Mechanism of Action

Liraglutide is an acylated human Glucagon-Like Peptide-1 (GLP-1) receptor agonist with 97% amino acid sequence homology to endogenous human GLP-1(7-37). GLP-1(7-37) represents < 20% of total circulating endogenous GLP-1. Like GLP-1(7-37), liraglutide activates the GLP-1 receptor, a membrane-bound cell-surface receptor coupled to adenylyl cyclase by the stimulatory G-protein, Gs, in pancreatic beta cells. Liraglutide increases intracellular cyclic AMP (cAMP) leading to insulin release in the presence of elevated glucose concentrations. This insulin secretion subsides as blood glucose concentrations decrease and approach euglycemia. Liraglutide also decreases glucagon secretion in a glucose-dependent manner. The mechanism of blood glucose lowering also involves a delay in gastric emptying.

GLP-1(7-37) has a half-life of 1.5-2 minutes due to degradation by the ubiquitous endogenous enzymes, dipeptidyl peptidase IV (DPP-IV) and neutral endopeptidases (NEP). Unlike native GLP-1, liraglutide is stable against metabolic degradation by both peptidases and has a plasma half-life of 13 hours after subcutaneous administration. The pharmacokinetic profile of liraglutide, which makes it suitable for once daily administration, is a result of self-association that delays absorption, plasma protein binding and stability against metabolic degradation by DPP-IV and NEP.

Pharmacodynamics

Victoza®'s pharmacodynamic profile is consistent with its pharmacokinetic profile observed after single subcutaneous administration as Victoza® lowered fasting, premeal and postprandial glucose throughout the day.

Fasting and postprandial glucose was measured before and up to 5 hours after a standardized meal after treatment to steady state with 0.6, 1.2 and 1.8 mg Victoza® or placebo. Compared to placebo, the postprandial plasma glucose AUC0-300min was 35% lower after Victoza® 1.2 mg and 38% lower after Victoza® 1.8 mg.

Glucose-dependent Insulin Secretion

The effect of a single dose of 7.5 mcg/kg (~ 0.7 mg) Victoza® on insulin secretion rates (ISR) was investigated in 10 patients with type 2 diabetes during graded glucose infusion. In these patients, on average, the ISR response was increased in a glucose-dependent manner (Figure 2).

Figure 2: Mean Insulin Secretion Rate (ISR) versus Glucose Concentration Following Single-Dose Victoza® 7.5 mcg/kg (~ 0.7 mg) or Placebo in Patients with Type 2 Diabetes (N=10) During Graded Glucose Infusion

Glucagon Secretion

Victoza® lowered blood glucose by stimulating insulin secretion and lowering glucagon secretion. A single dose of Victoza® 7.5 mcg/kg (~ 0.7 mg) did not impair glucagon response to low glucose concentrations.

Gastric Emptying

Victoza® causes a delay of gastric emptying, thereby reducing the rate at which postprandial glucose appears in the circulation.

Cardiac Electrophysiology (QTc)

The effect of Victoza® on cardiac repolarization was tested in a QTc study. Victoza® at steady state concentrations with daily doses up to 1.8 mg did not produce QTc prolongation.

Pharmacokinetics

Absorption

Following subcutaneous administration, maximum concentrations of liraglutide are achieved at 8-12 hours post dosing. The mean peak (Cmax) and total (AUC) exposures of liraglutide were 35 ng/mL and 960 ng·h/mL, respectively, for a subcutaneous single dose of 0.6 mg. After subcutaneous single dose administrations, Cmax and AUC of liraglutide increased proportionally over the therapeutic dose range of 0.6 mg to 1.8 mg. At 1.8 mg Victoza®, the average steady state concentration of liraglutide over 24 hours was approximately 128 ng/mL. AUC0-∞ was equivalent between upper arm and abdomen, and between upper arm and thigh. AUC0-∞ from thigh was 22% lower than that from abdomen. However, liraglutide exposures were considered comparable among these three subcutaneous injection sites. Absolute bioavailability of liraglutide following subcutaneous administration is approximately 55%.

Distribution

The mean apparent volume of distribution after subcutaneous administration of Victoza® 0.6 mg is approximately 13 L. The mean volume of distribution after intravenous administration of Victoza® is 0.07 L/kg. Liraglutide is extensively bound to plasma protein ( > 98%).

Metabolism

During the initial 24 hours following administration of a single [3H]-liraglutide dose to healthy subjects, the major component in plasma was intact liraglutide. Liraglutide is endogenously metabolized in a similar manner to large proteins without a specific organ as a major route of elimination.

Elimination

Following a [3H]-liraglutide dose, intact liraglutide was not detected in urine or feces. Only a minor part of the administered radioactivity was excreted as liraglutide-related metabolites in urine or feces (6% and 5%, respectively). The majority of urine and feces radioactivity was excreted during the first 6-8 days. The mean apparent clearance following subcutaneous administration of a single dose of liraglutide is approximately 1.2 L/h with an elimination half-life of approximately 13 hours, making Victoza® suitable for once daily administration.

Specific Populations

Elderly - Age had no effect on the pharmacokinetics of Victoza® based on a pharmacokinetic study in healthy elderly subjects (65 to 83 years) and population pharmacokinetic analyses of patients 18 to 80 years of age [see Use In Specific Populations].

Gender - Based on the results of population pharmacokinetic analyses, females have 34% lower weight-adjusted clearance of Victoza® compared to males. Based on the exposure response data, no dose adjustment is necessary based on gender.

Race and Ethnicity - Race and ethnicity had no effect on the pharmacokinetics of Victoza® based on the results of population pharmacokinetic analyses that included Caucasian, Black, Asian and Hispanic/ Non-Hispanic subjects.

Body Weight - Body weight significantly affects the pharmacokinetics of Victoza® based on results of population pharmacokinetic analyses. The exposure of liraglutide decreases with an increase in baseline body weight. However, the 1.2 mg and 1.8 mg daily doses of Victoza® provided adequate systemic exposures over the body weight range of 40 – 160 kg evaluated in the clinical trials. Liraglutide was not studied in patients with body weight > 160 kg.

Pediatric - Victoza® has not been studied in pediatric patients [see Use In Specific Populations].

Renal Impairment - The single-dose pharmacokinetics of Victoza® were evaluated in subjects with varying degrees of renal impairment. Subjects with mild (estimated creatinine clearance 50-80 mL/min) to severe (estimated creatinine clearance < 30 mL/min) renal impairment and subjects with end-stage renal disease requiring dialysis were included in the trial. Compared to healthy subjects, liraglutide AUC in mild, moderate, and severe renal impairment and in end-stage renal disease was on average 35%, 19%, 29% and 30% lower, respectively [see Use in Specific Populations].

Hepatic Impairment - The single-dose pharmacokinetics of Victoza® were evaluated in subjects with varying degrees of hepatic impairment. Subjects with mild (Child Pugh score 5-6) to severe (Child Pugh score > 9) hepatic impairment were included in the trial. Compared to healthy subjects, liraglutide AUC in subjects with mild, moderate and severe hepatic impairment was on average 11%, 14% and 42% lower, respectively [see Use in Specific Populations].

Drug Interactions

In Vitro Assessment of Drug-drug Interactions

Victoza® has low potential for pharmacokinetic drug-drug interactions related to cytochrome P450 (CYP) and plasma protein binding.

In Vivo Assessment of Drug-drug Interactions

The drug-drug interaction studies were performed at steady state with Victoza® 1.8 mg/day. Before administration of concomitant treatment, subjects underwent a 0.6 mg weekly dose increase to reach the maximum dose of 1.8 mg/day. Administration of the interacting drugs was timed so that Cmax of Victoza® (8-12 h) would coincide with the absorption peak of the co-administered drugs.

Digoxin

A single dose of digoxin 1 mg was administered 7 hours after the dose of Victoza® at steady state. The concomitant administration with Victoza® resulted in a reduction of digoxin AUC by 16%; Cmax decreased by 31%. Digoxin median time to maximal concentration (Tmax) was delayed from 1 h to 1.5 h.

Lisinopril

A single dose of lisinopril 20 mg was administered 5 minutes after the dose of Victoza® at steady state. The co-administration with Victoza® resulted in a reduction of lisinopril AUC by 15%; Cmax decreased by 27%. Lisinopril median Tmax was delayed from 6 h to 8 h with Victoza®.

Atorvastatin

Victoza® did not change the overall exposure (AUC) of atorvastatin following a single dose of atorvastatin 40 mg, administered 5 hours after the dose of Victoza® at steady state. Atorvastatin Cmax was decreased by 38% and median Tmax was delayed from 1 h to 3 h with Victoza®.

Acetaminophen

Victoza® did not change the overall exposure (AUC) of acetaminophen following a single dose of acetaminophen 1000 mg, administered 8 hours after the dose of Victoza® at steady state. Acetaminophen Cmax was decreased by 31% and median Tmax was delayed up to 15 minutes.

Griseofulvin

Victoza® did not change the overall exposure (AUC) of griseofulvin following co-administration of a single dose of griseofulvin 500 mg with Victoza® at steady state. Griseofulvin Cmax increased by 37% while median Tmax did not change.

Oral Contraceptives

A single dose of an oral contraceptive combination product containing 0.03 mg ethinylestradiol and 0.15 mg levonorgestrel was administered under fed conditions and 7 hours after the dose of Victoza® at steady state. Victoza® lowered ethinylestradiol and levonorgestrel Cmax by 12% and 13%, respectively. There was no effect of Victoza® on the overall exposure (AUC) of ethinylestradiol. Victoza® increased the levonorgestrel AUC0-∞ by 18%. Victoza® delayed Tmax for both ethinylestradiol and levonorgestrel by 1.5 h.

Insulin Detemir

No pharmacokinetic interaction was observed between Victoza® and insulin detemir when separate subcutaneous injections of insulin detemir 0.5 Unit/kg (single-dose) and Victoza® 1.8 mg (steady state) were administered in patients with type 2 diabetes.

Clinical Studies

A total of 6090 patients with type 2 diabetes participated in 8 phase 3 trials. There were 5 double-blind (one of these trials had an open-label active control insulin glargine arm), randomized, controlled clinical trials, one of 52 weeks duration and four of 26 weeks duration. There were also three 26 week open-label trials; one comparing Victoza® to twice-daily exenatide, one comparing Victoza® to sitagliptin and one comparing Victoza®+metformin+insulin detemir to Victoza®+metformin alone. These multinational trials were conducted to evaluate the glycemic efficacy and safety of Victoza® in type 2 diabetes as monotherapy and in combination with one or two oral anti-diabetic medications or insulin detemir. The 7 add-on combination therapy trials enrolled patients who were previously treated with anti-diabetic therapy, and approximately two-thirds of patients in the monotherapy trial also were previously treated with anti-diabetic therapy. In total, 272 (4%) of the 6090 patients in these 8 trials were new to anti-diabetic therapy. In these 8 clinical trials, patients ranged in age from 18-80 years old and 54% were men. Approximately 82% of patients were Caucasian, and 6% were Black. In the 5 trials where ethnicity was captured, 10% of patients were Hispanic/Latino (n=630).

In each of the placebo controlled trials, treatment with Victoza® produced clinically and statistically significant improvements in hemoglobin A1c and fasting plasma glucose (FPG) compared to placebo.

All Victoza®-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. Victoza® 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].

Monotherapy

In this 52-week trial, 746 patients were randomized to Victoza® 1.2 mg, Victoza® 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 Victoza® 1.8 mg and 1.2 mg resulted in a statistically significant reduction in HbA1c compared to glimepiride (Table 6). The percentage of patients who discontinued due to ineffective therapy was 3.6% in the Victoza® 1.8 mg treatment group, 6.0% in the Victoza® 1.2 mg treatment group, and 10.1% in the glimepiride-treatment group.

Table 6: Results of a 52-week monotherapy trial^a

Figure 3: Mean HbA1c for patients who completed the 52-week trial and for the Last Observation Carried Forward (LOCF, intent-to-treat) data at Week 52 (Monotherapy)

Combination Therapy

Add-on to Metformin

In this 26-week trial, 1091 patients were randomized to Victoza® 0.6 mg, Victoza® 1.2 mg, Victoza® 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 2000 mg/day. Treatment with Victoza® 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 7). The percentage of patients who discontinued due to ineffective therapy was 5.4% in the Victoza® 1.8 mg + metformin treatment group, 3.3% in the Victoza® 1.2 mg + metformin treatment group, 23.8% in the placebo + metformin treatment group, and 3.7% in the glimepiride + metformin treated group.

Table 7: Results of a 26-week trial of Victoza® as add-on to metformin^a

Victoza® Compared to Sitagliptin, Both as Add-on to Metformin

In this 26–week, open-label trial, 665 patients on a background of metformin ≥ 1500 mg per day were randomized to Victoza® 1.2 mg once-daily, Victoza® 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 primary endpoint was the change in HbA1c from baseline to Week 26. Treatment with Victoza® 1.2 mg and Victoza® 1.8 mg resulted in statistically significant reductions in HbA1c relative to sitagliptin 100 mg (Table 8). The percentage of patients who discontinued due to ineffective therapy was 3.1% in the Victoza® 1.2 mg group, 0.5% in the Victoza® 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 Victoza® 1.2 mg, 3.3 kg for Victoza® 1.8 mg, and 0.8 kg for sitagliptin 100 mg.

Table 8: Results of a 26-week open-label trial of Victoza® Compared to Sitagliptin (both in combination with metformin)^a

Figure 4: Mean HbA1c for patients 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 patients with inadequate glycemic control (HbA1c 7-10%) on metformin ( ≥ 1500 mg/day) alone or inadequate glycemic control (HbA1c 7-8.5%) on metformin ( ≥ 1500 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 Victoza® titrated to 1.8 mg once-daily. At the end of the run-in period, 498 patients (50%) achieved HbA1c < 7% with Victoza® 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]. 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 Victoza® 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 Victoza® 1.8 mg and metformin and 1.2% in the group randomized to add-on therapy with insulin detemir.

Treatment with insulin detemir as add-on to Victoza® 1.8 mg + metformin resulted in statistically significant reductions in HbA1c and FPG compared to continued, unchanged treatment with Victoza® 1.8 mg + metformin alone (Table 9). 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 Victoza® 1.8 mg + metformin alone.

Table 9: Results of a 26-week open label trial of Insulin detemir as add on to Victoza® + metformin compared to continued treatment with Victoza® + metformin alone in patients not achieving HbA1c < 7% after 12 weeks of Metformin and Victoza®^a

Add-on to Sulfonylurea

In this 26-week trial, 1041 patients were randomized to Victoza® 0.6 mg, Victoza® 1.2 mg, Victoza® 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.

Treatment with Victoza® 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 10). The percentage of patients who discontinued due to ineffective therapy was 3.0% in the Victoza® 1.8 mg + glimepiride treatment group, 3.5% in the Victoza® 1.2 mg + glimepiride treatment group, 17.5% in the placebo + glimepiride treatment group, and 6.9% in the rosiglitazone + glimepiride treatment group.

Table 10: Results of a 26-week trial of Victoza® as add-on to sulfonylurea

Add-on to Metformin and Sulfonylurea

In this 26-week trial, 581 patients were randomized to Victoza® 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 2000 mg/day and 4 mg/day, respectively. After randomization, patients randomized to Victoza® 1.8 mg underwent a 2 week period of titration with Victoza®. During the trial, the Victoza® 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.

Treatment with Victoza® 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 11). The percentage of patients who discontinued due to ineffective therapy was 0.9% in the Victoza® 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 11: Results of a 26-week trial of Victoza® as add-on to metformin and sulfonylurea

Victoza® Compared to Exenatide, Both as Add-on to Metformin and/or Sulfonylurea Therapy

In this 26–week, open-label trial, 464 patients on a background of metformin monotherapy, sulfonylurea monotherapy or a combination of metformin and sulfonylurea were randomized to once daily Victoza® 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.

Treatment with Victoza® 1.8 mg resulted in statistically significant reductions in HbA1c and FPG relative to exenatide (Table 12). The percentage of patients who discontinued for ineffective therapy was 0.4% in the Victoza® 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 12: Results of a 26-week open-label trial of Victoza® versus Exenatide (both in combination with metformin and/or sulfonylurea)^a

Add-on to Metformin and Thiazolidinedione

In this 26-week trial, 533 patients were randomized to Victoza® 1.2 mg, Victoza® 1.8 mg or placebo, all as add-on to rosiglitazone (8 mg) plus metformin (2000 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 2000 mg/day). Only patients who tolerated the final dose of rosiglitazone (8 mg/day) and metformin (2000 mg/day) and completed the 6-week dose maintenance phase were eligible for randomization into the trial.

Treatment with Victoza® 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 13). The percentage of patients who discontinued due to ineffective therapy was 1.7% in the Victoza® 1.8 mg + metformin + rosiglitazone treatment group, 1.7% in the Victoza® 1.2 mg + metformin + rosiglitazone treatment group, and 16.4% in the placebo + metformin + rosiglitazone treatment group.

Table 13: Results of a 26-week trial of Victoza® as add-on to metformin and thiazolidinedione^a

Last reviewed on RxList: 5/9/2013
This monograph has been modified to include the generic and brand name in many instances.