Examples of DPP-4 Inhibitors
The FDA-approved DPP-4 inhibitors for type 2 diabetes are alogliptin, linagliptin, saxagliptin, sitagliptin, and vildagliptin (available in some countries but not FDA-approved in the US). 1, 2
Available DPP-4 Inhibitors
FDA-Approved Agents in the United States
- Sitagliptin: Standard dosing 100 mg once daily; requires dose adjustment in renal impairment (50 mg daily if eGFR 30-44 mL/min/1.73 m², 25 mg daily if eGFR <30 mL/min/1.73 m²) 2
- Saxagliptin: Standard dosing 5 mg once daily; requires dose reduction to 2.5 mg daily when eGFR ≤45 mL/min/1.73 m² or when used with strong CYP3A4 inhibitors 1, 3
- Linagliptin: Standard dosing 5 mg once daily; unique among DPP-4 inhibitors as it requires no dose adjustment regardless of renal or hepatic function 2, 4
- Alogliptin: Standard dosing 25 mg once daily; requires dose adjustment in renal impairment (12.5 mg if eGFR 30-60 mL/min/1.73 m², 6.25 mg if eGFR <30 mL/min/1.73 m²) 2
Additional DPP-4 Inhibitors Available Internationally
- Vildagliptin: Typically dosed twice daily due to shorter half-life; available in many countries outside the US 5, 6
- Anagliptin, gemigliptin, teneligliptin: Available in select Asian markets 7
Key Pharmacological Distinctions
Metabolism and Drug Interactions
- Saxagliptin is the only DPP-4 inhibitor significantly metabolized by CYP3A4/A5, producing an active metabolite that is half as potent as the parent compound 1, 5
- Sitagliptin undergoes minimal CYP3A4 metabolism 5
- Linagliptin, alogliptin, and vildagliptin are not substrates for cytochrome P450 enzymes 5, 6
Renal Excretion Profiles
- Predominantly renal excretion (60-85% unchanged in urine): sitagliptin, saxagliptin, alogliptin, vildagliptin 5, 6
- Predominantly non-renal excretion (85% biliary/fecal): linagliptin, making it the preferred agent in advanced renal impairment 2, 6
Critical Safety Considerations
Heart Failure Risk
- Saxagliptin and alogliptin have been associated with increased heart failure hospitalization risk in cardiovascular outcomes trials and should be avoided in patients with heart failure or at high risk for heart failure 1, 2
- Sitagliptin demonstrated cardiovascular safety with no increased heart failure risk in the TECOS trial 1, 2
- Linagliptin showed cardiovascular safety (HR 1.02,95% CI 0.89-1.17) in the CARMELINA trial 2
Common Adverse Effects
- Upper respiratory tract infections, urinary tract infections, headache 3
- Peripheral edema, particularly when combined with thiazolidinediones 3
- Severe joint pain (class effect requiring discontinuation if severe) 3
- Rare but serious: pancreatitis, bullous pemphigoid, severe allergic reactions 3
Clinical Positioning
DPP-4 inhibitors are recommended as second-line therapy after metformin in patients with type 2 diabetes, particularly those with BMI <30 kg/m² who cannot use or do not require GLP-1 receptor agonists or SGLT2 inhibitors. 2
When to Avoid DPP-4 Inhibitors
- Patients with established atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease with albuminuria should receive GLP-1 receptor agonists or SGLT2 inhibitors instead, as these agents provide proven cardiovascular and renal benefits that DPP-4 inhibitors lack 2
- Patients with known heart failure should avoid saxagliptin and alogliptin specifically 1, 2