Empagliflozin for the Treatment of Nonalcoholic Steatohepatitis in Patients with Type 2 Diabetes Mellitus

Lai, Lee‐Lee; Vethakkan, Shireene Ratna; Mustapha, Nik Raihan Nik; Mahadeva, Sanjiv; Chan, Wah‐Kheong

doi:10.1007/s10620-019-5477-1

Cited by 130 publications

(111 citation statements)

References 33 publications

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“…A recent uncontrolled pilot study provided some evidence that EMPA treatment for 24 weeks could improve histological components of NASH and its resolution despite a mean reduction in BMI of only 20.7 kg/m 2 (36). The current trial did not observe placebocorrected changes in circulating surrogate markers of liver injury, such as transaminases or CK18-M30 fragment.…”

Section: Exploratory Analyses Of Circulating Parametersmentioning

confidence: 54%

Empagliflozin Effectively Lowers Liver Fat Content in Well-Controlled Type 2 Diabetes: A Randomized, Double-Blind, Phase 4, Placebo-Controlled Trial

et al. 2019

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To evaluate whether the sodium-glucose cotransporter 2 inhibitor empagliflozin (EMPA) reduces liver fat content (LFC) in recent-onset and metabolically wellcontrolled type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS Patients with T2D (n 5 84) (HbA 1c 6.6 6 0.5% [49 6 10 mmol/mol], known disease duration 39 6 27 months) were randomly assigned to 24 weeks of treatment with 25 mg daily EMPA or placebo. The primary end point was the difference of the change in LFC as measured with magnetic resonance methods from 0 (baseline) to 24 weeks between groups. Tissue-specific insulin sensitivity (secondary outcome) was assessed by two-step clamps using an isotope dilution technique. Exploratory analysis comprised circulating surrogate markers of insulin sensitivity and liver function. Statistical comparison was done by ANCOVA adjusted for respective baseline values, age, sex, and BMI. RESULTS EMPA treatment resulted in a placebo-corrected absolute change of 21.8% (95% CI 23.4, 20.2; P 5 0.02) and relative change in LFC of 222% (236, 27; P 5 0.009) from baseline to end of treatment, corresponding to a 2.3-fold greater reduction. Weight loss occurred only with EMPA (placebo-corrected change 22.5 kg [23.7, 21.4]; P < 0.001), while no placebo-corrected change in tissue-specific insulin sensitivity was observed. EMPA treatment also led to placebo-corrected changes in uric acid (274 mol/L [2108, 242]; P < 0.001) and high-molecular-weight adiponectin (36% [16, 60]; P < 0.001) levels from 0 to 24 weeks. CONCLUSIONS EMPA effectively reduces hepatic fat in patients with T2D with excellent glycemic control and short known disease duration. Interestingly, EMPA also decreases circulating uric acid and raises adiponectin levels despite unchanged insulin sensitivity. EMPA could therefore contribute to the early treatment of nonalcoholic fatty liver disease in T2D.

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Section: Exploratory Analyses Of Circulating Parametersmentioning

confidence: 54%

Empagliflozin Effectively Lowers Liver Fat Content in Well-Controlled Type 2 Diabetes: A Randomized, Double-Blind, Phase 4, Placebo-Controlled Trial

et al. 2019

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“…At present there are only small uncontrolled studies reporting anecdotal benefits to liver histology with SGLT2 inhibitors with improvement that is somewhat beyond what would be expected from the modest 2%‐3% weight loss. Whether this is an indication of weight‐independent mechanisms of action remains to be established.…”

Section: The Future Of Treating Nash In Patients With T2dmmentioning

confidence: 96%

“…In one study, more patients lost ≥5% of body weight and had a ≥30% reduction in liver fat on canagliflozin than with placebo (38% vs 7%, P = .009). 45 At present there are only small uncontrolled studies reporting anecdotal benefits to liver histology with SGLT2 inhibitors [49][50][51] with improvement that is somewhat beyond what would be expected from the modest 2%-3% weight loss. Whether this is an indication of weight-independent mechanisms of action remains to be established.…”

Section: Is There a Future Role For Sglt2i For The Treatment Of Nash?mentioning

confidence: 99%

A diabetologist’s perspective of non‐alcoholic steatohepatitis (NASH): Knowledge gaps and future directions

Cusi

2020

Liver International

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There is a close link between steatohepatitis (NASH) and Type 2 diabetes (T2DM). Recently, the American Diabetes Association (ADA) recommended screening for NASH and advanced fibrosis in patients with diabetes and hepatic steatosis or elevated plasma alanine aminotransferase (ALT). This is because as many as ~30% to 40% may have NASH and ~10% to 15% advanced fibrosis. The role of hyperglycemia and the natural history of NASH in diabetes remain poorly understood, as well as which diagnostic algorithm or interventions are most cost‐effective. There is significant clinical inertia and most patients today are still not receiving adequate lifestyle intervention or pharmacological treatment with diabetes agents known to be effective against NASH. Lifestyle intervention improves steatohepatitis in proportion to the magnitude of weight loss, but this trend is not as consistent for regression of fibrosis. This limited success supports the need for concomitant pharmacological therapy. Pioglitazone has been shown to consistently induce resolution of NASH in both patients with or without diabetes in a total of 498 participants in five randomized controlled trials (RCTs), but with modest effects on liver fibrosis. Proof‐of‐concept studies suggest a potential role for GLP‐1RAs and SGLT2 inhibitors. Combination therapy is on the horizon. Treating diabetes and NASH with a combination of pioglitazone, GLP‐1RAs or SGLT2i, could be a cost‐effective strategy to treat both diseases while reducing their high cardiovascular risk. Future combination therapies will likely combine existing diabetes agents with novel NASH‐spechfic drugs under development. This review highlights current knowledge gaps and proposes future directions for the treatment of NASH in diabetes.

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“…In the current study, FIB4 index was significantly decreased after 12-month SGLT2i treatment in the group with high value of the baseline FIB4 index, suggesting that SGLT2is may improve fibrosis in the liver in patients with advanced fibrosis. Several reports showed that SGLT2i treatment reduced scores of fibrosis as well as steatosis and ballooning by histological examinations [9,24]. Shimizu et al assessed fibrosis in the liver by measuring liver stiffness with the transient elastography and reported that a significant improvement of liver stiffness after 24-week dapagliflozin was only observed in the patients with high degree of baseline liver stiffness [10].…”

Section: Discussionmentioning

confidence: 99%

“…The improvement of hepatic steatosis was observed in human and animal studies, which could lead to reductions of inflammation and oxidative stress in the liver [8]. Moreover, several reports also demonstrated that SGLT2i treatment attenuated fibrosis in the liver by histological examinations or noninvasive measurements using transient elastography [9,10]. However, the number of studies evaluating the effects of SGLT2is on hepatic fibrosis in clinical practice is limited.…”

Section: Introductionmentioning

confidence: 99%

Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Hepatic Fibrosis in Patients With Type 2 Diabetes: A Chart-Based Analysis

et al. 2020

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Background:The presence of nonalcoholic fatty liver diseases (NAFLDs) and type 2 diabetes was associated with elevated risks of cardiovascular events as well as the progression of NAFLD to fibrosis/cirrhosis and hepatocellular carcinoma. Sodium-glucose cotransporter 2 inhibitor (SGLT2i) is a widely used antidiabetic drug, which promotes urinary excretion of glucose. Recent animal and human studies demonstrated the beneficial effects of SGLT2is on lipid accumulation and fibrosis in the liver. The purpose of the current study was to elucidate the effects of SGLT2is on hepatic fibrosis in the realworld setting. Methods:We selected patients with type 2 diabetes who had been prescribed SGLT2is continuously for 12 months between April 1, 2014 and March 31, 2018 by a chart-based analysis. We compared the data before the SGLT2is treatment with the data at 6 and 12 months after the SGLT2is treatment started. Fibrosis in the liver was evaluated by fibrosis-4 (FIB4) index. Results:We enrolled 315 patients in this study. The body weight, body mass index (BMI), serum levels of aspartate aminotransferase, alanine aminotransferase and γ-glutamyl transferase were significantly decreased at 6 months and maintained at 12 months, whereas there was no significant change in FIB4 index. We divided the studied patients into three groups according to the baseline FIB4 index. Only in the group of high value of the baseline FIB4 index, FIB4 index was significantly decreased at 12 months. The correlations between the change of FIB4 index during 12-month SGLT2i treatment was correlated inversely with the baseline FIB4 index. Conclusion:Present study demonstrated that SGLT2i could ameliorate fibrosis in the liver in high-risk patients for hepatic fibrosis.

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Empagliflozin for the Treatment of Nonalcoholic Steatohepatitis in Patients with Type 2 Diabetes Mellitus

Cited by 130 publications

References 33 publications

Empagliflozin Effectively Lowers Liver Fat Content in Well-Controlled Type 2 Diabetes: A Randomized, Double-Blind, Phase 4, Placebo-Controlled Trial

Empagliflozin Effectively Lowers Liver Fat Content in Well-Controlled Type 2 Diabetes: A Randomized, Double-Blind, Phase 4, Placebo-Controlled Trial

A diabetologist’s perspective of non‐alcoholic steatohepatitis (NASH): Knowledge gaps and future directions

Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Hepatic Fibrosis in Patients With Type 2 Diabetes: A Chart-Based Analysis

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