Introduction

Vericiguat is an orally available stimulator of soluble guanylate cyclase (sGC), a critical enzyme in the action of nitric oxide in inducing vascular relaxation, which is used in patients with chronic heart failure to reduce the risk of death and hospitalization. Vericiguat is associated with a low rate of serum aminotransferase elevations during therapy but has not been linked to instances of clinically apparent acute liver injury.

Background

Vericiguat (ver" i sig' ue at) is an orally available, small molecule stimulator of soluble guanylate cyclase which is used in patients with chronic heart failure to reduce the risk of death and hospitalizations for heart failure. Soluble guanylate cyclase (sGC) is responsible for the relaxation of smooth muscle cells and vasodilation mediated by nitric oxide, an important mediator of vascular tone. Patients with heart failure have a relative deficiency of nitric oxide, and guanylate cyclase activity is reduced. Stimulation of guanylate cyclase activity by vericiguat reduces blood pressure and improves cardiac efficiency. In large, randomized placebo controlled trials, therapy of patients with heart failure with vericiguat reduced cardiovascular mortality and decreased hospitalizations and chronic morbidity. Vericiguat was approved for use in the United States in 2021. Current formal indications are restricted to patients with symptomatic chronic heart failure with a left ventricular cardiac ejection fraction of less than 45% who have required hospitalization or outpatient treatment with intravenous diuretics for control of symptoms of heart failure. Vericiguat is available as tablets of 2.5, 5 and 10 mg under the brand name Verquvo. The recommended starting dose is 2.5 mg once daily (taken with food) with doubling of the dose every two weeks to a maintenance dose of 10 mg daily. Common side effects include symptomatic hypotension and anemia. Rare, but potential severe adverse reactions are embryo-fetal toxicity and a boxed warning cautions that women of child bearing potential should be on an effective means of birth control for the duration of treatment and at least one month thereafter.

Hepatotoxicity

In preregistration trials, serum aminotransferase elevations with mild bilirubin elevations were reported to occur in 2% of patients on vericiguat, but similar rates were reported with placebo therapy and the abnormalities resolved without dose modification or discontinuation of therapy. These abnormalities were considered the result of exacerbations of heart failure and congestive liver injury. There have been no published reports of clinically apparent liver injury with symptoms or jaundice attributed to vericiguat therapy, but the overall clinical experience with vericiguat has been limited.

Likelihood score: E (unlikely cause of clinically apparent liver injury).

Mechanism of Injury

The mechanism by which vericiguat might cause serum ALT elevations or liver injury is not known. Hepatic metabolism of vericiguat is via glucuronidation by UGT1A9 with minor involvement of the cytochrome P450 system. Vericiguat has not been associated with clinically significant drug-drug interactions.

Outcome and Management

The serum aminotransferase elevations that occur on vericiguat therapy are usually self-limited and rarely require dose modification or discontinuation. No instances of clinically apparent acute hepatitis, acute liver failure, chronic hepatitis or vanishing bile duct syndrome have been attributed to vericiguat. Cross sensitivity to liver related or other hypersensitivity reactions between vericiguat and other agents used in patients with heart failure (beta blockers, calcium channel blockers, angiotensin converting enzyme inhibitors, angiotensin receptor blockers) has not been demonstrated, and is unlikely to occur.

Drug Class: Cardiovascular Agents, Heart Failure Agents

Other Drugs in the Subclass, Guanylate Cyclase Inhibitors: Riociguat