Ipragliflozin Improves the Hepatic Outcomes of Patients With Diabetes with NAFLD

Abstract

Sodium glucose cotransporter-2 inhibitors (SGLT2is) are now widely used to treat diabetes, but their effects on nonalcoholic fatty liver disease (NAFLD) remain to be determined. We aimed to evaluate the effects of SGLT2is on the pathogenesis of NAFLD. A multicenter, randomized, controlled trial was conducted in patients with type 2 diabetes with NAFLD. The changes in glycemic control, obesity, and liver pathology were compared between participants taking ipragliflozin (50 mg/day for 72 weeks; IPR group) and participants being managed without SGLT2is, pioglitazone, glucagon-like peptide-1 analogs, or insulin (CTR group). In the IPR group (n = 25), there were significant decreases in hemoglobin A1c (HbA1c) and body mass index (BMI) during the study (HbA1c, −0.41%, P < 0.01; BMI, −1.06 kg/m 2 , P < 0.01), whereas these did not change in the CTR group (n = 26). Liver pathology was evaluated in 21/25 participants in the IPR/CTR groups, and hepatic fibrosis was found in 17 (81%) and 18 (72%) participants in the IPR and CTR groups at baseline. This was ameliorated in 70.6% (12 of 17) of participants in the IPR group and 22.2 % (4 of 18) of those in the CTR group (P < 0.01). Nonalcoholic steatohepatitis (NASH) resolved in 66.7% of IPR-treated participants and 27.3% of CTR participants. None of the participants in the IPR group developed NASH, whereas 33.3% of the CTR group developed NASH. Conclusion: Long-term ipragliflozin treatment ameliorates hepatic fibrosis in patients with NAFLD. Thus, ipragliflozin might be effective for the treatment and prevention of NASH in patients with diabetes, as well as improving glycemic control and obesity. Therefore, SGLT2is may represent a therapeutic choice for patients with diabetes with NAFLD, but further larger studies are required to confirm these effects. (Hepatology Communications 2021;0:1-13).

Old and new classes of glucose-lowering agents as treatments for non-alcoholic fatty liver disease: A narrative review

“…90 More recently, Takahashi et al conducted an open-label randomized controlled trial that aimed to examine the effect of ipragliflozin on hepatic pathology in 50 patients with T2DM and biopsyproven NAFLD. 91 These authors reported that patients treated with ipragliflozin (50 mg daily, n=24) for 72 weeks had better hepatic histology outcomes, including the severity of liver fibrosis and ballooning, compared to patients (n=26) who performed lifestyle modifications and/or took glucose-lowering drugs, with the exception of SGLT2 inhibitors, pioglitazone, or GLP-1RAs. 91 To date, however, no robust data from sufficiently large randomized controlled trials with liver histological endpoints are available to comment on the long-term efficacy of SGLT2 inhibitors as a treatment for NASH.…”

SGLT-2 Inhibitors in NAFLD: Expanding Their Role beyond Diabetes and Cardioprotection

“…A number of clinical studies have highlighted the benefit of SGLT-2i in patients with T2DM and NAFLD ( Table 5 ) [ 145 , 146 , 147 , 148 , 149 , 150 , 151 , 152 , 153 , 154 , 155 , 156 , 157 , 158 , 159 , 160 , 161 , 162 , 163 , 164 , 165 , 166 , 167 , 168 , 169 ]. In the majority of them, the administration of SGLT-2i has resulted in improvement of serum levels of liver enzymes and hepatic steatosis, as evaluated by magnetic resonance imaging (MRI), ultrasound (U/S), non-invasive biomarkers, such as AST to platelet ratio (APRI) index, NAFLD fibrosis score (NFS) and Fibrosis-4 (FIB-4) score, or even by liver biopsy (LB).…”

“…In the majority of them, the administration of SGLT-2i has resulted in improvement of serum levels of liver enzymes and hepatic steatosis, as evaluated by magnetic resonance imaging (MRI), ultrasound (U/S), non-invasive biomarkers, such as AST to platelet ratio (APRI) index, NAFLD fibrosis score (NFS) and Fibrosis-4 (FIB-4) score, or even by liver biopsy (LB). In some of these studies, improvement in hepatic fibrosis was found, using transient elastography (TE) or LB, even though this finding was not univocal [ 146 , 153 , 158 , 159 , 164 , 165 , 168 ].…”

Pharmacotherapy for Non-Alcoholic Fatty Liver Disease: Emerging Targets and Drug Candidates

“…Ipragliflozin (50 mg/d for 72 weeks) ameliorated liver fibrosis and enhanced NASH resolution [ 154 ], remogliflozin etabonate (50–1000 mg/d for 12 weeks) reduced FIB-4 and NAFLD-fibrosis scores [ 155 ], and ertugliflozin (5 or 15 mg/d for 52 weeks) reduced liver transaminase levels [ 156 ] in TD2M patients with different stages of NASH. Several pilot studies in T2DM/NAFLD subjects confirmed the antisteatotic properties of luseogliflozin and tofogliflozin [ 157 , 158 , 159 ].…”