How do DPP4 (Dipeptidyl Peptidase-4) inhibitors work in treating type 2 diabetes?

How DPP-4 Inhibitors Work in Treating Type 2 Diabetes

DPP-4 inhibitors work by increasing endogenous levels of GLP-1 by reducing its deactivation, enhancing insulin secretion and inhibiting glucagon secretion in a glucose-dependent manner, providing moderate glucose-lowering efficacy. 1

Mechanism of Action

• DPP-4 inhibitors are competitive inhibitors that slow the inactivation of incretin hormones (GLP-1 and GIP), thereby increasing their bloodstream concentrations and reducing both fasting and postprandial glucose levels 2
• When incretin hormones such as GLP-1 and GIP are released from the small intestine after meals, they cause insulin release from pancreatic beta cells in a glucose-dependent manner but are normally rapidly inactivated by the DPP-4 enzyme 2
• By inhibiting the DPP-4 enzyme, these medications increase active GLP-1 and GIP levels 2-3 fold, which leads to enhanced insulin secretion and decreased glucagon secretion 2, 1
• The decreased glucagon secretion from pancreatic alpha cells reduces hepatic glucose production, further contributing to glucose control 2

Clinical Efficacy

• DPP-4 inhibitors provide moderate glucose-lowering efficacy, reducing HbA1c by approximately 0.4% to 0.9% 1, 3
• These medications specifically target postprandial glucose control by reducing postprandial glucagon secretion 1
• Due to their glucose-dependent mechanism of action, DPP-4 inhibitors have minimal risk of hypoglycemia when used as monotherapy 4, 1

Pharmacokinetic Properties

• Most DPP-4 inhibitors have good oral bioavailability and are not significantly influenced by food intake 5
• Most DPP-4 inhibitors allow for once-daily dosing due to their prolonged half-life and sustained DPP-4 enzyme inactivation (except vildagliptin which requires twice-daily administration) 5, 4
• Most DPP-4 inhibitors are not substrates for cytochrome P450 (except saxagliptin which is metabolized via CYP3A4/A5) 5, 2
• Renal excretion is the primary elimination pathway for most DPP-4 inhibitors, except for linagliptin which is predominantly metabolized in the liver 5

Clinical Positioning

• The American College of Physicians strongly recommends against adding DPP-4 inhibitors to metformin and lifestyle modifications in adults with type 2 diabetes and inadequate glycemic control to reduce morbidity and all-cause mortality 6
• Instead, SGLT-2 inhibitors or GLP-1 agonists are recommended to add to metformin due to their proven benefits in reducing all-cause mortality, major adverse cardiovascular events, and other important outcomes 6
• DPP-4 inhibitors are generally weight-neutral, unlike some other diabetes medications 1

Safety Considerations

• DPP-4 inhibitors have minimal risk of hypoglycemia when used as monotherapy, but caution is needed when combined with insulin or sulfonylureas 1, 7
• Most DPP-4 inhibitors require dose adjustment in renal impairment, with linagliptin being the exception 1, 5
• Some DPP-4 inhibitors (saxagliptin and alogliptin) have been associated with increased risk of heart failure hospitalization, requiring caution in patients with cardiac disease 1, 6
• Rare but increased rates of pancreatitis and musculoskeletal side effects have been reported with DPP-4 inhibitors 1

Common Pitfalls and Caveats

• DPP-4 inhibitors have less potent glucose-lowering effects compared to GLP-1 receptor agonists 1
• For patients with established atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease, SGLT2 inhibitors or GLP-1 receptor agonists would be preferred over DPP-4 inhibitors 1
• When adding a DPP-4 inhibitor to sulfonylurea therapy, the risk for hypoglycemia increases by approximately 50% compared to sulfonylurea therapy alone 1
• DPP-4 inhibitors should not be used together with GLP-1 receptor agonists as they work through similar pathways 3