Background: Cardiometabolic dysregulation and kidney disease are commonly accepted to play a pivotal role in the pathophysiology of the heart failure (HF) syndrome. However, the importance of glucotoxicity and insulin resistance in the deterioration of renal function in HF is controversial. In light of this background, the aim of the project was to investigate the impact of glucose metabolism (as reflected by hemoglobin A1c, HbA1c) and insulin resistance (as reflected by Homeostatic Model Assessment for Insulin Resistance index, HOMA-IR) on the estimated glomerular filtration rate (eGFR) in HF.

Methods: Data of the MyoVasc study (N=3,289), a prospective cohort study on chronic HF (NCT04064450), were analyzed. During a highly standardized 5-hour examination in a dedicated study center, participants underwent in-depth (sub)clinical phenotyping and biobanking after overnight fasting. Levels of HbA1c, plasma glucose and insulin were measured from peripheral blood samples. The HOMA-IR index, as measure of insulin resistance, was calculated. All data were subject to a plausibility check and detailed quality control. Multivariable regression analyses with adjustment for potential confounders and effect mediators were performed to investigate the interrelation between HbA1c, HOMA-IR and eGFR.

Results: The analysis sample comprised 3,031 subjects (mean age 65.7±10.4 years; female sex: 34.9%). The median levels of HbA1c and HOMA-IR were 5.8% (interquartile range (IQR) 5.5%/6.2%) and 1.75 (IQR 1.16/2.89), respectively. In crude analysis, increasing HbA1c and HOMA-IR values were associated with a decline in renal function, which was reflected by eGFR. Linear regression analysis with adjustment for age, sex, traditional cardiovascular risk factors, comorbidities and medication showed that a one standard deviation (SD) increase in HbA1c predicted a lower eGFR (beta-estimate_{HbA1c per SD}: -0.62, 95% confidence interval (95%CI) -1.2/-0.032; P=0.039). In comparison, adjusted regression analysis for HOMA-IR revealed a stronger effect on eGFR: beta-estimate_{HOMA-IR per SD:} -1.4, 95% CI -2.1/-0.69; P<0.0001. Sensitivity analysis in individuals with symptomatic HF stage C/D and within HF phenotypes demonstrated the consistency and robustness of these findings. Subsequently, multivariable regression analyses with adjustment for age, sex, traditional cardiovascular risk factors, comorbidities, medication and inclusion of both cardiometabolic biomarkers in one model were performed. This analysis revealed a differential relationship between long-term glycemic status and insulin resistance on eGFR: a higher concentration of HbA1c was no longer an independent predictor of eGFR (beta-estimate_{HbA1c per SD:} 0.043, 95%CI -0.64/0.73; P=0.90), whereas a higher level of HOMA-IR was found to be predictive of lower eGFR (beta-estimate_{HOMA-IR per SD}: -1.4, 95%CI -2.2/-0.63; P=0.003).

Conclusion: The present study demonstrates that HbA1c and HOMA-IR influence renal functional status in individuals with HF. These data underscore the importance of hyperglycemia and, in particular, insulin resistance for chronic kidney disease in subjects with HF.