David Kim

The Centers for Disease Control and Prevention estimates that in 2015, 30.3 million people in the United States had diabetes.

 In recent years, different antidiabetic medications have been brought to market. Among them, glucagon-like peptide-1 receptor agonists (GLP-1 agonists) have been gaining popularity among patients and prescribers. Among GLP-1 agonists, liraglutide (Victoza) has been a popular option since gaining FDA approval in 2010.

 Let's look at the role of liraglutide in diabetes therapy, as well as the clinical benefits compared with its competitors in the US market, such as exenatide, albiglutide and lixisenatide.

Victoza is FDA-approved for type 2 diabetes mellitus (DM) and prophylaxis for disorder of 

 as a result of type 2 diabetes. Its dosing involves titration to reduce 

 symptoms, such as nausea, diarrhea, and vomiting: initiate 0.6 mg daily subcutaneous injection for 1 week; increase to maintenance dose of 1.2 mg daily; and increase to 1.8 mg daily, as needed.

Liraglutide is also FDA-approved as Saxenda for obesity with a body mass index of 30kg/m

with the presence of at least 1 weight-related comorbid condition. Saxenda is initiated at 0.6 mg subcutaneous daily injection for 1 week, with weekly increments of 0.6 mg per day, until the maintenance dosage of 3 mg once daily is reached.

 If the patient misses a dose of liraglutide injection for more than 3 days, re-initiation at 0.6 mg is recommended to mitigate gastrointestinal (GI) symptoms.

The FDA approved Xultrophy 100/3.6 as a combination product of insulin degludec and liraglutide. Each milliliter of this product contains 100 units of insulin degludec and 3.6 mg of liraglutide. Xultrophy is initiated at insulin degludec 16 units/liraglutide 0.58 mg subcutaneous, once daily. It may be increased or decreased by 2 units every 3 to 4 days until the desirable fasting plasma glucose is reached. Doses of less than 16 units are intended to be used only temporarily. The maximum dose of insulin degludec 50 units/liraglutide is 1.8 mg subcutaneous daily.

Liraglutide (Victoza) is a GLP-1 agonist that works by sensitization of beta islet cells of pancreas, which consequently reduces the threshold for insulin secretion in response to carbohydrate intake. It also suppresses postprandial glucagon release from the alpha cells of the pancreas. Therefore, it is effective at controlling the postprandial glucose level. Its additional effects include delayed gastric emptying and reduced appetite, which can lead to weight loss. Because its mechanism is glucose dependent and therefore is very unlikely to cause hypoglycemia.

LIRA-RENAL: Liraglutide was studied in a double-blind trial on 279 subjects with type 2 DM and moderate renal impairment (eGFR: 30-59ml/min). Liraglutide was an add-on therapy to other glucose-lowering treatment options, compared with placebo. Liraglutide demonstrated better glycemic control than placebo (A1C: -0.66% at week 26) but a higher withdrawal rate because of GI-adverse events. Liraglutide did not affect renal function or hypoglycemia risk.

LEADER: Liraglutide was studied in a double-blind trial on 9340 subjects with type 2 DM at high risk for cardiovascular disease. Lirglutide was compared with placebo when added to standard care. Lifestyle modification, metformin as foundational therapy and possible intensification with other oral, injectable agents; DPP4 inhibitors were not allowed. The LEADER trial demonstrated that liraglutide significantly reduced death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke by comparison with placebo. GI events were the leading cause of discontinuation of liraglutide.

The American Diabetes Association’s (ADA) 2017 Standards of Medical Care in Diabetes recommends GLP-1 agonists as an option for dual or triple therapy as an add on to metformin. The ADA classifies GLP-1 agonists as a class of medication with high efficacy and low hypoglycemia risk but high cost.

The American Association of Clinical Endocrinologists and American College of Endocrinology Comprehensive Type 2 Diabetes Management Algorithm recommends GLP-1 agonists as an option for mono (entry A1C <7%), dual (entry A1C ≥7%), or triple (entry A1C ≥7%) therapy. GLP-1 agonists are the most preferred add-on option to metformin for dual and triple therapy, according to the guideline.

Liraglutide causes delay in gastric emptying and therefore has the potential to affect the absorption of concomitantly administered oral medications. However, there were no clinically relevant drug interactions during clinical trials. Thyroid C-cell tumors were observed in both genders of rats and mice. Therefore, it is contraindicated in patients with personal or family history of Multiple Endocrine Neoplasia Syndrome type 2. There have been postmarketing reports involving fatal and nonfatal hemorrhagic or necrotizing pancreatitis.

Each Victoza pen contains 18 mg of liraglutide, which can be delivered in doses of 0.6 mg, 1.2 mg, or 1.8 mg. Each pen will last 30 days, with 0.6 mg, 15 days with 1.2 mg, and 10 days with 1.8 mg. This medication may be taken at any time of the day. The recommended pen needle is a 32G fine-tip needle, which can be capped on to the pen easily. The 32G needle is very thin, which may be comparable to the thickness of a human hair. This is something that we can counsel patients who are afraid of needles. When a new pen is opened, flow check needs to be conducted to ensure that the correct dose gets delivered to the patient. Flow check needs to be conducted only once with a new pen. The manufacturer suggests abdomen, thigh, or upper arm as injection sites. It is important to rotate the sites. After the injection, the manufacturer recommends leaving the needle in the skin for at least 6 seconds. The needle needs to be disposed of after each injection in a sharps container. The Victoza pen can be stored at room temperature for 30 days after the initial injection. However, unopened pens should remain refrigerated until they are ready to use.

Liraglutide provides multiple benefits to type 2 DM patients, such as glycemic control, weight loss, and reducing risk for cardiovascular events. Liraglutide is the only FDA-approved GLP-1 agonist on the market that provides cardiovascular benefit. Such properties make Victoza a competitive option among multiple GLP-1 agonists on the US market.

1. Centers for Disease Control and Prevention. National diabetes statistics report. cdc.gov/diabetes/data/statistics/statistics-report.html. Published July 17, 2017. Accessed November 15, 2017.

2. Victoza [prescribing information]. Plainsboro, NJ: Novo Nordisk, Inc; 2017. novo-pi.com/victoza.pdf. Accessed November 15, 2017.

3. Saxenda [prescribing information]. Plainsboro, NJ: Novo Nordisk, Inc; 2014. novo-pi.com/saxenda.pdf. Accessed November 15, 2017.

4. Truven Health Analytics. Micromedex Solutions. micromedexsolutions.com/home/dispatch. Accessed November 10, 2017.

5. Xultophy [prescribing information]. Plainsboro, NJ: Novo Nordisk, Inc; 2016. accessdata.fda.gov/drugsatfda_docs/label/2016/208583s000lbl.pdf. Accessed November 15, 2017.

6. American Pharmacists Association. The pharmacist & patient-centered diabetes care. pharmacist.com/pharmacist-patient-centered-diabetes-care. Accessed November 15, 2017.

7. Davies MJ, Bain SC, Atkin SL, et al. Efficacy and safety of liraglutide versus placebo as add-on to glucose-lowering therapy in patients with type 2 diabetes and moderate renal impairment (LIRA-RENAL): a randomized clinical trial. 

. 2016;39(2):222-30. doi: 10.2337/dc14-2883. 

8. Kalra S. Follow the LEADER—liraglutide effect and action in diabetes: evaluation of cardiovascular outcome results trial. 

9. American Diabetes Association. Standards of Medical Care in Diabetes - 2017. 

care.diabetesjournals.org/content/diacare/suppl/2016/12/15/40.Supplement_1.DC1/DC_40_S1_final.pdf. Accessed November 15, 2017.

10. The American Association of Clinical Endocrinologists and American College of Endocrinology. AACE/ACE comprehensive type 2 diabetes management algorithm 2017. aace.com/publications/algorithm. Accessed November 15, 2017.

11. Novo Nordisk. Have questions about the Victoza pen? victoza.com/faq/Using-the-Victoza-Pen.html. Accessed November 10, 2017

Articles

What role does this medication play in diabetes therapy, and what are its clinical benefits, compared with competitors?