Placebo Adverse Events in Non-alcoholic Steatohepatitis Clinical Trials: A Pooled Analysis of 2,944 Participants

IntroductionIn the absence of an effective treatment for non-alcoholic steatohepatitis (NASH), a randomized, placebo-controlled trial (RCT) remains the current gold standard study design in NASH. As NASH is a largely asymptomatic disease, the side effects of potential therapies require careful evaluation, therefore a pooled rate of the adverse events (AEs) in placebo-treated patients serves as a useful comparator for safety. Therefore, we performed a systematic review and meta-analysis to estimate the rate of AEs among participants in the placebo arm of NASH RCTs.MethodsMedline, Embase and Cochrane Central Register of Controlled Trials were searched to include clinical trials in phase 2-4 NASH RCTs with placebo treatment arms. A pooled proportions of AEs were analyzed using a generalized linear mixed model with Clopper-Pearson intervals.ResultsA total of 41 RCTs (2,944 participants on placebo) were included in this meta-analysis. A total of 68% (confidence interval [CI] 55%-77%) of participants on placebo experienced an AE, 7.8% (5.7%-10%) experienced serious AEs and 3.1% (CI: 1.9%-5.1%) experienced AEs leading to discontinuation. A significantly higher proportion of participants experienced serious AEs in phase 3 studies compared to in phase 2 studies ( P < 0.01) and in pharmaceutical funded studies as compared to studies which were federal-funded studies ( P < 0.01). An analysis of clinical trials evaluating bile acid modulating agents determined that 10% (CI: 5.5%-18%) of participants receiving placebo developed pruritus.DiscussionThe present study summarizes the AEs with NASH placebo. Among participants in the placebo arm in NASH, two-third experienced an AE, and nearly 10% experienced a serious AE

Patterns in Cancer Incidence Among People Younger Than 50 Years in the US, 2010 to 2019

ImportanceEmerging data suggest that the incidence of early-onset cancers, defined as cancers diagnosed in people younger than 50 years, is increasing, but updated data are limited.ObjectiveTo characterize the patterns in the incidence of early-onset cancers in the US from 2010 to 2019 and provide granular data on the cancers with the fastest-growing incidence rates.Design, setting, and participantsThis population-based cohort study analyzed data from 17 National Cancer Institute Surveillance, Epidemiology, and End Results registries from January 1, 2010, to December 31, 2019. Age-standardized incidence rates per 100 000 people were extracted for early-onset cancers, with rates age adjusted to the US standard population. A total of 562 145 patients with early-onset cancer between 2010 and 2019 were identified and included. Data were analyzed from October 16, 2022, to May 23, 2023.Main outcomes and measuresPrimary outcomes were incidence rates and descriptive epidemiological data for people younger than 50 years with cancer. The annual percentage change (APC) of the age-standardized incidence rate was estimated using the Joinpoint regression program.ResultsAmong 562 145 patients (324 138 [57.7%] aged 40-49 years; 351 120 [62.5%] female) with early-onset cancer, 4565 (0.8%) were American Indian or Alaska Native, 54 876 (9.8%) were Asian or Pacific Islander, 61 048 (10.9%) were Black, 118 099 (21.0%) were Hispanic, 314 610 (56.0%) were White, and 8947 (1.6%) were of unknown race and/or ethnicity. From 2010 to 2019, the age-standardized incidence rate of early-onset cancers increased overall (APC, 0.28%; 95% CI, 0.09%-0.47%; P = .01) and in female individuals (APC, 0.67%; 95% CI, 0.39%-0.94%; P = .001) but decreased in male individuals (APC, -0.37%; 95% CI, -0.51% to -0.22%; P < .001). In contrast, the age-standardized incidence rate of cancers in individuals aged 50 years and older decreased over the study period (APC, -0.87%; 95% CI, -1.06% to -0.67%; P < .001). In 2019, the highest number of incident cases of early-onset cancer were in the breast (n = 12 649). From 2010 to 2019, gastrointestinal cancers had the fastest-growing incidence rates among all early-onset cancer groups (APC, 2.16%; 95% CI, 1.66%-2.67%; P < .001). Among gastrointestinal cancers, those with the fastest-growing incidence rates were in the appendix (APC, 15.61%; 95% CI, 9.21%-22.38%; P < .001), intrahepatic bile duct (APC, 8.12%; 95% CI, 4.94%-11.39%; P < .001), and pancreas (APC, 2.53%; 95% CI, 1.69%-3.38%; P < .001).Conclusions and relevanceIn this cohort study, the incidence rates of early-onset cancer increased from 2010 to 2019. Although breast cancer had the highest number of incident cases, gastrointestinal cancers had the fastest-growing incidence rates among all early-onset cancers. These data may be useful for the development of surveillance strategies and funding priorities

Type 2 diabetes mellitus in metabolic-associated fatty liver disease vs. type 2 diabetes mellitus non-alcoholic fatty liver disease: a longitudinal cohort analysis

ABSTRACT: Introduction and Objectives: Type 2 Diabetes Mellitus (T2DM) is comorbidity commonly presenting with fatty liver. A recently proposed definition of ''metabolic associated fatty liver disease'' (MAFLD) is thought to replace non-alcoholic fatty liver disease (NAFLD). Yet, despite the significant prevalence of T2DM among fatty liver, there remains limited evidence on the impact of the change in the definition of T2DM. Materials and Methods: The current study uses data from the United States National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018. Survival analysis was conducted with a cox regression and sub-distribution hazard ratio for competing risk events. Results: 6727 patients had a diagnosis of T2DM. 4982 individuals with T2DM had MAFLD and 2032 were MAFLD(+)/NAFLD(-), while 2950 patients were MAFLD(+)/NAFLD(+). The new definition increased fatty liver diagnosis by 68.89%. Patients who were classified as MAFLD(+)/NAFLD(-) were at a higher risk of major adverse cardiovascular events, advanced fibrosis, all-cause and cardiovascular-related mortality compared to MAFLD(+)/NAFLD(+). In MAFLD(+)/NAFLD(-), viral hepatitis significantly increases the odds of advanced fibrosis (OR: 6.77, CI: 3.92 to 11.7, p < 0.001) and all-cause mortality (HR: 1.75, CI: 1.29 to 2.40, p < 0.001). Conclusions: The identification and treatment of NAFLD in patients with T2DM is a major concern and the premature change to MAFLD results in an over-diagnosis of fatty liver, exaggerated mortality, and morbidity in patients with T2DM. The definition of MAFLD causes further heterogeneity in fatty liver disease/NAFLD

A qualitative systematic review of anonymous/unspecified living kidney and liver donors' perspectives.

Objectives & backgroundAnonymous live organ donors or unspecified donors are individuals willing to be organ donors for any transplant recipient with whom they have no biological or antecedent emotional relationship. Despite excellent recipient outcomes and the potential to help address organ scarcity, controversy surrounds the unconditional act of gifting one's organs to an unrelated recipient. This qualitative systematic review provides insights into the first-hand experiences, motivations, and challenges that unspecified donors face.MethodsA systematic search was conducted on Medline, Embase, CINAHL, PsycINFO, and Web of Science database for qualitative literature regarding unspecified living donors' motivations and experiences in liver and kidney transplantation. An inductive thematic analysis was conducted to generate themes and supportive subthemes.Results12 studies were included. The four major themes were (i) motivations, (ii) perception of risks, (iii) donor support, and (iv) benefits of donation. Unspecified donors demonstrated a deep sense of social responsibility but tended to underestimate health risks in favour of benefits for recipients. Despite the lack of emotional support from family and friends, the decision to donate was a resolute personal decision for donors. Majority benefitted emotionally and did not express regret.ConclusionThis qualitative review bridges the gap in literature on unspecified living donor psychology and provides a comprehensive understanding of the decision-making matrix and experiences of donors

Living in the non-alcoholic fatty liver disease silent epidemic: a qualitative systematic review of patients' perspectives

10.1111/apt.17121ALIMENTARY PHARMACOLOGY & THERAPEUTIC

The prognostic value of including non‐alcoholic fatty liver disease in the definition of metabolic syndrome

Background/Aims Metabolic syndrome (MetS) affects over one third of the US adult population. Despite its close association with non-alcoholic fatty liver disease (NAFLD), the traditional definition of MetS does not account for the presence of NAFLD. The present study thus aims to evaluate the inclusion of NAFLD in the diagnostic criteria of metabolic syndrome on its accuracy of capturing individuals with metabolic dysregulation and its prediction of adverse events. Methods Data collected from NHANES between 1999 and 2018 was analysed. Clinical characteristics and outcomes between individuals with metabolic syndrome from both the American Heart Association/National Heart, Lung, and Blood Institute (MetS) and the study's proposed diagnostic criteria (MetS2) were evaluated. Outcomes in both groups were evaluated with multivariate analyses, and further subgroup analysis on individuals matched with Coarsened Exact Matching was performed. Results Of 46,184 individuals included, 32.54% and 40.54% fulfilled MetS and MetS2 criteria respectively. Considering NAFLD in the definition of metabolic syndrome, a further 8.00% (n = 3694) were included. MetS was significantly associated with all-cause (HR: 1.184, 95% CI: 1.110–1.263, p?<?0.001) and cardiovascular disease (CVD) mortality (SHR: 1.288, 95% CI: 1.233–1.347, p?<?0.001), and major adverse cardiovascular events (MACE). MetS2 was similarly associated with all-cause (HR: 1.175, 95% CI: 1.088–1.269, p?<?0.001), CVD mortality (SHR: 1.283, 95% CI: 1.245–1.323, p?<?0.001) and MACE. Conclusion Inclusion of NAFLD allows for identification a greater proportion of the population with metabolic risk. This allows for early intervention and potential to lift some burden off the global healthcare system