Abstract
Background and AimNon‐alcoholic fatty liver disease (NAFLD) is rapidly becoming the leading indication for liver transplant and is associated with increased cardiovascular and liver mortality, yet there are no licensed therapies. Sodium‐glucose cotransporter 2 (SGLT2) inhibitors are widely used for their glucose‐lowering effects in patients with type 2 diabetes (T2D). Preclinical models have suggested a beneficial impact on NAFLD, but clinical data are limited, and there are currently no data on patients without T2D. We aimed to investigate the impact of SGLT2 inhibition on NAFLD in overweight, nondiabetic patients and establish the effect these agents may have on the processes that regulate hepatic steatosis in vivo.MethodsWe conducted an open‐label, experimental medicine pilot study on insulin‐resistant overweight/obese individuals (n = 10) using gold‐standard noninvasive assessments of NAFLD phenotype, including magnetic resonance spectroscopy, two‐step hyperinsulinemic euglycemic clamps, and stable isotope tracers to assess lipid and glucose metabolism. Investigations were performed before and after a 12‐week treatment with the SGLT2 inhibitor, dapagliflozin.ResultsDespite a body weight reduction of 4.4 kg, hepatic steatosis was unchanged following treatment. Hepatic glucose production increased, and there was impairment of glucose disposal during the low‐dose insulin infusion. Although circulating, nonesterified, fatty acid levels did not change, the ability of insulin to suppress lipolysis was reduced.ConclusionsSGLT2 inhibition for 12 weeks does not improve hepatic steatosis in patients without T2D. Additional studies in patients with established T2D or impairments of fasting or postprandial glucose homeostasis are needed to determine whether SGLT2 inhibition represents a viable therapeutic strategy for NAFLD. (http://clinicaltrials.gov Number NCT02696941).
Highlights
Non-alcoholic fatty liver disease (NAFLD) has reached epidemic proportions affecting up to 30% of the general population and 70–90% of individuals with type 2 diabetes (T2D) and/or obesity.[1,2] It drives increased morbidity and mortality, both through a specific impact on the liver and through adverse cardiovascular outcomes[3]; by 2020, NAFLD will become the leading indication for liver transplantation worldwide.[4]
Using an experimental medicine approach incorporating currently accepted gold-standard noninvasive metabolic assessments in patients with NAFLD, we have assessed the impact of Sodium-glucose cotransporter 2 (SGLT2) inhibition using dapagliflozin on the tissue-specific insulinregulated processes that drive the accumulation of TAG within the liver
This is the first study to evaluate the effect of SGLT2 inhibition on NAFLD in patients without T2D and to assess hepatic steatosis using magnetic resonance spectroscopy (MRS)
Summary
Non-alcoholic fatty liver disease (NAFLD) has reached epidemic proportions affecting up to 30% of the general population and 70–90% of individuals with type 2 diabetes (T2D) and/or obesity.[1,2] It drives increased morbidity and mortality, both through a specific impact on the liver and through adverse cardiovascular outcomes[3]; by 2020, NAFLD will become the leading indication for liver transplantation worldwide.[4] NAFLD is a spectrum of disease ranging from simple steatosis to inflammation (nonalcoholic steatohepatitis [NASH]), cirrhosis, and hepatocellular carcinoma (HCC). Using hyperinsulinemic euglycemic clamp techniques incorporating the use of stable isotope infusions, studies have identified the liver (with increased glucose production), muscle (with decreased glucose disposal), and adipose tissue (failure of insulin to suppress lipolysis) as important sites of insulin resistance in patients with NAFLD.[7]. We aimed to investigate the impact of SGLT2 inhibition on NAFLD in overweight, nondiabetic patients and establish the effect these agents may have on the processes that regulate hepatic steatosis in vivo. Additional studies in patients with established T2D or impairments of fasting or postprandial glucose homeostasis are needed to determine whether SGLT2 inhibition represents a viable therapeutic strategy for NAFLD. (ClinicalTrials. gov Number NCT02696941)
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