NAFLD Tied to Higher Risk of Severe Hypoglycemia in T2D Patients

Independent of their obesity status, patients with type 2 diabetes (T2D) who also have non-alcoholic fatty liver disease (NAFLD) are at greater risk for severe hypoglycemia, a large claims-based study from Korea suggested.

Among over 1.9 million adults with T2D, adjusted analyses that factored in body mass index (BMI) — an established risk factor for severe hypoglycemia — found that those with NAFLD had a 26% greater risk of severe hypoglycemia when compared to those without NAFLD (adjusted hazard ratio [aHR] 1.26, 95% CI 1.22-1.30), reported Yong-ho Lee, MD, PhD, of the Yonsei University College of Medicine in Seoul, Korea, and colleagues.

The risk was greater for women (aHR 1.29, 95% CI 1.23-1.36) and for those who were underweight, a BMI below 18.5 (aHR 1.71, 95% CI 1.02-2.88), the authors wrote in JAMA Network Open.

“As lower BMI is known as an independent risk factor for severe hypoglycemia, patients with NAFLD seemed to have less risk of hypoglycemia without consideration of BMI,” they noted. “However, after adjusting for BMI, the risk of severe hypoglycemia was significantly increased among participants with NAFLD in a dose-dependent manner.”

Lee’s group found a J-shaped association between baseline fatty liver index (FLI) score — which was used as surrogate for NAFLD, as the claims data lacked histological, imaging, and liver biopsy information — and risk for severe hypoglycemia:

• Fifth FLI decile: aHR 0.86 (95% CI 0.83-0.90)
• Tenth FLI decile: aHR 1.29 (95% CI 1.22-1.37)

For those with more advanced NAFLD — FLI of ≥60 and a minimum aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio of ≥0.8 — the researchers saw a 38% greater risk of severe hypoglycemia (aHR 1.38, 95% CI 1.31-1.45) when compared to those with an FLI <30 and an AST/ALT ratio <0.8.

For their population-based cohort study, Lee and colleagues examined data from the National Health Insurance System of South Korea on 1,946,581 adults ages 20 and over who were diagnosed with T2D from 2009 to 2012. Patients were followed through the end of 2015.

T2D was defined by having an ICD-10 diagnostic code with a prescribed antidiabetic agent or minimum fasting plasma glucose level of 126 mg/dL at baseline or follow-up. Excluded were those with cirrhosis, pancreatic disorders, hepatitis B or C, and other conditions.

Over half (58%) of the participants were men. During the median 5.2 years of follow-up, 45,135 (2.3%) had at least one severe hypoglycemia event based on admission and emergency department visit records listing hypoglycemia as the primary diagnosis, including 22,213 with an FLI score of less than 30, another 14,632 with an FLI score of 30-59, and 8,290 with an FLI score of 60 or greater.

Those with severe hypoglycemia tended to be older than those without severe hypoglycemia (average age of 68 vs 57 years, respectively), had a lower BMI (mean 24 vs 25), and were more likely to have hypertension (77% vs 56%), cardiovascular disease (11% vs 6%), and chronic kidney disease (34% vs 11%). Those with severe hypoglycemia were also taking more sulfonylurea (75% vs 40%), metformin (66% vs 45%), and insulin (28% vs 7%).

Analyses adjusted for clinical covariables, such as BMI, age, gender, exercise, smoking, and alcohol use; severe hypoglycemia within the prior 3 years; use of glinides, sulfonylurea, or insulin; as well as patients’ history of comorbidities, including hypertension, chronic kidney disease, and cardiovascular disease.

The authors acknowledged several limitations to their findings, including the use of FLI as a surrogate for NAFLD, that claims data can also contain coding errors, and that asymptomatic severe hypoglycemic events or those occurring outside of the emergency department or hospital were excluded.