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Effects of dapagliflozin and n-3 carboxylic acids on non-alcoholic fatty liver disease in people with type 2 diabetes: a double-blind randomised placebo-controlled study
Open accessAbstract
AIMS/HYPOTHESIS: The EFFECT-II study aimed to investigate the effects of dapagliflozin and omega-3 (n-3) carboxylic acids (OM-3CA), individually or combined, on liver fat content in individuals with type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). METHODS: This randomised placebo-controlled double-blind parallel-group study was performed at five clinical research centres at university hospitals in Sweden. 84 participants with type 2 diabetes and NAFLD were randomly assigned 1:1:1:1 to four treatments by a centralised randomisation system, and all participants as well as investigators and staff involved in the study conduct and analyses were blinded to treatments. Each group received oral doses of one of the following: 10 mg dapagliflozin (n = 21), 4 g OM-3CA (n = 20), a combination of both (n = 22) or placebo (n = 21). The primary endpoint was liver fat content assessed by MRI (proton density fat fraction [PDFF]) and, in addition, total liver volume and markers of glucose and lipid metabolism as well as of hepatocyte injury and oxidative stress were assessed at baseline and after 12 weeks of treatment (completion of the trial). RESULTS: (3.5) and liver PDFF 18% (9.3). All active treatments significantly reduced liver PDFF from baseline, relative changes: OM-3CA, -15%; dapagliflozin, -13%; OM-3CA + dapagliflozin, -21%. Only the combination treatment reduced liver PDFF (p = 0.046) and total liver fat volume (relative change, -24%, p = 0.037) in comparison with placebo. There was an interaction between the PNPLA3 I148M polymorphism and change in liver PDFF in the active treatment groups (p = 0.03). Dapagliflozin monotherapy, but not the combination with OM-3CA, reduced the levels of hepatocyte injury biomarkers, including alanine aminotransferase, aspartate aminotransferase, γ-glutamyl transferase (γ-GT), cytokeratin (CK) 18-M30 and CK 18-M65 and plasma fibroblast growth factor 21 (FGF21). Changes in γ-GT correlated with changes in liver PDFF (ρ = 0.53, p = 0.02). Dapagliflozin alone and in combination with OM-3CA improved glucose control and reduced body weight and abdominal fat volumes. Fatty acid oxidative stress biomarkers were not affected by treatments. There were no new or unexpected adverse events compared with previous studies with these treatments. CONCLUSIONS/INTERPRETATION: Combined treatment with dapagliflozin and OM-3CA significantly reduced liver fat content. Dapagliflozin monotherapy reduced all measured hepatocyte injury biomarkers and FGF21, suggesting a disease-modifying effect in NAFLD. TRIAL REGISTRATION: ClinicalTrials.gov NCT02279407 FUNDING: The study was funded by AstraZeneca.
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“However, these weight loss effects are limited by a compensatory increase in food intake [150,151].”
From Obesity and MASLD: Is weight loss the (only) key to treat metabolic liver disease? (2024) · cites this paper as [150]
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Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes
Zinman, B., Wanner, C., Lachin, J. M., Fitchett, D., Bluhmki, E., Hantel, S., Mattheus, M., Devins, T., Johansen, O. E., Woerle, H. J., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1504720 · Cited by 12,315
Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes
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Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease
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Nonalcoholic Fatty Liver Disease
Rinella, M. E. (2015) · JAMA · doi:10.1001/jama.2015.5370 · Cited by 2,320
Neuschwander-Tetri, B. A., Loomba, R., Sanyal, A. J., Lavine, J. E., Van Natta, M. L., Abdelmalek, M. F., Chalasani, N., Dasarathy, S., Diehl, A. M., Hameed, B., et al. (2015) · The Lancet · doi:10.1016/s0140-6736(14)61933-4 · Cited by 2,237
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Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients
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Rinella, M. E., Neuschwander-Tetri, B. A., Siddiqui, M. S., Abdelmalek, M. F., Caldwell, S., Barb, D., Kleiner, D. E., & Loomba, R. (2023) · Hepatology · doi:10.1097/hep.0000000000000323 · Cited by 2,667
The complex link between NAFLD and type 2 diabetes mellitus - mechanisms and treatments
Targher, G., Corey, K. E., Byrne, C. D., & Roden, M. (2021) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-021-00448-y · Cited by 850
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NAFLD as a Continuum: From Obesity to Metabolic Syndrome and Diabetes
Godoy-Matos, A. F., Silva Júnior, W. S., & Valerio, C. M. (2020) · Diabetology & Metabolic Syndrome · doi:10.1186/s13098-020-00570-y · Cited by 643
Metadata
- Authors
- Eriksson, J. W., Lundkvist, P., Jansson, P.-A., Johansson, L., Kvarnström, M., Moris, L., Miliotis, T., Forsberg, G.-B., Risérus, U., Lind, L., & Oscarsson, J.
- Affiliations
- Uppsala University (SE)
- University of Gothenburg (SE)
- Antaros Medical (Sweden) (SE)
- AstraZeneca (Sweden) (SE)
- Karolinska University Hospital (SE)
- Corresponding author
- Eriksson, Jan W.
- ORCID
- Venue
- Diabetologia
- Published
- 2018-07-03
- Volume
- 61
- Issue
- 9
- Pages
- 1923-1934
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- PMC
- PMC6096619
- OpenAlex
- W2810729752
- Cited by
- 396
- References
- 41
- Citations by year
- 2026: 24 · 2025: 48 · 2024: 48 · 2023: 53 · 2022: 64 · 2021: 54 · 2020: 67 · 2019: 32 · 2018: 5
- FWCI
- 30.84
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Diabetologia (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- KTH Publication Database DiVA (KTH Royal Institute of Technology) (submittedVersion, other-oa)
- Funders
- AstraZeneca
- Topics
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- dapagliflozin, non-alcoholic fatty liver disease, type 2 diabetes, liver fat, proton density fat fraction, combination therapy, oxidative stress, fibrosis, SLC7A11, SLC17A1
- MeSH terms
- Aged, Benzhydryl Compounds, Carboxylic Acids, Diabetes Mellitus, Type 2, Double-Blind Method, Drug Therapy, Combination, Fatty Acids, Female, Glucose, Glucosides, Humans, Inflammation, Liver Function Tests, Magnetic Resonance Imaging, Male, Middle Aged, Sweden, Biomarkers, Oxidative Stress, Hepatocytes, Lipid Metabolism, Non-alcoholic Fatty Liver Disease
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