In healthy lean humans, endogenous glucose-dependent insulinotropic polypeptide (GIP) contributes significantly to the postprandial increase in arteria mesenterica superior blood flow. The vascular biology related to activation of the GIP receptor is markedly impaired in individuals with type 2 diabetes and is sometimes absent. In this population, we investigated the role of endogenous GIP on postprandial splanchnic blood flow by using the GIP receptor antagonist, GIP(3-30)NH2. The primary outcome of this study was the changes in blood flow in arteria mesenterica superior during oral glucose with or without GIP receptor antagonist infusion. Ten participants with type 2 diabetes (age 20-80 years, BMI 20-35 kg/m2, and HbA1c >48 mmol/mol and <75 mmol/mol) were investigated in a randomised, placebo-controlled, crossover study. On four separate occasions, participants received the following treatment: oral glucose + i.v. GIP(3-30)NH2; oral glucose + i.v. saline (154 mmol/l NaCl); oral water + i.v. GIP(3-30)NH2; oral water + i.v. saline. Participants were randomly assigned to intervention groups using (random.org). Participants were unaware of allocation, while investigators were aware. No additional allocation concealment procedures were used. During all four interventions, splanchnic blood flow was measured using phase-contrast MRI in the arteria mesenterica superior, truncus coeliacus and vena portae during oral glucose (75 g) or water ingestion. The study was conducted at Rigshospitalet, Copenhagen. Liver volume and oxygenation, as well as gallbladder volume, were assessed. Blood samples were collected and analysed for insulin, C-peptide, GIP, glucagon and glucose. Oral glucose alone increased mean blood flow in arteria mesenterica superior by 57% (95% CI 26, 88) and this was 15% (95% CI -2, 32) lower during concomitant GIP receptor antagonist infusion, p=0.012. Infusion of GIP receptor antagonist during oral glucose treatment did also result in lower insulin secretion, C-peptide and C-peptide/glucose ratio compared with saline infusion, whereas glucagon levels and plasma glucose were unaffected. Oral water did not affect any outcomes. Endogenous GIP contributes to postprandially increased splanchnic blood flow in people with type 2 diabetes. ClinicalTrials.gov NCT06426823 FUNDING: This work was supported by the Novo Nordisk Foundation.
Metabolic dysfunction-associated steatotic liver disease (MASLD) has become the most prevalent chronic liver disease worldwide and is tightly linked to cardiometabolic comorbidities. A major clinical focus on MASLD is the detection of hepatic fibrosis, which most strongly predicts liver-related events, hepatocellular carcinoma risk and mortality. While lifestyle modification and sustained weight loss remain foundational, therapeutic innovation has rapidly expanded, shifting the metabolic dysfunction-associated steatohepatitis (MASH) treatment landscape towards targeted pharmacotherapies that address metabolic stress, inflammation and fibrogenesis, particularly for moderate/advanced fibrosis (i.e., F2/F3 fibrosis and cirrhosis). This review summarises the burden and systemic complications of MASLD, highlights endocrine influences that modulate hepatic steatosis and disease severity and emphasises the central role of fibrosis staging and non-invasive risk stratification in clinical decision-making. We then synthesise emerging pharmacotherapies across key mechanistic axes, including incretin-based agents (GLP-1 receptor agonists and dual/triple agonists), hepatocyte-directed metabolic modulators (thyroid hormone receptor-β agonists, fatty acid synthase inhibitors, acetyl-CoA carboxylase and other de novo lipogenesis inhibitors), bile acid pathway therapies (FXR agonists) and pleiotropic metabolic-fibrotic regulators (fibroblast growth factor 21 [FGF21] analogues and peroxisome proliferator-activated receptor [PPAR] agonists). We also discuss combination strategies, candidate agents with potential direct antifibrotic activity and the growing role of genetic risk stratification and hepatocyte-targeted oligonucleotide therapeutics. Finally, we outline current surrogate endpoints used in clinical trials and propose future directions towards stage-specific, mechanism-informed and combination regimens to achieve persistent MASH resolution and meaningful fibrosis regression.
Externally controlled single-arm trials are critical to assess treatment efficacy across therapeutic indications for which randomized controlled trials are not feasible. A closely-related research design, the unanchored indirect treatment comparison, is often required for disconnected treatment networks in health technology assessment. We present a unified causal inference framework for both research designs. We develop an estimator that augments a popular weighting approach based on entropy balancing-matching-adjusted indirect comparison (MAIC)-by fitting a model for the conditional outcome expectation. The predictions of the outcome model are combined with the entropy balancing MAIC weights. While the standard MAIC estimator is singly robust where the outcome model is non-linear, our augmented MAIC approach is doubly robust (DR), providing increased robustness against model misspecification. This is demonstrated in a simulation study with binary outcomes and a logistic outcome model, where the augmented estimator demonstrates its DR property, while exhibiting higher precision than all non-augmented weighting estimators and near-identical precision to G-computation. We describe the extension of our estimator to the setting with unavailable individual participant data for the external control, illustrating it through an applied example. Our findings reinforce the understanding that entropy balancing-based approaches have desirable properties compared to standard "modeling" approaches to weighting, but should be augmented to improve protection against bias and guarantee double robustness.
Obicetrapib is a potent, selective cholesteryl ester transfer protein (CETP) inhibitor that lowers LDL-C and raises HDL-C. Although prior studies have demonstrated efficacy and general tolerability, a comprehensive evaluation of its safety profile across later-stage clinical trials is needed. Safety outcomes were assessed in a pooled analysis of two phase III trials comparing obicetrapib 10 mg daily with placebo in adults with heterozygous familial hypercholesterolemia (HeFH) or atherosclerotic cardiovascular disease (ASCVD). Participants received treatment for 365 days. Safety endpoints included treatment-emergent adverse events (TEAEs) and prespecified events of special interest including hepatic, muscular, glycemic, renal and ocular parameters as well as overall rates of discontinuation. A total of 2,880 participants were included (mean age 64 years; 36 % female; 82 % with ASCVD; 35.8 % with diabetes). Overall TEAE rates were similar between obicetrapib and placebo (60.2 % vs 62.0 %). AEs leading to treatment discontinuation occurred in 4.1 % of obicetrapib-treated participants and 5.3 % on placebo, Risk Ratio (RR) 0.77 [0.54-1.08]. No clinically significant change in blood pressure was observed between groups and hypertension events were comparable. There was no difference between the groups in liver or muscle-related endpoints. Reduction in eGFR occurred less often with obicetrapib ( compared to placebo (6.7 % vs. 8.7 % RR 0.77 [0.59, 1.00])). Macular degeneration was reported once in the obicetrapib group (n= 1 [0.1 %]). Deaths were similar between treatment groups. No new safety signals were identified. Obicetrapib demonstrated a favorable safety profile over 12 months, with AE rates comparable to placebo. These findings extend our understanding of the safety and tolerability of obicetrapib.
The 2026 ACC/AHA dyslipidemia guideline introduces PREVENT-based risk assessment, new direct-treatment pathways for comorbid conditions, and long-term risk estimation. The population-level effect of these changes on lipid-lowering therapy recommendations is unknown. To compare classification of U.S. adults under the 2018 and 2026 dyslipidemia guidelines for treatment recommendations. Cross-sectional study of the National Health and Nutrition Examination Survey (2013-2023) including adults aged 40-75 years with data suitable for guideline classification. Individuals already receiving lipid-lowering therapy were classified separately. Treatment recommendation categories of 'recommended/indicated', 'reasonable/favored/selective-consideration', and 'not-routinely-recommended' were constructed for cross-classification of untreated adults between the two guidelines. The analytic cohort included 6,118 adults representing 118.9 million U.S. adults; 1,984 [weighted, 36.0 million (30.3%)] were already receiving lipid-lowering therapy. Among 4,134 untreated adults [82.9 million], the 2026 guideline classified 1,868 [31.2 million (37.7%)] as recommended/indicated, 1,154 [27.1 million (32.7%)] as reasonable/favored/selectively-considered, and 1,112 [24.6 million (29.7%)] as not-routinely-recommended. Under the 2018 guideline, corresponding counts were 1,289 [21.2 million (25.6%)], 1,107 [21.2 million (25.6%)], and 1,738 [40.5 million (48.9%)]. All adults recommended/indicated under the 2018 framework remained so under the 2026 framework, 45.5% of those in the 2018 reasonable stratum moved to the 2026 recommended/indicated stratum, and 39.9% of the previously not-routinely-recommended moved to a higher-intensity category. PREVENT-based pathways accounted for 33.4% of the 2026 recommended/indicated stratum. Under the 2026 dyslipidemia guideline, an additional 15.9 million (14.1-17.7) untreated Americans aged 40-75 years would be newly identified for treatment consideration. The updated guideline substantially reallocates untreated adults toward consideration for treatment.
Rheumatic heart disease is increasingly recognized as an immunologically active condition characterized by persistent low-grade inflammation contributing to atrial dysfunction. The authors aimed to evaluate whether colchicine reduces systemic inflammation and improves left atrial (LA) mechanical function in chronic rheumatic mitral valve disease. In this prospective, double-blind, randomized controlled trial, 90 patients with chronic moderate-to-severe rheumatic mitral valve disease were randomized (1:1) to colchicine (0.5 mg twice daily) or placebo for 6 months in addition to standard therapy. The primary outcome was change in interleukin (IL)-6 at 6 months. Secondary outcomes included changes in other inflammatory markers, LA strain parameters, NYHA functional class, and correlations between inflammatory markers and LA mechanics. Colchicine significantly reduced inflammatory markers (IL-6, high-sensitivity C-reactive protein, erythrocyte sedimentation rate; all P < 0.001). IL-6 decreased from 98.0 (86.9-112.1) to 11.2 (7.3-21.5) pg/mL in the colchicine group, while increasing in placebo (P < 0.001). LA reservoir strain improved significantly (23.6% ± 2.0% vs 16.5% ± 1.6%, P < 0.001). IL-6 showed strong inverse correlation with LA reservoir strain (r = -0.65, P < 0.001). Functional status improved, with 69.2% of NYHA functional class III patients improving to class II. Colchicine significantly attenuates systemic inflammation and improves LA mechanical function and functional status in chronic rheumatic mitral valve disease, supporting an inflammation-driven atrial myopathy phenotype.
The glycemic response to metformin is highly variable, yet the genetic determinants of metformin pharmacokinetics remain poorly characterized. In the Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH), an ancestrally diverse cohort, we evaluated clinical and genetic factors associated with plasma metformin concentrations. Plasma metformin concentrations were measured in 745 participants who completed a standardized acute metformin challenge in SUGAR-MGH. Higher metformin concentrations were associated with older age (β=2.5 ng/mL per year, p = 0.02), lower eGFR (β=-3.5 ng/mL per ml/min/1.73m2, p = 4.5 × 10-4), and lower BMI (β=-7.3 ng/mL per kg/m2, p = 1.3 × 10-4). African ancestry was associated with lower metformin concentrations compared to European ancestry (β=-72.6 ng/mL, p = 0.036). A genome-wide association study (GWAS) identified four African ancestry-specific genetic variants significantly associated with higher metformin concentrations (p < 5 × 10-8) as well as several suggestive loci near genes implicated in glucose metabolism, including USP36 and DGKB. Top variants associated with metformin concentration were not associated with glycemic response endpoints following the metformin challenge, including fasting glucose at Visit 2, change in HOMA-IR, and change in fasting insulin between visits. Previously reported metformin transporter variants showed no significant associations with metformin concentration. These findings represent the first GWAS of metformin plasma concentrations and provide a novel resource for future studies of metformin pharmacogenetics.
To study associations between prediabetes, type 2 diabetes (T2D) and insulin resistance with incident atrial fibrillation (AF) in patients with hypertension. Patients with hypertension but no AF between 2006 and 2010 were identified in the Swedish Primary Care Cardiovascular Database. Patients with type 1 diabetes or pre-existing cardiovascular disease were excluded. Patients were categorized into normoglycemia, prediabetes or T2D and followed until 2023 or incident AF. Insulin resistance was assessed using triglyceride-glucose (TyG) index and TyG-BMI index. Associations with incident AF and mortality were evaluated using multivariable models. Among 15 715 patients (64 ± 11 years, 55 % women), 60 % were normoglycemic, 17 % had prediabetes and 23 % T2D. During a median follow-up of 14.7 years, AF occurred in 18 %, 21 % and 20 %, respectively. Neither prediabetes (HR 0.99, 95 % CI 0.87-1.13) nor T2D (HR 1.00, 95 % CI 0.89-1.11) was associated with incident AF compared with normoglycemia. In contrast, the TyG index demonstrated a U-shaped association with incident AF, whereas the TyG-BMI index showed a positive association. Both prediabetes and T2D were associated with increased all-cause mortality (HR 1.17, 95 % CI 1.06-1.30 and HR 1.62, 95 % CI 1.50-1.75, respectively). Prediabetes and T2D were not independently associated with AF in hypertensive patients. Our findings suggest a potential role for BMI and insulin resistance in AF risk, independent of glycemic category, warranting further prospective investigation.
GPR183, a G protein-coupled receptor activated by oxysterols, regulates immune and metabolic signaling in a sex-dependent manner. Lauroyl tryptamine (LT), a lipid-modified microbial metabolite, was recently identified as a GPR183 antagonist. We hypothesized that LT disrupts oxysterol-driven metabolic regulation by antagonizing GPR183 activity. LT's antagonistic properties were assessed using BRET-based assays for GPR183-mediated arrestin recruitment and G protein signaling. LT absorption was quantified in isolated perfused rat colon. Metabolic outcomes were evaluated in wild-type (WT) and Gpr183 knockout (Gpr183-/-) mice treated with LT or the synthetic antagonist NIBR189. To examine microbiota contributions, cecal contents from WT and Gpr183-/- mice were transplanted into germ-free recipients, and metabolic phenotypes were analyzed. LT selectively inhibited oxysterol (7α,25-OHC)-induced arrestin recruitment via human and mouse GPR183 without altering Gαi signaling. LT was absorbed across the colonic epithelium in a dose-dependent manner. Female mice treated with NIBR189 but not LT exhibited differences in body weight change and glucose homeostasis. Microbiota transfer did not reproduce the phenotype. LT induced weight loss in male WT mice, but not in Gpr183-/- males. LT functions as a pathway-specific antagonist of oxysterol signaling via GPR183, modulating lipid-sensitive metabolic pathways in a sex-dependent manner.
Fatty pancreas is a metabolically active ectopic fat depot, but its cardiometabolic implications have been assessed using heterogeneous thresholds. We investigated the association of fatty pancreas, quantified using MRI-derived proton density fat fraction (PDFF) and categorised according to 2026 international consensus thresholds, with prevalent and incident type 2 diabetes (T2D), chronic kidney disease (CKD) and major adverse cardiovascular events (MACE). We analysed 19,255 European-ancestry participants from the UK Biobank imaging sub-study. Pancreatic PDFF was categorised as normal (< 6%), mild (6 to < 16%) and moderate-to-severe fatty pancreas (≥ 16%). Outcomes were ascertained through national health records. Associations were estimated using multivariable logistic regression and Cox models, adjusted for age, sex, BMI-defined obesity, elevated MRI-derived visceral adipose tissue and outcome-specific covariates. Moderate-to-severe fatty pancreas was associated with prevalent and incident T2D (OR 3.25, 95% CI 2.49-4.27; p < 0.001; HR 2.72, 1.66-4.46; p < 0.001), incident CKD (HR 1.82, 1.29-2.57; p < 0.001), and prevalent and incident MACE (OR 1.26, 1.04-1.56; p = 0.022; HR 1.30, 1.02-1.66; p = 0.034). Mild fatty pancreas was associated with incident T2D (HR 2.19, 1.40-3.42; p < 0.001) and incident MACE (HR 1.29, 1.06-1.59; p = 0.013). Each 5% increase in pancreatic PDFF was associated with higher odds and hazard of T2D (OR 1.16, 1.12-1.21; HR 1.17, 1.09-1.25; both p < 0.001). Fatty pancreas was independently associated with prevalent and incident T2D, incident CKD and, more modestly, with MACE. These findings position fatty pancreas within the cardiovascular-kidney-metabolic continuum and support the clinical relevance of consensus-based PDFF thresholds for cardiometabolic risk assessment in European-ancestry populations.
The most common hereditary transthyretin (ATTRv) amyloidosis variant in the United States, Val122Ile (p.Val142Ile), is predominantly detected in populations of African ancestry. In this narrative review, we highlight the current challenges and discuss priority focus areas to improve the timely diagnosis and treatment of p.Val142Ile ATTRv amyloidosis across populations. Studies suggest geographic, economic, and socio-economic discordance in timely diagnosis, treatment access, and outcomes in regions with a high proportion of at‑risk individuals. Many ATTR amyloidosis symptoms overlap with other diseases due to their nonspecific and heterogenous nature. Consequently, optimized screening tools for biomarker identification and specialty care services/networks are required to determine at-risk individuals and improve clinical outcomes. However, access to genetic screening can be limited and diagnosis is complicated by variable p.Val142Ile ATTRv amyloidosis penetrance coupled with phenotypic evolution. To enhance existing treatment guidelines, regular monitoring of "at-risk" patients, multidisciplinary management, and purposeful clinical trial recruitment of minority populations are recommended.
Conventional biomarkers such as estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (uACR) primarily reflect glomerular damage and often fail to detect early tubular injury. Consequently, patients with "non-albuminuric diabetic kidney disease (DKD)" may be overlooked. This study evaluated the independent association between urinary post-translationally modified fetuin-A fragments (uPTM-FetA) and DKD risk stratification in Japanese patients with type 2 diabetes. We conducted a cross-sectional study of 219 outpatients with type 2 diabetes between November 2023 and February 2024 at Edogawa Hospital. First-morning urine samples were analyzed for uPTM-FetA and urinary liver-type fatty acid-binding protein (uL-FABP) using enzyme-linked immunosorbent assays. DKD risk was classified into four categories based on the KDIGO guidelines. The association between uPTM-FetA and higher DKD-risk (categories 2 + 3 + 4) was assessed using multiple logistic regression and restricted cubic spline (RCS) analyses, validated by bootstrapping. The optimal cutoff value for uPTM-FetA was determined to be 11.76 ng/mgCr. Multivariable analysis adjusted for potential confounders revealed that high uPTM-FetA levels were significantly and independently associated with DKD-risk categories 2 + 3 + 4 (adjusted odds ratio: 3.88; 95% CI: 2.02-7.45; P < 0.01). RCS analysis indicated a significant non-linear association (P = 0.04). Notably, high uPTM-FetA was detected in 38.8% of patients with normoalbuminuria and 42.0% of those with preserved eGFR. A striking discrepancy was observed compared to uL-FABP: while high uL-FABP was completely absent (0.0%) in patients within the low-to-moderate risk categories (categories 1 and 2), high uPTM-FetA was observed in 34.0% and 60.8% of these patients, respectively. uPTM-FetA is independently associated with DKD severity and is elevated in a substantial proportion of patients with early-stage disease where conventional markers remain normal. Unlike uL-FABP, which increases predominantly in advanced stages, uPTM-FetA appears to identify tubular stress earlier. Thus, uPTM-FetA serves as a valuable complementary biomarker to uACR for refining DKD risk stratification.
Tirzepatide, a multi-agonist incretin agent that targets body weight and metabolic parameters, has stronger weight reduction and glycemic control effects than existing agents. This study aimed to elucidate the effects of tirzepatide on vascular function in individuals with obesity complicated by type 2 diabetes (T2D). This retrospective observational cohort study evaluated the effects of weekly tirzepatide (5-15 mg, median treatment duration 12.7 months) on vascular function and body composition in 24 individuals [45.8% male, median 48.6 years, body mass index (BMI) 32.3 kg/m2] with obesity and T2D. Sixteen individuals (66.7%) were switched from glucagon-like peptide-1 receptor agonists (GLP-1 RAs). Vascular function was assessed using the cardio-ankle vascular index (CAVI), and body composition was evaluated using skeletal muscle index (SMI) and body fat index (BFI) measured by InBody720. Tirzepatide treatment significantly decreased CAVI (post-treatment to baseline: median 8.5 to 7.8) accompanied by significant reductions in BMI (mean 33.8 to 31.8 kg/m2), SMI (median 11.4 to 10.7 kg/m2), BFI (median 12.8 to 11.3 kg/m2) and glycemic parameters (including HbA1c: median 6.6 to 5.6%). The urinary albumin/creatinine ratio (UACR) tended to decrease with tirzepatide (median 11.9 to 7.2 mg/gCr, p = 0.067), and change in (Δ)UACR showed a trend of positive correlation with ΔCAVI (r s  = 0.403, p = 0.057). BMI reduction was greater (p = 0.040) and CAVI reduction tended to be greater (p = 0.089) at higher tirzepatide doses (10 and 15 mg) than at lower doses (5 and 7.5 mg). Prior GLP-1 RA use did not affect tirzepatide efficacy. Baseline SMI, but not BFI, correlated significantly and negatively with ΔCAVI (r s  = -0.424). Tirzepatide may dose-dependently reduce body weight and CAVI, contributed by decreased UACR and relatively high baseline SMI. Although tirzepatide is expected to improve kidney and vascular dysfunction in individuals with obesity complicated by T2D, careful attention to body composition is warranted.
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Eating disorders are more prevalent in people with higher weight than those with low weight. However, contention between the fields of obesity and eating disorders has prevented meaningful progress in research, prevention, identification and coordinated clinical services for people with co-occurring conditions. In Australia, public health approaches and provision of treatment services for people with eating disorders and clinical obesity are siloed, often resulting in contradictory messaging. To address this, a roundtable meeting was held in November 2024 in Sydney, Australia, with 28 experts in one or both of these fields, including researchers, clinicians and service leaders working across paediatric and adult care, and individuals with lived experience. Guided by the National Eating Disorders Collaboration stepped system of care framework, participants identified key challenges and possible solutions, and established five priority actions. The priority actions across sectors are: Health Campaigns focused on raising awareness of eating disorders at higher weight, using appropriate language and reducing weight stigma; improved Screening and Assessment using standardised protocols across healthcare settings; supporting Primary Healthcare and improving the use of Medicare items; Tailored Treatment Pathways including integrated care models; and building Workforce Capacity to upskill professionals to provide safe, person-centred care. These actions aim to promote improved cross-sector collaboration and effective, safe, coordinated and integrated approaches to prevention, identification and treatment across the fields of obesity and eating disorders. They address the complex medical and psychological needs of those with co-occurring eating disorders and higher weight or clinical obesity through a skilled workforce and improved access to care. Effective integration, collaboration and coordination across services is essential for long-term recovery support.
Understanding the determinants that influence parents' decisions to participate with their infants in primary prevention trials is essential for achieving representative study samples and ensuring the generalizability of outcomes. We analyzed quantitative and qualitative data collected from infants eligible for the Primary Oral Insulin Trial (N=2,750) or the Supplementation with B. INfantis for Mitigation of Type 1 Diabetes Autoimmunity Trial (N=3,309). Both trials were conducted within the Global Platform for the Prevention of Autoimmune Diabetes between 07/2017 and 04/2024. Among all eligible infants, a longer decision time (odds ratio: 1.01, 95% confidence interval: 1.00-1.01, and p=0.002), having a first-degree relative with type 1 diabetes (odds ratio: 2.18, 95% confidence interval: 1.95-2.43, and p<0.001), and a higher maternal age (odds ratio: 1.03, 95% confidence interval: 1.01-1.05, and p=0.003) were associated with a higher likelihood of participation, whereas infants born in fall (odds ratio: 0.85, 95% confidence interval: 0.73-0.98, and p=0.03) and families with longer travel distances to the study center (odds ratio: 0.97, 95% confidence interval: 0.95-0.99, and p=0.01) were less likely to participate. Participation was lower in the Supplementation with B. INfantis for Mitigation of Type 1 Diabetes Autoimmunity Trial than in the Primary Oral Insulin Trial (odds ratio: 0.86, 95% confidence interval: 0.78-0.96, and p=0.005), and stratified analyses indicated that some factors, such as recruitment during the COVID-19 pandemic, affected participation differently between studies. Analysis of qualitative data from 638 families identified additional factors, including the parental perception of the child's risk for type 1 diabetes and the burden of participation. In conclusion, this study identifies both general and study-specific determinants and reasons of participation and non-participation in infant primary prevention trials.
Effective treatments are available for obesity and for hypertension and hypercholesterolaemia, which mediate the cardiovascular and renal effects of obesity. Our aim was to compare blood pressure, cholesterol, and the use of antihypertensive and lipid-lowering medicines in people with obesity and normal weight and assess whether the BMI-associated excess risk has diminished. Our primary outcomes were mean systolic blood pressure (SBP), non-HDL cholesterol and HDL cholesterol, and the proportion of the participants who used antihypertensive and lipid-lowering medicines. We used data from 110 health surveys conducted from 1990 to 2024 with 978 425 participants aged 20-79 years sampled from national populations of seven countries: Japan, South Korea, Taiwan, Thailand, Finland, England, and the USA. We used graphical presentation and trend analysis to evaluate changes over time in these outcomes in participants in the normal BMI range (20·0 to <25·0 kg/m2), and changes in the difference between participants with obesity (separately for class I obesity [30·0 to <35·0 kg/m2] and class II and III obesity [BMI ≥35·0 kg/m2]) or overweight (25·0 to <30·0 kg/m2) and those in the normal BMI range. Mean non-HDL cholesterol and SBP declined over time, especially among those older than 40 years, with the notable exception of some sex-age groups in Thailand. When pooled across all countries, age groups, and obesity and overweight BMI ranges, the difference in mean non-HDL cholesterol with normal BMI became smaller by -0·05 mmol/L per decade (95% CI -0·07 to -0·03) for females and -0·07 mmol/L per decade (-0·09 to -0·05) for males. For SBP, the pooled estimate of change in the difference with normal BMI across all countries, age groups, and obesity and overweight BMI ranges was -0·7 mmHg per decade (95% CI -1·0 to -0·4) for females and -0·6 mmHg per decade (-0·9 to -0·4) for males. The declines were larger in individuals with obesity, especially class II and III obesity, than in normal BMI, leading to a convergence of these risk factors between obesity and normal BMI in people older than 40 years. As a result of these trends, in England, the USA, Thailand, South Korea, and Japan, older people with obesity often became indistinguishable from, or better off than, those with normal BMI in terms of non-HDL cholesterol and SBP. These trends accompanied a larger increase in the use of lipid-lowering and antihypertensive medicines in middle-aged and older people with obesity than in those with normal BMI. The pooled estimate for the increase in difference in lipid-lowering medicines compared with normal BMI across all countries, age groups, and obesity and overweight BMI ranges was 1·5 percentage points per decade (1·0-2·1) for females and 1·6 percentage points per decade (1·0-2·2) for males. For antihypertensive medicines, the pooled estimate was 0·7 percentage points per decade (0·3-1·0) for females and 2·0 percentage points per decade (1·3-2·8) for males. Mean HDL cholesterol increased more in people with normal BMI than those with obesity, leading to a divergence. For people younger than 40 years, there has been little change in the gap between those with obesity or overweight and those with normal BMI; young adults were rarely treated for high cholesterol or blood pressure regardless of their BMI. In industrialised countries, blood pressure and non-HDL cholesterol in older adults with obesity are increasingly similar to those with normal BMI, with higher use of antihypertensive and lipid-lowering medicines a possible driver of this convergence. There is nonetheless heterogeneity across countries in the extent of convergence. Young adults with obesity remain metabolically at higher risk than their counterparts with normal weight. UK Medical Research Council and UK Research and Innovation (Innovate UK).
Objectives Patient portal use has steadily increased across most populations. Prior, now dated, studies indicated lower adoption rates among Spanish- vs. English- speaking patients. This study compared patient portal activation and use patterns between Spanish- and English-speaking patients. Methods This retrospective cohort study was conducted at three North Texas health systems using the MyChart patient portal (Epic Systems Co.) and included patients ≥18 years with ≥1 completed clinician encounter between 4/5/2021 and 4/4/2022. The primary activation outcome was the baseline MyChart account activation rate. The secondary activation outcome was the MyChart account activation rate within the following year among patients without an account at baseline. The primary use outcome was the rate of patients logging in. Secondary use outcomes included rates of results review, notes review, and message initiation in the following year. We also evaluated the rates of proxy account use and mobile app use. We fit multivariable logistic regression models adjusting for health system, age, sex, comorbidity count, and the number of prior-year encounters. Results Spanish speakers represented 128,338 of 1,550,220 (8.3%) patients. Spanish speakers had lower odds of having an activated account at baseline (aOR 0.39 [0.39 - 0.40]) or activating one in the next year (aOR 0.68 [0.65 - 0.71]). Spanish speakers also had lower odds of logging in (aOR 0.62 [0.61 - 0.63]), reviewing results (aOR 0.79 [0.76 - 0.81]), reviewing notes (aOR 0.87 [0.84 - 0.89]), or sending messages (aOR 0.41 [0.40 - 0.42]). More Spanish than English speakers used the mobile app (59% vs 50%). There were inter-site differences in the rate of proxy account use. Conclusions Given lower levels of portal activation and use among Spanish-speaking patients, strategies are needed to identify and address barriers to activation and use. Qualitative studies could delineate these barriers and potential mitigating strategies.
The VICTORION-1 PREVENT (V-1P) trial is evaluating the efficacy of inclisiran versus placebo on cardiovascular events in primary prevention patients at high-risk for ASCVD. We assessed whether V-1P eligibility, based on Pooled Cohort Equations (PCE) and Predicting Risk of Cardiovascular Disease Events (PREVENT) equations, was associated with subclinical cardiovascular and inflammatory abnormalities in a healthy European population. We included individuals from the STANISLAS cohort in France aged 40-79 years, LDL-C 70-189 mg/dL and without ASCVD or liver disease. Participants were categorized as V-1P eligible using 10-year ASCVD risk using PCE and PREVENT. Associations with vascular, echocardiographic, and biomarkers were assessed using age- and sex-adjusted linear regression. Among 848 participants (mean age 60 years, 51% female), 16% were eligible per PCE, of which 7% were also eligible with PREVENT. Only one participant was eligible by PREVENT alone. Compared with non-eligible participants, V-1P-eligible individuals, whether by PCE alone or PCE and PREVENT, displayed significant subclinical abnormalities. Compared with V-1P ineligible participants, V-1P eligible participants had increased intima media thickness (+51 µm, p < 0.009 for PCE+PREVENT) and increased mean pulse wave velocity (+0.89 m/s, p < 0.001 for both PCE and PCE+PREVENT) on vascular ultrasound. V-1P eligible participants by PCE+PREVENT also showed signs of subclinical myocardial injury and inflammation, with a 1.3 fold higher troponin (p = 0.015), 1.6-fold higher interleukin-6 (p < 0.001) and a 2-fold higher high sensitivity C-reactive protein (p < 0.001). A large proportion of asymptomatic individuals without known cardiovascular disease would be eligible for the V-1P trial based on both PCE and PREVENT equations. V-1P eligible participants had evidence of subclinical cardiovascular and inflammatory abnormalities.
Tuberculosis (TB) is the leading global cause of death from a single infectious agent. Recent reductions in global health funding have threatened TB control, making comprehensive assessment of TB, HIV-related TB, and drug-resistant TB burdens before these disruptions essential for shaping effective responses. The WHO End TB Strategy sets targets of a 95% reduction in TB deaths and a 90% reduction in TB incidence between 2015 and 2035. Using results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023, this study aims to assess the burden of TB and multidrug-resistant TB (MDR-TB) across 204 countries and territories, and to evaluate progress towards the WHO End TB incidence and mortality targets. We quantified TB mortality using the Cause of Death Ensemble modelling platform with global vital registration, surveillance, verbal autopsy, and minimally invasive tissue sampling data. For TB morbidity estimation, we simultaneously modelled incidence, prevalence, and mortality by age and sex using DisMod-MR 2.1. A population attributable fraction (PAF) approach was applied to stratify morbidity and mortality estimates by HIV and drug-resistance status. We also calculated disability-adjusted life-years (DALYs) as the sum of years of life lost and years lived with disability. For the risk factor analysis, a comparative risk assessment framework was used and PAFs were derived for alcohol use, smoking, and high fasting plasma glucose to determine the proportion of TB burden associated with these risk factors. In 2023, there were an estimated 9·11 million (95% uncertainty interval 8·04-10·3) incident cases of all-form TB, 1·22 million (0·98-1·49) deaths, and 54·6 million (43·8-65·5) DALYs globally. HIV-related TB comprised 781 000 (690 000-879 000) incident cases and 210 000 (142 000-279 000) deaths, contributing 11·0 million (7·56-14·3) DALYs. MDR-TB accounted for 466 000 (198 000-1 080 000) incident cases, 102 000 (31 700-238 000) deaths, and 3·96 million (1·31-9·01) DALYs. From 2015 to 2023, global all-form TB incidence rates declined by 19·2% (17·8-20·5) and deaths declined by 22·6% (4·7-35·7); declines were larger for drug-susceptible TB than for MDR-TB. Sub-Saharan Africa and south Asia had the highest mortality burdens in 2023; reductions in all-form TB incidence and mortality were uneven between 2000 and 2023, with limited progress in both measures in Latin America and the Caribbean. Removing smoking, alcohol use, and high fasting plasma glucose would reduce global TB deaths to 768 000 (592 000-970 000) and DALYs to 34·9 million (27·8-43·8) in 2023; MDR-TB deaths would decrease to 77 200 (23 400-183 000) and DALYs to 3·12 million (1·03-7·29). Global progress towards WHO End TB targets is disparate and fragile. Although many regions achieved meaningful gains, others have stagnated in recent years. The complexity of TB prevention is amplified by divergent MDR-TB trends, the persistent burden of HIV, and growing exposure to modifiable risk factors. Recent volatility in global health financing threatens to further destabilise this vulnerable epidemiological landscape; concerted action is urgently needed to temper disruptions and preserve progress. Gates Foundation.