Letter: Lubiprostone Treatment for MASLD—Gender Imbalance and Blinding Considerations. Authors' Reply

Abstract

We appreciate the comments of Drs. Li and Shen [1] on our recent study [2] investigating the effects of lubiprostone in metabolic dysfunction-associated steatotic liver disease (MASLD). Their concerns regarding gender imbalance and blinding considerations provide an opportunity to further clarify our study design and findings.

First, we acknowledge that our study population had a higher proportion of female participants, with 83% in the control group and 91% in the lubiprostone group. This gender distribution reflects real-world epidemiological patterns, where MASLD is increasingly prevalent among women, particularly in regions with high obesity and metabolic syndrome rates [3]. Recent data from Egypt indicate that obesity prevalence in adults is among the highest globally, with significantly higher rates in females (49.5%) compared to males (29.5%) [4].

Secondly, while oestrogen may play a role in MASLD pathophysiology [5], the randomization process in our study ensured an equal distribution of potential confounders across both groups. Furthermore, baseline characteristics—including BMI, lipid profiles, and liver enzymes—were comparable, minimising the likelihood that hormonal differences influenced our results. Future studies may benefit from stratified randomisation based on menopausal status or direct oestrogen level assessments to explore this aspect further.

Additionally, Li and Shen raise concerns regarding the potential for participants to infer their treatment allocation due to lubiprostone's well-documented gastrointestinal effects. While we recognise that laxatives may induce a noticeable physiological response [6], our study adhered to a rigorous double-blind design in which both patients and healthcare providers were unaware of group allocation. Importantly, patient-reported outcomes were not a primary endpoint, reducing the potential for subjective bias. Although the suggestion of incorporating a dummy laxative as a control arm is theoretically appealing, it presents ethical and logistical challenges, including potential confounding effects. That said, future trials incorporating validated blinding assessment tools could provide additional reassurance regarding the robustness of blinding procedures.

Finally, our trial focused on MASLD patients without advanced fibrosis, with liver enzyme levels below 40 U/L. This was an intentional design choice to examine lubiprostone's effects on hepatic steatosis in a relatively homogenous population. We agree that studying patients with more severe MASLD, including those with elevated ALT and significant fibrosis, is crucial. The long-term safety of lubiprostone, particularly in patients with metabolic comorbidities, warrants further study in larger, multi-centre trials with extended follow-up periods.