Statins improve cardiac endothelial function to prevent heart failure with preserved ejection fraction through upregulating circRNA-RBCK1.

Heart failure with preserved ejection fraction (HFpEF) is associated with endothelial dysfunction. We have previously reported that statins prevent endothelial dysfunction through inhibition of microRNA-133a (miR-133a). This study is to investigate the effects and the underlying mechanisms of statins on HFpEF. Here, we show that statins upregulate the expression of a circular RNA (circRNA-RBCK1) which is co-transcripted with the ring-B-box-coiled-coil protein interacting with protein kinase C-1 (RBCK1) gene. Simultaneously, statins increase activator protein 2 alpha (AP-2α) transcriptional activity and the interaction between circRNA-RBCK1 and miR-133a. Furthermore, AP-2α directly interacts with RBCK1 gene promoter in endothelial cells. In vivo, lovastatin improves diastolic function in male mice under HFpEF, which is abolished by loss function of endothelial AP-2α or circRNA-RBCK1. This study suggests that statins upregulate the AP-2α/circRNA-RBCK1 signaling to suppress miR-133a in cardiac endothelial cells and prevent diastolic dysfunction in HFpEF.

FBXL8 inhibits post-myocardial infarction cardiac fibrosis by targeting Snail1 for ubiquitin-proteasome degradation.

Abnormal cardiac fibrosis is the main pathological change of post-myocardial infarction (MI) heart failure. Although the E3 ubiquitin ligase FBXL8 is a key regulator in the cell cycle, cell proliferation, and inflammation, its role in post-MI ventricular fibrosis and heart failure remains unknown. FBXL8 was primarily expressed in cardiac fibroblasts (CFs) and remarkably decreased in CFs treated by TGFß and heart subjected to MI. The echocardiography and histology data suggested that adeno-associated viruses (AAV9)-mediated FBXL8 overexpression had improved cardiac function and ameliorated post-MI cardiac fibrosis. In vitro, FBXL8 overexpression prevented TGFß-induced proliferation, migration, contraction, and collagen secretion in CFs, while knockdown of FBXL8 demonstrated opposite effects. Mechanistically, FBXL8 interacted with Snail1 to promote Snail1 degradation through the ubiquitin-proteasome system and decreased the activation of RhoA. Moreover, the FBXL8ΔC3 binding domain was indispensable for Snail1 interaction and degradation. Ectopic Snail1 expression partly abolished the effects mediated by FBXL8 overexpression in CFs treated by TGFß. These results characterized the role of FBXL8 in regulating the ubiquitin-mediated degradation of Snail1 and revealed the underlying molecular mechanism of how MI up-regulated the myofibroblasts differentiation-inducer Snail1 and suggested that FBXL8 may be a potential curative target for improving post-MI cardiac function.

Characteristics of Postoperative Heart Failure in Older Hip Fractures Patients Combined with Coronary Heart Disease and Construction of a Prediction Model of Nomogram, a Retrospective Cohort Study.

Introduction: Older patients combined with coronary heart disease (CHD) develop acute heart failure (AHF) after hip fracture surgery is common, and this study aimed to investigate the risk factors of postoperative AHF in older hip fracture patients and to construct a nomogram prediction model. Methods: We retrospectively collected older hip fracture patients with CHD who underwent hip fracture surgery at the Third Hospital of Hebei Medical University from January 2017 to December 2021. We divided them into a training set and a validation set. We collected the demographic data, laboratory indicators and imaging examination results. We identified risk factors for postoperative AHF and used R language software to establish a nomogram prediction model, plot ROC curves, calibration curves and DCA decision curves. Results: We retrospectively collected 1288 older hip fractures patients with CHD. After excluding 214 patients who did not meet the criteria, 1074 patients were included in our research and we divided them into the training set and the validation set. In the training set, a total of 346 (42.8%) patients developing postoperative AHF. Through univariate and multivariate logistic regression analysis, we identified the risk factors for postoperative AHF and constructed a nomogram prediction model. The AUC of the prediction model is 0.778. The correction curve shows that the model has good consistency. The decision curve analysis shows that the model has good clinical practicality. Conclusion: There were 42.8% older patients combined with CHD develop postoperative AHF. Among them, fracture type, age, anemia at admission, combined with COPD, ASA ≥ 3, and preoperative waiting time >3 days are risk factors for postoperative AHF. We constructed a nomogram prediction model that can effectively predict the risk of postoperative AHF in older hip fracture patients combined with CHD.

Percutaneous Intervention of LVAD Outflow Graft Obstruction and Thrombosis.

Left ventricular assist devices serve as a salvage therapy for patients with advanced heart failure. Complications such as thrombosis and obstruction can lead to acute device malfunction, posing significant clinical risks. A multidisciplinary approach is crucial for management. Few cases in the literature have demonstrated the safety and efficacy of percutaneous intervention, which holds significant value due to its less invasive nature and minimal risk of morbidity, especially in high-risk surgical patients.

A Murine Model of Hyperlipidemia-Induced Heart Failure with Preserved Ejection Fraction.

The pathophysiology of heart failure with preserved ejection fraction (HFpEF) driven by lipotoxicity is incompletely understood. Given the urgent need for animal models that accurately mimic cardio-metabolic HFpEF, a hyperlipidemia-induced murine model was developed by reverse engineering phenotypes seen in HFpEF patients. This model aimed to investigate HFpEF, focusing on the interplay between lipotoxicity and metabolic syndrome. Hyperlipidemia was induced in wild-type (WT) mice on a 129J strain background through bi-weekly intraperitoneal injections of poloxamer-407 (P-407), a block co-polymer that blocks lipoprotein lipase, combined with a single intravenous injection of adeno-associated virus 9-cardiac troponin T-low-density lipoprotein receptor (AAV9-cTnT-LDLR). Extensive assessments were conducted between 4 and 8 weeks post-treatment, including echocardiography, blood pressure recording, whole-body plethysmography, echocardiography (ECG) telemetry, activity wheel monitoring (AWM), and biochemical and histological analyses. The LDLR/P-407 mice exhibited distinctive features at four weeks, including diastolic dysfunction, preserved ejection fraction, and increased left ventricular wall thickness. Notably, blood pressure and renal function remained within normal ranges. Additionally, ECG and AWM revealed heart blocks and reduced activity, respectively. Diastolic function deteriorated at eight weeks, accompanied by a significant decline in respiratory rates. Further investigation into the double treatment model revealed elevated fibrosis, wet/dry lung ratios, and heart weight/body weight ratios. The LDLR/P-407 mice exhibited xanthelasmas, ascites, and cardiac ischemia. Interestingly, sudden deaths occurred between 6 and 12 weeks post-treatment. The murine HFpEF model offers a valuable and promising experimental resource for elucidating the intricacies of metabolic syndrome contributing to diastolic dysfunction within the context of lipotoxicity-mediated HFpEF.

Associations between cardiovascular diseases and cancer mortality: insights from a retrospective cohort analysis of NHANES data.

BACKGROUND: This study explored the association of cardiovascular disease (CVD) with cancer mortality risk in individuals with or without a history of cancer, to better understand the interplay between CVD and cancer outcomes. METHODS: Utilizing data from the National Health and Nutrition Examination Survey (NHANES) spanning 1999 to 2018, a retrospective cohort analysis was conducted. This analysis accounted for the survey's complex design to ensure national representativeness. The association of CVD with cancer mortality was assessed through multivariable Cox proportional hazards models. RESULTS: The present study included 59,653 participants, of whom 54,095 did not have cancer and 5558 had a history of cancer. In individuals without cancer, heart failure (HF) was associated with an increased risk of mortality from cancer (HR, 1.36; 95% CI, 1.09-1.69; P = 0.005). In participants with cancer, HF correlated with a higher risk of mortality from cancer (HR, 1.76; 95% CI, 1.32-2.34; P < 0.001). Diabetes (DM), hypertension (HBP) and coronary heart disease (CHD) were not significantly associated with an increased risk of mortality from cancer. Significant differences were observed in the interaction between cancer and CHD (HR, 0.68; 95% CI, 0.53-0.87; P = 0.002). For cancer and HBP, a similar trend was noted (HR, 0.75; 95% CI, 0.62-0.91; P = 0.003). No significant differences were found in interactions between HF, DM and cancer. CONCLUSIONS: HF was associated with an increased risk of mortality from cancer, regardless of cancer history, while HBP, CHD and DM showed no significant association. These findings underscore the importance of understanding the mechanisms behind the increased risk of cancer mortality following HF.

Identifying subgroups in heart failure patients with multimorbidity by clustering and network analysis.

This study presents a workflow for identifying and characterizing patients with Heart Failure (HF) and multimorbidity utilizing data from Electronic Health Records. Multimorbidity, the co-occurrence of two or more chronic conditions, poses a significant challenge on healthcare systems. Nonetheless, understanding of patients with multimorbidity, including the most common disease interactions, risk factors, and treatment responses, remains limited, particularly for complex and heterogeneous conditions like HF. We conducted a clustering analysis of 3745 HF patients using demographics, comorbidities, laboratory values, and drug prescriptions. Our analysis revealed four distinct clusters with significant differences in multimorbidity profiles showing differential prognostic implications regarding unplanned hospital admissions. These findings underscore the considerable disease heterogeneity within HF patients and emphasize the potential for improved characterization of patient subgroups for clinical risk stratification through the use of EHR data.

Development of a scale to gain insight into the experience of living with chronic heart failure: The UNAV-Experience of Living with Chronic Heart Failure Scale.

BACKGROUND: To date, there are no tools for the nursing staff to gain systematic insight on the experience lived by patients with chronic heart failure. The objective of this study was to develop a scale for this purpose. METHODS: The study was conducted between January 2018 and December 2020 in three Spanish hospitals. The process described by DeVellis was used for the development of the scale. The items were built based on a phenomenological study and a systematic review of the literature. Next, feedback from a panel of experts was obtained, the scale was administered to a sample of patients with chronic heart failure, and a cognitive interview and an observational study were conducted to create the final version of the scale. RESULTS: The first version of the scale had in seven domains and 76 items. After its evaluation by a panel of experts, it was reduced to a second version with six domains and 55 items. Following the administration of Version 2 to 17 patients (58.8% male, mean age 59.53, 70.6% classified as NYHA functional class II), five items were modified and two eliminated. Thus, the third version of the UNAV-CHF Experience Scale was composed of six domains and 53 items. CONCLUSIONS: This study presents the development of the UNAV-experience of living with chronic heart failure scale. It is an original and novel instrument that allows systematically explore this experience. A larger-scale study is necessary to confirm the validity of our scale.

Blood groups and Rhesus status as potential predictors of outcomes in patients with cardiac resynchronisation therapy.

Cardiac resynchronisation therapy (CRT) improves prognosis in patients with heart failure (HF) however the role of ABO blood groups and Rhesus factor are poorly understood. We hypothesise that blood groups may influence clinical and survival outcomes in HF patients undergoing CRT. A total of 499 patients with HF who fulfilled the criteria for CRT implantation were included. Primary outcome of all-cause mortality and/or heart transplant/left ventricular assist device was assessed over a median follow-up of 4.6 years (IQR 2.3-7.5). Online repositories were searched to provide biological context to the identified associations. Patients were divided into blood (O, A, B, and AB) and Rhesus factor (Rh-positive and Rh-negative) groups. Mean patient age was 66.4 ± 12.8 years with a left ventricular ejection fraction of 29 ± 11%. There were no baseline differences in age, gender, and cardioprotective medication. In a Cox proportional hazard multivariate model, only Rh-negative blood group was associated with a significant survival benefit (HR 0.68 [0.47-0.98], p = 0.040). No association was observed for the ABO blood group (HR 0.97 [0.76-1.23], p = 0.778). No significant interaction was observed with prevention, disease aetiology, and presence of defibrillator. Rhesus-related genes were associated with erythrocyte and platelet function, and cholesterol and glycated haemoglobin levels. Four drugs under development targeting RHD were identified (Rozrolimupab, Roledumab, Atorolimumab, and Morolimumab). Rhesus blood type was associated with better survival in HF patients with CRT. Further research into Rhesus-associated pathways and related drugs, namely whether there is a cardiac signal, is required.

Implementing a New Algorithm for Reinterpretation of Ambiguous Variants in Genetic Dilated Cardiomyopathy.

Dilated cardiomyopathy is a heterogeneous entity that leads to heart failure and malignant arrhythmias. Nearly 50% of cases are inherited; therefore, genetic analysis is crucial to unravel the cause and for the early identification of carriers at risk. A large number of variants remain classified as ambiguous, impeding an actionable clinical translation. Our goal was to perform a comprehensive update of variants previously classified with an ambiguous role, applying a new algorithm of already available tools. In a cohort of 65 cases diagnosed with dilated cardiomyopathy, a total of 125 genetic variants were classified as ambiguous. Our reanalysis resulted in the reclassification of 12% of variants from an unknown to likely benign or likely pathogenic role, due to improved population frequencies. For all the remaining ambiguous variants, we used our algorithm; 60.9% showed a potential but not confirmed deleterious role, and 24.5% showed a potential benign role. Periodically updating the population frequencies is a cheap and fast action, making it possible to clarify the role of ambiguous variants. Here, we perform a comprehensive reanalysis to help to clarify the role of most of ambiguous variants. Our specific algorithms facilitate genetic interpretation in dilated cardiomyopathy.

Renin-Angiotensin-Aldosterone System: From History to Practice of a Secular Topic.

Renin-angiotensin-aldosterone system (RAAS) inhibitors are standard care in patients with hypertension, heart failure or chronic kidney disease (CKD). Although we have studied the RAAS for decades, there are still circumstances that remain unclear. In this review, we describe the evolution of the RAAS and pose the question of whether this survival trait is still necessary to humankind in the present age. We elucidate the benefits on cardiovascular health and kidney disease of RAAS inhibition and present promising novel medications. Furthermore, we address why more studies are needed to establish a new standard of care away from generally prescribing ACEi or ARB toward an improved approach to combine drugs tailored to the needs of individual patients.

[Meleis theory: a tool for better understanding city-hospital transitions]. / La théorie de Meleis : un outil pour mieux comprendre les transitions ville-hôpital.

Meleis' theory: a tool for better understanding the hospital/town transitions. The purpose of this article is to provide a critique of the transition theory conceptualized by Afaf Meleis. A clinical vignette is used to highlight the strengths and limitations of the theory in the care of elderly people returning home after hospitalization for heart failure. The discussion is based on Peggy Chinn and Maeona Kramer's method of critical analysis.

[Optimizing the management of heart failure: structuring the care pathway]. / Optimisation de la prise en charge de l'insuffisance cardiaque : structuration du parcours de soins.

The incidence of chronic heart failure continues to rise in Western countries, justifying the implementation of an optimized multidisciplinary organization based on medical and nursing convergence. Around the main heart failure, assistance and transplantation unit at Toulouse University Hospital, several structures have been put in place to better manage heart failure patients and improve their care pathway.

Diagnostic performance of a clinical ultrasound-based algorithm for acute heart failure in patients presenting to the emergency department with dyspnea. / Rendimiento diagnóstico de un algoritmo basado en ecografía clínica para el diagnóstico de insuficiencia cardiaca aguda en pacientes que consultan en urgencias por disnea.

OBJECTIVES: To study the diagnostic performance of an ultrasound-based algorithm that includes the deceleration time (DT) of early mitral filling to establish a diagnosis of acute heart failure (AHF) in patients who come to an emergency department because of dyspnea. MATERIAL AND METHODS: Prospective analysis in a convenience sample of patients who came to a hospital emergency department with acute dyspnea. The algorithm included ultrasound findings and 4 echocardiographic findings as follows: mitral annular plane systolic excursion, Doppler mitral flow velocity, tissue Doppler imaging measure of the lateral annulus, and the DT of early mitral filling. The definitive diagnosis was made by 2 physicians blinded to each other's diagnosis and the ultrasound findings. RESULTS: A total of 166 adult patients with a mean (SD) age of 76 (13) years were included; 79 (48%) were women. AHF was the definitive diagnosis in 62 patients (37%). Diagnostic agreement was good between the 2 physicians (κ = 0.71). The algorithm classified all the patients, and there were no undetermined diagnoses. Diagnostic performance indicators for the ultrasound-based algorithm integrating early DT findings were as follows: area under the receiver operating characteristic curve, 0.91 (95% CI, 0.86-0.96); sensitivity, 87% (95% CI, 76%-94%); specificity, 95% (95% CI, 89%-98%); positive likelihood ratio, 18.1 (95% CI, 7.7-42.8); and negative likelihood ratio, 0.14 (95% CI, 0.07-0.26). CONCLUSION: The ultrasound-based algorithm integrating the DT of early mitral filling performs well for diagnosing AHF in emergency patients with dyspnea. The inclusion of early DT allows all patients to be diagnosed.

OBJETIVO: Analizar el rendimiento diagnóstico de un algoritmo ecográfico que incluye el tiempo de desaceleración precoz del flujo mitral (TD) para establecer el diagnóstico de insuficiencia cardiaca aguda (ICA) en pacientes que consultan en un servicio de urgencias hospitalario (SUH) por disnea. METODO: Análisis prospectivo de una muestra de conveniencia de pacientes que consultan por disnea aguda en un SUH. El algoritmo ecográfico incluyó la ecografía pulmonar y cuatro parámetros ecocardiográficos, se midió MAPSE (desplazamiento sistólico del plano del anillo mitral), medidas doppler de flujo mitral, medidas doppler tisular en el anillo mitral lateral y TD. El diagnóstico final fue asignado por 2 médicos ciegos entre sí y a los hallazgos ecográficos. RESULTADOS: Se incluyeron 166 pacientes adultos, la edad media fue de 76 años (DE 13) y 79 eran mujeres (48%). Hubo 62 pacientes (37%) con un diagnóstico final de ICA. La concordancia entre asignadores fue buena para el diagnóstico de ICA (κ = 0,71). El algoritmo clasificó a todos los pacientes, no hubo ningún diagnóstico indeterminado. El rendimiento diagnóstico del algoritmo mostró un área bajo la curva de 0,91 (IC 95%: 0,86-0,96), sensibilidad del 87% (IC 95%: 76%-94%), especificidad del 95% (IC 95%: 89%-98%), razón de verosimilitud positiva del 18,1 (IC 95%: 7,7-42,8), razón de verosimilitud negativa del 0,14 (IC 95%: 0,07-0,26). CONCLUSIONES: Un algoritmo ecográfico que incluye el TD tiene un buen rendimiento para el diagnóstico de ICA en pacientes que acuden a SUH por disnea. Además, el uso de TD permite clasificar a todos los pacientes.

Non-Invasive Heart Failure Evaluation Using Machine Learning Algorithms.

Heart failure is a prevalent cardiovascular condition with significant health implications, necessitating effective diagnostic strategies for timely intervention. This study explores the potential of continuous monitoring of non-invasive signals, specifically integrating photoplethysmogram (PPG) and electrocardiogram (ECG), for enhancing early detection and diagnosis of heart failure. Leveraging a dataset from the MIMIC-III database, encompassing 682 heart failure patients and 954 controls, our approach focuses on continuous, non-invasive monitoring. Key features, including the QRS interval, RR interval, augmentation index, heart rate, systolic pressure, diastolic pressure, and peak-to-peak amplitude, were carefully selected for their clinical relevance and ability to capture cardiovascular dynamics. This feature selection not only highlighted important physiological indicators but also helped reduce computational complexity and the risk of overfitting in machine learning models. The use of these features in training machine learning algorithms led to a model with impressive accuracy (98%), sensitivity (97.60%), specificity (96.90%), and precision (97.20%). Our integrated approach, combining PPG and ECG signals, demonstrates superior performance compared to single-signal strategies, emphasizing its potential in early and precise heart failure diagnosis. The study also highlights the importance of continuous monitoring with wearable technology, suggesting a significant stride forward in non-invasive cardiovascular health assessment. The proposed approach holds promise for implementation in hardware systems to enable continuous monitoring, aiding in early detection and prevention of critical health conditions.

Early Mortality, Cardiovascular, and Renal Diseases in Women's Lives Following Hypertensive Disorders of Pregnancy: The Prospective Nationwide Study CONCEPTION.

BACKGROUND: We aimed to evaluate the impact of hypertensive disorders of pregnancy occurrence, recurrence, onset time, and severity on mortality and on a wide range of cardiovascular outcomes in France. METHODS AND RESULTS: CONCEPTION (Cohort of Cardiovascular Diseases in Pregnancy) is a French nationwide prospective cohort using data from the National Health Data System. We included all women in CONCEPTION with no history of a cardiovascular event who delivered in France for the first time between 2010 and 2018 (N=2 819 655). Hypertensive disorders of pregnancy and cardiovascular outcomes during the study follow-up were identified using algorithms combining International Classification of Diseases, Tenth Revision (ICD-10) coded diagnoses during hospitalization and purchases of medication between 2010 and 2021. We fitted Cox models with time-varying exposure to assess the associations of hypertensive disorders of pregnancy with mortality and cardiovascular events. Women with gestational hypertension had a 1.25- to 2-fold higher risk of stroke, acute coronary syndrome, peripheral arterial disease, pulmonary embolism, and chronic kidney disease, and a 2- to 4-fold higher risk of rhythm and conduction disorder and heart failure. Women with preeclampsia had a 1.35- to 2-fold higher risk of rhythm or conduction disorder and pulmonary embolism during follow-up; a 2- to 4-fold higher risk of stroke, acute coronary syndrome, and peripheral arterial disease; and a 7- to 9-fold higher risk of heart failure and chronic kidney disease. They were 1.8 times more likely to die and 4.4 times more likely to die of cardiovascular causes. CONCLUSIONS: Hypertensive disorders of pregnancy drastically increase the risk of mortality, cardiovascular, and renal events early after pregnancy. Recurrent, severe, and early-onset preeclampsia further increases this risk.

Usefulness of Heart Failure Categories Based on Left Ventricular Ejection Fraction.

BACKGROUND: Heart failure guidelines have recently introduced a narrow category with mildly reduced left ventricular ejection fraction (LVEF) (heart failure with mildly reduced ejection fraction; LVEF 41%-49%) between the previous categories of reduced (heart failure with reduced ejection fraction; LVEF ≤40%) and preserved (heart failure with preserved ejection fraction; LVEF ≥50%) ejection fraction. Grouping of continuous measurements into narrow categories can be questioned if their variability is high. METHODS AND RESULTS: We constructed a cohort of all 9716 new cases of chronic heart failure with an available LVEF in Stockholm, Sweden, from January 1, 2015, until December 31, 2020. All values of LVEF were collected over time, and patients were followed up until death, moving out of Stockholm, or end of study. Mixed models were used to quantify within-person variance in LVEF, and multistate Markov models, with death as an absorbing state, to quantify the stability of LVEF categories. LVEF values followed a normal distribution. The SD of the within-person variance in LVEF over time was 7.4%. The mean time spent in any LVEF category before transition to another category was on average <1 year for heart failure with mildly reduced ejection fraction. Probabilities of transitioning between categories during the first year were substantial; patients with heart failure with mildly reduced ejection fraction had a probability of <25% of remaining in that category 1 year later. CONCLUSIONS: LVEF follows a normal distribution and has considerable variability over time, which may impose a risk for underuse of efficient treatment. The heart failure with mildly reduced ejection fraction category is especially inconstant. Assumptions of a patient's current LVEF should take this variability and the normal distribution of LVEF into account.

Sodium Glucose Transporter 2 Inhibitors Versus Metformin on Cardiovascular and Renal Outcomes in Patients With Diabetes With Low Cardiovascular Risk: A Nationwide Cohort Study.

BACKGROUND: This study investigated whether initial SGLT2 (sodium-glucose cotransporter 2) inhibitor-based treatment is superior to metformin-based regimens as a primary prevention strategy among low-risk patients with diabetes. METHODS AND RESULTS: In this nationwide cohort study, a total of 38 496 patients with diabetes with low cardiovascular risk were identified (age 62.0±11.6 years, men 50%) from January 1 to December 31, 2016. Patients receiving SGLT2 inhibitors-based and metformin-based regimens were 1:2 matched by propensity score. Study outcomes included all-cause mortality, cardiovascular death, hospitalization for heart failure, stroke, and progression to end-stage renal disease. Compared with 1928 patients receiving metformin-based regimens, 964 patients receiving SGLT2 inhibitor-based regimens had similar all-cause mortality (hazard ratio [HR], 0.75 [95% CI, 0.51-1.12]), cardiovascular death (HR, 0.69 [95% CI, 0.25-1.89]), hospitalization for heart failure (HR, 1.06 [95% CI, 0.59-1.92]), stroke (HR, 0.78 [95% CI, 0.48-1.27]), and progression to end-stage renal disease (HR, 0.88 [95% CI, 0.32-2.39]). However, SGLT2 inhibitors were associated with a lower risk of all-cause mortality (HR, 0.47 [95% CI, 0.23-0.99]; P for interaction=0.008) and progression to end-stage renal disease (HR, 0.22 [95% CI, 0.06-0.82]; P for interaction=0.04) in patients under the age of 65. CONCLUSIONS: In comparison to metformin-based regimens, SGLT2 inhibitor-based regimens showed a similar risk of all-cause mortality and adverse cardiorenal events. SGLT2 inhibitors might be considered as first-line therapy in select low-risk patients, for example, younger patients with diabetes.