To Compare the Effect of Liraglutide When Given Together With Metformin With the Effect of Metformin Given Alone and With the Effect of Glimepiride and Metformin Given Together - Study Results

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Safety/Efficacy Study; Intervention Model: Parallel Assignment; Masking: Double Blind (Subject, Investigator); Primary Purpose: Treatment
Condition:	Diabetes Mellitus, Type 2
Interventions:	Drug: liraglutide Drug: metformin Drug: glimepiride Drug: placebo

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
A total of 170 centres in 21 countries: Argentina (4), Australia (19), Belgium (6), Bulgaria (1), Germany (33), Denmark (9), Spain (14), United Kingdom (11), Croatia (2), Hungary (5), Ireland (4), India (5), Italy (10), The Netherlands (5), New Zealand (3), Norway (8), Romania (3), Russia (6), Sweden (8), Slovakia (7) and South Africa (7)

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Eligible subjects discontinued their oral anti-diabetic drug treatment and commenced a 3-week period of forced titration of metformin followed by a 3-week maintenance period. Subjects on current metformin therapy could go through a modified titration period or advance directly to the 3-week maintenance period at the discretion of the investigator.

Reporting Groups

	Description
Lira 0.6 + Met	Liraglutide 0.6 mg/day + glimepiride placebo + metformin 1.5-2.0 g/day, weeks 0-26 (double-blinded period) and open-label liraglutide 0.6 mg/day + metformin 1.5-2.0 g/day in the extension period (weeks 26-104)
Lira 1.2 + Met	Liraglutide 1.2 mg/day + glimepiride placebo + metformin 1.5-2.0 g/day, weeks 0-26 (double-blinded period) and open-label liraglutide 1.2 mg/day + metformin 1.5-2.0 g/day in the extension period (weeks 26-104)
Lira 1.8 + Met	Liraglutide 1.8 mg/day + glimepiride placebo + metformin 1.5-2.0 g/day, weeks 0-26 (double-blinded period) and open-label liraglutide 1.8 mg/day + metformin 1.5-2.0 g/day in the extension period (weeks 26-104)
Met Mono	Metformin 1.5-2.0 g/day + liraglutide placebo + glimepiride placebo, weeks 0-26 (double-blinded period) and open-label metformin 1.5-2.0 g/day in the extension period (weeks 26-104)
Met + Glim	Glimepiride 4 mg/day + metformin 1.5-2.0 g/day + liraglutide placebo, weeks 0-26 (double-blinded period) and open-label glimepiride 4 mg/day + metformin 1.5-2.0 g/day in the extension period (weeks 26-104)

Participant Flow for 2 periods

Period 1: Double-Blind, 6 Months

	Lira 0.6 + Met	Lira 1.2 + Met	Lira 1.8 + Met	Met Mono	Met + Glim
STARTED	242 ^[1]	241 ^[1]	242 ^[1]	122 ^[1]	244 ^[1]
Exposed to Study Drug	242	240 ^[2]	242	121 ^[2]	242 ^[3]
COMPLETED	208	197	191	74	210
NOT COMPLETED	34	44	51	48	34
Adverse Event	11	23	29	2	8
Lack of Efficacy	19	8	13	29	9
Protocol Violation	2	4	4	4	5
Lost to follow up	0	1	0	0	0
Poor compliance/Non-compliance	0	1	0	0	0
Consent withdrawn	0	3	4	10	4
Subject decision/No wish to continue	0	2	1	0	2
Move	0	1	0	0	0
Tendency to low blood glucose levels	0	0	0	0	1
FPG exceeds limits/too high	1	0	0	2	0
Work commitment	0	0	0	0	1
Investigator decision	0	0	0	0	1
Lack of time	1	0	0	0	0
Hypoglycaemia/Hypoglycemia	0	0	0	0	2
Hyperglicaemia	0	0	0	1	0
metformin titrated <1500 mg or >2000 mg	0	0	0	0	1
Fear of experiencing AE again	0	1	0	0	0

[1]	Randomised
[2]	Subject withdrew before exposure to drug, and thus not included in the safety and ITT analysis sets
[3]	Subjects withdrew before exposure to drug, and thus not included in the safety and ITT analysis sets

Period 2: Open-Label Extension, 18 Months

	Lira 0.6 + Met	Lira 1.2 + Met	Lira 1.8 + Met	Met Mono	Met + Glim
STARTED	208	197	191	74	210
COMPLETED	130	137	118	31	113
NOT COMPLETED	78	60	73	43	97
Withdrawals between 6 and 24 months	19	14	27	11	22
Adverse Event	11	8	6	1	6
Lack of Efficacy	41	33	37	27	63
Protocol Violation	7	5	3	4	6

Baseline Characteristics

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Reporting Groups

	Description
Lira 0.6 + Met	Liraglutide 0.6 mg/day + glimepiride placebo + metformin 1.5-2.0 g/day, weeks 0-26 (double-blinded period) and open-label liraglutide 0.6 mg/day + metformin 1.5-2.0 g/day in the extension period (weeks 26-104)
Lira 1.2 + Met	Liraglutide 1.2 mg/day + glimepiride placebo + metformin 1.5-2.0 g/day, weeks 0-26 (double-blinded period) and open-label liraglutide 1.2 mg/day + metformin 1.5-2.0 g/day in the extension period (weeks 26-104)
Lira 1.8 + Met	Liraglutide 1.8 mg/day + glimepiride placebo + metformin 1.5-2.0 g/day, weeks 0-26 (double-blinded period) and open-label liraglutide 1.8 mg/day + metformin 1.5-2.0 g/day in the extension period (weeks 26-104)
Met Mono	Metformin 1.5-2.0 g/day + liraglutide placebo + glimepiride placebo, weeks 0-26 (double-blinded period) and open-label metformin 1.5-2.0 g/day in the extension period (weeks 26-104)
Met + Glim	Glimepiride 4 mg/day + metformin 1.5-2.0 g/day + liraglutide placebo, weeks 0-26 (double-blinded period) and open-label glimepiride 4 mg/day + metformin 1.5-2.0 g/day in the extension period (weeks 26-104)

Baseline Measures

	Lira 0.6 + Met	Lira 1.2 + Met	Lira 1.8 + Met	Met Mono	Met + Glim	Total
Number of Participants [units: participants]	242	240	242	121	242	1087
Age [units: years] Mean ± Standard Deviation	56.0 ± 10.5	57.2 ± 9.2	56.8 ± 9.4	56.0 ± 9.4	57.3 ± 8.8	56.7 ± 9.5
Gender [units: participants]
Female	91	111	100	49	103	454
Male	151	129	142	72	139	633
Race (NIH/OMB) [units: participants]
American Indian or Alaska Native	0	0	0	0	0	0
Asian	31	19	18	9	21	98
Native Hawaiian or Other Pacific Islander	0	0	0	0	0	0
Black or African American	4	9	5	3	5	26
White	202	210	214	106	214	946
More than one race	0	0	0	0	0	0
Unknown or Not Reported	5	2	5	3	2	17
Previous anti-diabetic treatment [units: participants]
Mono-therapy	81	90	82	41	90	384
Combination therapy	161	150	160	80	152	703
BMI ^[1] [units: kg/m2] Mean ± Standard Deviation	30.5 ± 4.8	31.1 ± 4.8	30.9 ± 4.6	31.6 ± 4.4	31.2 ± 4.6	31.0 ± 4.7
Duration of diabetes ^[2] [units: years] Mean ± Standard Deviation	7.0 ± 4.8	6.8 ± 4.9	7.8 ± 5.2	7.9 ± 6.0	7.7 ± 5.3	7.4 ± 5.2
HbA1c ^[3] [units: percentage of total haemoglobin] Mean ± Standard Deviation	8.4 ± 0.9	8.3 ± 0.9	8.3 ± 0.9	8.4 ± 1.0	8.4 ± 0.9	8.4 ± 0.9
Height [units: m] Mean ± Standard Deviation	1.69 ± 0.10	1.68 ± 0.11	1.69 ± 0.10	1.69 ± 0.10	1.69 ± 0.11	1.69 ± 0.10

[1]	Body Mass Index
[2]	Number of years since diagnosis of diabetes
[3]	Glycosylated Haemoglobin at screening

Outcome Measures

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1. Primary:

Change in Glycosylated A1c (HbA1c) at Week 26 [ Time Frame: week 0, week 26 ]

Show Outcome Measure 1

2. Primary:

Change in Glycosylated A1c (HbA1c) at Week 104 [ Time Frame: week 0, week 104 ]

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3. Secondary:

Change in Body Weight at Week 26 [ Time Frame: week 0, week 26 ]

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4. Secondary:

Change in Body Weight at Week 104 [ Time Frame: week 0, week 104 ]

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5. Secondary:

Change in Fasting Plasma Glucose (FPG) at Week 26 [ Time Frame: week 0, week 26 ]

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6. Secondary:

Change in Fasting Plasma Glucose (FPG) at Week 104 [ Time Frame: week 0, week 104 ]

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7. Secondary:

Change in Mean Prandial Increments of Plasma Glucose Based on Self-measured 7-point Plasma Glucose Profiles at Week 26 [ Time Frame: week 0, week 26 ]

Show Outcome Measure 7

8. Secondary:

Change in Mean Prandial Increments of Plasma Glucose Based on Self-measured 7-point Plasma Glucose Profiles at Week 104 [ Time Frame: week 0, week 104 ]

Show Outcome Measure 8

9. Secondary:

Change in Mean Post Prandial Plasma Glucose Based on Self-measured 7-point Plasma Glucose Profiles at Week 26 [ Time Frame: week 0, week 26 ]

Show Outcome Measure 9

10. Secondary:

Change in Mean Post Prandial Plasma Glucose Based on Self-measured 7-point Plasma Glucose Profiles at Week 104 [ Time Frame: week 0, week 104 ]

Show Outcome Measure 10

11. Secondary:

Change in Beta-cell Function at Week 26 [ Time Frame: week 0, week 26 ]

Show Outcome Measure 11

12. Secondary:

Change in Beta-cell Function at Week 104 [ Time Frame: week 0, week 104 ]

Show Outcome Measure 12

13. Secondary:

Hypoglycaemic Episodes at Week 26 [ Time Frame: weeks 0-26 ]

Show Outcome Measure 13

14. Secondary:

Hypoglycaemic Episodes at Week 104 [ Time Frame: weeks 0-104 ]

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Serious Adverse Events

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Other Adverse Events

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More Information

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Certain Agreements:

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: Novo Nordisk acknowledges the Investigator’s right to publish the entire results of the trial. Any such scientific paper, presentation, communication or other information concerning the investigation described in this protocol, must be submitted in writing to Novo Nordisk Trial Manager prior to submission for publication/presentation for comments. Comments will be given within four weeks from receipt of the manuscript.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.

Results Point of Contact:

Name/Title: Public Access to Clinical Trials
Organization: Novo Nordisk A/S
e-mail: clinicaltrials@novonordisk.com

No publications provided by Novo Nordisk

Publications automatically indexed to this study:

Hegedüs L, Moses AC, Zdravkovic M, Le Thi T, Daniels GH. GLP-1 and calcitonin concentration in humans: lack of evidence of calcitonin release from sequential screening in over 5000 subjects with type 2 diabetes or nondiabetic obese subjects treated with the human GLP-1 analog, liraglutide. J Clin Endocrinol Metab. 2011 Mar;96(3):853-60. Epub 2011 Jan 5.

Nauck M, Marre M. Adding liraglutide to oral antidiabetic drug monotherapy: efficacy and weight benefits. Postgrad Med. 2009 May;121(3):5-15.

Sullivan SD, Alfonso-Cristancho R, Conner C, Hammer M, Blonde L. Long-term outcomes in patients with type 2 diabetes receiving glimepiride combined with liraglutide or rosiglitazone. Cardiovasc Diabetol. 2009 Feb 26;8:12.

Nauck M, Frid A, Hermansen K, Shah NS, Tankova T, Mitha IH, Zdravkovic M, Düring M, Matthews DR; LEAD-2 Study Group. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD (liraglutide effect and action in diabetes)-2 study. Diabetes Care. 2009 Jan;32(1):84-90. Epub 2008 Oct 17.

Responsible Party:	Public Access to Clinical Trials, Novo Nordisk A/S
ClinicalTrials.gov Identifier:	NCT00318461 History of Changes
Other Study ID Numbers:	NN2211-1572
Study First Received:	April 25, 2006
Results First Received:	February 23, 2010
Last Updated:	April 16, 2010
Health Authority:	Germany: Federal Institute for Drugs and Medical Devices; Spain: Spanish Agency of Medicines; Croatia: Ministry of Health and Social Care; Russia: Pharmacological Committee, Ministry of Health; Denmark: Danish Medicines Agency; Romania: State Institute for Drug Control; Hungary: National Institute of Pharmacy; Bulgaria: Bulgarian Drug Agency; South Africa: Medicines Control Council; Netherlands: Dutch Health Care Inspectorate; Argentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia; Italy: National Monitoring Centre for Clinical Trials - Ministry of Health; Ireland: Irish Medicines Board; Australia: Department of Health and Ageing Therapeutic Goods Administration; Norway: Norwegian Medicines Agency; Sweden: Medical Products Agency; India: Ministry of Health; United Kingdom: Medicines and Healthcare Products Regulatory Agency