A Randomized Clinical Trial

[Posted 10/Aug/2022]

AUDIENCE: Internal Medicine

KEY FINDINGS: In this randomized clinical trial, eTRE was more effective for losing weight and improving diastolic blood pressure and mood than eating over a window of 12 or more hours at 14 weeks.

BACKGROUND: It is unclear how effective intermittent fasting is for losing weight and body fat, and the effects may depend on the timing of the eating window. This randomized trial compared time-restricted eating (TRE) with eating over a period of 12 or more hours while matching weight-loss counseling across groups. Aim of this study is to determine whether practicing TRE by eating early in the day (eTRE) is more effective for weight loss, fat loss, and cardiometabolic health than eating over a period of 12 or more hours.

DETAILS: The study was a 14-week, parallel-arm, randomized clinical trial conducted between August 2018 and April 2020. Participants were adults aged 25 to 75 years with obesity and who received weight-loss treatment through the Weight Loss Medicine Clinic at the University of Alabama at Birmingham Hospital. All participants received weight-loss treatment (energy restriction [ER]) and were randomized to eTRE plus ER (8-hour eating window from 7:00 to 15:00) or control eating (CON) plus ER (>=12-hour window). The co–primary outcomes were weight loss and fat loss. Secondary outcomes included blood pressure, heart rate, glucose levels, insulin levels, and plasma lipid levels. Ninety participants were enrolled (mean [SD] body mass index, 39.6 [6.7]; age, 43 [11] years; 72 [80%] female). The eTRE+ER group adhered 6.0 (0.8) days per week. The eTRE+ER intervention was more effective for losing weight (-2.3 kg; 95% CI, -3.7 to -0.9 kg; P = .002) but did not affect body fat (-1.4 kg; 95% CI, -2.9 to 0.2 kg; P = .09) or the ratio of fat loss to weight loss (-4.2%; 95% CI, -14.9 to 6.5%; P = .43). The effects of eTRE+ER were equivalent to reducing calorie intake by an additional 214 kcal/d. The eTRE+ER intervention also improved diastolic blood pressure (-4 mm Hg; 95% CI, -8 to 0 mm Hg; P = .04) and mood disturbances, including fatigue-inertia, vigor-activity, and depression-dejection. All other cardiometabolic risk factors, food intake, physical activity, and sleep outcomes were similar between groups. In a secondary analysis of 59 completers, eTRE+ER was also more effective for losing body fat and trunk fat than CON+ER.

Copyright © American Medical Association. All Rights Reserved.

Source: Jamshed, H. Steger, F. L., Bryn, D. R., et al. (2022). Effectiveness of Early Time-Restricted Eating for Weight Loss, Fat Loss, and Cardiometabolic Health in Adults With Obesity: A Randomized Clinical Trial. JAMA Intern Med.. Published: August 8, 2022. DOI: 10.1001/jamainternmed.2022.3050.

Fluoropyrimidine Chemotherapy: Mortality and Cardiovascular Risk in Gastrointestinal Cancer

[Posted 4/Jul/2025]

AUDIENCE: Oncologists, Cardiologists, Cardio-Oncologists, and Researchers involved in the treatment of gastrointestinal cancers.

KEY FINDINGS:

• Fluoropyrimidine-based chemotherapy significantly reduced the absolute risk of all-cause mortality at 1 year (RD: -7.7%; 95% CI: -8.7% to -6.7%).
• There was a small increased risk of acute cardiovascular events (RD: 0.9%; 95% CI: 0.0% to 1.9%), primarily due to arrhythmias (RD: 0.8%; 95% CI: 0.1% to 1.6%) and cardiac arrest (RD: 0.3%; 95% CI: 0.1% to 0.5%).
• No increased risk of acute coronary syndromes was observed, even in patients with pre-existing coronary artery disease.
• The substantial survival benefit of fluoropyrimidines in GI cancer patients outweighs the small risk of cardiac arrhythmia and arrest.

BACKGROUND: Fluoropyrimidine chemotherapy is a primary first-line treatment for many gastrointestinal cancers. However, concerns regarding its cardiotoxicity often lead to the use of alternative treatments in patients with pre-existing cardiovascular disease. This study aimed to quantitatively assess the risks of all-cause mortality and acute cardiovascular events associated with fluoropyrimidine treatment to inform clinical decision-making.

DETAILS: This observational cohort study utilized a target trial emulation framework with linked national cancer, cardiac, and hospitalization registry data from the Virtual Cardio-Oncology Research Initiative. The study included 103,110 adult patients (mean age 69.7 years, 59% male) diagnosed with tumors eligible for first-line fluoropyrimidine-based chemotherapy. Researchers compared all-cause mortality and a composite of hospitalization for acute cardiovascular events (including acute coronary syndrome, heart failure, cardiac arrhythmia, cardiac intervention, cardiac arrest, and cardiac death) between patients receiving fluoropyrimidine-based chemotherapy and those undergoing alternative management. The findings indicate that the improved overall survival with fluoropyrimidines in patients with gastrointestinal cancer is a significant benefit that should encourage oncologists to avoid undue clinical conservatism, particularly when treating patients with co-existing cardiovascular disease.

Copyright © Authors. All rights reserved.

Source: Abiodun, A. T., Ju, C., Welch, C. A., et al. Fluoropyrimidine Chemotherapy and the Risk of Death and Cardiovascular Events in Patients With Gastrointestinal Cancer. J Am Coll Cardiol CardioOnc.. 2025; 7(4): 345-356. Published: June, 2025. DOI: 10.1016/j.jaccao.2025.01.019.

Immunogenicity, Safety, and Efficacy of the Vaccine H56:IC31 In Reducing the Rate of Tuberculosis Disease Recurrence In HIV-negative Adults Successfully Treated for Drug-Susceptible Pulmonary Tuberculosis: A Double-Blind, Randomised, Placebo-Controlled, Phase 2b Trial

[Posted 2/Jul/2025]

AUDIENCE: Infectious Disease, Family Medicine

KEY FINDINGS: Vaccination with H56:IC31 at treatment completion for pulmonary tuberculosis did not reduce the risk of recurrent disease. H56:IC31 was well tolerated and immunogenic but might have increased the risk of relapses by endogenous strains.

BACKGROUND: People with tuberculosis who complete treatment remain at risk of recurrent disease. The vaccine H56:IC31 has been shown to be safe and immunogenic in phase 1 and 2 studies, but whether it can reduce the risk of tuberculosis recurrence is unknown.

DETAILS: In a double-blind, randomised, placebo-controlled, phase 2b trial in South Africa (five clinical trial sites) and Tanzania (one clinical trial site), we enrolled participants aged 18-60 years, without HIV, who had completed more than 5 months (22 weeks) of treatment for drug-susceptible pulmonary tuberculosis. During trial screening (<=7 days after starting treatment), two sputum samples were obtained and frozen for later comparison to recurrent isolates by whole-genome sequencing (WGS). Eligible participants were randomly assigned (1:1; block size of four) to receive two intramuscular doses in the deltoid, 56 days apart, of H56:IC31 or placebo. After the first dose of H56:IC31 or placebo, participants were followed up until study day 421 (1 year after the second dose) and checked at each visit for tuberculosis signs and symptoms. If tuberculosis was suspected, two sputum samples were obtained: one sample was tested by automated molecular test (Xpert MTB/RIF Ultra) and sent for liquid culture; and the other sample was stored frozen for later analysis by whole-genome sequencing (WGS). At the last visit (day 421), two sputum samples were obtained from all sputum-productive participants, regardless of symptoms, to detect cases of asymptomatic tuberculosis. The primary endpoint was culture-confirmed recurrent pulmonary tuberculosis (due to relapse with the same strain, reinfection by a different strain, or indeterminate) occuring during the period starting at day 70 (14 days after the second dose) and ending on day 421 (1 year after the second dose). Vaccine efficacy against recurrent tuberculosis was derived from Cox proportional hazards models. Secondary endpoints included vaccine efficacy to prevent tuberculosis relapse or reinfection independently, as differentiated by WGS, and safety and immunogenicity outcomes (H56-specific CD4 T-cell responses and humoral anti-H56 IgG responses). Primary analysis of vaccine efficacy was based on modified intention-to-treat (mITT), in all randomly assigned participants except those with tuberculosis disease recurrence or who withdrew before day 70 (or 14 days after the second dose for those who received both doses). Safety was assessed in all randomly assigned participants who received at least one dose of vaccine or placebo. The trial was registered with ClinicalTrials.gov, NCT03512249, and is complete. 831 participants (mean age 34.7 years [SD 11.1]; 229 [28%] female and 602 [72%] male; 549 [66%] Black) were enrolled from Jan 31, 2019, to Jan 20, 2022; 415 participants were randomly assigned to receive H56:IC31 and 416 to receive placebo. Follow-up was completed by March 20, 2023 (mean follow-up duration 410.1 days [SD 82.8]). In the primary mITT analysis, recurrent tuberculosis occurred in 23 of 400 participants in the H56:IC31 group (12 relapses, eight reinfections, and three indeterminate); and in 14 of 406 in the placebo group (six relapses, seven reinfections, and one indeterminate). Vaccine efficacy for prevention of recurrence was -73.8% (95% CI -246.9 to 9.8; p=0.10). Vaccine efficacy for prevention of relapse was -116.1% (-522.2 to 16.3; p=0.11) and for prevention of reinfection was -21.1% (-245.3 to 56.5; p=0.71). 2 weeks after the planned second dose, H56:IC31 had significantly increased the frequencies of H56-specific CD4 T cells expressing interferon-γ, tumour necrosis factor, interleukin (IL)-2, or IL-17 in vaccinees (median percentage of CD4 T cells, 0.35% [IQR 0.19 to 0.57]) compared with placebo (0.11% [0.09 to 0.23]; p < 0.0001). H56-specific IgG responses were significantly higher in H56:IC31 recipients (median arbitrary units per mL, 6.84 [IQR 1.64 to 32.8]) than in placebo recipients (1.94 [1.05 to 3.86]; p < 0.0001). A greater proportion of H56:IC31 recipients had mild-to-moderate injection site reactions than placebo recipients (165 [40%] of 415 vs 78 [19%] of 416). No treatment-related serious adverse events were reported. Two participants who received H56:IC31 and six who received placebo died.

Copyright © Elsevier Ltd. All rights reserved.

Source: Borges, A. H., Russell, M., Tait, D., et al. Immunogenicity, Safety, and Efficacy of the Vaccine H56:IC31 In Reducing the Rate of Tuberculosis Disease Recurrence In HIV-negative Adults Successfully Treated for Drug-Susceptible Pulmonary Tuberculosis: A Double-Blind, Randomised, Placebo-Controlled, Phase 2b Trial. The Lancet Infectious Diseases. 2025; 25(7): 751-763. Published: July, 2025. DOI: 10.1016/S1473-3099(24)00814-4.

[Posted 1/Jul/2025]

AUDIENCE: Neurology, Internal Medicine, Ob/Gyn

KEY FINDINGS: This population-based study on dementia biomarkers found that P-tau181 was dependent on age and APOEe4; NfL on age and sex; and GFAP on age, sex, APOEe4, and menopause status. GFAP levels and rate of increase were higher in women, especially in premenopausal participants. Future research should confirm these findings and further explore the role of menopause in dementia pathogenesis among women.

BACKGROUND: Dementia-related blood biomarkers are the future of large-scale dementia risk stratification; however, the extent to which phosphorylated tau (P-tau181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) are associated with nonmodifiable risk factors has yet to be confirmed in the community, and the role of menopause has yet to be investigated. Therefore, the aim of this study was to examine the association of age, sex, APOEe4 status, and menopause, with dementia-related blood biomarker levels (P-tau181, NfL, and GFAP) and rate of change over 11 years in longitudinal biomarker measurements in community-dwelling adults.

DETAILS: Within this German population-based Epidemiologische Studie zu Chancen der Verhütung, Früherkennung und optimierten Therapie chronischer Erkrankungen in der älteren Bevölkerung cohort study (n = 9,940), a nested case-control study of 1,026 participants (1:1, without dementia during follow-up: incident dementia during follow-up) aged 50-75 years at baseline followed over 17 years was conducted. Blood biomarker measurements (P-tau181, NfL, and GFAP) were completed in blood from baseline, 8-year, and 11-year follow-ups, and cross-sectional and longitudinal regression analyses were used to assess the association with age, sex, APOEe4, and menopause. The mean age of participants was 64 years, and women accounted for slightly over half (54%) of the sample. Age was cross-sectionally and longitudinally significantly associated with all dementia-related biomarkers (p < 0.001). NfL and GFAP levels more strongly correlated (Spearman R = 0.55 and 0.49) with age at baseline than P-tau181 levels (Spearman R = 0.21). Women experienced significantly higher levels and rates of increase in GFAP (p < 0.001) while men experienced higher levels of NfL after adjusting for age and APOEe4 (p < 0.01). APOEe4 status was significantly associated with baseline and longitudinal levels of P-tau181 (baseline β = 0.30, p < 0.05) and GFAP (baseline β = 15.84, p < 0.001). Of interest, premenopausal status was significantly associated with higher GFAP levels after adjusting for age, sex, and APOEe4 (β = 19.09, p < 0.05).

Copyright © American Academy of Neurology. All Rights Reserved.

Source: Stocker, H., Beyer, L., Trares, K., et al. Association of Nonmodifiable Risk Factors With Alzheimer Disease Blood Biomarkers in Community-Dwelling Adults in the ESTHER Study. American Academy of Neurology. 2025; 104(9): 213500. Published: May 27, 2025. DOI: 10.1212/WNL.000000000021350.

[Posted 27/May/2025]

AUDIENCE: Gastroenterology, Ob/Gyn, Internal Medicine

KEY FINDINGS: Pregnancy MDC exposures may increase risk of liver injury and steatosis, particularly in children. Adequate FA supplementation and maternal cobalt levels may attenuate these associations.

BACKGROUND: Scarce knowledge about the impact of metabolism-disrupting chemicals (MDCs) on steatotic liver disease limits opportunities for intervention. We evaluated pregnancy MDC-mixture associations with liver outcomes, and effect modification by folic acid (FA) supplementation in mother-child pairs.

DETAILS: Authors studied ~200 mother-child pairs from the Mexican PROGRESS cohort, with 43 MDCs measured during pregnancy (estimated air pollutants, blood/urine metals or metalloids, urine high- and low-molecular-weight phthalate [HMWPs, LMWPs] and organophosphate-pesticide metabolites), and serum liver enzymes (ALT, AST) at ~9 years post-parturition. Outcomes included elevated liver enzymes in children and established clinical scores for steatosis and fibrosis in mothers (i.e., AST:ALT, FLI, HSI, FIB-4). Bayesian-weighted quantile sum regression assessed MDC-mixture associations with liver outcomes. We further examined chemical-chemical interactions and effect modification by self-reported FA supplementation. In children, many MDC-mixtures were associated with liver injury. Per quartile HMWP-mixture increase, ALT increased by 10.1% (95% CI 1.67%, 19.4%) and AST by 5.27% (95% CI 0.80%, 10.1%). LMWP-mixtures and air pollutant-mixtures were associated with higher AST and ALT, respectively. Air pollutant and non-essential metal/element associations with liver enzymes were attenuated by maternal cobalt blood concentrations (p-interactions <0.05). In mothers, only the LMWP-mixture was associated with odds for steatosis (odds ratio = 1.53, 95% CI 1.01-2.28 for HSI >36, and odds ratio 1.62, 95% CI 1.05-2.49 for AST:ALT <1). In mothers and children, most associations were attenuated (null) at FA supplementation >=600 µg/day (p-interactions <0.05).

Copyright © Elsevier Inc. All rights reserved.

Source: India-Aldana, S., Midya, V., Betanzos-Robledo, L., et al. Impact of Metabolism-Disrupting Chemicals and Folic Acid Supplementation on Liver Injury and Steatosis in Mother-Child Pairs. Journal of Hepatology. 2025; 82(6): 956-966. Published: June, 2025. DOI: 10.1016/j.jhep.2024.11.050 .

The ADVANCE Study

[Posted 26/May/2025]

AUDIENCE: Endocrinology, Family Medicine

KEY FINDINGS: The present ADVANCE analysis suggests that not having HbA_1c >=8.0%, rather than achieving HbA_1c <7.0%, was found to be particularly important for CAD prevention among people with type 2 diabetes and the common Hp2-2 phenotype. While the subgroup analyses were likely underpowered, their inclusion is hypothesis generating and can be used in future meta-analyses to improve power and generalizability.

BACKGROUND: This study sought to determine whether the association between attaining specific glycated hemoglobin (HbA1c) targets (<7.0% (<53 mmol/mol) and >=8.0% (>=64 mmol/mol) compared with 7.0%-7.9%) over time and risk of incident coronary artery disease (CAD) was dependent on haptoglobin (Hp) phenotype in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) study.

DETAILS: Prospectively collected HbA_1c data from the ADVANCE biomarker case-cohort study, updated at 6 months and every 12 months thereafter over a median of 5.0 (IQR 4.5-5.3) years, were analyzed in relation to incident CAD in the Hp2-2 (n=1323) and non-Hp2-2 (n=2069) phenotypes separately using weighted multivariable-adjusted Cox regression models. Additional a priori stratifications by sex, race, previous cardiovascular disease (CVD), and type 2 diabetes duration were performed. Mean HbA1c was similar in each phenotype group throughout the study. Compared with HbA1c of 7.0%-7.9%, HbA1c <7.0% was not associated with CAD risk for any phenotype group or subgroup. HbA1c >=8.0% compared with 7.0%-7.9% over time was associated with higher CAD risk for the Hp2-2 phenotype only (HR 1.53, 95% CI 1.01 to 2.32; no significant association in the non-Hp2-2 type: 1.26, 0.89 to 1.77, p-interaction=0.71); this was pronounced when those with previous CVD at baseline were excluded (Hp2-2: 2.80, 1.41 to 5.53, p-interaction=0.03). Compared with HbA1c of <8.0%, having HbA1c >=8.0% was associated with a 59% higher CAD risk among participants with the Hp2-2 phenotype (1.59, 1.12 to 2.26) and a 39% higher CAD risk among participants without the Hp2-2 phenotype (1.39, 1.03 to 1.88, p-interaction=0.97).

Copyright © BMJ Publishing Group Ltd. All rights reserved.

Source: Cahill, L. E., Warren, R. A., Lavallée, S. K., et al. Relationship Between Time-Varying Achieved HbA_1c and Risk of Coronary Artery Disease Events Among Common Haptoglobin Phenotype Groups With Type 2 Diabetes: The ADVANCE Study. BMJ Open Diabetes Research & Care. 2025; 13(3): e004713. Published: May 6, 2025. DOI: 10.1136/bmjdrc-2024-004713.