Type 2 Diabetes Increases Liver Decompensation, Cancer Risk in NAFLD Patients

Daniel Q. Huang, FRCP

Patients with non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D) are at a significantly greater risk of hepatic decompensation and hepatocellular carcinoma (HCC), according to data from a recent meta-analysis.¹

New research from a multinational team of investigators showed risk of HCC and/or hepatic decompensation was up to 13-fold greater over 5 among NAFLD patients with T2D than those without diabetes.

The findings further evidence the association between poor glycemic control and increased risk of hepatic disease, as well as calls to improve T2D prevention among patients with NAFLD.

Investigators led by Daniel Q. Huang, FRCP, of the NAFLD Research Center and the division of gastroenterology and hepatology at the University of California San Diego, sought to interpret the risk of hepatic decompensation in people with NAFLD with and without T2D. With approximately one-third of adults globally impacted by NAFLD and one-tenth of the overall population having T2D, the likelihood of comorbid disease is high. In fact, approximately 1 in 3 individuals with T2D are known to have non-alcoholic steatohepatitis (NASH).²

“Previous studies have shown that type 2 diabetes is associated with hepatic decompensation among people with cirrhosis, hepatitis C virus, and heavy alcohol consumption,” investigators wrote. “However, the risk of hepatic decompensation (development of ascites, hepatic encephalopathy, or variceal bleeding) among individuals with NAFLD with and without type 2 diabetes has not been systematically assessed.”

The team conducted a meta-analysis of data from participants with liver fibrosis across 6 cohorts in the US, Japan and Turkey. Their inclusion of studies required disease characterized by magnetic resonance elastography, a longitudinal assessment for hepatic decompensation and death, and adult patients ≥18 years old with NAFLD with available data regarding their presence of T2D at baseline.

Huang and colleagues sought a primary outcome of hepatic decompensation—including ascites, hepatic encephalopathy or variceal bleeding—and a secondary outcome of HCC development. A subdistribution hazard ratio (sHR) was defined to help compare the likelihood of hepatic outcomes in patients with and without T2D.

Their analysis included 2016 participants from the 6 cohorts. Approximately one-third (n = 736) of participants had T2D. Mean participant age was 57.8 years old; 53% were female.

Among the 1737 participants with available longitudinal data—including 602 with T2D at baseline—105 participants developed hepatic decompensation over a median 2.8 years follow-up. Hepatic decompensation risk was significant for patients with both NAFLD and T2D at 1 year (sHR, 3.37; 95% CI, 2.10 – 5.11); 3 years (sHR, 7.49; 95% CI, 5.36 – 10.08); and 5 years (sHR, 13.85; 95% CI, 10.43 – 17.75). Comparatively, sHR for patients with NAFLD and without T2D was 1.07, 2.92 and 3.95 at years 1, 3 and 5, respectively.

T2D (sHR, 2.15; 95% CI, 1.39 – 3.34) and glycated hemoglobin (sHR, 1.31; 95% CI, 1.10 – 1.55) were independent predictors of hepatic decompensation when investigators adjusted for patient age, body mass index (BMI), and race confounders.

Among the 22 of 1802 participants diagnosed with HCC over a median 2.9 follow-up years, 18 had baseline T2D and 4 did not. Risk of incident HCC per sHR was greater among patients with both NAFLD and T2D versus lone NAFLD at the observed time points:

• 1 year, 1.34 (95% CI, 0.64 – 2.54) vs 0.09 (95% CI, 0.01 – 0.50)
• 3 years, 2.44 (95% CI, 1.36 – 4.05) vs 0.21 (95% CI, 0.04 – 0.73)
• 5 years, 3.68 (95% CI, 2.18 – 5.77) vs 0.44 (95% CI, 0.11 – 1.33; P <.0001)

As an independent predictor of HCC development, T2D was associated with a more than 5-fold risk (sHR, 5.34; 95% CI, 1.67 – 17.09; P = .0048) in patients with NAFLD.

“These data highlight the importance of ensuring comparable proportions of participants with type 2 diabetes in the treatment and control groups of clinical trials in NAFLD,” investigators wrote. “These findings indicate the need for a concerted global effort to reduce the morbidity of NAFLD associated with type 2 diabetes.”

Though the retrospective nature of analysis may leave the data subject to bias, as well as potentially unmeasured confounders, the team concluded that patients with both NAFLD and T2D are at a significantly greater risk of hepatic decompensation and HCC than patients with lone NAFLD.

“The higher risk of hepatic decompensation and HCC in people with type 2 diabetes should be considered when designing clinical trials in NAFLD,” investigators concluded. “These data serve as a call to action to prevent type 2 diabetes and reduce the growing burden of NAFLD and NAFLD-related hepatocellular carcinoma.”

References

1. ^{Huang DQ, Noureddin N, Ajmera V, et al. Type 2 diabetes, hepatic decompensation, and hepatocellular carcinoma in patients with non-alcoholic fatty liver disease: an individual participant-level data meta-analysis [published online ahead of print, 2023 Jul 4]. Lancet Gastroenterol Hepatol. 2023;S2468-1253(23)00157-7. doi:10.1016/S2468-1253(23)00157-7}
2. ^{Younossi ZM, Golabi P, de Avila L, et al. The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: a systematic review and meta-analysis. J Hepatol. 2019; 71: 793-801}