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.

Keywords: diabetes mellitus; heart failure; risk factors; sodium-glucose cotransporter-2 inhibitors.

Figure 1.. Incidence rate of hospitalization for heart failure by risk score in the derivation and validation cohorts.

The incidence rates of hospitalization for heart failure in the derivation and validation cohorts are shown. The integer-based scheme identified a >20-fold gradient of risk in both the derivation (χ²_W 819.4; p-trend <0.001) and validation cohorts (χ²_W 724.3; p-trend <0.001). HHF indicates hospitalization for heart failure.

Figure 2.. Treatment effect of dapagliflozin by baseline risk of hospitalization for heart failure.

Whereas relative risk reductions were similar across risk score categories, absolute reductions in Kaplan-Meier estimates of hospitalization for heart failure (HHF) risk at 4 years (i.e., ARR) were greater in those at higher baseline risk (χ² 3.24; one-sided p-trend=0.04). ARR indicates absolute risk reduction; HR, hazard ratio; NNT, number needed to treat.