Low incidence of gastrointestinal adverse events over time with a combination of insulin glargine and lixisenatide
J. Trujillo1, M. Roberts2, T. Dex2, J. White3, J. Lasalle4
1University of Colorado, School of Pharmacy and Pharmaceutical Sciences, Aurora. CO, USA
2Sanofi US, Bridgewater- NJ, USA
3Washington State University, Washington, USA
4Excelsior Springs Clinic, Excelsior Springs, USA 

Aim
iGlarLixi, a titratable fixed-ratio combination of insulin glargine 100 U/mL (iGlar) and GLP-1 receptor agonist lixisenatide, was associated with low rates of nausea (N), vomiting (V), and diarrhea (D) (≤10% each) in the LixiLan phase 3 clinical program, leading to very low discontinuation rates (≤1% each). This post hoc analysis assessed frequency and timing of gastrointestinal adverse events (GI AEs) in two trials evaluating iGlarLixi in patients with T2D uncontrolled with oral antidiabetes agents and/or basal insulin vs iGlar alone or lixisenatide alone.
Method
Pertinent data on N/V/D from the randomized, open-label LixiLan-L and LixiLan-O trials were used in this analysis. The incidence of these GI AEs was calculated with descriptive statistics; results were summarized by treatment group.
Results
Within the first 60 days of treatment initiation, 9.6% and 11.7% of patients treated with iGlarLixi experienced N, V or D in the LixiLan-L and LixiLan-O trials, respectively, compared with 27.5% of patients on lixisenatide in LixiLan-O, and 1.4% and 4.7% of patients on iGlar in LixiLan-L and LixiLan-O.
The percentage of patients with onset of N, V and D from Day 60 to study end (~210 days) was 4.1% and 7.7% for iGlarLixi in LixiLan-L and LixiLan-O, respectively, 6.9% for lixisenatide in LixiLan-O, and 2.2% and 3.2% for iGlar in LixiLan-L and LixiLan-O. After 80 days, incidences of new N, V, or D events were 3.4%, 1.1% and 3.0%, respectively, for iGlarLixi, compared with 2.6%, 1.3% and 2.6% for lixisenatide in LixiLan-O.
Most GI AEs reported for iGlarLixi were mild (53-78%) to moderate (22-45%) in severity, with only 1 reported severe N in LixiLan-L and no severe GI AEs in LixiLan-O.
The median durations of N/V/D were 5.0, 1.0 and 3.5 days, respectively, with iGlarLixi vs 7.5, 3.0 and 3.0 days with lixisenatide, and 2.0 days for each GI AE with iGlar in LixiLan-O. In LixiLan-L, the median durations were 6.0, 2.0 and 2.5 days with iGlarLixi vs 3.0, 1.0 and 2.0 days with iGlar.
The mean daily doses of iGlar administered as part of the combination increased throughout the LixiLan-L and LixiLan-O studies for patients with and without GI AEs. Likewise, doses of lixisenatide in the iGlarLixi arm increased over time, and they were higher for patients in LixiLan-L compared to LixiLan-O influenced by the insulin experience of patients in Lixilan-L (mean dose of 10.5 µg/day at week 1 and 15.4 µg/day at week 30 for patients with GI AEs, and 10.7 µg/day at week 1 and 16.8 µg/day at week 30 for patients without GI AEs in LixiLan-L; mean dose of 5.1 µg/day at week 1 and 14.7 µg/day at week 30 for patients with GI AEs, and 5.1 µg/day at week 1 and 15.4 µg/day at week 30 for patients without GI AEs in LixiLan-O). In the lixisenatide arm of Lixilan-O, 77% of the patients experiencing GI AEs had a dose of 20 µg/day at week 30 vs. 94% of patients without GI AEs. In both trials, the lixisenatide dose in the iGlarLixi group was slightly lower in those patients with GI events compared to those without GI events. In the lixisenatide arm the occurrence of GI AEs may have contributed to the inability of reaching or maintaining the dose of 20µg/day. 
Discussion
The occurrence of GI AEs is expected with the use of GLP-1 receptor agonists. N/V/D events associated with iGlarLixi treatment were predominantly transient, mainly occurring during the initial 60-day titration period in a small proportion of patients, and they were very rare after 80 days. As expected, the overall proportion of patients with GI AEs was higher with iGlarLixi than with iGlar, but lower than with lixisenatide leading to less of an impact on dose achievement. This may be due to the slow increase in lixisenatide dose in the fixed-ratio iGlarLixi combination. In summary, patients with T2D treated with iGlarLixi show a low rate of GI AEs compared to lixisenatide, and these tend to occur early and to be transient and mild, rarely requiring discontinuation. 
Study Numbers: LixiLan-L: NCT02058160, LixiLan-O: NCT02058147

Conflict of interest: Conflict of interest 
Receipt of grants or research support: This study was funded by Sanofi US, Inc. Other support (please specify): Writing/editorial support was provided by Excerpta Medica funded by Sanofi US, Inc.