Sitagliptin Classification
Sitagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor, an oral antihyperglycemic medication class that enhances glucose-dependent insulin secretion and suppresses glucagon secretion by increasing endogenous levels of active GLP-1 and GIP. 1
Mechanism of Action
- DPP-4 inhibitors work by blocking the enzyme that degrades incretin hormones (GLP-1 and GIP), thereby increasing their circulating levels and duration of action 2
- This mechanism enhances glucose-dependent insulin secretion from pancreatic beta-cells and reduces glucagon secretion from alpha-cells, resulting in improved glycemic control without directly stimulating insulin release 1, 3
- The glucose-dependent nature of this mechanism minimizes hypoglycemia risk when used as monotherapy 1
Pharmacological Characteristics
- Sitagliptin is 87% orally bioavailable and undergoes minimal hepatic metabolism 3
- Approximately 79% is excreted unchanged in the urine, requiring dose adjustment in renal impairment 3
- At doses ≥100 mg once daily, DPP-4 activity is inhibited by >80%, resulting in a 2-fold increase in active GLP-1 levels 3
- The standard dosing is 100 mg once daily for patients with normal renal function 1
Clinical Efficacy Profile
- Sitagliptin reduces HbA1c by approximately 0.4% to 0.9% across various patient populations 1
- It provides effective control of both fasting plasma glucose (FPG) and postprandial glucose (PPG) 4, 5
- Markers of beta-cell function (HOMA-beta and proinsulin/insulin ratio) improve with sitagliptin treatment 4, 6
Therapeutic Positioning
- The American Diabetes Association recommends DPP-4 inhibitors like sitagliptin as second-line therapy after metformin, or as part of initial dual combination therapy in patients with HbA1c ≥1.5% above target 1
- Sitagliptin can be used as monotherapy or in combination with metformin, thiazolidinediones, sulfonylureas, or insulin 1
- For patients with established atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease with albuminuria, SGLT2 inhibitors or GLP-1 receptor agonists are preferred over DPP-4 inhibitors due to proven cardiovascular and renal benefits 1
Safety and Tolerability Profile
- Sitagliptin is generally well tolerated with an overall incidence of adverse events comparable to placebo 4
- It has minimal hypoglycemia risk when used as monotherapy, though risk increases approximately 50% when combined with sulfonylureas 1
- The medication is weight-neutral, neither causing significant weight gain nor weight loss 1
- Sitagliptin demonstrated cardiovascular safety in the TECOS trial with neutral effects on heart failure risk (HR 1.00,95% CI 0.83-1.20), unlike saxagliptin and alogliptin which increase heart failure hospitalization risk 1
Renal Dosing Requirements
- Standard dose (100 mg daily) for eGFR ≥45 mL/min/1.73 m² 1
- Reduced dose (50 mg daily) for moderate renal impairment (eGFR 30-44 mL/min/1.73 m²) 1
- Further reduced dose (25 mg daily) for severe renal impairment (eGFR <30 mL/min/1.73 m²) 1
- Regular monitoring of renal function is needed to adjust dosing appropriately 1
Important Clinical Caveats
- Cardiovascular outcomes trials showed cardiovascular safety but no cardiovascular benefit for sitagliptin 1
- DPP-4 inhibitors should not be combined with GLP-1 receptor agonists, as there is no additional glucose lowering beyond that of a GLP-1 receptor agonist alone 2
- Rare but increased rates of pancreatitis have been reported with DPP-4 inhibitors 1