BACKGROUND AND AIMS:Glucagon-like peptide-1 receptor agonists (GLP-1 RA) carry side-effects such as dizziness and nausea related to increased vagal tone. This study investigated associations between GLP-1 RA use and the risk of vagal activity related (VAR) events. METHODS:Using the Danish health registers, patients with type 2 diabetes mellitus (T2DM) first-time initiated on GLP-1 RA (exposure) or SGLT-2i (active control) were identified between January 2010 and October 2022. Standardized 1-year absolute risks of VAR events (syncope, fractures, bradyarrhythmia, or cardiac device implantation) were computed to compare risk associated with GLP-1 RA and SGLT-2i initiation. Complementary analyses in patients treated for obesity were performed as well. RESULTS:During the study period, 50 076 and 73 138 patients with T2DM were initiated on GLP-1 RA (47% women, median age: 59 years [IQR: 50-68]) or SGLT-2i (39% women, median age: 64 years [IQR: 55-72]). Comorbidity was equally prevalent. The standardized 1-year absolute risk of syncope was 0.58% (95% CI: 0.51%-0.66%) among patients initiated on GLP-1 RA and comparable to patients initiated on SGLT-2i (0.56% [95% CI: 0.50%-0.62%]). 1-year risks of fractures, bradyarrhythmia, and cardiac device implantation were equally low and with corresponding standardized risk ratios of 0.90 (95% CI: 0.79-1.01), 0.97 (95% CI: 0.67-1.28), and 0.86 (95% CI: 0.62-1.10), respectively. No associations were found in the group treated for obesity either. CONCLUSIONS:In nationwide cohorts of patients treated for T2DM or obesity, initiation of GLP-1 RA was not associated with an elevated risk of VAR events. Despite a proposed argumentation of vagal activity, GLP-1 RA use was not associated with an increased risk in real-life users.
Patients with Fontan circulation represent a pharmacologically distinct population in whom the haemodynamic consequences of single-ventricle physiology alter every phase of drug disposition in ways that current prescribing practice systematically fails to account for. Fontan-associated liver disease suppresses hepatic CYP enzyme activity and reduces first-pass metabolism, increasing bioavailability and systemic exposure of drugs. Hypoalbuminaemia from protein-losing enteropathy elevates the free fraction of highly protein-bound agents, rendering standard total drug concentration targets unreliable. Reduced cardiac output contracts the volume of distribution of hydrophilic drugs and diminishes renal perfusion, while creatinine-based glomerular filtration rate equations systematically overestimate true renal function due to reduced skeletal muscle mass, leading to inadequate dose reduction for renally cleared agents. These disturbances are predicted to affect the pharmacokinetics of every major cardiovascular drug class prescribed in this population, including anticoagulants, antiarrhythmics, neurohormonal antagonists, and pulmonary vasodilators, although direct Fontan-specific pharmacokinetic data remain scarce and confirm these effects for only a minority of agents, with dosing largely extrapolated from non-congenital populations. This review examines the mechanistic basis of pharmacokinetic alterations across drug disposition, evaluate available drug-class evidence, and outlines a research agenda including physiologically-based pharmacokinetic modelling, registry-embedded studies, and dedicated inclusion of Fontan patients in future trials.
AIMS:Evidence regarding statin adherence among patients with hypertension in primary care is limited. We assessed statin adherence in Swedish primary care and examined associations between patient characteristics and adherence. METHODS AND RESULTS:In this retrospective register-based cohort study from a large Swedish region, data from all primary health care centres were linked to data on comorbidities, dispensed drugs, and socioeconomic factors. Patients with hypertension who initiated statin therapy in 2012-2015 were included. Adherence during two years after initiation was measured using the proportion of days covered (PDC). Explainable machine learning with XGBoost and SHAP values identified baseline characteristics associated with adherence. Associations were estimated using adjusted multilevel regression and presented as odds ratios (ORs) and median odds ratio (MOR).Among 30 497 patients (mean age 66 years; 48% women), the mean two-year PDC was 73.2%, while 60.2% achieved adequate adherence (PDC >80%). Adequate adherence differed by indication (P <0.001): 54.0% in primary prevention, 61.3% in diabetes without cardiovascular disease, and 65.5% in secondary prevention. The five most important characteristics associated with adequate adherence according to SHAP values were dispensed antithrombotic therapy (OR 1.38, 95% CI 1.26-1.50), primary health care centre (MOR 1.16, 95% CI 1.12-1.20), 10-year increase in age (OR 1.14, 95% CI 1.12-1.17), initiation with atorvastatin (OR 1.33, 95% CI 1.24-1.44), and countries of birth outside Sweden (OR range 0.73-0.78). CONCLUSION:Only 60% of patients achieved adequate statin adherence, which varied substantially by indication. Patient- and provider-level factors identified could guide targeted interventions to optimize preventive cardiovascular care.
BACKGROUND:The API-CAT trial demonstrated that reduced-dose apixaban (2.5 mg twice daily) was noninferior to full-dose apixaban (5 mg twice daily) for the prevention of recurrent venous thromboembolism in patients with cancer, while resulting in fewer clinically relevant bleeding events. Although these findings are expected to influence clinical practice, real-world data on physicians' anticoagulation decisions in this setting remain limited. OBJECTIVES:To describe investigators' anticoagulant treatment decisions for patients enrolled in the API-CAT trial after discontinuation of blinded study treatment and prior to trial unblinding and dissemination of results. METHODS:This descriptive analysis included patients from the prospective, multicenter, randomized, double-blind API-CAT trial who received at least one dose of study medication. Investigators prospectively documented anticoagulation management following either premature or planned discontinuation of blinded apixaban. Decisions were categorized as treatment discontinuation, continuation at a reduced dose, or continuation at a full dose. Descriptive analyses examined treatment choices according to patient characteristics, cancer features, and contextual factors. RESULTS:Of 1,766 randomized patients, 1,458 (82.6%) were included in the analysis. After discontinuation of study treatment, anticoagulation was stopped in 198 patients (13.6%) and continued in 1,260 (86.4%). Among those continuing therapy, 790 patients (62.7%) received full-dose anticoagulation, 465 (36.9%) received a reduced dose, 5 unknown. Direct oral anticoagulants (DOACs) were prescribed in 89.6% of cases, and low-molecular-weight heparin in 9.9%. Treatment decisions were generally consistent across patient and cancer characteristics but varied according to timing of treatment discontinuation, physician specialty, and country. CONCLUSIONS:Prior to unblinding of the API-CAT trial, treatment decisions appeared poorly driven by clinical characteristics, reflecting a "therapeutic grey zone" where anticoagulation was continued in most patients but with highly variable dosing. This exploratory snapshot provides a baseline to monitor the anticipated shift toward wider adoption of reduced-dose apixaban for extended anticoagulation following publication of the API-CAT results. The substantial proportion of treatment discontinuation highlights the need for further studies to identify patients who may safely stop therapy.
AIMS:Rheumatoid arthritis (RA)-related physical limitations often hinder sustained physical activity and weight management, thereby amplifying cardiovascular risk through adverse metabolic profiles and chronic inflammation. We aimed to assess the effectiveness of semaglutide on the risk of incident major adverse cardiovascular and cerebrovascular events (MACCE) in obese adults with type 2 diabetes mellitus (T2DM) and RA in a primary-prevention setting. METHODS AND RESULTS:We emulated a target trial using data from the TriNetX US database, including obese adults [aged ≥18 years; body mass index (BMI) ≥30 kg/m2] with T2DM and comorbid RA and no prior history of stroke, heart failure (HF), acute coronary syndrome, or coronary revascularization. Using a new-user design, we compared patients initiating semaglutide with those initiating non-GLP-1 receptor agonist (GLP-1RA) second-line glucose-lowering therapies. Patients with contraindications to GLP-1RAs were excluded. Propensity-score matching (PS) (1:1) was used to balance baseline covariates. The primary outcome was incident MACCE, defined as a composite of all-cause mortality, myocardial infarction (MI), HF, or stroke. Secondary outcomes included individual MACCE components, HF hospitalization, and disease-modifying anti-rheumatic drug (DMARD) escalation, with Bonferroni correction applied for multiple comparisons. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models over a follow-up of up to 2 years. Between 1 January 2014 and 1 January 2025, we identified 1200 and 2972 patients who initiated semaglutide and non-GLP-1RA therapies, respectively, within 3 months of meeting eligibility. After PS matching, 1017 semaglutide users were compared with 1017 non-GLP-1RA users (mean age 59.5 vs. 59.3 years; women 81.3% vs. 81.0%; mean BMI 38.2 vs. 38.0 kg/m2; HbA1c, 6.8% vs. 7.0%). Semaglutide initiation was associated with a significantly lower risk of incident MACCE compared with non-GLP-1RA therapies (12.7% vs. 16.5%; HR, 0.75; 95% CI, 0.60-0.94; P = 0.01). This benefit was driven primarily by a lower risk of incident HF (8.9% vs. 12.5%; HR, 0.69, 95% CI, 0.53-0.91; P = 0·007). Semaglutide use was also associated with significantly lower DMARD escalation (16.6% vs. 21.6%; HR, 0.75; 95% CI, 0.60-0.90; P = 0.003). No significant differences were observed in all-cause mortality, MI, or stroke. CONCLUSION:Among obese adults with T2DM and comorbid RA, initiation of semaglutide was associated with a reduced risk of incident MACCE, driven predominantly by a reduction in incident HF, in a primary-prevention setting. Prospective studies are needed to confirm these observations and establish causality.
AIMS:Serum uric acid (SUA) and hyperuricaemia have re-emerged as determinants of cardiovascular (CV) risk beyond gout. This review integrates epidemiological, Mendelian randomization (MR), and pharmacological evidence to define the role of SUA and urate-lowering therapy (ULT) in contemporary CV pharmacotherapy. METHODS AND RESULTS:We synthesized population-based studies, MR and drug-target MR analyses, and randomized trials of xanthine oxidase inhibitors (XOIs), uricosurics/URAT1 inhibitors, biologic uricases, and CV drugs with urate-modifying effects. Hyperuricaemia is prevalent and rising, often closely accompanying obesity, hypertension, diabetes, and chronic kidney disease (CKD). Higher SUA correlates with coronary artery disease, heart failure, stroke, cardio-renal-metabolic syndromes, and mortality, with non-linear risk relationships and sex- and age-specific thresholds. Mendelian randomization suggests a modest causal contribution of genetically elevated SUA to blood pressure, coronary disease, and advanced CKD, partly mediated via haemodynamic, renal, and inflammatory pathways. Pharmacologically, XOIs, URAT1 inhibitors, and uricases differ in kinetics and safety profiles. However, large trials and real-world cohorts show no consistent reduction in CV events when ULT is added to guideline-directed therapy in asymptomatic hyperuricaemia, stable ischaemic heart disease, chronic heart failure, or CKD. Observational data suggest that long-term, adequately dosed XOIs and high cumulative uricosuric exposure may reduce coronary risk. CONCLUSION:Serum uric acid is a cardio-renal-metabolic biomarker and a plausible therapeutic target in selected cardio-renal-metabolic phenotypes. However, evidence does not support routine ULT for CV prevention in asymptomatic hyperuricaemia. Urate-lowering therapy should remain focused on gout and symptomatic hyperuricaemia, with phenotype-guided strategies to identify patients with asymptomatic hyperuricemia most likely to benefit.
AIMS:Current guidelines recommend considering long-term oral anticoagulation in patients with new-onset post-operative atrial fibrillation (POAF) after cardiac surgery, balancing stroke and bleeding risk. However, no specific approach to bleeding risk assessment is provided. We explored in a proof-of-concept study whether a bleeding risk score can identify patients with POAF after coronary artery bypass grafting (CABG) with increased risk of post-discharge major bleeding. METHODS AND RESULTS:This observational cohort study included 4436 patients with POAF after CABG in 2009-2020 without oral anticoagulation. The four-item PRECISE-DAPT score (based on age, creatinine clearance, preoperative haemoglobin concentration, and previous bleeding) was calculated for all patients. Bleeding risk was defined as high (≥25 points), medium (16-24 points), or low (≤15 points). Associations between bleeding risk and major bleeding events during the first post-operative year were assessed by Cox regression. Discrimination was evaluated with C-statistics, and calibration was assessed by comparing expected and observed bleeding rates. Major bleeding occurred in 2.1% of patients during the first year. The score classified 36.0% of patients as high bleeding risk. The hazard ratio for high vs. low bleeding risk was 4.81 (95% CI 2.59-8.96). The area under the receiver operating characteristic curve was 0.68 (95% CI 0.63-0.73). Calibration showed good agreement between expected and observed bleeding events in patients with an annual bleeding risk up to 7%. CONCLUSION:A bleeding risk score can be used to stratify patients with POAF after CABG into groups with different post-discharge bleeding risk. Further studies are necessary to identify the optimal risk score and its role in oral anticoagulation decision pathway to improve clinical outcomes.
