MANP: A natriuretic peptide-based therapy for cardiometabolic disease

Introduction

Hypertension (HTN) and metabolic syndrome (MetS) are leading and frequently coexisting risk factors for major cardiovascular diseases. The cardiac hormone atrial natriuretic peptide (ANP) plays a key role in blood pressure (BP) and metabolic regulation by activating guanylyl cyclase receptor A and generating cGMP as second messenger.

Objectives

We assessed cardiovascular, metabolic and cGMP properties of MANP, a novel ANP analog, in subjects with HTN and MetS.

Methods

We conducted a double-blind, placebo-controlled trial in 22 patients (17 receiving MANP) with HTN and MetS involving single subcutaneous injection of MANP (2.5 µg/kg) or placebo (NCT03781739).

Results

Compared to baseline, MANP increased plasma cGMP at 30 minutes (delta: 4.8±2.0 pmol/mL, P= 0.02) and 1 hour (delta: 2.9±1.3 pmol/mL, P= 0.03) post-injection. At 6 hours, systolic BP decreased by 5.7±2.9 mmHg (P= 0.06) in the MANP group, whereas no reduction in BP was observed in placebo group. After MANP injection, glucose levels decreased at 2 (delta: -4.7±2.1 mg/mL, P= 0.04) and 4 hours (delta: -13.1±3.9 mg/mL, P= 0.003) compared to baseline while insulin levels remained stable. In the 4 hours post-injection, we also observed a trend of increase in insulin sensitivity index (HOMA2-IS) and decrease in insulin resistance index (HOMA2-IR) in the MANP group, opposite trends were present in placebo group. At 1 hour post-MANP administration, circulating non-esterified fatty acids increased by 108.2±37.4 µM compared to baseline (P= 0.01).

Conclusions

Our findings support favorable cardiovascular and metabolic actions of MANP as a potential therapy for HTN with MetS.