Sabine Kahl1,2, Sofiya Gancheva1,2,3, Klaus Straßburger2,4, Christian Herder1,2, Jürgen Machann2,5, Hisayuki Katsuyama1,2, Stefan Kabisch2,6, Elena Henkel7, Stefan Kopf2,8, Merit Lagerpusch2,6, Konstantinos Kantartzis2,5, Yuliya Kupriyanova1,2, Daniel Markgraf1,2, Theresa van Gemert1,2,3, Birgit Knebel2,9, Martin F Wolkersdorfer10, Oliver Kuss2,4, Jong-Hee Hwang1,2, Stefan R Bornstein11, Christian Kasperk2,8, Norbert Stefan2,5, Andreas Pfeiffer2,6,12, Andreas L Birkenfeld2,9, Michael Roden13,2,3. 1. Institute for Clinical Diabetology, German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich-Heine University, Düsseldorf, Germany. 2. German Center for Diabetes Research, München-Neuherberg, Germany. 3. Division of Endocrinology and Diabetology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany. 4. Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich-Heine University, Düsseldorf, Germany. 5. Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany. 6. Department of Clinical Nutrition, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany. 7. Clinical Study Center of Metabolic Vascular Medicine, GWT-TUD GmbH, Dresden, Germany. 8. Department of Internal Medicine 1 and Clinical Chemistry, University Hospital of Heidelberg, Heidelberg, Germany. 9. Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich-Heine University, Düsseldorf, Germany. 10. Landesapotheke Salzburg, Salzburg, Austria. 11. Paul Langerhans Institute Dresden, Helmholtz Center Munich at University Hospital MKIII, and Faculty of Medicine, TU Dresden, Dresden, Germany. 12. Department of Endocrinology, Diabetes and Nutrition, Campus Benjamin Franklin, Charité University Medicine, Berlin, Germany. 13. Institute for Clinical Diabetology, German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich-Heine University, Düsseldorf, Germany michael.roden@ddz.de.
Abstract
OBJECTIVE: To evaluate whether the sodium-glucose cotransporter 2 inhibitor empagliflozin (EMPA) reduces liver fat content (LFC) in recent-onset and metabolically well-controlled type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: Patients with T2D (n = 84) (HbA1c 6.6 ± 0.5% [49 ± 10 mmol/mol], known disease duration 39 ± 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 -1.8% (95% CI -3.4, -0.2; P = 0.02) and relative change in LFC of -22% (-36, -7; P = 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 -2.5 kg [-3.7, -1.4]; 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 (-74 mol/L [-108, -42]; 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.
RCT Entities:
OBJECTIVE: To evaluate whether the sodium-glucose cotransporter 2 inhibitor empagliflozin (EMPA) reduces liver fat content (LFC) in recent-onset and metabolically well-controlled type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: Patients with T2D (n = 84) (HbA1c 6.6 ± 0.5% [49 ± 10 mmol/mol], known disease duration 39 ± 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 -1.8% (95% CI -3.4, -0.2; P = 0.02) and relative change in LFC of -22% (-36, -7; P = 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 -2.5 kg [-3.7, -1.4]; 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 (-74 mol/L [-108, -42]; 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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