Meta-Analysis

. 2023 Sep;8(9):829-836.

doi: 10.1016/S2468-1253(23)00157-7. Epub 2023 Jul 4.

Type 2 diabetes, hepatic decompensation, and hepatocellular carcinoma in patients with non-alcoholic fatty liver disease: an individual participant-level data meta-analysis

Daniel Q Huang¹, Nabil Noureddin², Veeral Ajmera², Maral Amangurbanova², Ricki Bettencourt², Emily Truong³, Tolga Gidener⁴, Harris Siddiqi², Abdul M Majzoub⁵, Tarek Nayfeh⁶, Nobuharu Tamaki⁷, Namiki Izumi⁸, Masato Yoneda⁹, Atsushi Nakajima⁹, Ramazan Idilman¹⁰, Mesut Gumussoy¹⁰, Digdem Kuru Oz¹¹, Ayse Erden¹¹, Alina M Allen⁴, Mazen Noureddin¹², Rohit Loomba¹³

Affiliations

¹ NAFLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California San Diego, La Jolla, CA, USA; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore.
² NAFLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California San Diego, La Jolla, CA, USA.
³ Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
⁴ Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
⁵ Evidence-Based Practice Center, Mayo Clinic, Rochester, MN, USA; Division of Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, MO, USA.
⁶ Evidence-Based Practice Center, Mayo Clinic, Rochester, MN, USA.
⁷ NAFLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California San Diego, La Jolla, CA, USA; Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan.
⁸ Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan.
⁹ Department of Gastroenterology and Hepatology, Yokohama City University, Yokohama, Japan.
¹⁰ Department of Gastroenterology, School of Medicine, Ankara University, Ankara, Turkey.
¹¹ Department of Radiology, School of Medicine, Ankara University, Ankara, Turkey.
¹² Houston Methodist Transplant Center, Houston, TX, USA; Houston Liver Institute, Houston, TX, USA.
¹³ NAFLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California San Diego, La Jolla, CA, USA. Electronic address: roloomba@ucsd.edu.

PMID: 37419133
PMCID: PMC10812844
DOI: 10.1016/S2468-1253(23)00157-7

Meta-Analysis

Type 2 diabetes, hepatic decompensation, and hepatocellular carcinoma in patients with non-alcoholic fatty liver disease: an individual participant-level data meta-analysis

Daniel Q Huang et al. Lancet Gastroenterol Hepatol. 2023 Sep.

. 2023 Sep;8(9):829-836.

doi: 10.1016/S2468-1253(23)00157-7. Epub 2023 Jul 4.

Authors

Affiliations

¹ NAFLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California San Diego, La Jolla, CA, USA; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore.
² NAFLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California San Diego, La Jolla, CA, USA.
³ Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
⁴ Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
⁵ Evidence-Based Practice Center, Mayo Clinic, Rochester, MN, USA; Division of Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, MO, USA.
⁶ Evidence-Based Practice Center, Mayo Clinic, Rochester, MN, USA.
⁷ NAFLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California San Diego, La Jolla, CA, USA; Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan.
⁸ Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan.
⁹ Department of Gastroenterology and Hepatology, Yokohama City University, Yokohama, Japan.
¹⁰ Department of Gastroenterology, School of Medicine, Ankara University, Ankara, Turkey.
¹¹ Department of Radiology, School of Medicine, Ankara University, Ankara, Turkey.
¹² Houston Methodist Transplant Center, Houston, TX, USA; Houston Liver Institute, Houston, TX, USA.
¹³ NAFLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California San Diego, La Jolla, CA, USA. Electronic address: roloomba@ucsd.edu.

PMID: 37419133
PMCID: PMC10812844
DOI: 10.1016/S2468-1253(23)00157-7

Erratum in

Correction to Lancet Gastroenterol Hepatol 2023; published online July 4. https://doi.org/10.1016/S2468-1253(23)00157-7.
[No authors listed] [No authors listed] Lancet Gastroenterol Hepatol. 2023 Sep;8(9):e7. doi: 10.1016/S2468-1253(23)00234-0. Epub 2023 Jul 18. Lancet Gastroenterol Hepatol. 2023. PMID: 37475118 No abstract available.

Abstract

Background: Data are scarce regarding the development of hepatic decompensation in patients with non-alcoholic fatty liver disease (NAFLD) with and without type 2 diabetes. We aimed to assess the risk of hepatic decompensation in people with NAFLD with and without type 2 diabetes.

Methods: We did a meta-analysis of individual participant-level data from six cohorts in the USA, Japan, and Turkey. Included participants had magnetic resonance elastography between Feb 27, 2007, and June 4, 2021. Eligible studies included those with liver fibrosis characterisation by magnetic resonance elastography, longitudinal assessment for hepatic decompensation and death, and included adult patients (aged ≥18 years) with NAFLD, for whom data were available regarding the presence of type 2 diabetes at baseline. The primary outcome was hepatic decompensation, defined as ascites, hepatic encephalopathy, or variceal bleeding. The secondary outcome was the development of hepatocellular carcinoma. We used competing risk regression using the Fine and Gray subdistribution hazard ratio (sHR) to compare the likelihood of hepatic decompensation in participants with and without type 2 diabetes. Death without hepatic decompensation was a competing event.

Findings: Data for 2016 participants (736 with type 2 diabetes; 1280 without type 2 diabetes) from six cohorts were included in this analysis. 1074 (53%) of 2016 participants were female with a mean age of 57·8 years (SD 14·2) years and BMI of 31·3 kg/m² (SD 7·4). Among 1737 participants (602 with type 2 diabetes and 1135 without type 2 diabetes) with available longitudinal data, 105 participants developed hepatic decompensation over a median follow-up time of 2·8 years (IQR 1·4-5·5). Participants with type 2 diabetes had a significantly higher risk of hepatic decompensation at 1 year (3·37% [95% CI 2·10-5·11] vs 1·07% [0·57-1·86]), 3 years (7·49% [5·36-10·08] vs 2·92% [1·92-4·25]), and 5 years (13·85% [10·43-17·75] vs 3·95% [2·67-5·60]) than participants without type 2 diabetes (p<0·0001). After adjustment for multiple confounders (age, BMI, and race), type 2 diabetes (sHR 2·15 [95% CI 1·39-3·34]; p=0·0006) and glycated haemoglobin (1·31 [95% CI 1·10-1·55]; p=0·0019) were independent predictors of hepatic decompensation. The association between type 2 diabetes and hepatic decompensation remained consistent after adjustment for baseline liver stiffness determined by magnetic resonance elastography. Over a median follow-up of 2·9 years (IQR 1·4-5·7), 22 of 1802 participants analysed (18 of 639 with type 2 diabetes and four of 1163 without type 2 diabetes) developed incident hepatocellular carcinoma. The risk of incident hepatocellular carcinoma was higher in those with type 2 diabetes at 1 year (1·34% [95% CI 0·64-2·54] vs 0·09% [0·01-0·50], 3 years (2·44% [1·36-4·05] vs 0·21% [0·04-0·73]), and 5 years (3·68% [2·18-5·77] vs 0·44% [0·11-1·33]) than in those without type 2 diabetes (p<0·0001). Type 2 diabetes was an independent predictor of hepatocellular carcinoma development (sHR 5·34 [1·67-17·09]; p=0·0048).

Interpretation: Among people with NAFLD, the presence of type 2 diabetes is associated with a significantly higher risk of hepatic decompensation and hepatocellular carcinoma.

Funding: National Institute of Diabetes and Digestive and Kidney Diseases.

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Conflict of interest statement

Declaration of interests RL serves as a consultant to Aardvark Therapeutics, Altimmune, Anylam/Regeneron, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Bristol-Myer Squibb, CohBar, Eli Lilly, Galmed, Gilead, Glympse bio, Hightide, Inipharma, Intercept, Inventiva, Ionis, Janssen, Madrigal, Metacrine, NGM Biopharmaceuticals, Novartis, Novo Nordisk, Merck, Pfizer, Sagimet, Theratechnologies, 89bio, Terns Pharmaceuticals, and Viking Therapeutics; and received research grants (via his institution) from Arrowhead Pharmaceuticals, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, Galectin Therapeutics, Galmed Pharmaceuticals, Gilead, Intercept, Hanmi, Intercept, Inventiva, Ionis, Janssen, Madrigal Pharmaceuticals, Merck, NGM Biopharmaceuticals, Novo Nordisk, Merck, Pfizer, Sonic Incytes, and Terns Pharmaceuticals; is a cofounder of LipoNexus; and has stock options in 89bio and Sagimet Biosciences. DQH has served as a consultant for Gilead Sciences and Eisai. AMA received grants from Novo Nordisk, Pfizer, and Target Pharma; payments were made to her institution. MN received grants from Allergan, Akero, Bristol-Myer Squibb, Gilead, Galectin, Genfit, GlaxoSmithKline, Conatus, Corcept, Enanta, Madrigal, Novartis, Novo Nordisk, Shire, Takeda, Terns, Viking, and Zydus. MN serves as a consultant to Altimmune, Boehringer-Ingelheim, Cytodyn, 89bio, EchoSens, GlaxoSmithKline, Madrigal, Merck, Novo Nordisk, Prespecturm, Roche diagnostic and Siemens, Terns, and Takeda; received speaker fees from Novo Nordisk, EchoSens; served as an advisory board or data safety monitoring board for Altimmune, Boehringer-Ingelheim, Cytodyn, 89bio, EchoSens, GlaxoSmithKline, Madrigal, Merck, Novo Nordisk, Prespecturm, Roche diagnostic and Siemens Altimmune, Boehringer-Ingelheim, Cytodyn, 89bio, EchoSens, GlaxoSmithKline, Madrigal, Merck, Novo Nordisk, Prespecturm, Roche diagnostic and Siemens, Terns and Takeda; and owns stock/stock options in Rivus Pharma, CIMA, and ChronWell. All other authors declare no competing interests.

Figures

Figure 1:. Risk of hepatic decompensation (A) and hepatocellular carcinoma (B) in participants with non-alcoholic fatty liver disease, with death as a competing risk, stratified by type 2 diabetes status
Hepatic decompensation was defined as ascites, hepatic encephalopathy, or variceal bleeding. Cumulative cases of decompensation, deaths, and hepatocellular carcinoma are shown until year 7 of follow-up. Graphs are truncated as the number of participants at risk was low after 7 years.

**Figure 2:. sHR for hepatic decompensation (A) and hepatocellular carcinoma (B)**
sHR=subdistribution=hazard ratio. MRE=magnetic resonance elastography.

See this image and copyright information in PMC

Comment in

NAFLD and liver-related events: does type 2 diabetes have a key role?
Vilar-Gomez E. Vilar-Gomez E. Lancet Gastroenterol Hepatol. 2023 Sep;8(9):777-778. doi: 10.1016/S2468-1253(23)00187-5. Epub 2023 Jul 4. Lancet Gastroenterol Hepatol. 2023. PMID: 37419134 No abstract available.

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Type 2 diabetes, hepatic decompensation, and hepatocellular carcinoma in patients with non-alcoholic fatty liver disease: an individual participant-level data meta-analysis

Affiliations

Type 2 diabetes, hepatic decompensation, and hepatocellular carcinoma in patients with non-alcoholic fatty liver disease: an individual participant-level data meta-analysis

Authors

Affiliations

Erratum in

Abstract

Conflict of interest statement

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Comment in

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