Hypoglycemia awareness in adults with diabetic autonomic neuropathy

Aim. The aim of this study was to examine the effects of cardiac autonomic neuropathy (CAN) on impaired awareness of hypoglycaemia (IAH) reversibility in people with type 1 diabetes mellitus (T1DM).

Methods. Sub-study of HypoCOMPaSS (Comparison of Optimised MDI versus Pumps with or without Sensors in Severe Hypoglycaemia) trial (Little SA et al Diabetes Care. 2014;37:2114-22) included participants with T1DM and IAH evaluated according to a Gold score ≥4 and assessed CAN through cardiovascular reflex tests. Three groups were identified: normal (no abnormal test), early or possible (one abnormal test), and definite CAN (≥2 abnormal tests). The ability of participants to improve hypoglycaemia awareness was defined as the reduction of Gold score ≥1. Further, responders were defined as those with Gold score improvement to <4 while non-responders had a Gold score ≥4 after completing the trial intervention.

Results. Eighty-three participants (62.7% women) were included with mean age of 48 ± 12 years, mean HbA1c of 66 ± 13 mmol/mol and mean duration of T1DM of 29 ± 13 years. The prevalence of CAN was low with 5/83 (6%) participants having definite and 11 (13%) possible/early CAN. All participants, regardless of the autonomic status, showed a mean improvement in Gold score of ≥1 (mean improvement −1.2 [95% CI −0.8, −1.6]; p<0.001). In early/possible and definite CAN groups, the mean Gold score improved from 5.5 to 4.1 (p<0.001) and from 5.0 to 4.0 (p<0.001) at 24 weeks, respectively. The presence of CAN did not impede the ability of participants to improve hypoglycaemia awareness (Gold score reduction ≥1): 64% of participants without CAN improved their Gold score, while 73% and 60% in early/possible and definite CAN groups. A Chi-square test for independence indicated no significant association between autonomic function and a reduction in Gold score of ≥1 (p=0.743).

Conclusions. CAN is not a prime driver of IAH as its presence does not appear to impede successful recovery of IAH.

Comments. It is known that recurrent episodes of hypoglycaemia lead to decreased sympatho-adrenal responses and attenuate the counter-regulatory responses resulting in IAH. Diabetic autonomic neuropathy is hypothesised to be one of the mechanisms implicated in the pathogenesis of IAH and its failure to recover, but there is no proven link. The present study demonstrates that IAH can improve in people with T1DM and a long duration of disease, with and without CAN, indicating that autonomic neuropathy may not be a prime driver in modulating reversibility of IAH. Moreover, the low incidence of CAN at baseline (possibly influenced by the use of fixed and not age-related reference normal values) can suggest that may not be a major contributor to the pathophysiology of IAH. Previous studies have been conducted in this field demonstrating an improvement in adrenergic response at hypoglycaemic clamp in participants with and without CAN after a 6-month treatment to avoid biochemical hypoglycaemia (Fanelli C et al Diabetes. 1997;46:1172-81) and reversal of IAH despite abnormal cardiac autonomic function tests achieved via either islet cell or whole pancreas transplants (Kamel JT et al Diabetes Metab Res Rev. 2015;31:646-50). Thus, CAN does not appear to impede successful recovery of IAH. Further mechanistic research with larger numbers is required to understand to what extent factors such age, sex, duration of diabetes, diabetes complications, residual C-peptide levels, recurrence and severity of hypoglycaemia predict the ability to regain awareness following specific intervention.

Carla Greco

Reference. Arshad MF, Walkinshaw E, Solomon AL, Bernjak A, Rombach I, Little SA, Shaw JAM, Heller SR, Iqbal A. Diabetic autonomic neuropathy does not impede improvement in hypoglycaemia awareness in adults: Sub-study results from the HypoCOMPaSS trial. Diabet Med. 2024 May 13:e15340. doi: 10.1111/dme.15340. Epub ahead of print. PMID: 38741266.

https://onlinelibrary.wiley.com/doi/10.1111/dme.15340