Analysis of Severe Hypoglycemia Among Adults With Type 2 Diabetes and Nonalcoholic Fatty Liver Disease

Abstract

Importance: Previous studies have indicated that liver cirrhosis is associated with hypoglycemia, but there have been no studies investigating the association between nonalcoholic fatty liver disease (NAFLD) and hypoglycemia in noncirrhotic populations with type 2 diabetes.

Objective: To explore the association of NAFLD with severe hypoglycemia among patients with type 2 diabetes.

Design, setting, and participants: This nationwide population-based retrospective cohort study using the National Health Insurance System of South Korea included individuals aged 20 years or older who had undergone a medical health examination between January 1, 2009, and December 31, 2012, and were diagnosed with type 2 diabetes. Participants were followed up until December 31, 2015. Data analyses were performed between January 1, 2019, and February 2, 2021.

Exposures: The baseline fatty liver index (FLI) was used as a surrogate marker for NAFLD.

Main outcomes and measures: The outcome of interest, severe hypoglycemia, was measured using hospital admission and emergency department visit records with a primary diagnosis of hypoglycemia.

Results: Among 1 946 581 individuals with type 2 diabetes, 1 125 187 (57.8%) were male. During a median (IQR) follow-up of 5.2 (4.1-6.1) years, 45 135 (2.3%) experienced 1 or more severe hypoglycemia events. Participants with severe hypoglycemia, vs those without severe hypoglycemia, were older (mean [SD] age, 67.9 [9.9] years vs 57.2 [12.3] years; P < .001) and had lower mean (SD) body mass index (24.2 [3.43] vs 25.1 [3.4]; P < .001). Patients with NAFLD tended to have less severe hypoglycemia without consideration of obesity status. However, after adjustment of multiple clinical covariates, including body mass index, there was a J-shaped association between FLI and severe hypoglycemia (5th decile: adjusted hazard ratio [aHR], 0.86; 95% CI, 0.83-0.90; 9th decile: aHR, 1.02; 95% CI, 0.96-1.08; 10th decile: aHR, 1.29; 95% CI, 1.22-1.37), and the estimated risk of hypoglycemia was higher in participants with NAFLD (aHR, 1.26; 95% CI, 1.22-1.30). The association was more prominent in female participants (aHR, 1.29; 95% CI, 1.23-1.36) and those with underweight (aHR, 1.71; 95% CI, 1.02-2.88).

Conclusions and relevance: In this study, NAFLD was associated with a higher risk of severe hypoglycemia in patients with type 2 diabetes independent of obesity status. Presence of NAFLD should be considered when evaluating vulnerability to hypoglycemia in patients with type 2 diabetes.

Figure 1.. Hazard Ratios for Severe Hypoglycemia According to Fatty Liver Index (FLI) Deciles

Model 1 was unadjusted. Model 2 was adjusted for age, sex, smoking and alcohol habits, exercise, and body mass index. Model 3 was further adjusted for severe hypoglycemia within previous 3 years; insulin, sulfonylurea, or glinides use; and history of hypertension, chronic kidney disease, and cardiovascular disease. Error bars indicate 95% CIs.

Figure 2.. Adjusted Hazard Ratios (HRs) for Severe Hypoglycemia in the Group With Fatty Liver Indices of 60 or Greater vs Those with Fatty Liver Indices of Less Than 0, by Subgroup

Cox proportional hazard regression models were used to estimate HRs and 95% CIs. Models were adjusted for age; sex; smoking and alcohol habits; exercise; body mass index (calculated as weight in kilograms divided by height in meters squared); severe hypoglycemia within previous 3 years; insulin, sulfonylurea, or glinides use; and history of hypertension, chronic kidney disease, and cardiovascular disease. Error bars indicate 95% CIs.