Converting to XULTOPHY 100/3.6 from GLP-1 receptor agonist

NCT01676116: The efficacy and safety of XULTOPHY 100/3.6 (once-daily) compared to unchanged pre-trial liraglutide up to a dose of 1.8 mg daily, were studied in a 26-week randomized, open-label, treat-to-target (fasting blood glucose goal of 72-90 mg/dL) trial. The trial included 348 patients with type 2 diabetes mellitus inadequately controlled on liraglutide and metformin alone or in combination with pioglitazone, sulfonylurea or both. Oral anti-diabetic drugs (OADs) were continued at pre-trial doses throughout the trial, and 22% of subjects were treated with sulfonylureas (SU) in combination with metformin with or without pioglitazone. The mean age of the population was 58 years, and mean duration of diabetes was 10 years. 49% were male. 91% were White, 8% Black or African American. 11% were Hispanic or Latino ethnicity, 6% of patients had eGFR < 60mL/min/1.73m2; no patient had eGFR < 30mL/min/1.73m2. The mean BMI was 33.1 kg/m2.

The starting dose of XULTOPHY 100/3.6 was 16 units (16 units insulin degludec/0.58 mg liraglutide), and the average starting dose of liraglutide was 1.7 mg. XULTOPHY 100/3.6 was titrated twice weekly to target a fasting blood glucose goal of 72-90 mg/dL. The end of trial dose of XULTOPHY 100/3.6 was 44 units (44 units insulin degludec/1.58 mg liraglutide). The primary endpoint, change in HbA1c, was tested for superiority of XULTOPHY 100/3.6 to unchanged liraglutide therapy.

At the end of 26 weeks, there was a reduction in HbA1c from baseline of 1.31% for XULTOPHY 100/3.6 and 0.36% for liraglutide (see Table 8).

Table 8: Results of a 26-Week Trial with XULTOPHY 100/3.6 in Patients with Type 2 Diabetes Mellitus Inadequately Controlled on Liraglutide up to 1.8 mg Daily

     ATest for superiority evaluated at 5.0% level for significance, (p<0.0001)
     #Estimated using an ANCOVA with treatment, pre-trial liraglutide and region as fixed factors and baseline response as covariate. Multiple imputation modelled “return to baseline” of the treatment effect for subjects having missing week 26 data. 
     ##Patients with missing HbA1c data at week 26 were considered as non-responders. 
    There were 5.2% of subjects in the XULTOPHY 100/3.6 arm and 19.0% in the liraglutide arm for whom HbA1c data was missing at week 26.

Figure 3: Mean HbA1c (%) By Treatment Week in Patients with Type 2 Diabetes Mellitus Inadequately Controlled on Liraglutide

IDegLira=XULTOPHY 100/3.6

Converting from basal insulin 

NCT01392573: The efficacy and safety of XULTOPHY 100/3.6 compared to insulin degludec, both once daily and added on to metformin, were studied in a 26-week randomized, double-blind, trial in 398 patients with type 2 diabetes mellitus inadequately controlled on basal insulin and metformin alone or in combination with sulfonylurea/glinides. Basal insulin and sulfonylurea/glinides were discontinued at randomization. 

The mean age of the trial population was 57 years, and mean duration of diabetes was 11 years. 55% were male. 77% were White, 5% Black or African American. 10% were Hispanic or Latino ethnicity, 7% of patients had eGFR < 60mL/min/1.73m2; no patient had eGFR < 30mL/min/1.73m2. The mean BMI was 33.7 kg/m2. The mean dose of metformin and basal insulin in patients entering the trial was approximately 2 g and 29 units, respectively. 

The starting dose of XULTOPHY 100/3.6 and insulin degludec was 16 units (16 units insulin degludec/0.58 mg liraglutide) and 16 units, respectively. XULTOPHY 100/3.6 and degludec were to be titrated twice weekly to target a fasting blood glucose goal of 72-90 mg/dL. Patients could not increase their dose by more than 4 units per week, and the maximum dose of insulin degludec was limited to 50 units. The targeted fasting blood glucose goal was achieved in 24.0% of patients randomized to insulin degludec and in 31.6% of the patients randomized to XULTOPHY 100/3.6 at 26 weeks.

At the end of 26 weeks, reductions in HbA1c from baseline of 1.94% for XULTOPHY 100/3.6 and 1.05% for insulin degludec limited to 50 units daily were observed (see Table 9). The mean difference (95% CI) in HbA1c reduction between XULTOPHY 100/3.6 and insulin degludec was -0.89 [-1.10; -0.68] and statistically significant. The trial was designed to show the contribution of the liraglutide component to glycemic lowering and the insulin degludec dosing algorithm was selected to isolate the effect of the GLP-1 component. At the end of the trial, the doses of insulin degludec were equivalent between treatment groups. The mean final dose of XULTOPHY 100/3.6 and insulin degludec was 46 units (for XULTOPHY 100/3.6: 46 units insulin degludec/1.66 mg liraglutide). The difference in glucose lowering effect observed in the trial may not necessarily reflect the effect that will be observed in the care setting where insulin degludec dosage can be different than that used in the trial.

Table 9: Results of a 26-Week Trial in Patients with Type 2 Diabetes Mellitus Inadequately Controlled on Basal Insulin

Ap<0.01. The trial was designed to show the contribution of the liraglutide component to glycemic lowering and the insulin degludec dosing algorithm was selected to isolate the effect of the GLP-1 component. At the end of the trial, the doses of insulin degludec were equivalent between treatment groups. The mean final dose of XULTOPHY 100/3.6 and insulin degludec was 46 units (for XULTOPHY 100/3.6: 46 units insulin degludec/1.66 mg liraglutide). The difference in glucose lowering effect observed in the trial may not necessarily reflect the effect that will be observed in the care setting where alternative insulin degludec dosage can be used.

*Maximum dose 50 units

     #Estimated using an ANCOVA with treatment, country, and previous antidiabetic treatment as fixed factors and baseline response as covariate. Multiple imputation modelled “jump to control” of the treatment effect for subjects having missing week 26 data. 
     ##Patients with missing HbA1c data at week 26 were considered non-responders. 
    There were 11.1% of subjects in the XULTOPHY 100/3.6 arm and 13.1% in the insulin degludec arm for whom HbA1c data was 
    missing at week 26.

NCT01952145: The efficacy and safety of XULTOPHY 100/3.6 compared to insulin glargine U-100, both once daily and added on to metformin, were studied in a 26-week randomized, open-label, two-arm parallel trial in 557 patients with type 2 diabetes mellitus inadequately controlled on insulin glargine U-100 and metformin. 

The mean age of the trial population was 59 years and mean duration of diabetes was 12 years. 50% were male. 95% were White, 2% Black or African American. 43% were Hispanic or Latino ethnicity, 6% of patients had eGFR < 60mL/min/1.73m2; one patient had eGFR < 30mL/min/1.73m2. The mean BMI was 32 kg/m2. The mean dose of insulin glargine U-100 in patients entering the trial was 32 units. 

XULTOPHY 100/3.6 and insulin glargine were to be titrated twice weekly to target a fasting blood glucose goal of 72-90 mg/dL. The starting dose of XULTOPHY 100/3.6 was 16 units (16 units insulin degludec/0.58 mg liraglutide). The average starting dose of insulin glargine U-100 was 32 units. Patients could not increase the dose of the two products by more than 4 units per week and there was no maximum allowed dose of insulin glargine. The targeted fasting plasma blood glucose goal was achieved in 39.6% of patients randomized to insulin glargine and 32.9% of the patients randomized to XULTOPHY 100/3.6 at 26 weeks. 

At the end of 26 weeks, treatment with XULTOPHY 100/3.6 resulted in a reduction in HbA1c from baseline of 1.67% and was 1.16% for insulin glargine U-100 (see Table 10) and excluded the pre-specified non-inferiority margin of 0.3%. At the end of the trial, the average dose of XULTOPHY 100/3.6 was 41 units (41 units insulin degludec/1.48 mg liraglutide) and the dose of glargine was 66 units, it is unclear that these observed differences in insulin doses are clinically important. The difference in HbA1c effect observed at 26 weeks may not necessarily reflect the effect in the care setting where insulin glargine may be more rapidly titrated.

Table 10: Results of a 26-Week Trial in Patients with Type 2 Diabetes Mellitus Inadequately Controlled on Insulin Glargine U-100

     Ap<0.01. Primary endpoint was tested for noninferiority of XULTOPHY 100/3.6 to insulin glargine U-100. The difference in glucose lowering effect observed in the trial may not necessarily reflect the effect that will be observed in the care setting where alternative insulin glargine dosage can be used.
     #Estimated using an ANCOVA with treatment and region as fixed factors and baseline response as covariate. Multiple imputation modelled “return to baseline” of the treatment effect for subjects having missing week 26 data. 
     ##Patients with missing HbA1c value at week 26 data were considered non-responder. 
    There were 10.1% of subjects in the XULTOPHY 100/3.6 arm and 4.7% in the insulin glargine U-100 arm for whom HbA1c data was missing at week 26.