Pharmacology Update

Liraglutide Injection (Victoza®)

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD. Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Elliott and Chan report no financial relationship to this field of study.

A second human glucagon-like peptide 1 (glp-1) analog/receptor agonist has been approved by the FDA for the treatment of type 2 diabetes mellitus (DM2). Liraglutide is produced by recombinant DNA technology and its amino acid sequence is more similar to native GLP-1 than exenatide (97% vs 53%). It is marketed by Novo Nordisk as Victoza®.

Indications

Liraglutide is indicated as an adjunct to diet and exercise to improve glycemic control in adults with DM2.1

Dosage

The recommended dose is 0.6 mg given as a subcutaneous injection once daily, independent of meals.1 This lower dose is recommended to reduce gastrointestinal symptoms. After one week the dose should be increased to 1.2 mg. If glycemic control is not achieved, the dose can be increased to 1.8 mg. The injection should be given in the abdomen, thigh, or upper arm. To reduce the risk of hypoglycemia, there should be a dose reduction of concomitant antidiabetic drugs that stimulate insulin secretion.

Liraglutide is available as a prefilled multidose pen (6 mg/mL, 3 mL) that is calibrated to deliver 0.6 mg, 1.2 mg, or 1.8 mg.

Potential Advantages

Liraglutide has an elimination half-life of 13 hours and is suitable for once-daily administration. It can be given independent of meals. It appears to be more effective in achieving glycemic control and may be better tolerated than exenatide.2

Potential Disadvantages

The most common adverse events are gastrointestinal in nature (e.g., nausea, 28.4%; diarrhea, 17.1%; and vomiting, 10.9%).1 These were the primary reasons for withdrawal from clinical trials (5% vs 0.5% for comparators). Pancreatitis and thyroid C-cell tumors are rare but serious adverse events associated with liraglutide.

Comments

GLP-1 and glucose-dependent insulinotropic polypeptide are hormones responsible for the incretin effect resulting in insulin secretion in response to oral glucose ingestion, inhibition of glucagon secretion, and delay in gastric emptying. The incretin effect may be diminished in DM2. GLP-1 receptor agonists (e.g., exenatide, liraglutide) and DPP-4 inhibitors (sitaglitin, saxaglitin) have been developed as incretin-based therapies. The approval of liraglutide was based on five double-blind trials, a 52-week monotherapy trial that compared the drug to glimepiride and four 26-week add-on studies.1,3-7 In the short-term studies, liraglutide or placebo was added to glimepiride, metformin, metformin + rosiglitazone, or metformin + glimepiride. The primary endpoint was the change in HbA1c and secondary endpoints included change in fasting plasma glucose (FPG) and body weight. In the 52-week trial (n = 745), liraglutide (1.2 mg and 1.8 mg) was compared to glimepiride (8 mg).5 Liraglutide showed statistically significant adjusted mean differences in HbA1c of -0.3% and -0.6% (for 1.2 mg and 1.8 mg, respectively) compared to glimepiride. Differences in FPG were -10 and -20 mg/dL and weight reductions were -3.2 and -3.6 kg. Systolic blood pressure was reduced by 3.64 mm Hg, while glimepiride was associated with a small mean increase in systolic BP. In the short-term studies (n = 3246), the addition of liraglutide showed a statistical difference in HbA1c of -0.9% to -1.4%, and -28 to -38 m/dL in FPG. Significant weight reduction was reported with the liraglutide + metformin compared to glimepiride + metformin. Liraglutide as monotherapy or added to metformin significantly reduced fat mass and fat percentage compared to glimepiride.8 When liraglutide or exenatide was added to existing oral antidiabetic drugs (n = 464), liraglutide was shown to be more effective than exenatide in terms of glycemic control (HbA1c reduction of 1.12% vs 0.79%, and FPG reduction of 29 mg/dL vs 11 mg/dL). However, postprandial glucose levels were better with exenatide. The addition of liraglutide or insulin glargine to metformin and glimepiride produced similar improvement in glycemic control.7 Liraglutide was better tolerated in terms of the frequency of nausea and minor hypoglycemia. Liraglutide is generally well tolerated. Common adverse events are gastrointestinal in nature (nausea, diarrhea, vomiting). These generally decline after several weeks of use and do not appear to be dose-dependent.9

Clinical Implications

Type 2 diabetes mellitus is a multifaceted progressive disorder. As the disease progresses, it becomes more difficult to maintain glycemic control. Liraglutide appears to be an improvement over the existing GLP-1 agonist, exenatide. GLP-1 agonists are considered tier 2 drugs in the ADA guidelines.

References

1. Victoza Prescribing Information. Princeton, NJ: Novo Nordisk Inc.; 2010.

2. Buse JB, et al. Liraglutide once a day versus exenatide twice a day for type 2 diabetes (LEAD-6). Lancet 2009; 374:39-47.

3. Marre M, et al. Liraglutide, a once-daily human GLP-1 analogue, added to a sulphonylurea over 26 weeks produces greater improvements in glycaemic and weight control compared with adding rosiglitazone or placebo in subjects with Type 2 diabetes (LEAD-1 SU). Diabet Med 2009;26:268-78.

4. Nauck M, et al. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: The LEAD-2 study. Diabetes Care 2009;32:84-90.

5. Garber A, et al. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono). Lancet 2009; 373:473-481.

6. Zinman B, et al. Efficacy and safety of the human glucagon-like peptide-1 analog liraglutide in combination with metformin and thiazolidinedione in patients with type 2 diabetes (LEAD-4 Met+TZD). Diabetes Care 2009;32:1224-1230.

7. Russell-Jones D, et al. Liraglutide vs insulin glargine and placebo in combination with metformin and sulfonylurea therapy in type 2 diabetes mellitus (LEAD-5 met+SU). Diabetologia 2009;52:2046-2055.

8. Jendle J, et al. Weight loss with liraglutide, a once-daily human glucagon-like peptide-1 analogue for type 2 diabetes treatment as monotherapy or added to metformin, is primarily as a result of a reduction in fat tissue. Diabetes Obes Metab 2009;11:1163-1172.

9. Montanya E, Sesti G. A review of efficacy and safety data regarding the use of liraglutide, a once-daily human glucagon-like peptide 1 analogue, in the treatment of type 2 diabetes mellitus. Clin Ther 2009;31:2472-2488.