Effect of Empagliflozin on Liver Fat in Patients With Type 2 Diabetes and Nonalcoholic Fatty Liver Disease: A Randomized Controlled Trial (E-LIFT Trial)

Kuchay, Mohammad Shafi; Krishan, Sonal; Mishra, Sunil Kumar; Farooqui, Khalid; Singh, Manish Kumar; Wasir, Jasjeet Singh; Bansal, Beena; Kaur, Parjeet; Jevalikar, Ganesh; Gill, Harmendeep Kaur; Choudhary, Narendra S.; Mithal, Ambrish

doi:10.2337/dc18-0165

Cited by 465 publications

(431 citation statements)

References 39 publications

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“…Ito et al previously reported that treatment with ipragliflozin, another SGLT2 inhibitor, reduced hepatic steatosis, which they evaluated from the liver‐to‐spleen attenuation ratio on CT. Very recently, Kuchay et al also demonstrated that empagliflozin reduced liver fat content, evaluated by MRI‐derived proton density fat fraction in patients with type 2 diabetes and NAFLD. Magnetic resonance elastography or MRI‐derived proton density fat fraction has a better diagnostic accuracy for assessing significant fibrosis than transient elastography, although the former techniques are expensive and time‐consuming to implement in clinical practice for screening liver fibrosis .…”

Section: Discussionsupporting

confidence: 87%

“…We demonstrated significant improvement in CAP (an indicator of hepatic steatosis) in the dapagliflozin group after 24 weeks of treatment, while there was no improvement in the control group, and the percent reduction in CAP from baseline to 24 weeks was significantly larger in the dapagliflozin group than in the control group. There has only been two previous prospective investigations into the effect of SGLT2 inhibitors on hepatic steatosis that employed imaging methods such as CT and MRI . In the present study, we investigated the effect of dapagliflozin by measuring CAP, a new quantitative index of hepatic steatosis .…”

Section: Discussionmentioning

confidence: 97%

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Evaluation of the effects of dapagliflozin, a sodium‐glucose co‐transporter‐2 inhibitor, on hepatic steatosis and fibrosis using transient elastography in patients with type 2 diabetes and non‐alcoholic fatty liver disease

Shimizu

Suzuki²,

Kato

et al. 2018

Diabetes Obesity Metabolism

281

219

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Based on these findings, the sodium-glucose co-transporter-2 inhibitor dapagliflozin improves liver steatosis in patients with type 2 diabetes and NAFLD, and attenuates liver fibrosis only in patients with significant liver fibrosis, although the possibility cannot be excluded that a reduction in body weight or visceral adipose tissue by dapagliflozin may be associated with a decrease of liver steatosis or fibrosis.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 97%

Evaluation of the effects of dapagliflozin, a sodium‐glucose co‐transporter‐2 inhibitor, on hepatic steatosis and fibrosis using transient elastography in patients with type 2 diabetes and non‐alcoholic fatty liver disease

Shimizu

Suzuki²,

Kato

et al. 2018

Diabetes Obesity Metabolism

281

219

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“…In humans, 2 pooled analyses reported a decrease in plasma aminotransferases with canagliflozin treatment that correlated with the magnitude of body weight loss. 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 .…”

Section: Discussionmentioning

confidence: 86%

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

Cusi

Bril

Barb

et al. 2018

Diabetes Obesity Metabolism

146

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Aim: To evaluate the impact of the sodium glucose co-transporter 2 inhibitor canagliflozin on intrahepatic triglyceride (IHTG) accumulation and its relationship to changes in body weight and glucose metabolism. Materials and methods:In this double-blind, parallel-group, placebo-controlled, 24-week trial subjects with inadequately controlled type 2 diabetes mellitus (T2DM; HbA1c = 7.7% AE 0.7%) from two centres were randomly assigned (1:1) to canagliflozin 300 mg or placebo. We measured IHTG by proton-magnetic resonance spectroscopy (primary outcome), hepatic/muscle/ adipose tissue insulin sensitivity during a 2-step euglycaemic insulin clamp, and beta-cell function during a mixed meal tolerance test. Analyses were per protocol. Results: Between 8 September 2014-13 June 2016, 56 patients were enrolled. Canagliflozin reduced HbA1c (placebo-subtracted change: −0.71% [−1.08; −0.33]) and body weight (−3.4% [−5.4; −1.4]; both P ≤ 0.001). A numerically larger absolute decrease in IHTG occurred with canagliflozin (−4.6% [−6.4; −2.7]) versus placebo (−2.4% [−4.2; −0.6]; P = 0.09). In patients withnon-alcoholic fatty liver disease (n = 37), the decrease in IHTG was −6.9% (−9.5; −4.2) versus −3.8% (−6.3; −1.3; P = 0.05), and strongly correlated with the magnitude of weight loss (r = 0.69, P < 0.001). Body weight loss ≥5% with a ≥30% relative reduction in IHTG occurred more often with canagliflozin (38% vs. 7%, P = 0.009). Hepatic insulin sensitivity improved with canagliflozin (P < 0.01), but not muscle or adipose tissue insulin sensitivity. Beta-cell glucose sensitivity, insulin clearance, and disposition index improved more with canagliflozin (P < 0.05).Conclusions: Canagliflozin improves hepatic insulin sensitivity and insulin secretion and clearance in patients with T2DM. IHTG decreases in proportion to the magnitude of body weight loss, which tended to be greater and occur more often with canagliflozin. K E Y W O R D Sfatty, liver, canagliflozin, insulin resistance, insulin secretion, liver, randomized trial

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“…Comments: The above studies only included patients with diabetes, and none of them involved histological assessment of outcomes. In the study by Seko et al alcohol intake was not regulated, and patients with an ALT/AST >2.5 × the upper limit of normal were excluded. Neither of the RCTs was placebo‐controlled, and participants were concurrently taking other medications that could have potentially impacted outcomes. …”

Section: Modulation Of Ir In Nafldmentioning

confidence: 99%

Modulation of Insulin Resistance in Nonalcoholic Fatty Liver Disease

et al. 2019

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Nonalcoholic fatty liver disease (NAFLD) has an estimated prevalence of 25% in the general population, and cirrhosis secondary to nonalcoholic steatohepatitis (NASH) is predicted to become the leading cause of liver transplantation, yet there is a lack of effective licensed treatments for these conditions. There is a close relationship between insulin resistance (IR) and NAFLD, with prevalence of NAFLD being 5‐fold higher in patients with diabetes compared to those without. IR is implicated both in pathogenesis of NAFLD and in disease progression from steatosis to NASH. Thus, modulation of IR represents a potential strategy for NAFLD treatment. This review highlights key proposed mechanisms linking IR and NAFLD, such as changes in rates of adipose tissue lipolysis and de novo lipogenesis, impaired mitochondrial fatty acid β‐oxidation (FAO), changes in fat distribution, alterations in the gut microbiome, and alterations in levels of adipokines and cytokines. Furthermore, this review will discuss the main pharmacological strategies used to treat IR in patients with NAFLD and their efficacy based on recently published experimental and clinical data. These include biguanides, glucagon‐like peptide 1 receptor (GLP‐1) agonists, dipeptidyl peptidase 4 (DPP‐4) inhibitors, peroxisome proliferator‐activated receptor (PPAR‐γ/α/δ) agonists, sodium glucose cotransporter 2 (SGLT2) inhibitors, and farnesoid X receptor (FXR) agonists, with further novel treatments on the horizon. Ideally, treatment would improve IR, reduce cardiovascular risk, and produce demonstrable improvements in NASH histology—this is likely to be achieved with a combinatorial approach.

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Effect of Empagliflozin on Liver Fat in Patients With Type 2 Diabetes and Nonalcoholic Fatty Liver Disease: A Randomized Controlled Trial (E-LIFT Trial)

Abstract: When included in the standard treatment for type 2 diabetes, empagliflozin reduces liver fat and improves ALT levels in patients with type 2 diabetes and NAFLD.

Cited by 465 publications

References 39 publications

Evaluation of the effects of dapagliflozin, a sodium‐glucose co‐transporter‐2 inhibitor, on hepatic steatosis and fibrosis using transient elastography in patients with type 2 diabetes and non‐alcoholic fatty liver disease

Evaluation of the effects of dapagliflozin, a sodium‐glucose co‐transporter‐2 inhibitor, on hepatic steatosis and fibrosis using transient elastography in patients with type 2 diabetes and non‐alcoholic fatty liver disease

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

Modulation of Insulin Resistance in Nonalcoholic Fatty Liver Disease

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