14.1 Glycemic Control Trials in Adults with Type 2 Diabetes Mellitus
In glycemic control trials in adults, liraglutide injection has been studied as monotherapy and in combination with one or two oral anti-diabetic medications or basal insulin.
In each of the placebo controlled trials, treatment with liraglutide injection produced clinically and statistically significant improvements in hemoglobin A1c and fasting plasma glucose (FPG) compared to placebo.
All liraglutide injection-treated patients started at 0.6 mg/day. The dose was increased in weekly intervals by 0.6 mg to reach 1.2 mg or 1.8 mg for patients randomized to these higher doses. Liraglutide injection 0.6 mg is not effective for glycemic control and is intended only as a starting dose to reduce gastrointestinal intolerance [see Dosage and Administration (2)].
Monotherapy
In this 52-week trial, 746 adult patients with type 2 diabetes mellitus were randomized to liraglutide injection 1.2 mg, liraglutide injection 1.8 mg, or glimepiride 8 mg. Patients who were randomized to glimepiride were initially treated with 2 mg daily for two weeks, increasing to 4 mg daily for another two weeks, and finally increasing to 8 mg daily. Treatment with liraglutide injection 1.8 mg and 1.2 mg resulted in a statistically significant reduction in HbA1c compared to glimepiride (Table 3). The percentage of patients who discontinued due to ineffective therapy was 3.6% in the liraglutide injection 1.8 mg treatment group, 6.0% in the liraglutide injection 1.2 mg treatment group, and 10.1% in the glimepiride-treatment group.
The mean age of participants was 53 years, and the mean duration of diabetes was 5 years. Participants were 49.7% male, 77.5% White, 12.6% Black or African American and 35.0% of Hispanic or Latino ethnicity. The mean BMI was 33.1 kg/m2.
Table 3 Results of a 52-week Monotherapy Trial in Adults with Type 2 Diabetes Mellitusa
aIntent-to-treat population using last observation on study
bLeast squares mean adjusted for baseline value
Figure 3 Mean HbA1c for Adult Patients with Type 2 Diabetes Mellitus who Completed the 52-week Trial and for the Last Observation Carried Forward (LOCF, intent-to-treat) data at Week 52 (Monotherapy)
In this 26-week trial, 1,091 adult patients with type 2 diabetes mellitus were randomized to liraglutide injection 0.6 mg, liraglutide injection 1.2 mg, liraglutide injection 1.8 mg, placebo, or glimepiride 4 mg (one-half of the maximal approved dose in the United States), all as add-on to metformin. Randomization occurred after a 6-week run-in period consisting of a 3-week initial forced metformin titration period followed by a maintenance period of another 3 weeks. During the titration period, doses of metformin were increased up to 2,000 mg/day. Treatment with liraglutide injection 1.2 mg and 1.8 mg as add-on to metformin resulted in a significant mean HbA1c reduction relative to placebo add-on to metformin and resulted in a similar mean HbA1c reduction relative to glimepiride 4 mg add-on to metformin (Table 4). The percentage of patients who discontinued due to ineffective therapy was 5.4% in the liraglutide injection 1.8 mg + metformin treatment group, 3.3% in the liraglutide injection 1.2 mg + metformin treatment group, 23.8% in the placebo + metformin treatment group, and 3.7% in the glimepiride + metformin treated group.
The mean age of participants was 57 years, and the mean duration of diabetes was 7 years. Participants were 58.2% male, 87.1% White and 2.4% Black or African American. The mean BMI was 31.0 kg/m2.
Table 4 Results of a 26-week Trial of Liraglutide Injection as Add-on to Metformin in Adults with Type 2 Diabetes Mellitusa
aIntent-to-treat population using last observation on study
bLeast squares mean adjusted for baseline value
†For glimepiride, one-half of the maximal approved United States dose.
Liraglutide Injection Compared to Sitagliptin, Both as Add-on to Metformin
In this 26 week, open-label trial, 665 adult patients with type 2 diabetes mellitus on a background of metformin ≥1,500 mg per day were randomized to liraglutide injection 1.2 mg once daily, liraglutide injection 1.8 mg once daily or sitagliptin 100 mg once daily, all dosed according to approved labeling. Patients were to continue their current treatment on metformin at a stable, pre-trial dose level and dosing frequency.
The mean age of participants was 56 years, and the mean duration of diabetes was 6 years. Participants were 52.9% male, 86.6% White, 7.2% Black or African American and 16.2% of Hispanic or Latino ethnicity. The mean BMI was 32.8 kg/m2.
The primary endpoint was the change in HbA1c from baseline to Week 26. Treatment with liraglutide injection 1.2 mg and liraglutide injection 1.8 mg resulted in statistically significant reductions in HbA1c relative to sitagliptin 100 mg (Table 5). The percentage of patients who discontinued due to ineffective therapy was 3.1% in the liraglutide injection 1.2 mg group, 0.5% in the liraglutide injection 1.8 mg treatment group, and 4.1% in the sitagliptin 100 mg treatment group. From a mean baseline body weight of 94 kg, there was a mean reduction of 2.7 kg for liraglutide injection 1.2 mg, 3.3 kg for liraglutide injection 1.8 mg, and 0.8 kg for sitagliptin 100 mg.
Table 5 Results of a 26-week Open-label Trial of Liraglutide Injection Compared to Sitagliptin (both in combination with metformin) in Adults with Type 2 Diabetes Mellitusa
aIntent-to-treat population using last observation on study
bLeast squares mean adjusted for baseline value
**p-value <0.0001
Figure 4 Mean HbA1c for Adult Patients with Type 2 Diabetes Mellitus who Completed the 26-week Trial and for the Last Observation Carried Forward (LOCF, intent-to-treat) data at Week 26
Combination Therapy with Metformin and Insulin
This 26-week open-label trial enrolled 988 adult patients with type 2 diabetes mellitus with inadequate glycemic control (HbA1c 7-10%) on metformin (≥1,500 mg/day) alone or inadequate glycemic control (HbA1c 7-8.5%) on metformin (≥1,500 mg/day) and a sulfonylurea. Patients who were on metformin and a sulfonylurea discontinued the sulfonylurea then all patients entered a 12-week run-in period during which they received add-on therapy with liraglutide injection titrated to 1.8 mg once-daily. At the end of the run-in period, 498 patients (50%) achieved HbA1c <7% with liraglutide injection 1.8 mg and metformin and continued treatment in a non-randomized, observational arm. Another 167 patients (17%) withdrew from the trial during the run-in period with approximately one-half of these patients doing so because of gastrointestinal adverse reactions [see Adverse Reactions (6.1)]. The remaining 323 patients with HbA1c ≥7% (33% of those who entered the run-in period) were randomized to 26 weeks of once-daily insulin detemir administered in the evening as add-on therapy (N=162) or to continued, unchanged treatment with liraglutide injection 1.8 mg and metformin (N=161). The starting dose of insulin detemir was 10 units/day and the mean dose at the end of the 26-week randomized period was 39 units/day. During the 26 week randomized treatment period, the percentage of patients who discontinued due to ineffective therapy was 11.2% in the group randomized to continued treatment with liraglutide injection 1.8 mg and metformin and 1.2% in the group randomized to add-on therapy with insulin detemir.
The mean age of participants was 57 years, and the mean duration of diabetes was 8 years. Participants were 55.7% male, 91.3% White, 5.6% Black or African American and 12.5% of Hispanic or Latino ethnicity. The mean BMI was 34.0 kg/m2.
Treatment with insulin detemir as add-on to liraglutide injection 1.8 mg + metformin resulted in statistically significant reductions in HbA1c and FPG compared to continued, unchanged treatment with liraglutide injection 1.8 mg + metformin alone (Table 6). From a mean baseline body weight of 96 kg after randomization, there was a mean reduction of 0.3 kg in the patients who received insulin detemir add-on therapy compared to a mean reduction of 1.1 kg in the patients who continued on unchanged treatment with liraglutide injection 1.8 mg + metformin alone.
Table 6 Results of a 26-week Open-label Trial of Insulin detemir as add on to Liraglutide Injection + Metformin Compared to Continued Treatment with Liraglutide Injection + Metformin alone in Adult Patients with Type 2 Diabetes Mellitus not Achieving HbA1c < 7% after 12 weeks of Metformin and Liraglutide Injectiona
aIntent-to-treat population using last observation on study
bLeast squares mean adjusted for baseline value
In this 26-week trial, 1,041 adult patients with type 2 diabetes mellitus were randomized to liraglutide injection 0.6 mg, liraglutide injection 1.2 mg, liraglutide injection 1.8 mg, placebo, or rosiglitazone 4 mg (one-half of the maximal approved dose in the United States), all as add-on to glimepiride. Randomization occurred after a 4-week run-in period consisting of an initial, 2-week, forced-glimepiride titration period followed by a maintenance period of another 2 weeks. During the titration period, doses of glimepiride were increased to 4 mg/day. The doses of glimepiride could be reduced (at the discretion of the investigator) from 4 mg/day to 3 mg/day or 2 mg/day (minimum) after randomization, in the event of unacceptable hypoglycemia or other adverse events.
The mean age of participants was 56 years, and the mean duration of diabetes was 8 years. Participants were 49.4% male, 64.4% White and 2.8% Black or African American. The mean BMI was 29.9 kg/m2.
Treatment with liraglutide injection 1.2 mg and 1.8 mg as add-on to glimepiride resulted in a statistically significant reduction in mean HbA1c compared to placebo add-on to glimepiride (Table 7). The percentage of patients who discontinued due to ineffective therapy was 3.0% in the liraglutide injection 1.8 mg + glimepiride treatment group, 3.5% in the liraglutide injection 1.2 mg + glimepiride treatment group, 17.5% in the placebo + glimepiride treatment group, and 6.9% in the rosiglitazone + glimepiride treatment group.
Table 7 Results of a 26-week Trial of Liraglutide Injection as add-on to Sulfonylurea in Adult Patients with Type 2 Diabetes Mellitusa
aIntent-to-treat population using last observation on study
bLeast squares mean adjusted for baseline value
†For rosiglitazone, one-half of the maximal approved United States dose.
In this 26-week trial, 581 adult patients with type 2 diabetes mellitus were randomized to liraglutide injection 1.8 mg, placebo, or insulin glargine, all as add-on to metformin and glimepiride. Randomization took place after a 6-week run-in period consisting of a 3-week forced metformin and glimepiride titration period followed by a maintenance period of another 3 weeks. During the titration period, doses of metformin and glimepiride were to be increased up to 2,000 mg/day and 4 mg/day, respectively. After randomization, patients randomized to liraglutide injection 1.8 mg underwent a 2 week period of titration with liraglutide injection. During the trial, the liraglutide injection and metformin doses were fixed, although glimepiride and insulin glargine doses could be adjusted. Patients titrated glargine twice-weekly during the first 8 weeks of treatment based on self-measured fasting plasma glucose on the day of titration. After Week 8, the frequency of insulin glargine titration was left to the discretion of the investigator, but, at a minimum, the glargine dose was to be revised, if necessary, at Weeks 12 and 18. Only 20% of glargine-treated patients achieved the pre-specified target fasting plasma glucose of ≤100 mg/dL. Therefore, optimal titration of the insulin glargine dose was not achieved in most patients.
The mean age of participants was 58 years, and the mean duration of diabetes was 9 years. Participants were 56.5% male, 75.0% White and 3.6% Black or African American. The mean BMI was 30.5 kg/m2.
Treatment with liraglutide injection as add-on to glimepiride and metformin resulted in a statistically significant mean reduction in HbA1c compared to placebo add-on to glimepiride and metformin (Table 8). The percentage of patients who discontinued due to ineffective therapy was 0.9% in the liraglutide injection 1.8 mg + metformin + glimepiride treatment group, 0.4% in the insulin glargine + metformin + glimepiride treatment group, and 11.3% in the placebo + metformin + glimepiride treatment group.
Table 8 Results of a 26-week Trial of Liraglutide Injection as Add-on to Metformin and Sulfonylurea in Adult Patients with Type 2 Diabetes Mellitusa
aIntent-to-treat population using last observation on study
bLeast squares mean adjusted for baseline value
†For insulin glargine, optimal titration regimen was not achieved for 80% of patients.
Liraglutide Injection Compared to Exenatide, Both as Add-on to Metformin and/or Sulfonylurea Therapy
In this 26week, open-label trial, 464 adult patients with type 2 diabetes mellitus on a background of metformin monotherapy, sulfonylurea monotherapy or a combination of metformin and sulfonylurea were randomized to once daily liraglutide injection 1.8 mg or exenatide 10 mcg twice daily. Maximally tolerated doses of background therapy were to remain unchanged for the duration of the trial. Patients randomized to exenatide started on a dose of 5 mcg twice-daily for 4 weeks and then were escalated to 10 mcg twice daily.
The mean age of participants was 57 years, and the mean duration of diabetes was 8 years. Participants were 51.9% male, 91.8% White, 5.4% Black or African American and 12.3% of Hispanic or Latino ethnicity. The mean BMI was 32.9 kg/m2.
Treatment with liraglutide injection 1.8 mg resulted in statistically significant reductions in HbA1c and FPG relative to exenatide (Table 9). The percentage of patients who discontinued for ineffective therapy was 0.4% in the liraglutide injection treatment group and 0% in the exenatide treatment group. Both treatment groups had a mean decrease from baseline in body weight of approximately 3 kg.
Table 9 Results of a 26-week Open-label trial of Liraglutide Injection versus Exenatide (both in combination with metformin and/or sulfonylurea) in Adult Patients with Type 2 Diabetes Mellitusa
aIntent-to-treat population using last observation carried forward
bLeast squares mean adjusted for baseline value
In this 26-week trial, 533 adult patients with type 2 diabetes mellitus were randomized to liraglutide injection 1.2 mg, liraglutide injection 1.8 mg or placebo, all as add-on to rosiglitazone (8 mg) plus metformin (2,000 mg). Patients underwent a 9 week run-in period (3-week forced dose escalation followed by a 6-week dose maintenance phase) with rosiglitazone (starting at 4 mg and increasing to 8 mg/day within 2 weeks) and metformin (starting at 500 mg with increasing weekly increments of 500 mg to a final dose of 2,000 mg/day). Only patients who tolerated the final dose of rosiglitazone (8 mg/day) and metformin (2,000 mg/day) and completed the 6-week dose maintenance phase were eligible for randomization into the trial.
The mean age of participants was 55 years, and the mean duration of diabetes was 9 years. Participants were 61.6% male, 84.2% White, 10.2% Black or African American and 16.4% of Hispanic or Latino ethnicity. The mean BMI was 33.9 kg/m2.
Treatment with liraglutide injection as add-on to metformin and rosiglitazone produced a statistically significant reduction in mean HbA1c compared to placebo add-on to metformin and rosiglitazone (Table 10). The percentage of patients who discontinued due to ineffective therapy was 1.7% in the liraglutide injection 1.8 mg + metformin + rosiglitazone treatment group, 1.7% in the liraglutide injection 1.2 mg + metformin + rosiglitazone treatment group, and 16.4% in the placebo + metformin + rosiglitazone treatment group.
Table 10 Results of a 26-week Trial of Liraglutide Injection as Add-on to Metformin and Thiazolidinedione in Adult Patients with Type 2 Diabetes Mellitusa
aIntent-to-treat population using last observation on study
bLeast squares mean adjusted for baselnie value
**p-value <0.0001
Liraglutide Injection Compared to Placebo Both With or Without metformin and/or Sulfonylurea and/or Pioglitazone and/or Basal or Premix insulin in Patients with Type 2 Diabetes Mellitus and Moderate Renal Impairment
In this 26-week, double-blind, randomized, placebo-controlled, parallel-group trial in adult patients with type 2 diabetes mellitus, 279 patients with moderate renal impairment, as per MDRD formula (eGFR 3059 mL/min/1.73 m2), were randomized to liraglutide injection or placebo once daily. Liraglutide injection was added to the patient's stable pre-trial antidiabetic regimen (insulin therapy and/or metformin, pioglitazone, or sulfonylurea). The dose of liraglutide injection was escalated according to approved labeling to achieve a dose of 1.8 mg per day. The insulin dose was reduced by 20% at randomization for patients with baseline HbA1c ≤ 8% and fixed until liraglutide dose escalation was complete. Dose reduction of insulin and SU was allowed in case of hypoglycemia; up titration of insulin was allowed but not beyond the pre-trial dose.
The mean age of participants was 67 years, and the mean duration of diabetes was 15 years. Participants were 50.5% male, 92.3% White, 6.6% Black or African American, and 7.2% of Hispanic or Latino ethnicity. The mean BMI was 33.9 kg/m2. Approximately half of patients had an eGFR between 30 and <45mL/min/1.73 m2.
Treatment with liraglutide injection resulted in a statistically significant reduction in HbA1c from baseline at Week 26 compared to placebo (see Table 11). 123 patients reached the 1.8 mg dose of liraglutide injection.
Table 11 Results of a 26-week Trial of Liraglutide Injection Compared to Placebo in Adult Patients with Type 2 Diabetes Mellitus and Moderate Renal Impairmenta
a Intent-to-treat population
b Estimated using a mixed model for repeated measurement with treatment, country, stratification groups as factors and baseline as a covariate, all nested within visit. Multiple imputation method modeled "wash out" of the treatment effect for patients having missing data who discontinued treatment.
c Early treatment discontinuation, before week 26, occurred in 25% and 22% of liraglutide injection and placebo patients, respectively.
d Based on the known number of subjects achieving HbA1c < 7%. When applying the multiple imputation method described in b) above, the estimated percents achieving HbA1c < 7% are 47.6% and 24.9% for liraglutide injection and placebo, respectively.
e Estimated using a mixed model for repeated measurement with treatment, country, stratification groups as factors and baseline as a covariate, all nested within visit.