Product Spotlight: Victoza

Product Spotlight
Victoza
(liraglutide)

Liraglutide (Victoza) is a once-daily injection that treats type 2 diabetes mellitus (T2DM) in adults. The product is in a class of medicines known as glucagon-like peptide-1 (GLP-1) receptor agonists that help the pancreas release more insulin after patients eat a meal. Liraglutide stimulates the release of insulin from the pancreatic beta cells only when blood sugar levels are high.

Along with diet, exercise, and selected other diabetes medicines in adults with T2DM, liraglutide is intended to improve glycemic control. It is not recommended as initial therapy in patients who have not achieved adequate diabetes control on diet and exercise alone. This provides for liraglutide to be used in monotherapy, as second-line treatment, and in combination with commonly prescribed oral medications for diabetes.

Although there are many antidiabetic medications available for use, patients with T2DM often require different or additional antidiabetic medications to control their blood sugar. Liraglutide adds to the list of medications that can be used to help control blood sugar, but it is not recommended as first-line therapy for patients whose blood sugar is not controlled through diet and exercise.

The FDA approved liraglutide on the basis of 5 randomized, controlled, double-blinded phase 3 studies comparing the product to commonly prescribed treatments. These multinational Liraglutide Effect and Action in Diabetes (LEAD) trials evaluated liraglutide in monotherapy as well as in combination with 1 or 2 oral antidiabetic medications and showed better or equivalent lowering of blood glucose than active comparators such as sulphonylureas and thiazolidinediones.

A total of 3978 patients with type 2 diabetes participated in the trials. One of the trials was 52 weeks long and 4 were 26 weeks long. Liraglutide provided better or equivalent lowering of blood glucose than active comparators. Body weight was a secondary end point, and liraglutide demonstrated a reduction in body weight for patients with T2DM.

This Managed Care – First Report Product Spotlight provides a summary of published results from a monotherapy trial that compared liraglutide with glimepiride as well as a combination trial that compared liraglutide to insulin glargine and placebo, all in combination with metformin and glimepiride.

MONOTHERAPY TRIAL
Below is summary of results from a phase 3 trial that compared the efficacy and safety of 2 doses of liraglutide with glimepiride in patients with type 2 diabetes treated with diet/exercise or not more than half the maximum dose of one oral antidiabetic drug for ≥2 months.

Reference: Garber A, Henry R, Ratner R, et al. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase 3, double-blind, parallel-treatment trial. Lancet. 2009;373:473-481.

Study Objectives:
The trial was designed to investigate the safety and efficacy of liraglutide as monotherapy for T2DM.

Method
The double-blinded, double-dummy, randomized, parallel group, actively controlled, multicenter, multinational 52-week trial compared 2 doses of liraglutide (1.2 mg and 1.8 mg once daily) to glimepiride (8 mg once daily). Patients were stratified by baseline diabetes treatment, and those receiving oral antidiabetic drugs discontinued them at randomization.

After randomization, patients in the liraglutide group had their once-daily dose increased every week from 0.6 mg to 1.2 mg and then to 1.8 mg, administered via subcutaneous injection. Patients in the glimepiride group had their dose increased over 2 weeks from 2 mg to 4 mg to 8 mg, and doses were administered orally or in the morning before or with the first meal of the day.

The intention-to-treat analysis of outcomes and efficacy included participants who received ≥1 dose of study drug.

Population
The study randomized 746 patients aged 18 to 80 years with early type 2 diabetes mellitus and body mass index (BMI) of 45 kg/m² or less. There were 251 patients in the liraglutide 1.2 mg group, 247 patients in the liraglutide or 1.8 mg group, and 248 in the glimepiride group.

Baseline characteristics of the treatment groups were well balanced at baseline. The study population was about half men and half women, and about 77% were white. At randomization, the 36.5% of patients treated with diet and exercise had an HbA1c between 7.0% and 11.0%. The 63.5% of patients previously treated with oral monotherapy had an HbA1c between 7.0% and 10.0%. Mean weight at baseline was about 92 kg.

At baseline, mean HbA1c was 8.4% in the glimepiride group and 8.3% in the liraglutide 1.2 mg and 1.8 mg groups.

The trial excluded patients who received insulin treatment during the previous 3 months except as a short-term treatment for intercurrent illness. Patients were also excluded if they received treatment with systemic corticosteroids, had hypoglycemia unawareness or recurrent severe hypoglycemia, or impaired liver function within 3 months of the trial.

Primary end point:
•    Change in proportion of glycosylated hemoglobin (HbA1c) from baseline to 52 weeks

Results
The decrease from baseline in HbA1c was 0.84% in the liraglutide 1.2 mg group, 1.14% in the liraglutide 1.8 mg group, and 0.51% in the glimepiride group.

In comparison with the glimepiride group, there were significantly greater decreases in proportion of HbA1c for patients in the liraglutide 1.2 mg group (–0.33%; 95% confidence interval, 0.53 to –0.13; P=.0014) and liraglutide 1.8 mg group (–0·62%; 95% CI, –0.83 to –0.42; P<.0001) than in the

There was also a significantly greater reduction in HbA1c for patients in the liraglutide 1.8 mg group than in the liraglutide 1.2 mg group (–0.29%; 95% CI, –0.50 to –0.09; P=.0046).

The HbA1c goal of <6.5% was achieved by 28% of patients in the liraglutide 1.2 mg group and 38% of patients in the liraglutide 1.8 mg group versus 16% of patients in the glimepiride group (P=.0025 and P<.0001 for liraglutide 1.2 mg and 1.8 mg, respectively).

In this study, 62% of patients treated with liraglutide 1.8 mg who had not been previously treated with diabetes medications achieved an average reduction in blood sugar that brought them below the ADA target for HbA1c of 7%, compared with 58.3% of the liraglutide 1.2 mg group and 30.8% of the glimepiride group.

There were no major hypoglycemic events in the study. Five patients in the liraglutide 1.2 mg group and 1 patient in the liraglutide 1.8 mg group discontinued treatment because of vomiting, compared with no patients in the glimepiride group. There were 9 serious adverse events in the liraglutide 1.8 mg group, 18 in the liraglutide 1.2 mg group, and 17 in the glimepiride group.

COMBINATION TRIAL
Below is summary of results from a phase 3 trial that compared the efficacy and safety liraglutide, placebo, and insulin glargine in combination with metformin and glimepiride.

Reference: Russell-Jones D, Vaag A, Schmitz O, et al. Liraglutide vs insulin glargine and placebo in combination with metformin and sulfonylurea therapy in type 2 diabetes mellitus (LEAD-5 met+SU): a randomised controlled trial Diabetologia. 2009;52(10);2046-2055.

Study Objectives: The trial was designed to assess the efficacy and safety of liraglutide for the treatment of patients with T2DM whose disease was not adequately controlled with metformin and glimepiride.

Method
The 26-week, randomized, parallel-group, placebo-controlled study began with a 2-week screening period and a 6-week run-in period. During the 6-week run-in, patients received standard metformin/glimepiride combination therapy, which included 3 weeks of dose escalation and 3 weeks of maintenance therapy. The treatment period then lasted 26 weeks before a 1-week follow-up period.

Patients were randomized in a 2:1:2 ratio to receive liraglutide, liraglutide placebo, or insulin glargine. Only those patients who received glimepiride (4 mg once daily) and metformin (1 g twice daily) treatment for at least 3 weeks and had a fasting plasma glucose (FPG) between 7.5 and 12.8 mmol/l after the 6-week run-in were randomized. At week 8 and afterwards, patients with an FPG measurement >13.3 mmol/l and no intercurrent treatable illness were withdrawn from the study.

HbA1c measurements were gathered at baseline and at weeks 12, 18, and 26. The intention-to-treat analysis of outcomes and efficacy included participants who received >1 dose of study drug.

Population
At 107 sites in 17 countries, the trial screened 973 patients and randomized 581 adult patients 18 to 80 years old with T2DM. Patients were receiving oral therapy to lower glucose for >3 months and had HbA1c of 7.5% to 10% if on oral glucose-lowering monotherapy or from 7% to 10% if on combination therapy, and BMI <45kg/m2.

The study excluded patients who received insulin within 3 month of enrollment. Patients with significant cardiovascular disease, impaired liver or kidney function, retinopathy, maculopathy, hypertension of other conditions were also excluded.

The proportion of males in the study was 57% in the liraglutide group, 49% in the placebo group, and 60% in the insulin glargine group. The mean age was about 57, and patients had diabetes for a mean of more than 9 years. Mean HbA1c at baseline was 8.3% in the liraglutide and placebo groups and 8.2 in the insulin glargine group.

Primary end point:
•    Change in HbA1c after 26 weeks of treatment

Results
Treatment with liraglutide resulted in significantly greater reductions in HbA1c than did treatment with insulin glargine or placebo. The reduction in HbA1c at 26 weeks was 1.33% in the liraglutide group, 0.24% in the placebo group, and 1.09% in the insulin glargine group (P<.05). Final mean HbA1c was 7.0% in the liraglutide group, 8.1% in the placebo group, and 7.2% in the insulin glargine group.

The difference in the reduction in HbA1c for liraglutide versus placebo was −1.09% (95% CI, −1.28 to −0.90; P<.0001). The difference in the reduction in HbA1c for liraglutide versus insulin glargine was −0.24% (95% CI, −0.39 to −0.08; P=.0015). There was also a significantly greater reduction in HbA1c for the insulin glargine group compared with the placebo group—difference in reduction of HbA1c was −0.85% (95% CI, −1.04 to −0.66; P<.0001).

Significantly more patients treated with liraglutide reached the American Association of Clinical Endocrinology HbA1c target of <6.5% (13) and American Diabetes Association HbA1c target of <7% (12) than in the placebo or insulin glargine groups.

There was also a significantly greater mean weight loss (1.8 kg) in the liraglutide group than in the placebo group (0.42 kg; P=.0001). There was a 1.6 kg mean weight increase for patients in the insulin glargine group. Although patients with sustained nausea tended to have more weight loss, weight loss overall was independent of nausea.

Adverse events leading to study withdrawal occurred in 4.7% of the liraglutide group, 0.9% of the placebo group, and 2.1% of the insulin glargine group. The highest rate of study withdrawals, however, was in the placebo group. Driven by ineffective therapy, 11.3% of patients in the placebo group withdrew from participation in the study.

Safety Notes
The FDA approval of liraglutide demonstrates that the agency the benefits of this drug for patients with T2DM outweigh potential risks associated with its use. There were, however, several safety concerns identified during the review of liraglutide that had to be evaluated in light of its benefits. These safety concerns included clinical trials that suggested liraglutide may be associated with pancreatitis. Other drugs that work through similar mechanisms as liraglutide have also been associated with pancreatitis. In addition, animal data showed a rare type of thyroid cancer known as medullary thyroid cancer associated with liraglutide, although the relevance of this finding to humans remains unknown.

To ensure that the benefits of liraglutide continue to outweigh any risks, the FDA has required a Risk Evaluation and Mitigation Strategy (REMS) as part of the product approval. This REMS includes a patient Medication Guide and a Communication Plan. The FDA has also required additional studies to better understand the risks associated with this medicine. In addition, the FDA has required a large cardiovascular safety trial to specifically evaluate the cardiovascular safety of liraglutide in a higher risk population.

The manufacturer is also required to conduct a 5-year epidemiological study using a health claims database to evaluate thyroid and other cancer risks as well as risks for seriously low blood glucose levels (hypoglycemia), pancreatitis, and allergic reactions. To specifically evaluate the risk of medullary thyroid cancer, the company is required to establish a cancer registry to monitor the rate of this type of cancer in the United States over the next 15 years.

The most common adverse events reported during the clinical development program in patients treated with liraglutide were associated with the gastrointestinal system. Gastrointestinal adverse events, including nausea, vomiting and diarrhea were reported most frequently in the early part of the treatment period with liraglutide, and few patients withdrew due to these adverse events.


Victoza Facts
•    Victoza is manufactured by Novo Nordisk
•    The FDA approved Victoza on January 25, 2010
•    Victoza can be given any time of day independent of meals
•    Victoza has been launched in the United Kingdom, Germany, Denmark, Norway and Ireland
•    Victoza has not been studied in combination with insulin