Background and Aim: T2D increases the prevalence of steatosis and steatohepatitis (NASH). The aim was to assess the relationship between T2D and two histological features of liver injury defining the need for therapy: disease activity grade (NAS) and fibrotic scar (F).

Methods: 2363 patients with metabolic steatosis were screened for the phase 3 elafibranor trial RESOLVE-IT (NTC02704403) with a liver biopsy centrally scored for NAS and F. 71% had obesity, 47% dyslipidemia, 81% MetS. 35% had T2D, 88% of them managed by ≥1 OAD or insulin. Prevalence of active disease (NAS≥4), significant fibrosis (F≥2) and progressive NASH (NAS≥4 with F≥2, i.e., "at-risk" of hepatic outcomes) and clinical and biochemical NASH phenotype was assessed according to the T2D status.

Results: The overall prevalence of "at-risk" NASH was 53%, 65% for T2Ds (n=835), and 45% for non-T2Ds (n=1528). T2D was a significant risk factor (p<0.001) for “at-risk” NASH (OR=2.20, 95% CI [1.85;2.62]), NAS≥4 (OR=1.74, 95% CI [1.40;2.16]) and F≥2 (OR=2.50, 95% CI [2.08;3.01]). The association between T2D and “at risk” NASH was independent of age, gender or BMI. T2D patients had higher mean NAS scores (4.96 vs. non-T2Ds: 4.47; p<0.001) and higher mean fibrosis stage (2.17 vs. non-T2D: 1.67; p<0.001). Liver injury markers ALT, AST, GGT or CK18 were higher (p<0.001) in “at-risk” NASH patients but were similar in T2Ds vs. non-T2Ds. Fibrosis serum markers such as TIMP-1, HA, A2M, or P3NP were elevated in “at-risk” NASH patients (p<0.001) and were higher in T2Ds vs. non-T2Ds (p<0.001). In both non-T2D and T2D, HbA1c and glucose homeostasis markers remained higher in “at-risk” NASH (p<0.001).

Conclusion: In patients with metabolic steatosis, T2D is associated with necroinflammation and fibrosis and independently increases the risk of developing “at-risk” NASH, highlighting the need for active surveillance of liver injury in T2D patients to identify those in need for clinical intervention.


B. Staels: None. V. Ratziu: Other Relationship; Self; Gilead Sciences, Inc. A.J. Sanyal: Consultant; Self; Ardelyx, Boehringer Ingelheim Pharmaceuticals, Inc., Exhalenz, Gilead Sciences, Inc., Hemoshear, Intercept Pharmaceuticals, Inc., Lilly, Mallinckrodt Pharmaceuticals, Nimbus Therapeutics, Nitto Denko, Novartis Pharmaceuticals Corporation, Pfizer Inc. Employee; Self; Sanyal Bio. Research Support; Self; Bristol-Myers Squibb Company, Conatus Pharmaceuticals Inc., Echosens, Galectin Therapeutics Inc., Immuron Ltd, Merck & Co., Inc., Salix Pharmaceuticals, Sequanna. Stock/Shareholder; Self; Akarna Therapeutics, GENFIT, Natural Shield, NewCo LLC, Tiziana. Other Relationship; Self; Elsevier, UpToDate. S. Francque: Consultant; Self; GENFIT. S.A. Harrison: Advisory Panel; Self; Gilead Sciences, Inc. A. Roudot: Employee; Self; GENFIT. J. Brozek: Employee; Self; GENFIT. Y. Hajji: Employee; Self; GENFIT. S. Megnien: Employee; Self; GENFIT. D.W. Hum: Employee; Self; GENFIT. P. Birman: Employee; Self; GENFIT. R. Hanf: Employee; Self; GENFIT. B. Cariou: Board Member; Self; Novo Nordisk A/S, Regeneron Pharmaceuticals. Consultant; Self; GENFIT, Sanofi-Aventis. Research Support; Self; Amgen Inc., Pfizer Inc. Speaker’s Bureau; Self; Abbott, Akcea Therapeutics, Merck Sharp & Dohme Corp.

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