Efficacy and Safety of the Human Glucagon-Like Peptide-1 Analog Liraglutide in Combination With Metformin and Thiazolidinedione in Patients With Type 2 Diabetes (LEAD-4 Met+TZD)

Zinman, Bernard; Gerich, John; Buse, John B.; Lewin, Andrew; Schwartz, Sherwyn; Raskin, Philip; Hale, Paula M.; Zdravkovic, Milan; Blonde, Lawrence; the LEAD-4 Study Investigators

doi:10.2337/dc08-2124

Cited by 848Diabetes Treatment and ManagementDiabetes Management and ResearchPharmacology and Obesity Treatment

Efficacy and Safety of the Human Glucagon-Like Peptide-1 Analog Liraglutide in Combination With Metformin and Thiazolidinedione in Patients With Type 2 Diabetes (LEAD-4 Met+TZD)

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Zinman, Bernard, Gerich, John, Buse, John B., Lewin, Andrew, Schwartz, Sherwyn, Raskin, Philip, Hale, Paula M., Zdravkovic, Milan +2 more·2009·Diabetes Care

DOI 10.2337/dc08-2124PMC PMC2699702

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Abstract

OBJECTIVE: To determine the efficacy and safety of liraglutide (a glucagon-like peptide-1 receptor agonist) when added to metformin and rosiglitazone in type 2 diabetes. RESEARCH DESIGN AND METHODS: This 26-week, double-blind, placebo-controlled, parallel-group trial randomized 533 subjects (1:1:1) to once-daily liraglutide (1.2 or 1.8 mg) or liraglutide placebo in combination with metformin (1 g twice daily) and rosiglitazone (4 mg twice daily). Subjects had type 2 diabetes, A1C 7–11% (previous oral antidiabetes drug [OAD] monotherapy ≥3 months) or 7–10% (previous OAD combination therapy ≥3 months), and BMI ≤45 kg/m2. RESULTS: Mean A1C values decreased significantly more in the liraglutide groups versus placebo (mean ± SE −1.5 ± 0.1% for both 1.2 and 1.8 mg liraglutide and −0.5 ± 0.1% for placebo). Fasting plasma glucose decreased by 40, 44, and 8 mg/dl for 1.2 and 1.8 mg and placebo, respectively, and 90-min postprandial glucose decreased by 47, 49, and 14 mg/dl, respectively (P < 0.001 for all liraglutide groups vs. placebo). Dose-dependent weight loss occurred with 1.2 and 1.8 mg liraglutide (1.0 ± 0.3 and 2.0 ± 0.3 kg, respectively) (P < 0.0001) compared with weight gain with placebo (0.6 ± 0.3 kg). Systolic blood pressure decreased by 6.7, 5.6, and 1.1 mmHg with 1.2 and 1.8 mg liraglutide and placebo, respectively. Significant increases in C-peptide and homeostasis model assessment of β-cell function and significant decreases in the proinsulin-to-insulin ratio occurred with liraglutide versus placebo. Minor hypoglycemia occurred more frequently with liraglutide, but there was no major hypoglycemia. Gastrointestinal adverse events were more common with liraglutide, but most occurred early and were transient. CONCLUSIONS: Liraglutide combined with metformin and a thiazolidinedione is a well-tolerated combination therapy for type 2 diabetes, providing significant improvements in glycemic control.

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Past GLP-1 RA studies reported mean weight change ranging from −1.0 kg to −3.78 kg over 6-12 months.
“In these studies, mean weight change ranged from −1.0 kg to −3.78 kg over 6–12 months.”
From Real-world weight change, adherence, and discontinuation among patients with type 2 diabetes initiating glucagon-like peptide-1 receptor agonists in the UK (2022) · cites this paper as [18]
The Results > Efficacy passage (page unavailable) reports mean weight losses of 1.0 and 2.0 kg in the liraglutide groups, supporting the −1.0 kg end of the cited range. The paper does not report a −3.78 kg mean weight change or establish the full 6–12-month range attributed to these studies. (LLM, conf=0.88)
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Authors: Zinman, B., Gerich, J., Buse, J. B., Lewin, A., Schwartz, S., Raskin, P., Hale, P. M., Zdravkovic, M., Blonde, L., & the LEAD-4 Study Investigators
Affiliations: Mount Sinai Hospital (CA)
University of Rochester Medicine (US)
University of North Carolina at Chapel Hill (US)
National Research Institute (US)
Diabetes and Glandular Disease Center, San Antonio, Texas;
Department of Medicine, University of Texas, Dallas, Texas;
Novo Nordisk (Denmark) (DK)
Ochsner Institute, New Orleans, Louisiana.
Corresponding author: Zinman, Bernard
ORCID: Zinman, Bernard
Buse, John B.
Blonde, Lawrence
Venue: Diabetes Care
Publisher: American Diabetes Association
Published: 2009-03-16
Volume: 32
Issue: 7
Pages: 1224-1230
ISSN: 0149-5992 (ISSN-L)
1935-5548
DOI: 10.2337/dc08-2124
PMC: PMC2699702
OpenAlex: W2160001758
Cited by: 848
References: 7
Citations by year: 2026: 8 · 2025: 21 · 2024: 16 · 2023: 19 · 2022: 12 · 2021: 16 · 2020: 19 · 2019: 27 · 2018: 28 · 2017: 42 · 2016: 57 · 2015: 61 · 2014: 75 · 2013: 59 · 2012: 106
FWCI: 94.21
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by-nc-nd
creativecommons.org/licenses/by-nc-nd/3.0/ (vor, 4548 d)
Locations: Diabetes Care (publishedVersion, cc-by-nc-nd)
PubMed Central (publishedVersion, cc-by-nc-nd)
PubMed (publishedVersion)
Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
UNC Libraries
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 › Pharmacology › Pharmacology and Obesity Treatment
Keywords: liraglutide, type 2 diabetes, GLP-1 receptor agonists, metformin, rosiglitazone, thiazolidinediones, glycemic control, HbA1c, fasting blood glucose, postprandial blood glucose, weight loss, blood pressure, C-peptide, beta-cell function, proinsulin/insulin ratio, drug safety
MeSH terms: Liraglutide, Adolescent, Adult, Aged, Blood Glucose, Blood Pressure, Diabetes Mellitus, Type 2, Double-Blind Method, Drug Therapy, Combination, Fasting, Glycated Hemoglobin, Humans, Hypoglycemic Agents, Metformin, Middle Aged, Placebos, Safety, Thiazolidinediones, Glucagon-Like Peptide 1, Young Adult

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Efficacy and Safety of the Human Glucagon-Like Peptide-1 Analog Liraglutide in Combination With Metformin and Thiazolidinedione in Patients With Type 2 Diabetes (LEAD-4 Met+TZD)

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