Introduction: Hyperthyroidism can be treated with antithyroid drugs (ATD), radioactive iodine (RAI), or surgery. We aimed to evaluate the long-term outcomes of these treatments through a systematic review and network meta-analysis (NMA). Methods: A systematic literature search of PubMed, EMBASE, Web of Science, and the Cochrane Library (from inception to March 7, 2025) was conducted to identify studies comparing the risks of all-cause mortality, cardiovascular mortality, major adverse cardiovascular events (MACE), and cancer mortality among patients with hyperthyroidism treated with ATD, RAI, or surgery. Pooled effect estimates were expressed as hazard ratios (HR) with confidence intervals (CI) using a random-effects model. The study was registered with PROSPERO (CRD420250543380) and adhered to the PRISMA-NMA guidelines. Results: Of the 8163 studies screened, 12 observational studies with an overall moderate risk of bias, comprising 192,208 patients were included in this NMA. Most patients received ATD (n = 142,622), followed by RAI (n = 19,303) and surgery (n = 10,360). Surgery was associated with decreased risks of all-cause mortality and cardiovascular mortality compared with both ATD and RAI. For all-cause mortality, the pooled HRs (CI, p-values) were 0.58 (0.45-0.75, p < 0.0001) for surgery versus ATD and 0.68 (0.56-0.84, p = 0.0004) for surgery versus RAI. For cardiovascular mortality, the pooled HR (CI, p-values) were 0.43 (0.19-0.98, p = 0.0445) for surgery versus ATD and 0.55 (0.33-0.93, p = 0.0269) for surgery versus RAI. No significant differences were observed in MACE or cancer mortality across the treatment groups. Conclusions: In patients with hyperthyroidism, surgery was associated with significantly decreased risks of all-cause mortality and cardiovascular mortality compared with ATD and RAI. Risks of MACE and cancer mortality did not differ by type of hyperthyroidism treatment. However, these findings should be interpreted with caution due to inherent methodological limitations of observational studies, including, but not limited to heterogeneity and potential selection bias.

Cardiovascular disease remains the leading cause of death worldwide, with a rising burden projected over the coming decades. Although traditional risk factors such as diabetes, hypertension, and dyslipidemia form the main targets of prevention strategies, many individuals carry a "residual" risk secondary to systemic inflammation which remains underrecognized. Landmark trials have established inflammation as a causal and modifiable driver of atherosclerotic cardiovascular disease. This review focuses on how inflammation can modulate interconnected diseases of the brain and heart. Growing evidence suggests that inflammation mediates a "brain-heart" axis, linking psychological stress, neuroinflammation, and cardiovascular pathology. Observational and mechanistic studies demonstrate that stress-induced neural activity, particularly within the amygdala, is associated with hematopoietic activation, arterial inflammation, and increased cardiovascular events. Models such as Takotsubo's cardiomyopathy and stroke-heart syndrome illustrate how acute brain injury can precipitate cardiovascular dysfunction via autonomic and inflammatory pathways. More recently, molecular imaging studies have provided direct evidence of stress-associated amygdalar activity being associated with both cardiovascular outcomes and cancer prognosis. This emerging framework reframes the brain and heart as interdependent organs connected through inflammatory and neurobiological processes, highlighting the potential for novel therapeutic targets, including modulation of stress-related neural pathways, alongside established anti-inflammatory strategies. Future directions include refinement of targeted therapies, use of advanced molecular imaging, and mechanistic studies to better delineate the pathways linking stress, inflammation, and cardiovascular disease.

The global type 2 diabetes epidemic is a major health crisis. Although the microbiome has roles in the onset of insulin resistance (IR), low-grade inflammation and diabetes, the microbial compounds controlling these processes remain to be discovered. Here, we show that the microbial metabolite trimethylamine (TMA) decouples inflammation and IR from diet-induced obesity by inhibiting interleukin-1 receptor-associated kinase 4 (IRAK4), a central kinase in the Toll-like receptor pathway sensing danger signals. TMA blunts TLR4 signalling in primary human hepatocytes and peripheral blood monocytic cells and rescues mouse survival after lipopolysaccharide-induced septic shock. Genetic deletion and chemical inhibition of IRAK4 result in metabolic and immune improvements in high-fat diets. Remarkably, our results suggest that TMA—unlike its liver co-metabolite trimethylamine N-oxide, which is associated with cardiovascular disease—improves immune tone and glycemic control in diet-induced obesity. Altogether, this study supports the emerging role of the kinome in the microbial–mammalian chemical crosstalk. The microbial metabolite trimethylamine (TMA), the precursor of TMAO, which is associated with adverse cardiometabolic outcomes, is shown to have beneficial metabolic and anti-inflammatory effects in the host in the context of obesity.

The Wnt/β-catenin pathway is critical in human tumor progression. Cell-surface transmembrane E3 ubiquitin ligase ring finger 43 negatively regulates Wnt signaling through ubiquitination of Wnt coreceptor Frizzled. Aberrant Wnt signaling through inactivating mutations of RNF43 has been identified in various forms of cancers, highlighting its significance in tumor biology. However, the precise mechanism underlying the function of RNF43 remains elusive, largely due to the absence of selective molecular tools allowing for detection or manipulation of endogenous RNF43. Here we present a series of disulfide-constrained peptides, including GUR-1.6.12.2, which exhibit high affinity and specificity against RNF43. GUR-1.6.12.2 can be used as a valuable research tool to delineate RNF43 activity in various contexts. We showcased its application in immunofluorescence, where RNF43 was detected in intestinal crypts using biotinylated GUR-1.6.12.2. We then combined experimental and computational structural approaches to propose a model of GUR-1.6.12.2 and its binding to RNF43. Importantly, we generated a functional RNF43-DCP by producing a hexavalent GUR-1.6.12.2 molecule, which exhibited inhibitory activity against Wnt signaling in cells by competing with R-spondin, a RNF43 ligand that potentiates signaling. The RNF43 binders presented here offer new opportunities for the research and development of anticancer therapies targeting Wnt signaling with improved selectivity.

INTRODUCTION:Brain and heart conditions are among the leading causes of illness and mortality in Canada. Heart failure is one of the fastest-growing cardiovascular conditions globally, with more than 100 000 Canadians diagnosed each year. Individuals with heart failure are at significantly increased risk of mental health challenges such as depression, anxiety and stress. However, healthcare services often remain siloed, treating physical and mental health separately. This complicates care for individuals with multiple chronic conditions. This multiyear study will adapt, test and accelerate changes to regional care delivery models in Eastern Ontario to optimise brain-heart health and generate knowledge to support the spread and scale of effective interventions that address community needs and priorities. We aim to: (1) identify resource gaps by mapping available services; (2) document strengths and challenges in care delivery; and (3) co-design, pilot test and evaluate an intervention developed based on the priority gap area(s) identified through objectives (1) and (2). METHODS AND ANALYSIS:This community-based participatory action research study is led by a research coalition of patient and caregiver partners, care providers and leadership staff from two Ontario Health Teams. In Year 1, we will conduct asset mapping and community consultations with individuals living with heart failure, caregivers, care providers and service organisations to identify care gaps, strengths and opportunities for improvement around modifiable behavioural risk factors and brain-heart health. A scoping review will identify evidence-based strategies to address care gaps and inform the co-design of an intervention focused on supporting individuals with brain-heart interconnected conditions. In Year 2, we will co-design an intervention with community partners for implementation with clinical test sites. Year 3 will involve pilot testing the intervention and conducting outcome and process evaluations. This will inform future spread and scale of the intervention to other brain-heart conditions and new jurisdictions. ETHICS AND DISSEMINATION:The study is approved by the Bruyère Health Research Ethics Board (M16-24-016). Findings will be disseminated through peer-reviewed publications, conference presentations and knowledge mobilisation activities such as social media, community events and local media outreach, as well as through dedicated engagement with Ontario Health partners and the Brain-Heart Interconnectome Network via retreats and collaborative forums.

Heart failure (HF) is a major contributor to global morbidity and mortality. While distinct clinical subtypes, defined by etiology and left ventricular ejection fraction, are well recognized, their genetic determinants remain inadequately understood. In this study, we report a genome-wide association study of HF and its subtypes in a sample of 1.9 million individuals. A total of 153,174 individuals had HF, of whom 44,012 had a nonischemic etiology (ni-HF). A subset of patients with ni-HF were stratified based on left ventricular systolic function, where data were available, identifying 5,406 individuals with reduced ejection fraction and 3,841 with preserved ejection fraction. We identify 66 genetic loci associated with HF and its subtypes, 37 of which have not previously been reported. Using functionally informed gene prioritization methods, we predict effector genes for each identified locus, and map these to etiologic disease clusters through phenome-wide association analysis, network analysis and colocalization. Through heritability enrichment analysis, we highlight the role of extracardiac tissues in disease etiology. We then examine the differential associations of upstream risk factors with HF subtypes using Mendelian randomization. These findings extend our understanding of the mechanisms underlying HF etiology and may inform future approaches to prevention and treatment.

Background:Both Nav1.5 and Cx43 are critical for the fast electrical impulse conduction in the myocardium and their reductions create the arrhythmogenic substrate. Wnt/β-catenin signaling is activated in arrhythmogenic myocardium, and although this signaling is known to downregulate cardiac Nav1.5, its regulation of Cx43 is unclear as conflicting results have been reported. The present study investigated how Wnt/β-catenin signaling regulates Cx43 in rat and human cardiomyocytes and if it is dependent on the sex of the cells or the metabolic substrates. Methods:Male and female neonatal rat ventricular myocytes (NRVMs) were treated with CHIR-99021 (CHIR) or Wnt3a protein, two different activators of the Wnt/β-catenin signaling, either in a medium rich in glucose (a preferred metabolic substrate in heart failure) or in a medium rich in lipid (∼150 μM fatty acid, a preferred substrate in healthy hearts). Both healthy and Brugada Syndrome human iPSC-derived cardiomyocytes (iPSC-CMs) were used to confirm observations in NRVMs. Results:When maintained in a glucose-rich medium, Gja1 mRNA (encoding Cx43) was reduced by a low concentration of CHIR (1 μM) in female NRVMs but only at a high concentration of CHIR (10 μM) in male NRVMs. However, reductions in Cx43 protein were observed at 1 μM CHIR in both male and female NRVMs, suggesting the involvement of both transcriptional and post-transcriptional mechanisms. When maintained in a lipid-rich medium, neither Gja1 mRNA nor Cx43 protein was altered by CHIR at 1 or 3 μM. In contrast, CHIR-induced reductions in Scn5a mRNA and Nav1.5 protein were observed in both glucose-rich and lipid-rich media, with no significant sex-specific differences detected. Consistent with studies using CHIR, which is a Wnt receptor-independent activator, Wnt3a protein also reduced both Gja1 mRNA and Cx43 protein in NRVMs in the glucose-rich medium but not in the lipid-rich medium. In human iPSC-CMs from two healthy volunteers and one Brugada Syndrome patient, Wnt/β-catenin signaling activation reduced GJA1 mRNA and Cx43 protein in a standard, glucose-containing medium. Conclusions:These data demonstrate that metabolic substrates regulate the effects of Wnt/β-catenin signaling in cardiomyocytes, with reductions in Cx43 mRNA and protein only observed when glucose is the primary metabolic substrate, which occurs in arrhythmogenic conditions such as cardiac hypertrophy and heart failure.

There is a lack of studies that concurrently differentiate the effect of the holiday season from the weekend effect on mortality risk in patients with acute myocardial infarction (AMI). We evaluated the mortality risk among patients admitted with AMI who underwent percutaneous coronary intervention, using data from the Taiwan National Health Insurance Research Database. Adult AMI patients admitted during January and February between 2013 and 2020 were enrolled and classified into the holiday season (using the Chinese New Year holiday seasons as an indicator) (n = 1729), weekend (n = 4725), and weekday (n = 14,583) groups according to the first day of admission. A multivariable logistic regression model was used to assess the risk. With the weekday group or the weekend group as the reference, the holiday season group did not have increased risks of in-hospital mortality (adjusted odds ratio [aOR] 1.15; 95% confidence intervals [CI] 0.93–1.42 or aOR 1.23; 95% CI 0.96–1.56) and 7-day mortality (aOR 1.20; 95% CI 0.90–1.58 or aOR 1.24; 95% CI 0.90–1.70). Stratified and subgroup analyses showed similar trends. We conclude that holiday season-initiated admissions were not associated with higher mortality risks in AMI admission cases than weekday or weekend admissions.

AbstractAimsAcute myocarditis, although a rare disease, can be associated with sudden cardiac death or the need for transplantation in both children and young adults. To date, there is no definitive evidence to support the routine use of immunosuppressive therapy or treatment targeting inflammation in patients with myocarditis. Animal models of cardiovascular (CV), as well as neurological diseases, have demonstrated that cannabidiol has significant anti‐inflammatory properties and may represent a promising therapy in acute myocarditis. This efficacy has been shown in a murine model of autoimmune myocarditis as well as in in vitro and in vivo models of heart failure (HF).Methods and resultsWe present the rationale and design of the ARCHER Trial, an international multicentre, double‐blind, randomized, placebo‐controlled, phase II study examining the safety and efficacy of a pharmaceutically produced cannabidiol formulation, in patients with mild to moderate acute myocarditis. Eligible patients are those with acute myocarditis, randomized within 10 days of the diagnostic cardiac MRI (CMR), which has met defined diagnostic criteria for myocarditis. Oral treatment (cannabidiol or placebo) is titrated from 2.5 mg/kg of body weight up to 10 mg/kg of body weight b.i.d. (or highest tolerated dose) and taken for 12 weeks in addition to standard of care therapy for HF. The primary endpoints are defined as changes in global longitudinal strain (GLS) and extra cellular volume (ECV), measured by CMR at 12 weeks. Assuming 80% power, a 5% alpha risk and 25% missing CMR follow‐up data at Week 12, 100 patients are required to demonstrate the desired treatment effect of 18%. The change in left ventricular ejection fraction (LVEF) from baseline to Week 12 was selected as the secondary endpoint. Additional exploratory endpoints include changes in hs‐troponin, NT‐proBNP, markers of inflammation and endothelial function during the 12‐week treatment period. The trial is ongoing but is now more than 50% recruited. As enrolment in the trial continues, no interim data are available for inclusion in this Design paper.ConclusionsThe ongoing ARCHER Trial is an international, multicentre, double‐blind, randomized, placebo‐controlled phase II study, designed to determine the effect of a pharmaceutically produced cannabidiol formulation on CMR parameters in patients presenting with acute myocarditis. Enrolment of 100 patients is expected to conclude in Q3 2024. Study results will be available in early 2025.

A 67-year-old man presented to the emergency department with epistaxis, pancytopenia, and renal failure (creatinine, 633 umol/L; normal, 52-112 umol/L). He was recently diagnosed with cytoplasmic-antineutrophil cytoplasmic autoantibody (c-ANCA)-associated glomerulonephritis. Three weeks earlier, he presented with new-onset renal failure (creatinine, 738 umol/L), hyperkalemia (6.2 mmol/L; normal, 3.5-5.0 umol/L), and normocytic anemia (hemoglobin, 91 g/L; normal, 130-170 g/L). Urine microscopy revealed red blood cell and heme granular casts, concerning for rapidly progressive glomerulonephritis. Autoimmune investigations were positive for PR3 (c-ANCA) (>200 RU/mL; normal, <20 RU/mL) and low complement (C3 and C4) levels. Cryocrit was positive (normal; negative). Antineutrophil cytoplasmic autoantibody autoantibodies to myeloperoxidase (p-ANCA) were negative. Initial investigations for infectious etiologies including blood cultures, hepatitis B surface antigen and core antibody, hepatitis C antibody, and HIV serology were negative. A diagnosis of c-ANCA-associated pauci-immune glomerulonephritis was made based on serologic findings. He was treated with oral cyclophosphamide and prednisone.

Skin is our first line of defense against harmful microbes. We aim to investigate if disruption of this defense in the form of cutaneous wounds will increase the incidence rate (IR) of infective endocarditis (IE) in a population with diabetes mellitus (DM). We performed a retrospective population-based study using Taiwan's National Health Insurance Database from 2003 to 2019. Self-controlled case series (SCCS) was used to investigate the association between cutaneous wounds and IE. Adult DM patients with both cutaneous wounds (exposure) and IE (outcome) in the overall study period were included in the study. Conditional Poisson regression adjusted with demographics, cardiac risk factors and comorbidities was used to calculate the incidence rate ratios (IRR) of IE in four weeks following wounds compare with the baseline period within the same individuals. We obtained 5,443 eligible patients in this SCCS setting. The adjusted IRRs (95% CI, p-value) were 2.52 (1.57–4.04, p< .001) for the second weeks after traumatic wound, and 2.46 (2.15–2.82, p< .001), 1.94 (1.64–2.30, p< .001), 1.57 (1.29–1.90, p< .001), and 1.54 (1.26–1.89, p< .001) for the first to fourth weeks following a non-traumatic wound, respectively. Subgroup and sensitivity analyses confirmed the robustness of the findings. This study provides evidence of the association between cutaneous wounds and the occurrence of IE among patients with DM in Taiwan. Future research should explore wound conditions and the need for prophylactic antibiotics.

Aim: To identify unique clinical phenotypes in type 2 diabetes (T2D) and investigate their treatment response to canagliflozin using latent class analysis. Methods: This was a pooled latent class analysis of the individuals in the CANVAS Program and CREDENCE trial. The co-primary endpoints were hospitalization for heart failure (HHF) and the composite of cardiovascular death (CVD) or HHF. Secondary endpoints included three-point major adverse CV events, its individual components, and all-cause mortality. We completed Cox proportional hazards models to evaluate the effect of canagliflozin across phenotypes. Results: Four distinct phenotypes were identified: Phenotype 1 (n = 966, 6.6%), with the lowest prevalence of heart failure, kidney dysfunction and hypertension; Phenotype 2 (n = 4169, 28.7%), primarily comprising females with a high prevalence of atherosclerotic vascular disease (ASCVD); Phenotype 3 (n = 7108, 48.9%), predominately males with a high prevalence of ASCVD; and Phenotype 4 (n = 2300, 15.8%), possessing the highest prevalences of HF and renal dysfunction. A hierarchical increase in the risk of the primary endpoint was observed across the phenotypes, with the highest CV risk observed for Phenotype 4 (hazard ratio for HHF: 7.57 [95% CI: 4.19-13.69]). Canagliflozin significantly reduced HHF and the composite CVD or HHF across phenotypes (all P values for interaction > .05). Conclusion: We identified four clinically distinct T2D phenotypes with differential CV risks. Canagliflozin reduced the risk of CV events, irrespective of the phenotype, emphasizing its broad therapeutic acceptability.

BACKGROUND AND OBJECTIVES:The impact of off-hours admission (such as weekends, nighttime, and non-working hours) vs. regular hours (weekdays and daytime working hours) on the mortality risk of patients undergoing surgery for type A aortic dissection (TAAD) repair is still uncertain. To address this uncertainty, we undertook a comprehensive systematic review and meta-analysis. We aimed to assess the potential link between off-hours admission and the risk of mortality in patients undergoing TAAD repair surgery. METHODS:We conducted a thorough search of the PubMed, Embase, and Cochrane Library databases, covering the period from their inception to May 20, 2023. Our inclusion criteria encompassed all studies that examined the potential relationship between off-hour admission and mortality in individuals who had undergone surgery for TAAD repair. The odds ratios (ORs) were extracted and combined utilizing a random effects model for our synthesis. RESULTS:Nine studies with 16,501 patients undergoing TAAD repair surgery were included in the meta-analysis. Overall, patients who underwent surgery during the weekend had higher in-hospital mortality (pooled OR, 1.41; 95% confidence interval [CI], 1.14-1.75; p=0.002) than those treated on weekdays. However, the mortality risks among patients who underwent TAAD surgery during nighttime and non-working hours were not significantly elevated compared to daytime and working hours admission. CONCLUSIONS:Weekend surgery for TAAD was associated with a higher in-hospital mortality risk than weekday surgery. However, further studies are warranted to identify and develop strategies to improve the quality of round-the-clock care for patients with TAAD.

This article discusses the complex approach to managing atherosclerotic cardiovascular disease (ASCVD), focusing on person-centred care (PCC) to align treatment strategies with individual patient narratives, values, and preferences. It identifies significant challenges in management of ASCVD, such as the necessity for multidisciplinary strategies and the need for enhanced patient care, particularly given the coexistence of ASCVD with other cardiometabolic risk factors. The paper points out existing practice gaps, including limited patient-provider information sharing and decision making, and considers the role of technology in personalizing care and improving outcomes. Strategies such as electronic health records, telehealth platforms, and motivational interviewing are examined for their potential to boost patient engagement and adherence to treatment. In addition, the article discusses systemic issues such as health care provider burnout and the importance of creating customized care plans for patients with multiple health conditions. The integration of varied approaches, including the involvement of community pharmacists and health coaches, is suggested as important for effective management of ASCVD. This review highlights the need for an innovative, holistic strategy for management of ASCVD and advocates for a transformative shift toward PCC that integrates individual, community, and system-level interventions to enhance patient engagement, therapy adherence, and overall outcomes.

Importance Denosumab, a humanized monoclonal antibody against receptor activator of nuclear factor κB ligand (RANKL), is a widely used antiresorptive medication for osteoporosis treatment. Recent preclinical studies indicate that inhibition of RANKL signaling improves insulin sensitivity, glucose tolerance, and β-cell proliferation, suggesting that denosumab may improve glucose homeostasis; however, whether denosumab reduces the risk of incident diabetes remains unclear. Objective To evaluate whether denosumab use is associated with a lower risk of developing diabetes in patients with osteoporosis. Design, Setting, and Participants This nationwide, propensity score–matched cohort study used administrative data from Taiwan’s National Health Insurance Research Database. Adult patients who received denosumab for osteoporosis therapy in Taiwan between 2012 and 2019 were included. To eliminate the inherent bias from confounding by indication, the patients were categorized into a treatment group (34 255 patients who initiated denosumab treatment and adhered to it) and a comparison group (34 255 patients who initiated denosumab treatment but discontinued it after the initial dose) according to the administration status of the second dose of denosumab. Propensity score matching was performed to balance patient characteristics and to control for confounders. Exposure Treatment with denosumab. Main Outcomes and Measures The primary outcome was incident diabetes requiring treatment with antidiabetic drugs. A Cox proportional hazards model was used to estimate the hazard ratio (HR) for incident diabetes. Data were analyzed from January 1 to November 30, 2023. Results After propensity score matching, 68 510 patients were included (mean [SD] age, 77.7 [9.8] years; 57 762 [84.3%] female). During a mean (SD) follow-up of 1.9 (1.6) years, 2016 patients developed diabetes in the treatment group and 3220 developed diabetes in the comparison group (incidence rate, 35.9 vs 43.6 per 1000 person-years). Compared with the comparison group, denosumab treatment was associated with a lower risk of incident diabetes (HR, 0.84; 95% CI, 0.78-0.90). Several sensitivity analyses also demonstrated similar results of lower diabetes risk associated with denosumab treatment. Conclusions and relevance The results from this cohort study indicating that denosumab treatment was associated with lower risk of incident diabetes may help physicians choose an appropriate antiosteoporosis medication for patients with osteoporosis while also considering the risk of diabetes.

Aims Social robots are arriving to the modern healthcare system. Whether patients with heart failure, a prevalent chronic disease with high health and human costs would derive benefit from a social robot intervention has not been investigated empirically. Diverse healthcare provider’s perspectives are needed to develop an acceptable and feasible social robot intervention to be adopted for the clinical benefit of patients with heart failure. Using a qualitative research design, this study investigated healthcare providers’ perspectives of social robot use in heart failure patient care. Methods and results Interdisciplinary healthcare providers from a tertiary care cardiac hospital completed a structured individual interview and a supplemental questionnaire. The framework method was used to analyse the qualitative data. Respondents (n = 22; saturation was reached with this sample; 77% female; 52% physicians) were open to using social robots to augment their practice, particularly with collecting pertinent data and providing patient and family education and self-management prompts, but with limited responsibility for direct patient care. Prior to implementation, providers required robust evidence of: value-added beyond current remote patient monitoring devices, patient and healthcare provider partnerships, streamlined integration into existing practice, and capability of supporting precision medicine goals. Respondents were concerned that social robots did not address and masked broader systemic issues of healthcare access and equity. Conclusion The adoption of social robots is a viable option to assist in the care of patients with heart failure, albeit in a restricted capacity. The results inform the development of a social robotic intervention for patients with heart failure, including improving social robot efficiencies and increasing their uptake, while protecting patients’ and providers’ best interest.

AIMS:Results from randomized trials suggest benefit of sodium-glucose cotransporter 2 (SGLT2) inhibitor initiation in clinically stable acute heart failure. We aim to examine the real-world effectiveness of early versus delayed post-discharge SGLT2 inhibitor initiation in people with acute heart failure and type 2 diabetes. METHODS AND RESULTS:Using linkable administrative databases in Ontario, Canada, individuals aged 66 years or older with type 2 diabetes who were discharged to the community from acute care hospitals for heart failure between 1 July 2016 and 31 March 2020 were included in this retrospective, population-based cohort study. The primary outcome was hospitalization for heart failure (HHF) or cardiovascular mortality as a composite. Follow-up started from discharge for maximum 1 year. We compared outcomes between post-discharge SGLT2 inhibitor initiation within 3 days, 4-90 days, or 91-180 days, versus delayed initiation for at least 180 days. The 'clone-censor-weight' approach with a target trial emulation framework was used to address time-related biases. There were 9641 eligible individuals. After cloning and artificial censoring, there were 38 564 clones, 12 439 person-years, and 7584 events. Compared to delayed initiation for at least 180 days, initiation within 3 days post-discharge was associated with a lower 1-year risk of HHF or cardiovascular mortality (risk ratio [RR] 0.65, 95% confidence interval [CI] 0.45-0.83), while initiation 4-90 days (RR 0.83, 95% CI 0.72-0.93) or 91-180 days (RR 0.89, 95% CI 0.79-0.97) showed smaller risk reduction. CONCLUSION:Real-world evidence supports early SGLT2 inhibitor initiation to reduce HHF or cardiovascular mortality in acute heart failure and type 2 diabetes.