What is the mechanism of action of DPP4 (Dipeptidyl Peptidase-4) inhibitors?

DPP-4 Inhibitor Mechanism of Action

DPP-4 inhibitors work by blocking the dipeptidyl peptidase-4 enzyme, which normally degrades incretin hormones (GLP-1 and GIP), thereby increasing circulating levels of these active incretins to stimulate glucose-dependent insulin secretion and suppress glucagon release. 1, 2

Primary Enzymatic Mechanism

• DPP-4 inhibitors competitively and reversibly bind to the DPP-4 enzyme, preventing it from breaking down incretin hormones in the peripheral circulation 1, 2
• This inhibition increases concentrations of active glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) by 2- to 3-fold after meals or oral glucose loads 2
• The increased incretin levels persist for 24 hours with once-daily dosing, providing sustained DPP-4 enzyme inhibition throughout the day 2

Downstream Glucose-Lowering Effects

The elevated incretin hormones produce multiple coordinated effects on glucose metabolism:

• Pancreatic beta cells respond to increased GLP-1 and GIP by releasing more insulin in a strictly glucose-dependent manner, meaning insulin secretion only increases when blood glucose is elevated 1, 2
• Pancreatic alpha cells decrease glucagon secretion in response to elevated GLP-1, which reduces hepatic glucose production and output 1, 2
• These dual actions—increased insulin and decreased glucagon—work together to lower both fasting and postprandial glucose concentrations 3, 2

Clinical Efficacy and Safety Profile

• DPP-4 inhibitors reduce HbA1c by approximately 0.4-0.9% through their glucose-dependent mechanism 4, 5
• The glucose-dependent nature of insulin secretion minimizes hypoglycemia risk when used as monotherapy, as insulin release stops when glucose normalizes 4, 2
• These agents are weight-neutral and generally well tolerated 3, 4

Important Cardiovascular Considerations

• Saxagliptin and alogliptin carry FDA warnings for increased heart failure hospitalization risk (26% increase with saxagliptin in SAVOR-TIMI 53 trial), requiring caution in patients with cardiac disease 3, 4
• Sitagliptin and linagliptin have demonstrated cardiovascular neutrality without increased heart failure risk in large outcome trials 3, 4
• All DPP-4 inhibitors have shown cardiovascular safety but no cardiovascular benefit, unlike SGLT2 inhibitors and GLP-1 receptor agonists 3, 5

Renal Dosing Requirements

• Most DPP-4 inhibitors require dose adjustment when eGFR falls below 45 mL/min/1.73 m² 4, 5
• Linagliptin is the notable exception, requiring no dose adjustment at any level of renal impairment due to its primarily hepatic elimination 4, 5