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The PNPLA3 I148M variant is associated with transaminase elevations in type 2 diabetes patients treated with basal insulin peglispro

The Pharmacogenomics Journal volume 18, pages 487–493 (2018)Cite this article

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Abstract

Basal insulin peglispro (BIL) is a novel insulin with hepato-preferential action. In phase 3 trials, BIL showed significantly improved glycemic control but higher levels of transaminases (alanine aminotransferase (ALT) and aspartate aminotransferase (AST)), triglycerides (TGs) and liver fat content (LFC) compared with insulin glargine (GL). As variants in PNPLA3 (I148M) and TM6SF2 (E167K) are associated with nonalcoholic fatty liver disease, we assessed these variants in type 2 diabetes (T2D) patients randomized to receive BIL (n=1822) or GL (n=1270) in three phase 3 trials. Magnetic resonance imaging assessments of LFC were conducted in a subset of patients (n=296). Analyses showed α-corrected significant increases in change from baseline in AST (P=0.0004) and nominal increases in ALT (P=0.019), and LFC (P=0.035) for PNPLA3 (148M/M) genotypes in the BIL arm at 26 weeks but no significant associations in GL. PNPLA3 (148M/M) was also associated with increases in total cholesterol (P=0.014) and low-density lipoprotein cholesterol (P=0.005) but not with hemoglobin A1c or TG. T2D patients with the PNPLA3 (148M/M) genotype treated with BIL may be more susceptible to increased liver fat deposition. The current data provide further insights into the biological role of PNPLA3 in lipid metabolism.

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Acknowledgements

We thank the patients who consented to participate in the IMAGINE 2, 4 and 5 trials. Eli Lilly and Company was the sponsor of this study. We also thank Robert Panek of INC Research LLC, Raleigh, NC, for providing medical writing assistance.

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  1. Eli Lilly and Company, Indianapolis, IN, USA

    S Pillai, S Duvvuru, P Bhatnagar, W Foster, M Farmen, S Shankar, C Harris, B Hoogwerf & A Haupt

  2. Division of Endocrinology and Metabolism, Indiana University School of Medicine, Indianapolis, IN, USA

    E Bastyr III

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Correspondence to S Pillai.

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The authors declare no conflict of interest. SP, SD, PB, WF, MF, SS, CH, BH and AH are employees and shareholders of Eli Lilly and Company. EB was an employee of Eli Lilly and Company during the trial and is currently a consultant to Viacyte, San Diego, CA, USA.

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Pillai, S., Duvvuru, S., Bhatnagar, P. et al. The PNPLA3 I148M variant is associated with transaminase elevations in type 2 diabetes patients treated with basal insulin peglispro. Pharmacogenomics J 18, 487–493 (2018). https://doi.org/10.1038/tpj.2017.45

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