Introduction
Januvia (sitagliptin) is an oral antihyperglycemic agent belonging to the dipeptidyl peptidase-4 (DPP-4) inhibitor class. Developed by Merck & Co., it received FDA approval in 2006 as a once-daily medication for the management of type 2 diabetes mellitus. Januvia works by enhancing the body's own incretin system to improve glycemic control with a low risk of hypoglycemia when used as monotherapy.
Mechanism of Action
Sitagliptin is a selective, reversible inhibitor of the enzyme dipeptidyl peptidase-4 (DPP-4). DPP-4 is responsible for the rapid degradation of incretin hormones, particularly glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). By inhibiting DPP-4, Januvia increases circulating levels of active incretin hormones, which:
- Stimulate glucose-dependent insulin release from pancreatic beta cells
- Suppress inappropriate glucagon secretion from pancreatic alpha cells
- Slow gastric emptying
- Promote satiety
This glucose-dependent mechanism provides the advantage of a low intrinsic risk of hypoglycemia.
Indications
- Adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus
- May be used as monotherapy or in combination with other antihyperglycemic agents including metformin, sulfonylureas, thiazolidinediones, or insulin
- Not indicated for type 1 diabetes mellitus or diabetic ketoacidosis
Dosage and Administration
Standard dosing: 100 mg orally once daily Renal impairment dosing:- eGFR ≥45 mL/min/1.73 m²: 100 mg daily
- eGFR 30 to <45 mL/min/1.73 m²: 50 mg daily
- eGFR <30 mL/min/1.73 m²: 25 mg daily
- End-stage renal disease requiring hemodialysis: 25 mg daily (may be administered without regard to timing of dialysis)
- Can be taken with or without food
- Tablets should not be split, except for the 100 mg tablet which has a score line for splitting to 50 mg
- No dosage adjustment required for hepatic impairment or geriatric patients based on age alone
Pharmacokinetics
Absorption: Rapidly absorbed with peak plasma concentrations achieved in 1-4 hours. Absolute bioavailability is approximately 87%. Food does not affect the extent of absorption. Distribution: Mean volume of distribution is approximately 198 L. Plasma protein binding is negligible (38%). Metabolism: Minimal hepatic metabolism. Approximately 79% of the administered dose is excreted unchanged in urine. Minor metabolism occurs via CYP3A4 and CYP2C8. Elimination: Primarily renal excretion with a half-life of approximately 12.4 hours. Total clearance is approximately 350 mL/min.Contraindications
- History of hypersensitivity reaction to sitagliptin, including anaphylaxis or angioedema
- Previous serious hypersensitivity reactions to other DPP-4 inhibitors
Warnings and Precautions
Pancreatitis: Postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. Discontinue promptly if pancreatitis is suspected. Hypersensitivity Reactions: Anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome have been reported. Hepatic Effects: Postmarketing reports of hepatic failure, sometimes fatal. causality not established. Severe and Disabling Arthralgia: Severe and persistent joint pain may occur. Bullous Pemphigoid: Reports of bullous pemphigoid requiring hospitalization. Heart Failure: In cardiovascular outcomes trials, increased risk of hospitalization for heart failure was observed with another DPP-4 inhibitor (saxagliptin). Consider risks and benefits. Macrovascular Outcomes: No clinical studies establishing conclusive evidence of macrovascular risk reduction.Drug Interactions
Strong CYP3A4/CYP2C8 Inducers: Rifampin may decrease sitagliptin exposure by approximately 40%. Consider alternative therapy. Digoxin: Minimal increase in digoxin AUC (11%). Monitor digoxin levels. Other Antidiabetic Agents: Increased risk of hypoglycemia when used with sulfonylureas or insulin. May require dose reduction of these agents.Adverse Effects
Common (≥5%):- Nasopharyngitis
- Headache
- Upper respiratory tract infection
- Hypoglycemia (when used with sulfonylureas or insulin)
- Diarrhea
- Nausea
- Abdominal pain
- Acute pancreatitis
- Severe hypersensitivity reactions
- Hepatic dysfunction
- Severe arthralgia
- Bullous pemphigoid
- Acute renal failure (sometimes requiring dialysis)
Monitoring Parameters
- Hemoglobin A1c every 3 months until stable, then every 6 months
- Fasting plasma glucose
- Renal function (serum creatinine/eGFR) at baseline and periodically
- Signs and symptoms of pancreatitis (nausea, vomiting, abdominal pain)
- Hypersensitivity reactions
- Hepatic function tests periodically
- Signs of heart failure (weight gain, dyspnea, edema)
- Hypoglycemia symptoms when used with insulin or sulfonylureas
Patient Education
- Take medication once daily with or without food
- Do not use during pregnancy without discussing with healthcare provider
- Report immediately: severe abdominal pain, nausea, vomiting; allergic reactions including rash, hives, swelling; unusual joint pain; blisters or erosion of skin
- Understand symptoms of hypoglycemia (shaking, sweating, rapid heartbeat) and how to treat it
- Continue dietary restrictions, exercise program, and regular blood glucose monitoring
- Inform all healthcare providers of all medications being taken
- Not for use in type 1 diabetes
- Store at room temperature in original container
References
1. FDA Prescribing Information: Januvia (sitagliptin). Revised 2022. 2. Herman GA, et al. Effect of single oral doses of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on incretin and plasma glucose levels after an oral glucose tolerance test in patients with type 2 diabetes. J Clin Endocrinol Metab. 2006;91(11):4612-4619. 3. Aschner P, et al. Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care. 2006;29(12):2632-2637. 4. Green JB, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373(3):232-242. 5. American Diabetes Association. Standards of Medical Care in Diabetes - 2023. Diabetes Care. 2023;46(Suppl 1):S1-S291. 6. Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006;368(9548):1696-1705.