Mechanism of Action of DPP-4 Inhibitors
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 active incretins that stimulate glucose-dependent insulin secretion and suppress glucagon release. 1, 2
Primary Enzymatic Mechanism
DPP-4 is an enzyme that rapidly degrades incretin hormones (glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic polypeptide [GIP]) within minutes of their release from the small intestine after meals 2
By competitively inhibiting DPP-4, these medications slow the inactivation of incretin hormones, resulting in 2- to 3-fold increases in circulating levels of active GLP-1 and GIP 2
The increased incretin levels produce coordinated downstream effects on glucose metabolism: increased glucose-dependent insulin secretion from pancreatic beta cells, decreased glucagon secretion from pancreatic alpha cells, and reduced hepatic glucose production 3, 4
Glucose-Dependent Action and Clinical Effects
The mechanism is inherently glucose-dependent, meaning insulin secretion stops when glucose normalizes, which minimizes hypoglycemia risk when used as monotherapy 5, 3
DPP-4 inhibitors specifically target postprandial glucose control by reducing postprandial glucagon secretion and working only when glucose levels are elevated 5
The glucose-lowering efficacy is moderate, reducing HbA1c by approximately 0.4% to 0.9% from baseline 6, 5, 3
Additional Physiological Effects
GLP-1 enhancement produces multiple coordinated metabolic effects beyond insulin and glucagon: these include effects on gastric emptying, appetite control, and potentially beta-cell preservation 4
Linagliptin binds reversibly and selectively to DPP-4, inhibiting DPP-4 but not DPP-8 or DPP-9 activity at therapeutic concentrations 1
The inhibition of DPP-4 enzyme activity persists for 24 hours, allowing once-daily dosing of these medications 2
Important Clinical Caveats
DPP-4 inhibitors are weight-neutral, unlike some other diabetes medications that cause weight gain 5, 4
When combined with insulin or sulfonylureas, the hypoglycemia risk increases approximately 50% compared to sulfonylurea alone, despite the glucose-dependent mechanism 5
Saxagliptin and alogliptin carry FDA warnings for increased heart failure hospitalization risk (saxagliptin showed a 27% relative increase in the SAVOR TIMI-53 trial), requiring caution in patients with cardiac disease 6, 5, 3
Sitagliptin and linagliptin have demonstrated cardiovascular neutrality without increased heart failure risk in large outcome trials 5, 3
Most DPP-4 inhibitors require dose adjustment when eGFR falls below 45 mL/min/1.73 m², with the notable exception of linagliptin which requires no dose adjustment at any level of renal impairment 3, 4, 1