SGLT2 Inhibitors and Metformin on Metabolism and Non-Alcoholic SteatoHepatitis
Status:
Completed
Trial end date:
2018-04-01
Target enrollment:
Participant gender:
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.