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

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.

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

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

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

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

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

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.

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)

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 |

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 |

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.

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