Prof. dr h.c. multi Krzysztof J. Filipiak, MD, PhD, FESC
Centre of Postgraduate Medical Education, Warsaw, Poland

Recently I had a great pleasure to deliver a lecture on new hypertension drugs during ISCP satellite conference in Targu Mures, Romania, at “Steps to new paradigms – 2th Edition Symposium endorsed by UMFST G.E. Palade, ISCP, and SRC” organized by prof. Alina Scridon and prof. G.Andrei Dan – important ISCP members, and animators.

I focused on the progress that has been done in the research and practice of using new methods of blocking and/or modulating renin-angiotensin-aldosterone (RAA) system, pointing out at least eight currently available or ready to come to pharmaceutical market methods of RAA blocking:

I summarized the new date that we have on mRNA methods to lower blood pressure (like zilebesiran or evazarsen), representing two different approach to mRNA modulation strategy.

ZILEBESIRAN is a small interfering RNA, so it is:

• Double strand (sense and antisense)

• It degradates RNA through RISC complex

• GalNAc conjugated is essential for targeted delivery to liver, while

EVAZARSEN is an antisense oligonucleotide, so it is:

• Single strand (antisense only)

• RNA degradation is by RNase H1

• Also GalNAc conjugated is essential for targeted delivery to liver

I cited Prof. Eugene Braunawald (an interview from Cardiovascular Research, 2022), who for many years has been saying that statins are the most important drug discovered in this century, and recently has changed his mind. Now, he is saying: “… the fundamental discovery, which will bring the most significant promise is … [zilbesiran] p the small interfering RNA (…) exiciting work that’s going on for blocking angiotensinogen. That could knock out hypertension”. We reviewed the recent clinical data on this drug and discussed once again its mechanism of action:

According to some experts, once yearly two injections of inclisiran (to lower your LDL-choelsterol level) and zilebesiran (to lower your RAA activity) could be the promising primary prevention in many groups at risk of cardiovascular events in the future.

We also presented the newest data of another exciting group of new potential antihypertensives which are aldosterone synthase inhibitors. Which one would be the first on the market? Maybe a single pill combination of those drugs – e.g. with SGLT2 inhibitor would be the ideal for chronic kidney disease (CKD) patients?

We also presented the data on new aldosterone antagonists, as from this group potential new agents affecting blood pressure could come to the pharmaceutical market, especially when you analyze data with ESAXERONE (already approved in Japan for arterial hypertension) and OCEDURENONE (researched in arterial hypertension indication):

As new drugs emerged on the market from endothelin-1 antagonists, we also presented new data on these promising agents, taking into consideration newly approved: APROCITENTAN (arterial hypertension) and SPARSENTAN (IgA nephropathy):

I concluded my lecture with the vision of future SPC (single-pill combinations), new concept of quadruple SPC – European one (perindopril-amlodipine-indapamide-bisoprolol like in QUADRO trial) or American one (candesartan-amlodipine-indapamide-bisoprolol like in QUARTET.USA study) and all of the drugs that are not hypotensive in their main mechanism of action, but in fact also lower blood pressure:

I had a great time in Romania, listened to world-class experts and clinicians from this country, and I am sure that the symposium represented the best what ISCP could bring to its members, and the audience. Thank you!