Liraglutide

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]

Pharmacology

Mechanism of Action

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 A_1c by approximately 1%.

Pharmacokinetics/Pharmacodynamics

Distribution

V_d: 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: SubQ: 8 to 12 hours

Half-Life Elimination

~13 hours

Protein Binding

>98%

Use in Specific Populations

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 (obese) or ≥27 kg/m² (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 children ≥10 years of age, adolescents, and adults with type 2 diabetes mellitus; risk reduction of major cardiovascular events (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke) in adults with type 2 diabetes mellitus and established cardiovascular disease.

Contraindications

Prior serious 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 (Saxenda, Victoza); breastfeeding

Dosage and Administration

Dosing: Adult

Note: Due to lack of additive glycemic benefit, use in combination with a dipeptidyl peptidase-4 (DPP-4) inhibitor (eg, sitagliptin) should be avoided (Dungan 2019; Nauck 2017).

Diabetes mellitus, type 2, treatment:

Note: May be used as an adjunctive agent or alternative monotherapy for select patients, including those who fail initial therapy with lifestyle intervention and metformin or who cannot take metformin. Liraglutide may be preferred as an additional antidiabetic agent or alternative first-line agent in patients with atherosclerotic cardiovascular disease (given liraglutide's demonstrated cardiovascular benefit) and/or in patients with an HbA_1c relatively far from goal (HbA_1c >9% and type 1 diabetes is not likely) (ACC [Das 2018]; ADA 2019; Dungan 2019; Marso 2016; Wexler 2019).

SubQ: Initial: 0.6 mg once daily for 1 week, then increase to 1.2 mg once daily; if optimal glycemic response is not achieved after an additional week of treatment, may increase further to 1.8 mg once daily. Note: The lower initial dose (0.6 mg daily) is intended to reduce GI symptoms; it 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.

Obesity and select overweight patients:

Note: For use as an adjunct to diet and exercise in obese patients or overweight patients with ≥1 weight-associated comorbidity (eg, hypertension, dyslipidemia). Considered a preferred pharmacologic weight-loss option in obese and overweight patients with type 2 diabetes mellitus, particularly in patients with atherosclerotic cardiovascular disease (AACE/ACE [Garvey 2016]; Endocrine Society [Apovian 2015]; Endocrine Society [Bray 2018]; Marso 2016; Perreault 2019).

SubQ: Initial: 0.6 mg once daily for 1 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 1 additional week. According to the manufacturer, efficacy has not been established at doses <3 mg/day; however, some experts will continue a patient on the maximum tolerated dose (even if <3 mg/day) if goal weight loss is achieved on that dose (Perreault 2019).

Note: Evaluate change in body weight after 12 weeks at maximum tolerated dose or 16 weeks after initiation of therapy; discontinue if at least 4% to 5% of baseline body weight loss has not been achieved (ADA 2019; manufacturer's labeling).

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 clinical judgment considering previous GI tolerability.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Diabetes mellitus, type 2; adjunct to diet and exercise: Children ≥10 years and Adolescents: Victoza: SubQ: Initial: 0.6 mg once daily for at least 1 week; may increase by 0.6 mg/day increments at weekly intervals to achieve glycemic control (week 2: increase to 1.2 mg once daily; week 3: increase to 1.8 mg once daily); maximum daily dose: 1.8 mg/day. In clinical trials, all patients were on concomitant stable doses of metformin (1,000 to 2,000 mg/day) with or without basal insulin; patients on basal insulin had insulin dose reductions (by 20%) during liraglutide therapy titration (Tamborlane 2019).

Missed doses: If more than 3 days of therapy are missed, therapy should be restarted at the initial dose (0.6 mg/day) and retitrated to avoid GI symptoms.

Obesity; adjunct to strict lifestyle interventions:

Children ≥12 years and Adolescents ≤17 years: Limited data available (Fox 2019; Srivastava 2019): SubQ: Initial: 0.6 mg once daily; increase by 0.6 mg/day increments at weekly intervals up to target dose of 3 mg once daily. Dosing based on a double-blind, parallel-group, placebo-controlled trial including 14 subjects in liraglutide treatment group (age range: 12 to 17 years; Tanner stage: 2 to 5) with a BMI corresponding to both a 95th percentile for age and sex and an adult BMI of 30 to 45 kg/m². After 6 weeks of therapy, results showed a decrease in mean BMI z-score and body weight with treatment and placebo; however, the difference between treatment and placebo did not reach statistical significance; safety analysis reported similar safety and tolerability profile as adults treated for obesity (Danne 2017)

Adolescents ≥18 years: Saxenda: SubQ: Initial: 0.6 mg once daily for 1 week; increase by 0.6 mg/day increments 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 additional week. If the 3 mg daily dose is not tolerated, discontinue use as efficacy has not been established at lower doses. After 16 weeks of therapy, assess body weight; if patient has not lost ≥4% of baseline bodyweight, discontinue therapy since patient is unlikely to achieve meaningful and sustainable results with liraglutide.

Missed doses: If more than 3 days of therapy are missed, therapy should be restarted at the initial dose (0.6 mg/day) and retitrated to avoid GI symptoms.

Administration

SubQ: Inject subcutaneously in the upper arm, thigh, or abdomen. Do not inject intravenously or intramuscularly. 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.

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

Direct Acting Antiviral Agents (HCV): May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

Guanethidine: May enhance the hypoglycemic effect of Antidiabetic Agents. 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

Insulins: Liraglutide may enhance the hypoglycemic effect of Insulins. 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

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

Monoamine Oxidase 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

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

Quinolones: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolones 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

Ritodrine: May diminish the therapeutic effect of Antidiabetic Agents. 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

Sincalide: Drugs that Affect Gallbladder Function may diminish the therapeutic effect of Sincalide. Management: Consider discontinuing drugs that may affect gallbladder motility prior to the use of sincalide to stimulate gallbladder contraction. Consider therapy modification

Sulfonylureas: Glucagon-Like Peptide-1 Agonists may enhance the hypoglycemic effect of Sulfonylureas. Management: Consider sulfonylurea dose reductions when used in combination with glucagon-like peptide-1 agonists. 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 (obesity patients with type 2 diabetics: combination therapy with sulfonylurea: 44%; monotherapy: 16%; nondiabetic patients: 2% to 3%)

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

Local: Injection site reaction (3% to 14%)

1% to 10%:

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

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

Dermatologic: Injection site pruritus (1% to 3%), rash at injection site (1% to 3%)

Endocrine & metabolic: Altered hormone level (1%; increased serum calcitonin)

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

Genitourinary: Urinary tract infection (4%)

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

Local: Erythema at injection site (1% to 3%)

Neuromuscular & skeletal: Asthenia (2%)

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

>10%:

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

Endocrine & metabolic: Hypoglycemia (children and adolescents: 21%)

Gastrointestinal: Gastrointestinal disease (43%), nausea (18% to 20%), diarrhea (10% to 12%)

Infection: Infection (patients with antibodies: 40%)

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

1% to 10%:

Dermatologic: Rash at injection site

Gastrointestinal: Decreased appetite (9% to 10%), dyspepsia (combination trials: 9%, monotherapy: 4% to 7%), vomiting (6% to 9%), increased serum lipase (8%), constipation (5%), cholelithiasis (2%), cholecystitis (1%), increased amylase (1%)

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

Immunologic: Antibody development (≤9%; neutralizing antibodies: 2%)

Local: Injection site reaction (monotherapy and combination trials: 2%), erythema at injection site

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

Respiratory: Nasopharyngitis (9% to 10%)

<1%, postmarketing, and/or case reports (any indication): Acute pancreatitis, acute renal failure, anaphylaxis, angioedema, asthma, benign gastrointestinal neoplasm (colorectal), bronchospasm, cholecystitis, cholestasis, dehydration, dysgeusia, exacerbation of renal failure, facial edema, first degree atrioventricular block, hemorrhagic pancreatitis, hepatitis, hypersensitivity reaction, increased liver enzymes, increased serum creatinine, increased susceptibility to infection, left bundle branch block, malaise, malignant neoplasm, malignant neoplasm of breast, malignant neoplasm of colon or rectum, medullary thyroid carcinoma, necrotizing pancreatitis, oropharyngeal edema, pancreatitis, papillary thyroid carcinoma, pharyngeal edema, pruritus, right bundle branch block, skin rash, suicidal ideation, systolic hypotension, thyroid disease (C-cell hyperplasia), urticaria

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 HbA_1C.
• Cardiovascular effects: Increased resting heart rate has been observed in placebo-controlled trials; monitoring is recommended. Discontinue use in patients who experience a sustained increase in resting heart rates.
• Gallbladder disease: Use of GLP-1 agonists may increase risk of gallbladder and bile duct disease (Faillie 2016). Cholelithiasis and cholecystitis have been reported in patients treated with liraglutide with the majority of patients requiring hospitalization or cholecystectomy; gallbladder studies and further clinical assessment are indicated if cholelithiasis is suspected.
• GI symptoms: Most common reactions are GI related; these symptoms may be dose related and may decrease in frequency/severity with gradual titration and continued use. Discontinue use if volume depletion develops (eg, due to nausea, vomiting, diarrhea) (AACE [Garvey 2016]).
• Hypersensitivity reactions: Serious hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported with use; permanently discontinue therapy in the event of a hypersensitivity reaction. Use with caution in patients with a history of anaphylaxis or angioedema to 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. It is not known if liraglutide increases risk for development of pancreatitis 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). Cases of MTC in humans have been reported in patients treated with liraglutide. 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.

Disease-related concerns:

• Bariatric surgery:

– Dehydration: Evaluate, correct, and maintain postsurgical fluid requirements and volume status prior to initiating therapy, and closely monitor the patient for the duration of therapy; acute and chronic kidney failure exacerbation may occur. A majority of cases occurred in patients with nausea, vomiting, diarrhea, and/or dehydration. Nausea is common and fluid intake may be more difficult after gastric bypass, sleeve gastrectomy, and gastric band (Mechanick 2013).

– Excessive glucagon-like peptide-1 exposure: Closely monitor for efficacy and assess for signs and symptoms of pancreatitis if therapy is initiated after surgery; gastric bypass and sleeve gastrectomy (but not gastric band) significantly increase endogenous postprandial glucagon-like peptide-1 (GLP-1) concentrations (Korner 2009; Peterli 2012). Administration of exogenous GLP-1 agonists may be redundant to surgery effects.

• 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).

Other warnings/precautions:

• Appropriate use: Diabetes mellitus: Victoza is not for 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, HbA_1c (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 2019]); renal function; signs/symptoms of pancreatitis; triglycerides; signs/symptoms of gallbladder disease; emergence of worsening depression, suicidal thoughts/behavior, changes in behavior; heart rate; body weight (at week 16 when used for chronic weight management)

Pregnancy

Pregnancy Considerations

Use of liraglutide for chronic weight management is contraindicated in pregnant women (lack of potential benefit and possible fetal harm). An increased risk of adverse maternal and fetal outcomes is associated with obesity; however, medications for weight loss therapy are not recommended at conception or during pregnancy (ACOG 156 2015).

Poorly controlled diabetes during pregnancy can be associated with an increased risk of adverse maternal and fetal outcomes, including diabetic ketoacidosis, preeclampsia, spontaneous abortion, preterm delivery, delivery complications, major birth defects, stillbirth, and macrosomia (ACOG 201 2018). To prevent adverse outcomes, prior to conception and throughout pregnancy, maternal blood glucose and HbA_1c should be kept as close to target goals as possible but without causing significant hypoglycemia (ADA 2020; Blumer 2013).

Agents other than liraglutide are currently recommended to treat diabetes in pregnant women (ADA 2020).

Patient Education

What is this drug used for?

• It is used to lower blood sugar in patients with high blood sugar (diabetes).
• It is used to lower the chance of heart attack, stroke, and death in some people.
• It is used to help you lose weight.

Frequently reported side effects of this drug

• Headache
• Diarrhea
• Constipation
• Nausea
• Vomiting
• Lack of appetite
• Stuffy nose
• Sore throat
• Back pain
• Abdominal pain
• Loss of strength and energy
• Injection site irritation

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Thyroid cancer like new lump or swelling in the neck, pain in the front of the neck, persistent cough, persistent change in voice like hoarseness, or difficulty swallowing or breathing.
• Pancreatitis like severe abdominal pain, severe back pain, severe nausea, or vomiting.
• Gallstones like pain in the upper right abdominal area, right shoulder area, or between the shoulder blades; yellow skin; or fever with chills.
• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain.
• Dizziness
• Passing out
• Fast heartbeat
• Abnormal heartbeat
• Mood changes
• Behavioral changes
• Depression
• Thoughts of suicide
• Slurred speech
• Low blood sugar like dizziness, headache, fatigue, feeling weak, shaking, fast heartbeat, confusion, increased hunger, or sweating
• Signs of a significant reaction like 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. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.