This Special Communication discusses the potential of the Ziltivekimab Cardiovascular Outcomes Trial (ZEUS) to provide a fully novel approach for prevention of myocardial infarction, stroke, cardiovascular death, and kidney function decline among high-risk patients with chronic kidney disease. ImportanceCardiovascular inflammation is a major determinant of atherosclerotic disease, and inhibition of the central signaling cytokine, interleukin 6 (IL-6), is a promising target for intervention. Patients with chronic kidney disease (CKD) commonly have plasma elevations of inflammatory biomarkers, such as high-sensitivity C-reactive protein (hsCRP) and IL-6, and are at high risk for life-threatening atherosclerotic events as well as loss of kidney function and might therefore benefit from IL-6 inhibition.ObservationsThe Ziltivekimab Cardiovascular Outcomes Trial (ZEUS; NCT05021835) will determine the safety and efficacy of IL-6 inhibition with ziltivekimab among patients with atherosclerotic cardiovascular disease (ASCVD), CKD, and systemic inflammation. ZEUS is a multinational, double-blind, placebo-controlled, event-driven, randomized clinical trial inclusive of 6376 participants with ASCVD, CKD, and an hsCRP level greater than or equal to 2 mg/L who were randomized in a 1:1 fashion to receive either ziltivekimab, 15 mg, administered subcutaneously every month or matching placebo. At randomization, mean age was 69.5 years, 27.5% were female, 92.0% had hypertension, 65.7% had diabetes, and 41.3% had heart failure. At baseline, the mean estimated glomerular filtration rate (eGFR) was 44.5 mL/min/1.73 m2, mean low-density lipoprotein cholesterol level was 77.7 mg/dL, median hsCRP level was 4.5 mg/L, and median IL-6 level was 4.9 pg/mL. At enrollment, sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists were being used by 36.8% and 11.3% of the cohort, respectively. The primary outcome is 3-point major adverse cardiovascular events. Secondary cardiovascular outcomes include (1) an expanded major adverse cardiovascular event outcome including hospitalization for unstable angina requiring urgent coronary revascularization, (2) hospitalizations for heart failure or urgent heart failure visits or cardiovascular death, and (3) all-cause mortality. The secondary kidney outcome is a composite of greater than 40% decline in eGFR, eGFR less than 15 mL/min/1.73 m2, dialysis, kidney transplant, death from kidney disease, or cardiovascular death.Conclusions and RelevanceThe ZEUS randomized clinical trial will formally test the hypothesis that IL-6 inhibition with ziltivekimab will lower incident cardiovascular event rates and potentially slow kidney decline among participants with known ASCVD, CKD, and elevated hsCRP. If successful, the ZEUS trial would provide a fully novel approach for prevention of myocardial infarction, stroke, cardiovascular death, and kidney function decline among high-risk patients with CKD.

The prevalence of obesity has reached pandemic proportions and is having enormous public health effects. Obesity increases the risk of type 2 diabetes, hypertension, chronic kidney disease, and cardiovascular (CV) disease including coronary artery disease, heart failure, atrial fibrillation, and stroke. Although initial randomized clinical trials of weight-loss strategies through diet and exercise or early medical therapies did not lead to improved CV outcomes, more recent trials using glucagon-like peptide-1 (GLP-1) receptor agonists in individuals with obesity have demonstrated CV benefits. At present, there are multiple cardiovascular outcome trials (CVOTs) of novel GLP-1 receptor agonists and investigational products targeting multiple hormonal pathways planned or underway. However, the optimal design features of CVOTs testing novel obesity medications may need to evolve. In this commentary, we discuss regulatory aspects and study design considerations of CVOTs for obesity medications in the context of previous and ongoing clinical trials and the future of CVOTs targeting obesity. We also propose 5 principles to help guide next-generation cardio-kidney-metabolic outcome trials.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with increased cardiovascular risk, yet whether it independently confers risk beyond established cardiometabolic factors remains debated. Herein, we critically appraise epidemiological, genetic, mechanistic, and large-cohort evidence. Many studies reporting independent associations are limited by small sample sizes, heterogeneous cardiovascular outcomes, potential selection and publication bias, and perhaps most importantly, incomplete adjustment for established continuous cardiovascular risk factors. Mendelian randomisation and large-scale cohort data suggest that excess liver fat per se is not independently atherogenic; rather, accompanying abnormalities in lipid profiles mediate the observed risk. Notably, no current cardiovascular risk model includes MASLD as an independent variable. Clinically, MASLD identifies individuals with higher than average cardiovascular risk who are frequently undertreated with preventive therapies. Thus, the priority for primary care physicians, hepatologists, endocrinologists, and cardiologists, among others, should be to adequately determine (using risk scores), communicate on and address the cardiovascular and related multimorbidity challenges inherent in MASLD care.

OBJECTIVE:This prespecified analysis of Effect of Evolocumab in Patients at High Cardiovascular Risk Without Prior Myocardial Infarction or Stroke (VESALIUS-CV) evaluated the efficacy of the PCSK9 inhibitor evolocumab for preventing first cardiovascular events in patients with high-risk diabetes. RESEARCH DESIGN AND METHODS:VESALIUS-CV randomized patients with high-risk diabetes (microvascular disease, insulin use, or duration ≥10 years) or qualifying atherosclerosis, but no prior myocardial infarction (MI) or stroke, and LDL cholesterol (LDL-C) ≥90 mg/dL to evolocumab 140 mg or matching placebo every 2 weeks. The dual primary end points were a composite of coronary heart disease death, MI or ischemic stroke (three-point major adverse cardiovascular event [3P-MACE]) and 3P-MACE plus ischemia-driven arterial revascularization (four-point [4P]-MACE). RESULTS:Of the 6,002 patients with high-risk diabetes, 67% were on a high-intensity statin and 24% were on a sodium-glucose cotransporter 2 inhibitor (SGLT2i) or a glucagon-like peptide 1 receptor agonist (GLP-1RA) at baseline. The median LDL-C at 48 weeks was 47 mg/dL and 109 mg/dL in the evolocumab and placebo arms, respectively (P < 0.0001). After a median follow-up of 4.6 years, evolocumab decreased the relative rates of 3P-MACE and 4P-MACE by 29% (hazard ratio [HR] 0.71; 95% CI 0.59, 0.86; P = 0.0004) and 21% (HR 0.79; 95% CI 0.69, 0.91; P = 0.0013), respectively. These findings were consistent regardless of the presence or absence of qualifying atherosclerosis, baseline LDL-C, statin intensity, and SGLT2i or GLP-1RA use (Pint > 0.05 for each). The porportion of patients with all-cause death was 8.8% vs. 11.0% in the evolocumab versus placebo arms (HR 0.79; 95% CI 0.67, 0.93). CONCLUSIONS:Evolocumab reduced the rate of cardiovascular events in patients with high-risk diabetes, regardless of the presence or absence of qualifying atherosclerosis and background use of other cardioprotective agents.

To evaluate shifts in waist-to-height ratio (WHtR) categories among adults with obesity or overweight, with or without prediabetes, treated with tirzepatide in the SURMOUNT-1 study. This post hoc analysis included 2,538 participants from the SURMOUNT-1 Phase 3, double-blind, randomized, placebo-controlled trial. Adults with BMI ≥ 30 or ≥ 27 kg/m² and at least one obesity-related complication (ORC), excluding diabetes, were randomized to receive once-weekly tirzepatide (5, 10, or 15 mg) or placebo, alongside a reduced-calorie diet and increased physical activity. Participants were grouped by baseline WHtR (≤ 0.49, > 0.49 to ≤ 0.59, > 0.59) according to the National Institute for Health and Care Excellence (NICE) framework. Participants with prediabetes at baseline had additional follow-up data beyond week 72, and shifts in their WHtR categories at week 176 were also included. Change from baseline in WHtR was analyzed using a mixed model for repeated measures (MMRM). Shift tables were used to summarize changes from baseline to post-baseline WHtR category levels. At baseline, 89.8

AIMS:In the AMPLITUDE O trial, efpeglenatide reduced major cardiovascular events by 27% in 4076 individuals with Type 2 diabetes and established cardiovascular or kidney disease compared to placebo during a median follow-up of 1.81 years. This exploratory mediation analysis evaluates the degree to which changes in measured clinical variables and biomarkers during the trial might explain the observed reduction in MACE. MATERIALS AND METHODS:Measured variables were considered potential mediators if they were significantly changed by the intervention. The hazard (95% CI) per 1-unit increase in each time-updated mediator (change from baseline or updated mean) was estimated using Cox models adjusted for the same variables as in the main AMPLITUDE-O results. Mediators whose hazard-ratio CIs excluded 1.0 were then included in the MACE Cox model to estimate how much of efpeglenatide's effect on MACE could be statistically explained by its effect on that mediator in uni- and multivariable analyses. RESULTS:Change in HbA1c, weight, pulse pressure, LDL cholesterol, urinary albumin: creatinine ratio (UACR), eGFR, heart rate, lipase and amylase were modified by efpeglenatide. Of these, univariable analyses showed that only changes in HbA1c, LDL cholesterol, UACR and amylase accounted for 14%, 11%, 16% and 10%, respectively, of the effect of efpeglenatide on MACE. In the multivariable analysis, LDL cholesterol together with UACR accounted for 29.6% mediation of this effect. CONCLUSION:In this post hoc analysis from the AMPLITUDE-O trial, changes in LDL cholesterol together with UACR but not weight were estimated to statistically account for a modest portion of the reduction in risk of MACE with efpeglenatide.

Health systems must adapt to a new era of obesity treatment.

Key advances from the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) pilot research grant program were presented at the GRAPPA 2025 annual meeting. Areas of study included hypoxia-inducible factor 1α (HIF1A) as a potential factor in psoriatic arthritis (PsA), plasma extracellular vesicle cytokines as potential biomarkers for predicting response to tumor necrosis factor inhibitors in PsA, bone properties and biomechanics in psoriatic disease (PsD), better understanding of differences in body composition in PsD, and the effect of sleep on PsD severity.

BACKGROUND:Raised cardiac troponin-I is a common finding in patients hospitalised with acute viral infections, including but not limited to COVID-19. This often occurs in the absence of overt myocardial injury presenting a challenge for interpretation. The mechanisms underlying troponin elevation are uncertain. METHODS:The CISCO-19 (Cardiovascular Imaging in SARS-CoV-19) study (NCT04403607) is a prospective, multicentre cohort study, in which hospitalised PCR-confirmed COVID-19 participants (N=267) underwent multisystem evaluation at enrolment and at 28-60 days. The study incorporated plasma proteomics (SOMAscan V.4.1), cardiovascular MRI and clinical biomarkers. Of these, 211 had baseline plasma proteomic data and 185 completed follow-up sampling. Matched proteomic and imaging data were available for 155 participants (mean age: 55 years (SD 12); 43% female). RESULTS:A high likelihood of myocarditis was identified in 13.2% (N=21/159) of participants. High-sensitivity troponin-I was modestly elevated at enrolment (median 3 ng/L; IQR 2-6; n=159). Among males (n=90), 9.3% had a high-sensitivity troponin that exceeded 34 ng/L. Among females (n=69), 4.5% exceeded 16 ng/L. Smooth muscle myosin light chain proteins were downregulated at follow-up (log2 fold change -0.12 to -0.6; all adjusted p<0.02) and positively correlated with high-sensitivity troponin-I, but not N-terminal brain natriuretic peptide or cardiac MRI indices (n=155). CONCLUSIONS:Troponin elevation, exemplified here by COVID-19, could reflect systemic vascular injury. Recognising this mechanism may refine interpretation of cardiac biomarkers in viral illness and supports the investigation of vascular injury in future therapeutic strategies and biomedical studies.

Importance Overweight and obesity affect 60% to 78% of patients with psoriasis, affecting disease severity, treatment response, and clinical outcomes. However, no large, randomized, active-controlled clinical trial has evaluated a treatment strategy that addresses both diseases simultaneously. Objective To evaluate the efficacy and safety of ixekizumab with or without tirzepatide in participants with psoriasis and overweight or obesity. Design, Setting, and Participants This phase 3b, randomized, open-label, 52-week clinical trial was conducted at 72 sites in the US in adults with moderate to severe plaque psoriasis who have overweight with 1 or more weight-related comorbidities or obesity. The trial started on September 30, 2024, and completed the week 36 primary end point on January 8, 2026. Data were analyzed from January to February 2026. Interventions Participants were randomized (1:1) to ixekizumab plus tirzepatide or ixekizumab as adjunct to diet and exercise in both treatment arms. Main Outcomes and Measures At week 36, the primary end point was simultaneous achievement of Psoriasis Activity and Severity Index (PASI) 100 and 10% or greater weight reduction. Key secondary end points were PASI 100 and simultaneous PASI 75 and 5% or greater weight reduction, as well as 10% or greater weight reduction. Results Among the 274 randomized participants (mean [SD] age, 45.6 [12.7] years; 123 [44.9%] women and 151 [55.1%] men; mean [SD] screening body mass index [calculated as weight in kilograms divided by height in meters squared], 39.2 [9.1]; mean [SD] duration of psoriasis, 14.6 [13.0] years; mean [SD] PASI, 19.7 [8.1]), 231 (84.3%) completed the treatment through week 36. Overall, 27.1% of participants simultaneously achieved PASI 100 and a 10% or greater weight reduction with ixekizumab plus tirzepatide vs 5.8% with ixekizumab (risk difference [RD], 21.2%; 95% CI, 12.8%-29.7%; P < .001). Also, 40.6% vs 29.0% of participants achieved PASI 100 (RD, 11.6%; 95% CI, 0.3%-22.9%; P = .04), 79.9% vs 17.9% simultaneously achieved PASI 75 and a 5% or greater weight reduction (RD, 62.0%; 95% CI, 51.7%-72.2%; P < .001), and 69.2% vs 9.1% achieved a 10% or greater weight reduction (RD, 60.0%; 95% CI, 50.4%-69.7%; P < .001), respectively. Adverse events were generally consistent with established drug safety profiles, the most common being gastrointestinal tract events and injection site reactions. Gastrointestinal tract events occurred more frequently with ixekizumab plus tirzepatide vs ixekizumab. Conclusions and Relevance The trial results suggest that concomitant ixekizumab and tirzepatide produced clinically meaningful, statistically significant improvements in skin clearance and reductions in weight in participants with moderate to severe psoriasis, with no new safety concerns, while providing additional cardiometabolic benefits and a potential to elevate care. Trial Registration ClinicalTrials.gov Identifier: NCT06588283

BACKGROUND:Evolocumab, a PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitor, significantly reduced the risk of cardiovascular events in patients without previous myocardial infarction or stroke in the VESALIUS-CV trial (Effect of Evolocumab in Patients at High Cardiovascular Risk without Prior Myocardial Infarction or Stroke). However, mortality results have yet to be fully characterized. METHODS:VESALIUS-CV was a double-blind study of 12 257 patients (median age, 66 years [interquartile range, 60-71]; 43% women) with qualifying atherosclerosis or high-risk diabetes without previous myocardial infarction or stroke, and low-density lipoprotein-cholesterol ≥90 mg/dL (or non-high-density lipoprotein-C ≥120 mg/dL or apolipoprotein B ≥80 mg/dL) who were randomized to evolocumab or placebo. Prespecified mortality outcomes of interest included all-cause mortality, subtypes of death (including cardiovascular [CV] and non-CV), and timing of events. Non-CV mortality was further investigated using multistate modeling to assess the contribution of prevention of nonfatal CV events (myocardial infarction, ischemic stroke, and ischemia-driven arterial revascularization) to non-CV mortality. RESULTS:Over a median of 4.6 years (interquartile range, 4.0-5.2), 973 (7.9%) patients died: 351 (36%) of CV causes, 497 (51%) of non-CV causes, and 125 (13%) of undetermined cause. All-cause mortality rates were 20% lower with evolocumab compared with placebo: 434 deaths (5-year Kaplan-Meier rate of 7.9%) with evolocumab versus 539 deaths (9.7%) with placebo (hazard ratio, 0.80, 95% CI, 0.70-0.91; P=0.0005). There was consistency of benefit for CV death (156 deaths [2.8%] versus 195 [3.6%]; hazard ratio, 0.79; 95% CI, 0.64-0.98), non-CV death (229 [4.2%] versus 268 [5.0%]; hazard ratio, 0.85; 95% CI, 0.71-1.01), and deaths of undetermined cause (49 [1.1%] versus 76 [1.4%]; hazard ratio, 0.64; 95% CI, 0.45-0.92). Results were consistent regardless of age, sex, region, race, qualifying atherosclerosis or high-risk diabetes, baseline low-density lipoprotein-cholesterol, or background lipid therapy. Postrandomization nonfatal myocardial infarction, ischemic stroke, and ischemia-driven arterial revascularization were associated with increased risk of subsequent non-CV death within the next 4 years, with the majority occurring during the first year after the event. Multistate modeling suggested the observations regarding non-CV death with evolocumab was largely (78%; bootstrap interquartile range, 71-92%) driven by the prevention of antecedent nonfatal CV events. CONCLUSIONS:These results support using evolocumab to improve survival in high-risk patients who have not experienced a previous myocardial infarction or stroke, including those with high-risk diabetes without qualifying atherosclerosis with low-density lipoprotein-cholesterol ≥ 90 mg/dl (or non-high-density lipoprotein-cholesterol ≥ 120 mg/dl or apolipoprotein B ≥ 80 mg/dl). REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT03872401.

OBJECTIVE:SURMOUNT-REAL UK will evaluate the effectiveness of tirzepatide when offered in addition to standard-of-care (SoC) in adults with Class I obesity (BMI ≥ 30 and ≤ 34.9 kg/m2) and without diabetes in a UK primary care setting. METHODS:A 5-year, phase 4, multicenter, open-label, pragmatic randomized clinical trial is enabled through access to participants' integrated electronic healthcare record data. The study will enroll approximately 3000 participants from Greater Manchester, UK, who are randomly assigned in a 1:1 ratio to receive either tirzepatide and SoC or SoC alone. RESULTS:The primary endpoint is the percent change in body weight from baseline to Month 24, with the time to onset of type 2 diabetes to Month 60 being the key secondary endpoint. Additional endpoints include the impact of tirzepatide versus SoC on obesity-related complications, health-related quality of life, healthcare resource utilization, productivity, employment, and sickness-related absences. CONCLUSIONS:SURMOUNT-REAL UK employs a novel study design to evaluate real-world health outcomes and potential long-term benefits for both participants and the healthcare system associated with the delivery of pharmacological obesity treatment at a population level. The study is intended to generate critical evidence to support informed decision-making in obesity management, clinical guideline development, and healthcare policy. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT07247084.

Background:In the pre-statin era, diabetes posed a similar cardiovascular risk as previous myocardial infarction in patients without diabetes. Since the development of statins, several primary preventive treatment strategies have been introduced. We investigated whether diabetes and coronary heart disease (CHD) confer similarly high cardiovascular risk in a semi-nationwide contemporary cohort. Methods:We included all individuals aged 50-89 residing in Western Denmark on January 1, 2012. Participants were categorized into four groups: diabetes alone, CHD alone, both diabetes and CHD, and neither condition. CHD was defined as previous myocardial infarction, coronary revascularization, or documented coronary artery disease. Participants were followed for up to seven years for major adverse cardiovascular events (MACE), coronary events (myocardial infarction, percutaneous coronary intervention, or coronary artery bypass grafting), non-coronary vascular events (ischemic stroke, lower limb revascularization, or amputation), and all-cause mortality. Findings:We included 1,116,456 people residing in Western Denmark on January 1, 2012. Of these, 7.5% (84,186/1,116,456) had diabetes alone; 5.0% (55,072/1,116,456) had CHD alone. Diabetes alone, compared with CHD alone, was associated with lower seven-year rates of MACE (10.8% versus 19.7%, adjusted hazard ratio (HR) 0.77, 95% CI 0.74-0.78) and coronary events (6.1% versus 16.0%, adjusted HR 0.46, 95% CI 0.44-0.48), but higher rates of non-coronary vascular events (9.4% versus 9.9%, adjusted HR 1.27, 95% CI 1.22-1.32) and all-cause mortality (25.6% versus 30.6%, adjusted HR 1.31, 95% CI 1.28-1.33). Interpretation:Diabetes alone does not carry the same coronary or cardiovascular risk as CHD alone, but it is associated with increased rates of non-coronary vascular events and all-cause mortality. Funding:This study was funded by the Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark.

Study objective:Systemic inflammation increases the risk of cardiovascular events and is often present in patients with atherosclerotic cardiovascular disease (ASCVD), particularly in those who also have chronic kidney disease (CKD). However, the prevalence of systemic inflammation in patients with ASCVD and CKD is not well characterized. Here, we estimate the prevalence of ASCVD with CKD and systemic inflammation in the US population and describe the characteristics of people with ASCVD, CKD stages 3-4, and systemic inflammation, who are at high risk for cardiorenal events. Design and setting:Cross-sectional study using data from the National Health and Nutrition Examination Survey (NHANES) 2015-2020 continuous cycles. Participants:Adults aged ≥ 20 years with ASCVD who had high-sensitivity C-reactive protein (hsCRP) measurements. Main outcome measures:Prevalence and characteristics of adults with systemic inflammation in groups with ASCVD, with ASCVD and CKD, and with ASCVD and CKD stages 3-4. Systemic inflammation was defined as hsCRP levels ≥ 2 mg/L. Results:Our study sample included 238,164,067 adults. In total, 8.5% had ASCVD, of whom 55.5% had systemic inflammation. The prevalence of systemic inflammation in individuals with ASCVD and CKD stages 3-4 (1.6% of the US population) was 59.1%, equating to 0.9% or > 2 million individuals in the general US adult population. Conclusions:In summary, over half of US adults with ASCVD and CKD stages 3-4 were estimated to have systemic inflammation. This group could benefit from weight loss strategies, lifestyle changes, and other approaches to improve cardiovascular outcomes.

Abstract Background Children exposed to maternal obesity in pregnancy are more likely to have altered heart structure and function and develop adult cardiovascular disease. Evidence suggests that diet and lifestyle interventions during obese pregnancy can limit the degree of cardiac remodelling, but existing studies are limited to small cohorts of young children (< 7 years old). Methods A follow-up study of 9–14-year-old children from the UK Pregnancies Better Eating and Activity Trial (UPBEAT) was conducted in four UK centres (Ethics Committee #23/LO/0410). Children had cardiac structure and function assessed by echocardiography (primary outcome: interventricular septal wall thickness). Linear regression adjusting for child age, sex and body surface area, maternal ethnicity and smoking in pregnancy, and study site was done. Analyses were also split by sex to determine sex-specific effects. Results An interim analysis of 210 children was completed; the mean (±SD) age was 11.8 ± 1.1 years, 50.5% were male (99 intervention, 111 control). There were no differences in baseline maternal or follow-up child characteristics between trial arms. The UPBEAT intervention did not reduce interventricular septal wall thickness when combining sexes (−0.02 cm, P = 0.16), but there was a sex-specific effect in boys (boys: −0.04 cm, P = 0.025; girls: <−0.01 cm, P = 0.86). Similar results were seen for posterior wall thickness (combined: −0.01 cm, P = 0.29; boys: - 0.04 cm, P = 0.054; girls: <+0.01 cm, P = 0.74) and left ventricular mass (combined: - 1.5 g, P = 0.52; boys: −6.6 g, P = 0.069; girls: +3.4, P = 0.24). There was no change in other echocardiography measures. Conclusions Preliminary findings indicate that the UPBEAT intervention in obese pregnancy reduces myocardial thickness in 9–14-year-old boys, which could indicate primordial prevention against future cardiovascular disease.

Background:Chronic obstructive pulmonary disease (COPD) is associated with cardiovascular disease and chronic kidney disease, but with conflicting estimates. We aimed to quantify the association of COPD and incident cardiovascular diseases, chronic kidney disease and death. Methods:In this systematic review and meta-analysis, we searched MEDLINE and Embase for case-control studies reporting associations between COPD and cardiovascular diseases, chronic kidney disease and death from database inception until 15 April 2026. Two reviewers independently extracted study characteristics and reported risk ratios of incident outcomes associated with COPD, specifically: atrial fibrillation and flutter, ventricular fibrillation and tachycardia, myocardial infarction, ischaemic stroke, heart failure, peripheral arterial disease, chronic kidney disease, cardiovascular mortality and all-cause mortality. Pooled estimates were obtained using random-effects models with restricted maximum likelihood estimation as substantial heterogeneity was anticipated. Ten sensitivity analyses stratifying studies by design, follow-up duration, region, clinical context, sample size, publication date, COPD ascertainment, leave-one-out, ratio adjustment and risk of bias, subgroup analyses by age and risk group were undertaken, and subsequent univariate and multivariate meta regression was performed. Study quality was assessed using the risk of bias in non-randomised follow-up studies of exposure effects (ROBINS-E) tool, and certainty of evidence was assessed using Grading of Assessment, Evaluation, Development and Evaluation (GRADE) criteria. Risk of publication bias was assessed using funnel plots and Egger's regression. This review was registered on PROSPERO (CRD42025639084). Findings:Of 140 case-control studies including 30,144,481 patients (3,062,712 with COPD) with median follow -up duration of 3.0 years (IQR 1.0-5.2), COPD was associated with increased risk of heart failure (risk ratio [RR] 2.33, 95% CI 1.78-3.06), ventricular tachycardia (2.05, 1.27-3.31), peripheral arterial disease (1.99, 1.49-2.65), heart failure hospitalisation (1.78, 1.28-2.47), chronic kidney disease (1.65, 1.25-2.16), all-cause mortality (1.55, 1.42-1.70), cardiovascular mortality (1.55, 1.33-1.82), myocardial infarction (1.47, 1.28-1.68), ischaemic stroke (1.38, 1.18-1.62), and atrial fibrillation (1.38, 1.19-1.61) when compared to those without COPD. Despite substantial heterogeneity for all outcomes, associations between COPD and outcomes were broadly consistent across sensitivity analyses. Interpretation:COPD is associated with an increased risk for a range of incident cardiovascular diseases, chronic kidney disease and mortality. The impact of current and novel treatments on a broader range of cardiovascular and kidney outcomes in patients with COPD requires prospective randomised assessment. Funding:The British Heart Foundation.

Semaglutide has demonstrated the ability to reduce the risk of progression to type 2 diabetes in patients with myocardial infarction and overweight or obesity without diabetes. However, implementation of semaglutide treatment in daily clinical care is challenging due to costs and limited supply. Thus, it is essential to identify patients who are most likely to benefit from this treatment. Therefore, we aimed to investigate the 5-year risk of progression to type 2 diabetes in SELECT-eligible patients with a recent myocardial infarction and overweight or obesity without diabetes, and to assess the estimated preventive potential of semaglutide in a real-world cohort. We included patients registered in the Western Denmark Heart Registry with first-time myocardial infarction and body mass index (BMI) ≥ 27 kg/m2 without diabetes, thus meeting the eligibility criteria of the SELECT trial. The cohort was grouped by glycemic status at baseline: HbA1c 6.0–6.4

OBJECTIVE:Overweight or obesity is prevalent in 72% to 82% of individuals with psoriatic arthritis (PsA). We assessed the efficacy and safety of ixekizumab (IXE) concomitantly administered with tirzepatide (TZP) compared with IXE alone in adult participants with active PsA and overweight with at least one weight-related comorbidity or obesity. METHODS:TOGETHER-PsA (ClinicalTrials.gov identifier: NCT06588296) is a phase 3b, randomized, 52-week trial in adults with active PsA and overweight (body mass index [BMI] ≥27 to <30) with at least one weight-related comorbidity or obesity (BMI ≥30) using US-approved doses for IXE and TZP. The primary end point was simultaneous achievement of 50% improvement in American College of Rheumatology response criteria (ACR50) and ≥10% weight reduction at 36 weeks. Key secondary outcomes included ACR50. Additional secondary outcomes and patient-reported outcomes (PROs) were assessed. Safety was assessed as adverse events (AEs), treatment-emergent AEs, and serious AEs. RESULTS:A total of 271 participants were randomized (IXE + TZP, n = 138; IXE, n = 133). The primary end point was achieved with significant improvements in the IXE + TZP arm (31.7%) compared to IXE alone (0.8%) (P < 0.001). Greater improvements in ACR50 were demonstrated in IXE + TZP (33.5%) versus IXE alone (20.4%) (P = 0.02), with significant early separation at week 4 (nominal P < 0.05). IXE + TZP demonstrated nominally significant improvements in ACR20 (P < 0.001), minimal disease activity (P < 0.05), and absolute Psoriasis Area and Severity Index score (P < 0.01) compared to IXE alone. IXE + TZP demonstrated significant improvements in PROs, including Health Assessment Questionnaire-Disability Index (∆ -0.2; nominal P < 0.001) and Functional Assessment of Chronic Illness Therapy-Fatigue (improvement of 3.8; nominal P < 0.01) compared to IXE alone. Safety profiles were consistent with previous studies for each drug. CONCLUSION:Participants with active PsA and complex inflammatory-metabolic disease achieved clinically meaningful improvement of PsA, physical function, weight reduction, and quality of life when treated with IXE + TZP compared to IXE alone, with no new safety concerns.