Introduction
Sitagliptin is an oral antihyperglycemic agent belonging to the dipeptidyl peptidase-4 (DPP-4) inhibitor class, commonly referred to as "gliptins." Approved by the FDA in 2006, it represents a significant advancement in the management of type 2 diabetes mellitus. Sitagliptin works through a glucose-dependent mechanism to improve glycemic control, offering a favorable safety profile with minimal risk of hypoglycemia when used as monotherapy.
Mechanism of Action
Sitagliptin exerts its therapeutic effect through selective, competitive inhibition of dipeptidyl peptidase-4 (DPP-4). DPP-4 is the enzyme responsible for the rapid degradation of endogenous incretin hormones, particularly glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). By inhibiting DPP-4, sitagliptin increases circulating levels of active incretins, which:
- Enhance glucose-dependent insulin secretion from pancreatic beta cells
- Suppress inappropriate glucagon secretion from pancreatic alpha cells
- Slow gastric emptying (minor effect)
- Promote satiety (minor effect)
This glucose-dependent mechanism results in improved glycemic control with minimal risk of hypoglycemia when not combined with insulin or insulin secretagogues.
Indications
Sitagliptin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. It may be used as:
- Monotherapy
- In combination with metformin, sulfonylureas, thiazolidinediones, insulin, or SGLT2 inhibitors
Dosage and Administration
Standard dosing: 100 mg once daily orally Renal impairment adjustments:- eGFR ≥45 mL/min: 100 mg daily
- eGFR 30 to <45 mL/min: 50 mg daily
- eGFR <30 mL/min: 25 mg daily
- Can be taken with or without food
- Tablet should be swallowed whole with water
- Dosing time can be adjusted to patient preference (consistent daily timing recommended)
- Hepatic impairment: No dosage adjustment necessary
- Elderly: Adjust based on renal function
- Pediatrics: Not recommended for use in children
Pharmacokinetics
Absorption: Rapidly absorbed with peak plasma concentrations achieved in 1-4 hours. Absolute bioavailability is approximately 87%. Food does not significantly affect absorption. Distribution: Mean volume of distribution is approximately 198 L. Plasma protein binding is low (38%). Metabolism: Minimal hepatic metabolism via CYP3A4 and CYP2C8. Majority of drug is excreted unchanged. Elimination: Primarily excreted renally (87% unchanged in urine). Terminal half-life is approximately 12.4 hours. Elimination is significantly reduced in renal impairment.Contraindications
- History of hypersensitivity reaction to sitagliptin, including anaphylaxis or angioedema
- Type 1 diabetes mellitus or diabetic ketoacidosis
- Severe renal impairment (eGFR <30 mL/min) without appropriate dose reduction
Warnings and Precautions
Pancreatitis: Postmarketing reports of acute pancreatitis, including fatal cases. Discontinue promptly if pancreatitis is suspected. Hypersensitivity reactions: Angioedema, anaphylaxis, and severe cutaneous adverse reactions (Stevens-Johnson syndrome) have been reported. Renal impairment: Requires dosage adjustment based on eGFR. Regular monitoring of renal function recommended. Hepatic impairment: Use with caution in patients with liver disease; monitor liver function. Macrovascular outcomes: No clinical studies establishing conclusive evidence of macrovascular risk reduction. Bullous pemphigoid: Reports of bullous pemphigoid requiring discontinuation.Drug Interactions
Strong CYP3A4/5 inducers: Rifampin, carbamazepine, phenytoin may decrease sitagliptin concentrations. Monitor glycemic control. Digoxin: Minimal increase in digoxin AUC (11%). Monitor digoxin levels when initiating or discontinuing sitagliptin. Insulin secretagogues: May increase risk of hypoglycemia. Consider lower dose of secretagogue. ACE inhibitors: Theoretical increased risk of angioedema (shared pathway).Adverse Effects
Common (≥5%):- Nasopharyngitis
- Upper respiratory tract infection
- Headache
- Hypoglycemia (when combined with sulfonylureas or insulin)
- Gastrointestinal effects (nausea, diarrhea)
- Peripheral edema
- Acute pancreatitis
- Severe hypersensitivity reactions
- Hepatic dysfunction
- Severe joint pain
- Bullous pemphigoid
- Rhabdomyolysis
Monitoring Parameters
- HbA1c every 3 months until stable, then every 6 months
- Renal function (serum creatinine, eGFR) at baseline and annually
- Liver function tests at baseline and periodically
- Signs and symptoms of pancreatitis (nausea, vomiting, abdominal pain)
- Hypoglycemic episodes, especially when used with insulin or sulfonylureas
- Weight and blood pressure regularly
- Signs of hypersensitivity reactions
Patient Education
- Take medication exactly as prescribed, typically once daily
- This medication helps control blood sugar but does not cure diabetes
- Continue following dietary restrictions, exercise program, and regular blood glucose monitoring
- Report immediately: severe abdominal pain, nausea/vomiting (possible pancreatitis)
- Report: rash, hives, swelling of face/lips/tongue (allergic reactions)
- Be aware of hypoglycemia symptoms when used with other diabetes medications
- Inform all healthcare providers about all medications being taken
- Regular follow-up with healthcare provider is essential
- Do not use during pregnancy without medical advice
References
1. FDA Prescribing Information: Januvia (sitagliptin). Revised 2022. 2. American Diabetes Association. Standards of Medical Care in Diabetes—2023. Diabetes Care. 2023;46(Suppl 1):S1-S291. 3. 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. 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. 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. 6. Williams-Herman D, et al. Safety and tolerability of sitagliptin in clinical studies: a pooled analysis of data from 10,246 patients with type 2 diabetes. BMC Endocr Disord. 2010;10:7. 7. Kaur P, et al. Efficacy and safety of dipeptidyl peptidase-4 inhibitors in type 2 diabetes mellitus patients with renal impairment: A systematic review. Diabetes Metab Syndr. 2017;11 Suppl 2:S705-S714.