Liraglutide is an acylated analogue of human GLP-1 (with 97% homology with native GLP-1), which was approved for clinical use in Europe in 2009 and in the U.S. in 2010. In liraglutide a C-16 acyl chain is linked to amino acid 20 via a γ-glutamic acid spacer and the lysine in position 28 of native GLP-1 is exchanged with arginine. These changes results in a half-life after sc administration of approximately 11 to 15 hours making it suitable for once-daily dosing.
The clinical effects of liraglutide treatment have been investigated in the Liraglutide Effect and Action in Diabetes (LEAD) series of phase III studies. These trials lasting up to 52 weeks, showed that treatment with liraglutide both as monotherapy and in combination with metformin, SU, or TZD plus metformin lowered HbA1c and body weight. Liraglutide-induced change in HbA1c varied from -0.8 to -1.6% (baseline HbA1c of 8.2 to 8.5%), reductions that in most cases were similar or greater than compared to the oral comparator drug. Overall a reduction in body weight was seen in all trials in the range of 2 to 3 kg, much like other phase III studies with liraglutide compared with placebo, and not different from exenatide. In the LEAD-6 study liraglutide and exenatide were compared head-to-head. A significantly greater reduction in HbA1c with liraglutide than with exenatide treatment was observed (1.1 vs. 0.8%), as well as greater reduction in fasting plasma glucose (1.6 vs. 0.6 mM, respectively). Greater reductions in triglycerides (0.4 vs. 0.2 mM) and free fatty acids (0.17 vs. 0.10 mM) in the liraglutide group were observed. Both liraglutide and exenatide caused significant decreases in blood pressure. Newly published data from a 14 weeks extension of the LEAD-6 phase IIIb study, where subjects either continued with liraglutide or switched from exenatide to liraglutide, showed that switching from exenatide to liraglutide further and significantly reduced HbA1c (0.3%), fasting plasma glucose (0.9 mM) and body weight (0.9 kg).