Clinical Outcomes of Patients with Diabetes Who Exhibit Upper-Quartile Insulin Antibody Responses After Treatment with LY2963016 or Lantus^® Insulin Glargine

Data from the ELEMENT-1 and ELEMENT-2 studies were analyzed. Both trials were registered at Clinical Trials.gov (NCT01421147 and NCT01421459). Detailed study methods and results for the primary endpoints for both studies have been previously described [5, 6]. Briefly, ELEMENT-1 was a 52-week (24-week treatment period plus 28-week extension period), open-label study of patients with T1D being treated with basal and bolus insulin [5]. ELEMENT-2 was a 24-week, double-blind study of patients with T2D who were insulin-naïve or previously treated with IGlar [6]. In both studies, patients were randomized to receive an LY IGlar or IGlar dose that was equivalent to their prestudy insulin dose except for patients with T2D who were insulin-naïve and started with 10 units of LY IGlar or IGlar. The LY IGlar or IGlar dose was titrated on the basis of daily blood glucose levels [5, 6]. The primary efficacy outcome in both studies was to demonstrate the non-inferiority (0.4% and then 0.3% margin) of LY IGlar to IGlar as measured by change in HbA1c from baseline to 24 weeks [5, 6]. Both of these studies were done in accordance with the International Conference on Harmonisation Guidelines for Good Clinical Practice and the Declaration of Helsinki [12], and written informed consent was obtained from all patients [5, 6].

Antibody determination methods have been described in greater detail previously [5‐7]. Briefly, samples used in this study for antibody determination were those collected before randomization (baseline) and at study endpoint. Insulin antibodies were quantified as percent binding using a classic radioimmunoassay format. The anti-LY IGlar antibody assay has cross-reactivity to IGlar and human insulin; hence, antibodies to LY IGlar and IGlar were measured using the same assay [5‐7]. Insulin antibody testing was conducted by Millipore (St. Charles, MO, USA).

In each study, patients in the upper quartile of maximum antibody percent binding (UQMAPB) were determined as follows: among all patients with postbaseline insulin antibodies, the maximum postbaseline insulin antibody level (percent binding) per patient was identified. Patients whose maximum postbaseline percent binding belonging to the highest 25% of the maximum values observed comprised the UQMAPB. Patients in the lower 75% and patients who did not have any detectable antibodies postbaseline comprised those patients not in the UQMAPB. Postbaseline maximum antibody percent binding (MAPB) levels and the proportions of patients who exhibited IARs in the UQMAPB with either treatment were evaluated to compare the IAR profiles of LY IGlar and IGlar. Separate analyses for each study also compared LY IGlar to IGlar for clinical outcomes [changes in glycated hemoglobin (HbA1c) (%), basal insulin dose (U/kg/day), weight (kg), incidence of adverse events, and incidence of total hypoglycemia] among patients who did or did not exhibit IARs in the UQMAPB. The potential differential treatment effects of UQMAPB status on clinical and safety outcomes were also assessed by interaction tests. Hypoglycemia was defined in accordance with American Diabetes Association [13] and European Medicine Agency [14] guidelines as having a blood glucose no greater than 3.9 mmol/L (70 mg/dL) or signs or symptoms attributable to low blood glucose levels. Analyses were also performed with hypoglycemia defined as having a blood glucose of less than 3.0 mmol/L (54 mg/dL), a cutoff that had been recommended in the past [15].