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

Jan W Eriksson, Per Lundkvist, Per-Anders Jansson, Lars Johansson, Mats Kvarnström, Linda Moris, Tasso Miliotis, Gun-Britt Forsberg, Ulf Risérus, Lars Lind, Jan Oscarsson, Jan W Eriksson, Per Lundkvist, Per-Anders Jansson, Lars Johansson, Mats Kvarnström, Linda Moris, Tasso Miliotis, Gun-Britt Forsberg, Ulf Risérus, Lars Lind, Jan Oscarsson

Abstract

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: Participants had a mean age of 65.5 years (SD 5.9), BMI 31.2 kg/m2 (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.

Keywords: Dapagliflozin; Docosahexaenoic acid; Eicosapentaenoic acid; Liver steatosis; Non-alcoholic fatty liver disease; Omega-3 fatty acids; Proton density fat fraction; Type 2 diabetes.

Conflict of interest statement

LJ is employed by Antaros Medical. MK, TM, G-BF and JO are employed by AstraZeneca. JWE, UR and LL have received consultancy fees for planning of this study. JWE has received research grants or honoraria from AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, Novo Nordisk and Sanofi. All other authors declare that there is no duality of interest associated with their contribution to this manuscript.

Figures

Fig. 1
Fig. 1
Effects of dapagliflozin and OM-3CA on liver PDFF (%) (a), liver volume (l) (b) and total liver fat (l) (c). Data are descriptive GMRs of post-treatment to baseline values with 95% CIs. *p < 0.05 vs placebo. Dapa, dapagliflozin
Fig. 2
Fig. 2
Effects of dapagliflozin and OM-3CA on levels of aspartate aminotransferase (μkat/l) (a), alanine aminotransferase (μkat/l) (b), γ-GT (μkat/l) (c), CK 18-M30 (U/l) (d), CK 18-M65 (U/l) (e) and plasma FGF21 (pg/ml) (f). Data are descriptive GMRs of post-treatment to baseline values with 95% CIs. *p < 0.05 vs placebo. Dapa, dapagliflozin

References

    1. Adams LA, Anstee QM, Tilg H, Targher G. Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases. Gut. 2017;66:1138–1153. doi: 10.1136/gutjnl-2017-313884.
    1. Rinella ME. Nonalcoholic fatty liver disease: a systematic review. JAMA. 2015;313:2263–2273. doi: 10.1001/jama.2015.5370.
    1. Sunny NE, Bril F, Cusi K. Mitochondrial adaptation in nonalcoholic fatty liver disease: novel mechanisms and treatment strategies. Trends Endocrinol Metab. 2017;28:250–260. doi: 10.1016/j.tem.2016.11.006.
    1. Koliaki C, Szendroedi J, Kaul K, et al. Adaptation of hepatic mitochondrial function in humans with non-alcoholic fatty liver is lost in steatohepatitis. Cell Metab. 2015;21:739–746. doi: 10.1016/j.cmet.2015.04.004.
    1. Romeo S, Kozlitina J, Xing C, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet. 2008;40:1461–1465. doi: 10.1038/ng.257.
    1. Bolinder J, Ljunggren O, Johansson L, et al. Dapagliflozin maintains glycaemic control while reducing weight and body fat mass over 2 years in patients with type 2 diabetes mellitus inadequately controlled on metformin. Diabetes Obes Metab. 2013;16:159–169. doi: 10.1111/dom.12189.
    1. DeFronzo RA, Norton L, Abdul-Ghani M. Renal, metabolic and cardiovascular considerations of SGLT2 inhibition. Nat Rev Nephrol. 2017;13:11–26. doi: 10.1038/nrneph.2016.170.
    1. Kosiborod M, Cavender MA, Fu AZ, et al. Lower risk of heart failure and death in patients initiated on SGLT-2 inhibitors versus other glucose-lowering drugs: the CVD-REAL study. Circulation. 2017;136:249–259. doi: 10.1161/CIRCULATIONAHA.117.029190.
    1. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:644–657. doi: 10.1056/NEJMoa1611925.
    1. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117–2128. doi: 10.1056/NEJMoa1504720.
    1. Sumida Y, Seko Y, Yoneda M, Japan Study Group of NAFLD Novel antidiabetic medications for nonalcoholic fatty liver disease with type 2 diabetes. Hepatol Res. 2017;47:266–280. doi: 10.1111/hepr.12856.
    1. Ito D, Shimizu S, Inoue K, et al. Comparison of ipragliflozin and pioglitazone effects on nonalcoholic fatty liver disease in patients with type 2 diabetes: a randomized, 24-week, open-label, active-controlled trial. Diabetes Care. 2017;40:1364–1372. doi: 10.2337/dc17-0518.
    1. Shibuya T, Fushimi N, Kawai M, et al. Luseogliflozin improves liver fat deposition compared to metformin in type 2 diabetes patients with non-alcoholic fatty liver disease: A prospective randomized controlled pilot study. Diabetes Obes Metab. 2018;20:438–442. doi: 10.1111/dom.13061.
    1. Davidson MH, Johnson J, Rooney MW, Kyle ML, Kling DF. A novel omega-3 free fatty acid formulation has dramatically improved bioavailability during a low-fat diet compared with omega-3-acid ethyl esters: the ECLIPSE (Epanova® compared to Lovaza® in a pharmacokinetic single-dose evaluation) study. J Clin Lipidol. 2012;6:573–584. doi: 10.1016/j.jacl.2012.01.002.
    1. Parker HM, Johnson NA, Burdon CA, Cohn JS, O'Connor HT, George J. Omega-3 supplementation and non-alcoholic fatty liver disease: a systematic review and meta-analysis. J Hepatol. 2012;56:944–951. doi: 10.1016/j.jhep.2011.08.018.
    1. Sanyal AJ, Abdelmalek MF, Suzuki A, Cummings OW, Chojkier M, EPE-A Study Group No significant effects of ethyl-eicosapentanoic acid on histologic features of nonalcoholic steatohepatitis in a phase 2 trial. Gastroenterol. 2014;147:377–384.e371. doi: 10.1053/j.gastro.2014.04.046.
    1. Dasarathy S, Dasarathy J, Khiyami A, et al. Double-blind randomized placebo-controlled clinical trial of omega 3 fatty acids for the treatment of diabetic patients with nonalcoholic steatohepatitis. J Clin Gastroenterol. 2014;49:137–144. doi: 10.1097/MCG.0000000000000099.
    1. Argo CK, Patrie JT, Lackner C, et al. Effects of n-3 fish oil on metabolic and histological parameters in NASH: a double-blind, randomized, placebo-controlled trial. J Hepatol. 2015;62:190–197. doi: 10.1016/j.jhep.2014.08.036.
    1. Li YH, Yang LH, Sha KH, Liu TG, Zhang LG, Liu XX. Efficacy of poly-unsaturated fatty acid therapy on patients with nonalcoholic steatohepatitis. World J Gastroenterol. 2015;21:7008–7013. doi: 10.3748/wjg.v21.i22.7008.
    1. De Caterina R, Madonna R, Bertolotto A, Schmidt EB. N-3 fatty acids in the treatment of diabetic patients: biological rationale and clinical data. Diabetes Care. 2007;30:1012–1026. doi: 10.2337/dc06-1332.
    1. Couet C, Delarue J, Ritz P, Antoine JM, Lamisse F. Effect of dietary fish oil on body fat mass and basal fat oxidation in healthy adults. Int J Obes. 1997;21:637–643. doi: 10.1038/sj.ijo.0800451.
    1. Kabir M, Skurnik G, Naour N, et al. Treatment for 2 mo with n 3 polyunsaturated fatty acids reduces adiposity and some atherogenic factors but does not improve insulin sensitivity in women with type 2 diabetes: a randomized controlled study. Am J Clin Nutr. 2007;86:1670–1679. doi: 10.1093/ajcn/86.5.1670.
    1. Lundgren M, Svensson M, Lindmark S, Renstrom F, Ruge T, Eriksson JW. Fat cell enlargement is an independent marker of insulin resistance and ‘hyperleptinaemia’. Diabetologia. 2007;50:625–633. doi: 10.1007/s00125-006-0572-1.
    1. Bjermo H, Iggman D, Kullberg J, et al. Effects of n-6 PUFAs compared with SFAs on liver fat, lipoproteins, and inflammation in abdominal obesity: a randomized controlled trial. Am J Clin Nutr. 2012;95:1003–1012. doi: 10.3945/ajcn.111.030114.
    1. Angulo P, Hui JM, Marchesini G, et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology. 2007;45:846–854. doi: 10.1002/hep.21496.
    1. Belfiore F, Iannello S, Volpicelli G. Insulin sensitivity indices calculated from basal and OGTT-induced insulin, glucose, and FFA levels. Mol Genet Metab. 1998;63:134–141. doi: 10.1006/mgme.1997.2658.
    1. Jiang S, Yan C, Fang QC, et al. Fibroblast growth factor 21 is regulated by the IRE1alpha-XBP1 branch of the unfolded protein response and counteracts endoplasmic reticulum stress-induced hepatic steatosis. J Biol Chem. 2014;289:29751–29765. doi: 10.1074/jbc.M114.565960.
    1. Mudaliar S, Henry RR, Boden G, et al. Changes in insulin sensitivity and insulin secretion with the sodium glucose cotransporter 2 inhibitor dapagliflozin. Diabetes Technol Ther. 2014;16:137–144. doi: 10.1089/dia.2013.0167.
    1. Ferrannini E, Muscelli E, Frascerra S, et al. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest. 2014;124:499–508. doi: 10.1172/JCI72227.
    1. Harris WS, Bulchandani D. Why do omega-3 fatty acids lower serum triglycerides? Curr Opin Lipidol. 2006;17:387–393. doi: 10.1097/01.mol.0000236363.63840.16.
    1. Shen J, Wong GL, Chan HL, et al. PNPLA3 gene polymorphism and response to lifestyle modification in patients with nonalcoholic fatty liver disease. J Gastroenterol Hepatol. 2015;30:139–146. doi: 10.1111/jgh.12656.
    1. Scorletti E, West AL, Bhatia L, et al. Treating liver fat and serum triglyceride levels in NAFLD, effects of PNPLA3 and TM6SF2 genotypes: results from the WELCOME trial. J Hepatol. 2015;63:1476–1483. doi: 10.1016/j.jhep.2015.07.036.
    1. Thulin P, Rafter I, Stockling K, et al. PPARalpha regulates the hepatotoxic biomarker alanine aminotransferase (ALT1) gene expression in human hepatocytes. Toxicol Appl Pharmacol. 2008;231:1–9. doi: 10.1016/j.taap.2008.03.007.
    1. Giannini C, Feldstein AE, Santoro N, et al. Circulating levels of FGF-21 in obese youth: associations with liver fat content and markers of liver damage. J Clin Endocrinol Metab. 2013;98:2993–3000. doi: 10.1210/jc.2013-1250.
    1. Li H, Dong K, Fang Q, et al. High serum level of fibroblast growth factor 21 is an independent predictor of non-alcoholic fatty liver disease: a 3-year prospective study in China. J Hepatol. 2013;58:557–563. doi: 10.1016/j.jhep.2012.10.029.
    1. Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet. 2015;385:956–965. doi: 10.1016/S0140-6736(14)61933-4.
    1. Kotronen A, Seppanen-Laakso T, Westerbacka J, et al. Hepatic stearoyl-CoA desaturase (SCD)-1 activity and diacylglycerol but not ceramide concentrations are increased in the nonalcoholic human fatty liver. Diabetes. 2009;58:203–208. doi: 10.2337/db08-1074.
    1. Yamada K, Mizukoshi E, Sunagozaka H, et al. Characteristics of hepatic fatty acid compositions in patients with nonalcoholic steatohepatitis. Liver Int. 2015;35:582–590. doi: 10.1111/liv.12685.
    1. Vessby B, Gustafsson IB, Tengblad S, Boberg M, Andersson A. Desaturation and elongation of fatty acids and insulin action. Ann N Y Acad Sci. 2002;967:183–195. doi: 10.1111/j.1749-6632.2002.tb04275.x.
    1. Adams SH, Hoppel CL, Lok KH, et al. Plasma acylcarnitine profiles suggest incomplete long-chain fatty acid beta-oxidation and altered tricarboxylic acid cycle activity in type 2 diabetic African-American women. J Nutr. 2009;139:1073–1081. doi: 10.3945/jn.108.103754.
    1. Koves TR, Ussher JR, Noland RC, et al. Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. Cell Metab. 2008;7:45–56. doi: 10.1016/j.cmet.2007.10.013.

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