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Liraglutide

Pronunciation

Pronunciation

(lir a GLOO tide)

Index Terms

  • NN2211

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Pen-injector, Subcutaneous:

Saxenda: 18 mg/3 mL (3 mL) [contains phenol, propylene glycol]

Victoza: 18 mg/3 mL (3 mL) [contains phenol, propylene glycol]

Brand Names: U.S.

  • Saxenda
  • Victoza

Pharmacologic Category

  • Antidiabetic Agent, Glucagon-Like Peptide-1 (GLP-1) Receptor Agonist

Pharmacology

Liraglutide is a long acting analog of human glucagon-like peptide-1 (GLP-1) (an incretin hormone) which increases glucose-dependent insulin secretion, decreases inappropriate glucagon secretion, increases B-cell growth/replication, slows gastric emptying, and decreases food intake. Liraglutide administration results in decreases in hemoglobin A1c by approximately 1%.

Distribution

Vd: SubQ: ~13 to 25 L; IV: 0.07 L/kg

Metabolism

Endogenously metabolized by dipeptidyl peptidase IV (DPP-IV) and endogenous endopeptidases (Croom, 2009); metabolism occurs slower than that seen with native GLP-1

Excretion

Urine (6%, as metabolites); feces (5%, as metabolites)

Time to Peak

Plasma: to 12 hours

Half-Life Elimination

~13 hours

Protein Binding

>98%

Special Populations: Renal Function Impairment

The AUC in mild, moderate, and severe renal impairment, and in ESRD was on average 35%, 19%, 29%, and 30% lower, respectively.

Special Populations: Hepatic Function Impairment

The AUC in patients with mild, moderate, and severe hepatic impairment was on average 11%, 14%, and 42% lower, respectively.

Special Populations: Gender

Women have a 24% (Saxenda) to 25% (Victoza) lower weight-adjusted clearance compared with men.

Special Populations Note

Body weight: Exposure decreases with an increase in baseline body weight; however, the 1.2 mg and 1.8 mg daily doses of liraglutide provided adequate systemic exposures over the body weight range of 40 to 160 kg.

Use: Labeled Indications

Chronic weight management (Saxenda): As an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adult patients with an initial body mass index of 30 kg/m2 or greater (obese) or 27 kg/m2 or greater (overweight) in the presence of at least one weight-related comorbid condition (eg, hypertension, type 2 diabetes mellitus, dyslipidemia)

Diabetes mellitus, type 2 (Victoza): As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Contraindications

Hypersensitivity to liraglutide or any component of the formulation; history of or family history of MTC; patients with multiple endocrine neoplasia syndrome type 2 (MEN2); pregnancy (Saxenda).

Canadian labeling: Additional contraindications (not in US labeling): Pregnancy; breast-feeding

Dosing: Adult

Chronic weight management: SubQ: Initial: 0.6 mg once daily for one week; increase by 0.6 mg daily at weekly intervals to a target dose of 3 mg once daily. If the patient cannot tolerate an increased dose during dose escalation, consider delaying dose escalation for one week. If the 3 mg daily dose is not tolerated, discontinue use as efficacy has not been established at lower doses.

Note: Evaluate change in body weight 16 weeks after initiation of therapy; discontinue if at least 4% of baseline body weight loss has not been achieved.

Diabetes mellitus, type 2: SubQ: Initial: 0.6 mg once daily for 1 week; then increase to 1.2 mg once daily; may increase further to 1.8 mg once daily if optimal glycemic response not achieved with 1.2 mg daily.

Note: Initial dose is intended to reduce GI symptoms; does not provide effective glycemic control.

Concomitant use with insulin and/or insulin secretagogues (eg, sulfonylurea): Reduced dose of insulin and/or insulin secretagogues may be needed

Missed doses: In the event of a missed dose, the once daily regimen can be resumed with the next scheduled dose (an extra dose or an increase in the next dose should not be attempted); if >3 days have passed since the last liraglutide dose, reinitiate therapy at 0.6 mg/day to avoid GI symptoms and titrate according to prescriber discretion.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

US labeling: Mild-to-severe impairment: There are no dosage adjustments provided in the manufacturer’s labeling; however, use with caution, due to reports of acute renal failure and exacerbation of chronic renal failure and limited experience in patients with severe renal impairment.

Canadian labeling:

Mild impairment: No dosage adjustment necessary.

Moderate-to-severe impairment: Use is not recommended.

Dosing: Hepatic Impairment

US labeling: Mild-to-severe impairment: There are no dosage adjustments provided in the manufacturer’s labeling; use with caution, due to limited experience.

Canadian labeling: Mild-to-severe impairment: Use is not recommended.

Administration

Do not inject intravenously or intramuscularly. Inject subcutaneously in the upper arm, thigh, or abdomen. Administer without regard to meals or time of day. Change needle with each administration. Use only if clear, colorless, and free of particulate matter. Do not share pens between patients even if needle is changed. If using concomitantly with insulin, administer as separate injections (do not mix); may inject in the same body region as insulin, but not adjacent to one another.

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 2]).

Dietary Considerations

Individualized medical nutrition therapy (MNT) based on ADA recommendations is an integral part of therapy.

Storage

Prior to initial use, store at 2°C to 8°C (36°F to 46°F); after initial use, may be stored at 2°C to 8°C (36°F to 46°F) or at 15°C to 30°C (59°F to 86°F). Do not freeze (discard if freezing occurs) or store directly adjacent to the refrigerator cooling element. Protect from heat and light. Pen should be discarded 30 days after initial use.

Drug Interactions

Alpha-Lipoic Acid: May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

Androgens: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Exceptions: Danazol. Monitor therapy

Hyperglycemia-Associated Agents: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Hypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Insulin: Liraglutide may enhance the hypoglycemic effect of Insulin. Management: If liraglutide is used for the treatment of diabetes (Victoza), consider insulin dose reductions. The combination of liraglutide and insulin should be avoided if liraglutide is used exclusively for weight loss (Saxenda). Consider therapy modification

MAO Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Pegvisomant: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Quinolone Antibiotics: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolone Antibiotics may diminish the therapeutic effect of Blood Glucose Lowering Agents. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Monitor therapy

Salicylates: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Sulfonylureas: GLP-1 Agonists may enhance the hypoglycemic effect of Sulfonylureas. Management: Consider sulfonylurea dose reductions when used in combination with glucagon-like peptide-1 agonists. Avoid the use of lixisenatide in patients receiving both basal insulin and a sulfonylurea. Consider therapy modification

Thiazide and Thiazide-Like Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Adverse Reactions

Obesity:

>10%:

Cardiovascular: Increased heart rate (>10 bpm from baseline: 34%; >20 bpm from baseline: 5%)

Central nervous system: Headache (14%)

Endocrine & metabolic: Hypoglycemia (Type 2 diabetics: Combination therapy with sulfonylurea: 44%; monotherapy: 16%; nondiabetic patients: 2% to 3%)

Gastrointestinal: Nausea (39%), diarrhea (21%), constipation (19%), vomiting (16%)

1% to 10%:

Cardiovascular: Tachycardia (6%; one resting heart rate >100 bpm)

Central nervous system: Fatigue (8%), dizziness (7%)

Gastrointestinal: Decreased appetite (10%), dyspepsia (10%), abdominal distension (5%), abdominal pain (5%), eructation (5%), gastroenteritis (5%), gastroesophageal reflux disease (5%), increased serum lipase (5%; >3 x ULN: 2%), upper abdominal pain (5%), flatulence (4%), viral gastroenteritis (3%), cholelithiasis (2%), xerostomia (2%)

Genitourinary: Urinary tract infection (4%)

Immunologic: Antibody development (3%; neutralizing: 1%)

Local: Injection site reactions (3% to 14%; including erythema [1% to 3%], itching [1% to 3%], rash [1% to 3%])

Neuromuscular & skeletal: Weakness (2%)

Type 2 diabetes mellitus: Incidence reported in monotherapy trials unless otherwise specified.

>10%:

Central nervous system: Headache (10% to 11%)

Endocrine & metabolic: Increased amylase (in patients with renal impairment: 15%)

Gastrointestinal: Gastrointestinal disease (43%), nausea (18% to 20%), diarrhea (10% to 12%), increased serum lipase (in patients with renal impairment: 33%)

Infection: Infection (patients with antibodies: 40%)

Respiratory: Upper respiratory tract infection (7%; patients with antibodies: 11%)

1% to 10%:

Gastrointestinal: Decreased appetite (9% to 10%), dyspepsia (combination trials: 9%, monotherapy: 4% to 7%), vomiting (6% to 9%), constipation (5%)

Hepatic: Hyperbilirubinemia (monotherapy and combination trials: 4%)

Immunologic: Antibody development: Low titers (concentrations not requiring dilution of serum), monotherapy and combination trials: 9%, neutralizing antibodies: 2%, antibodies did not reduce efficacy; cross-reacting antiliraglutide antibodies to native GLP-1 (monotherapy: 7%; combination trials: 5%)

Local: Injection site reactions (monotherapy and combination trials: 2% [includes rash, erythema])

Neuromuscular & skeletal: Back pain (4% to 5%)

Respiratory: Nasopharyngitis (9% to 10%)

<1% (Limited to important or life-threatening; any indication): Acute renal failure, asthma, benign gastrointestinal neoplasm (colorectal), carcinoma (papillary thyroid), cholecystitis, cholestasis, chronic renal failure (exacerbation), first degree atrioventricular block, hepatitis, hypersensitivity reaction, increased susceptibility to infection, left bundle branch block, malignant neoplasm (including colorectal carcinoma), malignant neoplasm of breast, medullary thyroid carcinoma, pancreatitis (including acute, chronic, hemorrhagic, and necrotizing), papillary thyroid carcinoma, right bundle branch block, suicidal ideation, systolic hypotension, thyroid disease (C-cell hyperplasia)

ALERT: U.S. Boxed Warning

Thyroid C-cell tumor risk:

Liraglutide causes dose-dependent and treatment duration–dependent thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether liraglutide causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, because the human relevance of liraglutide-induced rodent thyroid C-cell tumors has not been determined.

Liraglutide is contraindicated in patients with a personal or family history of MTC and in patients with multiple endocrine neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk for MTC with the use of liraglutide and inform them of symptoms of thyroid tumors (eg, a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with liraglutide.

Warnings/Precautions

Concerns related to adverse effects:

• Antibody formation: Use may be associated with the development of anti-liraglutide antibodies. Antibody formation was not associated with a loss of efficacy; however, patients with the highest titers of anti-liraglutide antibodies had no reduction in HbA1C.

• Cardiovascular effects: Increased resting heart rate has been reported in patients treated for obesity; monitoring is recommended. Discontinue use in patients who experience a sustained increase in resting heart rates.

• GI symptoms: Most common reactions are gastrointestinal related; these symptoms may be dose-related and may decrease in frequency/severity with gradual titration and continued use.

• Hypersensitivity reactions: Serious hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported with use; discontinue therapy in the event of a hypersensitivity reaction. Use with caution in patients with a history of angioedema to other GLP-1 receptor agonists (angioedema has been reported with other GLP-1 receptor agonists); potential for cross-sensitivity is unknown.

• Pancreatitis: Cases of acute and chronic pancreatitis (including fatal and nonfatal, hemorrhagic or necrotizing pancreatitis) have been reported; monitor for signs and symptoms of pancreatitis (eg, persistent severe abdominal pain which may radiate to the back and which may or may not be accompanied by vomiting). If pancreatitis is suspected, discontinue use. Do not resume unless an alternative etiology of pancreatitis is confirmed. Use with caution in patients with a history of pancreatitis, cholelithiasis, and/or alcohol abuse; limited data regarding use in patients with a history of pancreatitis. Consider antidiabetic therapies other than liraglutide in patients with a history of pancreatitis.

• Psychiatric effects: Suicidal behavior, with one case of attempted suicide, has been reported in patients treated for obesity; monitor for new or worsening depression, suicidal thoughts or behavior, or unusual changes in mood or behavior. Discontinue use if suicidal thoughts or behaviors occur. Avoid use in patients with history of suicidal attempts or active suicidal ideation.

• Renal effects: Acute renal failure and chronic renal failure exacerbation (including severe cases requiring hemodialysis) have been reported; some cases have been reported in patients with no known preexisting renal disease. Reports primarily occurred in patients with nausea, vomiting, diarrhea, or dehydration. Renal dysfunction was usually reversible with appropriate corrective measures, including discontinuation of liraglutide. Risk may be increased in patients receiving concomitant medications affecting renal function and/or hydration status.

• Thyroid tumors: [US Boxed Warning] Dose-dependent and treatment duration–dependent thyroid C-cell tumors have developed in animal studies with liraglutide therapy; it is unknown whether liraglutide will cause thyroid C-cell tumors, including MTC, in humans, as the human relevance of liraglutide-induced rodent thyroid C-cell tumors has not been determined. Patients should be counseled on the potential risk of MTC with the use of liraglutide and informed of symptoms of thyroid tumors (eg, neck mass, dysphagia, dyspnea, persistent hoarseness). Use is contraindicated in patients with a personal or a family history of MTC and in patients with multiple endocrine neoplasia syndrome type 2 (MEN2). Consultation with an endocrinologist is recommended in patients who develop elevated calcitonin concentrations or have thyroid nodules detected during imaging studies or physical exam. Routine monitoring of serum calcitonin or using thyroid ultrasound monitoring is of uncertain value for early detection of MTC in patients treated with liraglutide.

• Weight loss: Victoza: Use may be associated with weight loss (likely due to reduced intake) independent of the change in hemoglobin A1c

Disease-related concerns:

• Gallbladder disease: Cholelithiasis and cholecystitis have been reported in patients treated with liraglutide for obesity.

• Gastroparesis: Slows gastric emptying; has not been studied in patients with preexisting gastroparesis.

• Hepatic impairment: Use with caution in patients with hepatic impairment; limited experience.

• Renal impairment: Use with caution in patients with renal impairment, particularly during initiation of therapy and dose escalation.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage form specific issues:

• Multiple dose injection pens: According to the Centers for Disease Control and Prevention (CDC), pen-shaped injection devices should never be used for more than one person (even when the needle is changed) because of the risk of infection. The injection device should be clearly labeled with individual patient information to ensure that the correct pen is used (CDC, 2012).

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 2]).

Other warnings/precautions:

• Appropriate use: Diabetes mellitus: Victoza is not recommended for first-line therapy in patients inadequately controlled on diet and exercise alone. Do not use in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis; not a substitute for insulin. Saxenda is not indicated for the treatment of type 2 diabetes; concomitant use with insulin is not recommended.

• Patient education: Diabetes self-management education (DSME) is essential to maximize the effectiveness of therapy.

Monitoring Parameters

Plasma glucose, HbA1c (at least twice yearly in patients who have stable glycemic control and are meeting treatment goals; quarterly in patients not meeting treatment goals or with therapy change [ADA 2016a]); renal function; signs/symptoms of pancreatitis; emergence of worsening depression, suicidal thoughts/behavior, changes in behavior; heart rate

Pregnancy Risk Factor

X (Saxenda)/C (Victoza)

Pregnancy Considerations

Use for chronic weight management is contraindicated in pregnant women (lack of potential benefit and possible fetal harm). Weight loss therapy is generally not recommended for pregnant women. Obese and overweight women should be encouraged to participate in weight reduction programs prior to attempting pregnancy; weight gain during pregnancy should be determined by prepregnancy BMI and current guidelines (ACOG 549 2013; IOM 2009; NHLBI 1998).

In women with diabetes, maternal hyperglycemia can be associated with congenital malformations as well as adverse effects in the fetus, neonate, and the mother (ACOG 2005; ADA 2015; Kitzmiller 2008; Metzger 2007). To prevent adverse outcomes, prior to conception and throughout pregnancy maternal blood glucose and HbA1c should be kept as close to target goals as possible but without causing significant hypoglycemia (ACOG 137 2013; ADA 2015; Blumer 2013; Kitzmiller 2008). Prior to pregnancy, effective contraception should be used until glycemic control is achieved (Kitzmiller 2008). Other agents are currently recommended to treat diabetes in pregnant women (ACOG 137 2013; Blumer 2013).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, diarrhea, constipation, nausea, vomiting, lack of appetite, abdominal pain, loss of strength and energy, or injection site irritation. Have patient report immediately to prescriber signs of thyroid cancer (new lump or swelling in the neck, pain in the front of the neck, cough that does not go away, change in voice that does not go away like hoarseness, or trouble swallowing or breathing), signs of a pancreas problem (pancreatitis; severe abdominal pain, severe back pain, severe nausea, vomiting), signs of gallstones (pain in the upper right abdominal area, right shoulder area, or between the shoulder blades; yellow skin or eyes; fever with chills), dizziness, passing out, tachycardia, arrhythmia, jaundice, urinary retention, change in amount of urine passed, mood changes, behavioral changes, depression, suicidal ideation, or signs of low blood sugar (dizziness, headache, fatigue, feeling weak, shaking, a fast heartbeat, confusion, hunger, or sweating) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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