Can C-Peptide Levels Increase with DPP-4 Inhibitors?
Yes, C-peptide levels can increase with DPP-4 inhibitors because these medications enhance endogenous insulin secretion in a glucose-dependent manner, and C-peptide is co-secreted with insulin from pancreatic beta cells. 1, 2
Mechanism of C-Peptide Elevation
DPP-4 inhibitors work by preventing the degradation of endogenous GLP-1, which leads to:
- Increased insulin secretion from pancreatic beta cells in response to elevated glucose levels, and since C-peptide is released in equimolar amounts with insulin during proinsulin cleavage, C-peptide levels rise proportionally 1, 2
- Glucose-dependent enhancement of insulin release, meaning this effect only occurs when blood glucose is elevated, which minimizes hypoglycemia risk 1, 2
- Coordinated effects on glucose metabolism including both increased insulin and decreased glucagon secretion, working together to lower fasting and postprandial glucose concentrations 2
Clinical Significance and Magnitude
- DPP-4 inhibitors reduce HbA1c by approximately 0.4% to 0.9% through their glucose-dependent mechanism of enhancing endogenous insulin (and therefore C-peptide) secretion 1, 2
- The increase in C-peptide is physiologic and glucose-dependent, stopping when glucose normalizes, which explains the minimal hypoglycemia risk when used as monotherapy 1, 2
- This represents enhancement of endogenous insulin production rather than exogenous insulin administration, making C-peptide a useful marker to confirm preserved beta-cell function in patients on DPP-4 inhibitors 1
Important Clinical Caveats
- The C-peptide increase is modest compared to other insulin secretagogues like sulfonylureas, as DPP-4 inhibitors only work when glucose is elevated 1, 2
- When DPP-4 inhibitors are combined with sulfonylureas, the risk of hypoglycemia increases by approximately 50% compared to sulfonylurea alone, reflecting additive effects on insulin (and C-peptide) secretion 1, 3
- DPP-4 inhibitors are less potent than GLP-1 receptor agonists in terms of glucose-lowering effects and presumably in their effects on insulin/C-peptide secretion 1
Cardiovascular and Safety Considerations
While not directly related to C-peptide, clinicians should be aware:
- Saxagliptin and alogliptin have been associated with increased heart failure hospitalization risk and should be avoided in patients with heart failure 4, 1, 2
- Sitagliptin and linagliptin have demonstrated cardiovascular neutrality without increased heart failure risk 1, 2
- All DPP-4 inhibitors have shown cardiovascular safety but no cardiovascular benefit, unlike SGLT2 inhibitors and GLP-1 receptor agonists 1, 2