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

Circulation. 2019 Nov 5;140(19):1569-1577. doi: 10.1161/CIRCULATIONAHA.119.042685. Epub 2019 Aug 31.


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.

Publication types

  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Validation Study

MeSH terms

  • Adamantane / analogs & derivatives
  • Adamantane / therapeutic use
  • Aged
  • Benzhydryl Compounds / adverse effects
  • Benzhydryl Compounds / therapeutic use*
  • Clinical Decision-Making
  • Decision Support Techniques*
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / diagnosis
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / physiopathology
  • Diabetic Cardiomyopathies / diagnosis
  • Diabetic Cardiomyopathies / etiology
  • Diabetic Cardiomyopathies / physiopathology
  • Diabetic Cardiomyopathies / prevention & control*
  • Dipeptides / therapeutic use
  • Dipeptidyl-Peptidase IV Inhibitors / therapeutic use
  • Female
  • Glucosides / adverse effects
  • Glucosides / therapeutic use*
  • Health Status
  • Heart Failure / diagnosis
  • Heart Failure / etiology
  • Heart Failure / physiopathology
  • Heart Failure / prevention & control*
  • Humans
  • Male
  • Middle Aged
  • Patient Selection
  • Predictive Value of Tests
  • Randomized Controlled Trials as Topic
  • Reproducibility of Results
  • Risk Assessment
  • Risk Factors
  • Sodium-Glucose Transporter 2 Inhibitors / adverse effects
  • Sodium-Glucose Transporter 2 Inhibitors / therapeutic use*
  • Time Factors
  • Treatment Outcome


  • Benzhydryl Compounds
  • Dipeptides
  • Dipeptidyl-Peptidase IV Inhibitors
  • Glucosides
  • Sodium-Glucose Transporter 2 Inhibitors
  • dapagliflozin
  • saxagliptin
  • Adamantane

Associated data

  • ClinicalTrials.gov/NCT01107886
  • ClinicalTrials.gov/NCT01730534