Pioglitazone (PIO) therapy results in a ∼60% resolution of NASH in patients with prediabetes or T2DM. However, the effects of treatment discontinuation have not been carefully examined. To this end, we assessed plasma aminotransferases (LFTs) after study drug discontinuation among patients who had completed 36 months (n=63) of our randomized, controlled trial (RCT) of PIO for NASH (Cusi, et al. Ann Intern Med 2016). This was an 18 month RCT of PIO 45mg QD vs. placebo (and dietary counseling in all), followed by 18 months of open label PIO. We retrospectively assessed LFTs for 18 months following study discontinuation. PIO normalized plasma ALT, an indicator of hepatocyte injury in NASH, within 3 months of therapy initiation (from 61±5 to 35±2 U/L; p<0.001) and for the duration of treatment (Figure 1).
However, PIO discontinuation resulted in a rapid rebound of LFTs after 3 months (from 30±2 to 42±7 U/L, p=0.02), and continued to increase over time, reaching the highest levels 18 months after discontinuation (59±12 U/L, p<0.001 vs. end of the trial). Plasma AST followed a similar pattern during treatment and after discontinuation.
Conclusion: PIO rapidly normalizes LFTs in NASH and improves liver histology, but its discontinuation results in an abrupt increase in LFTs, likely reflecting NASH recurrence. Therefore, PIO therapy for NASH should be considered as a long-term management approach.
F. Bril: None. R. Lomonaco: None. S. Kalavalapalli: None. J. Lai: None. K. Cusi: Consultant; Self; Allergan, AstraZeneca, Genentech, Inc., Novo Nordisk Inc., Poxel SA, ProSciento. Research Support; Self; Cirius Therapeutics, Echosens, Eli Lilly and Company, Inventiva Pharma, Janssen Research & Development, Novartis AG, Novo Nordisk Inc.
American Diabetes Association (1-08-CR-08 to K.C.); Burroughs Wellcome Fund; National Center for Research Resources (M01-RR-01346); University of Texas Health Science Center at San Antonio; U.S. Department of Veterans Affairs