Introduction
Xultophy is a fixed-ratio combination product containing insulin degludec (a long-acting basal insulin analog) and liraglutide (a glucagon-like peptide-1 [GLP-1] receptor agonist). It is indicated for the treatment of adults with type 2 diabetes mellitus to improve glycemic control when both basal insulin and GLP-1 receptor agonist components are appropriate. This combination offers the advantage of addressing multiple pathophysiological defects in type 2 diabetes through complementary mechanisms.
Mechanism of Action
Xultophy exerts its glucose-lowering effects through two distinct mechanisms:
Insulin degludec component: Forms multihexamers upon subcutaneous injection, resulting in a soluble depot that slowly dissociates to release monomeric insulin degludec. This provides a flat and stable pharmacokinetic profile with an ultralong duration of action (beyond 42 hours) that mimics basal insulin secretion. Liraglutide component: Acts as a GLP-1 receptor agonist that:- Enhances glucose-dependent insulin secretion from pancreatic beta cells
- Suppresses glucagon secretion in a glucose-dependent manner
- Slows gastric emptying
- Promotes satiety and reduces food intake
The combination provides both basal insulin coverage and postprandial glucose control through GLP-1-mediated effects.
Indications
Xultophy is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when both basal insulin and liraglutide are appropriate treatments.
Dosage and Administration
Initial dose: 16 dose units (16 units insulin degludec/0.58 mg liraglutide) once daily Titration: Increase by 2 dose units (2 units insulin degludec/0.072 mg liraglutide) every 3-4 days until fasting glucose target is achieved Maximum dose: 50 dose units (50 units insulin degludec/1.8 mg liraglutide) once daily Administration:- Administer subcutaneously once daily at any time of day
- Rotate injection sites within the same region (abdomen, thigh, or upper arm)
- May be administered with or without food
- Use Xultophy FlexTouch pen only
- Renal impairment: Not recommended in severe renal impairment
- Hepatic impairment: Use with caution
- Elderly: No dosage adjustment required
Pharmacokinetics
Absorption:- Insulin degludec: Tmax 12 hours, bioavailability ~70%
- Liraglutide: Tmax 8-12 hours, bioavailability ~55%
- Insulin degludec: ~99% protein bound
- Liraglutide: ~98% protein bound to albumin
- Insulin degludec: Catabolized via protein degradation
- Liraglutide: Proteolytic cleavage followed by β-oxidation of fatty acid side chain
- Insulin degludec: Terminal half-life ~25 hours
- Liraglutide: Terminal half-life ~13 hours
- Both primarily eliminated renally
Contraindications
- History of hypersensitivity to any component
- Type 1 diabetes mellitus
- Diabetic ketoacidosis
- Personal or family history of medullary thyroid carcinoma
- Multiple Endocrine Neoplasia syndrome type 2
- Pregnancy
Warnings and Precautions
Boxed Warning: Risk of thyroid C-cell tumors- Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors in rodents
- Human relevance unknown
- Pancreatitis: Discontinue if pancreatitis is suspected
- Hypoglycemia: Risk increased when combined with other glucose-lowering agents
- Renal impairment: Monitor renal function; not recommended in severe impairment
- Hypersensitivity reactions: Including anaphylaxis
- Acute gallbladder disease: Has been reported with GLP-1 receptor agonists
Drug Interactions
Drugs that may increase hypoglycemia risk:- Insulin secretagogues (sulfonylureas)
- Other antidiabetic agents
- ACE inhibitors
- Disopyramide
- Fluoxetine
- MAO inhibitors
- Pentoxifylline
- Propoxyphene
- Salicylates
- Somatostatin analogs
- Sulfonamide antibiotics
- Corticosteroids
- Danazol
- Diuretics
- Estrogens
- Glucagon
- Isoniazid
- Niacin
- Phenothiazines
- Protease inhibitors
- Somatropin
- Sympathomimetic agents
- Thyroid hormones
- Anticholinergics and opioids may reduce liraglutide effect
Adverse Effects
Common adverse reactions (≥5%):- Hypoglycemia (29%)
- Nausea (21%)
- Diarrhea (12%)
- Headache (9%)
- Decreased appetite (8%)
- Vomiting (7%)
- Severe hypoglycemia
- Pancreatitis
- Allergic reactions
- Acute gallbladder disease
- Renal impairment
Monitoring Parameters
- HbA1c every 3 months until stable, then every 6 months
- Fasting plasma glucose regularly
- Serum creatinine and eGFR at baseline and periodically
- Lipase and amylase if symptoms of pancreatitis occur
- Thyroid nodules (palpation) at baseline and periodically
- Weight and BMI
- Signs and symptoms of hypoglycemia
- Injection site reactions
Patient Education
Key points for patients:- Administer once daily at the same time each day
- Rotate injection sites to prevent lipodystrophy
- Never share pen device with others
- Recognize and treat hypoglycemia (carry glucose source)
- Report symptoms of pancreatitis (severe abdominal pain with vomiting)
- Report symptoms of thyroid tumors (neck mass, dysphagia, dyspnea)
- Inform all healthcare providers about Xultophy use
- Proper storage: Refrigerate unused pens; may be kept at room temperature for 21 days
- Missed dose: Administer as soon as remembered if within 12 hours; skip if more than 12 hours have passed
References
1. FDA Prescribing Information: Xultophy (insulin degludec and liraglutide) injection. 2021. 2. Harris SB, et al. Safety and efficacy of IDegLira in patients with type 2 diabetes uncontrolled on GLP-1 receptor agonist therapy. Diabetes Obes Metab. 2018;20(4):931-938. 3. Rodbard HW, et al. Dual add-on therapy in type 2 diabetes poorly controlled with metformin monotherapy. Diabetes Care. 2017;40(7):887-894. 4. Lingvay I, et al. Efficacy and safety of IDegLira versus basal-bolus insulin therapy in patients with type 2 diabetes uncontrolled on metformin and basal insulin. Lancet Diabetes Endocrinol. 2016;4(11):885-893. 5. Buse JB, et al. Contribution of liraglutide in the fixed-ratio combination of insulin degludec and liraglutide (IDegLira). Diabetes Care. 2014;37(11):2926-2933.