Abstract
BackgroundNonalcoholic steatohepatitis (NASH) is an active form of nonalcoholic fatty liver disease. Risk factors for NASH include type 2 diabetes mellitus (T2DM) and obesity. Sodium–glucose cotransporter 2 (SGLT2) inhibitors used to treat T2DM prevent glucose reabsorption in the kidney and increase glucose urinary excretion. Dapagliflozin is a potent, selective SGLT2 inhibitor that reduces hyperglycemia in patients with T2DM and has been demonstrated to reduce some complications associated with NASH in rodent models. ObjectiveTo assess the efficacy and safety profile of dapagliflozin for the treatment of NASH-associated with T2DM. MethodsIn this single-arm, nonrandomized, open-label study, 16 patients with percutaneous liver biopsy-confirmed NASH and T2DM were enrolled to be prescribed dapagliflozin 5 mg/d for 24 weeks. Of these, 11 patients were evaluable. Patients with chronic liver disease other than NASH were excluded. Body composition, laboratory variables related to liver tests and metabolism, and glucose homeostasis were assessed at baseline and periodically during the study. Changes from baseline were evaluated with the Wilcoxon signed-rank test. ResultsAdministration of dapagliflozin for 24 weeks was associated with significant decreases in body mass index (P < 0.01), waist circumference (P < 0.01), and waist-to-hip ratio (P < 0.01). Changes in body composition were driven by reductions in body fat mass (P < 0.01) and percent body fat (P < 0.01), without changes in lean mass or total body water. Liver tests (ie, serum concentrations of aspartate aminotransferase, alanine aminotransferase, ferritin, and type IV collagen 7S) also significantly improved during the study. Insulin concentrations decreased (P < 0.01 by Week 24) in combination with significant reductions in fasting plasma glucose (P < 0.01) and glycated hemoglobin (P < 0.01) levels and increases in adiponectin (P < 0.01) levels from Week 4 onward. ConclusionsDapagliflozin was associated with improvements in body composition, most likely a reduction in visceral fat, which occurred together with improvements in liver tests and metabolic variables in patients with NASH-associated with T2DM.UMIN Clinical Trial Registry identifier: UMIN000023574.
Highlights
Nonalcoholic steatohepatitis (NASH) is an active form of nonalcoholic fatty liver disease (NAFLD)
Five patients discontinued or were excluded from the final analyses for the following reasons: 1 patient reported severe hunger and another patient reported epigastric discomfort, both after 4 weeks of treatment with dapagliflozin; 1 patient was excluded after Week 12 owing to poor compliance; 1 patient received glimepiride before starting this study and continued administration during the study; and 1 patient was confirmed to have colon
We showed that the administration of dapagliflozin, a potent and selective Sodium–glucose cotransporter 2 (SGLT2) inhibitor, was associated with improvements in liver tests and metabolic laboratory variables in patients with NASH and type 2 diabetes mellitus (T2DM) over the course of 24 weeks
Summary
Nonalcoholic steatohepatitis (NASH) is an active form of nonalcoholic fatty liver disease (NAFLD). NASH may progress to cirrhosis of the liver and hepatocellular carcinoma.[1] NAFLD significantly increases the risk of incident type 2 diabetes mellitus (T2DM) and metabolic syndrome.[2] Significant risk factors for NASH are T2DM and obesity.[3,4]. Dapagliflozin is a potent, selective SGLT2 inhibitor that reduces hyperglycemia in patients with T2DM and has been demonstrated to reduce some complications associated with NASH in rodent models. Laboratory variables related to liver tests and metabolism, and glucose homeostasis were assessed at baseline and periodically during the study. Conclusions: Dapagliflozin was associated with improvements in body composition, most likely a reduction in visceral fat, which occurred together with improvements in liver tests and metabolic variables in patients with NASH-associated with T2DM
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