Effects of Metformin Exposure on Survival in a Large National Cohort of Patients With Diabetes and Cirrhosis

Veterans Outcomes and Cost Associated with Liver disease Study Group

doi:10.1016/j.cgh.2020.08.026

Effects of Metformin Exposure on Survival in a Large National Cohort of Patients With Diabetes and Cirrhosis

Veterans Outcomes and Cost Associated with Liver disease Study Group

Medicine - Gastro, Hepatology, Nutrition Division

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Abstract

Background & Aims: Type II diabetes mellitus worsens the prognosis of cirrhosis. Multiple medications including metformin and statins often are co-administered to manage patients with diabetes. The aim of this study was to assess the impact of metformin exposure on mortality, hepatic decompensation, and hepatocellular carcinoma in individuals with diabetes and cirrhosis, controlling for multiple concomitant exposures. Methods: We performed a retrospective cohort study of patients with cirrhosis diagnosed between January 1, 2008, through June 30, 2016, in the Veterans Health administration. Marginal structural models and propensity-matching approaches were implemented to quantify the treatment effect of metformin in patients with pre-existing diabetes with or without prior metformin exposure. Results: Among 74,984 patients with cirrhosis, diabetes mellitus was present before the diagnosis of cirrhosis in 53.8%, and was diagnosed during follow-up evaluation in 4.8%. Before the diagnosis of cirrhosis, 11,114 patients had active utilization of metformin. In these patients, metformin, statin, and angiotensinogen-converting enzyme inhibitor/angiotensin-2–receptor blocker exposure were associated independently with reduced mortality (metformin hazard ratio, 0.68; 95% CI, 0.61–0.75); metformin was not associated with reduced hepatocellular carcinoma or hepatic decompensation after adjustment for concomitant statin exposure. For patients with diabetes before a diagnosis of cirrhosis but no prior metformin exposure, metformin similarly was associated with reduced mortality (hazard ratio, 0.72; 95% CI, 0.35–0.97), but not with reduced hepatocellular carcinoma or hepatic decompensation. Conclusions: Metformin use in patients with cirrhosis and diabetes appears safe and is associated independently with reduced overall, but not liver-related, mortality, hepatocellular carcinoma, or decompensation after adjusting for concomitant statin and angiotensinogen-converting enzyme inhibitor/angiotensin-2–receptor blocker exposure.

Original language	English (US)
Pages (from-to)	2148-2160.e14
Journal	Clinical Gastroenterology and Hepatology
Volume	19
Issue number	10
DOIs	https://doi.org/10.1016/j.cgh.2020.08.026
State	Published - Oct 2021

Bibliographical note

Funding Information:
Marina Serper (analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content; statistical analysis), Binu V. John (critical revision of the manuscript for important intellectual content; statistical analysis), Tamar H. Taddei (study concept and design; acquisition of data; analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content; statistical analysis; obtained funding; technical, or material support; study supervision), Kristen M. Tessiatore (acquisition of data; outcome validation; critical revision of the manuscript for important intellectual content), Renata Lerer (acquisition of data; outcome validation; critical revision of the manuscript for important intellectual content), Rajni Mehta (acquisition of data; technical, and material support), Ayse Aytaman (study concept and design; critical revision of the manuscript for important intellectual content; obtained funding), Michelle Baytarian (study concept and design; critical revision of the manuscript for important intellectual content; obtained funding), Rena Fox (study concept and design; critical revision of the manuscript for important intellectual content; obtained funding), Kristel Hunt (study concept and design; critical revision of the manuscript for important intellectual content; obtained funding), David E. Kaplan (study concept and design; acquisition of data; analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content; statistical analysis; obtained funding; technical, or material support; study supervision)

Publisher Copyright:
© 2020

Keywords

Alcohol
Cirrhosis
Diabetes
Fatty Liver
Hepatitis
Human
Metformin
NAFLD
Nonalcoholic Steatohepatitis
Statin

PubMed: MeSH publication types

Journal Article

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cgh.2020.08.026

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title = "Effects of Metformin Exposure on Survival in a Large National Cohort of Patients With Diabetes and Cirrhosis",

abstract = "Background & Aims: Type II diabetes mellitus worsens the prognosis of cirrhosis. Multiple medications including metformin and statins often are co-administered to manage patients with diabetes. The aim of this study was to assess the impact of metformin exposure on mortality, hepatic decompensation, and hepatocellular carcinoma in individuals with diabetes and cirrhosis, controlling for multiple concomitant exposures. Methods: We performed a retrospective cohort study of patients with cirrhosis diagnosed between January 1, 2008, through June 30, 2016, in the Veterans Health administration. Marginal structural models and propensity-matching approaches were implemented to quantify the treatment effect of metformin in patients with pre-existing diabetes with or without prior metformin exposure. Results: Among 74,984 patients with cirrhosis, diabetes mellitus was present before the diagnosis of cirrhosis in 53.8%, and was diagnosed during follow-up evaluation in 4.8%. Before the diagnosis of cirrhosis, 11,114 patients had active utilization of metformin. In these patients, metformin, statin, and angiotensinogen-converting enzyme inhibitor/angiotensin-2–receptor blocker exposure were associated independently with reduced mortality (metformin hazard ratio, 0.68; 95% CI, 0.61–0.75); metformin was not associated with reduced hepatocellular carcinoma or hepatic decompensation after adjustment for concomitant statin exposure. For patients with diabetes before a diagnosis of cirrhosis but no prior metformin exposure, metformin similarly was associated with reduced mortality (hazard ratio, 0.72; 95% CI, 0.35–0.97), but not with reduced hepatocellular carcinoma or hepatic decompensation. Conclusions: Metformin use in patients with cirrhosis and diabetes appears safe and is associated independently with reduced overall, but not liver-related, mortality, hepatocellular carcinoma, or decompensation after adjusting for concomitant statin and angiotensinogen-converting enzyme inhibitor/angiotensin-2–receptor blocker exposure.",

keywords = "Alcohol, Cirrhosis, Diabetes, Fatty Liver, Hepatitis, Human, Metformin, NAFLD, Nonalcoholic Steatohepatitis, Statin",

author = "{Veterans Outcomes and Cost Associated with Liver disease Study Group} and Kaplan, {David E.} and Marina Serper and John, {Binu V.} and Tessiatore, {Kristen M.} and Renata Lerer and Rajni Mehta and Rena Fox and Ayse Aytaman and Michelle Baytarian and Kristel Hunt and Jeffrey Albrecht and Taddei, {Tamar H.}",

note = "Funding Information: Marina Serper (analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content; statistical analysis), Binu V. John (critical revision of the manuscript for important intellectual content; statistical analysis), Tamar H. Taddei (study concept and design; acquisition of data; analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content; statistical analysis; obtained funding; technical, or material support; study supervision), Kristen M. Tessiatore (acquisition of data; outcome validation; critical revision of the manuscript for important intellectual content), Renata Lerer (acquisition of data; outcome validation; critical revision of the manuscript for important intellectual content), Rajni Mehta (acquisition of data; technical, and material support), Ayse Aytaman (study concept and design; critical revision of the manuscript for important intellectual content; obtained funding), Michelle Baytarian (study concept and design; critical revision of the manuscript for important intellectual content; obtained funding), Rena Fox (study concept and design; critical revision of the manuscript for important intellectual content; obtained funding), Kristel Hunt (study concept and design; critical revision of the manuscript for important intellectual content; obtained funding), David E. Kaplan (study concept and design; acquisition of data; analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content; statistical analysis; obtained funding; technical, or material support; study supervision) Publisher Copyright: {\textcopyright} 2020",

year = "2021",

month = oct,

doi = "10.1016/j.cgh.2020.08.026",

language = "English (US)",

volume = "19",

pages = "2148--2160.e14",

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T1 - Effects of Metformin Exposure on Survival in a Large National Cohort of Patients With Diabetes and Cirrhosis

AU - Veterans Outcomes and Cost Associated with Liver disease Study Group

AU - Kaplan, David E.

AU - Serper, Marina

AU - John, Binu V.

AU - Tessiatore, Kristen M.

AU - Lerer, Renata

AU - Mehta, Rajni

AU - Fox, Rena

AU - Aytaman, Ayse

AU - Baytarian, Michelle

AU - Hunt, Kristel

AU - Albrecht, Jeffrey

AU - Taddei, Tamar H.

N1 - Funding Information: Marina Serper (analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content; statistical analysis), Binu V. John (critical revision of the manuscript for important intellectual content; statistical analysis), Tamar H. Taddei (study concept and design; acquisition of data; analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content; statistical analysis; obtained funding; technical, or material support; study supervision), Kristen M. Tessiatore (acquisition of data; outcome validation; critical revision of the manuscript for important intellectual content), Renata Lerer (acquisition of data; outcome validation; critical revision of the manuscript for important intellectual content), Rajni Mehta (acquisition of data; technical, and material support), Ayse Aytaman (study concept and design; critical revision of the manuscript for important intellectual content; obtained funding), Michelle Baytarian (study concept and design; critical revision of the manuscript for important intellectual content; obtained funding), Rena Fox (study concept and design; critical revision of the manuscript for important intellectual content; obtained funding), Kristel Hunt (study concept and design; critical revision of the manuscript for important intellectual content; obtained funding), David E. Kaplan (study concept and design; acquisition of data; analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content; statistical analysis; obtained funding; technical, or material support; study supervision) Publisher Copyright: © 2020

PY - 2021/10

Y1 - 2021/10

N2 - Background & Aims: Type II diabetes mellitus worsens the prognosis of cirrhosis. Multiple medications including metformin and statins often are co-administered to manage patients with diabetes. The aim of this study was to assess the impact of metformin exposure on mortality, hepatic decompensation, and hepatocellular carcinoma in individuals with diabetes and cirrhosis, controlling for multiple concomitant exposures. Methods: We performed a retrospective cohort study of patients with cirrhosis diagnosed between January 1, 2008, through June 30, 2016, in the Veterans Health administration. Marginal structural models and propensity-matching approaches were implemented to quantify the treatment effect of metformin in patients with pre-existing diabetes with or without prior metformin exposure. Results: Among 74,984 patients with cirrhosis, diabetes mellitus was present before the diagnosis of cirrhosis in 53.8%, and was diagnosed during follow-up evaluation in 4.8%. Before the diagnosis of cirrhosis, 11,114 patients had active utilization of metformin. In these patients, metformin, statin, and angiotensinogen-converting enzyme inhibitor/angiotensin-2–receptor blocker exposure were associated independently with reduced mortality (metformin hazard ratio, 0.68; 95% CI, 0.61–0.75); metformin was not associated with reduced hepatocellular carcinoma or hepatic decompensation after adjustment for concomitant statin exposure. For patients with diabetes before a diagnosis of cirrhosis but no prior metformin exposure, metformin similarly was associated with reduced mortality (hazard ratio, 0.72; 95% CI, 0.35–0.97), but not with reduced hepatocellular carcinoma or hepatic decompensation. Conclusions: Metformin use in patients with cirrhosis and diabetes appears safe and is associated independently with reduced overall, but not liver-related, mortality, hepatocellular carcinoma, or decompensation after adjusting for concomitant statin and angiotensinogen-converting enzyme inhibitor/angiotensin-2–receptor blocker exposure.

AB - Background & Aims: Type II diabetes mellitus worsens the prognosis of cirrhosis. Multiple medications including metformin and statins often are co-administered to manage patients with diabetes. The aim of this study was to assess the impact of metformin exposure on mortality, hepatic decompensation, and hepatocellular carcinoma in individuals with diabetes and cirrhosis, controlling for multiple concomitant exposures. Methods: We performed a retrospective cohort study of patients with cirrhosis diagnosed between January 1, 2008, through June 30, 2016, in the Veterans Health administration. Marginal structural models and propensity-matching approaches were implemented to quantify the treatment effect of metformin in patients with pre-existing diabetes with or without prior metformin exposure. Results: Among 74,984 patients with cirrhosis, diabetes mellitus was present before the diagnosis of cirrhosis in 53.8%, and was diagnosed during follow-up evaluation in 4.8%. Before the diagnosis of cirrhosis, 11,114 patients had active utilization of metformin. In these patients, metformin, statin, and angiotensinogen-converting enzyme inhibitor/angiotensin-2–receptor blocker exposure were associated independently with reduced mortality (metformin hazard ratio, 0.68; 95% CI, 0.61–0.75); metformin was not associated with reduced hepatocellular carcinoma or hepatic decompensation after adjustment for concomitant statin exposure. For patients with diabetes before a diagnosis of cirrhosis but no prior metformin exposure, metformin similarly was associated with reduced mortality (hazard ratio, 0.72; 95% CI, 0.35–0.97), but not with reduced hepatocellular carcinoma or hepatic decompensation. Conclusions: Metformin use in patients with cirrhosis and diabetes appears safe and is associated independently with reduced overall, but not liver-related, mortality, hepatocellular carcinoma, or decompensation after adjusting for concomitant statin and angiotensinogen-converting enzyme inhibitor/angiotensin-2–receptor blocker exposure.

KW - Alcohol

KW - Cirrhosis

KW - Diabetes

KW - Fatty Liver

KW - Hepatitis

KW - Human

KW - Metformin

KW - NAFLD

KW - Nonalcoholic Steatohepatitis

KW - Statin

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JO - Clinical Gastroenterology and Hepatology

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IS - 10

ER -

Effects of Metformin Exposure on Survival in a Large National Cohort of Patients With Diabetes and Cirrhosis

Abstract

Bibliographical note

Keywords

PubMed: MeSH publication types

UN SDGs

Access

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