搜索结果：Nordisk

暂无摘要（点击查看详情）

暂无摘要（点击查看详情）

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&#x2008;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&#xb7;0 to <25&#xb7;0 kg/m2), and changes in the difference between participants with obesity (separately for class I obesity [30&#xb7;0 to <35&#xb7;0 kg/m2] and class II and III obesity [BMI &#x2265;35&#xb7;0 kg/m2]) or overweight (25&#xb7;0 to <30&#xb7;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&#xb7;05 mmol/L per decade (95% CI -0&#xb7;07 to -0&#xb7;03) for females and -0&#xb7;07 mmol/L per decade (-0&#xb7;09 to -0&#xb7;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&#xb7;7 mmHg per decade (95% CI -1&#xb7;0 to -0&#xb7;4) for females and -0&#xb7;6 mmHg per decade (-0&#xb7;9 to -0&#xb7;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&#xb7;5 percentage points per decade (1&#xb7;0-2&#xb7;1) for females and 1&#xb7;6 percentage points per decade (1&#xb7;0-2&#xb7;2) for males. For antihypertensive medicines, the pooled estimate was 0&#xb7;7 percentage points per decade (0&#xb7;3-1&#xb7;0) for females and 2&#xb7;0 percentage points per decade (1&#xb7;3-2&#xb7;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).

Monogenic diabetes covers single-variant inherited subtypes of diabetes, of which the most prevalent are HNF4A-MODY (MODY1), GCK-MODY (MODY2), HNF1A-MODY (MODY3), HNF1B-MODY (MODY5) and mitochondrial diabetes. Together, they account for about 1% of diabetes cases, but more than 70% of affected individuals are classified with other forms of diabetes. The classical phenotype is young-onset, non-autoimmune diabetes with partially preserved insulin secretion and a family history of diabetes. Correct genetic diagnosis is crucial for family counselling and optimal diabetes management, as reviewed in this article.

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.

To investigate glucose levels and hypoglycaemia risk during exercise or fasting in adults with type 2 diabetes (T2D) treated with once-weekly basal insulin icodec. Thirty basal insulin-treated, physically active individuals with T2D (18-75&#x2009;years, glycated haemoglobin &#x2264;&#x2009;75&#x2009;mmol/mol, peak oxygen uptake >&#x2009;20&#x2009;mL/kg/min) received once-weekly icodec for &#x2265;&#x2009;7&#x2009;weeks targeting pre-breakfast plasma glucose (PG) of 4.4-7.2&#x2009;mmol/L. The final three weeks at icodec steady state comprised a reference week (no additional intervention), an exercise week (40&#x2009;min cycling [60% peak oxygen uptake] 43&#x2009;h post-dose) and a fasting week (18&#x2009;h fasting 26&#x2009;h post-dose). PG was measured at prespecified time points related to exercise and fasting. If PG <&#x2009;5.0&#x2009;mmol/L before exercise, or <&#x2009;4.0&#x2009;mmol/L between exercise onset and 140&#x2009;min post-exercise or during fasting, oral carbohydrate (exercise) or intravenous glucose (fasting) was given. Blinded continuous glucose monitoring (CGM) data were collected throughout. Mean&#x2009;&#xb1;&#x2009;standard deviation CGM-based time below range <&#x2009;3.0&#x2009;mmol/L was 0.3%&#x2009;&#xb1;&#x2009;1.1% during 24&#x2009;h from exercise onset, 0.2%&#x2009;&#xb1;&#x2009;0.8% during 18&#x2009;h fasting and 0.0%&#x2009;&#xb1;&#x2009;0.0% during the corresponding reference period. No clinically significant or severe hypoglycaemia was reported. Oral carbohydrate was given to 1, 0 and 3 participants pre-, during and post-exercise. Intravenous glucose was given to 15 participants (50%) during fasting (earliest at 10.6&#x2009;h after start of fasting). The current results reinforce the safety profile of once-weekly basal insulin icodec and provide guidance on glycaemic management during exercise or fasting in people with T2D treated with icodec. NCT06288412.

Lipid management and risk assessment are key to preventing atherosclerotic cardiovascular disease (ASCVD). As part of the INTERASPIRE study, we conducted a sub-study to evaluate physician practices in cardiovascular risk assessment and lipid management. A total of 245 physicians, including cardiologists, general physicians, endocrinologists, and lipidologists across seven countries (China, Colombia, Kenya, Malaysia, Nigeria, Poland, United Arab Emirates) completed a structured questionnaire. Overall, 87 % of physicians reported estimating ASCVD risk, mainly using ASCVD Risk Estimator Plus (48 %) or SCORE/SCORE2 (26 %). ESC/EAS guidelines were followed by 55 % and AHA/ACC by 52 %. Treatment thresholds varied: 68 % initiated LDL-C lowering at &#x2265;3.0 mmol/L (&#x2265;116 mg/dL) in low-risk primary prevention, while 60 % targeted <1.4 mmol/L (<55 mg/dL) in coronary artery disease. Non-HDL-C targets were less frequently applied. Statins predominated (atorvastatin 58 %, rosuvastatin 40 %), but access to advanced agents was uneven: intercountry ranges of PCSK9 inhibitors (7-84 %), inclisiran (0-72 %), and bempedoic acid (0-73 %). Triglyceride therapy was usually initiated at >1.7 mmol/L (>150 mg/dL), mainly with fibrates (71 %). Cardiologists and lipidologists pursued lower LDL-C levels, whereas general physicians were more conservative. Guideline use varied regionally, with ESC guidance dominant in Poland, US guidance in China, Kenya, and the UAE, and national guidelines in Malaysia. Physicians support risk assessment and statin use, yet wide variation exists in lipid thresholds, non-HDL-C assessment, and access to novel therapies. Despite ESC/EAS and AHA/ACC guidelines uptake, LDL-C targets were often above recommendations, and treatment was predominantly monotherapy. Closing practice gaps requires guideline-aligned tools, stepwise LDL-C lowering, and improved access, particularly in low- and middle-income settings. Managing lipids and assessing risk are key to preventing disease of the heart and blood vessels caused by blockages (ASCVD).In this study, doctors from seven countries reported wide differences in how they check heart disease risk, set cholesterol goals, and use treatments.Most rely on statins, but many start therapy later than guidelines recommend and have uneven access to newer cholesterol-lowering medicines.Clearer guidance, better education, and improved access to therapies are needed to strengthen prevention worldwide.

暂无摘要（点击查看详情）

Metabolically healthy obesity account for approximately one-third of individuals with obesity and could affect up to 300million individuals worldwide. Whether this is a truly benign cardiometabolic phenotype as the name suggests is incompletely defined, leading to uncertainty regarding the optimal risk stratification and management strategies for these individuals. To assess the sex-specific independent and joint associations of obesity and metabolic health status on cardiometabolic outcomes and death. A prospective cohort study of UK Biobank participants free from cardiovascular diseases and not underweight. Participants were divided by BMI into normal, overweight or obese, and the presence or absence of &#x2265;1metabolic abnormality (hypertension, diabetes or dyslipidaemia). Exposures were assessed at baseline(2006-2010), with outcomes ascertained over a median follow-up of 12.9 years(IQR 12.6-13.3). Sex-specific outcomes were fatal or non-fatal atherosclerotic cardiovascular disease(ASCVD; a composite of coronary heart disease, ischaemic stroke, and peripheral artery disease), heart failure(HF), metabolic dysfunction-associated steatotic liver disease(MASLD), end-stage renal disease(ESRD) and all-cause mortality. Multivariable-adjusted cox regression models were used to estimate hazard ratio (HR) and 95 %CI. Among 157,159 participants (mean age 56.5years [SD 8.2]; 55.6 % women), 24.2 % were obese and 68.2 % had &#x2265;1 metabolic abnormality. Compared to normal BMI and no metabolic abnormality (reference group), obesity was associated with increased risk of ASCVD(HR 1.46, 95 %CI 1.24-1.73), HF(1.63,1.14-2.32), MASLD(2.37,1.22-4.61), all-cause mortality(1.36,1.10-1.69) but not ESRD in men without metabolic abnormalities, which increased when any metabolic abnormality was present: ASCVD(2.21,2.03-2.41), HF(2.91,2.41-3.50), MASLD(6.84,4.60-10.18), ESRD(5.42,2.94-10.02), and all-cause mortality(1.62,1.45-1.81). Corresponding risk from obesity in women without metabolic abnormalities were: ASCVD(1.34,1.14-1.58), HF(1.69,1.21-2.37), MASLD(4.44,3.00-6.59), and all-cause mortality(1.27,1.05-1.52) but not ESRD, which increased when metabolic abnormalities were present: ASCVD(2.51,2.30-2.74), HF(3.67,3.04-4.43), MASLD(8.17,6.13-10.89), ESRD(7.96,4.00-15.85) and all-cause mortality(1.67,1.51-1.85). Adverse outcomes increased with severity of obesity, the presence of central obesity, and with increasing numbers of metabolic abnormalities, with an effect modification by sex suggesting more harm from obesity, central obesity and metabolic abnormalities in women. Obesity without metabolic abnormalities is not benign and associated with multiple adverse cardiometabolic outcomes, further exacerbated when metabolic abnormalities occur. As 300million individuals may be considered metabolically healthy but obese, future studies should explore whether preventing or reversing obesity prior to the appearance of significant metabolic abnormalities results in improved health outcomes. This prospective cohort study of over 1.9 million person-years follow-up demonstrates that obesity without metabolic abnormality increases the risk of ASCVD by 46 % in men and 34 % in women respectively, HF by 63 % and 69 %, MASLD by 137 % and 344 % and all-cause mortality by 36 % and 27 %, compared to those with normal BMI, with graded increase as severity of obesity increases. The presence of metabolic abnormality doubles event rates associated with obesity, with risk increasing with number of metabolic abnormalities present. These findings suggest that obesity without metabolic abnormality is not benign and support efforts to prevent or reverse obesity before overt metabolic dysfunction manifests.

Plants respond to mechanical stimulations like wind, touching or wounding to safeguard their development and survival. Mitogen Activated Protein Kinases (MAPKs) activation by mechanostimuli was reported 26 years ago, but the upstream regulatory mechanism and function remained unknown. We report that mechanostimulation activates a MAPKKK3/4/5-MKK4/5-MPK3/6 cascade within 60&#x2009;seconds, leading to induction of ~800 genes, encompassing most of the early touch response. Most genes overlap with touch-responsive genes regulated by CAMTA1/2/3, exposing an interplay between MAPKs and CAMTA transcription factors. Furthermore, loss of MKK4/5 leads to global impairment of touch-regulated protein phosphorylation, demonstrating they are crucial regulators. In contrast, phosphorylation does not clearly affect early activation of the touch-induced jasmonic acid (JA) signalling pathway, nor does loss of JA affect the overall early touch-phosphoproteome. Lastly, loss of MAPKKK3/4/5 and MKK4/5 reduces thigmomorphogenesis, underlining the importance of the identified MAPK cascade for steering plant growth during stress. In summary, we have now identified a MAPKKK3/4/5-MKK4/5-MPK3/6 cascade as a key touch- and wounding signalling pathway in plants.

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 (<&#xa0;6%), mild (6 to <&#xa0;16%) and moderate-to-severe fatty pancreas (&#x2265;&#xa0;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&#xa0;<&#xa0;0.001; HR 2.72, 1.66-4.46; p&#xa0;<&#xa0;0.001), incident CKD (HR 1.82, 1.29-2.57; p&#xa0;<&#xa0;0.001), and prevalent and incident MACE (OR 1.26, 1.04-1.56; p&#xa0;=&#xa0;0.022; HR 1.30, 1.02-1.66; p&#xa0;=&#xa0;0.034). Mild fatty pancreas was associated with incident T2D (HR 2.19, 1.40-3.42; p&#xa0;<&#xa0;0.001) and incident MACE (HR 1.29, 1.06-1.59; p&#xa0;=&#xa0;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&#xa0;<&#xa0;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.

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 &#x2265;18 years with &#x2265;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.

Although the safety profile of lipid-lowering therapies (LLTs) is known, there are no comprehensive comparative assessments. We aimed to compare the risk of muscle-related events, diabetes, liver dysfunction, and cognitive disorders among LLTs through a network meta-analysis. Databases were searched from inception to May 2025. Eligible studies included adult patients, using statins, ezetimibe, PCSK9 monoclonal antibodies (PCSK9mAbs), inclisiran, bempedoic acid, or their combinations as intervention, reporting the information about any of the selected adverse events, a total sample size of &#x2265;200 subjects, and had &#x2265;1 month of intervention. Pooled estimates were assessed by fixed effects model within a frequentist setting. Pooled relative risks (RR) and their 95% confidence interval were estimated. A total of 303,397 subjects from 153 RCTs were included. Bempedoic acid ranked the lowest risk of myalgia (vs PCSK9mAbs, RR 0.80 [0.69, 0.93]). PCSK9mAbs were associated with lower incidence of creatine kinase (CK) elevation, diabetes, and liver dysfunction comparing to statins (statins vs PCSK9mAbs, RR 1.44 [1.14, 1.81], RR 1.13 [1.05, 1.22], and RR 1.38 [1.17, 1.62], respectively). In terms of muscle-related events and cognitive disorders, no significant risk differences were found among treatments and their combinations. PCSK9mAbs appear to have a more favourable safety profile regarding the risk of CK elevation, diabetes, and liver dysfunction. Bempedoic acid seem to be a better choice for subjects with high risk of myalgia. This information can be valuable when selecting therapy for specific patient subgroups at higher risk of certain adverse events.

Cardiovascular disease (CVD) prediction models recommended by guidelines are developed using different populations, predictors, and outcome definitions. The implications of this heterogeneity for risk estimation are unclear, and direct comparisons remain limited. Head-to-head comparison of the performance and transportability of three guideline-endorsed CVD risk prediction models, focusing on their sex-specific performance. We evaluated models recommended by the American Heart Association (PREVENT), European Society of Cardiology (SCORE2), and the National Institute for Health and Care Excellence (QRISK3). Risk of bias was assessed using the PROBAST tool. External validation was performed using the UK Biobank (UKBB) in a primary analysis including all participants with complete data for all models, enabling direct comparison, and in a secondary analysis applying each model to participants meeting its original eligibility criteria. Model performance was assessed using Brier scores, Area Under the Receiver Operating Characteristic Curve (AUC), and calibration across original and alternative outcome definitions, stratified by sex. The PREVENT, SCORE2, and QRISK3 models varied substantially in terms of predictors, populations, and outcome definitions. We used data from 502,157 UKBB participants for the external validation in the primary analysis. Overall predictive performance (discrimination & calibration), as measured by Brier scores, was generally better in females. The AUC (95% CI) ranged from 0.7092 (0.7090-0.7094) to 0.7468 (0.7465-0.7471) for female and 0.6813 (0.6812-0.6814) to 0.6946 (0.6945-0.6946) for male populations. Calibration was suboptimal, particularly for older individuals, with systematic overestimation of risk. The models showed consistent performance when applied to different outcomes. All models were at high risk of bias. Despite heterogeneity in populations, predictors, and outcome definitions, PREVENT, SCORE2, and QRISK3 showed similar performance in the UKBB. Future studies should focus on prospective and standardized definitions and assessment of candidate predictors and outcomes.

Excipients are essential components within pharmaceutical formulations that are used to enhance properties such as the binding, disintegration, preservation, and patient friendliness of common dosage forms such as tablets, capsules, and inhalers. Common excipients such as micro-crystalline cellulose (MCC), dibasic calcium phosphate dihydrate (DCPD), and partially pre-gelatinised corn starch (PGS) therefore play a critical role in the design and production process of both new and existing drug formulations. However, despite the importance of these powders, reference data are not publicly available. This report presents an extensive data set on MCC, DCPD, and PGS&#xa0;which includes detailed information on individual grains, including particle sizes, crushing, and geometries. Using a compaction simulator, the powders and various mixtures thereof were compressed to make tablets, which were later subjected to a wide range of mechanical tests. This data set provides a reference point for the pharmaceutical industry, educators, and process developers alike.

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 (&#x3b2;=2.5&#x2005;ng/mL per year, p&#x2009;=&#x2009;0.02), lower eGFR (&#x3b2;=-3.5&#x2005;ng/mL per ml/min/1.73m2, p&#x2009;=&#x2009;4.5&#x2009;&#xd7;&#x2009;10-4), and lower BMI (&#x3b2;=-7.3&#x2005;ng/mL per kg/m2, p&#x2009;=&#x2009;1.3&#x2009;&#xd7;&#x2009;10-4). African ancestry was associated with lower metformin concentrations compared to European ancestry (&#x3b2;=-72.6&#x2005;ng/mL, p&#x2009;=&#x2009;0.036). A genome-wide association study (GWAS) identified four African ancestry-specific genetic variants significantly associated with higher metformin concentrations (p&#x2009;<&#x2009;5&#x2009;&#xd7;&#x2009;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.

Heart failure with reduced ejection fraction carries a poor prognosis. Although guideline-directed medical therapy reduces morbidity and mortality, its real-world utilization is low. Accordingly, we conducted an open-label randomized trial (POLY-HF) at two centers enrolling a predominantly underserved population to test whether a polypill strategy improves cardiac function in heart failure. Adults with heart failure and left ventricular ejection fraction &#x2264;40% were randomized to a once-daily polypill containing metoprolol succinate (25/50/100/150&#x2009;mg), spironolactone 12.5&#x2009;mg and empagliflozin 10&#x2009;mg, or rapid uptitration of individual guideline-directed medical therapy medications ('enhanced usual care'). Participants also continued treatment with a renin-angiotensin system inhibitor or sacubitril/valsartan as a separate pill. The primary endpoint was ejection fraction as assessed by cardiac magnetic resonance imaging at 6&#x2009;months. Secondary endpoints included clinical outcomes and adherence. We randomized 212 patients (median age 54&#x2009;years, 22% female, 54% Black). Follow-up magnetic resonance imaging data were available for 187 (88%) participants who were included in the modified intention-to-treat analysis. Polypill treatment was associated with greater improvement in ejection fraction compared to enhanced usual care (between-group difference, 3.3 percentage points, 95% confidence interval, 0.2-6.4; P&#x2009;=&#x2009;0.039), meeting the primary outcome. Individuals randomized to the polypill also had a 60% lower rate of heart failure hospitalizations or emergency department visits (adjusted rate ratio, 0.40; 95% confidence interval, 0.18-0.88; P&#x2009;=&#x2009;0.024). Adherence, assessed by blood concentrations of metoprolol and spironolactone, was higher with polypill treatment than with enhanced usual care (79% versus 54%, P&#x2009;=&#x2009;0.001). The polypill was well tolerated, with fewer adverse events with polypill treatment as compared to enhanced usual care. A polypill for heart failure was associated with a significant improvement in cardiac function as compared with enhanced usual care. ClinicalTrials.gov registration: NCT04633005 .

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&#x2009;+&#x2009;3&#x2009;+&#x2009;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&#x2009;+&#x2009;3&#x2009;+&#x2009;4 (adjusted odds ratio: 3.88; 95% CI: 2.02-7.45; P&#x2009;<&#x2009;0.01). RCS analysis indicated a significant non-linear association (P&#x2009;=&#x2009;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.

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 &#xb1; 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.