Impact of angiotensin receptor neprilysin inhibitor on serum C-peptide levels in patients with type 2 diabetes.

Sacubitril/valsartan, an angiotensin receptor neprilysin inhibitor (ARNI), is becoming more common in the treatment of heart failure and hypertension. Neprilysin is highly expressed in the renal tubules, and reports have shown increases in urinary C-peptide reactivity (CPR) levels after administration of ARNI. However, the effect of ARNI on serum CPR levels, a critical marker of insulin secretion in diabetes, remains underexplored. We evaluated the effect of ARNI on serum CPR levels in patients with type 2 diabetes and its impact on the assessment of endogenous insulin secretion. We retrospectively investigated the medical records of patients with type 2 diabetes at two hospitals, where fasting plasma glucose and serum CPR levels were measured before and after administration of ARNI. All eleven patients (five males, six females) who met the criteria showed an increase in median fasting serum CPR levels following ARNI administration. The levels rose from a median of 1.78 ng/mL (IQR: 1.26-2.02) to 3.19 ng/mL (IQR: 2.71-5.12), accompanied by significant increases in the C-peptide index. Immunoreactive insulin levels barely changed after ARNI administration, but the ratio of immunoreactive insulin to CPR decreased significantly, from 3.3 (IQR: 2.5-3.9) to 1.6 (IQR: 1.3-1.9). The increase in serum CPR levels is attributed to inhibition of CPR degradation rather than an increase in endogenous insulin secretion, as fasting blood glucose levels remained unchanged. These findings suggest the need for caution when using serum CPR levels to evaluate endogenous insulin secretion in patients treated with an ARNI, which are increasingly being prescribed for heart failure and hypertension.