Heart Failure Risk Stratification and Efficacy of Sodium-Glucose Cotransporter-2 Inhibitors in Patients With Type 2 Diabetes Mellitus

Abstract

Background: Patients with type 2 diabetes mellitus (T2DM) are at increased risk of developing heart failure. Sodium-glucose cotransporter-2 inhibitors reduce the risk of hospitalization for heart failure (HHF) in patients with T2DM. We aimed to develop and validate a practical clinical risk score for HHF in patients with T2DM and assess whether this score can identify high-risk patients with T2DM who have the greatest reduction in risk for HHF with a sodium-glucose cotransporter-2 inhibitor. Methods: We developed a clinical risk score for HHF in 8212 patients with T2DM in the placebo arm of SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53). Candidate variables were assessed using multivariable Cox regression, and independent clinical risk indicators achieving statistical significance of P <0.001 were included in the risk score. We externally validated the score in 8578 patients with T2DM in the placebo arm of DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58). The relative and absolute risk reductions in HHF with the sodium-glucose cotransporter-2 inhibitor dapagliflozin were assessed by baseline HHF risk. Results: Five clinical variables were independent risk predictors of HHF: prior heart failure, history of atrial fibrillation, coronary artery disease, estimated glomerular filtration rate, and urine albumin-to-creatinine ratio. A simple integer-based score (0–7 points) using these predictors identified a >20-fold gradient of HHF risk ( P for trend <0.001) in both the derivation and validation cohorts, with C indices of 0.81 and 0.78, respectively. Although relative risk reductions with dapagliflozin were similar for patients across the risk scores (25%–34%), absolute risk reductions were greater in those at higher baseline risk (1-sided P for trend=0.04), with high-risk (2 points) and very-high-risk (≥3 points) patients having 1.5% and 2.7% absolute reductions in Kaplan-Meier estimates of HHF risk at 4 years, respectively. Conclusions: Risk stratification using a novel clinical risk score for HHF in patients with T2DM identifies patients at higher risk for HHF who derive greater absolute benefit from sodium-glucose cotransporter-2 inhibition. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifiers: NCT01107886 and NCT01730534.

Enhanced Cardiomyocyte Function in Hypertensive Rats With Diastolic Dysfunction and Human Heart Failure Patients After Acute Treatment With Soluble Guanylyl Cyclase (sGC) Activator

“…Numerous studies have demonstrated the cardioprotective effects of NO-sGC-cGMP-PKG signaling. sGC stimulation can attenuate LV remodeling after myocardial infarction in mice (Frankenreiter et al, 2018;Berg et al, 2019), decrease extracellular matrix protein production in human cardiac fibroblasts following TGF-β stimulation, and attenuate vascular dysfunction in diabetic rats (Grontved et al, 2014). The eNOS transcriptional enhancer (AVE9488) improves cardiac remodeling after myocardial infarction (Fraccarollo et al, 2008) and platelet NO availability and hyperactivity in HF.…”

Association of Longitudinal Trajectory of Albuminuria in Young Adulthood With Myocardial Structure and Function in Later Life

“…23 Indeed, UACR level, even in the microalbuminuric range, was incorporated in a novel risk score for incident HF hospitalizations. 23 Notably, patients with higher risk scores were more likely to derive cardiovascular benefit from the sodium-glucose cotransporter 2 inhibitor dapagliflozin. 23 Indeed, even among those with prevalent HF but without diabetes, dapagliflozin has demonstrated cardiovascular benefit.…”

Risk Prediction of the Diabetes Missing Million: Identifying Individuals at High Risk of Diabetes and Related Complications

“…Estimates of HF risk can be useful for both clinicians and people with T2D: for clinicians, it can support them in the choice of therapeutic and preventive strategies; and for individuals with T2D, it can be a motivation tool to adopt healthy lifestyle measures and to observe prescribed risk-modifying treatments. Risk scores for HF in T2D include the WATCH-DM (Weight [BMI], Age, hyperTension, Creatinine, HDL-C, Diabetes control [fasting plasma glucose], QRS Duration, MI and CABG) score which is a simple, user-friendly, integer-based risk score that calculates the 5-year risk of incident HF among people with T2D [ 72 ], the TIMI (Thrombolysis in Myocardial Infarction) Risk Score for Heart Failure in Diabetes (TRS-HFDM) which is a novel, integer-based clinical risk score for predicting hospitalization for HF in people with T2D that includes the risk predictors prior HF, history of atrial fibrillation (AF), CAD, estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio [ 73 ], and the Brest score which is a clinical prediction score for HF diagnosis in the emergency care setting that includes 11 variables: age at least 65 years, seizure dyspnoea, night outbreak, orthopnoea, history of pulmonary oedema, chronic pulmonary disease, myocardial infarction, crackles, leg oedema, ST segment abnormality, atrial fibrillation/flutter on electrocardiography [ 74 ].…”