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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
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.ORCID iD: 0000-0002-2639-9481
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
Univ Gothenburg, Dept Mol & Clin Med, Gothenburg, Sweden..
Antaros Med AB, Gothenburg, Sweden..
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2018 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 61, no 9, p. 1923-1934Article in journal (Refereed) Published
Abstract [en]

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 OM3-CA (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 Participants had a mean age of 65.5 years (SD 5.9), BMI 31.2 kg/m(2) (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 PNPLA31148M 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, gamma-glutamyl transfcrase (gamma-GT), cytokeratin (CK) 18-M30 and CK 18-M65 and plasma fibroblast growth factor 21 (FGF21). Changes in gamma-GT correlated with changes in liver PDFF (rho = 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.

Place, publisher, year, edition, pages
Springer, 2018. Vol. 61, no 9, p. 1923-1934
Keywords [en]
Dapagliflozin, Docosahexaenoic acid, Eicosapentaenoic acid, Liver steatosis, Non-alcoholic fatty liver disease, Omega-3 fatty acids, Proton density fat fraction, Type 2 diabetes
National Category
Endocrinology and Diabetes
Identifiers
URN: urn:nbn:se:uu:diva-364901DOI: 10.1007/s00125-018-4675-2ISI: 000440408500005PubMedID: 29971527OAI: oai:DiVA.org:uu-364901DiVA, id: diva2:1262619
Funder
AstraZenecaAvailable from: 2018-11-12 Created: 2018-11-12 Last updated: 2019-01-28Bibliographically approved
In thesis
1. Metabolic and endocrine effects of SGLT2 inhibition
Open this publication in new window or tab >>Metabolic and endocrine effects of SGLT2 inhibition
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Obesity and type 2 diabetes (T2D) are two growing global health problems with similar comorbidity profiles. SGLT2 inhibitors (SGLT2i) improve blood glucose control and can relieve both T2D and obesity, as well as their associated health problems such as hypertension, kidney failure, and cardiovascular disease.

In paper I, 50 obese patients without diabetes were treated for 24 weeks with SGLT2i dapagliflozin + GLP-1 receptor agonist (GLP-1RA) exenatide or placebo. They were examined regarding body weight loss and body composition. The placebo-adjusted weight loss was 4.13 kg, mostly attributable to adipose tissue loss.

In paper II, 43 completers of the study in paper I entered a 28-week extension phase in which all participants received active treatment. We found major reductions in body weight, adipose tissue volume, blood pressure and prediabetes that were sustained at 52 weeks. 

In paper III, 84 patients with T2D and non-alcoholic fatty liver disease underwent a 12-week treatment with dapagliflozin, omega-3 (n-3) carboxylic acids (OM-3CA), the combination of both or placebo to assess effects on liver fat content. MRI showed significant reductions of liver fat versus baseline and, for the combination, versus placebo.

In paper IV: 15 metformin-treated patients with T2D were assessed for changes in plasma glucagon levels following a single dose of dapagliflozin during experiments with stable versus falling plasma glucose. Changes in glucagon levels could largely be explained by changes in glucose levels.

In conclusion, SGLT2 inhibition can lower body weight and cardiovascular risk factors in obese patients without diabetes when combined with GLP-1RA, and it can reduce liver fat in T2D patients, in particular when given together with OM-3CA. SGLT2i effects on glucagon secretion can largely be explained by lower glucose levels rather than direct α-cell effects.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2019. p. 66
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1534
Keywords
SGLT2 inhibition, GLP-1 receptor agonism, DPP4 inhibition, NAFLD, prediabetes, type 2 diabetes, obesity, metabolic syndrome, glucagon.
National Category
Medical and Health Sciences
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-373522 (URN)978-91-513-0561-5 (ISBN)
Public defence
2019-03-08, Enghoff lecture-hall, Entrance 50, Uppsala academic hospital, Uppsala, 13:15 (English)
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Supervisors
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AstraZeneca
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Available from: 2019-02-13 Created: 2019-01-20 Last updated: 2019-02-18

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Eriksson, Jan W.Lundkvist, PerRisérus, UlfLind, Lars

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