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Consider Fatty Liver Disease for Hypoglycemia Risk in Diabetes

Among patients with type 2 diabetes in a nationwide study in Korea, those with noncirrhotic nonalcoholic fatty liver disease (NAFLD) had a 26% increased risk of severe hypoglycemia (requiring a visit to a hospital emergency or admission) after adjusting for variables including obesity.

The study by Ji-Yeon Lee, MD, PhD, of Yonsei University College of Medicine, Seoul, South Korea, and colleagues was published online February 23 in JAMA Network Open.

“The presence of NAFLD was associated with increased risk of severe hypoglycemia by 1.3-fold, a relatively modest association compared with established risk factors such as insulin or sulfonylurea use and [chronic kidney disease (CKD)],” the researchers write.

“However, considering the high prevalence of NAFLD in patients with type 2 diabetes, the contribution of NAFLD to hypoglycemia risk is not negligible.”   

Therefore, the “presence of NAFLD should be considered when evaluating vulnerability to hypoglycemia in patients with type 2 diabetes,” independent of obesity status, they conclude.

Subgroup analyses also identified that women with NAFLD and underweight patients “were more vulnerable” to developing severe hypoglycemia, they note, which “provides 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.”

Further studies are needed in other racial and ethnic populations and to evaluate causality and mechanisms linking NAFLD to hypoglycemia risk, the authors say.

Fatty Liver Index, a Surrogate for NAFLD

An estimated 6% of patients with type 2 diabetes have severe hypoglycemia, which is associated with falls, driving accidents, dementia, cardiovascular events, fear, distress, and death, not to mention added healthcare costs, the researchers explain.

And an estimated 55% of patients with type 2 diabetes have NAFLD, which is associated with obesity and insulin resistance.

However, the link between NAFLD and risk of severe hypoglycemia in type 2 diabetes had to date been unclear.

From the National Health Insurance Service of South Korea database, the researchers identified 1,946,581 adults who had a health examination during 2009 to 2013 and a diagnosis of type 2 diabetes. Patients who were hepatitis B or C carriers, had cirrhosis or cancer of the liver or pancreas, or had heavy alcohol consumption were excluded.

During a median 5.2 years, 2.3% of patients had at least one episode of severe hypoglycemia.

Patients with versus without severe hypoglycemia were more likely to be male (58% vs 45%), older (mean age 68 vs 57 years), have a lower mean body mass index (BMI, 24.2 vs 25.1 kg/m2), hypertension, CKD, cardiovascular disease (CVD), and take insulin, sulfonylurea, or a glinide, but less likely to smoke, drink alcohol, or be physically active (all P < .001).

Researchers used the fatty liver index (FLI) — calculated using triglycerides, BMI, gamma glutamyltransferase, and waist circumference — as a surrogate for NAFLD in the absence of imaging or a liver biopsy.

The association between severe hypoglycemia and FLI was J-shaped after adjusting for age, sex, smoking and alcohol habits, exercise, and BMI, and after further adjusting for severe hypoglycemia within the previous 3 years, insulin use, sulfonylurea, or glinide, and history of hypertension, CKD, and CVD.

Participants were then classified into three groups: low FLI score < 30 (absence of NAFLD); intermediate FLI score 30-59; and high FLI score ≥ 60 (presence of NAFLD).    

In the fully adjusted model, the incidence of severe hypoglycemia was similar in patients with low or intermediate FLI scores, but patients with a high FLI score had a greater risk of severe hypoglycemia than those with a low FLI score (adjusted hazard ratio [aHR], 1.26).

The risk of severe hypoglycemia in patients with versus without NAFLD was stronger among participants ≥ 60 years old versus younger people, as well as in women versus men (aHR, 1.29 vs 1.17), and in people who took a sulfonylurea or glinide versus those who did not. The risk was greatest in people who had a BMI < 18.5 kg/m2 (aHR, 1.71) and was lower in insulin users versus nonusers.

In this cohort study of more than 1.9 million individuals, “participants with type 2 diabetes and NAFLD without cirrhosis had an approximately 26% increased risk of severe hypoglycemia after adjustment for multiple clinical covariates,” the researchers reiterate.

“This result provides 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,” they conclude.

The research was supported by a grant from the Basic Science Research Program through the National Research Foundation of Korea funded by the Korean Government. The authors have reported no relevant financial relationships.

JAMA Netw Open. Published online February 23, 2022.

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