Differential Effect of Hypoalbuminemia on Hypoglycemia on Type 2 Diabetes Patients Treated with Insulin Glargine 300 U/ml and Insulin Degludec

Abstract

Introduction Hypoglycemia resulting from insulin therapy for treatment of diabetes increases the risk of adverse cardiovascular events. Determining biomarkers that provide accurate estimation of hypoglycemia risk may allow for more accurate patient management and care. The purpose of this study was to determine the cutoff value of serum albumin (s-alb) that increases the risk of hypoglycemia in patients treated with insulin degludec. Methods This study used a crossover design and randomized 30 patients admitted for glycemic control to compare differences between insulin glargine 300 U/ml (Gla300) and degludec treatments. Results The cutoff value of s-alb associated with 24-h hypoglycemia and nocturnal hypoglycemia in patients treated with degludec was 3.8 g/dl. In patients with s-alb levels < 3.8 g/dl, mean percentages of time with hypoglycemia, clinically important hypoglycemia, and nocturnal hypoglycemia were significantly lower in those treated with Gla300 compared with patients treated with degludec. Conclusion This study identified a cutoff value for s-alb levels that indicates risk of hypoglycemia in patients treated with degludec. Monitoring s-alb levels in patients treated with degludec will help to mitigate the risk of hypoglycemia. Trial Registration University Hospital Medical Information Network (UMIN 000031044). Electronic Supplementary Material The online version of this article (10.1007/s13300-019-0654-y) contains supplementary material, which is available to authorized users.

Commentary to “Differential Effect of Hypoalbuminemia on Hypoglycemia on Type 2 Diabetes Patients Treated with Insulin Glargine 300 U/ml and Insulin Degludec” by Kawaguchi et al. Diabetes Therapy 2019

“…If the findings of Kawaguchi et al [1,2] are genuine, they raise important considerations about the use of degludec with regard to patients' serum albumin level. We contend, however, that these findings are likely to be anomalous and actually reflect methodological flaws in the original cross-over study that relate to the well-documented lower unit potency of glargine U300 [4][5][6].…”

“…Kawaguchi et al have produced two publications of data from a small-scale cross-over study comparing insulin glargine 300 units/mL (glargine U300) with insulin degludec (degludec) in 30 patients with type 2 diabetes [1,2]. This cross-over study was approved by the ethics committee of Minami Osaka Hospital and executed in accordance with the Declaration of Helsinki, with all patients providing informed consent.…”

“…It should be noted that recently published recommendations suggest longer CGM data collection periods for individuals with variable glycaemic control-for example, 4 weeks of data to investigate hypoglycaemia exposure [3]. In a secondary analysis, the authors hypothesised that this apparent risk difference might derive from differences in the pharmacokinetic properties of the two basal insulins [2]. As degludec forms a circulating depot by reversibly binding to albumin after absorption from the subcutaneous depot, they hypothesised that patients with low albumin concentrations might be subject to greater exposure to unbound degludec.…”

“…As degludec forms a circulating depot by reversibly binding to albumin after absorption from the subcutaneous depot, they hypothesised that patients with low albumin concentrations might be subject to greater exposure to unbound degludec. The authors therefore assessed the relationship between time in hypoglycaemia and albumin concentration and found that the risk difference between the insulins was confined to the 15 patients with serum albumin levels of \ 3.8 g/dL when the cohort was stratified above or below this concentration [2].…”

“…This is especially pertinent as the majority of 'time in hypoglycaemia' occurred in the nocturnal interval, and if patients were titrated to a lower pre-breakfast glucose level, then this would directly impact nocturnal glycaemia. Finally, in the secondary publication stratifying patients by albumin concentration, in which the hypoglycaemia difference was reported to be confined to 15 patients with serum albumin levels \ 3.8 g/dL, there was a significantly higher mean 24-h glucose level with glargine U300 (143.0 ± 20.7 mg/dL [glargine U300] vs. 124.0 ± 25.3 mg/dL [degludec]; p = 0.033) [2]. In short, these data are all consistent with the glargine U300 treatment periods having less glucose-lowering potency on average-especially in the subset of patients with low albumin.…”