 weeks of treatment. Analysis population set: full analysis set (FAS); all randomised subjects receiving at least one dose of any of the trial products. Missing values were imputed using mixed model for repeated measurements (MMRM).
Time Frame	From baseline to week 26

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) -All randomised subjects receiving at least one dose of any of the trial product.

Arm/Group Title	Liraglutide	Sitagliptin
Arm/Group Description	Subjects in this arm received treatments for a duration of 26 weeks; once-daily (OD) liraglutide (s.c., [under the skin] injection 0.6 mg/day, with weekly dose escalations of 0.6 mg/day up to a maintenance dose of 1.8 mg/day) + metformin tablets (≥1500 mg/day [or documented maximum tolerated dose ≥1000 mg/day]) + OD sitagliptin placebo tablets.	Subjects in this arm received treatments for a duration of 26 weeks; OD sitagliptin tablets (100 mg) + metformin tablets (≥1500 mg/day [or documented maximum tolerated dose ≥1000 mg/day]) + OD s.c., injection of liraglutide placebo.
Measure Participants	176	182
Mean (Standard Deviation) [percentage of glycosylated haemoglobin]	-1.146 (0.9748)	-0.529 (1.0148)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Liraglutide, Sitagliptin
	Comments	Changes in HbA1c from baseline to the 26 weeks measurements were analysed using MMRM, with treatment, baseline HbA1c level (≤8.5% and >8.5%), metformin dose (<1500 mg/day and ≥1500 mg/day), the interaction between baseline HbA1c level and metformin dose, and country as factors and the HbA1c value at baseline as a covariate, all variables nested within week as a factor.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Superiority of liraglutide over sitagliptin was concluded if the 95% Confidence Interval for the treatment difference was entirely below 0%.
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	-0.61
	Confidence Interval	(2-Sided) 95%; -0.82 to -0.40
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change in Body Weight
Description	Change from baseline in body weight was analysed after 26 weeks of treatment. Analysis population set: FAS: all randomised subjects receiving at least one dose of any of the trial products. Missing values were imputed using MMRM.
Time Frame	From baseline to week 26

Outcome Measure Data

Analysis Population Description

FAS - All randomised subjects receiving at least one dose of any of the trial product.

Arm/Group Title	Liraglutide	Sitagliptin
Arm/Group Description	Subjects in this arm received treatments for a duration of 26 weeks; once-daily (OD) liraglutide (s.c., [under the skin] injection 0.6 mg/day, with weekly dose escalations of 0.6 mg/day up to a maintenance dose of 1.8 mg/day) + metformin tablets (≥1500 mg/day [or documented maximum tolerated dose ≥1000 mg/day]) + OD sitagliptin placebo tablets.	Subjects in this arm received treatments for a duration of 26 weeks; OD sitagliptin tablets (100 mg) + metformin tablets (≥1500 mg/day [or documented maximum tolerated dose ≥1000 mg/day]) + OD s.c., injection of liraglutide placebo.
Measure Participants	192	200
Mean (Standard Deviation) [kg]	-3.32 (3.135)	-1.80 (2.974)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Liraglutide, Sitagliptin
	Comments	Change in body weight from baseline to the 26 weeks measurements was analysed using MMRM, with treatment, baseline HbA1c level (≤8.5% and >8.5%), metformin dose (<1500 mg/day and ≥1500 mg/day), the interaction between baseline HbA1c level and metformin dose, and country as factors and the body weight at baseline as a covariate and all variables nested within week as a factor.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Superiority of liraglutide over sitagliptin was concluded if the 95% Confidence Interval for the treatment difference was entirely below 0%.
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	-1.67
	Confidence Interval	(2-Sided) 95%; -2.34 to -0.99
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change in Fasting Plasma Glucose
Description	Change from baseline in fasting plasma glucose was analysed after 26 weeks of treatment. Missing values were imputed using MMRM.
Time Frame	From baseline to week 26

Outcome Measure Data

Analysis Population Description

FAS - All randomised subjects receiving at least one dose of any of the trial product.

Arm/Group Title	Liraglutide	Sitagliptin
Arm/Group Description	Subjects in this arm received treatments for a duration of 26 weeks; once-daily (OD) liraglutide (s.c., [under the skin] injection 0.6 mg/day, with weekly dose escalations of 0.6 mg/day up to a maintenance dose of 1.8 mg/day) + metformin tablets (≥1500 mg/day [or documented maximum tolerated dose ≥1000 mg/day]) + OD sitagliptin placebo tablets.	Subjects in this arm received treatments for a duration of 26 weeks; OD sitagliptin tablets (100 mg) + metformin tablets (≥1500 mg/day [or documented maximum tolerated dose ≥1000 mg/day]) + OD s.c., injection of liraglutide placebo.
Measure Participants	190	199
Mean (Standard Deviation) [nmol/L]	-1.967 (2.3585)	-0.588 (2.1363)

4. Secondary Outcome

Title	Change in Fasting Blood Lipids
Description	Ratio to baseline in fasting blood lipids (total cholesterol, low density lipoprotein [LDL], very low density lipoprotein [VLDL], high density lipoprotein [HDL], triglycerides, and free fatty acids) were analysed after 26 weeks treatment. Missing values were imputed using MMRM. Here we are presenting ratio to baseline data.
Time Frame	From baseline to week 26

Outcome Measure Data

Analysis Population Description

FAS-All randomised subjects receiving at least one dose of any of the trial product. There were missing baseline values for free fatty acids in 1 subject in the liraglutide arm and 6 subjects in the sitagliptin arm.

Arm/Group Title	Liraglutide	Sitagliptin
Arm/Group Description	Subjects in this arm received treatments for a duration of 26 weeks; once-daily (OD) liraglutide (s.c., [under the skin] injection 0.6 mg/day, with weekly dose escalations of 0.6 mg/day up to a maintenance dose of 1.8 mg/day) + metformin tablets (≥1500 mg/day [or documented maximum tolerated dose ≥1000 mg/day]) + OD sitagliptin placebo tablets.	Subjects in this arm received treatments for a duration of 26 weeks; OD sitagliptin tablets (100 mg) + metformin tablets (≥1500 mg/day [or documented maximum tolerated dose ≥1000 mg/day]) + OD s.c., injection of liraglutide placebo.
Measure Participants	155	156
Total cholesterol	1.011 (0.1906)	1.045 (0.2323)
LDL cholesterol	1.049 (0.3899)	1.121 (0.4661)
VLDL cholesterol	1.062 (0.4236)	1.075 (0.4625)
HDL cholesterol	1.004 (0.1528)	0.997 (0.1548)
Triglycerides	1.089 (0.4975)	1.099 (0.4889)
Free Fatty acids	1.086 (0.774)	1.104 (0.5839)

5. Secondary Outcome

Title	Change in Systolic Blood Pressure and Diastolic Blood Pressure
Description	Change from baseline in systolic and diastolic blood pressure were analysed after 26 weeks of treatment. Missing values were imputed using MMRM.
Time Frame	From baseline to week 26

Outcome Measure Data

Analysis Population Description

FAS - All randomised subjects receiving at least one dose of any of the trial product

Arm/Group Title	Liraglutide	Sitagliptin
Arm/Group Description	Subjects in this arm received treatments for a duration of 26 weeks; once-daily (OD) liraglutide (s.c., [under the skin] injection 0.6 mg/day, with weekly dose escalations of 0.6 mg/day up to a maintenance dose of 1.8 mg/day) + metformin tablets (≥1500 mg/day [or documented maximum tolerated dose ≥1000 mg/day]) + OD sitagliptin placebo tablets.	Subjects in this arm received treatments for a duration of 26 weeks; OD sitagliptin tablets (100 mg) + metformin tablets (≥1500 mg/day [or documented maximum tolerated dose ≥1000 mg/day]) + OD s.c., injection of liraglutide placebo.
Measure Participants	192	200
Systolic Blood Pressure	-3.6 (11.596)	-2.57 (11.593)
Diastolic Blood Pressure	-0.23 (7.085)	-0.81 (7.193)

6. Secondary Outcome

Title	Subjects Who Achieve HbA1c Below 7.0% (53 mmol/Mol) (American Diabetes Association Target) (y/n)
Description	Number of subjects who achieve HbA1c <7.0% were analysed after 26 weeks of treatment. Missing values were imputed using MMRM.
Time Frame	After 26 weeks of treatment

Outcome Measure Data

Analysis Population Description

FAS-All randomised subjects receiving at least one dose of any of the trial product.

Arm/Group Title	Liraglutide	Sitagliptin
Arm/Group Description	Subjects in this arm received treatments for a duration of 26 weeks; once-daily (OD) liraglutide (s.c., [under the skin] injection 0.6 mg/day, with weekly dose escalations of 0.6 mg/day up to a maintenance dose of 1.8 mg/day) + metformin tablets (≥1500 mg/day [or documented maximum tolerated dose ≥1000 mg/day]) + OD sitagliptin placebo tablets.	Subjects in this arm received treatments for a duration of 26 weeks; OD sitagliptin tablets (100 mg) + metformin tablets (≥1500 mg/day [or documented maximum tolerated dose ≥1000 mg/day]) + OD s.c., injection of liraglutide placebo.
Measure Participants	176	182
Yes	50.6	26.9
No	49.4	73.1

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 an onset date (or increase in severity) on or after the first day of exposure to randomised treatment and no later than seven days after the last day of randomised treatment. The number of TEAEs was recorded during 26 weeks of treatment plus one week follow-up period.
Time Frame	During 26 weeks of treatment plus one week follow-up period.

Outcome Measure Data

Analysis Population Description

Safety analysis set-All randomised subjects receiving at least one dose of any of the trial product.

Arm/Group Title	Liraglutide	Sitagliptin
Arm/Group Description	Subjects in this arm received treatments for a duration of 26 weeks; once-daily (OD) liraglutide (s.c., [under the skin] injection 0.6 mg/day, with weekly dose escalations of 0.6 mg/day up to a maintenance dose of 1.8 mg/day) + metformin tablets (≥1500 mg/day [or documented maximum tolerated dose ≥1000 mg/day]) + OD sitagliptin placebo tablets.	Subjects in this arm received treatments for a duration of 26 weeks; OD sitagliptin tablets (100 mg) + metformin tablets (≥1500 mg/day [or documented maximum tolerated dose ≥1000 mg/day]) + OD s.c., injection of liraglutide placebo.
Measure Participants	202	204
Number [number of events]	455	318

Adverse Events

Time Frame	27 weeks (26 weeks of treatment period + 1 week of follow-up)
Adverse Event Reporting Description	Adverse events were collected for safety analysis set that included all subjects who received at least one dose of any of the trial products.
Arm/Group Title	Liraglutide		Sitagliptin
Arm/Group Description	Subjects in this arm received treatments for a duration of 26 weeks; once-daily (OD) liraglutide (s.c., [under the skin] injection 0.6 mg/day, with weekly dose escalations of 0.6 mg/day up to a maintenance dose of 1.8 mg/day) + metformin tablets (≥1500 mg/day [or documented maximum tolerated dose ≥1000 mg/day]) + OD sitagliptin placebo tablets.		Subjects in this arm received treatments for a duration of 26 weeks; OD sitagliptin tablets (100 mg) + metformin tablets (≥1500 mg/day [or documented maximum tolerated dose ≥1000 mg/day]) + OD s.c., injection of liraglutide placebo.
All Cause Mortality
	Liraglutide		Sitagliptin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Liraglutide		Sitagliptin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/202 (3%)		7/204 (3.4%)
Cardiac disorders
Acute coronary syndrome	1/202 (0.5%)	1	0/204 (0%)	0
Cardiac failure congestive	1/202 (0.5%)	1	0/204 (0%)	0
Myocardial ischaemia	0/202 (0%)	0	1/204 (0.5%)	1
Prinzmetal angina	1/202 (0.5%)	1	0/204 (0%)	0
General disorders
Non-cardiac chest pain	0/202 (0%)	0	1/204 (0.5%)	1
Infections and infestations
Pneumococcal sepsis	0/202 (0%)	0	1/204 (0.5%)	1
Pneumonia	1/202 (0.5%)	1	1/204 (0.5%)	1
Injury, poisoning and procedural complications
Fall	2/202 (1%)	2	0/204 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder cancer	0/202 (0%)	0	1/204 (0.5%)	1
Nervous system disorders
Cerebrovascular accident	0/202 (0%)	0	1/204 (0.5%)	1
Multiple sclerosis	0/202 (0%)	0	1/204 (0.5%)	1
Psychiatric disorders
Depression	1/202 (0.5%)	1	0/204 (0%)	0
Skin and subcutaneous tissue disorders
Acute febrile neutrophilic dermatosis	0/202 (0%)	0	1/204 (0.5%)	1
Surgical and medical procedures
Joint arthroplasty	1/202 (0.5%)	1	0/204 (0%)	0
Other (Not Including Serious) Adverse Events
	Liraglutide		Sitagliptin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	96/202 (47.5%)		61/204 (29.9%)
Gastrointestinal disorders
Diarrhoea	33/202 (16.3%)	45	19/204 (9.3%)	21
Nausea	44/202 (21.8%)	59	16/204 (7.8%)	21
Vomiting	15/202 (7.4%)	18	10/204 (4.9%)	15
Infections and infestations
Nasopharyngitis	12/202 (5.9%)	14	7/204 (3.4%)	7
Upper respiratory tract infection	12/202 (5.9%)	12	13/204 (6.4%)	15
Investigations
Lipase increased	11/202 (5.4%)	12	9/204 (4.4%)	9
Metabolism and nutrition disorders
Decreased appetite	18/202 (8.9%)	18	7/204 (3.4%)	7
Nervous system disorders
Headache	13/202 (6.4%)	16	12/204 (5.9%)	16

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

At the end of the trial, one or more public disclosures may be prepared collaboratively by the investigator(s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication and/or communication for up to 60 days to protect intellectual property. The results of this trial will be subject to public disclosure on external web sites according to international regulations, as reflected in the Novo Nordisk Code of Conduct for Clinical Trial Disclosure.