SGLT2 Inhibitors and Metformin on Metabolism and Non-Alcoholic SteatoHepatitis (SMASH)
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|ClinicalTrials.gov Identifier: NCT02696941|
Recruitment Status : Completed
First Posted : March 2, 2016
Last Update Posted : May 4, 2018
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.
|Condition or disease||Intervention/treatment||Phase|
|Non-alcoholic Fatty Liver Disease||Drug: Metformin Drug: SGLT2 inhibitor||Phase 1|
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||20 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||None (Open Label)|
|Primary Purpose:||Basic Science|
|Official Title:||SGLT2 Inhibitors and Metformin on Metabolism and Non-Alcoholic SteatoHepatitis|
|Study Start Date :||February 2016|
|Actual Primary Completion Date :||April 1, 2018|
|Actual Study Completion Date :||April 1, 2018|
Participants with insulin resistance who have not yet started any diabetic medication will be recruited and will be prescribed metformin at standard clinical doses.
Metformin 500mg once daily and titrated weekly to a dose of 1000mg twice daily for 3 months
Participants with poorly controlled type 2 Diabetes (T2DM) who have been recommended to start an SGLT2 inhibitor will be recruited.
Drug: SGLT2 inhibitor
SGLT2 inhibitor has been recommended to be started as part of routine clinical care
- Hepatic steatosis [ Time Frame: 3 months ]Liver fat measured by magnetic resonance imaging / spectroscopy (MRI/S)
- % contribution of newly synthesised lipid to circulating triglyceride levels [ Time Frame: 3 months ]deuterated water incorporation into palmitate
- Global insulin sensitivity [ Time Frame: 3 months ]two-step hyperinsulinaemic-euglycaemic clamp
- Hepatic insulin sensitivity [ Time Frame: 3 months ]two-step hyperinsulinaemic-euglycaemic clamp
- Intrabdominal fat [ Time Frame: 3 months ]Intrabdominal fat depot measured at level of L4-L5, visible on liver MRI.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02696941
|University of Oxford|
|Oxford, United Kingdom|
|Principal Investigator:||Jeremy W Tomlinson, MD PhD||University of Oxford|