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Randomized Controlled Trial
. 2022 Nov 15;17(11):e0277706.
doi: 10.1371/journal.pone.0277706. eCollection 2022.

Improvement of non-invasive tests of liver steatosis and fibrosis as indicators for non-alcoholic fatty liver disease in type 2 diabetes mellitus patients with elevated cardiovascular risk profile using the PPAR-α/γ agonist aleglitazar

Esmée J Grobbee  1 , Vivian D de Jong  2   3 , Ilse C Schrieks  3 , Maarten E Tushuizen  4 , Adriaan G Holleboom  5 , Jean-Claude Tardif  6 , A Michael Lincoff  7 , Gregory G Schwartz  8 , Manuel Castro Cabezas  3   9   10 , Diederick E Grobbee  2   3
Affiliations
Randomized Controlled Trial

Improvement of non-invasive tests of liver steatosis and fibrosis as indicators for non-alcoholic fatty liver disease in type 2 diabetes mellitus patients with elevated cardiovascular risk profile using the PPAR-α/γ agonist aleglitazar

Esmée J Grobbee et al. PLoS One. .

Abstract

Background: Peroxisome proliferator-activated receptor (PPAR) agonists may have favorable outcomes on non-alcoholic fatty liver disease. This study serves as proof of concept to evaluate whether dual PPAR-α/γ agonists improve non-invasive tests of liver steatosis and fibrosis.

Methods: This is a post-hoc analysis of a randomized, double-blind, placebo-controlled, multi-center trial comprising 7226 patients with type 2 diabetes mellitus and recent coronary artery disease randomized to receive aleglitazar, a PPAR-α/γ agonists, or placebo for two years. Main outcomes were change in non-invasive tests for liver steatosis and fibrosis: Liver Fat Score (LFS), Liver Accumulation Product (LAP), Fibrosis-4 (FIB-4), and NAFLD Fibrosis Score (NFS).

Results: LFS, LAP and FIB-4 decreased upon treatment, whereas scores in the placebo group remained the same or increased (P<0.001). NFS responded differently but remained consistently lower than placebo. In the treatment group more participants shifted to a lower FIB-4 and NFS category, or improved in respect to the LAP cut-off values compared to the placebo group (P<0.001 for FIB-4 and LAP, P<0.004 for NFS). LFS had a low discriminative power in this study.

Conclusion: This post-hoc analysis showed improvement of non-invasive tests of liver steatosis and fibrosis after starting dual PPAR-α/γ agonist treatment, adding to the evidence that this pathway has potential in non-alcoholic fatty liver disease treatment.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Change in NITs of liver steatosis and fibrosis from baseline.
Value at baseline for A: Median LFS of 0.60 for placebo and 0.63 for aleglitazar, B: Mean LAP of 69.5 for placebo and 67.8 for aleglitazar, C: Mean FIB-4 of 1.40 for placebo and 1.44 for aleglitazar, D: Mean NFS of -0.50 for placebo and -0.41 for aleglitazar. Error bars indicate 95% CIs. Change from baseline is significantly different in the aleglitazar and the placebo group at all timepoints ≥3 mohs for all proxies (all P<0.001).
Fig 2
Fig 2. Change in AST/ALT ratio and BMI from baseline.
Value at baseline for A: Mean AST/ALT of 1.21 for placebo and 1.22 for aleglitazar, B: Mean BMI of 29.5 kg/m2 for placebo and 29.3 kg/m2 for aleglitazar. Error bars indicate 95% CIs. Change from baseline is significantly different in the aleglitazar and the placebo group at all timepoints ≥1 month for both AST/ALT ratio and BMI (all P<0.001).
Fig 3
Fig 3. Change in FIB-4 and NFS category from baseline until 24 months follow-up.
Proportion of randomized patients that either improved (changed to a lower category), worsened (changed to a higher category) or did not change in category. Proportion of change is significantly different between treatment and placebo for FIB-4 (A) and NFS (B). FIB-4: Both improvement and worsening P<0.001, NFS: Improvement P<0.004, worsening P = 0.024.
Fig 4
Fig 4. Change in LFS and LAP compared to cut-off values at baseline until 24 months follow-up.
Proportion of randomized patients that either improved (lnLAP below cut-off <4 for males and <4.4 for females, LFS below cut-of <-0.640), worsened (lnLAP above cut-off >4 for males and >4.4 for females, LFS above cut-off >-0.064), or did not change in respect to respective cut-off value. Proportion of change is significantly different between treatment and placebo for LAP (A), both improvement and worsening P<0.001. For LFS (B) only worsening is significantly less in the treatment group, improvement P = 0.974, worsening P = 0.031.
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The author(s) received no specific funding for this work. The original AleCardio trial was sponsored by F. Hoffmann-La Roche (Basel, Switzerland). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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