How do DPP4 (dipeptidyl peptidase-4) inhibitors act?

Mechanism of Action of DPP-4 Inhibitors

DPP-4 inhibitors work by inhibiting the enzyme dipeptidyl peptidase-4, which prevents the degradation of incretin hormones, thereby increasing insulin secretion and decreasing glucagon secretion in a glucose-dependent manner. 1

Primary Mechanism

DPP-4 inhibitors function through a distinct mechanism compared to other antidiabetic medications:

• Enzyme Inhibition: They competitively inhibit DPP-4, an enzyme that rapidly degrades incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) 1, 2

• Incretin Hormone Preservation: By inhibiting DPP-4, these drugs increase the concentrations and prolong the action of active incretin hormones in the bloodstream 1

• Glucose-Dependent Effects: The preserved incretin hormones exert their effects in a glucose-dependent manner, which explains the low risk of hypoglycemia with these agents 3

Physiological Effects

DPP-4 inhibitors influence glucose homeostasis through multiple mechanisms:

1. Enhanced Insulin Secretion: They stimulate insulin biosynthesis and secretion from pancreatic beta cells in a glucose-dependent manner 1

2. Reduced Glucagon Secretion: They decrease glucagon secretion from pancreatic alpha cells, which reduces hepatic glucose output 1, 2

3. Improved Glucose Regulation: The combined effect of increased insulin and decreased glucagon leads to better regulation of both fasting and postprandial glucose levels 2

4. No Direct Effect on Insulin Sensitivity: Unlike thiazolidinediones, DPP-4 inhibitors do not directly improve insulin sensitivity 4

Clinical Pharmacology

The pharmacokinetic properties of DPP-4 inhibitors contribute to their clinical utility:

• Oral Bioavailability: All approved DPP-4 inhibitors are orally active small molecules 4

• Duration of Action: Most DPP-4 inhibitors have a long duration of action allowing for once-daily dosing 5

• Binding Characteristics: They bind to DPP-4 in a reversible manner, with varying selectivity for DPP-4 over related enzymes such as DPP-8 and DPP-9 1

• Elimination: Different DPP-4 inhibitors have varying elimination pathways. For example, linagliptin does not require dose adjustment in renal impairment, while others like saxagliptin require dose adjustments 3, 6

Clinical Efficacy and Safety

DPP-4 inhibitors have demonstrated consistent efficacy in clinical trials:

• Glycemic Control: They typically reduce HbA1c by approximately 0.4-0.9% from baseline 3, 5

• Low Hypoglycemia Risk: Due to their glucose-dependent mechanism of action, DPP-4 inhibitors have a low risk of hypoglycemia when used as monotherapy 6, 4

• Weight Neutral: Unlike some other antidiabetic medications, DPP-4 inhibitors are generally weight neutral 3, 4

• Cardiovascular Safety: Most DPP-4 inhibitors have demonstrated cardiovascular safety, though saxagliptin has been associated with an increased risk of hospitalization for heart failure 3

Practical Considerations

When using DPP-4 inhibitors in clinical practice:

• Renal Dosing: Most DPP-4 inhibitors require dose adjustment in renal impairment, with the exception of linagliptin 3, 6

• Combination Therapy: They can be effectively combined with other antidiabetic agents including metformin, sulfonylureas, thiazolidinediones, and insulin 3, 7

• Patient Selection: They may be particularly useful in elderly patients and those with renal impairment due to their favorable safety profile 6, 7

DPP-4 inhibitors represent an important class of oral antidiabetic medications with a unique mechanism of action that provides moderate glycemic efficacy with a favorable safety profile, particularly regarding hypoglycemia risk.