Author: Laura Moretti Challen, PharmD, BCPS, and Anh N. Nguyen, PharmD Candidate 2010
Novo Nordisk's Victoza (liraglutide), the first glucagon-like peptide-1 receptor agonist subcutaneous injection, received FDA approval for the treatment of type 2 diabetes mellitus.
Novo Nordisk’s Victoza (liraglutide), the first glucagon-like peptide-1 (GLP-1) receptor agonist subcutaneous (SC) injection, received FDA approval for the treatment of type 2 diabetes mellitus (T2DM). T2DM is a condition in which the beta cells of the pancreas fail to use insulin properly and is estimated to affect over 23.6 million individuals of all ages in the United States.1
If left untreated, T2DM can lead to heart disease, stroke, blindness, amputation, and many other complications. T2DM is the seventh leading cause of death in the United States, and the overall risk for death in patients with diabetes is about twice that of individuals without diabetes of similar age.1
Liraglutide is the first once-daily injectable incretin mimetic. It may be used with other oral antidiabetic medications but should not be used concurrently with insulin, due to lack of evidence. Liraglutide should not be used in patients with normal or low blood glucose levels, type 1 diabetes mellitus, or diabetic ketoacidosis.2
MECHANISM OF ACTION
GLP-1 is secreted by the intestinal L cell as a gut hormone and biologically activated to GLP-1-(7-37) and GLP-1-(336)NH2. Liraglutide is a GLP-1 receptor agonist that has an amino acid sequence of 97% homology to endogenous GLP-1-(7-37). Activation of GLP-1 receptors causes increased insulin secretion and synthesis, suppresses glucagon secretion, slows gastric emptying, reduces food intake, and promotes beta-cell proliferation.2
The studies that identified the efficacy of liraglutide were part of the Liraglutide Effect and Action in Diabetes (LEAD) program. LEAD was a series of 6 randomized, double-blind, phase 3 trials evaluating liraglutide as monotherapy or as add-on therapy to 1- or 2-drug oral regimens. Active comparators included sulfonylureas, thiazolidinediones, insulin glargine, and exenatide.3-8
DOSAGE AND ADMINISTRATION
Liraglutide is not recommended as firstline therapy for patients who have inadequate glycemic control on diet and exercise. In addition, liraglutide is not a substitute for insulin. Liraglutide should be initially dosed at 0.6 mg SC once daily for 1 week (this dose is not effective for glycemic control and is intended as a starting dose to reduce gastrointestinal [GI] symptoms). Then after 1 week, the dose should be increased to 1.2 mg SC once daily. If glycemic control is not achieved, the dose can be increased to 1.8 mg SC once daily.2
The safety and efficacy of liraglutide have not been established in children and adolescents. The maximum daily dosage of liraglutide for adults and elderly patients is 1.8 mg/day SC.2
Liraglutide has a black-box warning for and is absolutely contraindicated in patients with a personal or family history of thyroid cancer, specifically medullary thyroid carcinoma, or in patients with multiple endocrine neoplasia syndrome type 2. Caution should be used in patients with a history of pancreatitis due to reports of acute and chronic pancreatitis during premarketing trials.2
Caution should be used when liraglutide is coadministered with oral medications due to the delayed gastric emptying caused by liraglutide. Patients who concomitantly use quinolones and an antidiabetic agent have reported blood glucose disturbances; therefore, careful monitoring of blood glucose is recommended. Gatifloxacin is contraindicated, however, and should not be used in combination with antidiabetic agents, including liraglutide, due to serious alterations in blood glucose.2
The most common adverse events reported with liraglutide include nausea and vomiting, with nausea decreasing over time. Dose-dependent GI adverse events include diarrhea and constipation. Nonsevere hypoglycemia occurred at a high incidence when liraglutide was taken in combination with metformin and glimepiride. Rare cases of thyroid carcinoma have also been reported.2
Liraglutide is an FDA pregnancy category risk C. Breastfeeding should be discontinued due to potential risk of serious adverse events to infants.
Dr. Challen is a clinical pharmacist specialist in primary care at Casa de Amigos Health Center in Houston, Texas. Ms. Nguyen is a 2010 PharmD candidate at Texas Southern University College of Pharmacy.
1. National Diabetes Information Clearinghouse. National Diabetes Statistics 2007. Available at: http://diabetes.niddk.nih.gov/DM/PUBS/statistics/. Accessed April 22, 2010.
2. Clinical Pharmacology Web site. Available at: http://www.clinicalpharmacology.com. Accessed April 22, 2010.
3. Marre M, Shaw J, Brändle 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). Diabetic Med
4. Garber A, Henry R, Ratner R, et al. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomized, 52-week, phase III, double-blind, parallel-treatment trial. The Lancet
5. Zinman B, Gerich J, Buse JB, 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 Daibetes (LEAD-4 Met+TZD). Dabetes Care
6. Buse JB, Rosenstock J, Sesti G, et al. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomized, parallel-group, multinational, open-label trial (LEAD-6). The Lancet
7. Nauck M, Frid A, Hermansen K, et al. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD (Liraglutide Effect and Action in Diabetes)-2 Study. Diabetes Care.
8. Russell-Jones D, Vaag A, Schmitz O, et al. Significantly better glycemic control and weight reduction with liraglutide, a once-daily human GLP-1 analog, compared with insulin glargine: all as add-on to metformin and a sulfonylurea in type 2 diabetes. Presented at the 2008 American Diabetes Association Meeting (abstract #536-P). http://professional.diabetes.org/Abstracts_Display.aspx?TYP=1&CID=69843. Accessed September 23, 2009.