Original articleSevere hypoglycaemia is a major predictor of incident diabetic retinopathy in Japanese patients with type 2 diabetes
Introduction
Hypoglycaemia is the most common complication of intensive glucose-lowering therapy in diabetes patients. In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, which was prematurely stopped owing to increased mortality possibly related to hypoglycaemia, intensive glucose control in patients with type 2 diabetes (T2D) resulted in a threefold increase in hypoglycaemias requiring medical assistance [1]. Meta-analysis confirmed the adverse effects of intensive glucose control on hypoglycaemia [2], and similar associations were reported in a meta-analysis of the addition of dipeptidyl peptidase-4 inhibitors to sulphonylureas [3]. The prevalence of hypoglycaemia was estimated to be 45% for mild or moderate hypoglycaemia and 6% for severe hypoglycaemia in the entire study T2D population, whereas the prevalence was 50% for mild or moderate hypoglycaemia and 21% for severe hypoglycaemia in patients taking insulin [4]. It is well known that hypoglycaemia is a major cause of emergency hospitalizations in the elderly [5] and is life-threatening [6]. Moreover, a recent meta-analysis of six observational studies revealed that hypoglycaemia increases the risk of macrovascular complications threefold [7].
In earlier studies, rapid normalization of glucose status with intensive glucose management was suggested to have a potential role in aggravating the progression of diabetic retinopathy (DR), known as ‘early worsening’ [8]. The entire mechanism of this early worsening has not been fully elucidated, but hypoglycaemia is known to cause haemorheological changes, white cell activation, vasoconstriction, and the release of inflammatory mediators and cytokines [9]. Furthermore, fear of hypoglycaemia may have a negative impact by lowering adherence to diabetes management and glucose control regimens [10].
Data on microvascular complications related to hypoglycaemia in T2D are sparse. The Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) study reported that hypoglycaemia increases major microvascular events [11]. Zhao et al. [12] reported that the risk of microvascular complications was increased in those who had hypoglycaemia within a year. However, it remains unknown whether hypoglycaemia specifically increases the incidence of DR, as the ADVANCE and Zhao et al. studies examined a composite outcome of new or worsening nephropathy or retinopathy. Also, a combined analysis of the ADVANCE and ACCORD studies suggested that the inconsistencies in the risk associations for microvascular complications between studies aiming at near-normalization of glucose might have been due to the balance between the beneficial effects of intensive glucose management and harmful effects of hypoglycaemia [13].
These lines of evidence have prompted our investigation into the associations between mild, moderate and severe hypoglycaemia and the incidence and progression of DR in a cohort of Japanese patients with T2D followed for 8 years.
Section snippets
Study cohort
The present study was part of the Japan Diabetes Complications Study (JDCS), an open-labelled randomized trial originally designed to evaluate the efficacy of a long-term therapeutic intervention that was mainly focused on lifestyle education [14], [15]. Incidence rates of DR did not significantly differ between the two randomized groups in that trial; therefore, for our study, data from these two groups were combined [16]. Those eligible for the study were subjects previously diagnosed with
Results
Of the 1221 patients without DR at baseline, 127 (10.4%) had experienced non-severe hypoglycaemia within the previous year, while 10 (0.8%) reported hypoglycaemia episodes with coma or requiring treatment (Table 1). The severity of hypoglycaemia was significantly associated with gender, duration of diabetes, use of hypoglycaemic or lipid-lowering agents, C-peptide reactivity, BMI, and LDL and HDL cholesterol. Table S1 (see supplementary materials associated with this article online) describes
Discussion
Our present study of Japanese patients with T2D has demonstrated a significant increase in the risk of DR among patients who had experienced severe hypoglycaemia, but no notable effects from mild hypoglycaemia episodes on outcomes. The striking difference between our findings and those of the ADVANCE study [11] was that, in our cohort, severe hypoglycaemia was one of the strongest predictors of DR, showing an approximately fourfold increase in incidence rate, which is numerically larger than
Funding
Funding/Support: This work was financially supported by the Ministry of Health, Labor and Welfare, Japan.
Financial disclosures: No financial disclosures.
Disclosure of interest
The authors declare that they have no competing interest.
Acknowledgements
We sincerely thank the late Professor Nobuhiro Yamada, former director of the JDCS, who always provided warm spiritual support to us all. We thank all the patients and diabetologists at the 59 participating institutions for their long-standing collaboration in the JDCS. Thanks are extended to Ms Mami Haga and Ms Natsuko Tada, and Niigata University, for their excellent secretarial assistance. A medical editor in NAI Inc. reviewed the writing of the manuscript. The sponsor had no role in the
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