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SGLT2 inhibitors could ameliorate hepatic dysfunction through glycemic improvement

Diabetes
7 months ago, OP Editor

The benefits of sodium-glucose co-transporter 2 (SGLT2) inhibitors beyond their glucose-lowering effect continue to expand. In a study that included type 2 diabetes patients at the Diabetes Clinic of Queen Mary Hospital, Prof. Karen Lam and the research team from the University of Hong Kong (HKU) and Nantong University, China, explored the relationship between the amelioration of hepatic dysfunction and the improvement in various metabolic parameters brought about by dapagliflozin and empagliflozin.1 The findings from this clinical audit were published in Diabetes Therapy.1

A recent prospective cohort study of 1,918 type 2 diabetes patients in Hong Kong has revealed the high prevalence of non-alcoholic fatty liver disease (NAFLD).2 However, type 2 diabetes itself is an important risk factor for the development and progression of NAFLD.1,3 The reciprocal relationship between NAFLD and type 2 diabetes can therefore act synergistically to drive adverse outcomes, leading to not only a more severe form of NAFLD, but also chronic vascular complications of diabetes.3

Reduction in serum alanine transferase (ALT) levels in patients taking SGLT2 inhibitors have been reported in clinical trials, with the most recent evidence coming from the small E-LIFT study that was presented at the ENDO 2018: The Endocrine Society Annual Meeting.4 Nonetheless, the study by the researchers from the HKU and Nantong University, China, provided a timely evidence that SGLT2 inhibitors may improve metabolic parameters as well as ameliorate hepatic dysfunction as a class.1

Between July 2016 and February 2017, 115 patients with type 2 diabetes who received either dapagliflozin or empagliflozin were included in the analysis.1 Almost all patients (95.7%) were concurrently receiving metformin, but approximately one-third of the study population were also on dipeptidyl-peptidase-4 (DPP4) inhibitors or sulphonylureas.1 Of note, 66 patients were on background insulin therapy.1 At baseline, the mean body mass index (BMI) was 30.5 ± 5.8kg/m2 and the mean HbA1c was 8.6 ± 1.4%.1

After 6 months of treatment with SGLT2 inhibitors, the clinical audit found significant improvements in metabolic parameters (body weight, systolic blood pressure, fasting glucose, and HbA1c),1 which was consistent with the findings from major clinical trials of SGLT2 inhibitors.5

Serum ALT levels were significantly reduced from 40.3 ± 28.0U/L to 29.0 ± 14.1U/L (p<0.001).1 “The results were consistent among various subgroups, whether with or without background insulin therapy, and whether dapagliflozin-treated or empagliflozin-treated,” the researchers wrote.1

By using the serum ALT cut-off of 30U/L (suggested for Asians), more patients had normal ALT levels after 6 months of treatment, as compared with baseline (71% vs. 54%; p=0.002).1 Similar findings were demonstrated by using the conventional serum ALT cut-off of 40U/L (95% vs. 71%; p<0.001).1

Meanwhile, serum AST levels also decreased significantly from 28.2 ± 13.2U/L to 23.1 ± 7.5U/L (p<0.001), and serum albumin increased significantly from 43.3 ± 3.1U/L to 43.9 ± 3.1U/L (p=0.017).1

Multiple linear regression analysis revealed that the improvements in serum ALT levels were associated with the alleviation of hyperglycemia (i.e. changes in HbA1c [p=0.043] and fasting glucose [p=0.014]), independent of body weight reduction.1 This supports the notion of “the contribution of glycemic improvement towards the amelioration of hepatic dysfunction being much more important than body weight reduction,” they wrote.1

Nonetheless, the researchers did not exclude that the amelioration of hepatic dysfunction could also be due to factors other than weight reduction.1 “Further prospective studies with larger sample sizes are certainly warranted to provide mechanistic insights into the benefits of SGLT2 inhibitors in reversing hepatic dysfunction of type 2 diabetes,” they concluded.1

1. Lee PCH, Gu Y, Yeung MY, et al. Dapagliflozin and Empagliflozin Ameliorate Hepatic Dysfunction Among Chinese Subjects with Diabetes in Part Through Glycemic Improvement: A Single-Center, Retrospective, Observational Study. Diabetes Ther. 2018;9(1):285-295.

2. Kwok R, Choi KC, Wong GL, et al. Screening diabetic patients for non-alcoholic fatty liver disease with controlled attenuation parameter and liver stiffness measurements: a prospective cohort study. Gut. 2016;65(8):1359-68.

3. Targher G, Lonardo A, Byrne CD. Nonalcoholic fatty liver disease and chronic vascular complications of diabetes mellitus. Nat Rev Endocrinol. 2018;14(2):99-114.

4. Empagliflozin Eyed for Fatty Liver Disease in Type 2 Diabetes. Medscape. 2018 (Accessed April 25, 2018, at https://www.medscape.com/viewarticle/894326).

5. Kashiwagi A, Maegawa H. Metabolic and hemodynamic effects of sodium-dependent glucose cotransporter 2 inhibitors on cardio-renal protection in the treatment of patients with type 2 diabetes mellitus. J Diabetes Investig. 2017;8(4):416-427.

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