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

• DOI: 10.2337/dc19-0641
• Publication Date: 2019-09-20T14:14:06Z
• Authors: Sabine Kahl; Sofiya Gancheva; Klaus Straßburger; Christian Herder; Jürgen Machann; Hisayuki Katsuyama; Stefan Kabisch; Elena Henkel; Stefan Kopf; Merit Lagerpusch; Konstantinos Kant...; Yuliya Kupriyanova; Daniel Markgraf; Theresa van Gemert; Birgit Knebel; Martin F. Wolkers...; Oliver Kuss; Jong-Hee Hwang; Stefan R. Bornstein; Christian Kasperk; Norbert Stefan; Andreas Pfeiffer; Andreas L. Birken...; Michael Roden
• Keywords: Blood Glucose; Male; 0301 basic medicine; 2902 Advanced and Specialized Nursing; 10265 Clinic for Endocrinology and Diabetology; Down-Regulation; 610 Medicine & health; Placebos; 03 medical and health sciences; Double-Blind Method; Glucosides; Non-alcoholic Fatty Liver Disease; Germany; Weight Loss; Humans; Hypoglycemic Agents; Benzhydryl Compounds; Adiposity; Aged; Middle Aged; 3. Good health; 2712 Endocrinology, Diabetes and Metabolism; Adipose Tissue; Diabetes Mellitus, Type 2; Liver; 2724 Internal Medicine; Female; Insulin Resistance

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.