Even mild hypoglycemia episodes might be related to diabetic neuropathy

Aims: To create and use a dataset of pooled clinical trials in people with type 1 or type 2 diabetes to examine the association of exposure to all hypoglycemia episodes across the range of severity with incident event outcomes: death, CVD, neuropathy, kidney disease, retinal disorders, and depression.

Methods: Data from 84 trials with 39,373 participants were pooled. For event outcomes, time-updated Cox regression models adjusted for age, sex, diabetes duration, and HbA1c were fitted to assess the association of outcomes with cumulative exposure to hypoglycemia episodes and with exposure to a recent hypoglycemia episode within the last 10 days.

Results: In type 1 diabetes cumulative exposure to hypoglycemia episodes of any level was associated with higher risks of neuropathy, kidney disease, retinal disorders, and depression. The risk ratio for neuropathy was 3.048 (1.837, 5.057). For type 2 diabetes cumulative exposure to hypoglycemia episodes of any level was associated with higher risks of death, acute CVD, kidney disease, retinal disorders, and depression. The risk ratio for neuropathy was 2.539 (1.746, 3.691).

Conclusions: These data are consistent with hypoglycemia being associated with an increased risk of adverse events across several body systems in diabetes. These associations are not confined to severe hypoglycemia requiring assistance.

Comments. Most of the literature on hypoglycemia in diabetes focuses on the severe forms of this condition and their impact on cardiovascular events and mortality. However, there is limited information on the effects of milder hypoglycemia (levels 1 [<70 mg/dl] and 2 [<54 mg/dl]) on diabetic complications, particularly microangiopathy, including neuropathy. Firstly, the analysis presented here reveals a notable risk association between hypoglycemia exposure and the incidence of neuropathy. This finding was quite unexpected, as diabetes-related microvascular complications (neuropathy, retinopathy, nephropathy) have traditionally been linked to chronic hyperglycemia. Secondly, the incidence of neuropathy reported in clinical trials included in this large analysis was relatively low: 4.3% in type 1 diabetes and 6.8% in type 2 diabetes. These figures suggest a possible underestimation of the true incidence of neuropathy in the diabetic population. Acute and recurrent hypoglycemia can significantly influence the inflammatory response and oxidative stress levels. Research indicates that during the recovery phase from hypoglycemia, there is an increase in neuronal superoxide production and oxidative damage as glucose levels rise. This phenomenon suggests that fluctuations in glucose levels are particularly harmful to neuronal cells, contributing to oxidative stress. Finally, no evidence was found for a threshold effect below a blood glucose of 3.9 mmol/l (70 mg/dl). Given the continuous risk increase with lower glucose levels, it is crucial to implement strategies to prevent even mild hypoglycemia episodes. This approach is essential not only for improving the quality of life for individuals with diabetes but also for preventing long-term adverse clinical outcomes, including neuropathy. In summary, while severe hypoglycemia has well-documented adverse effects, this analysis highlights the significant and often underestimated impact of milder hypoglycemia on diabetic microvascular complications. Future research is needed to understand the mechanisms linking mild hypoglycemia to neuropathy and to develop targeted interventions.

Aleksandra Araszkiewicz

Reference. Mellor J, Kuznetsov D, Heller S, Gall MA, Rosilio M, Amiel SA, Ibberson M, McGurnaghan S, Blackbourn L, Berthon W, Salem A, Qu Y, McCrimmon RJ, de Galan BE, Pedersen-Bjergaard U, Leaviss J, McKeigue PM, Colhoun HM. Estimating risk of consequences following hypoglycaemia exposure using the Hypo-RESOLVE cohort: a secondary analysis of pooled data from insulin clinical trials. Diabetologia. 2024 Jul 22. doi: 10.1007/s00125-024-06225-1. Epub ahead of print. PMID: 39037602.

https://link.springer.com/article/10.1007/s00125-024-06225-1