Background and objective: In a 30 week, double-blind, randomized, controlled Phase 3 study in patients with type 2 diabetes mellitus, the addition of fixed-dose exenatide twice daily (BID) to titrated insulin glargine resulted in significant glycated hemoglobin (HbA(1c)) lowering and weight loss without increased hypoglycemia risk versus titrated insulin glargine alone. Because individualized insulin titration contributed to these results, this post-hoc analysis examined the results in the context of the degree of insulin titration that occurred.
Methods: Subjects on pre-existing insulin glargine (with or without oral antidiabetes agents) were randomized to placebo (n = 123) or exenatide BID (n = 138; 5 µg for 4 weeks, then 10 µg ongoing). Insulin glargine was titrated in both arms per the Treat-to-Target algorithm. Tertiles (T1, T2, T3) were based on change in insulin dose from baseline to endpoint. Change in HbA(1c), hypoglycemia risk, and weight gain were assessed per insulin dose tertile.
Results: The population comprised adult patients (mean age = 59 y) with type 2 diabetes and an HbA(1c) level between 7.0% and 10.5% (mean HbA(1c) = 8.4%). Insulin titration ranged from modest reductions in T1 to substantial increases in T3. Greater improvements in HbA1c were demonstrated with exenatide BID versus placebo in all tertiles (statistically significant in T2 and T3). With exenatide BID, more subjects achieved HbA(1c) <7.0% vs. placebo: T1, 44% vs. 29% (P = not significant); T2, 65% vs. 26%; T3, 54% vs. 29% (P < 0.05 for T2 and T3). Incidence of hypoglycemia was numerically lower with exenatide BID in all tertiles. Adjunctive exenatide BID was associated with statistically significantly greater weight loss (T1, T2) or mitigation of weight gain (T3) compared with placebo. Rates of nausea (42% vs. 8%), diarrhea (18% vs. 7%), and vomiting (18% vs. 4%) were higher with exenatide BID than with placebo and did not vary by tertile.
Conclusions: Addition of fixed-dose exenatide BID to optimized insulin glargine, regardless of the extent of insulin titration, significantly improved glycemia without increasing hypoglycemia risk, while mitigating insulin-induced weight gain in this post-hoc analysis.
Trial registration: ClinicalTrials.gov NCT00765817.
Keywords: Diabetes; Exenatide; GLP-1 receptor agonist; Insulin.