Heart failure with improved ejection fraction: patient characteristics, clinical outcomes and predictors for improvement.

Background: Heart failure with improved ejection fraction (HFimpEF) is a recently recognized entity presenting a diagnostic and therapeutic challenge. Our aim was to characterize the profile of HFimpEF patients and evaluate predictors for EF lack of improvement among heart failure with reduced ejection fraction (HFrEF) patients. Methods: We included ambulatory HFrEF patients (EF≤40%) between January 1, 2015, and September 1, 2022, with two consecutive echocardiography exams at least 6 months apart. HFimpEF was defined as improved EF from ≤40%->40% and by ≥10%. Results: A total of 567 HFrEF patients (72% male, 54.3 ± 14.4 years old) were analyzed. Patients without EF improvement were more likely to be male, had more comorbidities, ischemic cardiomyopathy (ICMP), markers of adverse cardiac remodeling (lower EF and higher left and right ventricular diameters) and presence of late gadolinium enhancement (LGE) in MRI (P < 0.05 for all). In a multivariate analysis, male sex, ICMP, lower EF, larger ventricular size and LGE remained independent predictors for lack of EF improvement. A prediction model for lack of EF improvement including LVEF, LV diameter, diastolic blood pressure and ischemic etiology exhibited an area under the ROC curve of 0.77 (95% CI 0.73-0.81; P < 0.001). HFimpEF patients had better prognosis with lower hospitalizations and mortality rates. Guideline directed medical therapy (GDMT) were associated with improved outcomes in both groups regardless of EF improvement. Conclusions: Lack of improvement in EF among HFrEF patients may be predicted by HF etiology and imaging parameters of adverse cardiac remodeling, and is associated with worse prognosis. GDMT were associated with improved outcomes in both HFimpEF and HFrEF patients.

Seated Pulmonary Artery Pressure Monitoring in Patients With Heart Failure: Results of the PROACTIVE-HF Trial.

BACKGROUND: Monitoring supine pulmonary artery pressures to guide heart failure (HF) management has reduced HF hospitalizations in select patients. OBJECTIVES: The purpose of this study was to evaluate the effect of managing seated mean pulmonary artery pressure (mPAP) with the Cordella Pulmonary Artery sensor on outcomes in patients with HF. METHODS: Following GUIDE-HF (Hemodynamic-GUIDEd Management of Heart Failure Trial), with U.S. Food and Drug Administration input, PROACTIVE-HF (A Prospective, Multi-Center, Open Label, Single Arm Clinical Trial Evaluating the Safety and Efficacy of the Cordella Pulmonary Artery Sensor System in NYHA Class III Heart Failure Patients trial) was changed from a randomized to a single-arm, open label trial, conducted at 75 centers in the USA and Europe. Eligible patients had chronic HF with NYHA functional class III symptoms, irrespective of the ejection fraction, and recent HF hospitalization and/or elevated natriuretic peptides. The primary effectiveness endpoint at 6 months required the HF hospitalization or all-cause mortality rate to be lower than a performance goal of 0.43 events/patient, established from previous hemodynamic monitoring trials. Primary safety endpoints at 6 months were freedom from device- or system-related complications or pressure sensor failure. RESULTS: Between February 7, 2020, and March 31, 2023, 456 patients were successfully implanted in modified intent-to-treat cohort. The 6-month event rate was 0.15 (95% CI: 0.12-0.20) which was significantly lower than performance goal (0.15 vs 0.43; P < 0.0001). Freedom from device- or system-related complications was 99.2% and freedom from sensor failure was 99.8% through 6 months. CONCLUSIONS: Remote management of seated mPAP is safe and results in a low rate of HF hospitalizations and mortality. These results support the use of seated mPAP monitoring and extend the growing body of evidence that pulmonary artery pressure-guided management improves outcomes in heart failure. (Multi-Center, Open Label, Single Arm Clinical Trial Evaluating the Safety and Efficacy of the Cordella Pulmonary Artery Sensor System in NYHA Class III Heart Failure Patients trial [PROACTIVE-HF]; NCT04089059).

Qualitative Evaluation to Understand Barriers and Facilitators to Prescribing Angiotensin Receptor-Neprilysin Inhibitors (ARNi) and Sodium-Glucose Cotransporter Inhibitors (SGLT2i) in Patients with Heart Failure with Reduced Ejection Fraction (HFrEF).

BACKGROUND: Despite sodium-glucose cotransporter-2 inhibitors (SGLT2i) and angiotensin receptor/neprilysin inhibitors (ARNi) being cost-effective evidenced-based therapies for the management of Heart Failure with Reduced Ejection Fraction (HFrEF), research shows that less than 30% of patients with HFrEF are prescribed these agents. OBJECTIVE: This study aimed to understand clinician-perceived barriers and facilitators to prescribing ARNi and SGLT2i in patients with HFrEF. METHODS: We conducted virtual and in-person semi-structured interviews in a large integrated healthcare delivery system in the United States. Twenty cardiology clinicians managing patients with HFrEF were recruited using purposeful sampling to target providers across professions and practice sites. The interview guide was developed based on a literature review and insights from a practicing cardiologist. It inquired about perceived prescribing behaviors, focusing on factors affecting the use of ARNi and SGLT2i. We identified key themes using rapid qualitative analysis. RESULTS: Twenty clinicians were interviewed: 13 physicians, five advanced practitioners, and two clinic-based pharmacists. Eighteen interviews were analyzed; we excluded two as the clinicians interviewed did not meet the inclusion criteria. Three major themes were identified: 1) clinician-reported prescribing patterns don't always align with the American College of Cardiology/American Heart Association guidelines for the use of SGLT2i and ARNi due to clinical inertia, lack of familiarity, knowledge, and comfort with use, and concerns over polypharmacy or adverse events, 2) clinician-perceived and actual out-of-pocket cost reduced prescribing of ARNi or SGLT2i to patients, exacerbated by a lack of visibility into patients' prescription coverage, denials of coverage by insurance, and navigating prior authorization related workflows, and 3) incorporation of a clinic-based pharmacist increased the prescribing of these medications. CONCLUSIONS: Increasing cost transparency, implementing interventions to overcome clinical inertia and cost hurdles, and increasing clinic-based pharmacist support may improve evidenced-based prescribing in patients with HFrEF, especially for comparatively novel classes such as ARNi and SGLT2i.

Changes in Left Ventricular Function and Outcomes After Trancatheter Edge-to-Edge Repair for Secondary Mitral Regurgitation.

Background: Transcatheter edge-to-edge repair (TEER) improved outcomes in patients with heart failure (HF) and severe secondary mitral regurgitation (SMR) compared with guideline-directed medical therapy (GDMT) alone regardless of the severity of baseline left ventricular ejection fraction (LVEF). The study aimed to evaluate the effect of early changes in LVEF after TEER and GDMT alone in patients with HF and severe SMR. Methods: Within the COAPT trial, we evaluated outcomes according to changes in LVEF from baseline to 30 days. The primary outcome was all-cause death or HF hospitalization (HFH) between 30 days and 2 years. Results: Among 432 patients with paired echocardiographic data, 182 (42.1%) had increased LVEF (LVEF change 6.0% ± 4.9%) and 250 (57.9%) had a decrease or no change in LVEF (LVEF change -6.6% ± 5.6%) from baseline to 30 days. LVEF at 30 days increased more frequently with GDMT alone compared with TEER plus GDMT (51.4% vs 33.0%; P = .0001). Between 30 days and 2 years, there were no significant differences in death or HFH in the increase LVEF and the decrease LVEF groups (58.8% vs 51.4%; multivariable-adjusted HR, 0.97; 95% CI, 0.87-1.08; P = .59). TEER plus GDMT reduced the 30-day to 2-year rate of death or HFH compared with GDMT alone consistently in patients with increase LVEF and decrease LVEF (Pint = 0.75). Conclusions: Among patients with HF and severe SMR, early improvements in LVEF were more frequent with GDMT alone compared with TEER plus GDMT but were not associated with subsequent outcomes at 2 years. TEER reduced death or HFH during 2-year follow-up irrespective of early LVEF changes.

Transthyretin Cardiac Amyloidosis in an Elderly Male With Heart Failure Intolerant to Guideline-Directed Medical Therapy.

Cardiac amyloidosis arises when there is a deposition of abnormal proteins, called amyloids, in the myocardium. It can manifest as overt heart failure, conduction abnormalities, atrial and ventricular arrhythmia, cardiomyopathy, and aortic stenosis. Two main types of proteins identified in cardiac amyloidosis are light-chain amyloid and transthyretin amyloid. Cardiac amyloidosis, although common, is an underdiagnosed cause of heart failure in many cases. A high index of suspicion is needed to make a diagnosis, given that symptoms are not specific. Early diagnosis and treatment of cardiac amyloidosis are associated with reduced morbidity and improved survival. We present a case of a 73-year-old African American male with decompensated heart failure with reduced ejection fraction intolerant to guideline-directed medical therapy who was later found to have cardiac amyloidosis.

Are Sodium-Glucose Cotransporter-2 Inhibitors the Cherry on Top of Cardio-Oncology Care?

The increasing aging of the population combined with improvements in cancer detection and care has significantly improved the survival and quality of life of cancer patients. These benefits are hampered by the increase of cardiovascular diseases being heart failure the most frequent manifestation of cardiotoxicity and becoming the major cause of morbidity and mortality among cancer survivor. Current strategies to prevent cardiotoxicity involves different approaches such as optimal management of CV risk factors, use of statins and/or neurohormonal medications, and, in some cases, even the use of chelating agents. As a class, SGLT2-i have revolutionized the therapeutic horizon of HF patients independently of their ejection fraction or glycemic status. There is an abundance of data from translational and observational clinical studies supporting a potential beneficial role of SGLT2-i in mitigating the cardiotoxic effects of cancer patients receiving anthracyclines. These findings underscore the need for more robust clinical trials to investigate the effect on cardiovascular outcomes of the prophylactic SGLT2-i treatment in patients undergoing cancer treatment.

High-intensity care for GDMT titration.

Heart failure (HF) is a systemic disease associated with a high risk of morbidity, mortality, increased risk of hospitalizations, and low quality of life. Therefore, effective, systemic treatment strategies are necessary to mitigate these risks. In this manuscript, we emphasize the concept of high-intensity care to optimize guideline-directed medical therapy (GDMT) in HF patients. The document highlights the importance of achieving optimal recommended doses of GDMT medications, including beta-blockers, renin-angiotensin-aldosterone inhibitors, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter inhibitors to improve patient outcomes, achieve effective, sustainable decongestion, and improve patient quality of life. The document also discusses potential obstacles to GDMT optimization, such as clinical inertia, physiological limitations, comorbidities, non-adherence, and frailty. Lastly, it also attempts to provide possible future scenarios of high-intensive care that could improve patient outcomes.

Optimizing Guideline-Directed Medical Therapy During Hospitalization Improves Prognosis in Patients With Worsening Heart Failure Requiring Readmissions.

BACKGROUND: We previously demonstrated that higher simple guideline-directed medical therapy (GDMT) scores (comprising renin-angiotensin system inhibitors, ß-blockers, mineralocorticoid antagonists, and sodium-glucose cotransporter 2 inhibitors) at discharge were correlated with improved prognosis in heart failure (HF) patients. HF readmissions are linked to adverse outcomes, emphasizing the need for enhanced optimization of GDMT. METHODS AND RESULTS: Using the simple GDMT score, we evaluated the effect of revising and modifying in-hospital GDMT on the prognosis of patients with HF readmissions. In this retrospective analysis of 2,100 HF patients, we concentrated on 1,222 patients with HF with reduced ejection/moderately reduced ejection fraction, excluding patients with HF with preserved ejection fraction, on dialysis, or who died in hospital. A higher current GDMT score was associated with better HF prognosis. Of the 1,222 patients in the study, we analyzed 372 cases of rehospitalization, calculating the simple GDMT scores at admission and discharge. Patients were divided into groups according to score improvement. Multivariate analysis showed a significant association between improved in-hospital simple GDMT score and the composite outcome (HF readmission+all-cause mortality; hazard ratio 0.459; 95% confidence interval 0.257-0.820; P=0.008). Even after propensity score matching to adjust for background, among rehospitalized patients, those with an improved in-hospital simple GDMT score had a better prognosis. CONCLUSIONS: Our results highlight the potential of robust interventions and score elevation during hospitalization leading to improved outcomes.

Effects of Rapid Uptitration of Neurohormonal Blockade on Effective, Sustainable Decongestion and Outcomes in STRONG-HF.

BACKGROUND: Comprehensive uptitration of neurohormonal blockade targets fundamental mechanisms underlying development of congestion and may be an additional approach for decongestion after acute heart failure (AHF). OBJECTIVES: This hypothesis was tested in the STRONG-HF (Safety, Tolerability, and Efficacy of Rapid Optimization, Helped by N-Terminal Pro-Brain Natriuretic Peptide Testing of Heart Failure Therapies) trial. METHODS: In STRONG-HF, patients with AHF were randomized to the high-intensity care (HIC) arm with fast up-titration of neurohormonal blockade or to usual care (UC). Successful decongestion was defined as an absence of peripheral edema, pulmonary rales, and jugular venous pressure <6 cm. RESULTS: At baseline, the same proportion of patients in both arms had successful decongestion (HIC 48% vs UC 46%; P = 0.52). At day 90, higher proportion of patients in the HIC arm (75%) experienced successful decongestion vs the UC arm (68%) (P = 0.0001). Each separate component of the congestion score was significantly better in the HIC arm (all, P < 0.05). Additional markers of decongestion also favored the HIC: weight reduction (adjusted mean difference: -1.36 kg; 95% CI: -1.92 to -0.79 kg), N-terminal pro-B-type natriuretic peptide level, and lower orthopnea severity (all, P < 0.001). More effective decongestion was achieved despite a lower mean daily dose of loop diuretics at day 90 in the HIC arm. Among patients with successful decongestion at baseline, those in the HIC arm had a significantly better chance of sustaining decongestion at day 90. Successful decongestion in all subjects was associated with a lower risk of 180-day HF readmission or all-cause death (HR: 0.40; 95% CI: 0.27-0.59; P < 0.0001). CONCLUSIONS: In STRONG-HF, intensive uptitration of neurohormonal blockade was associated with more efficient and sustained decongestion at day 90 and a lower risk of the primary endpoint.

Heart Failure With Improved Ejection Fraction: Prevalence, Predictors, and Guideline-Directed Medical Therapy.

Recently, a new category of heart failure with improved ejection fraction (HFimpEF) has emerged in the classification system. This is defined as the subgroup of patients with heart failure with reduced ejection fraction (HFrEF) whose left ventricular ejection fraction has recovered partially or completely, with no specific cut-off values established yet in the guidelines. In our review, we aim to provide an overview of prevalence, predictors, mechanism of remodeling, and management strategies regarding HFimpEF. These patients constitute a sizeable cohort among patients with reduced ejection fraction. Certain patient characteristics including younger age and female gender, absence of comorbid conditions, low levels of biomarkers, and non-ischemic etiology were identified as positive predictors. The heart undergoes significant maladaptive changes post failure leading to adverse remodeling influenced etiology and duration. Goal-directed medical therapy including beta-blockers, angiotensin-converting enzyme inhibitors (ACEIs), and angiotensin II receptor blockers (ARBs) have notably improved cardiac function by inducing reverse remodeling. Despite a more favorable prognosis compared to HFrEF, patients with improved ejection fraction (EF) still face clinical events and reduced quality of life, and remain at risk of adverse outcomes. Although the evidence is scarce, it is advisable to continue treatment modalities despite improvement in EF, including device therapies, to prevent relapse and clinical deterioration. It is imperative to conduct further research to understand the mechanism leading to EF amelioration and establish guidelines to identify and direct management strategies.

A Case-based Implementation of Heart Failure Therapies, a Consensus Pathway by the Saudi Heart Failure Working Group.

The implementation of guideline-directed medical therapy (GDMT) in heart failure (HF) has many challenges in real-world clinical practice. The consensus document is written considering the variability of the clinical presentation of HF patients. HF medical therapies need frequent dose adjustment during hospital admission or when patients develop electrolyte imbalance, acute kidney injury, and other acute illnesses. The paper describes clinical scenarios and graphs that will aid the managing physicians in decision-making for HF therapy optimization.

The national financial burden of guideline directed medical therapy for heart failure patients from 2013 to 2021.

BACKGROUND: Guideline Directed Medical Therapy (GDMT) has been revolutionary in improving outcomes of heart failure patients. However, with the addition of more medication classes, the annual cost of these medications on the US healthcare system needs further evaluation. OBJECTIVES: We aim to evaluate the trend of annual cost of GDMT from 2013 to 2021 using the Medicare-part D Database. METHODS: Using Medicare Part D database (2013-2021), we determined the number of beneficiaries receiving these drugs, the total number of 30-day fills for each medication, and the total annual spending on these medications. Linear regression was used to analyze data using Python Programming Language. P value of less than 0.05 was considered to be statistically significant. RESULTS: The estimated annual Medicare- part D spending on empagliflozin had a 50 % increase in cost between 2020 and 2021, which could be attributed to its FDA approval for heart failure with reduced ejection fraction. Empagliflozin cost Medicare 3.73 billion USD in 2021 alone. In addition, sacubitril-valsartan had a strong trajectory since its introduction to the market in 2015. Since its approval in July 2015, it cost Medicare 4.51 billion USD. The Mineralocorticoid Receptor Antagonist class was the least costly class of GDMT. CONCLUSION: The rise in the cost of GDMT is not proportionate amongst the different classes of GDMT. Newer classes of medications cast a significant cost on Medicare in recent years.

Differences in provider approach to initiating and titrating guideline directed medical therapy in heart failure with reduced ejection fraction.

BACKGROUND: Despite the strong evidence supporting guideline-directed medical therapy (GDMT) in patients with heart failure with reduced ejection fraction (HFrEF), prescription rates in clinical practice are still lacking. METHODS: A survey containing 20 clinical vignettes of patients with HFrEF was answered by a national sample of 127 cardiologists and 68 internal/family medicine physicians. Each vignette had 4-5 options for adjusting GDMT and the option to make no medication changes. Survey respondents could only select one option. For analysis, responses were dichotomized to the answer of interest. RESULTS: Cardiologists were more likely to make GDMT changes than general medicine physicians (91.8% vs. 82.0%; OR 1.84 [1.07-3.19]; p = 0.020). Cardiologists were more likely to initiate beta-blockers (46.3% vs. 32.0%; OR 2.38 [1.18-4.81], p = 0.016), angiotensin receptor blocker/neprilysin inhibitor (ARNI) (63.8% vs. 48.1%; OR 1.76 [1.01-3.09], p = 0.047), and hydralazine and isosorbide dinitrate (HYD/ISDN) (38.2% vs. 23.7%; OR 2.47 [1.48-4.12], p < 0.001) compared to general medicine physicians. No differences were found in initiating angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACEi/ARBs), initiating mineralocorticoid receptor antagonist (MRA), sodium-glucose transporter protein 2 (SGLT2) inhibitors, digoxin, or ivabradine. CONCLUSIONS: Our results demonstrate cardiologists were more likely to adjust GDMT than general medicine physicians. Future focus on improving GDMT prescribing should target providers other than cardiologists to improve care in patients with HFrEF.

Reinforcement of pimobendan with guideline-directed medical therapy may reduce the rehospitalization rates in patients with heart failure: retrospective cohort study.

BACKGROUND: Pimobendan reportedly improves the subjective symptoms of heart failure. However, evidence of improved prognosis is lacking. This study aimed to determine whether reinforcing guideline-directed medical therapy (GDMT) improved rehospitalization rates for worsening heart failure in patients administered pimobendan. METHODS: A total of 175 patients with heart failure who were urgently admitted to our hospital for worsening heart failure and who received pimobendan between January 2015 and February 2022 were included. Of the 175 patients, 44 were excluded because of in-hospital death at the time of pimobendan induction. The remaining 131 patients were divided into two groups, the reduced ejection fraction (rEF) (n = 93) and non-rEF (n = 38) groups, and further divided into the GDMT-reinforced and non-reinforced groups. RESULTS: In patients with rEF, the rate of rehospitalization for heart failure was significantly lower in the GDMT-reinforced group than in the non-reinforced group (log-rank test, P = .04). However, the same trend was not observed in the non-rEF group. CONCLUSIONS: Reinforcing GDMT may reduce the heart failure rehospitalization rate in patients with pimobendan administration and rEF. However, multicenter collaborative research is needed. TRIAL REGISTRATION: IRB Approval by the Nippon Medical School Hospital Ethics Committee B-2021-433 (April 10, 2023).

Real-World Clinical Burden of Newly Diagnosed Heart failure in Thai Patients.

INTRODUCTION: There are limited data on the burden of newly diagnosed patients with heart failure (HF) in Thailand. Thus, this study aimed to fully understand the hospitalization, rehospitalization, mortality rates, demographics and characteristics, and quality of care in these patients. METHOD: A retrospective review of all eligible adult patients' medical records from 2018 and 2019 was conducted at five hospitals. The patients were newly diagnosed with HF, as indicated by the International Classification of Diseases (ICD)-10 code "I50." Descriptive statistics was used to investigate patients' hospital burden and clinical outcome data. RESULTS: There were 1134 patients newly diagnosed with HF, classified as HF with reduced ejection fraction (HFrEF), HF with preserved ejection fraction (HFpEF), and HF with mildly reduced ejection fraction (HFmrEF) (44.0, 40.0, and 16.0%, respectively). The male-to-female ratios in HFmrEF and HFpEF were similar. In contrast, the proportion of men with HFrEF was greater. The mean age of all patients was 66.0 years. The hospitalization rate was 1.3. Rehospitalization rates for HF-related issues were 0.1, 0.2, 0.4, and 0.5 at 30 days, 60 days, 180 days, and 1 year, respectively. The percentage of deaths from all causes among these patients was 9.8%, while the percentage of deaths from cardiovascular-related causes was 8.5%. Only a small proportion of patients received a target dose of guideline-directed medical therapy (GDMT). CONCLUSIONS: The study revealed that the characteristics, hospitalization rate for HF, and in-hospital mortality rate among newly diagnosed patients with HF were higher compared to similar studies conducted in Thailand and other countries. Moreover, a high quality of care is needed to improve the morbidity and mortality associated with HF in Thailand.

Heart in Disguise: Unmasking a Novel Gene Deletion in Dilated Cardiomyopathy.

Dilated cardiomyopathy (DCM) is an underrecognized condition with a myriad of etiologies, but it is often labeled idiopathic. However, genetic mutations are emerging as a more common cause of idiopathic DCM than previously believed. Herein, we present a case of a previously healthy 45-year-old woman who presented with three weeks of exertional dyspnea and orthopnea. An echocardiogram showed DCM with severely reduced systolic function and diastolic dysfunction. She was extensively worked up for potential etiologies of her heart failure which included HIV testing, parasite smear, viral serologies, autoimmune testing, cardiac MRI for infiltrative diseases, and coronary catheterization. She was ultimately tested for genetic mutations which revealed a 49-51 exon deletion of the dystrophin (Duchenne muscular dystrophy (DMD)) gene. This case highlights the guideline-based evaluation and management of new-onset heart failure in a healthy 45-year-old female without known predisposing risk factors or family history. It also sheds light on the expansive genetic etiologies that have only recently been identified in those with idiopathic cardiomyopathy. Further research is crucial to improve our understanding of genetic associations of cardiomyopathy.

Guideline directed medical therapy induced nephrotoxicity in HFrEF patients; an insight to its mechanism.

Guideline Directed Medical Therapy (GDMT) has been the standard pharmacotherapy for the treatment of Heart Failure patients with reduced Ejection Fraction (HFrEF) recommended by the European Society of Cardiology (ESC). However, patients on GDMT are likely to possess nephrotoxicity as an adverse effect. We utilized multiple system biology tools like ADVER-Pred, gene enrichment analysis, molecular docking, molecular dynamic simulations, and MMPBSA analysis to predict a possible molecular mechanism of how selected combinations of GDMT may cause nephrotoxicity. As per the ACC/AHA/ESC guidelines, we categorized the drugs as category 1 including ß-blockers (BB), angiotensin receptor blockers (ARB), and sodium-glucose cotransporter-2 inhibitors (SGLT2I), category 2 includes BB's, SGLT2I, and angiotensin receptor-neprilysin inhibitors (ARNI), and category 3 includes BB's, SGLT2I, and angiotensin-converting enzyme (ACE) inhibitors. Enrichment analysis predicted category 2 drugs to possess the highest number of proteins to be involved in the development of nephrotoxicity i.e. 79.41%. The targets HBA1, CBR1, ATG5, and SLC6A3 were the top hub genes with an edge count of 7 followed by GPX1 with an edge count of 6. Molecular docking studies revealed candesartan-SLC6A3 to possess the highest binding affinity of -10.2 kcal/mol. In addition, simulation studies displayed empagliflozin-CBR1 to possess the highest stability followed by candesartan-ATG5. A combination of ß-blockers, ARBs, and SGLT2I are predicted to likely possess nephrotoxicity which may be due to the modulation of HBA1, CBR1, ATG5, and GPX1. In conclusion, candesartan and empagliflozin are most likely to cause nephrotoxicity via the modulation of HBA1, CBR1, ATG5, and GPX1.Communicated by Ramaswamy H. Sarma.

GDMT drugs were predicted to possess nephrotoxicity as an adverse effectCategory 2 drugs BB's, SGLT2I, and ARNI were assessed to possess highest number of proteins to be involved in the development of nephrotoxicity which may be by modulating HBA1, CBR1, ATG5, and GPX1.Candesartan and empagliflozin are most likely to cause nephrotoxicity.