#474 Resistant Hypertension the Next Frontier

Summary

The Curbsiders Internal Medicine Podcast

Episode #474: Resistant Hypertension – The Next Frontier

Date: March 10, 2025
Guest Expert: Dr. Jordana “Jordi” Cohen, MD, MSCE, Nephrologist and Hypertension Specialist, University of Pennsylvania

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Episode Overview

This episode dives into resistant hypertension: defining it, identifying pseudo-resistance, thoroughly covering current guideline-based management, and taking an in-depth look at emerging novel therapies—including new medication classes and procedures such as renal denervation. Dr. Jordi Cohen, a repeatedly featured expert in hypertension, brings practical insights and the latest evidence for internists and primary care clinicians.

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Key Discussion Points & Clinical Insights

1. Defining and Diagnosing Resistant Hypertension

• Accurate Measurement is Essential
  • Dr. Cohen emphasizes that correctly measured blood pressure is critical to avoid diagnostic error.

    "We've got really good data... blood pressures that were 40 millimeters... higher or 20 lower. You could not find a single predictor... measure it correctly." (05:40)

  • Automated Office BP machines that average several readings are now the standard. Manual, aneroid cuffs are rarely preferred—unless in persistent arrhythmias.
• Pseudo-resistance is Common
  • White coat effect and cuff size/fit are big contributors.
  • Clinicians should always recheck abnormal readings after proper rest/placement and educate patients on technique.
  • Home BP, if measured correctly, is valuable for diagnosis and management.

Timestamps:

• Blood pressure measurement pitfalls and standardization: 05:40–09:42
• Cuff size and special considerations: 12:15–14:57

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2. Treatment Thresholds & Medication Inertia

• Target Blood Pressures

  • The AHA/ACC guideline: <130/80 mm Hg for most, even older adults unless frail. (19:25)
  • KDIGO is pushing for <120/80 mm Hg in patients with kidney disease, but most can’t tolerate this.
  • Dr. Cohen notes a cultural shift:

    "I think that when I was in training, many people treated 140s as normal. Now it's about shifting expectations." (21:48)

• Starting & Advancing Therapy

  • Most patients require >1 medication. Fixed-dose combination pills are preferred to improve adherence.
  • Clinicians' fear of overtreating—especially in younger, otherwise healthy patients—should be tempered by the reality that low blood pressure is rarely induced with typical regimens.

Timestamps:

• Target discussion: 19:25–22:46
• Medication initiation and combinations: 23:10–25:09

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3. Practical Steps for Resistant Hypertension

• If BP Remains High on Three Agents:
  1. Confirm true resistance (adherence, proper measurement, lifestyle factors).
  2. Address lifestyle contributors: obesity, alcohol, medications raising BP (e.g., NSAIDs, stimulants), secondary causes.
  3. Add a mineralocorticoid receptor antagonist (MRA) unless contraindicated.
  4. Check for primary aldosteronism with plasma renin and aldosterone levels.

  “At least 20%... have primary aldosteronism—check renin and aldosterone. Look for suppressed renin (<1), high aldosterone (>15), and a ratio >20:1.” (60:54)

  5. If aldosterone excess is confirmed, MRA or possible surgery.

Timestamps:

• Triple therapy, adherence, and next steps: 27:51–32:15
• Lifestyle and medication contributors: 32:15–36:07
• Primary aldosteronism and secondary workup: 60:54–69:17

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4. Novel & Emerging Therapies

a) New Drug Classes

• Endothelin Antagonists (e.g., Aprocitentan)
  • Approved for resistant HTN, particularly CKD.
  • Modest benefit (approx. 4 mm Hg over placebo) but possible volume overload.
  • More for use by specialists. (39:02)
• GLP-1 Agonists (Semaglutide, etc.)
  • Not FDA-approved for HTN, but cause predictable BP reduction in parallel with weight loss.

  • “It’s a straight line—you lose weight, your BP drops.” (41:44)

• Aldosterone Synthase Inhibitors (e.g., Baxtrostat)
  • Oral, once daily.
  • Suppress aldosterone production without androgenic effects.
  • Promising for future use, maybe as early as second/third agent. (43:33)
• Small Interfering RNA against Angiotensinogen (e.g., Zilbesiran)
  • Injection, effect lasts ~6 months.
  • Major issue: risk of loss of RAS activity when needed (e.g., sepsis, pregnancy)—antidote in development.

b) Renal Denervation

• Recently FDA-approved catheter-based procedure
  • Provides mean BP reduction of ~6 mm Hg (about 1 medication).
  • Not a “cure”; most patients will need to continue meds.
  • Appropriate only for highly selected, refractory, or intolerant patients.

  • “It really only works in about two-thirds... the procedures are very expensive, and a third who go through this will get zero benefit.” (53:14–60:18)

Timestamps:

• Endothelin antagonists and GLP-1 agonists: 37:01–41:44
• Aldosterone synthase inhibitors and RNA therapy: 43:33–49:55
• Renal denervation: 53:14–60:18

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5. Approach to Primary Aldosteronism

• When to test: All patients with resistant HTN before adding an MRA.
• What to order:
  • Plasma renin activity (not direct renin)
  • Aldosterone level (ideally off MRA, but not required to hold most meds)
  • BMP for potassium (must be repleted if low for accurate Aldo)
  • Ratio threshold: Suppressed renin (<1), elevated aldosterone (>15 ng/dL), and Aldo-renin ratio > 20:1.
• What next: Surgical referral if confirmed and patient is young/otherwise healthy (mortality benefit).
• Future: Aldosterone synthase inhibitors expected to revolutionize this area, perhaps rendering confirmatory testing/surgery obsolete.

Timestamps:

• Testing and interpretation: 60:54–69:17

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6. Referral Guidance & Take-home Messages

• When to refer to a specialist:

  • Uncertain kidney safety with MRAs
  • On 4–5+ meds and still uncontrolled
  • Help needed for secondary cause workup
  • Please check renin/aldosterone, rule out sleep apnea yourself

    “It’s really unfortunate: more people get metanephrines than renin and aldosterone checked…” (72:15)

• Practice-changing Pearls:

  • Improved adherence with combination pills; always prefer 1 pill when possible.
  • Use GLP-1 agonists for eligible patients; monitor for spontaneous BP improvement and consider deprescribing.
  • Watch for new agents (esp. aldosterone synthase inhibitors), which may soon alter frontline therapy.
  • Be realistic about the impact of procedures and new drugs—effect sizes are often modest, adherence remains key.

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Notable Quotes & Memorable Moments

• On importance of accurate BP measurement:

  “You could have blood pressures 40 mm higher... or 20 lower... measure it correctly.” — Dr. Cohen (05:40)

• On the demise of manual BP as gold standard:

  “As soon as [mercury cuffs] were no longer allowed... these aneroid devices are miscalibrated if you blow on them funny. Be very cautious.” — Dr. Cohen (09:42)

• On guideline targets:

  “Older age itself isn’t enough [to loosen targets]. If they can tolerate it, push for lower.” — Dr. Cohen (19:25)

• On combo pills:

  “It builds so much trust when somebody says, ‘I thought you were going to add meds, and you’re reducing them.’” — Dr. Cohen (29:00)

• On renal denervation reality check:

  “Most people... are still going to need blood pressure medications on top of [the procedure].” — Dr. Cohen (53:14)
  “A third… get zero benefit from it. Just blows my mind.” (60:18)

• On primary aldosteronism prevalence:

  “At least 20% of people with resistant hypertension have primary aldosteronism… There’s so much benefit from treating it.” (60:54)

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Segment Timestamps

| Segment/Topic | Start | End | |:---|:---|:---| | Comedy & Intro | 00:00 | 04:27 | | Guest intro & case | 04:27 | 05:40 | | BP measurement best practices | 05:40 | 09:42 | | Cuff size, wrist cuffs | 12:15 | 14:57 | | Target BP & therapy inertia | 19:25 | 25:09 | | Fixed-dose combo pills & adherence | 27:51 | 31:46 | | When triple therapy fails | 32:15 | 34:18 | | Lifestyle, secondary factors | 34:18 | 36:07 | | Emerging therapies | 37:01 | 52:33 | | Renal denervation | 53:14 | 60:18 | | Primary aldosteronism—workup and therapy | 60:54 | 69:17 | | Referral, take-home points | 71:01 | 74:56 |

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Summary Table: Emerging Therapies Quick Reference

| Therapy | Core Benefit | Key Side Effects / Notes | Status | |:---|:---|:---|:---| | Aprocitentan (Endothelin Antagonist) | Lowers BP, esp. in CKD | Volume overload/edema | FDA-approved (specialist) | | GLP-1 Agonists | BP decreases with weight loss | GI side effects, rare serious | FDA-approved (DM, obesity), not HTN | | Aldosterone Synthase Inhibitors | Dramatic BP lowering, fewer side effects vs. MRAs | Early data promising, some hyperkalemia | In trials (not yet available) | | Zilbesiran (siRNA) | 6-month BP effect, adherence solution | Concern if RAS needed, need antidote | Phase 3 trials | | Renal Denervation | ~6 mm Hg reduction, off-pills “option” | Invasive, not curative, costly | FDA-approved, limited role |

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Final Take-home Points & Panel Votes

• Most promising: Keep an eye on aldosterone synthase inhibitors—highly likely to alter hypertension management in the near future.
• Renal Denervation: Still only for highly selected patients; use caution and manage expectations.
• Always: Confirm resistance (adherence, measurement, secondary causes).
• Refer: Refractory/unusual cases, kidney concerns, or diagnostic dilemmas.
• Dr. Cohen’s pick for the future:

  “Keep an eye out for aldosterone synthase inhibitors… [GLP-1s]—think about deprescribing antihypertensives if your patient loses weight.” (73:01)

Panel’s “NephMadness” pick:

• Matt and Jordi: Novel therapeutics (aldosterone synthase inhibitors, etc.)
• Paul (tongue-in-cheek): “Renal denervation” — because sometimes the underdog wins.

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For comprehensive show notes and clinical pearls, visit curbsiders.com

Transcript

[A]

Hey, before we get to the show, I wanted to remind you to check out our [e-mail] curbsiders if you haven't signed up yet, sign up now to get ad free episodes, twice monthly, bonus episodes and a whole bunch of other Cool [e-mail] curbsiders did you hear about the group of boats which crushed each other against their mooring structure?

[B]

No, Matt. Tell me about them.

[A]

It was yet another casualty of peer pressure.

[B]

Okay, Peer p. Yeah, no, I, I, I got it. I, I was trying to make Armada work and I thought, well, that's probably not it. And I was doing for fleet. That didn't happen. Um, I did try to. I looked up Aldosterone pun, Matt. And Google's just like, nope, I'm not even like. They're just, you're. Here's what Aldosterone does. So. So Google AI has given up on me.

[A]

Yeah, we're audience. We're running out of puns. Deal with it.

[B]

The Curbsiders podcast is for entertainment, education and information purposes only. And the topics discussed should not be used solely to diagnose, treat, cure or prevent any diseases or conditions. Furthermore, the views and statements expressed on this podcast are solely those of those and should not be interpreted to reflect official policy or position of any entity aside from bossly cash, like moral hospital and affiliate outreach programs, if indeed there are any. In fact, there are none. Pretty much. We are responsible. If you screw up, you should always do your own homework and let us know.

[A]

Welcome back to the curbsiders. I'm Dr. Matthew Frank Watto, here with my great friend and America's primary care physician, probably the primary care physician, Dr. Paul Nelson Williams. Hey, Paul.

[B]

Hey, Matt. How are you?

[A]

You know, Paul, I'm always good when we have a fantastic guest, a returning guest, Dr. Jordi Cohen, talking to us about resistant hypertension. Some new therapies that are in the pipeline, some of them already available. We're going to get all into that and also just kind of go over some just really bread and butter basics of resistant hypertension. Checking a blood pressure. Because, Paul, turns out that's harder than it seems. But Paul, before I tell them about our wonderful guest, what the heck do we do on this show?

[B]

Sure, Matt, we are the internal medicine podcast. We use expert interviews to bring you clinical pearls and practice changing knowledge. Our expert tonight, as you mentioned, is Dr. Jordi Cohen, who's been on the show a bunch of times before, is probably our favorite hypertension nerd. Though, you know, it's hard to pick a favorite, but she's certainly she's top tier a number one and one of my faves for sure. And we talked about a lot of stuff that is potentially practice changing. So why don't I let you tell us a little bit more about her.

[A]

So Dr. Jordana Jordi Cohen, MD, MSCE, is a nephrologist, hypertension specialist and epidemiologist at the University of Pennsylvania, where she spends most of her time geeking out about blood pressure and she is a member of the freely filtered podcast team. She is the principal investigator for several NIH studies investigating the treatment and measurement of hypertension in high risk patients and has leadership roles related to this with the American Heart association and American Medical association, and she teaches us all about resistant hypertension. As I said, we start with the basics. We build up talking about some of the newer agents. It's a fantastic episode, so enjoy a reminder that this and most episodes will be available for CME credit for all health professionals through VCU healthcirbsiders.vcuhealth.org Jordi, welcome back to the show. You becoming basically like a perennial guest on hypertension. Certainly one of our favorite people to talk to. What is a current hobby or interest? I'm sure the audience has heard a couple of your hobbies by now, I think. One time you told us you almost lost a toe on a hike. But what else is happening?

[C]

Currently all I can really fit in is reading classic sci fi novels, which is something I've always really been into golden age sci fi and I'm catching up on ones that I'd really never gotten to read. Currently it's Hyperion that it was basically based off of Canterbury Tales and is super dark and intense and fantastic.

[A]

Yeah, that one I did not, I did not love. It was too dark for me.

[C]

So.

[A]

But I read it.

[B]

I don't know who's the author.

[C]

I'm blinking.

[B]

Oh, sorry. Put you both on the spot.

[A]

I couldn't tell you who the author is.

[C]

The moment of collective It's Dan Simmons.

[B]

Okay.

[C]

Yeah, all right.

[A]

I have that right.

[C]

It's older. I think it's probably from the 90s and it was intending to sort of be like that era of harsher, like sci fi. It tries to be a little bit like Neuromancer in some places and to do the like you think you're reading and hearing prodigy at the same time sort of stuff.

[A]

Yeah, that one wasn't for me. But I, you know, I'm like you. I'll try out all the if people are like, this is a sci fi novel you have to read, I will read it. Paul, let's get to the first case. Would you do the honors?

[B]

I would be thrilled to. So, Jordi, we're gonna talk about Joanne. Joanne is a 56 year old woman. She's coming back for a follow up appointment for her high blood pressure. Two weeks ago, her blood pressure in the clinic was 170. 98. I'm just watching you for your reaction. So you started her on 5 milligrams of amlodipine. Today in the clinic, you might be shocked to hear that her blood pressure reading is not well controlled. She is still 160 over 96. Initially you do a recheck with all 11 points recommended by the AMA and is still 150 over 94 upon repeat. So I guess I hate to start out this basic, but I feel like it's always good to sort of start really broad, then kind of narrow things in. So can maybe you can just even define hypertension for us and then we can sort of get to how we might actually help Joanne and maybe perhaps a little bit better than just 5 milligrams be on lodipine. Yeah.

[C]

I think the key for defining it, you hit on it, is that it has to be measured correctly. We've got really good data. Paul Droz did this fantastic paper that came out probably now about five years ago in JAMA Internal Medicine, where he collected all the routine clinic blood pressures at the exact same time as people who'd had their blood pressures checked in the Sprint trial perfectly and found that it was like a random number generator. You could have blood pressures that were 40 millimeters of mercury higher, you could have blood pressures that were 20 millimeters of mercury lower. And you could not find a single predictor of which direction direction any given person would go in. And that's essentially what happens with our routine clinic blood pressure. So the key is measure it correctly, which is not that easy given how much time it takes to measure correct blood pressure. But do our best to get a really accurate one. And if we can't get home blood pressures from the patient, making sure that they've gotten instructions on how to do it correctly. And ideally, try to use your nurses or NM to train the patients and leverage the whole team to try to get people getting numbers that we can get more accurate information and more numbers are better. So that's why home blood pressures are fantastic, because people regress towards their mean the more information you get.

[A]

Yeah. And a lot of the Modern cuffs, they. They'll do the average blood pressures too, Right. So like some of the clinics I've worked in, they have the machine where you press a button and it'll like, start a countdown, and then over the course of three minutes, it'll do two or three blood pressures and give an average and you can leave the room. Which is what they did in Sprint, right?

[C]

Yeah. So in Sprint, they didn't all leave the room. And that was an entire other drama where half the centers did leave the room and half didn't because there were no instructions on this.

[B]

Oh, my God.

[C]

So then someone actually did a study looking to see if it made a difference if you left the room or not, and it did not. But these devices overcome white code effect either way because you're getting a bunch of readings. They're not perfect at it, but they do a great job at it. And I can't tell you how many, like, wonderful little old ladies come into my clinic with their initial blood pressure of 170 over like 86, or exactly 170 over 98. Like this person, she's not a little old lady, she's younger. But then you recheck their blood pressure correctly after they've sat for a bit, and you get that 120 over, like 52. And it's not unheard of, this extreme white coat effect. And it's more common in women. That's why I say little old lady. And that's not. It's not actually a sexist thing. It has actually been shown epidemiologically to be more common in women for that to happen, but happens in everybody. Always worth rechecking and getting a really good value and not rechecking it with that blood pressure cuff that's stuck to the wall that hasn't been calibrated in 10 years with the person's leg dangling and their back unsupported and their arm dangling by their side. And all of the other steps that make me get white coat hypertension whenever someone checks my blood pressure in a clinic.

[B]

It's funny because our medical assistants know that I'm a maniac about measuring blood pressure. Like they know at this point. And they're excellent, by the way. They do a great job like this. But one of the reasons I will recheck it in the room is not only the Paul Williams technique to try to get a number I like better, but then also as a way to demonstrate to patients how I would like them to check their blood pressure at home. So I'm Very explicit out loud as I'm saying things. All right. Make sure your feet are flat on the floor, back against the chair. Here's where the cuff goes. No, no, no. Bare skin. Arm has to be rest. So I just. I'm very explicit about those things, not just to confirm the number, but also to do the education piece at the same time. It actually, I think, saves time in the long run.

[C]

Totally agree. And that's, like, exactly the perfect way to do it. And one thing I'm starting to do is the American Medical association put out a free training for staff and anybody like physicians, too, for how to do correct office blood pressure. And it's available now for free. They used to charge for this stuff, and it's on their website, and anyone can do it, and you don't even have to create an account. So I feel like there are now a lot of tools that we can try to use to get people to do it better.

[A]

And can we just get you to say this on air just for the audience? Because I still ask so many people this, and every time I ask, they're like, oh, yeah, the blood pressure was really high, but I did a manual recheck, and it was better. So are the days of, like, the manual recheck is the gold standard. They're gone, Right? The automatic blood pressure with, you know, where you do the average of a couple, that's the gold standard now?

[C]

Yeah. So that's a really great point. Thanks for bringing it up. It's like, one of my favorite nerdy topics. Those were based on mercury blood pressure cuffs that have not been allowed in our clinics since the 1990s. And so, like, the people who trained. The people who trained us were essentially the ones using those perfect mercury cuffs where you could actually get a really accurate manual blood pressure better than any automated device. But as soon as those were no longer allowed because everybody started to, you know, get worried about environmental mercury, I, you know, can't imagine why they. They now have these aneroid devices that are very dependent on these two tiny little screws that as soon as you bump into the device, they get, like, dislodged. And so these devices are miscalibrated if you blow on them. Funny. And you should just be very cautious about the accuracy of them. We went around with a mercury cuff that we're not allowed to have, but we might have hoarded that. And we were checking the accuracy of all these devices because clinical engineering won't calibrate them. And we found that several of them were, like, 7 millimeters of mercury lower, 12 millimeters of mercury higher, and it can go in any direction. And it's just across the board. Almost all of them were very, very off. Much more so than, like, the home devices that most of them, especially if you get one from validatebp.org, which is the American Medical Association's website for validated blood pressure cuffs. Many of them have been validated across broad populations. And we know that they're usually accurate in the vast majority of people, maybe not perfectly in everybody. And that's why some patients complain it's like, less accurate on one than the other. But in the majority of cases, you're going to get a much, much better value with those than you will with an. With a manual cuff. The manual aneroid devices also don't overcome the fact that we lose hearing as we get older and we often cannot hear those lower croc cough sounds that are so important for us to actually define the blood pressure on. And then the other issue being that many patients have auscultatory gaps. So I have one patient that kept getting told that she had, like, incredibly low blood pressures, not to escalate her blood pressure medication, because all of the manual readings that her docs were doing were, like, perfect. But as soon as she was put on an automated cuff, she was getting blood pressures of like 190 over 110. And those were the real ones. She just had an auscultatory gap where you don't hear a croc cough sound for, like three 60 millimeters of mercury in this woman. And so this is a real phenomenon. The only people I use manual in is people with persistent arrhythmias because most of the automated cuffs can't handle it. There are some that can, but the majority of automated cuffs do really poorly with persistent afib particularly.

[A]

That's so great.

[B]

I'm so happy right now between what's called dori gaps and groguff sounds.

[A]

And we're talking about resistant hypertension. Pseudo resistant hypertension is on the differential. So I wanted to just ask about cuff size with the automated cuffs, because if. Do most of the cuffs come with a cuff that can go from regular to xl or do you have to get a specific XL or double xl? If you have a patient with a really big arm, there are cuffs that.

[C]

Come with the broad range, and it goes up to 42cm for most of them. And then there are other cuffs that go up to about 52 to 55 centimeters that you often have to buy special. It's very unusual for cuffs to just come with the extra large one. And I know some people who will use like BMI thresholds to determine who needs that extra large cuff. And they don't really work that fantastically because a lot of it has to do with the arm shape too. And some patients have these more conical arms that you really need the larger cuff for and you have to go off the largest part of the arm when you measure. And so none of us sit around with like, you know, measurement tape to be able to measure our patients arm circumferences and know exactly what to do. I find that my patients where with my judgment, I'm noticing that we're really struggling to get a cuff to fit their arm. Well, I tend to recommend recommend in just in those patients to use a wrist cuff. Wrist cuffs typically are more operator dependent so more prone to error than upper arm cuffs. So we very, very significantly prefer upper arm cuffs in general. But for really obese patients who are struggling to get an accurate reading, a wrist cuff can be fantastic. It of course needs to fit them and it needs to be a validated one. There are several validated ones on validatebp.org it actually can be fantastic for them. But make sure you pair it with instructions on how to do it correctly because a lot of the devices come with instruct to say telling people to hold their arm out in front of them outstretched and that's actually incorrect. And I've spoken to some of the engineers who create these devices and they argue with companies about like how to set out these instructions and that is not how you should do it. You should have your arm resting with your elbow on a table and you should have two fingers on the opposite clavicle. And it's really easy to explain that to a patient. And they're great pictorial representations of how to do it. TargetBP.org has like a beautiful one pager just showing patients this is exactly how to do it. And here's an X through how not to do it. But I always caution patients, that's probably why everybody doesn't trust the wrist cuffs because you can get these crazy labile readings on it. Because people have their arms sort of outstretched and it's in a different position each time.

[A]

I have seen that where they have the person supposed to have their elbow on the table with their hand out in front of them like this. And I'm like, I thought they were supposed to have it across towards their heart. Okay, so two fingers on the clavicle that's Paul. This is like, I mean, this could be a four hour episode. Paul.

[B]

Yep.

[A]

You're talking to the wrong guys if you want to get this granular about. But this is important stuff because like, well, that's, I just feel like when you're, when you're talking about blood pressure, like the reading is everything and then like, how are you gonna, you're trying to hit a number, but if your reading is garbage, how do you know if you hit the number or if you even need to escalate de, escalate all that stuff? So that's why we talk about this.

[B]

It's the golden age, baby. We got the arms trial, we got what the cuff size, BP. Like it's, we're still the year of our Lord 2024, 2025, and we're still looking at how to actually put a blood pressure cuff on an arm. It is wild, but it's, it is wild.

[C]

But I'm thrilled that, that they did this. I'm friendly. So Tammy Brady, who's the PI of those trials that came out with like cuff size and position of the arm, she is a pediatric nephrologist at Johns Hopkins and we co chair validate bp.org where we just completely volunteer to be the most anal humans on the planet by like completely checking every box to make sure that the companies sufficiently validated their devices using this like 200 page manual that every device company has to use. So that's, that's what we do as our hobby. I wasn't going to mention that when you asked me at the beginning.

[A]

I'm so proud. I'm so proud to know you. I mean, this is amazing. Yeah.

[B]

Is it wrong that I was a little bit jealous when I heard that? I'm like, that sounds amazing.

[C]

It's really. Cut the heartache.

[B]

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[A]

All right, so we should talk a little bit about. So this person, Joanne, she's 56. She's coming in with a blood pressure that was 170 over 98 and we started her on 5 of amlodipine. Then she's coming back at 160 over 96. It's a high blood pressure. So what are we telling her her target should be these days? Is it now? Is it now one less than 130 over 80 for everyone? Is that just the easier way to go or do we have different thresholds?

[C]

So the AHA ACC guideline in 2017 put out 130 over 80 or less than 130 over 80 for everybody as your goal. Once you have a diagnosis of hypertension, with a couple of like, small caveats, for instance, use your judgment in really older frail patients when you're worried they might fall, like, that's up to you and they're not taking that away from us. Then like, there's all this controversy because the AFP doesn't agree with that and they really think that if it doesn't, if the data hasn't shown that there is specifically just a mortality benefit, not like cardiovascular benefit, but just mortality benefit, that it's not strong enough. And so that's why they're saying 140 over 90. This was all like sort of had also come up with JNC7. And we have a lot more trials now. We have now four trials that have come out in the last four years that have all shown that intensive blood pressure lowering across broad ranges of patients is beneficial. In sprint, they found that it was even slightly more beneficial in some of the analyses in people over 75. And so that older patient thing doesn't necessarily apply. It's the older plus frail patient that you really might want to be more concerned about. But older age itself isn't enough. So pretty much in Everybody. We're using 130, 80 kdigo, which is the kidney clearinghouse for international guidelines. They are pushing for less than 120 over 80, claiming that they're the only ones really making the caveat that it has to be a standardized blood pressure. Everyone else is also saying, please make sure it is a truly correctly performed blood pressure. I think the reason for KDIGO is that our kidney patients have more to lose. There's a lot, lot higher risk of patients with chronic kidney disease having major cardiac events. And so there could be the potential for greater benefit by more intensive blood pressure lowering. More and more of the international guidelines are pushing more towards if somebody can tolerate it, maybe think if you can go lower. I think the goal of all of this is a little bit paternalistic, to just get us thinking that 120s are normal as opposed to 130s being normal. Whereas I think that when I was in training, many people sort of treated 140s as normal. So it's all just sort of attempting to try to swing the pendulum more and change our sort of expectations of what a normal blood pressure is. But I don't think that in most people we can reasonably achieve consistent blood pressures less than 120 over 80 without seeing a lot more side effects. And There are meta analyses that support that.

[A]

I think it's like a negotiating tactic where you're just like. They're like, what do you want your salary to be? And you just name some like really high number. So that way, like, if you even get close to it, you're like, oh, we're doing pretty good. Like, I think that's what it's like with blood pressure. They're like, we gotta really. Because if we're like 140 over 90, we know people aren't gonna hit that. They're gonna let the blood pressure ride in the 140s, 150. So now most people, we're trying to get blood pressure down 120s, 130s systolic. And pertinent to this case. I have so many patients and so many trainees or other clinicians just say, well, you know, I started one medication at like a medium dose because I was worried I was gonna drop their blood pressure too much. And I was. And I'm just like, I'm just not seeing that clinically. Like, it's hard. I'm mostly having to add three medications to get people to goal of less than 130 over 80. Like, I'm not bottoming out people's blood pressures. Now, of course, older and frail patients, I'm more careful. But I don't know, do you all.

[B]

But that patient's not coming to de novo. Right. So if you have this older patient who has sarcopenia, who's multimorbid and they have new hypertension, like for something else weird is going on, first of all, you know what I mean? So this is not the patient we're going to be starting medications for the clear blue sky, probably. So I think I'm agreeing with you.

[A]

These are mostly younger patients.

[B]

These younger patients that are relatively healthy that have the capacity and can tolerate sort of a little bit more aggressive medication management, I think.

[C]

Yeah, totally agree. And we've been. So we'd started a QI project here a couple of years ago where we created a new algorithm where we're sort of nudging clinicians to start with the two medication fixed dose combination exactly as you're describing. And it's really helped improve blood pressure control quite impressively. And I think part of it is that it overcomes a lot of clinician inertia in case you can't get the person back in and not even our like or if the patient can't get back in quickly, least gets them covered faster. And yeah, you're not going to see extreme blood pressure lowering, typically by using two agents at a moderate or lower dose to start off. With the reason being that these medications all take a long time to take effect. And I always make sure to tell patients that because it's really important to set their expectations, especially if they're doing home blood pressure monitoring. Because you know those patients who are like, well, I took the medication and it doesn't work. And it's because it doesn't work for a couple of weeks. And I always let them know that, like it is working a little bit initially, but, but it's really going to have its biggest effect when you take it consistently for two weeks. Watch it, look at the numbers. You don't, I don't want you to necessarily check your blood pressure every day because I don't want you to get anxious about it. I usually tell people check it three days a month. But I think there's a lot of value in making sure that you set people's expectations and that a lot of patients upfront when they're first being started on these medications, expect them to work right away. And when they see they don't, they're like, this is, these are the patients that end up on like clonidine as their agent. And I just think it's a lot of that could be prevented up front by just setting those expectations appropriately. I always tell people, I'm starting you on amlodipine and random ARB and as a fixed dose combination and you're going to see this medication, full effect somewhere between two and four weeks from now. So if you're not seeing a great blood pressure just yet, not a problem, we don't expect it. You're going to see it later on. So you can even just wait a month and then check your blood pressure if you're okay with that. And if you're really not okay with that, just hold your breath.

[A]

That's great.

[B]

Paul, this is a little bit of a. I know this is not quite in keeping with our topic, but since we have you here, it's just stupid not take advantage of you. I, I feel like the paradigm has shifted and that I'm, I'm seeing better focus on diastolic blood pressures. I feel like historically everyone is very fixated on the systolic, but someone lets someone ride in the 90s diastolic all day and all night and I feel like people are getting better with that. But I do feel that people sort of struggle what to do with sort of isolated diastolic hypertension. Or when that's the bigger issue, does that change treatment selection or sort of how you think about those patients or how do you manage those patients specifically?

[C]

It's actually really difficult. It's a very controversial area because all the data are conflicting. Some data suggests that if you have isolated diastolic hypertension, treating it does help. And there's other data that suggests that it's very rare, that you'll have people, that it's real and that it could be actually more artifactual and, and that you aren't necessarily benefiting people by treating it and you could be causing more side effects from lowering the systolic below normal. I think some of it is hopefully going to get better as we're starting to have a new normal systolic. And so I think that if we're okay with lowering our systolics to less than 120, then we'll feel more comfortable lowering the diastolics too. And so I think that's part of it because the ones that I've had in my clinic are usually people who, their blood pressure was like in the 120s over high 90s and everyone's afraid to treat it because they think they're going to make them sick. And I give, put them on an ARB or a calcium calcium channel blocker, get them into the one teens over low 80s and they're doing great. And those people, I really struggle to get them under 80 diastolic often because there's no medication that's just going to lower diastolic. But at least I think we should get more comfortable treating it because we do know that. I think in most cases it is associated with harm and I'm not so comfortable just attributing it to artifact without knowing what's going to happen to these young. It's usually younger men and you don't know what's gonna happen to them 40, 50 years from now. Cause we just don't have that data really well ascertained. And so I'm a big fan of treating it just. Cause personally if it was me, I'd rather treat it not knowing if it's beneficial rather than treat it not knowing if I'm gonna have a stroke at a younger age because this wasn't treated.

[B]

That's great.

[A]

So to go back to our patient, you mentioned a calcium channel blocker and ARB. So what if we put her on 5, 40 of 5 milligrams of amlodipine and 40 of telmisartan and we say we're gonna see you back in a month or so, see how your blood pressure's doing. If she comes back in that month, is your move to max out that agent or is it usually to go to a diuretic like our next of the first line agents?

[C]

Yeah, let's say we'd done things correctly the first time and she came back with those same elevated blood pressures in a month. I would have added a third agent because it's telling me that she's not gonna hit goal. Two agents adding and increasing the dose. You're only going to get incremental benefit once you get past that median dose. Doesn't mean I don't max out the doses eventually. But in somebody like that who needs a lot more to respond, I'm adding a third agent to try to minimize side effects. She's new to me. I don't want her distrusting me. You get more side effects and less blood pressure, lowering the higher dose you go to. So I start off with adding the next agent and then I increase doses later.

[A]

And there's two triple pills in the US That I'm aware of. Amlodipine is paired with either Valsartan or Olmesartan and then hydrochlorothiazide in varying doses since we last talked. I have a couple patients that are on that. Sometimes the pharmacy won't have it in stock and they'll give them some combination of a combination pill. And then the other one is a single, which kind of annoys me. But it is what it is. But at least they're taking three agents. So are you still using a lot of those and are there any new triple pills in the pipeline?

[C]

They're the only ones I'm aware of. I use them almost exclusively. Cause my clinic has a huge amount of resistant hypertension. And that one change very frequently gets my patients under control. It's like the one big sweeping change when they come into my clinic on 17 meds and I put them on that and try to reduce pills. I just find it builds so much trust when somebody says, I thought you were gonna be adding medication and you're reducing medication. And also just. Just psychologically seeing less pills in the morning. I think they're. Not everybody is like that. But a huge proportion of patients, I think it just benefits them, it reduces their anxiety, it helps them help themselves more. So, yeah, we carry it in our hospital because I think they're used to us ordering it a lot. And I think our local, like pharmacies all seem to typically have it. The Biggest issue we run into is, like, whichever one you order, you'll find out that this year the insurance company wants you to order the other one. And so I just. I pretty much just go by what the insurance is willing to cover, but I usually have success getting one of them, especially in a resistant hypertensive patient.

[A]

Paul, have you ordered any yet?

[B]

I have. I think a couple on, but, yeah, I'm still. I'm not. I've not reached the level of wild enthusiasm that you have, Matt. I should just embrace it.

[A]

It's not wild enthusiasm, but it's just like, there's so many people, if I start with, like, a calcium channel blocker and an arb, and then they need another agent, you know, that's keeping them on a single pill. That's pretty much your only option, we're sure.

[B]

And above and beyond that, I think, you know, I probably have plenty of patients who are on three of the first line agents that are actually doing okay, that I could probably just make their life easier by switching over to a triple pill, too. So I think that that's. That's another consideration I should be a little bit more mindful of now that you're shaming me publicly.

[C]

And there are, like, a lot of people who have these opinions that, like, oh, nifedipine is more potent, and so if I just add the nifedipine, I'm gonna get that extra bang for my buck. And my sort of take on all of that is, yes, that's. That's true. But when someone needs three agents, they're resistant. Like, you're. You're running into a struggle already, and you're not gonna get out of, like, not needing more agents. And the key is, like, figuring out what's driving this, making sure we're not missing things and just getting them the treatment they need and making it as easy on them as possible so they can be adherent. Because the biggest issue is the vast majority of people, not the vast majority, but a huge subset of people with resistant hypertension. It's pseudo resistant, as you mentioned, Matt, and it's because they're not taking their medication in a large portion of those. And depending on which study you look at, it's somewhere between 20% and 50% of people with resistant hypertension just aren't taking their meds or are not taking a large portion of their meds. And so if we can make this one step, just get them to take their meds. This is why I feel like I get told I work magic in my clinic. And I will say that most of the time it's from that one change to change people from three pills or 17 pills to three pills. And so I think that patients appreciate it a lot.

[A]

If she comes back and we've put her on a triple pill and let's say we've even tried to tweak it a little bit, she's on a max dose of one of the triple pills, amlodipine, an ARB and hydrochlorothiazide, 25 milligrams. What is your next move? Just remind the audience, I know we talked to you about this in the past, but what would you be thinking of next with her or what questions would you be asking? Maybe just to make sure that is this resistant hypertension? What else should we think about?

[C]

Yeah, I would check her pharmacy fills, make sure she's filling. It's not a great perfect surrogate for adherence, but that's the first thing I do is just, just am I sure that she's actually at least trying to take the medication and able to access it? Because that's of course financially another important factor, then what I'll do is make sure I'm confident that it's not white code hypertension. We have the luxury in our ivory tower of having 24 hour ambulatory blood pressure monitoring. Not everywhere has that, but most people can get a home blood pressure device that's valid and if they can't, we have a bunch of loaners and just make sure we get some readings outside of the office and are really confident that it's not white coat. Then at that point I make sure that we are certain that there aren't other lifestyle factors that we can address. And we'll talk about BMI a bit more or at least not BMI is the wrong term, but obesity a bit more and sort of what can be done there. Obviously exercise, weight loss, help. But historically it had been slow and many patients were resistant from to going for surgery. Alcohol is a big factor and increasing evidence is showing how much alcohol is a big factor. And so the old AHA ACC guidelines from 2017 had said less than or equal to one drink or less than or equal to two drinks in, in in women and men respectively. But now actually the ESC guidelines in Europe just said, and I wonder, I think other guidelines might start growing the backbone to do that too. Which is I think in some ways hard because no patients are willing to be fully abstinent from the things they love. But in some ways good messaging in that this is causing a lot of hypertension. And I think we under ask about.

[A]

It at least it'll make people, you know, think, oh, okay, I guess they're thinking that this is a big player and why hypertension is a problem. So, so maybe some people make them drink less or if they don't mind it, stop drinking altogether if they need that for their blood pressure.

[C]

And then I ask myself about other drugs too. Right. So we obviously encounter a lot of drugs we can't stop that increase patients blood pressure like stimulants that they need to take for ADHD, like NSAIDs, that they need to take for their pain in lieu of taking opioids. And so I mean, I think there are times where we have to treat the side effects of other medications with other medications, unfortunately. And I just always have that conversation with the patient so that they're aware of that. But then there are other times that we can make changes. And so I think that that's really important to just have in our mind as well.

[B]

We'd be remiss if we didn't mention tizanidine just because it's the coolest. And Matt Luther with is the case study of the fact that patients tend to take it and load up at nighttime because that's when it cause it causes somnolence and they like sleeping well and as a result they can have rebound hypertension throughout the day. So there's a great write up in 2019. Is it in hypertension?

[C]

In hypertension, yeah.

[B]

Yeah. That is a case report that sort of speaks to this and talks about a patient who's actually hospitalized for this. We've been through another episode, but I give that paper out to every single trainee who even says something that sounds kind of like tizanidine because I love it so much and I think it's probably underappreciated as a cause of hypertension.

[C]

And just so people are aware too, it's the same mechanism of action as clonidine. So it's that same rebound effect you get from clonidine. It's essential alpha agonist. And one potential treatment for that and one of the other treatments I like having in my back pocket, for instance, for people who need stimulants for their ADHD is guanfaccine. Because if they can't stop the tizanidine, a way to prevent it from creating issues is to use guanfacine because it is a long acting central alpha agonist that prevents that rebound effect and it's an antihypertensive and so I use it a lot in my patients with ADHD who are really struggling with their hypertension. I use it a lot in patients with more blood pressure, lability, too. It's not something that's necessarily something we should be thinking about as like a first line agent by any means, but it definitely is good to have in your back pocket for those situations.

[A]

Yeah. There was a line from last. The last time we interviewed you where Paul was like, so you're telling me that it's like if I had patients on four agents, you know, they're on an mra, that your fifth agent might be guanfacin?

[C]

Yeah, yeah, yeah.

[A]

Well, all right. That's why we do the show, Paul. We gotta learn new things. So let's just say that for some reason, Ms. Joanne, she was uncontrolled on three agents. We added an MRA, we added spironolactone, and her potassium shot through the roof. And her kidneys are not. Well, let's just say her potassium shot through the roof. So we're just not really feeling that. There's gotta be some new stuff out there. Maybe it's exciting. And what is in the pipeline that might be available to her or what's already here?

[C]

Yeah. So I'll say for old stuff, I would throw more diuretics at her because it's probably a kidney issue, even if her creatinine is normal. Check us a statin C, please, for the newer stuff. There's some really exciting stuff coming through the pipeline. And this gets at the Neff Madness categories that we're representing as well. And so there are several new agents that are either FDA approved now for managing hypertension or not FDA approved for hypertension, but sort of have that benefit or are likely to be in the next few years and are undergoing phase three trials right now. And so the ones that are FDA approved, I'd say, are more like the nephrologist should probably still be prescribing those. Or the hypertension specialist. Well, one of them, at least. So episotentin is the name of it. It's a dual endothelin antagonist. Endothelin is one of these, like. More. Is one of these pathways that causes hypertension that we didn't really learn about in medical school, but it was pretty important. It impacts smooth muscle cells and blood vessels, and there are multiple different types of these receptors. These drugs have existed for a very long time, and everybody was struggling to find one that was safe enough to use because they kept causing so much volume overload. That it was just not acceptable for use for something like hypertension. So there is one, for instance, that was FDA approved a long time ago for pulmonary hypertension, but nothing that's been approved for like routine. Right. Regular use in patients that we see every day in like a typical clinic. This newer one, Apiso Tentin, does cause volume overload still, but not nearly as badly as the ones that had, that had preexisted it and not as badly as for instance, a drug like minoxidil, which is still being used for as like one of these nth line agents. When you're out of options and your patients on eight antihypertensives and you need another one, then that, that actually increases the risk of like pericardial effusions and huge volume overload and other issues. And so apryltensin isn't quite as bad that and has some other benefits in that it's more effective in CKD patients than in non CKD patients in that it lowers nighttime.

[B]

That's great.

[C]

Yeah. And it lowers nighttime blood pressure more than it lowers daytime blood pressure. We don't have any other agents that do that. And so I think it's really promising. I don't think it should ever be a first line agent, but I think it's going to be really cool for resistant hypertension and that there was some better benefit, for instance in black patients than in, than in non black patients. There were some really sort of of cool subgroup analyses from it. There's only been one big trial though. There won't be, I don't think there will be more. It was called the precision trial in Lancet and I think it's going to have its place and I don't think we're going to be seeing it every day. There's a REMS warning for the fluid.

[A]

Overload and I was just surprised. The difference versus placebo according to the NEF Madness write up was only like it was 15 points lower. It lowered blood pressure by 15 points, but placebo lowered blood pressure by 11 millimeters mercury. So it's like a four point difference, which is, you know, it's like, okay, so I'm potentially getting someone hospitalized for heart failure for a 4 point blood pressure lowering. It's kind of humbling when you actually study the meds, like how much do they actually drop. Drop blood pressure?

[C]

Yeah. And this is the FDA requirement is on ambulatory blood pressure monitoring, which is typically more precise than what we get with office blood pressures, that you have to have at least a 4 millimeter mercury, blood pressure lowering for it to be considered like FDA approvable efficacy. And so the, that's, that's actually like a known threshold and that's what a lot of the drugs that have been FDA approved on average showed. So it's, it's a little sobering.

[A]

Yeah. Okay, what, what's next?

[C]

Yeah, so next, so I'm, I'm going to pair that with the other FDA approved one. It's not indicated for hypertension, but it's very intuitive. It's semaglutide and any GLP1 agonist essentially because it's the act of the weight loss. And so there are two really great meta analyses that have come out on the, the GLP1 agonist trials that have shown that, that these drugs lower blood pressure quite predictably with weight loss. And that could be part of the mechanism for why we're seeing all these cardiac benefits from the drug too, and kidney benefits from the drug. And so there was a mediation analysis showing that for basically every certain amount of weight that you lost, this is how much blood pressure you lost. And it's basically just a straight line of like, you lose weight, you lose blood pressure. And so it's, I think that there are obviously other potential benefits of the drug. It should only be used, this class should only be used, obviously, if the patient has another indication for its use, not just for blood pressure lowering, but it's a nice happy accident and another one of these positive side effects amidst the very unusual but scary negative side effects of this class of drugs. So I think it's just worth thinking about because I don't think it's always on the top of everyone's mind that there could be these wonderful peripheral benefits.

[A]

I'm sure if they study tirzepatite, I'm sure it will have the same effect as well. Yeah.

[B]

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[A]

Okay, so those are the two ones that are currently FDA approved. And Semaglutide, as you said, was not for blood pressure, but it's FDA approved obviously for weight loss and for diabetes.

[C]

Yeah. And now for obstructive sleep apnea also causes higher blood pressure. And it's FDA approved now for I think for kidney disease as well, or is about to be.

[A]

What are the other two agents that are in this region that we wanted to talk about?

[C]

Yes, they're not yet FDA approved yet. The first set are currently finishing up phase three trials. They're aldosterone synthase inhibitors. Even going to give the names of them because they're like impossible to pronounce. It's things like Baxter Stat, Larundrostat, Dextrostat, but they're. I guess I went back on that and gave the names, but they are like really, really promising. Basically they prevent aldosterone from being produced instead of the whole issue that we have with blocking the receptors for aldosterone with spironolactone and eplerenone. Because when we use spironolatrin and eplerenone to block the receptors for aldosterone, we end up with these of peripheral other androgenic effects, especially from the spironolactone because of the fact that it's having other non mineralocorticoid steroid effects. And so we really needed a class that wasn't going to have those androgenic side effects. The nonsteroidal MRAs have that promise but don't really lower blood pressure. And so the aldosterone synthase inhibitors are class that are able to prevent aldosterone from actually being synthesized and are going to very effectively lower blood pressure by means of reducing your body's or basically turning your body's aldosterone to zero. It's pretty exciting. The reason it took so long for these to be developed is because the enzyme for aldosterone synthase is very, very similar to the enzyme that breaks down cortisone to cortisol and you end up with a lot of cross reactivity, similar to our issues with mineralocorticoid receptor antagonists and the androgenic activities. And so they had to find the ones that were, they had to find drugs that were extremely spec for the enzyme and they're now doing that. And there are some still around that they've been testing for years that are not as specific, but the ones that are rising to the top are the ones that seem to be really, really specific. They're testing for this in all the trials to make sure that they're not seeing any activity on cortisol. And so far so good. And so basically the benefits of these are that they probably increase potassium a bit less than mineralocorticoid receptor antagonists. They're not going to have any of the adrogenic side effects. So we're not going to see gynecomastia, we're not going to see anything else that we're really worried about. The biggest issue is that when we, if we treat huge numbers of patients, we may end up seeing some cortisol lowering and like the rare patients, so it'll be something to just keep an eye out for. But I think they're very, very promising. The blood pressure lowering was much more impressive than with the, with the percytentin and the two trials that have been published and it's so far being studied in patients with resistant hypertension, in patients with uncontrolled hypertension on at least two agents, and in patients who have chronic kidney disease in combination with an SGLC2 inhibitor to make sure, you know, that like our kidneys tolerate being pounded with all of this medication that reduces hyperfiltration.

[A]

Yeah, those sound cool. And these are pills, right? These are not injections?

[C]

Yep.

[A]

Okay.

[C]

These are all pills. So they're all like, they're typically once daily pills and so all pretty promising. Tolerability so far seems really good. Biggest issue is gonna be a little bit of hyperkalemia.

[A]

Okay, well, I'll let you prescribe it for a year or two before I venture into this. Probably these are probably gonna be locked down to specialists anyway, don't you think, Paul?

[C]

I don't.

[B]

Yeah.

[C]

You think so? I don't think so. I think they're gonna be. So the phase three trials, one finished and another phase three trial is finishing right now. And so we're gonna get results in the next like six months or so, hopefully safe and good. And we'll go through FDA evaluation if the FDA still exists. And we will, sorry. And the. I think, I think the likelihood that it'll be broadly used is going to be higher because one of the sets of trials is in people with uncontrolled hypertension, not in people with resistant hypertension. So these are people that are just on two drugs. And I think there's some elegance to that because they're basically saying, hey guys, think about this as a first line agent. Because for years people had wished that some of the MRAs had been tested as first line agents, but they never were and no one really paid for big, big trials of that. And so this is the opportunity to sort of do that.

[A]

That very cool. What else is out there in the pipeline?

[C]

The last one is like really innovative and I mean we're seeing some similar drugs in other spaces, like the lipid space right now, but these are small interfering RNAs that block angiotensinogen and so basically prevents your highest upstream effect in the RAS system from ever being produced. And they last for about six months, it seems like There was a phase one and half the phase two trial published in New England Journal of Medicine last year, a couple of years ago, and they're now in the phase three trials for it. The biggest concern with it is, I mean, if you block the entire renin angiotensin system for six months, what do you do if you need it? And so you need it in sepsis, you need it in pregnancy. There are like certain scenarios where we've seen in, at least in rodent studies that if you don't have a renin angiotensin system, it's really bad news. And so the company, I don't do anything with drug companies but like they reached out to everyone, like all the hypertension folks that are like loud and they were just like, what do you guys need to see to feel comfortable ever prescribing this? And I think every one of us said an antidote. And so they, they produced one, they created an antibody that binds to it. That, and at least so far in animal studies seem safe, that will be able to just completely knock it out. So if you need your RAS system, you'll be able to like stop the drug from working. And I think that's the key. I think it's going to be really cool and it's going to be fantastic for people who struggle with adherence and that it's going to have potentially some great benefits. I think think there could be some negative effects. So far they haven't seen it, but the trials are really small and like we saw with like Aliskiron, which is a direct renin inhibitor, which is like high up in the RAS pathway, that it wasn't that great. And so it's possible. It's not going to be amazing, but I think there's a lot of hope, like I think that this could be like the lifesaver for so many of our scenarios where we just like cannot get drug into a patient that is.

[A]

Wild, an antidote for a blood pressure medication. Paul?

[B]

Yes. I'm going to be making the same face for the remainder of the episode. I'm just going to think sort of long and hard about I guess the patient acceptance of something that lasts four, six months for blood pressure. It's fascinating and I can understand the appeal, but I can also understand hesitation around something without the possibility of being able to reverse it at least. So yeah, it's wild.

[A]

And we think from the early studies the effect size here is more than 4 millimeters mercury. Hopefully if we're blocking for six months.

[C]

Months, yeah. It's all like phase one, phase two trials. So it's so hard to tell, but it looked like it was quite larger, more in that like 10 millimeter mercury range. And so we'll see. I never trusted after we're going to get to renal denervation soon, but after seeing the original renal renal denervation studies, I don't trust that sort of initial blood pressure lowering effect until you see a really, really well controlled, like longer term, larger scales trial. Because there's so much in hypertension that is like Hawthorne effect and like all these scenarios where as soon as the being watched and measured carefully and like actually taking their medication consistently that their blood pressure plummets. And that's why we see this massive placebo effect in every blood pressure trial, especially resistant hypertension trials. And it says a lot about how important all those questions are that we were just talking about of like really making sure that your patient's like doing okay on their medication.

[A]

Okay, I want to do try a little bit of a recap just because these drug names and all, most of them are probably very new to people. So. So first we talked about the two newer agents that are FDA approved. So that was one, the first one was an endothelialin receptor antagonist and that was aprocetentin and that lowered blood pressure about 4 millimeters mercury. It was effective in CKD, lowers nighttime blood pressure and there were some concerns there as far as like edema and we mentioned heart failure in some patients and then the other FDA approved is semaglutide, which we're all used to prescribing for obesity, type 2 diabetes, and that lowered blood pressure, basically. You mentioned a straight line with weight loss. Like, as weight comes off, blood pressure goes down in those patients. So that's something that we wouldn't prescribe specifically for blood pressure, but for some of the comorbidities around it. And then we have the aldosterone synthase inhibitors, which are very promising, and there's a bunch of them out there. Baxtrostat, I think, is one of them that we mentioned. And these ones, it took them a while to figure these out because we had to make sure they didn't mess with cortisol and didn't mess with androgens. And it seems like the ones that are rising to the top don't. And that they'll probably be approved sometime in the next year for uncontrolled hypertension. Those are pills. And then finally is the once every six month zilbesiran, which is a small interfering rna, which is going to block angiotensinogen production, and that's going to need an antidote before anybody signs off on it. Did I miss anything there? It's just a lot to go through, and it took me a couple times reading it to get it straight.

[B]

It's always magical to hear your recap, Matt. I do just one point of clarification. The naprosa tentin, which I was hoping I wouldn't have to say the entire episode. Episode. I think it was 4 millimeters mercury more than placebo. Right. Because I think it was actually 16 millimeters mercury compared to 11 millimeters mercury with placebo. So I just wanted to make that I was clear on the treatment effect with it, even though recognizing it's not much more than placebo, still, the number itself is a little bit higher than that, right?

[A]

Yes, that's true. That's true. Okay, so what if our patient says, all right, they don't want any medication. They heard that there's a procedure that can just stop. Cure their hypertension. Let's say they use the word cure. Is that true, Jordi?

[C]

Oh, there's a lot of weight behind that. So the FDA approved two renal denervation systems. So procedures that are similar to undergoing a cardiac catheterization, where a interventional cardiologist typically will insert this device or this catheter into your groin and will then go into the kidney arteries and essentially cauterize part of the kidney arteries, hoping that they hit the parts of the nerves that stimulate blood pressure and not so much the parasympathetic nerves that reduce blood pressure. And there were all these iterations of these devices because there used to be devices that sort of had a different shape to them and they were accidentally stimulating who knows which nerves and not having as much of an effect in large scale. And then they've made newer, fancier catheters that have different shapes and different technologies that are supposedly just more of a shotgun approach. And so you'll get, by nature of getting more nerves, you'll get more of the bad nerves. So many, many, many patients want this. There have been a bunch of qualitative studies done, asking, like, patients, would you do this? And a shockingly high number of patients would prefer this over medication in a heartbeat. And I think that as clinicians, so many of us are skeptical, at least I am. I'm at a center that was, like, part of the people who created these, like, like the. The studies and, like, undertook all the trials to make these devices happen. And like, all of my mentors were heavily involved in this. And I'm still the skeptic. I've referred, like, three patients or two patients. And it's typically the patients who are, like, admitting to you, like, I will never take a drug or really severe multidrug intolerance, like, where every drug they take causes some intolerable side effect and they just can't take it anymore. And, like, those are the scenarios where I think are very appropriate for this. I think that the people who are looking for it more, though, are the, like, younger patients who are like, I don't. Not ready to admit that I need to take pill permanently for the rest of my life. And the patients who are just, like, again, struggling with polypharmacy. And I think it's going to be tough because it really only works in about 2/3 of people who undergo it, but it works in those 2/3 of people who undergo it, but it doesn't necessarily cure your hypertension. It works about the equivalence of one antihypertensive drug. And so it lowers blood pressure, on average, depending on the trial, somewhere around 6 millimeters of mercury. And. And that is what we've learned with the fda. Approval of these drugs is about one agent, and many patients will go through a whole procedure for that purpose. The procedures are very expensive. A bunch of people affiliated with the trials did cost effectiveness studies that show it's cost effective, but they have no outcome data. So they're sort of just saying, well, your blood pressure lowers this much, it will prevent a risk of stroke. My concern with it is I think that some people will see it as a cure because. Because they went through this whole procedure, they're going to hear like the parts of it that they want to hear and then stop taking medications. And I think the key to it is most people who are going to end up having an indication to go for this are still going to need blood pressure medications on top of it. And that's going to be what's hard to swallow. So I'm a skeptic, but I think that there is a place for it and I do have a few. Like as I said, I had a couple of patients who've really benefited from it and who really did need to do it because they were short on options.

[B]

Yeah, I mean certainly I wouldn't argue with the qualitative data, but I just feel like that's wild to me. I can maybe see a scenario where we're talking someone is trying to achieve secondary prevention after something catastrophic has already happened and they're struggling with the medications. I can see that person being interested in something like this. But what I struggle with, at least in a primary care clinic, is hypertension is asymptomatic until it's not. Until it causes some sort of catastrophic problem. And it's hard for me to envision someone one not being willing to take medications was it's asymptomatic thing, but willing to undergo a procedure. That's just, it's. I'm so, I'm so surprised at the, at the outcomes that you guys have looked at. That's just, that's counterintuitive to me. But again, I'm not arguing with them. It's just, it's. I don't think I've explored this as thoroughly as I should have apparently.

[C]

Yeah, the. There are a lot of patients who want it and I see that like, because I don't take the referrals in our center because I'm sort of have been not familiar with the entire process. But the. I'm constantly getting messages of like this patient really wants to innervation, like how do we set it up? And me like referring them to our team that sets it up. And I'd say I probably get those messages even like two, three times a week now. And I literally am like not involved in that space at all. So the people who are involved in it are obviously getting a lot more referrals and it's desired.

[A]

I will say that, yeah, I can understand where the hope comes from that there's a procedure that can cure hypertension. But, but I was just so underwhelmed after reviewing all the trials and I was just shocked that they even got approved because some of the trials had conflicting evidence. It's like, oh, it worked in this unblinded trial that wasn't sham controlled, but then it didn't work when you did the sham control and got more patients. And it just seemed to me, I'm like, how was this approved? And it sounded like some of them were narrowly approved. So. So I just, you know, I would, if a patient was asking me what I thought about it, I would say it doesn't sound like it's ready for prime time. And then I read in the Neff Madness write up they were talking about some people are worried about nerve regrowth or nerve regeneration, like that it's going to grow back. And are people getting repeat procedures in that scenario?

[B]

It's like hair, it grows back even thicker. So like, you have to be really careful because it becomes really hypertensive.

[C]

So I'll step in on that. In defense of it, there's one study that has shown long term data. It had a lot of dropout and, and then a lot of people transferred over because if you already enrolled in the study, you were interested in getting the procedure, you had a sham procedure done, so you thought you might have had it done, then they let you get it done if you didn't already have it. And that study showed that people had a long term effect from it. It does last for a few years and it seems to even, maybe even get a little better over time in that subset of people that were still being followed. So it's hard to interpret that. I'd written an editorial on this in one of the kidney journals a few years back because a lot of people were asking about this, well, what about kidney disease, Pat? And they weren't even allowed in a lot of the trials because there was this concern of what if it causes renal artery stenosis? It doesn't seem to. So that's great. I think the biggest downsides of it are that it's an expensive big procedure and you're sticking a needle in someone's groin. I think that that's it. Like, I don't think the regrowth is. It hasn't panned out, but there is some theoretical concern for it. I think the biggest issue is just like it's super expensive and like it's, it's not even necessarily being covered right now by most insurance setups. And like everyone's sort of struggling to figure out how to pay for it. And so I think eventually some insurers probably will cover it and that there will be like a pipeline for it. But I agree with everybody else's hesitance in that it's really just not that impressive of a blood pressure lowering. And the fact that a third of people who go through this procedure will get zero benefit from it just blows my mind.

[A]

Yes, I agree.

[B]

All right, so let's take it back to the case. So let's back to Joanne. She's coming back into her office and I think we've already put her in the situation. Say that she. Her blood pressure remains elevated. Let's give her like 146 over 92. Despite the fact that she's on three appropriately dosed anti hypertensive agents, she's on the first line medications from three different classes. We feel that the blood pressure measured has been done exactly according to Hoyle. We feel fairly confident that she's adherent with her medications. Jordi, I'd love to know, sort of, I think we've heard you talk about this before, but it's always so compelling. Just sort of if you could recap what your sort of next step in working up would be and sort of how that would guide your management from there.

[C]

Yeah, definitely. And so in every single patient like this with resistant hypertension, we talked about how the next drug would be a mineralocorticoid receptor antagonist. But before I get there, I always like to just check arena and aldosterone, because so many of these patients end up having primary aldosteronism. The data's showing somewhere at least around 20% of people with resistant hypertension have primary aldosteronism, probably even before they reach resistant hypertension. And there's just so much potential benefit from treating it that there's just no question that we need to check arena and aldosterone. I strongly urge people to try to get a renin activity if you can. The reason being that it's easier to interpret the results than direct renin. Direct renins vary from lab to lab. And so it's just very hard to know what's normal. Even if it's like the normal for that lab, you still need sort of some guidance on exactly how to look at your ratios and everything. And so renin activity is pretty standardized across the board, as long as it's drawn correctly and like put in the fridge in time. And so I typically tell people, try to get it done at least about an hour after getting up because like sleeping and being in bed doesn't your, your renin is less likely to be stimulated. So you have to like be moving a little bit to stimulate your renin. This is why I don't love testing it in the hospital. And somebody who's like supine lying in bed for a long time, it does not need to be fasting. Nothing else fancy. Just try to get it about like now, a couple of hours after getting up. Then it should be the renin activity and the aldosterone level. You should be looking for a suppressed renin. Definitely less than 1. Ideally even less than 0.5 is like a truly suppressed renin. Aldosterone level should be elevated. Most labs it should be over 15. And you also need that elevated aldosterone to renin ratio of at least 20 to 1. And so all three of those need to be true. I think I'm seeing a lot of struggling with the interpretation of renin and Aldo where people just cherry pick like one or two of those and don't look at all three. But you really need all three of those to be true. According to the endocrine guidelines, according to the AHA guidelines that it's a pretty broad consensus that that's the definition. There are some borderline situations. For instance, if you see suppressed renin but normal or low aldosterone, that's an indicator that people still have some aldosterone excess. It could be either because they're just taking in a huge amount of salt, or it could be because they're truly salt sensitive or have a littles like state, if you remember, like the studying that for the boards. But it's basically like an abnormal handling of potassium in your tubules of the ENAC channel. I won't bore people, but essentially all of these patients respond really, really, really well to some drug that will cause them to hold on to more potassium and urinate out more sodium, like either a mineralocorticoid receptor antagonist like spironolactone or plarinone or amiloride. The spironolactone and flarenone are great to go for if you can because they help if it's primary aldosteronism in particular the most, and that that's really where they're most beneficial. You also can then work these patients up and identify whether or not they may be surgical candidates and may benefit from removal of a single aldosterone secreting either tumor or hyper secreting gland, adrenal gland, and then in that case it's typically Curative. If they've had severe hypertension for like decades and, and just really have always been uncontrolled, it may not cure them. They may still need drugs. So we get back to that renal denervation issue of am I going to go through surgery if I'm not going to benefit? But there is increasing evidence now since the last time I spoke to you guys, that there does seem to be an association of surgery with mortality benefit. We're never going to have a randomized trial, randomizing people to go for surgery versus going for mineralocorticoid receptors. But in pretty well done observational studies that are meta analyzed, you see that there's, there's like cutting in half of death in people who undergo surgery. And so we think that it's because you're just completely getting rid of that excess aldosterone. And we think that it's because you're no longer sort of hoping that the patient will consistently take their medication and not miss it because there is a potential for adherence issues with the medication. And it may just be that blocking the mineralocorticoid receptor isn't enough and that you just need to get rid of aldosterone. The cool thing with it is the medication we talked about earlier, the aldosterone synthase inhibitors, is that those are going to completely knock out aldosterone and they may end up making the need for the surgery completely go away. And so that's something we're hoping for. There are some studies looking at this in primary aldosteronism. So I think that that would be incredibly cool if we could use these drugs for that purpose. And I also think that we're going to start with more empiric management of that aldosterone excess earlier in hypertension. If this drug ends up showing that it's beneficial just in uncontrolled hypertension, even as a second or third drug, and that we may end up bypassing the stage and using it empirically moving forward. And that also would be pretty cool because we may get to not have to test for primary aldosteronism anymore in the future.

[A]

Yeah. And if that's the big bad actor, you would really hope that you'd see a lot better. Just like hard endpoints like improved too mortality, cardiovascular disease, renal disease, all that stuff as well. So hopefully.

[B]

And Jordi, just to keep it with the fundamentals, I know there's sometimes the other hesitation for actually checking these labs is a lot of hand wringing about what antihypertensives to hold and how they're Gonna actually affect interpretation, that kind of stuff. Can you speak to sort of what the current thoughts in terms of like, should we be holding aces or arbs or changing around other medications before actually checking these if we suspect hyper auto is a potential cause?

[C]

Oh, yes, great question. So there's growing data now supporting that we don't need to hold any medication unless they're already on a mineralocorticoid receptor antagonist. And even if there are some people that can use their magic vision to interpret the results, I'm not one of them. But I think that there's a lot to be said for. There was a lot of fear and a lot of barriers to testing in the past and those have been overcome now with data. And so we've found that in general, beta blockers tend to suppress renin, then first line antihypertensives tend to raise renin a tiny bit and raise aldosterone a tiny bit. But if you have true primary aldosteronism, those drugs aren't able to overcome that. They're not able to unsuppress your renin or to unsuppress your renin. And so if you still have a suppressed renin despite being on those, it's pretty compelling. If you have a really borderline finding, then I guess then you could consider holding agents. And we do sometimes in patients where we're really struggling and we think they may have it, but alternatively instead what you can do is salt, load them, tell them, have an extra bowl of chicken soup for a couple of days, do a 24 hour urine aldosterone. And that's sort of a poor man's version of a confirmatory test. And so I do that a lot instead of holding agents. And then the other thing related to all of that is you need to make sure their potassium is normal when you're doing all of this. So get a BMP when you're checking the renin and Aldo, because if the potassium is low, that suppresses aldosterone. And so if somebody who has hypokalemia and hypertension who are more of the people we think of for primary aldosteronism, if their k is like 3.6, 3.5 and you check an Aldo, it may be fall asleep low. And so you may miss a primary aldosteronism case and so replete their K, recheck it.

[A]

So you want potassium 4 or higher, something like that when you're checking their reninaldo.

[C]

At least high threes.

[A]

Yeah, yeah, okay. That's new. I haven't, I hadn't heard that before. Okay, that's a good tip because I definitely have had a fair number of patients when I've tested, tested with suppressed renin and the Aldo is sort of borderline. It's like 10 or 12. You know, it's not a slam dunk diagnosis. And I don't know that I've paid attention to the potassium at all in that case. And I've also read in, I think it was in hypertension a couple years ago, that the aldosterone testing can be a little bit like, from time to time it will be different. So you might want to check it more than once or you might want to go, like you said, go to the 24 hour urine. Urine aldosterone?

[C]

Yeah. If it's borderline, I always recheck it. Or I do. If I really have a high level of suspicion and I get a borderline one a couple times, I'll do a 24 hour urine aldosterone.

[A]

Yeah, with the salt load. The urine. When you do the urine aldosterone, do you always do the salt load prior?

[C]

I typically do a salt load if the person has really severely uncontrolled hypertension. I don't, because I don't want to cause a stroke. And so this is what we've seen a few cases where they do those formal salt loading tests to confirm primary aldosteronism. And our groups, really, and the main groups that are writing like the guidelines on this too, are starting to push away from doing that confirmatory testing because almost all of it requires salt loading. And when you're dealing with people with uncontrolled hypertension and then you add to their salt load and raise their blood pressure further, there is definitely non zero risk there. And we've anecdotally seen bad outcomes from that and just are not doing that anymore.

[A]

Paul, you made the joke, remember? I can't remember Bill's last name off the top of my head at this time of night, but we were talking about adrenal incidentalomas. He was talking to us about the salt load and he made the point like, yeah, just tell people to eat french fries and pizza and stuff. And Paul's like, oh, so I'll just go get tested on Monday morning after a weekend. And you know, there you go. I've had my salt load over the weekend.

[C]

That's the other thing. The average American is salt loaded. So that's the problem is like if you're adding to their already sufficient salt loading, then you're in trouble because the average person in takes in three and a half grams of sodium a day.

[B]

So super. Yeah. Diet put on blast and cold, average within the span of two minutes in the same podcast. Great episode.

[A]

But you're America's primary care physician. I mean, you're not average in that regard, Paul. Sure, that's what counts. Paul, I think we probably need to start wrapping up here. So I know you always like to ask about referrals, so if you wanted to ask about that. But we're probably moving towards take home points at this, at this time.

[B]

Yeah, I guess I just, just to. I think we've, we've talked about this before, Jordi, but just to sort of recap for our listeners, like, who, who do you want to see? Like, I feel we now armed our primary care providers with a lot of great information. But at what point should we start thinking about actually sending a patient to a hypertension specialist?

[C]

I think if you're struggling with this patient has chronic kidney disease and I'm not sure if it's safe to give them a mineralocorticoid receptor antagonist. That's a great person to refer to nephrology, obviously, to help. I think that the patients that are really refractory on like five or more agents and you're struggling, always happy to help. I see a lot of just helping with the workup for resistant hypertension in my clinic too, because I, I love that and I'm always happy to do that. But I think that if you're, if you are in an area that has limited access to people to refer to and you're sort of being selective about who you refer, it's going to be the refractory hypertension period patients and help them out by doing some of the secondary workup before you send them. Like, please send arena. Aldo, please check for obstructive sleep apnea. If they're an obese person or have symptoms, please make sure that you've sort of thought about like, some of the more obvious ones. It's really unfortunate. I saw a statistic recently in the literature that more people have metanephrines checked than have Rena and Aldose checked.

[B]

Holy smokes.

[C]

We don't need a metanephrine check in these patients. I will say that the funnier thing is when I see a lot of the cardiologists check catecholamines, which are not indicated to be as a screening test for pheochromocytoma. That happens a lot too, which I find pretty great. And the patient still has not had ARENA and Aldosterone checked well, not our.

[A]

Listeners, because you've taught them the right way, so they know not to do that. Let's get some take home points and then we'll do our picks for the Neph Madness regions. I think it's going to be a quick one, but let's get some take home points. So in talking about resistant hypertension, the new advanced therapies, we talked about anything that you want the audience to really remember from this episode?

[C]

Yeah, I think keep an eye out for the Aldosterone synthase inhibitors. They're obviously not approved yet, but I think they're going to be really promising and we may be thinking about considering using them before the fourth agent, which would be pretty exciting because it'd be the first time that it had happened since the 90s. I think a Percytentin is going to just be something used by nephrologists for a while, so that's probably not as big of a thing. But with the GLP1 agonists, I'm really excited about the possibilities there. And I think that there are some potential big impacts that we can make with those agents and patients. And those patients that you already are prescribing them for. Think about deprescribing their antihypertensives. Think about asking your patient to monitor their blood pressure at home and whether they still need all the drugs that they're on. They may be self deprescribing, and so it's worth a conversation.

[A]

Wonderful. All right, so we have our two Neff Madness regions, and the first region is the novel therapeutic agents. So that's the medications we talked about. And the other region they're going against is this renal denervation. So. So, Jordi, which do you think is going to win in Neff Madness this year, out of the two?

[C]

Yeah. Obviously you heard a lot of my biases that I am not such a big fan of renal denervation. It has a time and a place. There are lots of people who are big fans of it and I can appreciate them, but I think that's definitely got nothing compared to a drug that can lower your blood pressure for six months straight.

[A]

Paul, what about you?

[B]

No, I'm going to do the George Costanza move of doing the opposite of my gut, since I'm wrong all the time, and I might even be wrong in this. I don't think renal denervation doesn't make any sense to me. So that's the one I'm going to go with because I feel like it's because like you said, there is enthusiasm for it. It's kind of a new toy, procedures people like for whatever reason. So. And also, I just don't like it for now. So I think that's the one I'm going to pick because why not try my luck in that direction?

[C]

Man, forever is better than six. Six months.

[B]

Yes. No, I mean, there's arguments to be made for it.

[A]

Yeah, yeah, yeah. The Costanza, the I'm unemployed and I live with my parents. Yeah, that's a good line. I'm still gonna go with the novel therapeutics, I think. You know, these aldosterone synthase inhibitors sound super cool. I like the idea of prescribing a medication or an injection that and I tell the patient they might need an if anything goes south, we might need to give them an antidote for it. You know, I really like that. So I think the novel therapeutics are definitely going to win. All right, well, Jordi, as always, thank you so much for coming on the show and hanging out. You're welcome back anytime. I know Paul feels the same way. And we will let you get back to we didn't hear any scratching at the door, but I'm sure your family wants you back right now. So thank you again.

[B]

This has been another episode of the Curbsiders bringing you a little knowledge food for your brain hole.

[A]

Yummy.

[B]

Still hungry for more. Join our Patreon. Get all of our episodes ad free, plus twice monthly bonus episodes at patreon.com curbsiders you can find our [e-mail] and while you're there, sign up for our mailing list to get our weekly show notes in your inbox. This includes our Curbsiders Digest, which recaps the latest practice changing articles, guidelines and news in internal medicine.

[A]

And we're committed to high value practice changing knowledge. And to do that, we need your feedback. So please email [e-mail] reminder that this and most episodes are available for CME for all health professionals through VCU. Healtherbsiders.vcuhealth.org a special thanks to our writer and producers for this episode, Dr. Deb Gorth, with some help from Ben Fuhrman and to our whole Curbsiders team. Our technical production is done by the team at Podpaste. Elizabeth Proto does our social media. Jen Watto runs our Patreon. Chris Tachumanchu moderates our discord. Stuart Brigham composed our theme music. And with all that, until next time, I've been Dr. Matthew Frank Watto, and.

[B]

As always, our main doctor, Paul Nelson Williams. Thank you and goodbye.

[A]

Sam.