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

Abstract

Aims/hypothesisThe 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).MethodsThis 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).ResultsParticipants 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/interpretationCombined 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 NCT02279407Funding:The study was funded by AstraZeneca.Electronic supplementary materialThe online version of this article (10.1007/s00125-018-4675-2) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Exenatide and dapagliflozin combination improves markers of liver steatosis and fibrosis in patients with type 2 diabetes

“…However, the number of participants with fibrosis or severe fibrosis was small, which affects the interpretability of these results. Extending recent data demonstrating the individual effects of GLP‐1RAs or SGLT2 inhibitors on NAFLD, the present results are the first to demonstrate the effect of this combination in reducing NAFLD biomarkers in people with type 2 diabetes, and indicate that combining these two agents may exert stronger beneficial effects on NAFLD than each drug alone. Moreover, as NAFLD is independently associated with cardiovascular disease, and the cardiovascular benefits of GLP‐1RAs and SGLT2 inhibitors are now well established, the EXE once weekly + DAPA combination may confer a reduction in cardiovascular risk in patients with type 2 diabetes and NAFLD.…”

“…However, in overweight, insulin‐resistant patients without type 2 diabetes, it has been reported that 12 weeks of DAPA treatment had no impact on hepatic steatosis despite a mean weight loss of 4.4 kg . Recent evidence suggests that DAPA reduces specific hepatocyte injury biomarkers, such as cytokeratin 18‐M30 and plasma fibroblast growth factor 21, suggesting an intrinsic disease‐modifying effect in NAFLD . Regarding hyperglycaemia, excess dietary sugars can induce liver glucotoxicity by increasing hepatic steatosis, via de novo lipogenesis, and exacerbating insulin resistance and cellular demise, through mechanisms including the activation of oxidative and endoplasmic reticulum stress responses .…”

“…Pioglitazone has demonstrated reductions in fatty liver content and has provided some resolution of NASH in patients with type 2 diabetes, but with the side effect of significant weight gain . Evidence indicates that glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) and sodium‐glucose co‐transporter‐2 (SGLT2) inhibitors have some benefits in patients with type 2 diabetes and NAFLD/NASH . For example, in a phase 2 study, 48 weeks of liraglutide treatment led to biopsy‐confirmed resolution of NASH in 39% of overweight patients with or without type 2 diabetes .…”

“…2,13 Evidence indicates that glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose co-transporter-2 (SGLT2) inhibitors have some benefits in patients with type 2 diabetes and NAFLD/ NASH. [14][15][16][17][18][19] For example, in a phase 2 study, 48 weeks of liraglutide treatment led to biopsy-confirmed resolution of NASH in 39% of overweight patients with or without type 2 diabetes. 14 Furthermore, semaglutide treatment reduced markers of NAFLD (ie, alanine aminotransferase [ALT] and high-sensitivity C-reactive protein) in patients with obesity and/or type 2 diabetes.…”

A diabetologist’s perspective of non‐alcoholic steatohepatitis (NASH): Knowledge gaps and future directions

“…However, their impact on liver histology remains to be established. Table summarizes several recent RCTs in NAFLD . Taken together, this class has been remarkably consistent in causing a 2% to 3% decrease in total body weight (1.5‐3.0 kg) and in lowering plasma aminotransferases with a placebo‐corrected reduction in intrahepatic triglyceride content of 10%‐30%.…”