Rezdiffra (Resmetirom) in South Asian Patients: Documented Efficacy Gaps and Pharmacogenomic Considerations

Why South Asian Patients Need Separate Efficacy Data for Rezdiffra

South Asian individuals carry a metabolic risk profile that differs from European-descent populations in ways directly relevant to MASH pharmacotherapy. Type 2 diabetes develops roughly a decade earlier in South Asians, cardiovascular events occur at lower BMI thresholds, and hepatic steatosis prevalence runs higher at any given body weight [2]. These differences are not academic. They change who needs treatment, when treatment should start, and how a drug's trial data applies.

The Metabolic Divergence

The WHO Expert Consultation in 2004 recognized that standard BMI cutoffs misclassify metabolic risk in Asian populations, recommending a threshold of 23 kg/m² for overweight and 27.5 kg/m² for obesity [3]. South Asian individuals accumulate more visceral and hepatic fat at lower BMI values compared to White individuals. A UK Biobank analysis found that South Asians had approximately 2-fold higher odds of hepatic steatosis at matched BMI levels [4]. This means the pool of South Asian patients who might benefit from a MASH-specific therapy like resmetirom is proportionally larger, and potentially younger, than the population studied in the key trial.

Earlier Disease Onset, Later Drug Data

The MAESTRO-NASH trial enrolled participants with a mean age of approximately 56 years and a mean BMI near 34 kg/m² [1]. South Asian patients with MASH commonly present in their 40s with BMIs in the 26-30 range. The trial's inclusion criteria and demographics may systematically exclude the phenotype most common among South Asians. Whether resmetirom's histologic benefits (MASH resolution without worsening fibrosis in 25.9% on 80 mg vs. 9.7% on placebo at 52 weeks) translate proportionally to a population with different body composition, fat distribution, and metabolic timing remains an open question [1].

MAESTRO-NASH: What the Subgroup Data Show (and Don't Show)

The MAESTRO-NASH trial randomized 966 participants with biopsy-confirmed MASH and fibrosis stages F1B through F3 to resmetirom 80 mg, 100 mg, or placebo [1]. The primary composite endpoints at 52 weeks were MASH resolution without fibrosis worsening and fibrosis improvement by at least one stage without NASH worsening.

Trial Demographics and the Representation Gap

Published demographic tables report the racial composition as approximately 95% White and roughly 3% Asian, with no separate South Asian subcategory [1]. "Asian" as an aggregate category masks enormous heterogeneity. East Asian, Southeast Asian, and South Asian populations differ in MASH prevalence, body fat distribution, insulin resistance patterns, and drug metabolism enzyme frequencies. Grouping them together for subgroup analysis, even if one were performed, would produce clinically misleading results.

Missing Subgroup Analyses

The MAESTRO-NASH publication in the New England Journal of Medicine reported subgroup analyses by sex, age, diabetes status, fibrosis stage, BMI category, and baseline NAS score [1]. Ethnicity-stratified subgroup analyses were not presented in the primary publication. This is a common limitation in hepatology trials, not unique to resmetirom, but it leaves prescribers without evidence when treating South Asian patients with MASH.

The Endocrine Society and the American Association of Clinical Endocrinology have both called for ethnicity-stratified metabolic disease research, noting that "extrapolation of trial data from predominantly White cohorts to South Asian and other underrepresented populations introduces unquantified uncertainty into clinical decision-making" [5].

Pharmacogenomic Considerations for Resmetirom in South Asians

Resmetirom is a selective agonist of thyroid hormone receptor beta (THR-β), encoded by the THRB gene. It works by activating hepatic THR-β to increase mitochondrial fatty acid β-oxidation and reduce hepatic lipotoxicity. The pharmacogenomic question is whether THRB variants, or variants in resmetirom's metabolic pathway, differ in frequency between South Asian and European populations.

THR-β Receptor Variants

The THRB gene sits on chromosome 3 (3p24.2). Resistance to thyroid hormone beta (RTHβ), caused by loss-of-function THRB mutations, has been described in multiple ethnic groups, but systematic population-frequency data from South Asian cohorts are sparse [6]. PharmGKB does not currently list resmetirom-specific pharmacogenomic annotations, and no published study has evaluated whether common THRB polymorphisms in South Asian populations affect resmetirom binding affinity or downstream signaling.

Drug Metabolism Pathway

Resmetirom is metabolized primarily by CYP2C8, with minor contributions from CYP3A4 [7]. CYP2C8 exhibits clinically relevant genetic polymorphism. The CYP2C82 allele (found primarily in African-descent populations) and CYP2C83 (found in European populations at ~13% frequency) both reduce enzyme activity. South Asian CYP2C8 allele frequencies have been less thoroughly characterized. A study in an Indian population reported CYP2C83 frequencies of approximately 3-5%, notably lower than European frequencies [8]. If CYP2C83 is a significant determinant of resmetirom clearance, the lower allele frequency in South Asians could mean fewer slow metabolizers, potentially affecting steady-state drug levels.

What PharmGKB and CPIC Data Tell Us

As of mid-2026, PharmGKB lists no clinical pharmacogenomic guidelines for resmetirom [9]. The Clinical Pharmacogenetics Implementation Consortium (CPIC) has not issued resmetirom-specific guidance. This is expected for a recently approved drug but creates a gap. For drugs metabolized through CYP2C8, population differences in allele frequency can shift the distribution of poor, intermediate, and normal metabolizers by 5-15 percentage points across ethnic groups [8].

MASH Epidemiology in South Asians: A Disproportionate Burden

South Asian populations bear a disproportionate burden of nonalcoholic fatty liver disease (NAFLD/MASLD) and its progressive form, MASH. Understanding this burden is necessary context for interpreting the absence of ethnicity-specific resmetirom data.

Prevalence Data

A meta-analysis published in the Journal of Hepatology estimated NAFLD prevalence in South Asia at approximately 33.8%, compared to 24-25% globally [10]. Indian studies using ultrasonography have reported prevalence as high as 40% in urban populations. The NASH Clinical Research Network has documented that South Asian patients referred for liver biopsy present with more advanced fibrosis at lower BMI and younger age compared to non-Hispanic White patients [11].

The "Lean MASH" Phenotype

Between 15% and 20% of South Asian MASH patients have BMI values below 25 kg/m², the standard "normal weight" threshold for European populations [12]. This lean MASH phenotype is characterized by higher visceral adiposity relative to total body fat, more pronounced insulin resistance per unit of BMI, and potentially faster progression to advanced fibrosis. MAESTRO-NASH required a minimum BMI of 25 kg/m² for enrollment, which would have excluded a substantial proportion of South Asian patients with biopsy-confirmed MASH [1].

Dr. Rohit Loomba, director of the MASLD Research Center at UC San Diego, has noted: "The lean NAFLD phenotype, particularly common in South Asian populations, is underrepresented in every major MASH therapeutic trial to date. We cannot assume equivalent drug efficacy in a metabolically distinct phenotype that was largely excluded from study enrollment" [13].

Fibrosis Progression Dynamics

South Asian patients with MASH may progress through fibrosis stages at different rates than European-descent patients. A longitudinal study from the NASH Clinical Research Network found that Asian participants (broadly defined) had numerically higher rates of fibrosis progression over 5 years compared to White participants, though the sample size limited statistical power [11]. If fibrosis progresses faster, the time window during which a drug like resmetirom might arrest or reverse fibrosis could be narrower, making early and accurate treatment decisions more consequential.

Current Dosing and What May Need to Change

The FDA-approved dosing of Rezdiffra is weight-based: 80 mg once daily for patients weighing less than 100 kg, and 100 mg once daily for patients weighing 100 kg or more [7]. This straightforward cutoff does not account for ethnic differences in body composition.

Body Weight vs. Body Composition

A South Asian man weighing 82 kg and a European man weighing 82 kg receive the same 80 mg dose. But the South Asian man, on average, carries a higher percentage of visceral fat, lower lean muscle mass, and a greater hepatic fat fraction at that weight [3]. Whether these body composition differences affect resmetirom's volume of distribution, hepatic drug concentration, or therapeutic index is unknown. No population pharmacokinetic study has been published with ethnicity as a covariate.

Hepatic Fat Fraction as an Alternative Metric

Some hepatologists have proposed using MRI-derived proton density fat fraction (MRI-PDFF) rather than BMI as a treatment selection and monitoring biomarker for MASH therapies [14]. This approach would inherently account for ethnic differences in fat distribution. In MAESTRO-NASH, MRI-PDFF served as a secondary endpoint, with resmetirom 80 mg reducing hepatic fat by a mean relative change of approximately -32.9% vs. -10.4% on placebo at 52 weeks [1]. Whether this relative reduction is consistent across ethnic groups cannot be determined from published data.

Practical Monitoring Recommendations

Until ethnicity-specific data emerge, clinicians treating South Asian patients with resmetirom should consider monitoring hepatic function more frequently during the initial treatment period. The prescribing information recommends checking ALT, AST, and bilirubin prior to treatment, at months 3, 6, 9, and 12, and periodically thereafter [7]. Given the potentially different disease trajectory and body composition, some hepatologists recommend monthly liver function testing for the first 3 months in South Asian patients with lean MASH, though this represents expert opinion rather than guideline-based recommendation.

What Should Happen Next: The Research Gaps

Three specific research priorities would close the most pressing evidence gaps for South Asian patients.

Priority 1: Ethnicity-Stratified Subgroup Analysis from MAESTRO-NASH and MAESTRO-NAFLD

The MAESTRO trials collectively enrolled over 2,000 participants. Even if South Asian representation is limited, a post hoc analysis stratifying by self-reported ethnicity (not just race) could provide preliminary signal data. Madrigal Pharmaceuticals has not announced plans for such an analysis.

Priority 2: Population Pharmacokinetic Modeling

A population PK study incorporating South Asian participants, with ethnicity and body composition metrics as covariates, would clarify whether the current weight-based dosing achieves equivalent hepatic drug exposure. CYP2C8 genotyping within such a study would add pharmacogenomic resolution.

Priority 3: Real-World Evidence from South Asian Cohorts

Post-marketing registries in India, Pakistan, Bangladesh, Sri Lanka, and among South Asian diaspora populations in the UK and North America could generate the observational data needed to identify efficacy or safety signals that trials missed. The UK's OpenSAFELY platform and India's ICMR-INDIAB study infrastructure could support such efforts [15].

Dr. Anoop Misra, chairman of the Fortis C-DOC Centre of Excellence for Diabetes in New Delhi, has stated: "South Asian populations cannot wait for dedicated Phase III trials for every hepatic drug. We need pragmatic post-marketing studies that capture efficacy signals in our patients as prescribing begins" [16].

The Statin and Metformin Precedent

South Asian patients have well-documented differences in response to two of the most commonly prescribed metabolic drugs, and these precedents should inform expectations for resmetirom.

Statin Response Variability

The INTERHEART study demonstrated that South Asians had the highest population-attributable risk of myocardial infarction related to dyslipidemia of any ethnic group studied [17]. Rosuvastatin pharmacokinetic studies have shown approximately 2-fold higher systemic exposure in Asian participants compared to White participants, leading the FDA to recommend a lower starting dose (5 mg) in Asian patients [18]. Whether similar pharmacokinetic differences exist for resmetirom is unknown but biologically plausible given partial overlap in hepatic metabolic pathways.

Metformin and Earlier Intervention

South Asian patients with type 2 diabetes are more likely to be prescribed metformin at lower glucose thresholds and younger ages than European patients. The UK Prospective Diabetes Study (UKPDS) included South Asian participants and found consistent metformin benefits across ethnic groups, but post hoc analysis suggested that the magnitude of HbA1c reduction may differ [19]. This pattern of broadly similar drug effects with quantitatively different magnitudes is precisely the type of signal that needs evaluation for resmetirom.

Bottom Line for Clinicians

Prescribe resmetirom for South Asian patients with biopsy-confirmed MASH and F2-F3 fibrosis using current FDA-approved dosing (80 mg for body weight <100 kg, 100 mg for ≥100 kg), but recognize that trial evidence supporting this decision derives almost entirely from White participants [1]. Screen South Asian patients for MASH at lower BMI thresholds (≥23 kg/m²), consider MRI-PDFF for baseline and follow-up assessment, monitor liver function at least monthly for the first 3 months, and document treatment response systematically so that real-world data can begin to fill the evidence gap that trials left open.