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)
- Bernard Zinman, MD1,
- John Gerich, MD2,
- John B. Buse, MD, PHD3,
- Andrew Lewin, MD4,
- Sherwyn Schwartz, MD5,
- Philip Raskin, MD6,
- Paula M. Hale, PHD7,
- Milan Zdravkovic, PHD7,
- Lawrence Blonde, MD8 and
- the LEAD-4 Study Investigators*
- 1Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada;
- 2Department of Medicine, University of Rochester, Rochester, New York;
- 3University of North Carolina, Chapel Hill, North Carolina;
- 4National Research Institute, Los Angeles, California;
- 5Diabetes and Glandular Disease Center, San Antonio, Texas;
- 6Department of Medicine, University of Texas, Dallas, Texas;
- 7Novo Nordisk, Copenhagen, Denmark;
- 8Ochsner Institute, New Orleans, Louisiana.
- Corresponding author: Bernard Zinman, .
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.
Clinical trial reg. no. NCT00333151, clinicaltrials.gov.
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- Received December 8, 2008.
- Accepted March 8, 2009.
- © 2009 by the American Diabetes Association.
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