SGLT2 Inhibitors and Metformin on Metabolism and Non-Alcoholic SteatoHepatitis
SGLT2 Inhibitors and Metformin on Metabolism and Non-Alcoholic SteatoHepatitis
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:
There are two arms to this study.
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.
Inclusion Criteria:
Arm 1: SGLT2 inhibitors
Volunteers with diagnosis of Type 2 Diabetes on oral anti-diabetic therapy at a stable dose for ≥3 months including one of the following:
i. Metformin monotherapy ii. Sulphonylurea monotherapy iii. Metformin and Sulphonylurea dual therapy
All volunteers will be due to start SGLT2 inhibitor therapy for inadequate glycaemic control and it will be prescribed according to licensed indications.
Arm 2: metformin
• Insulin resistant treatment naive individuals as defined by fasting insulin and / or glucose in top 10th percentile
Both arms:
Exclusion Criteria:
Arm 1: SGLT2 inhibitors Volunteers taking insulin, glucagon-like peptide 1 analogues, thiazolidinediones, or dipeptidyl peptidase IV inhibitors
Arm 2: metformin Volunteers taking insulin, glucagon-like peptide 1 analogues, thiazolidinediones, SGLT2 inhibitors, metformin or dipeptidyl peptidase IV inhibitors
Both arms