Neprilysin inhibitors(Birla Institute of Technology & Science)

Debates have been existed regarding the treatment of moderate ischemic mitral regurgitation (IMR) in patients undergoing coronary artery bypass grafting (CABG). While it might have priority on reducing the risk of recurrent IMR, studies showed that concomitant mitral valve repair increases the risk of adverse outcomes, such as neurological events, as well as the in-hospital costs. In recent studies, angiotensin receptor/neprilysin inhibitor (ARNI) was discovered to have potential benefit in reducing the severity of IMR. The ARNI-MIMIC is a randomized controlled clinical trial aiming to reduce the risk of recurrent IMR in isolated CABG patients. A total of 220 eligible patients with moderate IMR will be allocated into control (non-ARNI) and intervention (ARNI) groups in a 1:1 pattern after isolated CABG. Patients in the intervention group will be administered with continuous sacubitril/valsartan for 6 months postoperatively, while patients in the control group will receive guideline recommended therapy only. All of the patients will be invited to complete 6-month follow-up. The primary endpoint is the change in the effective regurgitant orifice area (EROA) of the mitral valve, which is obtained by echocardiography and calculated by subtracting the follow-up EROA from the preoperative EROA. This trial aims to investigate the potential role of ARNI as compared to the control in moderate IMR patients undergoing isolated CABG. If ARNI is proven to reduce the risk of moderate IMR recurrence, patients will benefit from both improved life quality and decreased medical costs. The This study was approved by the Institutional Review Board of Fuwai Hospital on October 18th 2024, with an approval number of 2024-2446. The results of this trail will be disseminated through international academic conferences and publication in medical journals regardless of the study outcomes. ClinicalTrials.gov ID NCT06917664.

Measuring glucagon-like peptide-1 (GLP-1) in plasma from rodents is difficult since the active peptide GLP-1(7-36)NH2 is rapidly degraded into the inactive GLP-1(9-36)NH2 by the enzyme dipeptidyl peptidase 4 (DPP-4). Additionally, the endopeptidase neprilysin (NEP24.11) further degrades both forms of GLP-1.In mice, in vivo inhibition of DPP-4, preferably combined with inhibition of neprilysin, enables measurement of GLP-1 secretion in plasma. We investigated whether the same inhibitions enable measurement of GLP-1 secretion in rats based on quantification of intact GLP-1.To investigate in vivo degradation of exogenous GLP-1, the neprilysin inhibitor (sacubitril 0.3 mg/kg) and the DPP-4 inhibitor (sitagliptin 10 mg/kg) were injected intravenously 15 minutes before IV administration of GLP-1(7-36)NH2 (2 pmol). For endogenous GLP-1, sacubitril and sitagliptin were administered orally to 7-hours fasted rats 60 minutes prior to oral glucose administration (2 g/kg). In both experiments blood was collected, and intact GLP-1 plasma concentrations were measured.The inhibitors stabilized exogenous GLP-1 and resulted in a 13-fold higher net area under the curve of intact GLP-1 plasma concentrations (509.3 ± 70.62 vs 39.0 ± 21.65 pmol/L*min). The peak of intact GLP-1 concentrations in response to oral glucose was 7-fold higher in inhibitor-treated rats compared to control rats, in which the GLP-1 response was barely detectable.Thus, in vivo inhibition of both DPP-4 and neprilysin activity stabilized newly secreted GLP-1, thereby enabling estimation of GLP-1 secretion in rats, which is otherwise notoriously difficult due to rapid degradation.