What is the Purpose of DPP-4?
DPP-4 (dipeptidyl peptidase-4) is a cell-surface enzyme that deactivates incretin hormones, particularly glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), thereby regulating glucose metabolism through multiple mechanisms including insulin secretion, glucagon suppression, gastric emptying, and appetite control. 1
Physiological Role of DPP-4
DPP-4 functions as an ubiquitous protease with several key actions:
Primary enzymatic function: DPP-4 deactivates incretin hormones (GLP-1 and GIP) in the peripheral circulation, which normally stimulate glucose-dependent insulin secretion and suppress glucagon release 1
Metabolic regulation: Beyond incretin degradation, DPP-4 regulates glucose and lipid metabolism throughout the body 2
Systemic effects: DPP-4 acts on multiple substrates including cytokines, growth factors, and neurotransmitters, influencing endothelial function, oxidative stress, inflammatory states, and renal function 2
Adipokine activity: DPP-4 is secreted by adipose tissue (particularly visceral fat) and acts as an adipokine, disrupting insulin signaling within adipocytes and promoting proinflammatory environments 3
Clinical Significance: DPP-4 Inhibitors
The therapeutic importance of DPP-4 is demonstrated through DPP-4 inhibitor medications:
Mechanism of DPP-4 inhibitors: These drugs block DPP-4 enzyme activity, preventing the breakdown of endogenous GLP-1 and GIP, thereby increasing circulating levels of active incretins 1, 4, 5
Glucose-lowering effects: DPP-4 inhibitors enhance glucose-dependent insulin secretion, slow gastric emptying, reduce postprandial glucagon secretion, and decrease food intake, resulting in HbA1c reductions of approximately 0.4-0.9% 1, 6, 7
FDA-approved indication: DPP-4 inhibitors (saxagliptin, linagliptin, sitagliptin, vildagliptin, alogliptin) are approved as adjuncts to diet and exercise for improving glycemic control in adults with type 2 diabetes 4, 5
Important Clinical Considerations
Cardiovascular safety concerns: Saxagliptin and alogliptin have been associated with increased risk of heart failure hospitalization in patients with diabetes and high cardiovascular risk, requiring caution in patients with cardiac disease 1, 6
Hypoglycemia risk: DPP-4 inhibitors have minimal hypoglycemia risk as monotherapy due to their glucose-dependent mechanism, but caution is needed when combined with insulin or sulfonylureas 1, 6
Weight neutrality: Unlike some other diabetes medications, DPP-4 inhibitors do not cause weight gain 1, 6
Renal considerations: Most DPP-4 inhibitors require dose adjustment in renal impairment (eGFR <45 mL/min/1.73 m²), with linagliptin being the notable exception requiring no dose adjustment 6, 4