Introduction: Diabetes and liver disease are prevalent chronic conditions in China, with interconnections in terms of pathogenesis, clinical manifestations, diagnostic and therapeutic targets, making their combined management essential for alleviating the burden of these diseases. In support of the development of diabetes and liver disease co-management initiatives in China, this publication Hepatology Digest, collaborates with the co-management of diabetes-liver diseases strategy(CDL) to introduce the CDL Literature Review column. Each month, we share literature related to the mechanisms and advancements in the diagnosis and treatment of diabetes-related liver diseases. We also invite experts in the field to provide commentary, aiming to offer insights and assistance to experts, researchers, and frontline healthcare professionals engaged in scientific research and clinical care.In this issue of CDL Literature Review, we present six clinical research papers focusing on the association between diabetes and fatty liver, liver fibrosis, cirrhosis, and liver cancer. Our invited expert commentators for this issue are Dr. Wang Jie from Peking University School of Basic Medical Sciences, Dr. Feng Liu from Peking University People’s Hospital, and Dr. Wang Lu from the Second Affiliated Hospital of Xi’an Jiaotong University.
Expert Commentary:
Dr. Jie Wang, Peking University School of Basic Medical Sciences
Dr. Jie Wang is an Associate Researcher and Ph.D. supervisor in the Department of Pathogenic Biology at Peking University School of Basic Medical Sciences. He holds positions as a committee member in the Youth Group, Liver Cancer Group, Hepatitis Group, and Collaborative Group for Basic Medical and Experimental Diagnostics of the Chinese Medical Association Hepatology Branch. Additionally, he is a committee member of the Youth Group of the Chinese Medical Association Medical Virology Branch, a member of the China Preventive Medicine Association’s Committee for the Elimination of Viral Hepatitis, and a member of the Virus Oncology Professional Committee of the China Research Hospital Association. Dr. Wang has led multiple research projects funded by the National Natural Science Foundation, Beijing Natural Science Foundation, JM Fusion Key Project (subproject), and the Ministry of Science and Technology’s Major Special Project for Infectious Disease Prevention and Control. He has published over 80 articles in both Chinese and English and holds six granted national invention patents.
01
Comparative effectiveness of multiple different treatment regimens for nonalcoholic fatty liver disease with type 2 diabetes mellitus: a systematic review and Bayesian network meta-analysis of randomised controlled trials
Deng M, Wen Y, Yan J, et al. BMC Medicine, 2023, 21(1): 447.
Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are closely related, mutually promoting the progression of both diseases. For patients with NAFLD combined with T2DM, there are various treatment options available. The researchers conducted a systematic review and meta-analysis of the treatment effects of several potential interventions for NAFLD combined with T2DM. The results indicate that in terms of glycemic control, dapagliflozin and pioglitazone have certain therapeutic effects, while liraglutide has a weight-reducing effect on abdominal obesity patients. Existing evidence cannot prove the effectiveness of other interventions in reducing liver fat content, visceral fat area, ALT, and insulin resistance. Future research should focus on the clinical application of GLP-1RA and the long-term prognosis of patients.
The study searched for randomized controlled trials on the treatment of NAFLD combined with T2DM published on PubMed, Embase, Cochrane Library, and Web of Science from inception to June 30, 2023. Bayesian network meta-analysis summarized the effect estimates of interventions compared. The GRADE framework was used to classify all effect estimates, and interventions were categorized accordingly. A total of 4369 records were retrieved, and 24 records were finally included, involving 1589 participants, 8 clinical indicators, and 14 interventions. According to the surface under the cumulative ranking curve (SUCRA) and league table, exenatide and liraglutide demonstrated excellent potential in reducing liver fat content, controlling blood sugar, weight loss, improving liver function, and insulin resistance. Compared with liraglutide, exenatide was more effective in lowering glycated hemoglobin (HbA1c) (MD: 0.32, 95% CI: 0.12–0.52), BMI (MD: 0.81, 95% CI: 0.18–1.45), and ALT (MD: 10.96, 95% CI: 5.27–16.66). However, this evidence was assessed as low certainty. Omega-3 was the only intervention that did not lower HbA1c levels compared to standard treatment (MD: 0.17, 95% CI: 0.42–0.07), and gemigliptin was the only intervention that led to an increase in ALT levels (MD: 11.72, 95% CI: 17.82–5.57). Based on the available evidence, dapagliflozin, pioglitazone, and liraglutide have higher credibility for the treatment of NAFLD combined with T2DM.
Expert Commentary (by Dr. Jie Wang)
NAFLD and type 2 diabetes mellitus (T2DM) often coexist and mutually accelerate the progression of the diseases. For patients with NAFLD combined with T2DM, current treatment mainly focuses on glycemic control measures. However, applying treatment solely based on T2DM protocols may not achieve optimal therapeutic outcomes. In such patients, in addition to controlling blood sugar and improving insulin resistance, treatment measures should also consider reducing liver fat content and improving liver function.
This article, through a systematic review and Bayesian network meta-analysis, comparatively analyzes the therapeutic effects and limitations of different types of antidiabetic drugs in patients with NAFLD combined with T2DM. It highlights the advantages of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in controlling blood sugar and improving liver function, providing important reference value for future guideline development and clinical practice. Overall, the article emphasizes the potential value of GLP-1RA drugs and proposes that future research should focus on the clinical application of GLP-1RAs and the long-term prognosis of patients.
Limitations of this study include the relatively limited number of included patients, with the majority being overweight (BMI > 24), limiting the applicability of the findings to normal-weight patients. Additionally, due to the quantity of included literature and study limitations, bias related to racial differences cannot be ruled out.
02
Lower risks of cirrhosis and hepatocellular carcinoma with GLP-1RAs in type 2 diabetes: A nationwide cohort study using target trial emulation framework
Yang C-T, Yao W-Y, Yang C-Y, et al. Journal of Internal Medicine, 2023. Nov 22.
For type 2 diabetes mellitus (T2DM) patients with oral antidiabetic treatment failure, glucagon-like peptide-1 receptor agonists (GLP-1RAs) and long-acting insulin (LAI) are two commonly used injectable antidiabetic drugs. To assess the relationship between the use of GLP-1RAs or LAI and the risk of developing cirrhosis and hepatocellular carcinoma (HCC), Yang et al. used a target trial emulation framework to simulate a nationwide cohort study using Taiwan T2DM cohort data. The results show that, among T2D patients requiring injectable antidiabetic treatment, the use of GLP-1RAs is associated with a lower risk of cirrhosis and HCC compared to LAI.
The study included patients who initiated treatment with GLP-1RAs or LAI between 2013 and 2018, and propensity score matching was applied to ensure comparability of baseline characteristics among patients. The primary study outcomes were cirrhosis and HCC, with patient follow-up until December 31, 2019, or until the occurrence of the primary study outcomes, death, or the end of the study, whichever came first. Subdistribution hazard ratios were used to assess the relationship between treatment and outcomes. Additionally, inverse probability weighting analysis, time-dependent analysis, E-value analysis, and negative control outcome analysis were performed to test the robustness of the study results. The study included 7171 matched pairs of GLP-1RA and LAI users, and there were no significant differences in baseline characteristics between the two groups. The results indicate that compared to LAI, the use of GLP-1RAs significantly reduces the risk of composite liver disease (sHR 0.56, 95% CI: 0.42–0.76), cirrhosis (sHR 0.59, 95% CI: 0.43–0.81), and liver cancer (sHR 0.47, 95% CI: 0.24–0.93). These results were confirmed in sensitivity analyses across different subgroups and among patients with different baseline characteristics.
Expert Commentary (by Dr. Jie Wang)
Recent studies suggest an increased risk of cirrhosis and hepatocellular carcinoma (HCC) in patients with type 2 diabetes mellitus (T2DM). Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been shown to reduce liver fat content and improve liver function. However, the real-world application value of these drugs needs further confirmation.
This cohort study assessed the impact of GLP-1RAs and long-acting insulin (LAI) on the risk of cirrhosis and HCC using a subdistribution hazard ratio within a target trial emulation framework. The results demonstrate that GLP-1RA drugs significantly reduce the risk of end-stage liver disease in different subgroups and among patients with different baseline characteristics compared to LAI. Therefore, this study suggests that GLP-1RA drugs used to treat T2DM patients, especially those with concomitant liver diseases such as nonalcoholic fatty liver or hepatitis, have potential advantages.
Since this study did not compare GLP-1RAs with antidiabetic drugs other than LAI, it is not sufficient to prove that GLP-1RA drugs have a significant advantage in treating T2DM patients compared to other antidiabetic drugs. Future research should focus more on the efficacy of different antidiabetic treatment regimens for T2DM patients with different complications/comorbidities, providing more precise treatment strategies for patients.
Dr. Feng Liu
Peking University People’s Hospital Medical Doctor, Associate Researcher, Ph.D. Supervisor, Vice Director of Peking University People’s Hospital and Peking University Liver Research Institute, Committee Member of the Youth Group of the Chinese Medical Association Hepatology Branch, Committee Member of the Fatty Liver and Alcoholic Liver Disease Group of the Chinese Medical Association Hepatology Branch, Committee Member of the Beijing Medical Association Hepatology Branch.
03
Plasma ceramides are associated with MRI-based liver fat content but not with noninvasive scores of liver fibrosis in patients with type 2 diabetes
Denimal D, Béland-Bonenfant S, Pais-de-Barros J-P, et al. Cardiovascular Diabetology, 2023, 22(1): 310.
More and more evidence suggests that ceramides play a crucial role in the occurrence and development of nonalcoholic fatty liver disease (NAFLD). However, the relationship between plasma ceramide levels and the severity of NAFLD in patients with type 2 diabetes (T2DM) remains unclear. This study aimed to investigate the association between plasma ceramide levels in patients with type 2 diabetes and liver fat deposition assessed by MRI proton density fat fraction (MRI-PDFF), as well as the relationship with noninvasive scores of liver fibrosis. The results indicate that, independent of traditional NAFLD risk factors, plasma ceramide levels are associated with liver fat deposition in patients with type 2 diabetes.
This cross-sectional single-center study included 255 patients with type 2 diabetes (GEPSAD cohort), and plasma concentrations of seven ceramides were measured using liquid chromatography-mass spectrometry. Liver fat content was assessed by MRI-PDFF, and noninvasive scores of liver fibrosis, including Fibrosis-4 index, NAFLD Fibrosis Score, FibroTest®, and Fibrosis NASH Score, were calculated. An external validation cohort included 80 patients with type 2 diabetes from the LIRA-NAFLD cohort. A liver fat content greater than 5.56% was diagnosed as hepatic steatosis, with 62.4% and 82.5% of type 2 diabetes patients diagnosed with hepatic steatosis in the GEPSAD and LIRA-NAFLD cohorts, respectively. Single-factor analysis showed a positive correlation between liver fat content and plasma total ceramide levels (r=0.232, P=0.0002), as well as ceramides 18:0, 20:0, 22:0, and 24:0 (all P≤0.0003). In multiple-factor analysis, after adjusting for age, duration of diabetes, body mass index, and dyslipidemia, liver fat content remained positively correlated with total ceramide (P=0.001), 18:0 (P=0.006), 22:0 (P=0.0009), and 24:0 (P=0.0001). Similar results were obtained in the external validation cohort of LIRA-NAFLD. After adjusting for age in both cohorts, no significant association was found between plasma ceramides and fibrosis scores.
Expert Commentary (by Dr. Feng Liu)
Nonalcoholic fatty liver disease (NAFLD) is a common condition in patients with type 2 diabetes mellitus (T2DM) and is associated with an increased risk of adverse liver and cardiovascular events. Ceramides, bioactive lipids, have been implicated in the mechanisms related to cardiovascular metabolic diseases. Recent studies have highlighted the role of ceramides in the development of NAFLD. However, there is limited research on the relationship between plasma ceramides in patients with type 2 diabetes and the severity of NAFLD.
This study, which included two independent cohorts totaling 335 patients with type 2 diabetes, assessed liver fat content using MRI-PDFF and noninvasive scores for liver fibrosis. The findings suggest a positive correlation between plasma ceramide levels and liver fat deposition in type 2 diabetes patients, independent of traditional NAFLD risk factors. However, the study has some limitations, including the relatively small sample size in both cohorts, potentially affecting the robustness of the correlation results. Additionally, the medications used for treating diabetes and dyslipidemia could influence ceramide metabolism, impacting the accuracy of the relationship between plasma ceramides and liver outcomes. Furthermore, the study did not utilize more accurate standards such as liver biopsy or magnetic resonance elastography for diagnosing liver fibrosis. Finally, the GEPSAD cohort had a cross-sectional design, revealing the correlation between plasma ceramides and liver fat content rather than causation, requiring further validation through prospective cohorts.
04
Serum Tsukushi level is associated with the severity of liver fibrosis independent of type 2 diabetes
Lam S, Lee C-H, Fong CHY, et al. The Journal of Clinical Endocrinology and Metabolism, 2023: Nov 2.
Tsukushi (TSK) is a protein secreted by the liver, and research suggests that obesity can promote the expression and secretion of TSK in the liver. This study aimed to evaluate the relationship between plasma TSK levels in patients with type 2 diabetes (T2DM) and nonalcoholic fatty liver disease’s (NAFLD) severity, comparing it to patients without T2DM. The results show that, in both T2DM and non-T2DM patients with NAFLD, serum TSK levels are elevated, reflecting the severity of liver fibrosis.
The study included 393 diabetes patients and 289 non-diabetes patients. Transient elastography was performed on all patients to assess liver fat deposition and fibrosis. Serum TSK levels were measured using enzyme-linked immunosorbent assay (ELISA), and NAFLD was diagnosed with a controlled attenuation parameter (CAP) ≥ 248 dB/m. In the T2DM and non-T2DM groups, 276 (70.2%) and 129 (44.6%) patients had NAFLD, respectively, with serum TSK levels higher in those with NAFLD compared to those without. In the T2DM group, the levels were 91.0 ng/ml (61.7-133.8) for NAFLD and 82.5 ng/ml (60.9-118.5) for no NAFLD. In the non-T2DM group, the levels were 97.1 ng/ml (69.3-148.6) for NAFLD and 80.8 ng/ml (53.4-111.6) for no NAFLD (P<0.01). Single-factor analysis demonstrated a significant correlation between serum TSK and the severity of both fatty liver and fibrosis, irrespective of T2DM status. In multiple regression analysis, liver stiffness (LS) and estimated glomerular filtration rate (eGFR) were significant influencing factors for TSK levels, and this relationship was independent of diabetes and serum adiponectin levels. Among 405 patients with NAFLD, 49 experienced progressive fibrosis or cirrhosis. The serum TSK’s area under the receiver operating characteristic curve (AUROC) for predicting progressive fibrosis or cirrhosis was 0.70 (95% CI: 0.62-0.77), significantly higher than the Fibrosis-4 (FIB-4) index of 0.64 (95% CI: 0.55-0.72), P<0.05.
Expert Commentary (by Dr. Feng Liu)
Nonalcoholic fatty liver disease (NAFLD) is a common etiology for chronic liver disease, and its prevalence is on the rise globally. In NAFLD, changes in hepatokine secretion can affect metabolic aspects of the disease, as well as cardiovascular metabolism. Tsukushi (TSK) has recently been identified as a hepatokine. However, there is currently a lack of research data on TSK in patients with NAFLD.
This study from Hong Kong assessed the relationship between serum TSK levels and the severity of NAFLD. The results indicate a significant elevation of circulating TSK in patients with NAFLD, and serum TSK levels are correlated with the severity of liver fat deposition and fibrosis, independent of type 2 diabetes.
Nevertheless, the study has several limitations. Firstly, it is a cross-sectional study, and therefore, it cannot determine whether TSK is involved in the pathogenesis of NAFLD and drives disease progression, necessitating further validation through prospective cohorts. Secondly, despite insulin resistance being a major driving factor for NAFLD, the study did not evaluate the relationship between insulin resistance and TSK. Additionally, the study included a limited number of subjects with advanced fibrosis, requiring a larger sample size to determine TSK’s potential as a biomarker for advanced liver fibrosis. Finally, the severity of liver fat deposition and fibrosis was based on transient elastography rather than the gold standard of liver biopsy.
Dr. Lu Wang
Associate Chief Physician, Department of Gastroenterology, the Second Affiliated Hospital of Xi’an Jiaotong University Medical Doctor, Ph.D., Youth Committee Member of the Hepatology Branch of the Chinese Medical Association, Member and Secretary of the Autoimmune Liver Disease Group of the Hepatology Branch of the Chinese Medical Association, Deputy Secretary-General of the Liver Disease Special Committee of the Shaanxi Medical Doctor Association, and Standing Committee Member. Published over 30 papers in domestic and international academic journals, with more than 10 as the first or corresponding author of SCI papers, and over 10 in domestic core journals. Principal Investigator for 4 national and provincial-level research projects, including the National Natural Science Foundation of China and the National Postdoctoral Program for Innovative Talents. Holder of 1 national invention patent and co-author of 1 English monograph.
05
Non-alcoholic fatty liver disease is associated with brain function disruption in type 2 diabetes patients without cognitive impairment
Li X, Zhang W, Bi Y, et al. Diabetes, Obesity & Metabolism, 2023: Nov 14.
This study aimed to investigate the static and dynamic functional connections within and between brain networks in type 2 diabetes (T2D) patients with non-alcoholic fatty liver disease (NAFLD) and those without NAFLD (T2noNAFLD). The research also explored the relationship between network connections and metabolism. The study recruited 56 T2NAFLD patients, 78 T2noNAFLD patients, and 55 healthy controls (HC). All participants had normal cognitive function and underwent functional magnetic resonance imaging (fMRI) scans, clinical index measurements, and global cognitive assessments. Independent component analysis was used to identify spectral parameters, static functional network connections, and time attributes of dynamic functional network connections.
The results show that: 1) T2NAFLD patients had more severe disturbances in glucose and lipid metabolism, increased insulin resistance, and higher obesity compared to T2noNAFLD patients. 2) T2D patients, even without clinically detectable cognitive impairment, exhibited brain function impairment associated with changes in network topology within/between networks. 3) The degree of decline in cognitive execution and visual network spectral parameters was more significant in T2NAFLD patients than in T2noNAFLD patients. 4)Changes in brain function in T2D patients were correlated with postprandial blood glucose, high-density lipoprotein cholesterol, and waist-hip ratio.
Commentary (by Dr. Lu Wang)
Type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD) are common metabolic disorders with overlapping pathophysiological mechanisms. Previous research has shown that NAFLD can exacerbate organ damage associated with T2D, including cardiovascular and renal damage. However, whether NAFLD worsens brain damage in T2D patients remains unclear.
This study, led by Dr. Bing Zhang ‘s team at Nanjing Drum Tower Hospital affiliated with Nanjing University, stratified T2D patients into T2NAFLD and T2noNAFLD groups and included healthy controls. Utilizing functional MRI for early assessment of brain damage and overall cognitive evaluation, the study analyzed the static and dynamic activity of neural network connections within and between groups. The findings include a higher prevalence of disturbances in glucose and lipid metabolism, increased insulin resistance, and greater obesity in T2NAFLD patients compared to T2noNAFLD patients. Additionally, T2D patients, even without clinically measurable cognitive impairment, exhibited brain function disruption.
The study provides new insights into the neuroimaging presentation of T2D patients with concurrent NAFLD, emphasizing the importance of screening and managing liver disease in these individuals. Controlling blood glucose levels, lipid levels, and abdominal obesity may reduce the risk of brain damage in such patients.
However, the study has limitations. T2NAFLD patients lacked histopathological data, making it challenging to determine the severity of liver damage. The cross-sectional design limits the ability to establish causal relationships between brain function and metabolism, emphasizing the need for longitudinal follow-up studies. Dietary and exercise patterns may impact blood glucose and lipid levels, but the study couldn’t quantify their effects. Lastly, the Montreal Cognitive Assessment Scale aims to exclude clinical cognitive impairment but may lack sensitivity to detect subtle cognitive dysfunction.
06
Liver disease mortality and hospitalisations among people with type 2 diabetes mellitus: A population-based study
Tomic D, Salim A, George J, et al. Liver International, 2023: Nov 27.
This study aimed to explore the burden and trends of liver disease-related mortality and hospitalizations among people with type 2 diabetes (T2D) in Australia. The results showed that the proportion of deaths due to liver disease among people with diabetes increased nearly three-fold among all deaths. The incidence of diabetes is increasing, therefore, attention should be paid to the screening and management of liver diseases in diabetic patients.
The study linked data from the National Diabetes Services Scheme for T2D patients with the National Death Index from 2002 to 2019. It determined trends in liver disease-related mortality rates during this period. Additionally, it identified the main reasons and risk factors for liver disease-related hospitalizations among T2D patients and compared the hospitalization burden with the general population using excess hospitalization rates per 100,000 person-years. The results showed liver disease accounted for 1.5-1.9% of total deaths in the Australian population with type 2 diabetes (n=1,122,431) from 2002 to 2019.Deaths due to liver disease constituted approximately one-third of the proportion of deaths related to kidney disease. The proportion of deaths from inflammatory liver disease in T2D patients increased over threefold from 0.08% in 2002 to 0.27% in 2019.Although alcohol-related liver disease had the highest proportion (22.7%) of hospitalizations among T2D patients, the number of these patients gradually decreased over time.T2D patients had a higher risk of hospitalization for fibrosis and cirrhosis compared to the general population, with relative risks of 3.63 (95% CI: 3.44–3.84) for males and 4.49 (95% CI: 4.21–4.78) for females.
Commentary (by Dr. Lu Wang)
The significant relationship between diabetes and liver disease is gaining attention. However, current efforts in preventing and managing diabetes complications mainly focus on cardiovascular and renal diseases, with limited understanding of the burden of liver disease in diabetic patients. This Australian study, utilizing data from the National Diabetes Services Scheme, the National Death Index, and the Australian Bureau of Statistics, analyzed liver disease mortality and hospitalization rates among people with type 2 diabetes.
Key findings include a liver disease mortality rate of 1.5–1.9%, accounting for approximately one-third of kidney disease-related deaths. Deaths due to inflammatory liver disease in T2D patients increased more than threefold over the study period. While alcohol-related liver disease had the highest proportion of hospitalizations among T2D patients, their numbers decreased gradually. The study underscores the importance of recognizing and addressing the burden of liver disease in patients with diabetes, emphasizing the need for effective management of alcohol consumption in T2D patients. The study’s main strength lies in its use of a population-based dataset, providing comprehensive insights into the landscape and burden of diabetes-related liver disease in Australia. This research serves as a valuable reference for understanding and addressing liver complications in diabetes.
*Editors: Jie Li, Xiaolong Qi
*Executive Editors: Yue Yang, Fajuan Rui, Xiaorong Ji
