SGLT2 Inhibitors and Metformin on Metabolism and Non-Alcoholic SteatoHepatitis
Condition: Non-alcoholic Fatty Liver Disease
MeSH terms: Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease
Study type: Interventional
Phase: Phase 1

Summary: 
      SGLT2 inhibitors have been proven to be effective in several preclinical rodent models of
      non-alcoholic fatty liver disease (NAFLD). Using a choline deficient diet to recapitulate
      some of the histological features of human non-alcoholic steatohepatitis (NASH), it was found
      that 5 weeks of SGLT2 inhibition led to significant reductions in hepatic triglyceride
      content and improved markers of liver fibrosis. Similarly, 4 weeks of treatment in obese mice
      led to improved glucose tolerance, reduced hepatic steatosis and reduced markers of liver
      oxidative stress in a dose dependent manner. These findings corresponded with an improvement
      in traditional liver function tests including the aminotransferases (ALT and AST). The widely
      used antidiabetic agent metformin has been shown in rodent models to increase hepatic insulin
      sensitivity and lower liver fat content which is in contrast to the findings in humans where
      metformin increases hepatic insulin sensitivity, reduces body weight but does not decrease
      liver fat content. The reason for the discrepancy between the animal and human studies, with
      regards to liver fat content remains unclear.

      The investigators hypothesise the following:

        -  SGLT2 Inhibitors have the potential to decrease lipid accumulation in the liver through
           reduced de novo lipogenesis (DNL)

        -  There will be no decrease in endogenous lipid synthesis (DNL) with metformin and thus no
           change in liver fat content.

      There are two arms to this study.

        -  Arm 1: x10 participants with poorly controlled type 2 Diabetes (T2DM) who have been
           recommended to start an SGLT2 inhibitor called dapagliflozin will be recruited.

        -  Arm 2: x13 participants with insulin resistance who have not yet started any diabetic
           medication will be recruited and will be prescribed metformin at standard clinical
           doses.

      The two arms will run in parallel and all participants will undergo identical investigations
      before and after 3 months of treatment with either dapagliflozin or metformin. Investigations
      will include liver magnetic resonance imaging/spectroscopy, fat biopsy, fat microdialysis
      sampling, two-step hyperinsulinaemic euglycaemic clamp, breath sampling and stable glucose
      and palmitate isotope infusions.

      The investigators aim to show that SGLT2 inhibition decreases liver fat whereas we aim to
      demonstrate why liver fat remains unchanged in humans, treated with metformin. These data
      will provide the first evidence for the use SGLT2 inhibitors in NAFLD, and will be highly
      informative for the design of future clinical studies. Moreover, the data gained from the
      metformin arm of the study will provide the first mechanistic evidence in humans of the
      effects of metformin on hepatic fatty acid metabolism.
    


Intervention name(s): Metformin; SGLT2 inhibitor
Intervention type(s): Drug; Drug
Intervention description(s): Metformin 500mg once daily and titrated weekly to a dose of 1000mg twice daily for 3 months; SGLT2 inhibitor has been recommended to be started as part of routine clinical care
Intervention MeSH terms: Metformin; Sodium-Glucose Transporter 2 Inhibitors
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Basic Science