Insulin Degludec and Liraglutide

Dosage Forms

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

Solution Pen-injector, Subcutaneous:

Xultophy: 100/3.6: Insulin degludec 100 units and liraglutide 3.6 mg per mL (3 mL) [contains phenol]

Pharmacology

Mechanism of Action

Refer to individual agents.

Use: Labeled Indications

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

Contraindications

Hypersensitivity to insulin degludec, liraglutide, or any component of the formulation; history of or family history of medullary thyroid carcinoma (MTC); patients with multiple endocrine neoplasia syndrome type 2 (MEN2); during episodes of hypoglycemia

Canadian labeling: Additional contraindications (not in US labeling): Pregnant or breastfeeding women

Dosage and Administration

Dosing: Adult

Diabetes mellitus, type 2: SubQ: Note: Discontinue therapy with basal insulin or a GLP-1 agonist prior to initiation of therapy.

Initial:

Patients naive to basal insulin or a GLP-1 agonist: 10 units (insulin degludec 10 units/liraglutide 0.36 mg) once daily.

Patients currently on basal insulin or a GLP-1 agonist: 16 units (insulin degludec 16 units/liraglutide 0.58 mg) once daily.

Dose titration: Titrate dosage upwards or downwards by 2 units (insulin degludec 2 units/liraglutide 0.072 mg) once or twice weekly (every 3 to 4 days) until the desired fasting plasma glucose is achieved. Maximum dose: 50 units (insulin degludec 50 units/liraglutide 1.8 mg)/day

Missed dose: Resume with next regularly scheduled dose; do not administer an extra dose or increase dose to account for missed dose. If more than 3 days have elapsed since last dose, reinitiate at the initial dosage once daily

Dosing: Geriatric

Refer to adult dosing.

Administration

SubQ: For SubQ use only. Do not administer IM, IV, or via an insulin pump. Cold injections should be avoided. Inject into the abdomen, thigh, or upper arm. Rotate injection sites for each dose; do not use the same site for each injection to avoid lipodystrophy or localized cutaneous amyloidosis. Rotating from an injection site where lipodystrophy/cutaneous amyloidosis is present to an unaffected site may increase risk of hypoglycemia. Administer once daily at the same time each day with or without food. Do not split the dose. Solution should appear clear and colorless; do not use if particulate matter or coloration is seen. Do not mix or dilute with any other insulin or solution. Prefilled pen dials in 1-unit increments.

Dietary Considerations

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

Storage

Prior to initial use, store pens at 2°C to 8°C (36°F to 46°F). Do not freeze (discard if frozen). Protect from light. After initial use, may store for up to 21 days at room temperature (15ºC to 30°C [59ºF to 86°F]) or under refrigeration (2ºC to 8ºC [36ºF to 46ºF]). Replace the pen cap after each use, do not store with needle attached.

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

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

Beta-Blockers: May enhance the hypoglycemic effect of Insulins. Exceptions: Levobunolol; Metipranolol. Monitor therapy

Dipeptidyl Peptidase-IV Inhibitors: May enhance the hypoglycemic effect of Insulins. Management: Consider a decrease in insulin dose when initiating therapy with a dipeptidyl peptidase-IV inhibitor and monitor patients for hypoglycemia. Consider therapy modification

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

Edetate CALCIUM Disodium: May enhance the hypoglycemic effect of Insulins. Monitor therapy

Glucagon-Like Peptide-1 Agonists: May enhance the hypoglycemic effect of Insulins. Management: Consider insulin dose reductions when used in combination with glucagon-like peptide-1 agonists. Exceptions: Liraglutide. Consider therapy modification

Guanethidine: May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

Herbs (Hypoglycemic Properties): May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

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

Hypoglycemia-Associated Agents: May enhance the hypoglycemic effect of other Hypoglycemia-Associated 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

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

Macimorelin: Insulins may diminish the diagnostic effect of Macimorelin. Avoid combination

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

Metreleptin: May enhance the hypoglycemic effect of Insulins. Management: Insulin dosage adjustments (including potentially large decreases) may be required to minimize the risk for hypoglycemia with concurrent use of metreleptin. Monitor closely. Consider therapy modification

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

Pioglitazone: May enhance the adverse/toxic effect of Insulins. Specifically, the risk for hypoglycemia, fluid retention, and heart failure may be increased with this combination. Management: If insulin is combined with pioglitazone, dose reductions should be considered to reduce the risk of hypoglycemia. Monitor patients for fluid retention and signs/symptoms of heart failure. Consider therapy modification

Pramlintide: May enhance the hypoglycemic effect of Insulins. Management: Upon initiation of pramlintide, decrease mealtime insulin dose by 50% to reduce the risk of hypoglycemia. Monitor blood glucose frequently and individualize further insulin dose adjustments based on glycemic control. Consider therapy modification

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

Rosiglitazone: Insulins may enhance the adverse/toxic effect of Rosiglitazone. Specifically, the risk of fluid retention, heart failure, and hypoglycemia may be increased with this combination. Avoid combination

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

Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors: May enhance the hypoglycemic effect of Insulins. Management: Consider a decrease in insulin dose when initiating therapy with a sodium-glucose cotransporter 2 inhibitor and monitor patients for hypoglycemia. 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

Also see individual agents.

>10%:

Endocrine & metabolic: Hypoglycemia (22% to 37%)

Immunologic: Antibody development (2% to 11%; antibody formation has not been associated with reduced efficacy)

1% to 10%:

Central nervous system: Headache (9%)

Gastrointestinal: Diarrhea (8%), nausea (8%), increased serum lipase (7%)

Local: Injection site reaction (3%; mild and transitory)

Respiratory: Nasopharyngitis (10%), upper respiratory tract infection (6%)

Frequency not defined:

Cardiovascular: Increased heart rate

Local: Hypertrophy at injection site, lipoatrophy at injection site

<1%, postmarketing, and/or case reports: Abdominal distension, abdominal pain, allergic skin reaction, anaphylaxis, angioedema, constipation, decreased appetite, dyspepsia, eructation, flatulence, gastritis, gastroesophageal reflux disease, hypersensitivity reaction, severe hypoglycemia, urticaria, vomiting

Warnings/Precautions

Concerns related to adverse effects:

• Antibody formation: Development of antibodies to insulin and liraglutide may occur. In clinical trials with insulin degludec/liraglutide combination, antibody formation was not associated with reduced efficacy. In clinical trials with liraglutide, patients with the highest titers of anti-liraglutide antibodies had no reduction in HbA_1C.
• Gallbladder disease: 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 gastrointestinal related; these symptoms may be dose-related and may decrease in frequency/severity with gradual titration and continued use.
• Glycemic control: Hyper- or hypoglycemia may result from changes in insulin strength, manufacturer, type, and/or administration method. The most common adverse effect of insulin is hypoglycemia. The timing of hypoglycemia differs among various insulin formulations. Hypoglycemia may result from changes in meal pattern (eg, macronutrient content, timing of meals), changes in the level of physical activity, increased work or exercise without eating, or changes to coadministered medications. Use of long-acting insulin preparations (eg, insulin degludec, insulin detemir, insulin glargine) may delay recovery from hypoglycemia. Patients with renal or hepatic impairment may be at a higher risk. Symptoms differ in patients and may change over time in the same patient; awareness may be less pronounced in those with long-standing diabetes, diabetic nerve disease, patients taking beta-blockers, or in those who experience recurrent hypoglycemia. Profound and prolonged episodes of hypoglycemia may result in convulsions, unconsciousness, temporary or permanent brain damage, or even death. Insulin requirements may be altered during illness, emotional disturbances, or other stressors. Instruct patients to use caution with ethanol; may increase risk of hypoglycemia.
• Hypersensitivity: Serious hypersensitivity reactions including anaphylaxis and angioedema have been reported with liraglutide and with insulin degludec; discontinue use if hypersensitivity reactions occur and treat promptly as indicated. It is not known if patients with a history of hypersensitivity to other GLP-1 agonists are at increased risk for hypersensitivity reactions with liraglutide; patients with prior serious reactions to similar agents should be monitored closely.
• Hypokalemia: Insulin (especially IV insulin) causes a shift of potassium from the extracellular space to the intracellular space, possibly producing hypokalemia. If left untreated, hypokalemia may result in respiratory paralysis, ventricular arrhythmia and even death. Use with caution in patients at risk for hypokalemia (eg, loop diuretic use). Monitor serum potassium and supplement potassium when necessary.
• Pancreatitis: Cases of acute and chronic pancreatitis (including fatal and nonfatal, hemorrhagic or necrotizing pancreatitis) have been reported with GLP-1 receptor agonists; 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. It is not known if liraglutide increases risk for development of pancreatitis in patients with a history of pancreatitis.
• Renal effects: Acute renal failure and chronic renal failure exacerbation (including severe cases requiring hemodialysis) have been reported with liraglutide; 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). Patients who develop elevated calcitonin concentrations or have thyroid nodules detected during imaging studies or physical exam should be further evaluated. 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.

– Type 2 diabetes, hypoglycemia: Closely monitor insulin dose requirement throughout active weight loss with a goal of eliminating antidiabetic therapy or transitioning to agents without hypoglycemic potential; hypoglycemia after gastric bypass, sleeve gastrectomy, and gastric band may occur (Mechanick 2013). Insulin secretion and sensitivity may be partially or completely restored early after these procedures (gastric bypass is most effective, followed by sleeve and finally band) (Korner 2009; Peterli 2012). Monitoring of hospital insulin requirements is recommended to guide discharge insulin dose. Rates and timing of type 2 diabetes improvement and resolution vary widely by patient; insulin dose reduction of 75% has been suggested after gastric bypass for patients without severe β-cell failure (fasting c-peptide <0.3 nmol/L) (Cruijsen 2014). ­

– Weight gain: Evaluate risk versus benefit and consider alternative therapy after gastric bypass, sleeve gastrectomy, and gastric banding; weight gain may occur (Apovian 2015).

• Cardiac disease: Concurrent use with peroxisome proliferator-activated receptor (PPAR)-gamma agonists, including thiazolidinediones (TZDs) may cause dose-related fluid retention and lead to or exacerbate heart failure, particularly when used in combination with insulin. If PPAR-gamma agonists are prescribed, monitor for signs and symptoms of heart failure. If heart failure develops, consider PPAR-gamma agonist dosage reduction or therapy discontinuation.
• Gastroparesis: Liraglutide slows gastric emptying; has not been studied in patients with preexisting gastroparesis.
• Hepatic impairment: Use with caution in patients with hepatic impairment, insulin requirements may be reduced due to changes in insulin clearance or metabolism; monitor blood glucose closely. Dosage adjustments may be necessary.
• Renal impairment: Use with caution in patients with renal impairment. Dosage adjustments may be necessary.

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: Not approved for use in patients with diabetic ketoacidosis (DKA) or patients with type 1 diabetes mellitus.
• Patient education: Diabetes self-management education (DSME) is essential to maximize the effectiveness of therapy.

Monitoring Parameters

Plasma glucose (typically before meals and snacks and at bedtime; occasionally additional monitoring may be required), electrolytes, 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, hepatic function, weight

Gestational diabetes mellitus: Blood glucose 4 times daily (1 fasting and 3 postprandial) until well controlled, then as appropriate (ACOG 190 2018).

Pregnancy

Pregnancy Considerations

Adverse events were observed in some animal reproduction studies. Refer to individual agents.

Patient Education

What is this drug used for?

• It is used to lower blood sugar in patients with high blood sugar (diabetes).

Frequently reported side effects of this drug

• Nasal irritation
• Throat irritation
• Common cold symptoms
• Headache
• Nausea
• Vomiting
• Abdominal pain
• Passing gas
• Lack of appetite
• Diarrhea
• Burping
• Constipation
• 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 trouble 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 eyes; or fever with chills
• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes
• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain
• Low potassium like muscle pain or weakness, muscle cramps, or an abnormal heartbeat
• Vision changes
• Dizziness
• Passing out
• Slurred speech
• Seizures
• Injection site thick skin, pits, or lumps
• Mood changes
• Shortness of breath
• Excessive weight gain
• Swelling of arms or legs
• 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.