An evaluation of the fixed-dose combination sacubitril/valsartan for the treatment of arterial hypertension

ABSTRACT

Introduction

Essential hypertension is a significant risk factor for cardiovascular disease, renal disease, and mortality with increasing prevalence. Despite the availability of various antihypertensive agents, hypertension is still poorly controlled. Therefore, new chemical compounds with antihypertensive efficacy need to be developed. The dual angiotensin II receptor-neprilysin inhibitor LCZ696 is a single molecule synthesized by co-crystallization of valsartan and the neprilysin inhibitor prodrug sacubitril (1:1 molar ratio).

Areas covered

This review includes an overview of hypertension and the current pharmacotherapy. The authors summarize the LCZ696 drug chemistry, pharmacodynamics, pharmacokinetics, metabolism, randomized control trials (RCTs), and safety concerns. Databases searched included PubMed, Google Scholar, Embase, and ClinicalTrials.gov.

Expert opinion

LCZ696 is effective in hypertension treatment. Short-term RCTs have shown that the highest doses of LCZ696 (200 and 400 mg [q.d.]) were more effective at lowering office and ambulatory blood pressure than angiotensin II receptor blockers (ARB) alone while having a similar tolerability profile. The effects of LCZ696 on hypertensive organ damage are only sparsely investigated and so far no studies have established the impact of LCZ696 on cardiovascular event rates. Future studies should focus on the comparison of LCZ696 and combination therapies already in use such as ARB and calcium channel blockers.

KEYWORDS:

• Hypertension
• valsartan
• sacubitril
• angiotensin receptor-neprilysin inhibitors
• clinical trials

Article highlights

• The dual angiotensin II receptor-neprilysin inhibitor LCZ696 (sacubitril/valsartan) is a single molecule synthesized by the co-crystallization of valsartan and the neprilysin inhibitor prodrug sacubitril.

• Dosing schedules for LCZ696 comprise 100, 200, or 400 mg. Bioavailability studies showed that a 400 mg dose of LCZ696 was equivalent to a single dose of 320 mg valsartan. 400 mg LCZ696 represents the optimal antihypertensive dose for any age.

• LCZ696 was developed by Novartis Pharmaceuticals Corp. and approved by the FDA on July 7th, 2015 for heart failure and on October 1, 2019 for the treatment of HF in pediatric patients aged 1 year and older. Until today the drug is not approved for hypertension.

• Sacubitril/valsartan is more effective for the management of hypertensive patients compared with an ARB. The current knowledge on the BP-lowering effects of LCZ696 originates mainly from short-term trials. Long-term clinical trials with patients of all ages have to be performed in the future.

• Eight phase II studies and seven phase III trials of LCZ696 in hypertensive patients were completed and have data published. They demonstrated that LCZ696 is more effective than a monotherapy in lowering blood pressure.

• Overall, the RCTs revealed that LCZ696 was well-tolerated and did not cause severe drug-related adverse effects after short-term treatment. In case of approval for hypertension, a prolonged monitoring of brain function and ophthalmologic examinations to determine early changes in mental and visual function should be performed.

Declaration of Interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership, or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

One referee is a speaker and advisor for Novartis. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This manuscript was not funded.