Efficacy and safety of the human GLP-1 analog liraglutide in combination with metformin and TZD in patients with type 2 diabetes mellitus (LEAD-4 Met+TZD)

Abstract

Objective – To determine the efficacy and safety of liraglutide (a GLP-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 1.2mg, liraglutide 1.8mg, or liraglutide placebo in combination with metformin (1g BID) and rosiglitazone (4mg BID). Subjects had type 2 diabetes, HbA1c of 7-11% (previous OAD monotherapy ≥3 months) or 7-10% (previous OAD combination therapy ≥3 months), and BMI ≤45 kg/m².

Results – Mean HbA1c values decreased significantly more in the liraglutide groups vs. placebo (−1.5±0.1% for both liraglutide 1.2 and 1.8mg and −0.5±0.1% for placebo [values±SE]). Fasting plasma glucose decreased by 40, 44, and 8mg/dl for liraglutide 1.2, 1.8, and placebo, respectively, and 90-min PPG decreased by 47, 49, and 14mg/dl, respectively (P<0.001 for all liraglutide groups vs. placebo). Dose-dependent weight loss occurred with liraglutide 1.2 and 1.8mg (1.0±0.3, and 2.0±0.3kg, respectively) (P<0.0001) compared to weight gain with placebo (0.6±0.3kg). Systolic blood pressure (SBP) decreased by 6.7, 5.6, and 1.1mmHg with liraglutide 1.2, 1.8mg, and placebo, respectively. Significant increases in C-peptide and HOMA-B and significant decreases in pro-insulin:insulin ratio occurred with liraglutide vs. 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.