Patrick Campbell is the managing editor of HCPLive. Formerly the editorial lead of Endocrinology Network, Practical Cardiology, and Rheumatology Network, Patrick has spent years spearheading coverage surrounding cardiometabolic health and rheumatic disease for MJH Life Sciences. He now helps to lead coverage in each of these respective areas for HCPLive. Before joining MJH Life Sciences in 2019, he spent time as a beat reporter with the Pocono Record in Stroudsburg, PA, and Star News Group in Manasquan, NJ. He also touts experience in multimedia, having spent time as a multimedia specialist with NJ Advance Media and multimedia coordinator at the Pocono Record. Follow him on Twitter @RealPatCampbell or reach him via email at PCampbell@mjhlifesciences.com.

Patrick Campbell

Jörn M. Schattenberg, MD
Credit: LinkedIn

An analysis of real-world data more than 18,000 US patients with 

metabolic dysfunction-associated steatohepatitis (MASH)

 is shedding light on mortality rates, causes of death and impact of biomarkers and socioeconomic factors on mortality rates among this patient population.

22nd Annual World Congress Insulin Resistance Diabetes & Cardiovascular Disease (WCIRDC)

, data from the study provide valuable insight into factors influencing risk of mortality among these patients.

“In MASH patients, mortality risks were higher in presence of metabolic risk factors, including kidney disease. Regional differences also impacted MASH mortality rates,” wrote investigators.

With 2024 welcoming approvals for resmetirom as well as positive phase 2 and phase 3 trials, healthcare providers are eager to welcome a new era in management of MASH. Just as the therapeutic pipeline for MASH has begun to bear fruit, the medical community has begun to recognize and investigate MASH, obesity, and other chronic illnesses as part of a spectrum of metabolic disease.

Supported and funded by Boehringer Ingelheim, the current study was designed by Jörn M. Schattenberg, MD, professor of medicine and director of the department of Internal Medicine at Saarland University Hospital, to evaluate trends in mortality rates, causes of death, and the role of socioeconomic risk factors in mortality risk among patients with MASH using deidentified data recorded from 2016 to 2021 within the Optum Market Clarity linked claims database. Of note, the investigators identified MASH patients using the ICD-10 diagnosis code K75.81 for nonalcoholic steatohepatitis.

Outcomes of interest for the analysis included associations between risk factors of disease progression, such as age, region, and biomarkers, and mortality. For the purpose of analysis, investigators calculated crude and stratified mortality incidence rates among MASH patients based on presence of elevated body mass index (BMI) and type 2 diabetes.

A total of 18,710 MASH patients with a mean follow-up of 6.5 years were identified for incision in the study. Among this group, 1465 patient deaths occurred during the follow-up period. Of these, 70% were attributed to cardiovascular disease and 17% were attributed to liver-related causes.

Results of the investigators’ analyses indicated having an eGFR of less than 60mL/min/1.73m2 (Hazard ratio [HR], 3.01) and having 3 or more metabolic comorbidities (HR, 1.93) were associated with increased mortality. Investigators also highlighted findings pointing to an increased rate of all-cause mortality among those living in the Southern United States relative to their counterparts in the Northeast (HR, 1.56).

Results of secondary analyses offered evidence suggesting MASH patients with a BMI of 25 kg/m2 or greater and type 2 diabetes had a mortality rate of 31 per 1000 patient-years, which investigators noted was 5 times greater than the rate observed among those with a BMI of 25 kg/m2 or greater but without liver disease and type 2 diabetes.

“Incident mortality was higher in patients living with overweight/obesity and MASH vs overweight/obesity without MASH, but further analysis is needed to take confounding factors into account,” investigators noted.

Schattenberg JM, Martini C, Herrera R, Raluy M, Yates M, Younes R. 

Causes of Death, Mortality Rates, and the Role of Socio-demographic Risk Factors and Biomarkers in Metabolic Dysfunction-associated Steatohepatitis Mortality in More than 18,000 Real World Patients from the United States

. Presented at the 22nd Annual World Congress Insulin Resistance Diabetes & Cardiovascular Disease (WCIRDC). Los Angeles, California. December 12-14, 2024.

Brooks A. Resmetirom (Rezdiffra) receives historic FDA approval for noncirrhotic Nash. HCP Live. March 14, 2024. Accessed December 15, 2024. https://www.hcplive.com/view/resmetirom-rezdiffra-receives-historic-fda-approval-for-noncirrhotic-nash.

Brooks A. FDA grants breakthrough therapy designation to Survodutide for Noncirrhotic Mash. HCP Live. October 8, 2024. Accessed December 15, 2024. https://www.hcplive.com/view/fda-grants-breakthrough-therapy-designation-survodutide-noncirrhotic-mash.

Articles

Real-world data from 18,710 MASH patients highlight the impact of comorbidities, biomarkers, and region on mortality, with 70% of deaths CVD-related.

Study Highlights Real-World Mortality Rates, Factors Increasing Mortality Risk in MASH 

Christos S. Mantzoros, MD, DSc
Credit: BIDMC

New data suggest leveraging artificial intelligence, more specifically metabolomics-based machine learning models, could help revolutionize screening for identifying patients with 

 who would be candidates for resmetirom (Rezdiffra).

, results of the study demonstrate the limitations of current noninvasive testing methods for detecting noncirrhotic MASH with moderate-to-severe fibrosis while highlighting the potential of machine learning models to improve accuracy, sensitivity, and predictive ability of current testing methods.

“We present the first assessment of [noninvasive tests] in identifying MASH with fibrosis F2 to F3,” wrote investigators. “We further develop and demonstrate that novel [machine-learning]-based [noninvasive tests] can accurately determine treatment eligibility alone or in combination with other [noninvasive tests].”

As the hepatology community prepares to enter 2025, the field is in a position it has never found itself in before following the historic FDA approval of resmetirom as the first therapy indicated for noncirrhotic nonalcoholic steatohepatitis with moderate to advanced fibrosis. This approval, which was awarded to Madrigal Pharmaceuticals, was based on a clinical development program that included 12 phase 1 studies, a pair of phase 2 studies, and 4 phase 3 studies.

After decades without effective options for the disease, which is now recognized as MASH, conversations among specialists have begun to include the urgent need for improved screening efforts and methodologies.

As investigators highlighted in the current study, which was led by Christos Mantzoros, MD, DSc, endocrinologist and principal investigator of the Mantzoros Laboratory at Beth Israel Deaconess Medical Center, and presented by Konstantinos Stefanakis, MD, there are no noninvasive tests developed for detecting MASH with fibrosis stages F2 to F3 but without cirrhosis. Mantzoros, Stefanskis, and fellow investigators launched the current study with the intent of evaluating and optimizing noninvasive tests as well as developing machine learning models to detect MASH with fibrosis stages F2 to F3 and rule out cirrhosis across a diverse multinational cohort.

Investigators leveraged a multinational biobank of 905 biopsy-confirmed participants representative of the entire spectrum of MASH and health controls as a data source. Using this study population, investigators assessed 28 biomarker-, imaging-, and algorithm-based NITs using both standard and re-optimized cutoffs to detect MASH F2 to F3 and rule out cirrhosis.

For the purpose of analysis, investigators also developed clinical/hormonal-based machine learning models and replicated the analysis to create metabolomics-based models among a 443-patient subgroup. Investigators pointed out these machine learning models were cross-validated in a 4:1 training:validation scheme.

Results of the analysis suggested the existing noninvasive tests attained suboptimal area under the curve (AUC), positive predictive value, and accuracy for MASH F2 to F3, except Fibroscan-AST (FAST) (AUC, 0.67; Negative Predictive Value [NPV], 92%; sensitivity, 81%). Results indicated novel clinical/hormonal machine learning models achieved greater values for AUC (0.86), sensitivity (93%), and NPV (97%) relative to all previously known noninvasive tests among the validation cohort.

Investigators also pointed out the addition of aminotransferases, metabolic syndrome components, BMI, and 3-ureidopropionate to metabolomics-based machine learning models contributed to a mean cross-validated AUC of 0.89 in the validation cohort, which increased to 0.91 following hyperparameter optimization and the addition of alpha-ketoglutarate.

When assessing noninvasive detection of cirrhosis, results indicated AGILE4+ had the highest sensitivity (92%) and NPV (99.7%), but investigators also called attention to results demonstrating machine learning models achieved an AUC up to 0.98, sensitivity of 98%, and NPV up to 99.9% among the validation cohort.

Stefanskis C, Mingrone G, George J, Mantzoros CS. 

Performance of Established and Novel Non-invasive Tests, Including New Clinical and Metabolomics-Based Machine Learning Models, for Detecting MASH with Fibrosis Stages F2-F3: A First-in-Class Approach in the post-Resmetirom approval era

Machine learning models improve accuracy in detecting MASH with F2-F3 fibrosis, surpassing noninvasive tests in sensitivity, specificity, and predictive value.

Machine-Learning Models Could Help ID MASH Patients Considered Candidates for Resmetirom

Kristin Shimano, MD
Credit: UCSF Benioff Children's Hospitals

Data from the PINES trial indicate children with newly diagnosed immune thrombocytopenia (ITP) receiving eltrombopag could achieve better outcomes with eltrombopag (Promacta) than with standard first-line therapies.

66th American Society of Hematology (ASH) Annual Meeting and Exposition

, the trial findings suggest use of eltrombopag was associated with a significantly greater rate of a durable response in the absence of rescue treatments relative to standard first-line therapies, which included prednisone, Intravenous immunoglobulin (IVIG), or anti-D globulin at specified doses.

“This is the first time in 30 years that a new drug is being tested for newly diagnosed pediatric ITP,” said lead investigator Kristin A. Shimano, MD, professor of pediatrics at the University of California, San Francisco Benioff Children’s Hospital.

 “Patients who received eltrombopag during the first three months of their ITP diagnosis had a more sustained platelet response than patients who were treated with standard therapies. That means during this time period, kids taking eltrombopag were also likely to have a lower risk of having bleeding events.”

A oral thrombopoietin receptor agonist, eltrombopag first received approval from the US Food and Drug Administration in 2008 as the first oral agent awarded an indication for treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura.

Launched 4 years after the FDA approval of eltrombopag in adults and children with chronic ITP in 2015, the PINES trial was an endeavor conducted by the ITP Consortium of North America to assess the safety and efficacy of eltrombopag as a first-line therapy in pediatric ITP. A prospective, open label, randomized trial conducted at 23 medical centers, the study enrolled 118 patients diagnosed with ITP less than 3 months prior to enrollment and who required pharmacologic treatment in the opinion of their treating hematologist.

Among the 118 patients, 46 were aged 1 to 6 years, 42 were aged 6 to 12 years, and 30 were aged 12 to 18 years. At enrollment, the median platelet count was 4 × 10⁹/L (range, 1 to 23) in the eltrombopag arm and 8 × 10⁹/L (range, 1 to 28) in the standard of care arm.

Investigators noted 40% of the study cohort had not yet taken any medications for ITP before enrolling while the other 60% had taken at least 1 medication but not seen a lasting benefit. Investigators pointed out those with a history of prior medication were not randomized to the same medication after enrollment.

Study participants were randomized in a 2:1 ratio, with stratification by age and prior treatment status, to eltrombopag or standard of care.

The primary outcome of interest for the study was sustained platelet response at 12 weeks, which investigators defined as having 3 or 4 platelet counts higher than 50 x 109/L during weeks 6 to 12 without additional treatment.

Result of the primary endpoint analysis indicated platelet response was achieved by 65% patients of the eltrombopag arm and 33% of the SOC arm (

= .0007). Further analysis suggested rescue therapy was received among 19% of the eltrombopag arm and 46% of the standard of care arm (

When assessing quality of life changes, results indicated the mean absolute change from baseline in parent-proxy reported KIDS ITP Tool scores appeared to favor eltrombopag relative to standard of care at 1 week (

= .14). Investigators pointed out these differences were consistent with a clinically meaningful improvement in quality of life at all time points in both arms.

“Eltrombopag could certainly be added to the medication choices hematologists consider as they are making treatment decisions with families, and it is an option that could potentially raise platelets for a more sustained period in children with ITP in the newly diagnosed period, which is one of the most difficult times for patients with regard to the impact of the disease on bleeding symptoms and quality of life,” Shimano added.

Shimano KA, Grimes AB, Rose MJ, et al. Efficacy Findings in a Phase 3, Randomized Trial of Eltrombopag Vs. Standard First-Line Treatment for Newly Diagnosed Immune Thrombocytopenia in Children. Presented at: 66th American Society of Hematology (ASH) Annual Meeting and Exposition; December 7-10; San Diego, California.

American Society of Hematology. Putting women and children first to optimize their Hematology Health. Hematology.org. December 7, 2024. Accessed December 8, 2024. https://www.hematology.org/newsroom/press-releases/2024/putting-women-and-children-first-to-optimize-their-hematology-health.

US Food and Drug Administration. Drug approval package. Promacta (Eltrombopag) NDA #022291. Accessed December 8, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2008/022291s000_TOC.cfm.

The PINES trial demonstrated that eltrombopag, an oral thrombopoietin receptor agonist, offers superior outcomes for children with newly diagnosed immune thrombocytopenia (ITP) compared to standard first-line therapies. Conducted by the ITP Consortium of North America, the trial involved 118 pediatric patients and showed a significantly higher rate of sustained platelet response with eltrombopag. The study also indicated a reduced need for rescue treatments and potential improvements in quality of life. These findings suggest eltrombopag as a viable first-line treatment option for pediatric ITP.

Data from the PINES trial at ASH 2024 suggest eltrombopag could outperform current standard of care for platelet response in newly diagnosed pediatric ITP.

Eltrombopag Bests Standard of Care as First-Line Therapy in Pediatric Immune Thrombocytopenia

New research from Yale School of Medicine provides insight into potential avenues to improve the diagnosis and management of 

A cost-effectiveness analysis examining varying ferritin thresholds for diagnosing iron deficiency, results indicate use of a 25 µg/L threshold for diagnosing iron deficiency in adult women was a cost-effective intervention, regardless of whether these patients received subsequent treatment with oral or intravenous iron supplementation.

“Our models show that setting this threshold at 25 μg/L would improve the quality of life for numerous individuals and do it for cents on the dollar,” said lead investigator, Daniel Wang, a medical student at the Yale School of Medicine, in a press release.

“The incremental cost-effectiveness ratio of this strategy compared to no screening is well below all accepted willingness-to-pay thresholds in the US.”

A significant burden on population-level health and public health systems, iron deficiency is linked to adverse effects on social, emotional, and health-related well-being of affected individuals, as Wang and team note in the current study. Citing the absence of universal screening for adult women in the US, Wang and George Goshua, MD, MSc, of Hematology-Oncology and Yale CORE at the Yale School of Medicine and Yale Cancer Center, launched the current study to estimate the potential benefit of varying thresholds for diagnosis.

The study, which investigators purport is the first cost-effectiveness analysis of varying ferritin thresholds for iron deficiency diagnosis and treatment, was presented at the 

For the purpose of analysis, investigators designed Markov simulation model of adult women within the US to assess the cost-effectiveness of 3 iron deficiency screening strategies, which were defined by a ferritin threshold of less than 25 µg/L, a ferritin threshold of less than 15 µg/L, and no screening. The investigators’ model used a lifetime time horizon with a willingness-to-pay threshold of $100,000 per quality-adjusted life-year (QALY) and costs were assessed in 2024 US dollars, which was determined using the US Medical Expenditures Panel Survey.

Investigators leveraged National Health and Nutrition Examination Survey data for cycles spanning 2003 through 2010 and 2015 through 2020 to identify the epidemiological prevalence of iron deficiency whereas randomized clinical trials and the World Health Organization’s Vigibase to determine the probability of adverse events. Investigators pointed out once daily oral ferrous sulfate was used as the base-case iron supplement for treatment of iron deficiency and a scenario analysis examined treatment with intravenous iron dextran, with effectiveness measured in QALY.

The study's primary outcome was the incremental cost-effectiveness ratio (ICER) of the different screening approaches relative to no screening.

Upon analysis of the base case scenario, results suggested screening for iron deficiency with a ferritin threshold of less than 25µg/L was the cost-effective strategy in 100% of 10,000 Monte Carlo iterations, with $212,000 in costs and generating 24.3 QALYs compared $211,000 and 23.3 QALYs at the less than 15µg/L threshold and $210,000 and 22.3 QALYs relative to no screening. Investigators highlighted the ICER of 25µg/L compared to no screening is $940 per QALY and “well under” all accepted willingness-to-pay thresholds in the US.

Investigators called attention to results pointing to similar cost-effectiveness when patients with iron deficiency were treated with iron dextran. Additionally, data from a deterministic sensitivity analysis suggested no parameter variations changed the study conclusion.

“The current reference ranges we have for ferritin are outdated and come from a biased sample; a majority of hematologists agree that the current threshold is far too low,” Wang explained.

 “We need to recognize that this is an issue for all persons with the capacity to menstruate, and we need to raise the bar on determining the proper cutoff and effectively disseminate that information to care providers and labs.”

Wang D, Glaeser-Khan S, Wang DY, et al. Sex, Lies, and Iron Deficiency in 2024: Cost-Effectiveness of Screening Ferritin Thresholds for the Treatment of Iron Deficiency in Women of Reproductive Age. Presented at: 66th American Society of Hematology (ASH) Annual Meeting and Exposition; December 7-10; San Diego, California.

New research from Yale School of Medicine suggests that using a ferritin threshold of 25 µg/L for diagnosing iron deficiency in adult women is cost-effective, improving quality of life at minimal cost. The study, presented at the 66th ASH Annual Meeting, utilized a Markov simulation model to compare screening strategies. Results showed that the 25 µg/L threshold was cost-effective in all simulations, with an ICER of $940 per QALY. The study emphasizes the need to update ferritin reference ranges and improve diagnosis and management of iron deficiency.

Yale study at ASH 2024 finds screening adult women for iron deficiency with a ferritin threshold of 25 µg/L is cost-effective. 