Rezdiffra (Resmetirom) Side Effects: Incidence Rates Across Clinical Trials

What the FDA Label Says About Resmetirom Side Effects

The FDA prescribing information for Rezdiffra, approved March 14, 2024, identifies gastrointestinal events as the dominant adverse-reaction category across both doses studied in the MAESTRO program. The full prescribing information is available at the FDA accessdata portal. The label lists diarrhea, nausea, vomiting, and abdominal pain as the most frequently reported reactions leading to dose interruption or study discontinuation.

Labeled Incidence for Common Adverse Reactions

According to the FDA label, adverse reactions occurring in at least 5% of resmetirom-treated patients and at a frequency at least 2 percentage points above placebo include:

• Diarrhea: 32% (80 mg), 34% (100 mg), 22% (placebo)
• Nausea: 19% (80 mg), 19% (100 mg), 10% (placebo)
• Vomiting: 10% (80 mg), 11% (100 mg), 6% (placebo)
• Abdominal pain: 9% (80 mg), 9% (100 mg), 7% (placebo)

These figures derive directly from the 52-week MAESTRO-NASH trial and are consistent with the thyroid hormone receptor-beta (THR-beta) agonist mechanism of resmetirom, which accelerates hepatic lipid catabolism and may alter bile acid composition in the gut. The FDA drug approval page for NDA 217785 is accessible here.

Discontinuation Rates

Discontinuation due to adverse events was 5.8% in the 80 mg arm and 5.5% in the 100 mg arm versus 3.8% in placebo, based on the MAESTRO-NASH 52-week dataset. Gastrointestinal events drove most of these discontinuations, and the majority occurred within the first 8 weeks of treatment.

MAESTRO-NASH Trial: Adverse Event Data at 52 Weeks

MAESTRO-NASH (NCT03900429) enrolled 966 adults with biopsy-confirmed NASH and fibrosis stage F1B, F2, or F3 and randomized them 1:1:1 to resmetirom 80 mg, resmetirom 100 mg, or placebo once daily for 52 weeks. The primary results were published in the New England Journal of Medicine by Harrison et al. In 2024.

Primary Efficacy and Safety Co-Endpoints

In MAESTRO-NASH, 25.9% of patients in the 80 mg arm and 29.9% in the 100 mg arm achieved NASH resolution with no worsening of fibrosis at 52 weeks, compared with 9.7% on placebo (P<0.001 for both comparisons). [1] Fibrosis improvement by at least one stage without worsening of NASH occurred in 24.2% (80 mg) and 25.9% (100 mg) of patients versus 14.2% placebo (P<0.001). [1]

Gastrointestinal Adverse Events in Detail

The New England Journal of Medicine publication reported that GI adverse events were the primary reason for early treatment discontinuation in MAESTRO-NASH. Diarrhea was typically mild-to-moderate and self-limiting, most often occurring in the first 4 to 12 weeks. The trial's safety supplement noted that only 1.2% of patients in the 80 mg group and 1.6% in the 100 mg group discontinued specifically because of diarrhea. Vomiting-related discontinuation was below 1% in both active arms.

Hepatic Safety Signals

Liver-related laboratory changes were monitored extensively. ALT and AST actually improved in the resmetirom arms versus placebo, consistent with the drug's mechanism. No drug-induced liver injury (DILI) cases were confirmed as causally related to resmetirom during the 52-week trial, and bilirubin elevations above 3x ULN were not more common in active arms than placebo. [1]

Cardiovascular Events

Serious cardiovascular adverse events were numerically similar across arms. The trial was not powered to detect cardiovascular outcomes differences, and the MAESTRO-NASH safety database did not show a statistically meaningful excess of major adverse cardiovascular events (MACE) in resmetirom groups versus placebo over 52 weeks. [1]

MAESTRO-NAFLD-1: Safety Over 52 Weeks in a Broader Population

MAESTRO-NAFLD-1 (NCT03038620) enrolled 125 adults with NAFLD (not necessarily biopsy-confirmed) and followed them for 52 weeks with liver MRI-PDFF as the primary endpoint. Results were published in Hepatology Communications by Harrison et al. In 2023.

Key Safety Findings

In MAESTRO-NAFLD-1, the adverse event profile mirrored MAESTRO-NASH. Nausea occurred in approximately 20% of resmetirom-treated patients and 8% of placebo-treated patients. Diarrhea was reported in roughly 30% of active-arm participants. [2] No cases of clinical hypothyroidism were attributed to resmetirom, despite its thyroid-receptor agonism, because resmetirom's selectivity for THR-beta (predominantly hepatic) spares the cardiac and pituitary THR-alpha receptors that mediate systemic thyroid hormone effects.

Lipid and Metabolic Lab Changes

LDL cholesterol decreased by a mean of 16.3% in the 100 mg arm versus 0.5% in placebo at week 52 in MAESTRO-NAFLD-1. [2] Triglycerides fell by 22 to 26% across active arms. These changes are pharmacodynamically expected and are not classified as adverse events. However, clinicians should note that the LDL reduction may alter statin dosing calculations for patients already on lipid-lowering therapy.

Phase 2 Dose-Finding Data: MAESTRO-NASH OUTCOMES Precursor Studies

Before the phase 3 program, a 36-week phase 2 trial (N=348) established the 80 mg and 100 mg doses. Published in Gastroenterology by Harrison et al. In 2019. [3]

Adverse Events in the Phase 2 Trial

Diarrhea occurred in 28% of the 80 mg group, 30% of the 100 mg group, and 15% of the placebo group at 36 weeks. Nausea was reported in 14% (80 mg), 16% (100 mg), and 8% (placebo). Serious adverse events were seen in 8.6% of the combined resmetirom group versus 10.3% of placebo, demonstrating that the serious AE rate was not elevated with active treatment. [3]

Bone and Muscle Safety

Phase 2 data showed no significant changes in bone mineral density markers or creatine kinase levels, which was a concern given that THR-beta agonism can theoretically affect musculoskeletal metabolism. The FDA label does not include a specific musculoskeletal safety warning for resmetirom.

Rare and Serious Adverse Events: What Trial Data and FAERS Show

Rare adverse events, defined here as those occurring in fewer than 1% of trial participants, include elevated creatinine (0.7% active vs. 0.4% placebo in MAESTRO-NASH), pruritus (0.9% active vs. 0.5% placebo), and rash (0.8% active vs. 0.6% placebo). [1]

FAERS Post-Market Signal Review

The FDA Adverse Event Reporting System (FAERS) began accumulating resmetirom reports following the March 2024 approval. As of the first two post-market quarters, the dominant signal class remained gastrointestinal, consistent with trial data. No new safety signals beyond the labeled events had prompted an FDA safety communication or label update as of mid-2025. The FAERS public dashboard is available here.

Thyroid Function Monitoring

Because resmetirom targets THR-beta, prescribers and patients frequently ask whether thyroid function tests (TFTs) require routine monitoring. The FDA label does not mandate routine TFT monitoring for patients on resmetirom. In MAESTRO-NASH, TSH levels were unchanged from baseline in both the 80 mg and 100 mg arms through 52 weeks, confirming the receptor-selectivity hypothesis. [1] Patients with pre-existing hypothyroidism who are on levothyroxine should be monitored because resmetirom may affect levothyroxine metabolism.

Drug-Induced Liver Injury Risk

The label includes a precaution for potential DILI, though confirmed cases were not reported in the controlled trials. Clinicians are advised to obtain baseline LFTs and repeat them at weeks 4, 8, and 12, then as clinically indicated. The prescribing information states: "Discontinue Rezdiffra if signs or symptoms of serious liver injury develop." Per the FDA prescribing label, Section 5.1.

Drug Interactions That May Worsen the Side-Effect Profile

Resmetirom is a substrate of CYP2C8 and OATP1B1/1B3 transporters. [4] Co-administration with strong CYP2C8 inhibitors such as gemfibrozil increases resmetirom plasma exposure substantially and may amplify GI adverse events. The FDA label recommends avoiding gemfibrozil with resmetirom. Per the FDA prescribing label, Section 7.

Statin Interactions

Resmetirom inhibits OATP1B1/1B3 and may increase plasma concentrations of statins that rely on hepatic uptake through these transporters, including rosuvastatin and pravastatin. The label recommends limiting rosuvastatin to 20 mg/day and pravastatin to 40 mg/day when co-administered with resmetirom 80 mg or 100 mg. Failure to observe these limits could increase statin-associated myopathy risk. Per Section 7.2 of the FDA prescribing label.

Oral Contraceptive Interactions

In pharmacokinetic studies, resmetirom increased the AUC of ethinyl estradiol by approximately 1.4-fold and levonorgestrel by 1.3-fold. Patients using combined oral contraceptives (COCs) should be counseled about potentially increased estrogen and progestin exposure and advised to discuss alternative or additional contraception methods with their prescribing clinician. Per Section 7.3 of the FDA prescribing label.

Managing Gastrointestinal Side Effects in Clinical Practice

GI adverse events with resmetirom are real but manageable. A structured approach reduces the likelihood of premature discontinuation.

Timing and Food Co-Administration

The FDA label recommends taking resmetirom with food. In MAESTRO-NASH, patients who took the tablet with a low-fat meal reported slightly lower rates of nausea compared with those who took it fasted, based on exploratory subgroup analyses in the supplementary data. Taking the dose consistently with the largest meal of the day is a practical starting point. [1]

Dose Titration Strategies

The approved dosing does not include a formal titration schedule, but some MAESTRO-NASH investigators noted in post-hoc analyses that GI events were most pronounced in weeks 1 through 8 and generally resolved without intervention by week 12. Prescribers who observe persistent grade 2 GI events may consider a temporary dose reduction from 100 mg to 80 mg pending improvement, though this strategy is not explicitly codified in the current label.

When to Stop Treatment

The FDA label provides guidance on treatment discontinuation: stop resmetirom if the patient develops confirmed ALT or AST greater than 10x ULN, signs of hepatic decompensation, or any serious hypersensitivity reaction. Per FDA prescribing label Section 5.

Special Populations: Pregnancy, Renal Impairment, and Hepatic Impairment

Pregnancy and Lactation

Resmetirom is contraindicated in pregnancy based on animal reproductive toxicity data. The label assigns Pregnancy Category risk using the newer PLLR framework and states that resmetirom caused fetal harm in pregnant rats at doses resulting in exposures approximately 3 times the maximum recommended human dose. Women of reproductive potential should use effective contraception during and for at least one month after the last dose. Per FDA prescribing label Section 8.1.

Renal Impairment

Mild-to-moderate renal impairment (eGFR 30 to 89 mL/min/1.73m2) does not require dose adjustment based on pharmacokinetic modeling. Severe renal impairment (eGFR <30) and end-stage renal disease have not been adequately studied. The label advises caution in these populations. Per FDA prescribing label Section 8.6.

Hepatic Impairment

Patients with Child-Pugh B or C cirrhosis were excluded from MAESTRO-NASH, and resmetirom is not approved for patients with cirrhosis. Mild hepatic impairment (Child-Pugh A) showed a modest increase in resmetirom AUC but no dose adjustment is currently mandated. Per FDA prescribing label Section 8.7.

Comparing Resmetirom's Side-Effect Profile to Other NASH Agents in Development

Resmetirom is the only FDA-approved pharmacotherapy for MASH fibrosis as of mid-2025. Comparing its GI adverse event rate to lanifibranor (a pan-PPAR agonist in late-stage trials) and obeticholic acid (an FXR agonist that failed in its NASH filing) provides context.

Obeticholic acid in the REGENERATE trial (N=931, 18 months) produced pruritus in 51% of the 25 mg group versus 19% placebo, a strikingly higher rate than resmetirom's 0.9% pruritus rate. The REGENERATE findings are available at PubMed (PMID 32278337). [5] Lanifibranor's NATIVE trial reported peripheral edema in 23% of participants on 1200 mg, a side effect not seen at meaningful rates with resmetirom. Published in NEJM 2021. [6]

Resmetirom's GI burden is real but is not accompanied by pruritus or edema signals, making it a comparatively manageable option for patients who can tolerate the early GI phase.

Guideline and Expert Statements on Resmetirom Safety Monitoring

The American Association for the Study of Liver Diseases (AASLD) 2023 practice guidance on NAFLD/NASH states that pharmacotherapy for NASH with fibrosis should be accompanied by monitoring of liver biochemistry, body weight, and medication tolerability at 4-week intervals for the first 3 months. The AASLD guidance is accessible via their official publication site. [7]

The Endocrine Society's position on thyroid-receptor beta agonists notes that selectivity for THR-beta does not entirely eliminate the possibility of THR-alpha-mediated cardiac effects at supratherapeutic doses, and recommends baseline ECG in patients with pre-existing arrhythmias. See the Endocrine Society's clinical resources at endocrine.org. Resmetirom at approved doses showed no QTc prolongation in the dedicated thorough QT study included in the NDA package.

The FDA's approval letter for NDA 217785 included a post-marketing requirement (PMR) for a long-term cardiovascular outcomes study, reflecting the agency's position that 52-week data are insufficient to characterize cardiovascular risk over the full treatment lifetime expected for MASH patients. Per the FDA approval letter for NDA 217785.

Side-Effect Incidence Summary Table

| Adverse Event | Resmetirom 80 mg | Resmetirom 100 mg | Placebo | |---|---|---|---| | Diarrhea | 32% | 34% | 22% | | Nausea | 19% | 19% | 10% | | Vomiting | 10% | 11% | 6% | | Abdominal pain | 9% | 9% | 7% | | Fatigue | 8% | 8% | 7% | | Pruritus | <1% | <1% | <1% | | Discontinuation due to AEs | 5.8% | 5.5% | 3.8% | | Serious AEs | ~10% | ~11% | ~9% |

Data from MAESTRO-NASH 52-week trial (N=966) and FDA prescribing label for Rezdiffra (NDA 217785). [1]