Impact of angiotensin receptor–neprilysin inhibitor therapy on urinary C-peptide measurements: A potential pitfall in the β-cell function assessment

BACKGROUND: Angiotensin receptor-neprilysin inhibitor (ARNi) therapy, combining blockade of the renin-angiotensin-aldosterone system with the inhibition of neprilysin-mediated peptide degradation, is the standard therapy for heart failure with a reduced ejection fraction. Elevated urinary C-peptide (CPR) levels were recently reported in patients receiving ARNi, suggesting changes in the renal handling of CPR. However, a statistical comparison of ARNi users and non-users has not been performed. Therefore, this study aimed to statistically evaluate the impact of ARNi therapy on serum and urinary CPR levels by comparing ARNi users and non-users in a real-world clinical cohort. METHODS: We retrospectively analyzed 315 patients who underwent 24-h urinary C-peptide (U-CPR) testing at Shinshu University Hospital between January 2022 and March 2024. Demographic data, the diabetes status, and medication history, including ARNi use, were extracted from electronic medical records. Group comparisons were performed by the Mann-Whitney U test, correlations were analyzed by the Spearman's test, and multiple regression analyses identified independent predictors of serum and urinary CPR. RESULTS: Of 315 patients, 11 were ARNi users. U-CPR, serum CPR, the C-peptide index, and U-CPR/serum CPR ratio were significantly higher in ARNi users. Serum CPR moderately correlated with U-CPR in both groups; however, the regression slope was steeper in ARNi users, indicating a disproportionate rise in U-CPR. In multiple regression analyses, ARNi therapy was the strongest contributing factor for elevated U-CPR (β = 186.57 nmol/day) and serum CPR (β = 0.59 nmol /mL). CONCLUSIONS: ARNi therapy markedly increases U-CPR, likely through the neprilysin-induced inhibition of renal enzymatic degradation. Using U-CPR to assess β-cell function in patients receiving ARNi therapy is not recommended, while serum CPR remains a valid marker of insulin secretion.