Effects of Dapagliflozin on Body Composition and Liver Tests in Patients with Nonalcoholic Steatohepatitis Associated with Type 2 Diabetes Mellitus: A Prospective, Open-label, Uncontrolled Study

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.

Pharmacokinetics and pharmacodynamics of rongliflozin, a novel selective inhibitor of sodium‐glucose co‐transporter‐2, in people with type 2 diabetes mellitus

“…Although the drug had a mild osmotic diuretic effect, it did not increase the occurrence of electrolyte or acid‐base balance disorders. These safety and tolerability findings are consistent with those reported for canagliflozin and dapagliflozin in clinical studies conducted in the United States …”

“…These safety and tolerability findings are consistent with those reported for canagliflozin and dapagliflozin in clinical studies conducted in the United States. 15,17 The PK characteristics of rongliflozin observed in participants with T2DM were similar to those observed in healthy participants, as predicted by a two-compartment model with first-order (two-stage) absorption. 18 Rapid oral absorption of rongliflozin was observed in the SAD and MAD groups.…”

Effect of canagliflozin treatment on hepatic triglyceride content and glucose metabolism in patients with type 2 diabetes

“…17 In a pooled analysis in 232 Japanese patients, Seko et al also found a significant reduction in plasma ALT with canagliflozin. 18 Similar results have been reported in recent small uncontrolled studies with other SGLT inhibitors, [19][20][21][22][23] some with a reduction in IHTG on liver imaging, [21][22][23] while a larger placebo-controlled study with dapagliflozin did not observe an improvement in IHTG despite a reduction in subcutaneous and visceral fat. 24 Taken together, the role of SGLT2 inhibitors on IHTG and glucose metabolism remains unclear.…”

“…Tobita et al showed additional improvement in histology in a small, uncontrolled study in patients with biopsy-proven NASH. 20 In contrast, a larger placebo-controlled study in 80 patients with type 2 diabetes and NAFLD was negative. 24 While the reasons for the above discordant results remain unclear, in positive studies a decrease in IHTG has usually correlated with a reduction in BMI, visceral fat, and HbA1c levels.…”

“…A reduction in ALT and/or IHTG has been reported in small, open‐label studies of 5‐ to 6‐months duration with luseogliflozin, ipragliflozin, and empagliflozin, associated with reductions in BMI, visceral fat, and HbA1c. Tobita et al showed additional improvement in histology in a small, uncontrolled study in patients with biopsy‐proven NASH . In contrast, a larger placebo‐controlled study in 80 patients with type 2 diabetes and NAFLD was negative .…”