A Population-Based Cohort Study

[Posted 28/Dec/2021]

AUDIENCE: Internal Medicine, Orthopedic

KEY FINDINGS: Discontinuation of denosumab resulted in an increased risk of major osteoporotic fractures, especially vertebral fractures. The increased risk tends to reveal within 1 year post-discontinuation and be greater after a longer treatment duration. Notably, only fracture with hospitalization was identified as research outcome, the real risk of osteoporotic fracture post discontinuation is believed to be higher, especially for vertebral fracture.

BACKGROUND: Purpose of this study was to compare the risks of major osteoporotic, vertebral, and non-vertebral fractures between patients who discontinued anti-osteoporosis medications.

DETAILS: Conducted a comparative effectiveness study with a nationwide population-based cohort study design. Patients aged >=50 years admitted between 2012 and 2015 for incident hip fractures and receiving denosumab or bisphosphonates with sufficient compliance for at least 1 year were included. Patients were categorized into persistent or non-persistent denosumab or bisphosphonates users based on their subsequent use pattern. The main outcomes were subsequent hospitalizations for a major osteoporotic, vertebral or non-vertebral fracture. Multivariate, time-varying Cox proportional hazards model was used to evaluate the risk of major outcomes. Compared with persistent denosumab users, non-persistent denosumab users had a significantly higher risk of major osteoporotic fractures (hazard ratio [HR] = 1.60; 95% confidence interval [CI], 1.20-2.14), vertebral fractures (HR = 2.18; 95% CI, 1.46-3.24) and death (HR = 3.57; 95%CI, 2.63-4.84). However, the increased risk of fracture was not found in both persistent and non-persistent bisphosphonates users. Noteworthy, the increased risk of vertebral fractures in non-persistent denosumab users was more pronounced within 1 year post-discontinuation (HR = 2.90; 95% CI, 1.77-4.74) and among patients who discontinued from 2-year denosumab therapy (HR = 3.58; 95% CI, 1.74-7.40).

Copyright © John Wiley & Sons, Inc. All rights reserved

Source: Fu, S., Wang, C., Hung, C., et al. (2021). Increased Fracture Risk After Discontinuation Of Anti-Osteoporosis Medications Among Hip Fracture Patients: A Population-Based Cohort Study. J Intern Med. 2021; 290(6): 1194-1205. Published: December, 2021. DOI: 10.1111/joim.13354.

[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.

A Randomized Controlled Trial.

[Posted 19/May/2025]

AUDIENCE: Endocrinology, Family Medicine

KEY FINDINGS: In older adults with T1D and high risk of hypoglycemia, CGM use enhanced by geriatric principles can lower hypoglycemia without worsening glycemic control in a cost-effective fashion.

BACKGROUND: Continuous glucose monitoring (CGM) use in older adults with type 1 diabetes (T1D) has shown benefits. However, the impact of CGM use, coupled with simplified treatment regimens and personalized glycemic goals that are better suited for older patients with multiple comorbidities and hypoglycemia, is not known.

DETAILS: Older adults (>=65 years) with T1D with hypoglycemia (two or more episodes of hypoglycemia [blood glucose <70 mg/dL for >=20 min over 2 weeks]) who were CGM naive or CGM users were randomized to intervention and control groups. The intervention consisted of the combined use of CGM with geriatric principles (i.e., adjusting goals based on overall health, and simplification of regimens based on CGM patterns and clinical characteristics) over 6 months. The control group received usual care by their endocrinologist. The primary end point was change in time when blood glucose was <70 mg/dL from baseline to 6 months. Cost-effectiveness was calculated using a health care sector perspective. Authors randomized 131 participants (aged 71 ± 5 years; 21% >=75 years old) to the intervention (n = 68; CGM users = 33) or the control (n = 63; CGM users = 40) group. The median change in hypoglycemia from baseline to 6 months was -2.6% in the intervention group and -0.3% in the control group (median difference, -2.3% [95% CI -3.7%, -1.3%]; P < 0.001). This improvement was seen in both CGM naive (-2.8%; 95% CI -5.6%, -0.8%) and CGM users (-1.2%; 95% CI -2.7%, -0.1%). The HbA1c did not differ between the groups (7.5% vs. 7.3%). The intervention was cost-effective (incremental cost-effectiveness ratio $71,623 per quality adjusted life-year).

Copyright © American Diabetes Association. All rights reserved.

Source: Munshi, M., N., Slyne, C., Adam, A., et al. Continuous Glucose Monitoring with Geriatric Principles in Older Adults with Type 1 Diabetes and Hypoglycemia: A Randomized Controlled Trial. Diabetes Care. 2025; 48(5):694-702. Published: May, 2025. DOI: 10.2337/dc24-1069.

A Cohort Study From the EINSTEIN-Jr Phase 3 Trial

[Posted 18/May/2025]

AUDIENCE: Hematology, Pediatric

KEY FINDINGS: Incidences of recurrent venous thromboembolism and bleeding during extended-phase anticoagulant treatment were low and similar to those observed during acute-phase treatment and adult studies on extended-phase anticoagulant treatment, providing valuable information for clinical practice on extended anticoagulation in children.

BACKGROUND: Extended-phase anticoagulation of venous thromboembolism in children is not well documented nor systematically reported. Previously, we reported on recurrent venous thromboembolism and bleeding during acute-phase anticoagulation in EINSTEIN-Jr, a randomised controlled study in 500 children with venous thromboembolism comparing rivaroxaban to standard anticoagulants. The aim of the present study was to evaluate the efficacy and safety of extended-phase anticoagulant therapy in children and to characterise factors associated with the decision to extend anticoagulation.

DETAILS: Children aged 17 years or younger, who were enrolled in the EINSTEIN-Jr trial (NCT02234843) from 107 paediatric hospitals in 28 countries, and who had previously completed a 3-month acute anticoagulation treatment phase (1-month in children <2 years with catheter-related venous thromboembolism) for acute venous thromboembolism within the trial were included in this cohort study. After completion of the preceding acute anticoagulation treatment phase, children could extend study treatment for up to 9 months (or up to 2 months for children <2 years with catheter-related venous thromboembolism). Study anticoagulants were bodyweight-adjusted rivaroxaban (tablets or suspension) in a 20 mg equivalent dose or standard anticoagulants (heparin or vitamin K antagonist). The main outcomes were suspected recurrent venous thromboembolism (primary efficacy outcome) and clinically relevant bleeding (principal safety outcome), both confirmed or refuted by appropriate objective testing. Cumulative incidences of efficacy and safety outcomes are reported for children who received extended anticoagulation within the framework of the study. We also compared demographic and clinical characteristics of those administered any extended-phase anticoagulation (whether within or outside the framework of the study) with those not administered extended-phase anticoagulation, applying multivariable logistic regression. 248 (51%) children received extended-phase anticoagulation between Nov 14, 2014, and Jan 15, 2019, 214 within the study and 34 outside the framework of the study. During extended-phase anticoagulant treatment, recurrent venous thromboembolism occurred in three (1%) of the 214 children within the study (cumulative incidence 3.0%; 95% CI 0.9-9.8). Clinically relevant non-major bleeding occurred in four (2%) of 214 children (3.3%; 1.2-9.2). Fatal venous thromboembolism or major bleeding did not occur. Outcome rates were similar with rivaroxaban or standard anticoagulants. Symptomatic index venous thromboembolism (odds ratio 1.88; 95% CI 1.14-3.11), unprovoked venous thromboembolism or persistent risk factor (2.16; 1.46-3.19), and residual thrombosis on repeat imaging (3.79; 2.52-5.71) were associated with the decision to extend anticoagulation.

Copyright © Elsevier Ltd. All rights reserved.

Source: Male, C., Lensing, A. W. A., Chan, A. K. C., et al. Extended-Phase Anticoagulant Treatment of Acute Venous Thromboembolism in Children: A Cohort Study From the EINSTEIN-Jr Phase 3 Trial. The Lancet Haematology. 2025; 12(5):5, e357-e364. Published: April, 2025. DOI: PIIS2352-3026(25)00067-5.

The EMPEROR Program

[Posted 16/May/2025]

AUDIENCE: Cardiology, Emergency Medicine

KEY FINDINGS: The erythropoietin-erythroferrone-TfR1-hepcidin axis is activated in patients with heart failure as the disease advances and is further heightened by SGLT2 inhibitors, in parallel with their effect to enhance erythropoiesis and iron mobilization and use. These changes have important implications for understanding the mechanism of action of SGLT2 inhibitors and for monitoring the response to treatment.

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors stimulate erythropoiesis, but the mechanisms and clinical relevance of the effect of SGLT2 inhibitors on systemic iron metabolism in patients with heart failure is not well understood. The authors sought to characterize a comprehensive suite of iron metabolism biomarkers—particularly the erythroblast signaling molecule, erythroferrone—in patients with heart failure before and after short- and long-term treatment with empagliflozin in patients with heart failure and a reduced or preserved ejection fraction.

DETAILS: Authors measured serum iron metabolism biomarkers at baseline, 12 weeks, and 52 weeks in 1,139 patients who were treated with placebo or empagliflozin in the EMPEROR (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure) program, and characterized the inter-relationships of these biomarkers with clinical status and with the effect of empagliflozin on erythropoiesis and heart failure outcomes. Correlations among iron biomarkers indicated the presence of a functional erythropoietin-erythroferrone-transferrin-receptor-protein-1 (TfR1)-hepcidin axis. As heart failure advanced, patients showed higher levels of erythropoietin, erythroferrone, and TfR1 (P trend <0.01), and levels of these proteins predicted a heightened risk of cardiovascular death or heart failure hospitalization (all P < 0.01). Compared with placebo, at 12 weeks, empagliflozin increased hemoglobin by 0.6 to 0.9 g/dL (P < 0.001), an effect that was accompanied by further activation of the erythropoietin-erythroferrone-TfR1 axis and increased iron use. Empagliflozin increased serum levels of erythroferrone by >40% (along with increases in erythropoietin and TfR1), while simultaneously decreasing hepcidin levels and reducing serum iron concentrations and transferrin saturation (all P < 0.01). When treated with empagliflozin, patients with evidence of iron deficiency at baseline showed attenuation of the erythrocytic response (P trend = 0.04) but no diminution of the heart failure benefits.

Copyright © American College of Cardiology Foundation. All rights reserved.

Source: Ferreira, J. P., Anker, S. D., Butler, J., et al. (20245). Effect of Empagliflozin on the Mechanisms Driving Erythropoiesis and Iron Mobilization in Patients With Heart Failure: The EMPEROR Program. J Am Coll Cardiol.. 2025; 85(18): 1757-1770. Published: May, 2025. DOI: 10.1016/j.jacc.2025.03.503.