Version October 2024
The FDA has been evaluating reports of suicidal thoughts or actions in patients treated with glucagon-like peptide-1 receptor agonists (GLP-1 RAs). A preliminary evaluation has not found evidence that the use of these medicines causes suicidal thoughts or actions, but the FDA is continuing to investigate this issue. Patients should not stop taking GLP-1 RAs without consulting their health care provider. Health care providers should monitor for and advise patients using GLP-1 RAs to report new or worsening depression, suicidal thoughts, or any unusual changes in mood or behavior.
Further information may be found at https://www.fda.gov/drugs/drug-safety-and-availability/update-fdas-ongoing-evaluation-reports-suicidal-thoughts-or-actions-patients-taking-certain-type.
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.
Dosage guidance:
Clinical considerations: May require a dose reduction of insulin and/or insulin secretagogues (sulfonylureas, meglitinides) to avoid hypoglycemia (Ref).
Diabetes mellitus, type 2, treatment:
Note: May be used as an adjunctive agent or alternative monotherapy for patients in whom initial therapy with lifestyle intervention and metformin failed or who cannot take metformin. May be preferred in patients who have or are at risk for atherosclerotic cardiovascular disease, when weight loss is desired, and/or in patients with an HbA1c relatively far from goal (eg, HbA1c 9% to 10%) and type 1 diabetes is not likely (Ref). Due to lack of additive glycemic benefit, avoid concomitant use with a dipeptidyl peptidase-4 inhibitor (Ref).
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.
Weight management, chronic:
Note: For use as an adjunct to diet and exercise in patients with a BMI ≥30 kg/m2 or patients with a BMI ≥27 kg/m2 and ≥1 weight-associated comorbidity (eg, hypertension, dyslipidemia). Considered a preferred pharmacologic weight-loss option in patients with a BMI ≥27 kg/m2 and type 2 diabetes mellitus, particularly in those with atherosclerotic cardiovascular disease (Ref).
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. Patients may continue on the maximum tolerated dose (even if <3 mg/day) if goal weight loss is achieved on that dose (Ref).
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 (Ref).
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.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Altered kidney function: Mild to severe impairment: No dosage adjustment necessary (Ref). Use with caution in severe impairment; limited data are available in this population (Ref).
Hemodialysis, intermittent (thrice weekly): Not dialyzable (Ref): No dosage adjustment necessary (Ref); use with caution due to limited clinical evidence. One small, short-term study demonstrated efficacy in patients with type 2 diabetes receiving hemodialysis, although liraglutide steady-state trough concentrations were ~49% higher and increased rates of nausea and vomiting (self limited, usually during initiation and dose increases) were reported (Ref).
Peritoneal dialysis: Not likely dialyzable (Ref): No dosage adjustment necessary (Ref); use with caution due to limited clinical evidence. One small, retrospective study suggests efficacy and safety of once-daily 0.6 to 0.9 mg doses of liraglutide in patients with type 2 diabetes receiving peritoneal dialysis (Ref).
No dosage adjustment necessary; use with caution due to limited experience.
Refer to adult dosing.
(For additional information see "Liraglutide: Pediatric drug information")
Diabetes mellitus, type 2; adjunct to diet and exercise: Note: Glucagon-like peptide-1 (GLP-1) receptor agonists may be considered an additional therapeutic option in pediatric patients with type 2 diabetes mellitus who are ≥3 months post diagnosis with an HbA1c of ≥7% while on metformin therapy (maximized) in addition to a healthy lifestyle (eg, diet, exercise) with or without insulin (Ref).
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 (Ref).
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.
Weight management, chronic; adjunct to strict lifestyle interventions:
Children ≥12 years and Adolescents: Saxenda: SUBQ: Initial: 0.6 mg once daily for 1 week; increase as tolerated 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 lowering dose to the previous level. If the 3 mg target daily dose is not tolerated, reduce dose to 2.4 mg daily; discontinue if the 2.4 mg dose is not tolerated. After 12 weeks on the maintenance dose, assess BMI; if patient has not had a reduction ≥1% from baseline, discontinue therapy since patient is unlikely to achieve meaningful and sustainable results with liraglutide.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Children ≥10 years and Adolescents: SUBQ:
Altered kidney function:
Mild to severe impairment: No dosage adjustment necessary; use with caution, particularly when initiating therapy and with dose escalation; there is limited data in this population. Acute renal failure and worsening of chronic kidney disease (may require hemodialysis) has been reported; provide supportive care and consider discontinuation of liraglutide or other causative agents as necessary. Note: Some experts do not recommend use for weight loss in patients with severe renal impairment (Ref).
End-stage kidney disease (ESKD): No dosage adjustment necessary; use with caution when initiating therapy and with dose escalation; there are limited data in this population. Acute renal failure and worsening of chronic kidney disease (may require hemodialysis) has been reported; provide supportive care and consider discontinuation of liraglutide or other causative agents as necessary.
Hemodialysis, intermittent (thrice weekly): Not dialyzable (Ref); there are no dosage adjustments provided in the manufacturer's labeling; use with caution due to limited clinical evidence in patients with ESKD. Note: Some experts do not recommend use for weight loss in patients with ESKD (Ref).
Peritoneal dialysis: Not likely dialyzable (Ref); there are no dosage adjustments provided in the manufacturer's labeling.
Children ≥10 years and Adolescents: SUBQ: Mild to severe impairment: No dosage adjustment necessary; use with caution due to limited experience.
Acute kidney injury (AKI), including acute interstitial nephritis and acute tubular necrosis which sometimes require dialysis, has been reported (Ref). According to the manufacturer, altered kidney function has been reversed following discontinuation of liraglutide and initiation of supportive treatment.
Mechanism: Non-dose-related; exact mechanism is unknown. Prerenal AKI may occur due to dehydration and volume contraction secondary to GI symptoms (eg, nausea, vomiting, diarrhea) (Ref).
Onset: Varied; because the mechanism is thought to be related to volume contraction, timing may be dependent on GI symptoms, initiation or dosage adjustment of concomitant medications, and/or comorbid conditions (Ref).
Risk factors:
• Volume contraction (eg, during periods of severe vomiting or diarrhea) (Ref)
• Coadministration of medications known to result in kidney injury during episodes of dehydration (eg, drugs that inhibit the renin-angiotensin system) (Ref)
• Preexisting kidney impairment
Gallbladder disease and biliary tract disease, including cholelithiasis, cholecystitis, and cholangitis have been reported with glucagon-like peptide-1 (GLP-1) receptor agonists, including liraglutide; some have required hospitalization or cholecystectomy (Ref). Resolution of biliary stones following discontinuation has been documented (Ref).
Mechanism: Dose- and time-related (Ref); not fully understood. Animal studies and in vitro data have demonstrated that glucagon-like peptide 1 enhances the proliferation and functional activity of cholangiocytes, which may result in gallbladder diseases (Ref). Some authors have postulated a change in bile acid production and secretion, suppressed secretion of cholecystokinin, decreased gallbladder emptying, prolonged gallbladder refilling, weight loss, or potentially a combination of these factors (Ref).
Onset: Varied; onset has occurred as quickly as 4 to 8 weeks and as long as >1 year following initiation (Ref).
Risk factors:
• Higher doses (Ref)
• Longer duration of treatment (eg, >26 weeks (Ref)
• Patients who experience above-average weight loss with liraglutide treatment (Ref)
GI effects are the most common adverse reactions associated with glucagon-like peptide 1 receptor agonists, mainly diarrhea, nausea, and vomiting (Ref). Constipation, dyspepsia, and abdominal pain may also occur. GI effects tend to decrease over time (Ref).
Mechanism: Dose-related; however, the exact mechanism is not fully understood. May be a result of delayed gastric emptying or activation of centers involved in appetite regulation, satiety, and nausea (Ref).
Onset: Intermediate; nausea, vomiting, and diarrhea are most common soon after initiation (eg, the first 4 weeks of treatment) (Ref).
Risk factors:
• Dose; generally greater with higher doses
• Rapid titration
Serious, immediate hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with glucagon-like peptide 1 (GLP-1) receptor agonists, including liraglutide (Ref). Exendin-based GLP-1 receptor agonists (eg, exenatide, lixisenatide) are associated with a doubling of reporting odds of anaphylactic reaction, compared with human-analogue GLP-1 receptor agonists (eg, liraglutide, dulaglutide, semaglutide) (Ref).
Delayed hypersensitivity reactions, such as psoriasiform eruption (either generalized or at the site of the injection), pustular rash (photodistributed exanthematous pustulosis), and vesicular eruption (vesiculopustular dermatosis) have been documented (Ref). Time to resolution is variable occurring 2 weeks to up to 5 months after discontinuation of liraglutide (Ref).
Mechanism: Non-dose-related; immunologic
Immediate hypersensitivity reactions: IgE-antibodies are formed against a drug allergen following initial exposure (Ref).
Delayed hypersensitivity reactions: T-cell mediated (Ref).
Note: Formation of neutralizing antibodies to liraglutide has no apparent effect on efficacy or safety, including hypersensitivity reactions (Ref).
Onset:
Immediate hypersensitivity reactions: Rapid; generally occur within 1 hour of administration but may occur up to 6 hours after exposure (Ref).
Delayed hypersensitivity reactions: Varied; may occur from 1 day after initiation of liraglutide to 6 weeks (Ref).
Risk factors:
• Cross-reactivity between GLP-1 receptor agonists is unknown (Ref); until further studies are available, liraglutide should be used with caution in patients with a history of anaphylaxis or angioedema to other GLP-1 receptor agonists. Skin tests have been used in patients with histories of immediate hypersensitivity reactions to GLP-1 receptor agonists (Ref).
In the early stages of drug development, thyroid C-cell tumors were noted to have developed during animal studies with liraglutide. It is unknown whether liraglutide causes thyroid C-cell tumors in humans, as the human relevance of liraglutide-induced rodent thyroid C-cell tumors has not been determined. According to the manufacturer, human cases of medullary thyroid carcinoma (MTC) have been reported.
Mechanism: Unknown. Animal studies have shown dose-dependent and treatment duration-dependent harmful effects in rodents but not primates, thereby indicating that proliferative C-cell effects of liraglutide may be rodent-specific. Humans have far fewer C-cells than rodents, and expression of the glucagon-like peptide 1 receptor in human C-cells is very low (Ref).
Risk factors:
• Patients with a personal or family history of MTC or patients with multiple endocrine neoplasia syndrome type 2 may be at an increased risk
Cases of acute pancreatitis (including hemorrhagic pancreatitis and necrotizing pancreatitis with some fatalities), chronic pancreatitis, and pancreatic adenocarcinoma have been reported with use of incretin-based therapies (eg, dipeptidyl peptidase 4 inhibitors, glucagon-like peptide 1 [GLP-1] receptor agonists) (Ref).
Mechanism: Causality has not been firmly established (Ref). GLP-1 receptor agonists directly stimulate GLP-1 receptors in pancreatic islet beta cells and exocrine duct cells, which may cause an overgrowth of the cells that cover the smaller ducts, thereby resulting in hyperplasia, increased pancreatic weight, duct occlusion, back pressure, and subsequent acute or chronic pancreatic inflammation (Ref).
Onset: Not well characterized.
Risk factors:
• Patients with a prior history of pancreatitis may be at an increased risk for acute pancreatitis
• Patients with acute pancreatitis due to any cause are at an increased risk for progression to recurrent acute pancreatitis and then to chronic pancreatitis; patients with chronic pancreatitis are at an increased risk for pancreatic cancer (Ref)
• Risk factors for pancreatitis due to any cause include, but are not limited to, hypertriglyceridemia, cholelithiasis, alcohol use, and obesity
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adults unless otherwise specified.
Obesity:
>10%:
Cardiovascular: Increased heart rate (>10 bpm from baseline: 34%; >20 bpm from baseline: 5%)
Endocrine & metabolic: Hypoglycemia (monotherapy without type 2 diabetes: adolescents: 15%, adults: 2%; monotherapy with type 2 diabetes: adults: 13%; combination therapy with sulfonylurea: adults: 28%; severe hypoglycemia [requiring the assistance of another person] in combination therapy: adults: ≤2%)
Gastrointestinal: Constipation (adolescents: 5%; adults: 19%) (table 1), diarrhea (adolescents and adults: 21% to 22%) (table 2), gastroenteritis (adolescents and adults: 5% to 13%), nausea (adolescents and adults: 39% to 42%) (table 3), vomiting (adolescents: 34%; adults: 16%) (table 4)
|
Drug (Liraglutide) |
Placebo |
Population |
Dose |
Indication |
Number of Patients (Liraglutide) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|
|
19% |
9% |
Adults |
3 mg |
Obesity |
3,384 |
1,941 |
|
5% |
2% |
Children ≥12 years and adolescents |
3 mg |
Obesity |
125 |
126 |
|
Drug (Liraglutide) |
Placebo |
Population |
Dose |
Indication |
Number of Patients (Liraglutide) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|
|
21% |
10% |
Adults |
3 mg |
Obesity |
3,384 |
1,941 |
|
22% |
14% |
Children ≥12 years and adolescents |
3 mg |
Obesity |
125 |
126 |
|
Drug (Liraglutide) |
Placebo |
Population |
Dose |
Indication |
Number of Patients (Liraglutide) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|
|
39% |
14% |
Adults |
3 mg |
Obesity |
3,384 |
1,941 |
|
42% |
14% |
Children ≥12 years and Adolescents |
3 mg |
Obesity |
125 |
126 |
|
Drug (Liraglutide) |
Placebo |
Population |
Dose |
Indication |
Number of Patients (Liraglutide) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|
|
16% |
4% |
Adults |
3 mg |
Obesity |
3,384 |
1,941 |
|
34% |
4% |
Children ≥12 years and Adolescents |
3 mg |
Obesity |
125 |
126 |
Immunologic: Antibody development (adolescents: 12%; adults: 3%; neutralizing: adults: 1%)
Local: Injection-site reaction (including erythema at injection site, injection site pruritus, rash at injection site) (1% to 14%) (Carvallo 2020; Neel 2019)
Nervous system: Headache (14%)
1% to 10%:
Cardiovascular: Circulatory shock (≤1%), hypotension (≤1%), orthostatic hypotension (≤1%)
Dermatologic: Skin rash (adolescents: 3%)
Endocrine & metabolic: Altered hormone level (1%; increased serum calcitonin), dyslipidemia (adolescents: 5%)
Gastrointestinal: Abdominal distension (5%), abdominal distress (adolescents: 5%), abdominal pain (adults: 5%) (table 5), cholelithiasis (2%) (table 6), dyspepsia (adolescents and adults: 4% to 10%) (table 7), eructation (5%), flatulence (adolescents and adults: 3% to 4%), gastroesophageal reflux disease (5%), increased serum lipase (adolescents and adults: 2% to 5%), upper abdominal pain (5%), viral gastroenteritis (3%), xerostomia (2%)
|
Drug (Liraglutide) |
Placebo |
Population |
Dose |
Indication |
Number of Patients (Liraglutide) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|
|
5% |
3% |
Adults |
3 mg |
Obesity |
3,384 |
1,941 |
|
5% |
1% |
Children ≥12 years and adolescents |
3 mg |
Obesity |
125 |
126 |
|
Drug (Liraglutide) |
Placebo |
Population |
Dose |
Indication |
Number of Patients (Liraglutide) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|
|
2% |
0.8% |
Adults |
N/A |
Obesity |
N/A |
N/A |
|
Drug (Liraglutide) |
Placebo |
Population |
Dose |
Indication |
Number of Patients (Liraglutide) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|
|
10% |
3% |
Adults |
3 mg |
Obesity |
3,384 |
1,941 |
|
4% |
2% |
Children ≥12 years and adolescents |
3 mg |
Obesity |
125 |
126 |
Genitourinary: Urinary tract infection (4%)
Nervous system: Asthenia (2%), depression (adolescents: 4%), dizziness (adolescents and adults: 7% to 10%), fatigue (adolescents and adults: 5% to 8%)
Neuromuscular & skeletal: Increased creatine phosphokinase in blood specimen (adolescents: 3%), limb pain (adolescents: 4%)
Respiratory: Cough (adolescents: 4%)
Miscellaneous: Fever (adolescents: 8%)
<1%:
Cardiovascular: First degree atrioventricular block, left bundle branch block, right bundle branch block, systolic hypotension, tachycardia
Endocrine & metabolic: Papillary thyroid carcinoma
Gastrointestinal: Cholecystitis (table 8), malignant neoplasm of colon or rectum, pancreatitis (including chronic pancreatitis) (Ref)
|
Drug (Liraglutide) |
Placebo |
Population |
Dose |
Indication |
Number of Patients (Liraglutide) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|
|
0.8% |
0.4% |
Adults |
N/A |
Obesity |
N/A |
N/A |
Genitourinary: Malignant neoplasm of breast
Nervous system: Suicidal tendencies
Type 2 diabetes mellitus: Incidence reported with adult patients in monotherapy trials unless otherwise specified.
>10%:
Endocrine & metabolic: Hypoglycemia (children and adolescents: 21%; literature suggests an increased risk of hypoglycemia in pediatric patients regardless of concomitant use of other antidiabetic agents [Danne 2017; Mastrandea 2019; Tamborlane 2019])
Gastrointestinal: Diarrhea (10% to 12%) (table 9), nausea (18% to 20%) (table 10)
|
Drug (Liraglutide) |
Placebo |
Population |
Dose |
Indication |
Number of Patients (Liraglutide) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|
|
12% |
4% |
Adults |
1.8 mg |
Diabetes |
1,024 |
661 |
|
10% |
4% |
Adults |
1.2 mg |
Diabetes |
645 |
661 |
|
Drug (Liraglutide) |
Placebo |
Population |
Dose |
Indication |
Number of Patients (Liraglutide) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|
|
20% |
5% |
Adults |
1.8 mg |
Diabetes |
1,024 |
661 |
|
18% |
5% |
Adults |
1.2 mg |
Diabetes |
645 |
661 |
Nervous system: Headache (10% to 11%)
1% to 10%:
Gastrointestinal: Constipation (5%) (table 11), gallbladder disease (3%; including cholecystitis [1%] and cholelithiasis [2%] requiring cholecystectomy) (table 12) (table 13), dyspepsia (4% to 7%) (table 14), increased amylase (1%), increased serum lipase (8%), vomiting (6% to 9%) (table 15)
|
Drug (Liraglutide) |
Placebo |
Population |
Dose |
Indication |
Number of Patients (Liraglutide) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|
|
1% |
0.7% |
Adults |
1.8 mg |
Diabetes |
4,668 |
4,672 |
|
Drug (Liraglutide) |
Placebo |
Population |
Dose |
Indication |
Number of Patients (Liraglutide) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|
|
2% |
1% |
Adults |
1.8 mg |
Diabetes |
4,668 |
4,672 |
|
Drug (Liraglutide) |
Placebo |
Population |
Dose |
Indication |
Number of Patients (Liraglutide) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|
|
5% |
1% |
Adults |
1.8 mg |
Diabetes |
1,024 |
661 |
|
5% |
1% |
Adults |
1.2 mg |
Diabetes |
645 |
661 |
|
Drug (Liraglutide) |
Placebo |
Population |
Dose |
Indication |
Number of Patients (Liraglutide) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|
|
7% |
1% |
Adults |
1.8 mg |
Diabetes |
1,024 |
661 |
|
4% |
1% |
Adults |
1.2 mg |
Diabetes |
645 |
661 |
|
Drug (Liraglutide) |
Placebo |
Population |
Dose |
Indication |
Number of Patients (Liraglutide) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|
|
9% |
2% |
Adults |
1.8 mg |
Diabetes |
1,024 |
661 |
|
6% |
2% |
Adults |
1.2 mg |
Diabetes |
645 |
661 |
Hepatic: Hyperbilirubinemia (monotherapy and combination trials: 4%)
Immunologic: Antibody development (≤9%; neutralizing antibodies: 2%)
Local: Injection-site reaction (including erythema, rash) (monotherapy and combination trials: 2%)
Neuromuscular & skeletal: Back pain (4% to 5%)
Respiratory: Nasopharyngitis (9% to 10%), upper respiratory tract infection (7%)
<1%: Endocrine & metabolic: Papillary thyroid carcinoma
Postmarketing (any indication):
Dermatologic: Psoriasiform eruption (Bovijn 2019), pustular rash (exanthematous pustulosis) (Cogen 2019), vesicular eruption (vesiculopustular dermatosis) (Besemer 2012)
Endocrine & metabolic: Amyloidosis (cutaneous), medullary thyroid carcinoma, thyroid disease (C-cell hyperplasia)
Gastrointestinal: Acute pancreatitis (including hemorrhagic pancreatitis and necrotizing pancreatitis) (Dolan 2020, FDA 2013), biliary tract disease (He 2022), cholangitis (Faillie 2016), cholestasis (Faillie 2016; Pi-Sunyer 2015), delayed gastric emptying (gastroparesis) (Almustanyir 2020), intestinal obstruction
Hematologic & oncologic: Pancreatic adenocarcinoma (Alves 2012)
Hepatic: Acute hepatotoxicity (Parvataneni 2021), hepatitis (Kern 2014)
Hypersensitivity: Anaphylaxis (FDA 2017), angioedema (FDA 2017)
Renal: Acute interstitial nephritis (Gariani 2014), renal tubular necrosis (Kaakeh 2012)
Serious hypersensitivity (eg, anaphylactic reactions, angioedema) 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): Hypersensitivity to liraglutide or any component of the formulation; pregnancy (Victoza); breastfeeding.
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.
• Cardiovascular effects: Increased resting heart rate has been observed in placebo-controlled trials; monitoring is recommended. When used for chronic weight management, the manufacturer recommends discontinuation in patients who experience a sustained increase in resting heart rate.
• 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.
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 2020).
– 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 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 severe renal impairment; limited data are available in this population (Mann 2018; Mann 2020). A single-dose pharmacokinetic study suggests that liraglutide pharmacokinetics are unaffected by kidney dysfunction (Jacobsen 2009). Post hoc analyses of the LEADER trial, which included patients with type 2 diabetes at high risk for cardiovascular events, suggest equal safety and efficacy of unadjusted dosing in patients with eGFR <60 mL/minute/1.73 m2 compared to patients with eGFR ≥60 mL/minute/1.73 m2.
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; not a substitute for insulin. Saxenda is not indicated for the treatment of type 2 diabetes.
• Appropriate use: Weight loss: Safety and effectiveness in combination with other products intended for weight loss have not been established.
• Surgical and endoscopic procedures: Use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) has been associated with elevated residual gastric contents, which may increase the risk for adverse events during anesthesia and deep sedation (including aspiration) (Kobori 2023; Marroquin-Harris 2023; Silveira 2023). In some studies, delayed gastric emptying induced by GLP-1 RAs returned to baseline after 8 to 12 weeks of continuous therapy; therefore, risk may be higher in patients who recently initiated therapy or who use GLP-1 RAs intermittently (Raven 2024; van Zuylen 2024). Although the American Society of Anesthesiologists has suggested holding GLP-1 RAs prior to planned procedures requiring general anesthesia, the risks and benefits of this approach have not been evaluated (AGA [Hashash 2024]; ASA [Joshi 2023]). For example, in patients using GLP-1 RAs for glycemic control, holding the medication may result in perioperative hyperglycemia and increase the risk of adverse postoperative outcomes (AGA [Hashash 2024]; van Zuylen 2024). Individualize the decision to hold the GLP-1 RA based on patient-specific factors such as the indication (eg, glycemic control vs weight management), duration and frequency of therapy, presence of adverse GI symptoms, and concomitant medications that may slow gastric emptying (eg, opioids, proton pump inhibitors); may consider additional preoperative interventions (eg, clear liquid diet, full stomach precautions, gastric ultrasound) on a case-by-case basis to reduce risk (ASA [Hashash 2024]; Marroquin-Harris 2023; Raven 2024; van Zuylen 2024). Refer also to institutional protocols.
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]
No
Solution Pen-injector (Saxenda Subcutaneous)
18 mg/3 mL (per mL): $107.92
Solution Pen-injector (Victoza Subcutaneous)
18 mg/3 mL (per mL): $108.70
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
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: 6 mg/mL (3 mL) [contains phenol, propylene glycol]
SUBQ: Inject SUBQ in the upper arm, thigh, or abdomen; rotate injection sites within the same body region. Do not inject IV or IM. 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. For each new prefilled pen (Saxenda or Victoza), prime the needle before the first injection by turning the dose selector to the flow check symbol and injecting into the air (priming is not required for subsequent injections). Use a new needle for each injection. Once injected, continue to depress the button until the dial has returned to 0 and for an additional 6 seconds. Then, remove the needle.
SUBQ: Inject SUBQ in the upper arm, thigh, or abdomen; rotate injection sites within the same body region. Do not inject IV or IM. Administer any time of day without regard to meals. If using concomitantly with insulin, administer as separate injections (do not mix in same syringe); may inject in the same body region, but not adjacent to one another. Change needle with each administration; do not share pens between patients even if needle is changed. In pediatric obesity trials, doses were administered at 8 AM (± 2 hours) (Ref). For each new prefilled pen (Saxenda or Victoza), prime the needle before the first injection by turning the dose selector to the flow check symbol and injecting into the air (priming is not required for subsequent injections). Use a new needle for each injection. Once injected, continue to depress the button until the dial has returned to 0 and for an additional 6 seconds. Then, remove the needle.
Missed doses:
Diabetes mellitus, type 2: Victoza: If a dose is missed, 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 initial doses to avoid GI symptoms and titrate according to prescriber discretion (see "Dosing: Pediatric").
Weight management, chronic: Saxenda: If ≤3 days of therapy are missed, resume once-daily dosing with the next prescribed dose; do not administer extra or doubled doses. If >3 days of therapy are missed, therapy should be restarted at the initial dose (see "Dosing: Pediatric") and retitrated to avoid GI symptoms.
Hazardous agent (NIOSH 2016 [group 2]).
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).
Note: Facilities may perform risk assessment of some hazardous drugs to determine if appropriate for alternative handling and containment strategies (USP-NF 2020). Refer to institution-specific handling policies/procedures.
An FDA-approved patient medication guide, which is available with the product information, and as follows, must be dispensed with this medication:
Saxenda: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/206321s016lbl.pdf#page=30
Victoza: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/022341s039lbl.pdf#page=31
Diabetes mellitus, type 2, treatment (Victoza): As an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients ≥10 years of age 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.
Weight management, chronic (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 (obesity) or ≥27 kg/m2 (overweight) in the presence of at least 1 weight-related comorbid condition (eg, hypertension, type 2 diabetes mellitus, dyslipidemia) and pediatric patients ≥12 years of age with body weight >60 kg and an initial BMI corresponding to ≥30 kg/m2 for adults (obesity) by international cut-offs (Cole Criteria).
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs (contraindicated in pregnancy [Saxenda]) which have a heightened risk of causing significant patient harm when used in error (High-Alert Medications in Community/Ambulatory Care Settings).
Cross-contamination may occur if pens are shared among multiple patients. Steps should be taken to prohibit sharing of pens.
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
Alpha-Lipoic Acid: May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Androgens: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Beta-Blockers (Beta1 Selective): May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Beta-Blockers (Nonselective): May enhance the hypoglycemic effect of Antidiabetic Agents. Beta-Blockers (Nonselective) may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Bortezomib: May enhance the therapeutic effect of Antidiabetic Agents. Bortezomib may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Direct Acting Antiviral Agents (HCV): May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Etilefrine: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Glucagon-Like Peptide-1 Agonists: Liraglutide may enhance the adverse/toxic effect of Glucagon-Like Peptide-1 Agonists. Risk X: Avoid combination
Guanethidine: May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Hyperglycemia-Associated Agents: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Hypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Risk C: Monitor therapy
Insulins: Liraglutide may enhance the hypoglycemic effect of Insulins. Management: Consider reducing the liraglutide dose if coadministered with insulin. Prescribing information for the Saxenda brand of liraglutide recommends a dose decrease of 50%. Monitor blood glucose for hypoglycemia. Risk D: Consider therapy modification
Maitake: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Meglitinides: Glucagon-Like Peptide-1 Agonists may enhance the hypoglycemic effect of Meglitinides. Management: Consider meglitinide dose reductions when used in combination with glucagon-like peptide-1 agonists, particularly when also used with basal insulin. Risk D: Consider therapy modification
Monoamine Oxidase Inhibitors: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Pegvisomant: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Propranolol: May enhance the hypoglycemic effect of Liraglutide. Liraglutide may diminish the therapeutic effect of Propranolol. Specifically, the heart rate lowering effect of propranolol may be diminished. Propranolol may diminish the therapeutic effect of Liraglutide. Risk C: Monitor therapy
Prothionamide: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Quinolones: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Quinolones may diminish the therapeutic effect of Agents with Blood Glucose Lowering Effects. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Risk C: Monitor therapy
Ritodrine: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Salicylates: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Semaglutide: May enhance the adverse/toxic effect of Glucagon-Like Peptide-1 Agonists. Risk X: Avoid combination
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. Risk D: 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. Risk D: Consider therapy modification
Thiazide and Thiazide-Like Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Tirzepatide: May enhance the adverse/toxic effect of Glucagon-Like Peptide-1 Agonists. Risk X: Avoid combination
Obesity increases the risk of infertility. Optimal weight control prior to conception improves pregnancy outcomes. However, medications for weight loss are not recommended prior to pregnancy due to safety issues and adverse events. Weight loss medications should be discontinued prior to conception (ACOG 2021; Wharton 2020).
Glucagon-like peptide-1 (GLP-1) receptor agonists are not recommended for patients with type 2 diabetes mellitus planning to become pregnant. Patients who could become pregnant should use effective contraception during therapy. Transition to a preferred therapy should be initiated prior to conception and contraception should be continued until glycemic control is achieved (ADA 2021; Alexopoulos 2019; Egan 2020)
An increased risk of adverse maternal and fetal events is associated with obesity. However, moderate gestational weight gain based on pre-pregnancy BMI is required for positive fetal outcomes in all pregnancies, including patients who are overweight or obese. Therefore, medications for weight loss therapy are not recommended during pregnancy (ACOG 2021; Wharton 2020). Use of liraglutide for chronic weight management is contraindicated in pregnant patients (lack of potential benefit and possible fetal harm).
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 malformations, stillbirth, and macrosomia (ACOG 201 2018). 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 (ADA 2021; Blumer 2013).
Agents other than liraglutide are currently recommended to treat diabetes during pregnancy (ADA 2021).
It is not known if liraglutide is present in breast milk.
According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother. Due to safety concerns, medications for weight loss therapy are not recommended for patients who are breastfeeding (Wharton 2020).
Individualized medical nutrition therapy (MNT) based on ADA recommendations is an integral part of therapy.
Plasma glucose; renal function; signs/symptoms of pancreatitis (eg, persistent severe abdominal pain, which may radiate to the back and which may or may not be accompanied by vomiting); triglycerides; signs/symptoms of gallbladder disease; gallbladder studies and further clinical assessment are indicated if cholelithiasis is suspected; emergence of worsening depression, suicidal thoughts/behavior, changes in behavior; heart rate; body weight (at week 16 when used for chronic weight management).
HbA1c: Monitor at least twice yearly in patients who have stable glycemic control and are meeting treatment goals; monitor quarterly in patients in whom treatment goals have not been met, or with therapy change. Note: In patients prone to glycemic variability (eg, patients with insulin deficiency), or in patients whose HbA1c is discordant with serum glucose levels or symptoms, consider evaluating HbA1c in combination with blood glucose levels and/or a glucose management indicator (ADA 2021; KDIGO 2020).
Recommendations for glycemic control in patients with diabetes:
Nonpregnant adults (AACE [Samson 2023]; ADA 2023):
HbA1c: <7% (a more aggressive [<6.5%] or less aggressive [<8%] HbA1c goal may be targeted based on patient-specific characteristics). Note: In patients using a continuous glucose monitoring system, a goal of time in range >70% with time below range <4% is recommended and is similar to a goal HbA1c <7%.
Preprandial capillary blood glucose: 80 to 130 mg/dL (SI: 4.4 to 7.2 mmol/L) (more or less stringent goals may be appropriate based on patient-specific characteristics).
Peak postprandial capillary blood glucose (~1 to 2 hours after a meal): <180 mg/dL (SI: <10 mmol/L) (more or less stringent goals may be appropriate based on patient-specific characteristics).
Older adults (≥65 years of age) (ADA 2023):
Note: May consider less strict targets in patients who are using insulin and/or insulin secretagogues (sulfonylureas, meglitinides) (ES [LeRoith 2019]).
HbA1c: <7% to 7.5% (healthy); <8% (complex/intermediate health). Note: Individualization may be appropriate based on patient and caregiver preferences and/or presence of cognitive impairment. In patients with very complex or poor health (ie, limited remaining life expectancy), consider making therapy decisions based on avoidance of hypoglycemia and symptomatic hyperglycemia rather than HbA1c level.
Preprandial capillary blood glucose: 80 to 130 mg/dL (SI: 4.4 to 7.2 mmol/L) (healthy); 90 to 150 mg/dL (SI: 5 to 8.3 mmol/L) (complex/intermediate health); 100 to 180 mg/dL (SI: 5.6 to 10 mmol/L) (very complex/poor health).
Bedtime capillary blood glucose: 80 to 180 mg/dL (SI: 4.4 to 10 mmol/L) (healthy); 100 to 180 mg/dL (SI: 5.6 to 10 mmol/L) (complex/intermediate health); 110 to 200 mg/dL (SI: 6.1 to 11.1 mmol/L) (very complex/poor health).
Children and adolescents:
Preprandial glucose: 70 to 130 mg/dL (SI: 3.9 to 7.2 mmol/L) (ISPAD [Dimeglio 2018]).
Postprandial glucose: 90 to 180 mg/dL (SI: 5 to 10 mmol/L) (ISPAD [Dimeglio 2018]).
Bedtime/overnight glucose: 80 to 140 mg/dL (SI: 4.4 to 7.8 mmol/L) (ISPAD [Dimeglio 2018]).
HbA1c: <7%; target should be individualized; a more stringent goal (<6.5%) may be reasonable if it can be achieved without significant hypoglycemia; less aggressive goals (<7.5% or <8%) may be appropriate in patients who cannot articulate symptoms of hypoglycemia, cannot check glucose frequently, have a history of severe hypoglycemia, or have extensive comorbid conditions (ADA 2023; ISPAD [Dimeglio 2018]).
Surgical patients (ISPAD [Jefferies 2018]):
Intraoperative: 90 to 180 mg/dL (SI: 5 to 10 mmol/L).
ICU, postsurgery: 140 to 180 mg/dL (SI: 7.8 to 10 mmol/L).
Classification of hypoglycemia (ADA 2023):
Level 1: 54 to 70 mg/dL (SI: 3 to 3.9 mmol/L); hypoglycemia alert value; initiate fast-acting carbohydrate (eg, glucose) treatment.
Level 2: <54 mg/dL (SI: <3 mmol/L); threshold for neuroglycopenic symptoms; requires immediate action.
Level 3: Hypoglycemia associated with a severe event characterized by altered mental and/or physical status requiring assistance.
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%.
Note: Pharmacokinetic data in type 2 diabetes mellitus pediatric patients (10 to 17 years) is similar to adult patients.
Distribution: Vd: SUBQ: ~13 L; IV: 0.07 L/kg.
Protein binding: >98%.
Metabolism: Endogenously metabolized by dipeptidyl peptidase 4 (DPP-4) and endogenous endopeptidases (Croom 2009); metabolism occurs slower than that seen with native GLP-1.
Bioavailability: SUBQ: ~55%.
Half-life, elimination: ~13 hours.
Time to peak, plasma: SUBQ: 8 to 12 hours.
Excretion: Urine (6%, as metabolites); feces (5%, as metabolites).
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.
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