A PCP Guide to Emerging Therapies for Resistant Hypertension

Medscape

06-06-2025

This transcript has been edited for clarity.
Matthew F. Watto, MD: Welcome back to The Curbsiders . I'm Dr Matthew Frank Watto, here with my great friend and America's primary care physician, Dr Paul Nelson Williams. Paul, this is a topic you know a ton about, isn't it?
Paul N. Williams, MD: It's one I always have questions about; I think this is our 37th episode on high blood pressure, if I'm not mistaken.
Watto: The audience can't get enough of it — turns out, neither can I.
Williams: Me neither!
Watto: I love talking about high blood pressure, and this was with a great guest, Dr Jordy Cohen. She's a hypertension expert and a nephrologist. Paul, to start us off, what are we doing with blood pressure cuffs these days? Those manual ones on the wall, those are the way to go, right?
Williams: This is a scenario we talk about all the time, and we've beat this drum a lot in prior episodes. I think we've all experienced a patient whose initial triage blood pressure reading is elevated, and either you or the patient will ask for a recheck and you're tempted to use a blood pressure cuff that's been hanging on the wall, has not been calibrated in 17 years, has a decaying spiral cord, and looks like it would fall apart if you touched it. Turns out that's probably not the best way to do it, Matt.
So, to reiterate: Automated cuffs are the preferred option. They are more accurate. In this episode with Dr Cohen, we talked about making sure we use the appropriate cuff size and when we have patients who have large arms, you may have to use a wrist measurement every so often. In these circumstances, positioning matters: feet flat, back supported, elbow resting on a table, and have two fingers on the opposite clavicle so that everything is at heart level.
If you're taking the blood pressure reading using a cuff around the arm itself, again, you should make sure the patient's arm is resting on a tabletop, bedside, or even on your own arm to ensure it's at heart level. You also shouldn't talk with the patient during that process so you can give them every chance to have an accurate blood pressure reading. That's the first thing: Get an accurate reading. Then everything else follows that step, as you should only treat a diagnosis that you've appropriately made.
Watto: All the goals are based on a properly taken blood pressure, so if your patient's blood pressure hasn't been appropriately measured, you might overtreat or undertreat someone.
For most patients who are nonfrail, we're now shooting for a blood pressure that is below 130/80 mm Hg. The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines for patients with chronic kidney disease state that normal blood pressure should be below 120/80, which is very hard to do. If we're getting people with a systolic in the 120s, that's probably about as good as we're going to get.
For treatment, Dr Cohen and I have adopted this practice of using combination pills for hypertension management — either a calcium-channel blocker with an angiotensin-converting enzyme inhibitor or an angiotensin II receptor blocker (ARB). I usually prefer a calcium-channel blocker with an ARB or the 'triple pill,' a single-pill combination of a calcium-channel blocker, an ARB, and a diuretic. That's what I go to now as my first-line agent.
I'm using a lot of either low-dose or medium-dose combination therapy. I don't usually go to the highest dose unless I'm in a situation where I have to decide between starting a fourth medication or going to a higher dose. That's really been a practice change for me. Dr Cohen reiterated that point and emphasized that it's easiest for the patient and they usually experience fewer side effects when you choose a low-to-moderate dose in comparison to a high dose.
Williams: It's a point that we've made in prior episodes, as well. As you start to max out the doses of these medications, you get diminishing returns in terms of their efficacy in lowering blood pressure efficacy and patients can start to experience increased side effects. It's a far better option to start with a kind of median dose as opposed to really trying to crank up the dose, because you just don't get that much more benefit with that approach.
Watto: We're going to discuss some of the newer blood pressure–lowering agents.
Paul, the first one I want to ask you about is not quite a blood pressure medication, but it does lower blood pressure. Which medication am I talking about here?
Williams: I think you're probably referring to semaglutide, Matt. I think we all have a fair amount of comfort with these diabetes and weight loss medications. These are remarkable medications and the indications keep piling on, which is great. Semaglutide, in particular, is not approved for hypertension, but it does lower blood pressure, likely as a result of the weight loss that is achieved with the medication. So, it's not technically an antihypertensive, but it provides a great blood pressure benefit.
I think there's also some 'fancy pants' medications coming down the pipeline that we should probably be aware of, right?
Watto: Yes, and the first one I'll mention is endothelin receptor antagonists. As a generalist, you're probably not going to be prescribing these; they will probably be prescribed by a hypertension specialist. Compared with placebo, they have a modest effect in lowering blood pressure (~4 mm Hg), but they are officially approved, so they're out there.
What's more exciting, Paul, are aldosterone synthase inhibitors. The generic names for these include baxdrostat and lorundrostat. They're not yet approved, but I believe they are in phase 2 or phase 3 trials, depending on the indications. They seem promising, as they have a much stronger effect on blood pressure (~10-15 mm Hg) compared with placebo. Dr Cohen thinks these medications are probably going to be in the primary care wheelhouse soon. Cost will probably an issue with these medications at the start, but otherwise, these are pills that are taken once a day and they don't have the antiandrogen side effects that you can get with the mineralocorticoid receptor antagonists (MRAs), like spironolactone. Dr Cohen was really excited about being able to prescribe these at some point.
Williams: And the MRAs are traditionally a fourth-line medication (unless you have compelling indications), so to have something else in your armamentarium that has less side effects is super exciting. It'll be great to see these in the pipeline.
Watto: Now, what would you say, Paul, if I told you there was a medication for blood pressure that is only administered once every 6 months and will shut down the renin-angiotensin-aldosterone system (RAAS)? How does that sound?
Williams: As someone who's taken medical school physiology, it sounds lightly terrifying! It feels like you do need the RAAS for some things, but I think for patients that are less interested in taking medications — which turns out to be most patients — it could potentially be exciting. I think as long as we have a way to reverse the effects of this medication if needed, then I think there's potential for excitement around this medication.
Watto: I'm of course talking about a small interfering RNA (siRNA) agent. The one we talked about in this episode was zilebesiran; it's an siRNA agent and is administered once every 6 months. But no one would feel comfortable giving this unless there's an antidote, because if a patient gets septic, they probably need their RAAS to help them out there.
Williams: Or if you have a patient who is pregnant — lots of reasons why you might actually want that system working.
Watto: Exactly. Now, some people just don't want to take medications even if they need them, Paul. What else might be offered to a patient with high blood pressure? And how excited should we be about this next therapy?
Williams: I feel like you're asking the wrong guy, Matt! I think you're alluding to renal denervation therapy. I feel it had a lot of wild enthusiasm initially, then it kind of waned, and now I feel like enthusiasm is back, baby — we're back into renal denervation. It sounds like a great option and I think we're doing a little better job with it, but its effect on lowering blood pressure is about equivalent to the effect you observe with a single-agent medication. So, realistically, these patients may still need to be on medications for blood pressure control. It's only effective for about two thirds of patients who get the procedure; that's 33% of your patients who would go through this invasive procedure where we're frying a nerve and in the end, they may not actually experience any blood pressure benefit.
I think there's still a population that would benefit from and be interested in this option, but I don't think it's something that we should consider as first-line therapy for the majority of folks because of that potential for treatment failure and the continued need for medications among a substantial portion of the patients who undergo this procedure. It's still exciting that there's evidence for it and it does cause significant blood pressure lowering, so it's nice to have another option.
Watto: Yeah, and I think patients are going be coming in and asking about it, so having some knowledge about the pros and cons of the procedure is important.