General Information

Victoza is specifically indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Victoza was subsequently approved for use in children ages 10 to 17 years who have type 2 diabetes.

Mechanism of Action

Victoza contains liraglutide, an analog of human GLP-1, and acts as a GLP-1 receptor agonist. 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.

Side Effects

Adverse events associated with the use of Victoza may include, but are not limited to, the following:

• Nausea
• Vomiting
• Diarrhea
• Constipation
• Headache

Dosing/Administration

Victoza is supplied as solution designed for subcutaneous injection. Victoza can be administered once daily at any time of day, independently of meals, and can be injected subcutaneously in the abdomen, thigh or upper arm. The recommended initial dose is 0.6 mg per day for one week. After one week at 0.6 mg per day, the dose should be increased to 1.2 mg. If the 1.2 mg dose does not result in acceptable glycemic control, the dose can be increased to 1.8 mg.

Clinical Trial Results

FDA Approval
The FDA approval of Victoza in adults was based on five double-blind, randomized, controlled clinical trials, one of 52 weeks duration and four of 26 weeks duration, in 3,978 subjects.

Monotherapy
This 52-week trial enrolled 746 patients who 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.

Combination Therapy
Add-on to Metformin
This 26-week trial enrolled 1,091 patients who 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 six-week run-in period consisting of a three-week initial forced metformin titration period followed by a maintenance period of another three weeks. During the titration period, doses of metformin were increased up to 2,000 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.

Add-on to Sulfonylurea
This 26-week trial enrolled 1,041 patients who 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 four-week run-in period consisting of an initial two-week, forced-glimepiride titration period followed by a maintenance period of another two weeks. During the titration period, doses of glimepiride were increased to 4 mg/day. 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.
 

Add-on to Metformin and Sulfonylurea
This 26-week trial enrolled 581 patients who were randomized to Victoza 1.8 mg, placebo or insulin glargine, all as add-on to metformin and glimepiride. Randomization took place after a six-week run-in period consisting of a three-week forced metformin and glimepiride titration period followed by a maintenance period of another three 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 Victoza 1.8 mg underwent a two-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. 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.
 

Add-on to Metformin and Thiazolidinedione
This 26-week trial enrolled 533 patients who were randomized to Victoza 1.2 mg, Victoza 1.8 mg or placebo, all as add-on to rosiglitazone (8 mg) plus metformin (2,000 mg). Patients underwent a nine-week run-in period (three-week forced dose escalation followed by a six-week dose maintenance phase) with rosiglitazone (starting at 4 mg and increasing to 8 mg/day within two 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 six-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.

FDA approval of Victoza for use in children ages 10 to 17 years who have type 2 diabetes

The FDA approval of Victoza for use in children ages 10 to 17 years who have type 2 diabetes was based on phase 3 ELLIPSE trial. Patients ages 10 to 17 years were randomized to receive Victoza or placebo in combination with or without basal insulin for a more than 26-week double-blinded period followed by a 26-week open-label extension period. Victoza when added to metformin, with or without concurrent insulin treatment, significantly reduced A1C levels at 26 weeks to a level of 0.64 percent in comparison to placebo, which reduced AIC to 0.42 percent. That was the primary end point of the phase 3 study. The drug also maintained that AIC reduction through 52 weeks to 0.5 percent at 52 weeks, which was the secondary end point.