Victoza Drug Information

Glycemic Control Trials in Adults with Type 2 Diabetes Mellitus In glycemic control trials, VICTOZA has been studied as monotherapy and in combination with one or two oral anti-diabetic medications or basal insulin. VICTOZA was also studied in a cardiovascular outcomes trial (LEADER trial). In each of the placebo controlled trials, treatment with VICTOZA produced clinically and statistically significant improvements in hemoglobin A 1c 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.

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 HbA 1c compared to glimepiride (Table 3). The mean age of participants was 53 years, and the mean duration of diabetes was 5 years.

The mean BMI was 33.1 kg/m 2. Table 3 Results of a 52-week monotherapy trial a a Intent-to-treat population using last observation on study b Least squares mean adjusted for baseline value *p-value <0.05 *p-value <0.0001 Figure 3 Mean HbA 1c 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 HbA 1c reduction relative to placebo add-on to metformin and resulted in a similar mean HbA 1c reduction relative to glimepiride 4 mg add-on to metformin (Table 4). 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/m 2. Table 4 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 mean age of participants was 56 years, and the mean duration of diabetes was 6 years. The mean BMI was 32.8 kg/m 2.

The primary endpoint was the change in HbA 1c from baseline to Week 26. Table 5 Results of a 26-week open-label trial of VICTOZA Compared to Sitagliptin (both in combination with metformin) a a Intent-to-treat population using last observation on study b Least squares mean adjusted for baseline value *p-value <0.0001 Figure 4 Mean HbA 1c 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 (HbA 1c 7-10%) on metformin (≥1500 mg/day) alone or inadequate glycemic control (HbA 1c 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.

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. The remaining 323 patients with HbA 1c ≥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. The mean BMI was 34.0 kg/m 2. Treatment with insulin detemir as add-on to VICTOZA 1.8 mg + metformin resulted in statistically significant reductions in HbA 1c and FPG compared to continued, unchanged treatment with VICTOZA 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 VICTOZA 1.8 mg + metformin alone. Table 6 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 HbA 1c < 7% after 12 weeks of Metformin and VICTOZA a a Intent-to-treat population using last observation on study b Least squares mean adjusted for baseline value *p-value <0.0001 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. Participants were 49.4% male, 64.4% White and 2.8% Black or African American.

The mean BMI was 29.9 kg/m 2. 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. 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/m 2. 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 8 Results of a 26-week trial of VICTOZA as add-on to metformin and sulfonylurea a a Intent-to-treat population using last observation on study b Least squares mean adjusted for baseline value For insulin glargine, optimal titration regimen was not achieved for 80% of patients. *p-value <0.05 *p-value <0.0001 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. The mean BMI was 32.9 kg/m 2.

Treatment with VICTOZA 1.8 mg resulted in statistically significant reductions in HbA 1c and FPG relative to exenatide (Table 9). 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 9 Results of a 26-week open-label trial of VICTOZA versus Exenatide (both in combination with metformin and/or sulfonylurea) a a Intent-to-treat population using last observation carried forward b Least squares mean adjusted for baseline value *p-value <0.0001 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). 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. The mean BMI was 33.9 kg/m 2.

Treatment with VICTOZA as add-on to metformin and rosiglitazone produced a statistically significant reduction in mean HbA 1c 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 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 10 Results of a 26-week trial of VICTOZA as add-on to metformin and thiazolidinedione a a Intent-to-treat population using last observation on study b Least squares mean adjusted for baseline value *p-value <0.0001 VICTOZA 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, 279 patients with moderate renal impairment, as per MDRD formula (eGFR 30−59 mL/min/1.73 m 2 ), were randomized to VICTOZA or placebo once daily.

VICTOZA was added to the patient’s stable pre-trial antidiabetic regimen (insulin therapy and/or metformin, pioglitazone, or sulfonylurea). The dose of VICTOZA 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 HbA 1c ≤ 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. Approximately half of patients had an eGFR between 30 and <45mL/min/1.73 m 2.

Table 11 Results of a 26-week trial of VICTOZA compared to placebo in Patients with Renal Impairment a 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 VICTOZA and placebo patients, respectively. d Based on the known number of subjects achieving HbA 1c < 7%. When applying the multiple imputation method described in b above, the estimated percents achieving HbA 1c < 7% are 47.6% and 24.9% for VICTOZA 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. *p-value <0.0001 *p-value <0.05 Figure 3 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

Glycemic Control Trial in Pediatric Patients 10 Years of Age and Older with Type 2 Diabetes Mellitus VICTOZA was evaluated in a 26-week, double-blind, randomized, parallel group, placebo controlled multi-center trial (NCT01541215), in 134 pediatric patients with type 2 diabetes aged 10 years and older. Patients were randomized to VICTOZA once-daily or placebo once-daily in combination with metformin with or without basal insulin treatment. All patients were on a metformin dose of 1000 to 2000 mg prior to randomization.

The mean duration of diabetes was 1.9 years and the mean HbA 1c was 7.8%. At week 26, treatment with VICTOZA was superior in reducing HbA 1c from baseline versus placebo. The estimated treatment difference in HbA 1c reduction from baseline between VICTOZA and placebo was -1.06% with a 95% confidence interval of (see Table 12).

Table 12 Results at week 26 in a trial comparing VICTOZA in combination with metformin with or without basal insulin versus Placebo in combination with metformin with or without basal insulin in Pediatric Patients 10 Years of Age and Older with Type 2 Diabetes Mellitus Treatment difference VICTOZA vs Placebo Treatment difference VICTOZA vs Placebo -33.83 a The change from baseline to end of treatment visit in HbA 1c and FPG was analyzed using a pattern mixture model with multiple imputation. Missing observations (10.6% in the VICTOZA, 14.5% in the placebo) were imputed from the placebo arm based on multiple (x10,000) imputations. The data for week 26 was then analyzed with an ANCOVA model containing treatment, sex and age group as fixed effects and baseline value as covariate. b Categories are derived from continuous measurements of HbA 1c using a pattern mixture model with multiple imputation for missing observations. p-value <0.001

Cardiovascular Outcomes Trial in Patients with Type 2 Diabetes Mellitus and Atherosclerotic Cardiovascular Disease The LEADER trial (NCT01179048) was a multi-national, multi-center, placebo-controlled, double-blind trial. The study compared the risk of major adverse cardiovascular events between VICTOZA and placebo when these were added to, and used concomitantly with, background standard of care treatments for type 2 diabetes. The primary endpoint, MACE, was the time to first occurrence of a three part composite outcome which included; cardiovascular death, non-fatal myocardial infarction and non-fatal stroke.

Patients eligible to enter the trial were; 50 years of age or older and had established, stable, cardiovascular, cerebrovascular, peripheral artery disease, chronic kidney disease or NYHA class II and III heart failure (80% of the enrolled population) or were 60 years of age or older and had other specified risk factors for cardiovascular disease (20% of the enrolled population). At baseline, demographic and disease characteristics were balanced. In the study, 12.1% of the population identified as Hispanic or Latino.

A history of previous myocardial infarction was reported in 31% of randomized individuals, a prior revascularization procedure in 39%, a prior ischemic stroke in 11%, documented symptomatic coronary disease in 9%, documented asymptomatic cardiac ischemia in 26%, and a diagnosis of New York Heart Association (NYHA) class II to III heart failure in 14%. The most common background antidiabetic drugs used at baseline and in the trial were metformin, sulfonylurea and insulin. Use of DPP-4 inhibitors and other GLP-1 receptor agonists was excluded by protocol and SGLT-2 inhibitors were either not approved or not widely available.

During the trial, investigators could modify anti-diabetic and cardiovascular medications to achieve local standard of care treatment targets with respect to blood glucose, lipid, and blood pressure, and manage patients recovering from an acute coronary syndrome or stroke event per local treatment guidelines. For the primary analysis, a Cox proportional hazards model was used to test for non-inferiority against the pre-specified risk margin of 1.3 for the hazard ratio of MACE and to test for superiority on MACE if non-inferiority was demonstrated. Type 1 error was controlled across multiple tests.

VICTOZA significantly reduced the occurrence of MACE. The estimated hazard ratio (95% CI) for time to first MACE was 0.87. Refer to Figure 5 and Table 13.

Vital status was available for 99.7% of subjects in the trial. A total of 828 deaths were recorded during the LEADER trial. A majority of the deaths in the trial were categorized as cardiovascular deaths and non-cardiovascular deaths were balanced between the treatment groups (3.5% in patients treated with VICTOZA and 3.6% in patients treated with placebo).

The estimated hazard ratio of time to all-cause death for VICTOZA compared to placebo was 0.85. Figure 5 Kaplan-Meier: Time to First Occurrence of a MACE in the LEADER Trial (Patients with T2DM and Atherosclerotic CVD) Table 13 Treatment Effect for the Primary Composite Endpoint, MACE, and its Components in the LEADER Trial (Patients with T2DM and Atherosclerotic CVD) a a Full analysis set (all randomized patients) b Cox-proportional hazards model with treatment as a factor c p-value for superiority (2-sided) 0.011 d Number and percentage of first events Figure 5