What is Januvia (sitagliptin)?

What is Januvia (Sitagliptin)?

Januvia (sitagliptin) is an oral dipeptidyl peptidase-4 (DPP-4) inhibitor that enhances insulin secretion and suppresses glucagon release in a glucose-dependent manner, approved for treating type 2 diabetes as monotherapy or in combination with other antihyperglycemic agents. 1, 2

Mechanism of Action

Sitagliptin works by selectively inhibiting the DPP-4 enzyme, which normally degrades incretin hormones like glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide. 1, 3 By blocking this degradation, sitagliptin increases circulating incretin levels, which:

• Stimulates insulin secretion from pancreatic beta cells only when glucose levels are elevated 1, 4
• Inhibits glucagon secretion in a glucose-dependent manner 5
• Reduces both fasting and postprandial glucose levels 1, 3

This glucose-dependent mechanism is critical because it minimizes hypoglycemia risk compared to agents like sulfonylureas. 5, 6

Clinical Efficacy

Sitagliptin reduces HbA1c by approximately 0.4% to 0.9%, which is moderate compared to other diabetes medications. 5, 2 The drug demonstrates:

• Similar efficacy to glipizide when added to metformin, but without weight gain or hypoglycemia 3, 6
• Non-inferior glycemic control compared to metformin monotherapy 6
• Effective as add-on therapy to metformin, thiazolidinediones, sulfonylureas, or insulin 6, 4

Dosing and Administration

Standard dosing is 100 mg once daily, with no need for dose titration or home glucose monitoring. 3, 4 However, renal function dictates dose adjustments:

• eGFR ≥45 mL/min/1.73 m²: 100 mg daily 5, 7
• eGFR 30-44 mL/min/1.73 m²: 50 mg daily 5, 7
• eGFR <30 mL/min/1.73 m² or dialysis: 25 mg daily 5, 7

Safety Profile

Sitagliptin is generally well tolerated with minimal adverse effects. 2, 6 Key safety features include:

• Low hypoglycemia risk when used as monotherapy (similar to placebo) 1, 6
• Weight-neutral effect (no weight gain or loss) 1, 6
• Most common side effects are mild gastrointestinal complaints (abdominal pain, nausea, diarrhea up to 16%), upper respiratory symptoms, and headache 1, 4
• Hypoglycemia risk increases approximately 50% when combined with sulfonylureas 5, 8

Cardiovascular Safety

The TECOS trial demonstrated cardiovascular safety with no increased risk of major adverse cardiac events or heart failure hospitalization. 9, 5, 2 This distinguishes sitagliptin from saxagliptin and alogliptin, which have been associated with increased heart failure risk. 9, 5

Clinical Positioning

Sitagliptin is NOT recommended as first-line therapy—metformin remains the preferred initial agent. 8 The American Diabetes Association and American College of Physicians recommend sitagliptin as:

• Second-line therapy after metformin when HbA1c targets are not achieved within 3 months 5, 8
• Part of initial dual combination therapy if HbA1c is ≥1.5% above target at diagnosis 5
• An alternative for patients with contraindications to metformin 4

Important Caveats

For patients with established atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease with albuminuria, GLP-1 receptor agonists or SGLT2 inhibitors are strongly preferred over sitagliptin because these agents provide proven cardiovascular and renal benefits, while sitagliptin shows only cardiovascular safety without benefit. 5, 8

Contraindications

Sitagliptin is contraindicated in patients with a history of serious hypersensitivity reactions to the drug, including anaphylaxis or angioedema. 10

Special Populations

Renal Impairment

Sitagliptin can be safely used in all stages of chronic kidney disease, including dialysis, with appropriate dose adjustment. 5, 7 This makes it particularly useful when other agents like metformin (contraindicated at eGFR <30) or SGLT2 inhibitors (ineffective at eGFR <30) cannot be used. 7

Hospitalized Patients

Sitagliptin combined with basal or correction insulin provides similar glycemic control to basal-bolus insulin regimens with significantly lower hypoglycemia risk in hospitalized patients with mild-to-moderate hyperglycemia. 5, 8