Breakthrough Findings from the MOMENTUM Study

The MOMENTUM study has emerged as a pivotal piece of research in understanding why some patients' high blood pressure remains stubbornly high despite multiple medications. Conducted across 50 sites in the United States, this prospective, cross-sectional observational trial enrolled 1,086 adults with resistant hypertension, defined as systolic blood pressure of 130 mm Hg or higher despite treatment with three or more antihypertensive drugs at optimal doses, including a diuretic. Researchers used a simple 1-mg overnight dexamethasone suppression test (DST)—where patients take the medication at bedtime and have cortisol measured the next morning—to identify endogenous hypercortisolism, indicated by cortisol levels exceeding 1.8 μg/dL after confirming adequate dexamethasone absorption (≥140 ng/dL).

The results were striking: 27% of participants (297 individuals) showed elevated cortisol levels. This prevalence jumped to 32.6% among those with poor glycemic control (HbA1c ≥7.5%) on three or more blood pressure medications. Notably, about 20% had primary hyperaldosteronism, and 6% exhibited both conditions, highlighting overlapping endocrine drivers of hard-to-control blood pressure.

Understanding Resistant Hypertension in the US Context

Resistant hypertension, or apparent treatment-resistant hypertension (aTRH), affects roughly 10 to 18% of the 120 million US adults with high blood pressure, translating to nearly 10 million individuals at heightened risk for heart attacks, strokes, heart failure, and kidney disease. Recent NHANES data from 2021-2023 indicate that prevalence among treated hypertensives has declined slightly from 17.7% to 12.6%, yet overall hypertension rates continue to rise, reaching 54% of adults. Traditional management focuses on medication adherence, lifestyle changes, and secondary causes like obstructive sleep apnea or renal artery stenosis, but endocrine factors like hypercortisolism have been underappreciated.

Step-by-step, diagnosing rHTN involves confirming adherence (e.g., via pill counts or urine assays), excluding white-coat effects with ambulatory monitoring, and optimizing regimens. Yet, up to 50% of cases may stem from pseudoresistance or secondary causes, making studies like MOMENTUM crucial for identifying treatable culprits.

The Role of Cortisol: From Stress Hormone to Blood Pressure Culprit

Cortisol, produced by the adrenal glands under regulation from the hypothalamic-pituitary-adrenal (HPA) axis, is essential for stress response, metabolism, and immune function. Endogenous hypercortisolism—excess cortisol not due to exogenous steroids—ranges from overt Cushing's syndrome (rare, ~10-15 cases per million annually) to milder autonomous cortisol secretion (MACS), affecting up to 36% in some high-risk groups.

In hypertension, cortisol promotes sodium retention via mineralocorticoid receptor activation (despite 11β-hydroxysteroid dehydrogenase type 2 protection in kidneys), vascular stiffness, insulin resistance, and sympathetic overactivity. A 2012 Brazilian study reported 27% prevalence in rHTN, but MOMENTUM is the first large-scale US confirmation. Patients with reduced kidney function (common in rHTN) were more prone, as impaired clearance exacerbates cortisol buildup.

Collaborative Effort by Leading US Academic Medical Centers

MOMENTUM exemplifies the strength of US higher education in clinical research. Led by Dr. Deepak L. Bhatt, Valentin Fuster Professor at Icahn School of Medicine at Mount Sinai, the trial drew expertise from institutions like University of California San Diego School of Medicine (Pam R. Taub), University of North Carolina at Chapel Hill (John B. Buse), University of Texas Health Science Center (Ralph DeFronzo), University of Miami Miller School of Medicine, and Medical University of South Carolina. These academic hubs, spanning cardiology, endocrinology, and nephrology, underscore universities' role in tackling public health challenges.

Funded by Corcept Therapeutics but designed independently, the study reflects academic rigor. Mount Sinai's Fuster Heart Hospital, a key site, highlights how university-affiliated hospitals drive translational research from bench to bedside.

Photo by Vignesh Jayaprakash on Unsplash

Clinical Characteristics and Risk Factors Uncovered

Participants averaged older age, higher BMI, and comorbidities like diabetes (prevalent in 40-50%) and chronic kidney disease. Poor renal function correlated strongly with hypercortisolism, as kidneys metabolize ~90% of cortisol. Overlaps with hyperaldosteronism (elevated aldosterone) suggest combined mineralocorticoid excess in 6%, complicating diagnosis.

• Higher HbA1c and polypharmacy increased odds.
• 20% primary aldosteronism prevalence aligns with prior estimates.
• No significant sex or race disparities noted preliminarily, though further analysis pending.

This profile aids clinicians in risk-stratifying rHTN patients for screening.

Implications for Diagnosis and Screening Protocols

The DST's simplicity—low cost, high sensitivity—makes it ideal for primary care or cardiology clinics. Current AHA guidelines recommend secondary cause evaluation in rHTN but don't specify cortisol screening routinely; MOMENTUM advocates for high-risk subsets (e.g., diabetes, CKD). For confirmed cases, adrenal imaging or ACTH stimulation may delineate causes like adrenal adenomas (common in MACS).

The study's protocol paper in JACC Advances details DST validation. Early detection could shift paradigms, as untreated hypercortisolism doubles cardiovascular risk.

Treatment Horizons: Cortisol Modulators on the Rise

Corcept's relacorilant, a selective glucocorticoid receptor antagonist, spares mineralocorticoid effects unlike mifepristone. Phase 3 ROSELLA trial showed hypertension control in Cushing's; ROADS extension confirmed durability. Despite FDA complete response letter for hypercortisolism hypertension (citing manufacturing), resubmission looms. Academic trials will test efficacy in MOMENTUM-identified MACS patients.

Surgical options for adenomas or lifestyle (stress reduction, sleep) complement pharmacotherapy. University researchers like those at UNC and UTHealth pioneer mineralocorticoid antagonists too.

Broader Impacts on US Public Health and Research Landscape

With hypertension costing $131 billion yearly, targeting cortisol could save lives. MOMENTUM spotlights academic medicine's value: Icahn Mount Sinai's leadership fosters multi-site collaborations, training fellows in endocrinology-cardiology interfaces.

Stakeholders—patients frustrated by uncontrolled BP, physicians facing trial-and-error—gain actionable insights. Future NIH-funded extensions may explore genomics or wearables for cortisol monitoring.

View full trial details on ClinicalTrials.gov.

Photo by Mostafa (Mfnctn) on Unsplash

Expert Perspectives from US Medical Schools

"This challenges textbook teachings; screen more aggressively," says Dr. Bhatt (Mount Sinai). Dr. Buse (UNC) notes diabetes overlap demands integrated care. Nephrologists at UCSD emphasize renal-cortisol links.

Balanced views: Not all hypercortisolism needs intervention; mild cases may respond to lifestyle. Yet, ignoring it risks progression to overt Cushing's.

Future Outlook: Trials, Guidelines, and Academic Innovations

Ongoing Corcept trials and university-led RCTs will validate cortisol-lowering in rHTN sans Cushing's. Expect guideline updates from AHA/Endocrine Society. US colleges like Miami Miller advance precision medicine via AI-phenotyping.

• Randomized cortisol modulator trials.
• Genomic profiling for susceptibility.
• Telemedicine DST integration.
• Training modules for residents.

Optimism prevails: MOMENTUM paves personalized hypertension care.

Read the full ScienceDaily coverage. EurekAlert press release.