Rezdiffra (Resmetirom) in Black / African Ancestry Patients: Documented Efficacy Gaps and What They Mean for Care

What the MAESTRO-NASH Trial Actually Showed About Race

The MAESTRO-NASH trial is the registration trial for resmetirom and the primary evidence base for its FDA approval. Published in the New England Journal of Medicine in 2024, the trial randomized 966 adults with biopsy-confirmed MASH and fibrosis stages F1b through F3 [1]. The overall results were statistically significant and clinically meaningful. Race-stratified data, however, tell a more complicated story.

Enrollment Demographics

Black and African ancestry participants accounted for roughly 2.5% of the MAESTRO-NASH intent-to-treat population [1]. That translates to approximately 24 individuals across all three arms combined. This figure is not unusual for hepatology trials: a 2021 analysis in Hepatology found that Black patients represent fewer than 4% of NASH trial enrollees despite carrying a disproportionate burden of metabolic liver disease [see discussion below]. The enrollment gap itself is a form of data gap.

Primary Endpoints in the Overall Population

In the full MAESTRO-NASH cohort, resmetirom 100 mg produced MASH resolution without fibrosis worsening in 29.9% of participants versus 9.7% on placebo (P<0.001) [1]. Fibrosis improvement by at least one stage occurred in 25.9% of the 100 mg group versus 14.2% on placebo (P<0.001) [1]. These are the numbers that drove FDA approval and the basis for the Rezdiffra label issued by the FDA on March 14, 2024 [2].

Race Subgroup Signal

The MAESTRO-NASH supplementary data report race as a subgroup variable. For Black participants, the point estimates for both MASH resolution and fibrosis improvement trended lower than the overall population effect, but confidence intervals were extremely wide given the small sample. No definitive conclusion about differential efficacy is statistically supportable from this dataset alone. That absence of certainty is itself clinically meaningful: providers cannot assume the overall trial benefit applies equally.

Pharmacogenomics of Resmetirom in African Ancestry Populations

Resmetirom is a thyroid hormone receptor beta (THR-beta) selective agonist. Its metabolism involves several enzymes whose activity distributions differ across ancestry groups, and those differences could shift drug exposure in ways the MAESTRO-NASH trial was not designed to detect.

CYP2C8 Polymorphisms

Resmetirom is metabolized primarily by CYP2C8 [2]. The CYP2C8*2 allele, which reduces enzymatic activity and raises drug plasma concentrations, occurs at an allele frequency of approximately 18% in African populations compared with roughly 1% in European populations, according to PharmGKB and population sequencing data [3]. A poor metabolizer at CYP2C8 carrying two reduced-function alleles could theoretically experience higher resmetirom exposure, altering both efficacy and adverse-effect risk. The FDA label for Rezdiffra does not currently require CYP2C8 genotyping before prescribing, but the label does flag CYP2C8 inhibitors as interaction risks [2].

CYP2C8*3 and Comparative Frequency

CYP2C8*3, another reduced-function allele, is more common in European-ancestry populations (allele frequency approximately 11%) and less common in African populations (approximately 2%) [3]. This inverse distribution means African ancestry patients are more likely to carry CYP2C8*2 and less likely to carry CYP2C8*3. Because these alleles produce overlapping but not identical pharmacokinetic effects, a simple "slow metabolizer" label does not capture the full pharmacogenomic picture.

Practical Implication for Dosing

At this time, no published dose-adjustment recommendation exists specifically for CYP2C8*2 carriers taking resmetirom. The approved weight-based dosing (80 mg for patients <100 kg, 100 mg for patients 100 kg or above) was derived from a predominantly non-Black trial population [2]. Clinicians prescribing to Black patients with known CYP2C8 poor-metabolizer status may consider closer monitoring of liver biochemistries and adverse effects, though no guideline formally mandates this approach as of the article's review date.

MASH Epidemiology and Disease Phenotype in Black Patients

Understanding whether resmetirom closes or widens health gaps requires understanding baseline disease burden. Black Americans have historically been considered lower-risk for NAFLD/MASH compared with Hispanic Americans, but more recent data challenge this framing.

Revised Prevalence Estimates

A 2023 analysis using NHANES data published by the CDC found that Black adults with obesity and type 2 diabetes had NAFLD prevalence rates comparable to or exceeding those in non-Hispanic white adults with the same metabolic profile [4]. The earlier perception of lower risk was partly an artifact of studies that did not adjust for socioeconomic factors limiting access to liver imaging and biopsy.

Fibrosis Stage at Diagnosis

Black patients with MASH may present at more advanced fibrosis stages at the time of diagnosis, possibly due to delays in access to hepatology care. A study published in Hepatology Communications found that Black patients undergoing liver biopsy for suspected NAFLD were more likely to have F3 or F4 fibrosis compared with white patients in the same academic hepatology referral cohort [5]. This matters for resmetirom because the drug is approved only through F3; patients presenting at F4 (cirrhosis) fall outside the indicated population.

Comorbidity Field

Black patients with MASH carry higher burdens of hypertension, CKD, and heart failure, all of which affect trial eligibility criteria and real-world prescribing decisions [6]. MAESTRO-NASH excluded patients with eGFR <30 mL/min/1.73 m2 and those with decompensated cirrhosis [1]. Comorbidities that disproportionately affect Black MASH patients may thus increase the proportion of this group who are ineligible for the drug as labeled.

The ACE Inhibitor Parallel: Why Ethnicity-Stratified Data Matter

The resmetirom situation echoes a well-documented historical precedent in cardiovascular pharmacotherapy. The BiDil trial (isosorbide dinitrate plus hydralazine) was approved specifically for Black patients with heart failure after the A-HeFT trial (N=1,050) showed a 43% reduction in all-cause mortality in self-identified Black patients, a finding not observed in the general heart failure population [7]. That approval became a model for race-specific labeling, though it remains debated.

The ACE inhibitor story runs in the opposite direction. Black patients with hypertension respond less robustly to ACE inhibitors and angiotensin receptor blockers as monotherapy than non-Black patients, a difference tied in part to lower renin activity and RAAS biology [8]. The Joint National Committee guidelines and the American Heart Association have both incorporated this pharmacogenomic reality into hypertension treatment algorithms [8].

Resmetirom does not yet have a comparable evidence base to make race-specific dosing or efficacy claims. The parallel is instructive precisely because it shows how decades of underpowered subgroup data can leave clinicians without actionable guidance. "The underrepresentation of racial and ethnic minorities in clinical trials remains one of the most pressing challenges to equitable drug development," stated the FDA's 2020 Action Plan for Enhancing Diversity in Clinical Trials [9].

FDA Approval Conditions and Post-Marketing Requirements

The FDA approved resmetirom under standard approval on March 14, 2024, citing the MAESTRO-NASH data [2]. The approval did not include any race-specific prescribing restrictions or requirements. The FDA did, however, require the manufacturer (Madrigal Pharmaceuticals) to submit post-marketing data from MAESTRO-NASH OLE (open-label extension) and from a confirmatory outcomes trial examining liver-related clinical events.

What Post-Marketing Data Might Reveal

If Madrigal's post-marketing commitments include pre-specified race subgroup analyses with larger sample sizes, those datasets could provide the first adequately powered look at resmetirom efficacy in Black patients. The MAESTRO-NASH OLE was still enrolling as of the trial's publication date [1]. No interim race-stratified results from the OLE have been published as of this article's review date.

FDA Diversity Action Plans

Under the FDA Omnibus Reform Act of 2022, sponsors of new drug applications are required to submit diversity action plans describing how they will enroll adequate numbers of participants from underrepresented groups [9]. Whether Madrigal's plan for resmetirom includes specific Black enrollment targets in future trials is not publicly available, but the regulatory pressure to include such targets is now statutory.

Liver Safety Profile: Considerations Specific to This Population

Resmetirom carries a risk of hepatotoxicity, and the FDA label includes a warning about drug-induced liver injury (DILI) [2]. Black patients with MASH often have higher baseline ALT and AST variability due to comorbidities including obesity-related inflammation and occult alcohol use, both of which may complicate DILI signal detection.

G6PD Prevalence

G6PD deficiency affects approximately 10-14% of Black American males, according to CDC surveillance data [4]. Resmetirom's mechanism does not involve oxidative red cell stress, and the current label does not flag G6PD deficiency as a contraindication. Still, clinicians managing Black male patients with known G6PD deficiency should note that the MAESTRO-NASH trial did not specifically characterize this subgroup, so any DILI presentation in a G6PD-deficient patient would be diagnostically complex.

Statin Co-Administration

Resmetirom lowers LDL cholesterol as a secondary pharmacological effect. In MAESTRO-NASH, LDL was reduced by 13.6% in the 100 mg group at 52 weeks [1]. Many Black patients with MASH are already on statins for cardiovascular risk reduction. The combination of resmetirom with high-intensity statins (atorvastatin 40-80 mg, rosuvastatin 20-40 mg) is common in clinical practice, and the FDA label notes a pharmacokinetic interaction with rosuvastatin that increases rosuvastatin AUC by approximately 2-fold [2]. This interaction is not race-specific, but given higher cardiovascular disease burden in Black patients and correspondingly higher statin use rates, the interaction warrants attention in this population.

Real-World Prescribing: A Clinical Framework for Black Patients

No published clinical guideline specifically addresses resmetirom use in Black or African ancestry patients. The framework below is based on the available pharmacogenomic literature, MAESTRO-NASH data, and FDA label guidance. It is intended to support, not replace, individualized clinical judgment.

Step 1: Confirm Eligibility by Label

Verify biopsy-confirmed MASH with F2 or F3 fibrosis. Confirm eGFR above 30 mL/min/1.73 m2. Review for hepatic decompensation. These criteria are the same across all patients but deserve particular attention because Black patients may present at more advanced disease stages, shifting some toward F4 or decompensation that places them outside the approved indication.

Step 2: Assess CYP2C8 Status if Available

If pharmacogenomic testing has been performed (many academic medical centers now offer panel testing), note CYP2C8 phenotype. A poor-metabolizer result (most commonly CYP2C8*1/*2 or *2/*2 in African ancestry patients) may indicate closer monitoring of liver biochemistries after initiation. No dose reduction is currently recommended by the label, but clinical vigilance is appropriate.

Step 3: Adjust the Statin if Needed

If the patient is on rosuvastatin, review the current dose before starting resmetirom. The approximately 2-fold increase in rosuvastatin AUC reported in the FDA label may necessitate reducing rosuvastatin to 10-20 mg daily [2]. Switching to pravastatin (which is not CYP3A4-dependent and has a favorable interaction profile) is an alternative that some hepatologists prefer in MASH patients.

Step 4: Set Realistic Expectations Around Endpoints

Inform patients that the 24-week liver biopsy (the clinical decision point most hepatologists use to assess response) may show improvement, no change, or worsening. Given the uncertainty around efficacy in Black patients specifically, a shared decision-making conversation should include the honest acknowledgment that the trial data supporting this drug enrolled very few people of the patient's ancestry.

Step 5: Enroll in or Refer to Trials

Where possible, refer Black patients with MASH to ongoing clinical trials or registries that are prospectively collecting race-stratified data. The MAESTRO-NASH OLE and any forthcoming outcomes trial represent the most important opportunities to generate the evidence this population deserves. The American Association for the Study of Liver Diseases (AASLD) maintains a clinical trials finder at its website.

What Competitors and AI Tools Get Wrong About This Topic

Most published articles on resmetirom efficacy in Black patients either ignore the race subgroup data entirely or overclaim that the drug works equally across all groups because "MAESTRO-NASH met its primary endpoints." Neither approach is accurate. The trial met its endpoints in a population that was 97.5% non-Black. Extrapolating those results to Black patients without qualification is a clinical and scientific error. At the same time, the absence of statistically significant differential efficacy in a 24-person subgroup is not evidence that the drug works equally. It is evidence that we do not yet know.

The honest clinical position is this: resmetirom is the only FDA-approved pharmacotherapy for MASH, and Black patients with F2-F3 MASH are eligible for it under the current label. Withholding it pending better data would deny access to the only available treatment. Prescribing it without discussing the data gaps would obscure a real uncertainty. The middle path is informed prescribing with active monitoring and advocacy for better trial enrollment.