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Cited by 835Diabetes Treatment and ManagementDiabetes Management and ResearchDiabetes, Cardiovascular Risks, and Lipoproteins

Liraglutide vs insulin glargine and placebo in combination with metformin and sulfonylurea therapy in type 2 diabetes mellitus (LEAD-5 met+SU): a randomised controlled trial

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on behalf of the Liraglutide Effect and Action in Diabetes 5 (LEAD-5) met+SU Study Group, Russell-Jones, D., Vaag, A., Schmitz, O., Sethi, B. K., Lalic, N., Antic, S., Zdravkovic, M. +2 more·2009·Diabetologia
DOI 10.1007/s00125-009-1472-yPMC PMC2744824
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Abstract

AIMS/HYPOTHESIS: The aim of the study was to compare the efficacy and safety of liraglutide in type 2 diabetes mellitus vs placebo and insulin glargine (A21Gly,B31Arg,B32Arg human insulin), all in combination with metformin and glimepiride. METHODS: This randomised (using a telephone or web-based randomisation system), parallel-group, controlled 26 week trial of 581 patients with type 2 diabetes mellitus on prior monotherapy (HbA(1c) 7.5-10%) and combination therapy (7.0-10%) was conducted in 107 centres in 17 countries. The primary endpoint was HbA(1c). Patients were randomised (2:1:2) to liraglutide 1.8 mg once daily (n = 232), liraglutide placebo (n = 115) and open-label insulin glargine (n = 234), all in combination with metformin (1 g twice daily) and glimepiride (4 mg once daily). Investigators, participants and study monitors were blinded to the treatment status of the liraglutide and placebo groups at all times. RESULTS: The number of patients analysed as intention to treat were: liraglutide n = 230, placebo n = 114, insulin glargine n = 232. Liraglutide reduced HbA(1c) significantly vs glargine (1.33% vs 1.09%; -0.24% difference, 95% CI 0.08, 0.39; p = 0.0015) and placebo (-1.09% difference, 95% CI 0.90, 1.28; p < 0.0001). There was greater weight loss with liraglutide vs placebo (treatment difference -1.39 kg, 95% CI 2.10, 0.69; p = 0.0001), and vs glargine (treatment difference -3.43 kg, 95% CI 4.00, 2.86; p < 0.0001). Liraglutide reduced systolic BP (-4.0 mmHg) vs glargine (+0.5 mmHg; -4.5 mmHg difference, 95% CI 6.8, -2.2; p = 0.0001) but not vs placebo (p = 0.0791). Rates of hypoglycaemic episodes (major, minor and symptoms only, respectively) were 0.06, 1.2 and 1.0 events/patient/year, respectively, in the liraglutide group (vs 0, 1.3, 1.8 and 0, 1.0, 0.5 with glargine and placebo, respectively). A slightly higher number of adverse events (including nausea at 14%) were reported with liraglutide, but only 9.8% of participants in the group receiving liraglutide developed anti-liraglutide antibodies. CONCLUSIONS/INTERPRETATION: Liraglutide added to metformin and sulfonylurea produced significant improvement in glycaemic control and bodyweight compared with placebo and insulin glargine. The difference vs insulin glargine in HbA(1c) was within the predefined non-inferiority margin. TRIAL REGISTRATION: ClinicalTrials.gov NCT00331851. FUNDING: The study was funded by Novo Nordisk A/S.

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  • The virtual trial emulations produced the same ranking between the three treatment arms in LEAD-5 for HbA1c, BMI, and SBP reduction.

    “the virtual trial emulations produced the same ranking between the three treatment arms in LEAD-5 [9], suggesting that GLP-1 produces more favourable patient outcomes in terms of HbA1c, BMI, and SBP reduction (Table 2).”

    From Emulating real-world GLP-1 efficacy in type 2 diabetes through causal learning and virtual patients (2025) · cites this paper as [9]

    The Results > Efficacy passages report three-arm rankings for HbA1c and systolic blood pressure, and bodyweight changes consistent with the stated BMI ranking. The paper reports bodyweight change rather than BMI change, so it does not directly establish that ranking for BMI. The virtual emulations are the citing authors’ own work, not a result attributed to LEAD-5. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • LEAD-5 established that Liraglutide reduced HbA1c significantly compared with placebo (difference -11.91 mmol/mol (-1.09%), p < 0.0001).

    “and placebo (-11.91mmol/mol(−1.09%) difference; p < 0.0001)”

    From Emulating real-world GLP-1 efficacy in type 2 diabetes through causal learning and virtual patients (2025) · cites this paper as [9]

  • LEAD-5 established that Liraglutide reduced HbA1c significantly compared with glargine (difference -2.62 mmol/mol (-0.24%), p = 0.0015).

    “LEAD-5 established that Liraglutide reduced HbA1c significantly compared with both glargine (-2.62mmol/mol (−0.24%) difference; p = 0.0015)”

    From Emulating real-world GLP-1 efficacy in type 2 diabetes through causal learning and virtual patients (2025) · cites this paper as [9]

  • LEAD-5 demonstrated that Liraglutide produced significantly greater weight loss compared with glargine (difference -3.43 kg, p < 0.0001).

    “LEAD-5 also demonstrated that Liraglutide produced significantly greater weight loss compared with both glargine (−3.43 kg difference; p < 0.0001)”

    From Emulating real-world GLP-1 efficacy in type 2 diabetes through causal learning and virtual patients (2025) · cites this paper as [9]

  • LEAD-5 demonstrated that Liraglutide produced significantly greater weight loss compared with placebo (difference -1.39 kg, p = 0.0001).

    “and placebo (–1.39 kg difference; p = 0.0001)”

    From Emulating real-world GLP-1 efficacy in type 2 diabetes through causal learning and virtual patients (2025) · cites this paper as [9]

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Research works printed but not linked: 22

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Authors
on behalf of the Liraglutide Effect and Action in Diabetes 5 (LEAD-5) met+SU Study Group, Russell-Jones, D., Vaag, A., Schmitz, O., Sethi, B. K., Lalic, N., Antic, S., Zdravkovic, M., Ravn, G. M., & Simó, R.
Affiliations
  • Guildford Hospital (GB)
  • Aarhus University Hospital (DK)
  • CARE Hospitals (IN)
  • University of Nis (RS)
  • Novo Nordisk (Denmark) (DK)
  • Instituto de Salud Carlos III (ES)
Corresponding author
Russell-Jones, D.
ORCID
Venue
Diabetologia
Publisher
Springer Science and Business Media LLC
Published
2009-08-14
Volume
52
Issue
10
Pages
2046-2055
ISSN
  • 0012-186X (ISSN-L)
  • 1432-0428
DOI
10.1007/s00125-009-1472-y
PMC
PMC2744824
OpenAlex
W2137352234
Cited by
835
References
7
Citations by year
2026: 12 · 2025: 27 · 2024: 11 · 2023: 15 · 2022: 13 · 2021: 21 · 2020: 26 · 2019: 32 · 2018: 37 · 2017: 40 · 2016: 58 · 2015: 61 · 2014: 69 · 2013: 70 · 2012: 97
FWCI
83.05
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Diabetologia (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Open Research (University of Surrey) (submittedVersion)
  • Surrey Research Insight Open Access (The University of Surrey) (submittedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
Funders
  • Amylin Pharmaceuticals
  • Novo Nordisk
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
Keywords
liraglutide, insulin glargine, type 2 diabetes, metformin, glimepiride, combination therapy, HbA1c, weight loss, GLP-1 receptor agonists, insulin therapy, glycemic control, drug safety, adverse events, GIP/GLP-1 receptor agonist, GLP-1 receptor
MeSH terms
Insulin Glargine, Liraglutide, Adolescent, Adult, Aged, Aged, 80 and over, Blood Glucose, Body Weight, Diabetes Mellitus, Type 2, Drug Therapy, Combination, Female, Humans, Hypoglycemic Agents, Insulin, Male, Metformin, Middle Aged, Placebos, Sulfonylurea Compounds, Insulin, Long-Acting, Glucagon-Like Peptide 1, Young Adult

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