Previous focus on treatment of comorbidities
EPLs currently the most promising adjunctive treatment option
Some recently published therapeutic guidelines recommend limiting the damage to the liver by administering “hepatoprotective” medicinal products [1–3]. Figure 1 from a recent narrative review  presents a schematic diagram summarising the currently available data concerning the efficacy of and the evidence for different hepatoprotective agents in the treatment of NAFLD. As can be seen from Figure 1, no convincing data exists for ursodeoxycholic acid (UDCA), vitamin D, resveratrol, Phyllanthus, garlic, coenzyme Q10 (ubiquinone), ademetionine, milk thistle seed extract (silymarin) or glycyrrhizic acid concerning their efficacy in NAFLD. There are indications of a therapeutic effect for metadoxine and artichoke, but the evidence level here is low. However, vitamin E (potentially combined with vitamin C) and essential phospholipids (EPLs) show positive effects for which there is a high level (Vit. C) or medium level (EPLs) of evidence. For vitamin E, though, there is an increased risk of side effects following longer-term use of high doses (symbolised by the asterisk in Fig. 1) . This makes EPLs medicinal products currently the most promising (adjuvant) therapy option for NAFLD.
Fig. 1. Schematic diagram on the available data concerning the efficacy of and the evidence for different hepatoprotective agents in the treatment of NAFL . * long-term use of high doses
Meta-analysis confirms benefit of EPLs
A recent meta-analysis  comprehensively investigated the state of knowledge concerning the use of EPLs in patients with NAFLD. Although many of the analysed studies are relatively small, in total they provide several pieces of evidence indicating the therapeutic benefit of EPLs in NAFLD. In nearly all studies, EPLs – either on their own or as part of combination therapy – improved the course of the disease. NAFLD patients with type 2 diabetes and/or obesity profited from the administration of EPLs by a reduction of alanine aminotransferase (ALT; Fig. 2A), triglyceride (Fig. 2B), and cholesterol levels (Fig. 2C), and experienced an improvement in the severity of the disease (Fig. 2D) . Most studies lasted at least several months, providing evidence for the safety of EPLs with longer-term use.
When compared to antidiabetic therapy alone, the meta-analysis showed that a combination of antidiabetic therapy with EPLs is more likely to improve the overall disease while reducing the probability of developing severe steatosis. The aggregated estimated value for the proportion of patients showing clinical improvement was 87%, based on data from three studies (n = 205) over a mean duration of 2.47 months. The aggregated estimated value for the proportion of patients showing significant clinical improvement was 58%, based on data from four studies (n = 357) with a mean duration of 3.97 months.
Overall, the meta-analysis  provided good evidence of beneficial effects of EPLs in NAFLD patients with diabetes and/or obesity. Administration of EPLs is already recommended for NAFLD in Russian  and Latvian  guidelines. Based on the data presented here, additional countries could soon follow.
Fig. 2. Results of the direct meta-analyses (random effects model) of randomized controlled trials comparing EPLs and antidiabetic therapy with antidiabetic therapy (control). A: Change in alanine aminotransferase levels; B: Change in triglyceride levels; C: Change in total cholesterol levels; D: Relative risk of recovery  MD: Mean difference; CI: Confidence interval; RE: Random effects; RR: Relative risk; ALT: Alanine aminotransferase.
- Fan JG, Wei L, Zhuang H, et al. Guidelines of prevention and treatment of non-alcoholic fatty liver disease (2018, China). J Dig Dis 2019;20(4):163–73
- Russian Scientific Liver Society. Diagnosis and treatment of non-alcoholic fatty liver disease. 2015. http://www.rsls.ru/files/Guidelines-RSLS-NASH-2016-01-03.pdf
- Society of Digestive Diseases (Latvia). [Clinical practical guidelines for diagnostics, treatment and monitoring of non-alcoholic fatty liver disease]. 2020. https://www.globalliverforum.com/-/media/Project/One-Sanofi-Web/Websites/Chc/Essentiale/Liver-Health-forum-HCP/Home/resources-for-your-clinical-practice/Vadlinijas_en-GB.pdf
- Dajani AI, Abuhammour A. Agents for the treatment of fatty liver disease: focus on essential phospholipids. Drugs Ther Perspect 2021;37:249–64. https://doi.org/10.1007/s40267-021-00838-x
- Dajani AI, Popovic B. Essential phospholipids for non-alcoholic fatty liver disease associated with metabolic syndrome: A systematic review and network meta-analysis. World J Clin Cases 2020;8(21):5235–49
Conflict of interest: L. Petcu and B. Popovic are employees of Sanofi.
Disclosures: Medical writing and publication funded by Sanofi.