Liver–heart connection in diabetes mellitus (2021)

Type 2 diabetes mellitus (T2DM) is one of the most important risk factors of non-alcoholic fatty liver disease (NAFLD).1 NAFLD is the most common chronic liver disease worldwide, characterized by hepatic steatosis, or the excess accumulation of fat in the liver, in the absence of excessive alcohol consumption or viral hepatitis.2 Patients with the progressive form of NAFLD, known as non-alcoholic steatohepatitis (NASH), are also at a higher risk of advanced liver disease, including advanced liver fibrosis and cirrhosis.3 The risk of cardiovascular (CV) events and mortality is higher in patients with NAFLD4; CV mortality is the top killer in NAFLD patients.5 In the recent Asia-Pacific Working Party on NAFLD Guidelines, screening of NAFLD is advised in people with a history of weight gain, or family history of T2DM or premature CV disease (CVD), and personal history of important risk factors, namely, T2DM and obesity.2 As these important risk factors of NAFLD overlap with those of CV events, it would be clinically meaningful to identify a connecting point between liver and heart in T2DM patients. In this issue of Journal of Gastroenterology and Hepatology, Chun et al. from Korea report their retrospective cohort of 1481 T2DM patients (58.4% had NAFLD). They estimated liver fibrosis using the serum fibrosis formulae of the fibrosis-4 index, NAFLD fibrosis score, and BARD (BMI, AST/ALT ratio and DM, predictor of hepatic fibrosis) score.6 With a long median follow-up of more than 7 years, the authors demonstrated a relationship between liver fibrotic burden and CVD development.6 This highlights the important role of liver fibrosis in adverse clinical outcomes, not limiting to liver-related outcomes but also incident CVD. It is sensible to utilize liver fibrosis assessment to predict CVD in T2DM patients, as more than 50–70% of them have NAFLD.1 Serum fibrosis formulae have the beauty of high applicability with common clinical and laboratory parameters as the components.7 But why was there liver fibrosis even in the absence of NAFLD? In Chun et al.'s study, NAFLD was defined as a hepatic steatosis index (HSI) > 36 in the absence of a potential cause of chronic liver disease.6 Hence, mild hepatic steatosis might have been missed. HSI was not associated with CVD development, while liver fibrotic burden had a strong association with CVD. This echoes our previous findings that severity of liver fibrosis but not steatosis is prognostically important.8 While both Chun et al.’s and previous studies suggest a high risk of CVD in patients with NAFLD who have significant liver fibrosis, it would be important to identify patients with NAFLD first, followed by appropriate liver assessment. While mild NAFLD may be missed by HSI, models that aim at identifying NAFLD in the general population can play a role in picking up missing NAFLD cases.9 These models should be based on common clinical parameters in order to increase the utilization. During the long follow-up period, patients could leave the cohort due to different reasons including loss to follow-up and death. The occurrence of death can indeed lead to an overestimation of cumulative incidence of CVD by the Kaplan–Meier method due to its competing nature with CVD that precludes the subsequent CVD occurrence. To avoid the overestimation, Chun et al. applied the Gray's method to estimate the cumulative incidence function of CVD. This approach of competing risk analysis can provide a more accurate estimation on the cumulative incidence of event of interest under the presence of significant competing events such as mortality. In modeling risk factors for CVD occurrence, Fine–Gray proportional subdistribution hazards model would be one of the popular approaches to account for competing events. The projected T2DM and NAFLD disease burdens increase alongside the rising trends in obesity, leading to more cases of advanced liver disease, as well as liver-associated and CV-associated mortality in the Asia-Pacific region.10 Preventing the growth of T2DM and obese populations, together with the treatment for the components of the metabolic syndrome will be key factors to reduce the ongoing increases in liver-related and CV-related disease burden in the Asia-Pacific region.11 While we are enthusiastically expecting the first registered drug for NASH, some existing antidiabetic agents may kill two birds with one stone by helping the liver and heart at the same time. Glucagon-like peptide-1 receptor agonists, for example, liraglutide and semaglutide, reduce CV complications and possibly improves NASH; hence, it may be considered in T2DM patients with NAFLD or NASH.12, 13 Future studies on the impact of the new drugs on both liver-related and CV outcomes are eagerly awaited.14 Terry Yip has served as an advisory committee member and a speaker for Gilead Sciences. Vincent Wong has served as an advisory committee member for 3V-BIO, AbbVie, Allergan, Boehringer Ingelheim, Echosens, Gilead Sciences, Intercept, Janssen, Novartis, Novo Nordisk, Perspectum Diagnostics, Pfizer, TARGET-NASH, and Terns and a speaker for Bristol-Myers Squibb, Echosens, Gilead Sciences, and Merck. He has also received a research grant from Gilead Sciences. Grace Wong has served as an advisory committee member for Gilead Sciences; as a speaker for Abbott, Abbvie, Bristol-Myers Squibb, Echosens, Furui, Gilead Sciences, Janssen and Roche; and received research grant from Gilead Sciences. All authors were responsible for the study concept, interpretation of data, the drafting, and critical revision of the manuscript for important intellectual content. This work was supported by the Direct Grant of The Chinese University of Hong Kong (Reference 2019.042) awarded to Grace Wong.