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Treatment of patients with type 2 diabetes and non-alcoholic fatty liver disease: current approaches and future directions.
Diabetologia. 2016 06; 59(6):1112-20.D

Abstract

Non-alcoholic fatty liver disease (NAFLD) is reaching epidemic proportions in patients with type 2 diabetes. Patients with NAFLD are at increased risk of more aggressive liver disease (non-alcoholic steatohepatitis [NASH]) and at a higher risk of death from cirrhosis, hepatocellular carcinoma and cardiovascular disease. Dysfunctional adipose tissue and insulin resistance play an important role in the pathogenesis of NASH, creating the conditions for hepatocyte lipotoxicity. Mitochondrial defects are at the core of the paradigm linking chronic excess substrate supply, insulin resistance and NASH. Recent work indicates that patients with NASH have more severe insulin resistance and lipotoxicity compared with matched obese controls with only isolated steatosis. This review focuses on available agents and future drugs under development for the treatment of NAFLD/NASH in type 2 diabetes. Reversal of lipotoxicity with pioglitazone is associated with significant histological improvement, which occurs within 6 months and persists with continued treatment (or for at least 3 years) in patients with prediabetes or type 2 diabetes, holding potential to modify the natural history of the disease. These results also suggest that pioglitazone may become the standard of care for this population. Benefit has also been reported in non-diabetic patients. Recent promising results with glucagon-like peptide 1 receptor agonists have opened another new treatment avenue for NASH. Many agents in Phase 2-3 of development are being tested, aiming to restore glucose/lipid metabolism, ameliorate adipose tissue and liver inflammation, or to inhibit liver fibrosis. By targeting a diversity of relevant pathways, combination therapy in NASH will likely provide greater success in the future. In summary, increased clinical awareness and improved screening strategies (as currently done for diabetic retinopathy and nephropathy) are needed, to translate recent treatment progress into early treatment and improved quality of life for patients with type 2 diabetes and NASH. This review summarises a presentation given at the symposium 'The liver in focus' at the 2015 annual meeting of the EASD. It is accompanied by two other reviews on topics from this symposium (by John Jones, DOI: 10.1007/s00125-016-3940-5 , and by Hannele Yki-Järvinen, DOI: 10.1007/s00125-016-3944-1) and a commentary by the Session Chair, Michael Roden (DOI: 10.1007/s00125-016-3911-x).

Authors+Show Affiliations

Division of Endocrinology, Diabetes and Metabolism, University of Florida, 1600 SW Archer Road, Room H-2, Gainesville, FL, 32610, USA. Kenneth.Cusi@medicine.ufl.edu. Malcom Randall Veterans Administration Medical Center, Gainesville, FL, USA. Kenneth.Cusi@medicine.ufl.edu.

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

27101131

Citation

Cusi, Kenneth. "Treatment of Patients With Type 2 Diabetes and Non-alcoholic Fatty Liver Disease: Current Approaches and Future Directions." Diabetologia, vol. 59, no. 6, 2016, pp. 1112-20.
Cusi K. Treatment of patients with type 2 diabetes and non-alcoholic fatty liver disease: current approaches and future directions. Diabetologia. 2016;59(6):1112-20.
Cusi, K. (2016). Treatment of patients with type 2 diabetes and non-alcoholic fatty liver disease: current approaches and future directions. Diabetologia, 59(6), 1112-20. https://doi.org/10.1007/s00125-016-3952-1
Cusi K. Treatment of Patients With Type 2 Diabetes and Non-alcoholic Fatty Liver Disease: Current Approaches and Future Directions. Diabetologia. 2016;59(6):1112-20. PubMed PMID: 27101131.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Treatment of patients with type 2 diabetes and non-alcoholic fatty liver disease: current approaches and future directions. A1 - Cusi,Kenneth, Y1 - 2016/04/21/ PY - 2016/02/09/received PY - 2016/02/19/accepted PY - 2016/4/22/entrez PY - 2016/4/22/pubmed PY - 2017/8/29/medline KW - Fatty liver KW - Insulin resistance KW - NAFLD KW - NASH KW - Non-alcoholic steatohepatitis KW - Pioglitazone KW - Prediabetes KW - Treatment KW - Type 2 diabetes SP - 1112 EP - 20 JF - Diabetologia JO - Diabetologia VL - 59 IS - 6 N2 - Non-alcoholic fatty liver disease (NAFLD) is reaching epidemic proportions in patients with type 2 diabetes. Patients with NAFLD are at increased risk of more aggressive liver disease (non-alcoholic steatohepatitis [NASH]) and at a higher risk of death from cirrhosis, hepatocellular carcinoma and cardiovascular disease. Dysfunctional adipose tissue and insulin resistance play an important role in the pathogenesis of NASH, creating the conditions for hepatocyte lipotoxicity. Mitochondrial defects are at the core of the paradigm linking chronic excess substrate supply, insulin resistance and NASH. Recent work indicates that patients with NASH have more severe insulin resistance and lipotoxicity compared with matched obese controls with only isolated steatosis. This review focuses on available agents and future drugs under development for the treatment of NAFLD/NASH in type 2 diabetes. Reversal of lipotoxicity with pioglitazone is associated with significant histological improvement, which occurs within 6 months and persists with continued treatment (or for at least 3 years) in patients with prediabetes or type 2 diabetes, holding potential to modify the natural history of the disease. These results also suggest that pioglitazone may become the standard of care for this population. Benefit has also been reported in non-diabetic patients. Recent promising results with glucagon-like peptide 1 receptor agonists have opened another new treatment avenue for NASH. Many agents in Phase 2-3 of development are being tested, aiming to restore glucose/lipid metabolism, ameliorate adipose tissue and liver inflammation, or to inhibit liver fibrosis. By targeting a diversity of relevant pathways, combination therapy in NASH will likely provide greater success in the future. In summary, increased clinical awareness and improved screening strategies (as currently done for diabetic retinopathy and nephropathy) are needed, to translate recent treatment progress into early treatment and improved quality of life for patients with type 2 diabetes and NASH. This review summarises a presentation given at the symposium 'The liver in focus' at the 2015 annual meeting of the EASD. It is accompanied by two other reviews on topics from this symposium (by John Jones, DOI: 10.1007/s00125-016-3940-5 , and by Hannele Yki-Järvinen, DOI: 10.1007/s00125-016-3944-1) and a commentary by the Session Chair, Michael Roden (DOI: 10.1007/s00125-016-3911-x). SN - 1432-0428 UR - https://www.unboundmedicine.com/medline/citation/27101131/Treatment_of_patients_with_type_2_diabetes_and_non_alcoholic_fatty_liver_disease:_current_approaches_and_future_directions_ L2 - https://doi.org/10.1007/s00125-016-3952-1 DB - PRIME DP - Unbound Medicine ER -