Saturday, April 19, 2025

Breakthrough Oral GLP-1 Drug Orforglipron Shows Strong Results

                                         

🌟 Orforglipron in Phase III ACHIEVE-1 Trial

In a major breakthrough for diabetes and obesity management, orforglipron, an oral GLP-1 receptor agonist, has demonstrated impressive results in the Phase III ACHIEVE-1 trial, outperforming placebo and showing safety comparable to injectable GLP-1 therapies.


                                                

🔬 A Game-Changer in Oral Diabetes Treatment

Orforglipron, taken as a once-daily pill, stands apart from other oral GLP-1 drugs like semaglutide (Rybelsus) by eliminating dietary and fluid restrictions. This could significantly improve patient adherence and treatment convenience.

The ACHIEVE-1 trial enrolled 559 patients with type 2 diabetes and obesity, randomizing them to three orforglipron doses—3 mg, 12 mg, and 36 mg—or placebo for 40 weeks.

📊 Efficacy: HbA1c and Weight Loss

All doses of orforglipron significantly reduced HbA1c levels from a baseline of 8.0%, with the highest dose achieving notable results:

  • HbA1c reduction:

    • 3 mg: 1.3%

    • 12 mg: 1.6%

    • 36 mg: 1.5%

    • Placebo: 0.1%

More than 65% of patients on the 36 mg dose reached an HbA1c ≤ 6.5%, below the American Diabetes Association’s target for diabetes diagnosis.

Weight loss also favored orforglipron:

  • Percent weight reduction:

    • 3 mg: 4.7%

    • 12 mg: 6.1%

    • 36 mg: 7.9%

    • Placebo: 1.6%

  • Weight loss in kilograms:

    • 3 mg: 4.4 kg

    • 12 mg: 5.5 kg

    • 36 mg: 7.3 kg

    • Placebo: 1.3 kg

Importantly, participants had not yet reached a weight plateau, suggesting further weight loss potential if treatment continued longer.

🛡️ Safety: GI Side Effects Predominate

Orforglipron was generally well tolerated, with the most common side effects being gastrointestinal (GI) in nature—mild to moderate in severity:

  • Diarrhea (up to 26% at highest dose)

  • Nausea (up to 18%)

  • Dyspepsia (up to 20%)

  • Constipation (up to 17%)

  • Vomiting (up to 14%)

Importantly, there were no signs of liver toxicity.

🔄 What’s Next?

The ACHIEVE-1 trial is part of a broader Phase III program of seven studies being conducted by Eli Lilly, aiming to evaluate orforglipron in various populations with diabetes and obesity. Detailed findings are expected to be presented at the upcoming American Diabetes Association meeting in June 2025.

Another key study, ATTAIN, is also underway, focusing solely on weight management outcomes with orforglipron.

✅ Take-Home Points

  • Orforglipron, a once-daily oral GLP-1 receptor agonist, significantly lowers HbA1c and promotes weight loss in patients with type 2 diabetes and obesity.

  • It does not require dietary or fluid intake restrictions, unlike some other oral GLP-1 drugs.

  • Over 65% of high-dose patients achieved an HbA1c ≤ 6.5%.

  • Weight loss continued at study end, indicating potential for even greater reductions.

  • GI side effects were the most common, but generally mild to moderate.

  • Full study results will be shared in June 2025, with more data to come from related trials like ATTAIN.

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Saturday, April 5, 2025

Passive Alerts, Powerful Impact: How DETECT-AS is Reshaping Aortic Valve Care

 A silent revolution is taking shape in cardiology, and it's not coming from a scalpel or a stethoscope—it’s arriving in your inbox.

The DETECT-AS trial is sounding a clarion call to action. This clever, personalized alert system—a seemingly modest notification integrated into the electronic medical record (EMR)—has done something remarkable: it increased the number of aortic valve replacements (AVR) in patients with severe aortic stenosis (AS). And not just in the obvious candidates, but even among groups historically left behind—elderly patients and women.

But here’s the kicker: the alert was entirely passive. No sirens. No red flags. Just an email and EMR note with tailored guideline-based recommendations on what to do when severe AS is spotted on echocardiography.

The Study Pulse: What Was DETECT-AS?

Conducted across a large academic health system, DETECT-AS was a single-blinded, cluster randomized trial. It included nearly 1,000 patients with severe AS identified by transthoracic echocardiography (TTE)—specifically those with an aortic valve area ≤1.0 cm².

Two Paths, One Diagnosis:

  • Intervention Group: Clinicians got an automated notification via EMR and email.

  • Control Group: Usual care, no alerts.

These notifications weren’t generic. They were smartly customized, based on mean valve gradient and left ventricular ejection fraction (LVEF), giving clinicians specific, actionable next steps—from diagnostic testing to referrals and even AVR recommendations.

The Results: Numbers That Speak Louder Than Words

  • AVR at 1 year:
    48.2% in the alert group vs 37.2% with usual care (P = 0.009)

  • AVR in symptomatic patients at 1 year:
    >60% vs 47% (P = 0.001)

  • AVR within 90 days:
    25.8% vs 19.0% (P = 0.02)

  • AVR within 90 days in symptomatic patients:
    37.7% vs 26.6% (P = 0.04)

The gains were even more pronounced in patients >80 years and women—a demographic too often under-treated.

Also notable: primary-care physicians and non-cardiologists were far more likely to refer to cardiology when alerted (63.4% vs 39.5%, P = 0.004).



The Not-So-Golden Silence

Despite these improvements, a cloud looms. Even with the alert, only 60% of symptomatic patients received AVR at 1 year. That’s not even close to the benchmark set by AHA/ACC guidelines, which emphasize timely AVR within 90 days of diagnosis.

So, what’s holding us back?

The study authors suggest the next frontier is an “active alert”—one that doesn’t just inform, but requires action. A sort of clinical safety net to catch patients at risk of slipping through the cracks.

The Quiet Power of EMR-Based Innovation

No extra devices. No expensive new therapies. Just a low-cost, scalable, EMR-integrated tool that changed behavior. It didn’t overwhelm—it nudged. And the longer it ran, the more effective it became, debunking fears of alert fatigue.

Still, implementation in less integrated health systems may pose challenges. Also, awareness of the trial itself may have influenced physician behavior. And since the study included some asymptomatic or pseudosevere AS patients, the results may even underestimate the alert’s full impact.

💡 Take-Home Points

  • DETECT-AS used a passive EMR/email alert to increase AVR rates in patients with severe aortic stenosis.

  • The system boosted treatment especially among women and the elderly, reducing clinical disparities.

  • AVR rates improved significantly at 90 days and 1 year—but are still far from optimal.

  • The tool improved referrals and repeat diagnostic testing across all provider types.

  • There's a need for a next-gen "active" alert that gently forces clinician engagement to further enhance outcomes.

  • This study demonstrates the power of simple, smart technology in transforming cardiovascular care—silently, but significantly.

Cardiology may often be a story of loud murmurs and louder interventions, but DETECT-AS reminds us that sometimes, all it takes is a whisper in a provider's inbox to change a patient's future.

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FAIR-HF2: The Iron Trials Continue, But Do They Deliver?

 A fresh chapter in the quest for better heart failure care opens… and it’s complicated.

The stage was set once again in ACC Chicago 2025, where another major trial of intravenous (IV) iron therapy—FAIR-HF2—took the spotlight. This time, the question was familiar: Can replenishing iron stores in patients with heart failure with reduced ejection fraction (HFrEF) actually shift the tide on hard clinical outcomes like death and hospitalization?

The answer? A murmur of hope, but no triumphant roar.

A Trial with High Hopes, But Soft Endpoints

FAIR-HF2 enrolled over 1,100 patients across six European countries, testing ferric carboxymaltose, an IV iron formulation, against placebo. Patients were followed for nearly two years, with iron dosing front-loaded and then spaced out every four months.

Three primary endpoints were designed, shaped in part by data limitations during the pandemic:

  1. Cardiovascular (CV) death or first heart failure hospitalization

  2. Total heart failure hospitalizations

  3. CV death or first hospitalization in those with low transferrin saturation (<20%)

Each one teased promise, especially the first. The iron group saw fewer events (16.7% vs. 21.9%), but the statistical line in the sand—P < 0.02—wasn’t crossed. The trend was there. The math wasn’t impressed.




Symptom Relief: A Silver Lining

While iron didn’t stop the train of clinical events, it did make people feel better. Patients reported better global well-being, a key marker of quality of life (QoL). In heart failure, where every step can feel like a mountain, that matters.

There were small gains in walk distance and a nudge in patient-reported outcomes, though nothing statistically jaw-dropping. Still, these are the kinds of outcomes that clinicians and patients feel—even if they don’t headline.

The Dosing Dilemma

A central flaw may lie in dosing inconsistency. In year one, the iron group averaged over 2,000 mg. By year three, that dose had dropped by two-thirds. The initial momentum? Possibly lost. A deeper dive showed that within the first 12 months, results were far more encouraging—a 20% reduction in total heart failure hospitalizations. After that? The benefit blurred.

It begs the question: Is iron therapy a sprint or a marathon? If we don’t maintain the pace, do we lose the race?

A Pattern in the Chaos

FAIR-HF2 isn’t alone. Other trials—IRONMAN, AFFIRM-AHF, HEART-FID—have waltzed this dance before. Some showed promise early, only to fade under statistical scrutiny. Yet, pooled together in a meta-analysis of over 7,000 patients, IV iron did cut recurrent HF hospitalizations and CV death by 28% in the first year. Again, it seems: early and consistent treatment might be key.

Who Really Benefits?

Subgroup hints suggest men may respond better than women—a pattern seen but not fully understood. The trial also raised fresh questions about how we define iron deficiency. Traditionally, we’ve looked at serum ferritin and transferrin saturation. But emerging metrics like hepcidin and soluble transferrin receptor (sTfR) might sharpen our focus, helping us find the patients who stand to gain the most.

Interestingly, while nearly 70% of FAIR-HF2 patients had transferrin saturation <20%, this didn’t guarantee a stronger response. So while this threshold is a start, it may not be the golden ticket we hoped for.

What Now?

The FAIR-HF2 trial adds weight to the iron story—but it’s not the final word. Patients felt better, yes. But the holy grail—fewer deaths, fewer ER visits—remains elusive.

So where do we go from here?

  • Optimize dosing. Don’t let early momentum fade.

  • Refine selection. Use better biomarkers to target the right patients.

  • Redefine success. Sometimes, feeling better is the first step to living longer.

The iron saga isn’t over. It’s just... evolving.

In heart failure, nothing is simple. But every insight inches us forward. FAIR-HF2 didn’t deliver the knockout punch—but maybe, just maybe, it handed us a sharper blade for the next round.

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Friday, April 4, 2025

ALIGN-AR Trial: Dedicated TAVI Device for Aortic Regurgitation Shows Strong Early Results

 In a Late-Breaking Clinical Trial at ACC 2025, investigators presented updated data from the ALIGN-AR trial, revealing that the Trilogy valve system (by JenaValve)—a TAVI device designed specifically for aortic regurgitation (AR)—has demonstrated promising safety, efficacy, and hemodynamic performance in high-risk surgical patients.

The new results, drawn from the first 500 patients, showed lower-than-expected mortality, excellent procedural success, and marked functional improvement—strengthening the case for a dedicated transcatheter option in patients with native AR, who have traditionally had few choices.




Study Overview

  • Trial: ALIGN-AR

  • Device: Trilogy Valve System (self-expanding, designed for AR)

  • Participants: 500 high-surgical-risk patients

  • Mean age: 76.6 years

  • Female: 46.2%

  • Mean STS Score: 3.9

  • Baseline NYHA Class III or IV: 61.6%

  • Geography: Multicenter international trial

Inclusion Criteria

  • Severe native aortic regurgitation

  • High surgical risk or contraindicated for surgery

  • NYHA Class II–IV symptoms

  • Anatomy suitable for TAVI using Trilogy valve

Exclusion Criteria

  • Active endocarditis

  • Severe annular calcification

  • Bicuspid aortic valve

  • Life expectancy <12 months from non-cardiac causes

Key Outcomes

Efficacy Endpoint (All-cause mortality at 1 year):

  • Observed: 8.1%

  • Noninferiority threshold: 25%

  • P < 0.001

Primary Safety Endpoint (30-day composite):

  • Includes death, stroke, bleeding, vascular complications, AKI, valve dysfunction, new pacemaker

  • Observed rate: 26.2%

  • Noninferiority margin: 40.5%

  • P < 0.001

Disabling Stroke Rates:

  • 1 year: 3.1%

  • 2 years: 3.6%

Mortality:

  • 1 year: 8.1%

  • 2 years: 15.5%

  • Rise primarily due to noncardiac causes

Device Performance

  • Mean effective orifice area (EOA): 2.8 cm²

  • Mean gradient: 4.2 mm Hg

  • Trace or no paravalvular leak:

    • 1 year: 93.4%

    • 2 years: 95.7%

  • Procedural success: 95.2%

  • Average procedure time: 69 minutes

  • Pacemaker implantation:

    • 23–24% (higher than surgical AR treatment)

  • Complications:

    • Valve embolization: 1.6%

    • Aortic dissection: 0.6%

    • No intraprocedural deaths or annular rupture

Functional and Quality of Life Gains

  • Significant LV remodeling with reduction in LV volume and mass

  • KCCQ scores (quality of life) improved substantially

  • NYHA Class III/IV patients:

    • 1 year: 8%

    • 2 years: 10%

More details on KCCQ can be found through the ACC’s documentation.

What’s Next? The ARTIST Trial

With these strong results, the upcoming ARTIST trial will compare the Trilogy system directly to surgery in 1,110 lower-risk patients, with 10 years of follow-up. This marks a pivotal step in the evolution of TAVI beyond stenosis into the AR space.

Take-Home Points

  • The Trilogy valve, a dedicated TAVI device for AR, shows strong safety and performance in high-risk patients.

  • Mortality, stroke, and valve complications are much lower than what’s historically seen with off-label devices used for AR.

  • LV function, valve hemodynamics, and quality of life all improved post-TAVI.

  • The need for pacemakers remains a challenge (23–24%), potentially linked to anatomical features unique to AR.

  • The field is moving toward randomized trials in lower-risk populations—a possible paradigm shift in how AR is treated.

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Evolut Low Risk Trial: TAVI Matches Surgery at 5 Years for Low-Risk Patients With Aortic Stenosis

 At the ACC 2025 Scientific Session, 5-year results from the Evolut Low Risk trial confirmed what many clinicians hoped: transcatheter aortic valve implantation (TAVI) continues to perform on par with surgery in low-risk patients with severe aortic stenosis. The trial results, also published in the Journal of the American College of Cardiology (JACC), offer long-term reassurance for a younger, healthier patient group.



Study Overview

  • Trial: Evolut Low Risk

  • Design: International, multicenter, randomized controlled trial

  • Sites: 86 locations in Australia, Canada, France, Japan, Netherlands, New Zealand, and the US

  • Participants: 1,414 patients with severe aortic stenosis and low surgical risk

    • Mean age: 74 years

    • 35% women

    • STS score: ~2%

  • Intervention:

    • TAVI Group: CoreValve, Evolut R, or Evolut PRO (n = 730)

    • SAVR Group: Surgical aortic valve replacement with bioprosthetic valve (n = 684)

Inclusion Criteria

  • Diagnosed with severe aortic stenosis

  • Low predicted surgical mortality risk (<3%)

  • Eligible for both TAVI and SAVR based on heart team assessment

Exclusion Criteria

  • Bicuspid aortic valve

  • Inadequate femoral access

  • Active endocarditis or bleeding disorders

  • Previous valve surgery or TAVI

  • Life expectancy <1 year

Key 5-Year Outcomes

Primary Endpoint: All-cause mortality or disabling stroke

  • TAVI: 15.5%

  • SAVR: 16.4%

  • P = 0.47 → No significant difference

Cardiovascular mortality

  • TAVI: 7.2%

  • SAVR: 9.3%

  • P = 0.15

Disabling stroke

  • TAVI: 3.6%

  • SAVR: 4.0%

  • P = 0.57

KCCQ Health Status (quality of life)

Valve Function & Complications

  • Echocardiographic performance favored TAVI:

    • Lower mean aortic valve gradient

    • Larger effective orifice area

  • Paravalvular regurgitation (mild or greater):

    • TAVI: 17.0%

    • SAVR: 5.7%

    • P < 0.001

  • Pacemaker implantation by 5 years:

    • TAVI: 27%

    • SAVR: 11.3%

    • P < 0.001

  • Valve reintervention:

    • Similar in both groups (3.3% vs. 2.5%, P = 0.44)

  • Valve thrombosis (clinical or subclinical):

    • Rare and not different between groups

Durability & Surveillance

While TAVI performed impressively through 5 years, researchers emphasized the importance of ongoing follow-up through 10 years to confirm valve durability, especially in younger patients. Recommendations include:

  • Annual echocardiographic surveillance

  • Continued study of technique improvements (e.g., cusp overlap technique) to reduce pacemaker rates

Take-Home Points

  • TAVI is noninferior to SAVR at 5 years in low-risk patients with severe aortic stenosis

  • Mortality and disabling stroke rates are similar between groups

  • TAVI patients feel better sooner, with earlier improvements in quality of life

  • Pacemaker requirement remains higher after TAVI—but without impacting long-term survival

  • Paravalvular leak remains more frequent with TAVI, but procedural refinements continue to address this

  • TAVI continues to evolve into a safer, more predictable procedure with excellent midterm outcomes

For patients and clinicians wondering "Can TAVI hold up over time?"—this trial answers with a confident yes—at least for five years. The future looks increasingly favorable for less invasive solutions to aortic stenosis.

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FRESH-UP Trial: Fluid Restriction May Be Unnecessary in Stable Heart Failure Patients

 In a practice-changing revelation presented at ACC.25 in Chicago and published in Nature Medicine, the FRESH-UP trial has challenged a long-standing recommendation: limiting fluid intake in heart failure (HF) patients.

The trial found no benefit from fluid restriction in patients with mild to moderate heart failure symptoms, raising the question—is it time to retire the water bottle warnings?




Study Snapshot

  • Name: FRESH-UP

  • Design: Randomized, multicenter, controlled trial

  • Participants: 504 patients from 7 medical centers in the Netherlands

    • Mean age: 69.2 years

    • 67.3% male

    • 87.1% with NYHA Class II symptoms

    • 51% on loop diuretics

  • Groups:

    • Fluid restriction: Max 1,500 mL/day (n=250)

    • Liberal intake: Drink as desired (n=254)

Inclusion Criteria

  • Diagnosed with heart failure (mild to moderate symptoms)

  • NYHA Class II or III

  • Stable on standard HF therapy, including beta-blockers, ACE inhibitors/ARBs/ARNI, and/or loop diuretics

Exclusion Criteria

  • Advanced kidney disease or severe electrolyte imbalances

  • Recent HF hospitalization (within the past 30 days)

  • Life expectancy <6 months due to non-cardiac illness

  • Cognitive impairments affecting adherence

Key Measures

What Did the Trial Find?

At 3 months, the KCCQ-OSS scores showed no significant difference:

  • Liberal intake group: Score = 74.0

  • Fluid restriction group: Score = 72.2

And at 6 months, there were no differences in:

  • Mortality

  • HF hospitalizations

  • Use of IV diuretics

  • Acute kidney injury

However, thirst-related distress was significantly worse in the fluid restriction group.

Actual fluid consumption:

  • Liberal intake group: ~1,764 mL/day

  • Restricted group: ~1,480 mL/day

Clinical Meaning?

According to the researchers:

“We found no signal that fluid restriction offers benefit—or that liberal intake causes harm. Patients with stable HF can safely drink to thirst.”

This aligns with growing views that over-restricting fluids may add burden without benefit, especially in outpatient HF care.

Take-Home Points

  • Fluid restriction (1,500 mL/day) in stable heart failure patients did not improve quality of life or clinical outcomes.

  • Liberal fluid intake was not harmful—no increase in mortality, hospitalization, or kidney injury.

  • Patients allowed to drink freely had less thirst distress.

  • Study supports individualized, patient-centered hydration plans rather than blanket fluid restrictions.

  • These findings are ready for immediate implementation in stable outpatient HF care.

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HOST-BR Trial: Three-Month DAPT Shows Sweet Spot for Both High and Low Bleeding Risk Patients

 In a Late-Breaking Clinical Trial at ACC.25, the HOST-BR study delivered new clarity on the optimal duration of dual antiplatelet therapy (DAPT) following stent implantation. The key finding? Three months of DAPT appears to be the Goldilocks zone—long enough to prevent events but short enough to reduce bleeding, across both high and low bleeding risk patients.


Study Overview

  • Type: Multicenter, randomized, investigator-initiated trial

  • Population: 4,897 patients from South Korea

    • 1,598 patients with high bleeding risk (HBR)

    • 3,299 patients with low bleeding risk (LBR)

  • DAPT Regimens Compared:

    • HBR: 1 month vs. 3 months

    • LBR: 3 months vs. 12 months

Note: Use of P2Y12 inhibitors during or after DAPT was clinician’s choice.

Inclusion Criteria

  • Adults undergoing coronary stenting

  • Ability to tolerate DAPT for at least 1 month post-procedure

  • Classified as either high or low bleeding risk based on validated criteria

Exclusion Criteria

  • Planned surgery requiring interruption of antiplatelet therapy

  • Contraindication to aspirin or P2Y12 inhibitors

  • Active bleeding or bleeding diathesis

  • Life expectancy <1 year

  • History of nonadherence

Primary Endpoints

  1. Net Adverse Clinical Events (NACE):

    • Composite of all-cause death, myocardial infarction (MI), stent thrombosis, stroke, or major bleeding

  2. Major Adverse Cardiac or Cerebral Events (MACCE):

    • Composite of cardiovascular death, MI, stent thrombosis, or ischemic stroke

  3. Actionable Bleeding:

    • Clinically significant bleeding requiring medical intervention

Key Findings

High Bleeding Risk (HBR) Patients:

  • Three-month DAPT had fewer events than one-month:

    • NACE: 14.4% (3 mo) vs. 18.4% (1 mo)

    • MACCE: 6.4% (3 mo) vs. 10.3% (1 mo)

  • Bleeding rates were similar:

    • 17.9% (3 mo) vs. 15.6% (1 mo)

Low Bleeding Risk (LBR) Patients:

  • Similar efficacy between three-month and twelve-month DAPT:

    • NACE: 4% (3 mo) vs. 5.7% (12 mo)

    • MACCE: 2.5% (3 mo) vs. 2.8% (12 mo)

  • Significantly less bleeding in three-month group:

    • 9.2% vs. 13.7%

Study Limitations

  • Conducted exclusively in South Korea

  • Clopidogrel was used in ~80% of patients as the second antiplatelet agent, reflecting East Asian practice

  • Results may vary in populations using more potent agents like ticagrelor

Still, the findings provide valuable insight into tailoring DAPT duration globally.

Take-Home Points

  • Three months of DAPT is superior to one month in HBR patients—reduces cardiac events without increasing bleeding.

  • In LBR patients, three months is safer than 12 months—less bleeding with similar efficacy.

  • These results may support redefining standard DAPT duration for both high and low bleeding risk populations.

  • A pragmatic approach using shorter DAPT could improve patient safety, especially in older adults and those with multiple comorbidities.

  • Further studies needed for non-Asian populations and those using different P2Y12 inhibitors.

The HOST-BR trial reminds us that less can sometimes be more, and in the case of DAPT, three months might be just right.

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Lorundrostat Shows Promise in Lowering Blood Pressure in Patients With Uncontrolled Hypertension

In a Late-Breaking Clinical Trial presented at ACC.25 in Chicago, the investigational drug lorundrostat significantly lowered systolic blood pressure (SBP) in patients with uncontrolled hypertension. This Phase 2b, double-blind, randomized trial offers encouraging results for a population that often struggles with resistant blood pressure despite multiple medications.

What Is Lorundrostat?

Lorundrostat is a novel aldosterone synthase inhibitor, targeting a key pathway in blood pressure regulation. Unlike current antihypertensive agents, this drug works by inhibiting aldosterone production, offering a new mechanism for tackling tough-to-control blood pressure.



Trial Design

  • Study Type: Phase 2b, randomized, double-blind

  • Participants: 285 patients across 103 U.S. sites

  • Demographics:

    • Average age: 60 years

    • 40% women

    • 53% Black patients (a focus group often underrepresented in trials)

  • Duration: 12 weeks

  • Intervention Arms:

    • Placebo

    • Lorundrostat 50 mg once daily

    • Lorundrostat 50 mg with potential increase to 100 mg at 4 weeks if BP remained uncontrolled

Inclusion Criteria

Patients were included if they had:

  • Uncontrolled hypertension, defined as elevated BP despite treatment with two to five antihypertensive medications

  • Stable regimen of standard BP meds for at least three weeks prior to randomization

  • Willingness to undergo 24-hour ambulatory blood pressure monitoring (ABPM)

Exclusion Criteria

Patients were excluded for:

  • History of significant renal impairment (e.g., low glomerular filtration rate)

  • Hyperkalemia or potassium imbalance at baseline

  • Secondary causes of hypertension other than primary aldosteronism

  • Recent cardiovascular events (e.g., stroke, MI within last 6 months)

  • Current use of mineralocorticoid receptor antagonists (e.g., spironolactone)

  • Pregnancy or breastfeeding

Key Results

At 12 weeks, average reductions in ambulatory SBP were:

  • −15.4 mm Hg in 50 mg lorundrostat group

  • −13.9 mm Hg in 50–100 mg group

  • −7.4 mm Hg in the placebo group

At 4 weeks, 42% of patients in lorundrostat arms had BP under control vs 19% in placebo.

Secondary endpoints (office BP readings) followed similar trends.

Safety & Tolerability

  • Side effects were mild and manageable, including:

    • Mild hyperkalemia in some patients

    • Small declines in GFR (kidney filtration rate)

  • No serious safety signals

  • Described as well tolerated overall

Take-Home Points

  • Lorundrostat, a new aldosterone synthase inhibitor, showed significant SBP reductions in patients with uncontrolled hypertension.

  • Effect was seen as early as 4 weeks, with further reductions by 12 weeks.

  • Drug was well tolerated, with manageable effects on potassium and kidney function.

  • Racial subgroup analysis showed no differences in efficacy—encouraging for inclusivity.

  • More trials are needed, but this agent may become a game-changer in resistant hypertension management.

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