NAFLD Linked With Increased Risk of Hypoglycemia in T2D, Independent of Obesity Status

New data revealed that among patients with type 2 diabetes (T2D), presence of nonalcoholic fatty liver disease (NAFLD) may raise the risk of severe hypoglycemia episodes.

Results of a South Korean population-based study revealed that nonalcoholic fatty liver disease (NAFLD) was associated with a higher risk of severe hypoglycemia in those with type 2 diabetes (T2D), regardless of obesity status. Based on these findings, NAFLD presence should be considered when evaluating hypoglycemia vulnerability among patients with T2D, authors wrote. The study was published in JAMA Network Open.

Hypoglycemia is the most commonly reported adverse effect in diabetes management, and severe hypoglycemia can result in emergency department (ED) visits or hospitalization, researchers explained. The condition is also associated with falls and driving accidents, dementia, cardiovascular events, and mortality, they added.

NAFLD affects approximately 25% of individuals worldwide and prevalence is expected to increase alongside the rise in obesity and as populations live longer. In addition, around 55% of patients with T2D also have NAFLD.

Although previous research has found that older age, kidney insufficiency, and insulin therapy are risk factors for hypoglycemia in the T2D population, the association of NAFLD with severe hypoglycemia remains unclear.

To address this knowledge gap, investigators assessed data from South Korea's National Health Insurance Service (NHIS).

All individuals 20 years or older who had completed a health examination between January 2009 and December 2012 were evaluated; all those with T2D at baseline or who developed the disease within this window were included in analyses.

Patients who reported heavy alcohol consumption, a diagnosis of liver cirrhosis, or other potentially confounding conditions were excluded.

The final cohort included 1,946,581 individuals who were followed-up with until December 31, 2015, for a median (interquartile range) of 5.2 (4.1-6.1) years. The majority of patients (57.8%) were men, and during this follow-up period, 45,135 (2.3%) participants experienced at least 1 episode of severe hypoglycemia. Baseline fatty liver index (FLI) served as a surrogate marker of NAFLD.

Additional analyses revealed the following:

  • 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 (BMI) (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.
  • After adjustment of multiple clinical covariates, including BMI, there was a J-shaped association between FLI and severe hypoglycemia (5th decile: adjusted HR [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).
  • 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).

Those who experienced severe hypoglycemia throughout the study window also had higher rates of hypertension, chronic kidney disease, and cardiovascular disease, and used insulin, sulfonylurea, and glinides more than those without severe hypoglycemia. Researchers also found a strong association between NAFLD and severe hypoglycemia in patients with newly diagnosed T2D.

“In this large, population-based longitudinal study, we found that participants with T2D and NAFLD had an approximately 26% increased risk of severe hypoglycemia after adjustment for multiple clinical covariates,” they wrote.

When individuals have chronic liver disease, their glucose metabolism can be dysregulated, potentially causing hypoglycemia. In the current analysis, authors found a dose-dependent relationship between hepatic steatosis and incidence of severe hypoglycemia in those with T2D.

Regarding the role of obesity and body weight, authors noted that because “lower BMI can reflect malnutrition and coexisting chronic disease, individuals with a lower BMI might be susceptible to the development of hypoglycemia.”

Instances of hypoglycemia that took place outside of EDs or hospitals were not captured in the data, marking a limitation to the study. Coding errors may also have been present in the data sets employed.

Overall, results provide “clinicians with additional information about which patients might have a high risk of hypoglycemia to hopefully reduce its incidence and ultimately improve patient safety via individualized therapy,” authors wrote.

“Further validation studies in other racial and ethnic populations and to evaluate causality and mechanisms regarding NAFLD and hypoglycemia risk are warranted,” they concluded.


Lee J, Kim Y, Han K, et al. Analysis of severe hypoglycemia among adults with type 2 diabetes and nonalcoholic fatty liver disease. JAMA Netw Open. Published online February 23, 2022. doi:10.1001/jamanetworkopen.2022.0262

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