Estimated glucose disposal rate, a novel biomarker for insulin sensitivity, predicts risk for incident heart failure in patients with type 2 diabetes

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Singapore National Medical Research Council Singapore Khoo Teck Puat Hospital STAR grant Background Although a low insulin sensitivity (insulin resistance) has been considered as one of the drivers for heart failure, data on the role of insulin resistance in incident HF in diabetic population are still scarce. Estimated glucose disposal rate (eGDR), a novel biomarker for insulin sensitivity derived from three clinically available variables, was developed in type 1 diabetes and recently validated in type 2 diabetes by the gold standard euglycaemic hyperinsulinaemic clamp. We hypothesize that a high level of eGDR is associated with a low risk for incident HF in patients with type 2 diabetes. Objective In this prospective cohort study, we aim to examine whether eGDR, the novel biomarker for insulin sensitivity in diabetic population, predicts risk for incident HF in individuals with type 2 diabetes. Methods 1685 outpatients with type 2 diabetes were recruited from a regional hospital and a primary care centre from January 2011 to March 2014. Incident HF was defined by European Society of Cardiology 2016 criteria (NT-proBNP > 125 pg/ml with echocardiographic evidence). eGDR (mg/kg/min) was calculated as: 21.158 - (0.09 × waist circumference in cm)- (3.407 × hypertension, 1=yes 0=no) - (0.551 × HbA1c%). A higher eGDR indicates a high insulin sensitivity. The association of baseline eGDR with risk for incident HF was examined by survival analysis. Results The average age of participants was 57 (SD 11) years old, diabetes duration 11 (SD 9) years, Chinese 52.4%, Malay 21.2% and Asian Indian 26.4. During 6.6 (SD 1.5) years follow-up (11092 patient-years), 155 incident HF events (88 HFpEF with LVEF > 50%, 67 HFrEF with LVEF <= 50%) were identified (crude incident rate 1.4, 95% CI 1.2-1.6, per 100 patient-years). Cox regression model suggested that, as compared to the lowest tertile, participants with eGDR in the highest tertile had 88% lower risk (unadjusted HR 0.12, 95% CI 0.06-0.22) for development of incident HF. The association was only moderately attenuated (adjusted HR 0.32, 95% CI 0.16-0.63) after adjustment for demographic (age, sex, ethnicity) and cardio-renal variables (smoking, body mass index, diabetes duration, resting heart rate, lipid profile, kidney filtration function and albuminuria). As a continuous variable, one SD increment in eGDR was associated with 57% lower risk for HF after adjustment for multiple clinical risk factors (adjusted HR 0.43, 95% CI 0.31-0.59). In the fully adjusted model, a higher level of eGDR was significantly associated with a lower risk for both HFrEF and HFpEF (adjusted HR 0.40, 95% CI 0.23-0.67, and 0.40, 95% CI 0.26-0.63, respectively). Conclusion A higher level of eGDR is strongly associated with a lower risk for incident HF in patients with type 2 diabetes, suggesting that insulin resistance may play an important role in pathogenesis of HF. This simple novel biomarker may be explored to stratify risk for incident HF in individuals with type 2 diabetes.