Should a patient with a low C-peptide (Connecting Peptide) level take a GLP-1 (Glucagon-Like Peptide-1) receptor agonist?

GLP-1 Receptor Agonists in Patients with C-peptide of 1.8

A C-peptide level of 1.8 indicates sufficient beta cell function, making a GLP-1 receptor agonist an appropriate and beneficial treatment option for glycemic control.

Understanding C-peptide and Its Significance

C-peptide is a biomarker of endogenous insulin production and beta cell function. A level of 1.8 nmol/L indicates:

• Preserved beta cell function
• Endogenous insulin production capability
• Likely type 2 diabetes or early-stage type 1 diabetes with residual beta cell function

Evidence Supporting GLP-1 RA Use with Detectable C-peptide

The American Diabetes Association (ADA) and European Society of Cardiology (ESC) guidelines strongly support GLP-1 RA use in patients with detectable C-peptide:

• ADA/KDIGO consensus (2022): "A GLP-1 receptor agonist with proven cardiovascular benefit is recommended for patients with T2D and CKD who do not meet their individualized glycemic target with metformin and/or an SGLT2i or who are unable to use these drugs" 1

• ESC Guidelines (2024): "GLP-1 receptor agonists with proven CV benefit are recommended in patients with T2DM and CCS to reduce CV events, independent of baseline or target HbA1c and independent of concomitant glucose-lowering medication" 1

Benefits of GLP-1 RAs in Patients with Adequate C-peptide

1. Glucose-dependent insulin secretion: GLP-1 RAs enhance insulin secretion only when glucose levels are elevated, reducing hypoglycemia risk

2. Suppression of inappropriate glucagon secretion: Addresses alpha cell dysfunction 2

3. Weight management: Consistent evidence shows weight loss with GLP-1 RA therapy 2

4. Cardiovascular benefits: Reduced risk of major adverse cardiovascular events in those with established cardiovascular disease 1

5. Reduced insulin requirements: Studies show decreased total daily insulin needs when GLP-1 RAs are added 2

C-peptide as a Predictor of GLP-1 RA Response

Research indicates that C-peptide levels correlate with response to GLP-1 RAs:

• Patients with detectable C-peptide (>0.2 nmol/L) show better glycemic responses to GLP-1 RAs 2
• Higher C-peptide levels (>0.4 pmol/mL) are associated with better glycemic control, including lower mean glucose and more time in range 3

Clinical Decision Algorithm for GLP-1 RA Therapy Based on C-peptide

1. C-peptide <0.2 nmol/L: Limited benefit from GLP-1 RAs; insulin therapy is primary approach
2. C-peptide 0.2-0.4 nmol/L: Moderate benefit; consider GLP-1 RA as adjunct therapy
3. C-peptide >0.4 nmol/L (including 1.8): Excellent candidate for GLP-1 RA therapy; likely to have significant clinical benefit

Practical Considerations for Implementation

• Start with lower doses and titrate based on glycemic response and tolerability
• Monitor for gastrointestinal side effects, which typically improve with continued use
• Consider cardiovascular and renal benefits when selecting specific GLP-1 RA
• Evaluate response after 3-6 months with A1C and weight measurements

Potential Pitfalls to Avoid

1. Misinterpreting C-peptide levels: A value of 1.8 indicates substantial beta cell function, not insulin deficiency

2. Overlooking cardiovascular benefits: Beyond glycemic control, GLP-1 RAs offer cardiovascular protection in patients with established cardiovascular disease 1

3. Failing to adjust concomitant medications: May need to reduce insulin or sulfonylurea doses to prevent hypoglycemia when adding GLP-1 RA

4. Not considering specific GLP-1 RA properties: Different agents have varying durations of action, cardiovascular benefit evidence, and side effect profiles

In conclusion, with a C-peptide of 1.8, the patient demonstrates sufficient beta cell function to benefit from GLP-1 receptor agonist therapy, which can improve glycemic control, reduce weight, and potentially offer cardiovascular protection.