**Background:** iGlarLixi, a fixed-ratio combination of insulin glargine 100 U/mL and the short-acting GLP-1 receptor agonist lixisenatide, exploits complementary mechanisms to control both fasting and postprandial glucose. While clinical trials have demonstrated its efficacy and safety, these trials predominantly administered iGlarLixi before breakfast. The product label recommends injection within 1 hour before a meal, preferably the same meal each day, but does not specify which meal. Whether administration timing affects real-world outcomes was unknown.
**Methods:** Data were pooled from two prospective, multicenter, open-label observational studies conducted across European countries. The analysis included 1,303 adults with T2DM inadequately controlled on OADs with or without basal insulin who initiated iGlarLixi for 24 weeks. Participants were classified into four subgroups based on injection timing: pre-breakfast (n=436, 33.5%), pre-lunch (n=262, 20.1%), pre-dinner (n=399, 30.6%), and those who changed injection time during the study (n=206, 15.8%). The primary endpoint was change in HbA1c from baseline to week 24, analyzed using a mixed model for repeated measures (MMRM) adjusted for study, visit, subgroup, prior insulin use, baseline HbA1c, age, and baseline BMI. Secondary endpoints included HbA1c targets, FPG, 2-hour PPG, hypoglycemia, gastrointestinal AEs, and body weight change.
**Key Results:** Baseline characteristics were similar across groups: mean age 61.0 years, mean BMI 32.2 kg/m², median diabetes duration 9.0 years, and 45.3% previously treated with basal insulin. Mean baseline HbA1c was 9.11%. The LS mean HbA1c reduction from baseline to week 24 in the overall population was -1.43% (95% CI -1.50 to -1.36%). Pre-breakfast injection yielded the largest reduction (-1.57%), which was significantly greater than pre-lunch (-1.27%; difference 0.30%, p=0.002) and changed injection time (-1.33%; difference 0.24%, p=0.02), but not significantly different from pre-dinner (-1.42%; difference 0.15%, p=0.08). At week 24, 33.7% of the pre-breakfast group achieved HbA1c <7.0%, compared with 19.0% (pre-lunch), 25.6% (pre-dinner), and 23.2% (changed time). FPG reductions were similar across groups (overall mean change -49.97 mg/dL). Safety outcomes were favorable across all groups: gastrointestinal AEs occurred in 1.3% overall (nausea 1.0%), any hypoglycemia in 4.0% (annualized rate 0.19 events/patient-year), and severe hypoglycemia in only 0.08% (1 patient). Mean body weight decreased by 1.8 kg overall (range -1.3 to -2.3 kg across groups). iGlar dose increased from 18.9 U/day at baseline to 33.3 U/day at week 24, with comparable titration across groups.
**Clinical Implications:** iGlarLixi is effective and safe regardless of administration timing, offering patients flexibility to suit their lifestyle and meal patterns. Pre-breakfast injection may be preferable when convenient, as it was associated with numerically greater HbA1c reductions. The lower proportion of patients achieving HbA1c <7.0% compared to prior RCTs (26.4% overall vs 54.9-73.7% in LixiLan trials) likely reflects less stringent titration in real-world practice. These findings support a patient-centered approach to iGlarLixi dosing, with the main/largest meal and patient preference guiding the choice of injection time.