Abstract
Aims/hypothesisIn addition to beneficial effects on glycaemia and cardiovascular death, empagliflozin improves adiposity indices. We investigated the effect of empagliflozin on aminotransferases (correlates of liver fat) in individuals with type 2 diabetes.MethodsChanges from baseline alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were assessed in the EMPA-REG OUTCOME® trial (n = 7020), pooled data from four 24-week placebo-controlled trials (n = 2477) and a trial of empagliflozin vs glimepiride over 104 weeks (n = 1545). Analyses were performed using data from all participants and by tertiles of baseline aminotransferases.ResultsIn the EMPA-REG OUTCOME® trial, mean ± SE changes from baseline ALT at week 28 were −2.96 ± 0.18 and −0.73 ± 0.25 U/l with empagliflozin and placebo, respectively (adjusted mean difference: −2.22 [95% CI −2.83, −1.62]; p < 0.0001). Reductions in ALT were greatest in the highest ALT tertile (placebo-adjusted mean difference at week 28: −4.36 U/l [95% CI −5.51, −3.21]; p < 0.0001). The adjusted mean difference in change in ALT was −3.15 U/l (95% CI −4.11, −2.18) with empagliflozin vs placebo at week 24 in pooled 24-week data, and −4.88 U/l (95% CI −6.68, −3.09) with empagliflozin vs glimepiride at week 28. ALT reductions were largely independent of changes in weight or HbA1c. AST changes showed similar patterns to ALT, but the reductions were considerably lower.Conclusions/interpretationThese highly consistent results suggest that empagliflozin reduces aminotransferases in individuals with type 2 diabetes, in a pattern (reductions in ALT>AST) that is potentially consistent with a reduction in liver fat, especially when ALT levels are high.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is estimated to affect more than half of those with type 2 diabetes [1,2,3].The first recognisable stage of NAFLD is hepatic steatosis, when the fat content exceeds 5% of the liver volume [4].Mechanistic insights suggest that ectopic liver fat is probably part of the pathogenic process in diabetes, contributing to hepatic insulin resistance, excess gluconeogenesis and higher fasting glucose levels [5]
The adjusted mean difference in change in ALT was −3.15 U/l with empagliflozin vs placebo at week 24 in pooled 24-week data, and −4.88 U/l with empagliflozin vs glimepiride at week 28
Conclusions/interpretation These highly consistent results suggest that empagliflozin reduces aminotransferases in individuals with type 2 diabetes, in a pattern that is potentially consistent with a reduction in liver fat, especially when ALT levels are high
Summary
Non-alcoholic fatty liver disease (NAFLD) is estimated to affect more than half of those with type 2 diabetes [1,2,3].The first recognisable stage of NAFLD is hepatic steatosis, when the fat content exceeds 5% of the liver volume [4].Mechanistic insights suggest that ectopic liver fat is probably part of the pathogenic process in diabetes, contributing to hepatic insulin resistance, excess gluconeogenesis and higher fasting glucose levels [5]. Non-alcoholic fatty liver disease (NAFLD) is estimated to affect more than half of those with type 2 diabetes [1,2,3]. In a minority of individuals, hepatic steatosis progresses to non-alcoholic steatohepatitis (NASH), at which point liver inflammation and fibrosis necessitate monitoring and interventions to prevent progression to cirrhosis and other life-threatening sequelae [4]. In individuals with type 2 diabetes and elevated liver enzymes or NAFLD, improved glucose control may be important to delay the progression of liver disease [10, 11]. The glucose-lowering agents pioglitazone [12] and liraglutide [13] have been shown to reduce liver fat in individuals with NASH with and without type 2 diabetes, but the effects of newer agents on liver fat are less well studied
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