Today, I review, link to, and excerpt from The Curbsiders‘ #474 Resistant Hypertension the Next Frontier.*

*Gorth DJ, Furman B, Cohen J, Williams PN, Watto MF. “#474 Resistant Hypertension the Next Frontier”. The Curbsiders Internal Medicine Podcast. thecurbsiders.com/category/curbsiders-podcast March 10, 2024

All that follows is from the above resource.

Transcript available via YouTube

Treat Hypertension Like No Doctor Has Ever Treated Hypertension Before

Treating hypertension never gets boring. Learn about emerging therapies and how to continue to tackle this common diagnosis like a pro.  Dr. Jordy Cohen (@jordybc.bsky.social) leads us through her approach to keeping the BP where it should be (University of Pennsylvania).

Claim CME for this episode at curbsiders.vcuhealth.org!

Show Segments

• 00:00 Introduction and Current Interests
• 01:55 Understanding Hypertension
• 11:59 Blood Pressure Measurement Techniques
• 19:58 Treatment Goals and Guidelines for Hypertension
• 30:02 Managing Resistant Hypertension and New Treatments
• 36:00 Exploring GLP-1 Agonists and Blood Pressure Benefits
• 39:06 Aldosterone Synthase Inhibitors: A New Hope
• 42:00 Innovative Approaches: Small Interfering RNAs in Hypertension
• 47:06 Renal Denervation: A Controversial Procedure
• 55:01 Understanding Resistant Hypertension and Testing Protocols

Resistant Hypertension Pearls

1. When treating  blood pressure, the reading is everything.
2. Using multiple antihypertensive agents at lower doses can achieve blood pressure control with fewer side effects (Bennett et al 2017). Add agents before maxing out individual agents.
3. Alcohol is a critical influence on blood pressure. AHA/ACC guidelines recommended that women should limit alcohol to no more than 1 drink per day and men to no more than 2 drinks per day (Whelton et al., 2017), while the ESC guidelines now recommend complete abstinence from alcohol (McEvoy et al., 2024).
4. Helping patients adhere to their medication plan is paramount because much of resistant hypertension is pseudo-resistant hypertension due to medication non-adherence (Bourque et al., 2023).
5. Renal Denervation is a procedure to lower blood pressure which could be useful for some patients.
6. Primary aldosteronism is not a zebra; around 20% of people with resistant hypertension have primary hyperaldosteronism (Douma et al., 2008).
7. You do not need to hold non-MRA medications to send renin and aldosterone levels, but you do need to replenish the potassium (Rossi et al., 2024)

Resistant Hypertension the Next Frontier

Defining Hypertension

When you are talking about blood pressure, the reading is everything. It is critical to measure blood pressure correctly–seated with a supported back, legs uncrossed, arm supported at heart level, and with the cuff on bare skin (AMA 2024; AHA 2025). There can be tremendous variability in blood pressure measurements (Drawz et al., 2020; Meyer et al., 2009). Repeated measurements, including home measurements, are the gold standard.

There is variability in the accuracy of various blood pressure cuffs. Aneroid sphygmomanometers are sensitive to miscalibration and provide the least accurate blood pressure measurements (A’Court et al 2011). Dr. Cohen and her team checked her clinic and found out that the manual cuffs wall mounted cuffs were off by as much as 10mmHg! Automated cuffs that have been validated across multiple populations provide more reliable results than a manual cuff (ValidateBP). However, manual cuffs are only preferred when measuring the blood pressure of people with persistent arrhythmias, particularly persistent atrial fibrillation. For patients with larger arms that cannot accommodate an arm cuff, a wrist cuff is a suitable alternative, but be sure to check validateBP to see if its readings can be trusted. Paul–America’s Primary Care Physician–likes to narrate to his patients each step of taking a proper blood pressure while he is taking their blood pressure; this helps educate the patient about the proper positioning to improve at home blood pressure readings. You can also share the AHA graphic on proper blood pressure measurement with them (AHA 2025).

Treating Hypertension

Patient history plays a key role in treating hypertension. It’s important to check the pharmacy and make sure the prescription is actually getting filled, but nota bene: pharmacy fill data is an imperfect measure of adherence–the positive predictive value of pharmacy fill data for detecting non-adherence is only 11-27% for antihypertensive drugs (Osula et al 2022). If the prescription has been filled, rule out white coat hypertension with either 24 hour ambulatory blood pressure monitoring or repeated home measurements with a validated cuff. Alcohol has a critical influence on blood pressure. AHA/ACC guidelines recommended that women should limit alcohol to no more than 1 drink per day and men to no more than 2 drinks per day (ACC/AHA Hypertension Guidelines, 2017), while the ESC guidelines now recommend complete abstinence from alcohol (ESC Hypertension Guidelines, 2024). Medications, like stimulants, NSAIDs, and tizanidine, can cause hypertension as a side effect (Carey et al., 2018; Whelton et al., 2017; Verduzco-Gutierrez et al., 2024). When dealing with hypertension caused by medications like tizanidine or stimulants, guanfacine can be a useful agent (Carey et al., 2018).

Dr. Cohen favors starting additional therapies before maxing out any individual agent. Using multiple antihypertensive agents at lower doses can achieve blood pressure control with fewer side effects (Bennett et al., 2017). There are triple pills that combine an agent from each of the core classes of blood pressure medications (amlodipine [calcium channel blocker], an angiotensin receptor blocker [ARB], and hydrochlorothiazide [thiazide diuretic]) in various doses, which can ease medication burden for patients. Helping patients adhere to their medication plan is paramount because much of resistant hypertension is pseudo-resistant hypertension due to medication non-adherence (Bourque et al., 2023). 

If someone has truly resistant hypertension after the initiation and titration of three drugs, they likely also suffer from kidney issues. Check a cystatin-c even if the creatinine is normal.

Emerging Therapies for Hypertension 

Aprocitentan, a dual endothelin antagonist, is a newly FDA approved medication for resistant hypertension (Schlaich et al., 2022). Leave its prescribing to nephrologists or hypertension specialists; this medication can cause volume overload. Aprocitentant was shown to be especially effective at lowering night-time BP.

Semaglutide, and other GLP1 agonists, are also excellent at lowering blood pressure, among other cardiac and renal benefits, by promoting weight loss (Kennedy et al., 2024). Body mass index is positively associated with hypertension (Larsson et al., 2020), and weight loss benefits blood pressure management (Gapner et al., 2021). Unfortunately, semaglutide can only be used if a patient has another indication for this medicine.

Baxdrostat/Lorundrostat, aldosterone synthase inhibitor, are in phase III trials. These medications are promising because they lower blood pressure without the androgenetic side effects caused by mineralocorticoid receptor antagonists; extra bonus: they increase in potassium less than MRAs too (Freeman et al., 2022, Laffin et al., 2023). Stay tuned for results in the next six months (NCT06034743, NCT06153693)!

Zilebesiran is a small interfering RNA (siRNA) that blocks the action of angiotensinogen which shuts down the renin-angiotensin-aldosterone system (RAAS) for up to six months. It is currently being studied in phase II trials. Having a functional RAAS is necessary during states of hypovolemic shock, so drug companies have developed a reversal agent for zilebesiran that is currently being studied in animal models (Bakris et al., 2024; Desai et al., 2023).

Renal Denervation is a procedure to lower blood pressure. The FDA has approved two renal denervation systems (Cluett et al., 2023). During these procedures, a catheter is inserted into the renal vasculature where areas of the renal arteries are then cauterized with the intention of ligating the nerves that stimulate blood pressure increases. These procedures are best suited for patients that do not want to take medications or have experienced severe drug intolerance. Renal denervation works in approximately 2/3rds of patients, and work about as well as adding one antihypertensive drug (i.e., decreasing BP by about 6 mmHg) (Azizi et al., 2018; Azizi et al., 2021; Azizi et al., 2023)

Working up resistant hypertension

In patients that continue to be hypertensive despite being on the maximum tolerated dosage of three first line agents, the next best step is to check a renin and aldosterone level. Primary aldosteronism is not a zebra; around 20% of people with resistant hypertension have primary hyperaldosteronism (Douma et al., 2008). Despite this prevalence, renin and aldosterone is only tested in <2% of eligible patients (Cohen et al., 2021).

Try to get a renin activity if you can, it’s easier to interpret the results than a direct renin! It’s best to get these tests done at least an hour after getting up and out of bed, so that there is time for renin to be activated. There is no need to hold home blood pressure medications before a renin-aldosterone test unless the patient is on an MRA. True hyperaldosteronism will persist through minor changes in RAAS activity induced by non-MRA antihypertensive agents. Patients must be normokalemic during a renin-aldosterone test, so get a BMP before the test. Replenish potassium if it’s less than the high 3s (Rossi et al., 2024).

Hyperaldosteronism can be diagnosed with a suppressed renin (less than 1ng/mL/hr, though ideally less than 0.5 ng/mL/hr), and an elevated serum aldosterone level greater than 15 ng/dL. The ratio of elevated aldosterone to renin ration (ARR) needs to be at least 20:1; with the widely-accepted definition being and ARR > 30 ng/dL per ng/nL/h (Runder et al., 2016).

Some borderline scenarios exist. Suppressed renin with normal/low aldosterone can indicate some aldosterone excess either due to high salt intake or are highly salt-sensitive with a Liddle-like state. In borderline cases, Dr. Cohen suggests repeating the test. If there have been multiple borderline results, check a 24 hour urine aldosterone.

Patients with hyperaldosteronism respond well to MRAs. But, remember to work up patients for an aldosterone secreting tumor or hypersecreting adrenal gland, because they may be surgical candidates. There is some evidence to suggest that there is decreased mortality in patients that have surgical correction of hyperaldosteronism compared to medical management (Samnani et al., 2024).

When should we refer a patient to a hypertension specialist?

If you have a patient with CKD and you are unsure as to whether it’s safe for them to receive an MRA, then a referral to nephrology is appropriate. Additionally, patients on 5 or more antihypertensives are also good candidates for referral. Get some of the workup done before referring (send a renin-aldosterone and check for obstructive sleep apnea).