This is a retrospective study about SGLT2 inhibitors and GLP-1 analogues’ impact on various parameters such as liver function tests, HbA1c levels, and weight/BMI.

As the authors mentioned in the article, there are few studies about the aforementioned drugs’ effects on solid organ transplant patients, especially the liver, and their lab values.

Therefore, this work should be counted as an original scientific investigation. However, I have some suggestions and concerns about the article:

Major:

1. Investigators should specify in the methods section which PTDM criteria they used to include patients in this study since definitions evolved over the years.

2. Exclusion and inclusion criteria should be defined delicately (for example by using a flowchart) because many other drugs, adverse effects, and non-hepatologic comorbidities could alter eGFR, AST/ALT, and weight.

Even though their primary values are not significantly different, they can change along the way.

1. Unfortunately, the groups are unmatched; investigators did not pair immunosuppressive or other antidiabetic treatments like insulin and metformin (mentioned in the limitations paragraph), and many other variables between the case and comparison groups.

Indeed, the given parameters are not sufficient to conclude. As mentioned we cannot decide without the proper histology. This aspect decreases the clinical significance of the ultimate product.

1. Personalized diabetic treatments in liver transplantation (SGLT-2i and GLP-1 analogues are important components) might be added to the discussion section to stress the importance of individualised treatment models.

For instance, Richardson et. al. or Adnan Sharif et. al. could be integrated into the discussion as the authors wish. (1,2)

Minor:

1. Missing data should be highlighted since there are different statistical methods to incorporate these cases into the study. For example, did you omit cases with missing data, or imputations or use statistical estimation techniques?

2. How did you decide to involve this many patients in this study, any preliminary analysis? It is better to discuss generalizability in the limitations section.

3. (Between lines 38-41, page 12) The reference article’s investigational population is mixed such as heart, kidney and liver therefore should be mentioned.

4. (Between lines 17-21, page 13) The reference article is not directly related to the correlation between subsequent weight loss and transaminase levels.

Therefore, that should be revised. For example, this statement could be revised by using Atthota et. al. or Rezaei S et. al. as the authors wish. (3,4)

References:

1. Richardson B, Khan MQ, Brown SA, Watt KD, Izzy M. Personalizing Diabetes Management in Liver Transplant Recipients: The New Era for Optimizing Risk Management. Hepatol Commun. 2022 Jun;6(6):1250-1261. doi: 10.1002/hep4.1876. Epub 2021 Dec 17. PMID: 34921530; PMCID: PMC9134800.

2. Adnan Sharif, Harini Chakkera, Aiko P J de Vries, Kathrin Eller, Martina Guthoff, Maria C Haller, Mads Hornum, Espen Nordheim, Alexandra Kautzky-Willer, Michael Krebs, Aleksandra Kukla, Amelie Kurnikowski, Elisabeth Schwaiger, Nuria Montero, Julio Pascual, Trond G Jenssen, Esteban Porrini, Manfred Hecking, International consensus on post-transplantation diabetes mellitus, Nephrology Dialysis Transplantation, Volume 39, Issue 3, March 2024, Pages 531–549, https://doi.org/10.1093/ndt/gfad258

3. Atthota S, Joyal K, Cote M, Scalzo R, Singh R, Consul N, Kilcoyne A, Bethea ED and Dageforde LA (2023) Modern glucose-lowering drugs in liver transplant recipients: improvement in weight, glycemic control, and potentially allograft steatosis. Front. Transplant. 2:1223169. doi: 10.3389/frtra.2023.1223169

4. Rezaei S, Tabrizi R, Nowrouzi-Sohrabi P, Jalali M, Atkin SL, Al-Rasadi K, Jamialahmadi T, Sahebkar A. GLP-1 Receptor Agonist Effects on Lipid and Liver Profiles in Patients with Nonalcoholic Fatty Liver Disease: Systematic Review and Meta-Analysis. Can J Gastroenterol Hepatol. 2021 Nov 12;2021:8936865. doi: 10.1155/2021/8936865. PMID: 34805029; PMCID: PMC8604595.

Dear Researchers,

Your retrospective study exploring the impact of SGLT-2 inhibitors and GLP-1 analogues in the context of liver transplantation presents valuable insights, yet it is crucial to address some notable limitations.

While acknowledging the shared pathophysiologic features between diabetes mellitus (DM) and post-transplant diabetes mellitus (PTDM), I concur with the decision to conduct separate analyses of different endocrinologic entities with different clinical outcomes.

(1) This approach is prudent for mitigating heterogeneity and facilitating the generation of compelling insights for the literature. I want to stress that differences between clinical profiles of these two groups is delicately defined in many studies.

(2,3) The presence of numerous confounders, including unmatched groups, specific drug indications, and background comorbidities, underscores the importance of this parting of analyses. By isolating DM and PTDM cohorts, the study can more effectively disentangle the intricate interplay of factors influencing outcomes post-liver transplantation.

Your inclusion of new figures is commendable, as they serve to enrich the reader's understanding. Specifically, incorporating variables like metformin and insulin into the analysis is pivotal.

These additions provide a more comprehensive view of the factors influencing outcomes, enhancing the utility of your research.

It's heartening to note that your responses to critiques have been thorough and elucidating.

By addressing unclear points and offering clarification, you've bolstered the overall quality of your paper.

Despite the acknowledged limitations, I believe your study holds significant merit and contributes meaningfully to the literature. With careful consideration of these limitations and transparent reporting, your findings offer valuable insights into the management of diabetes post-liver transplantation.

1.Lieber SR, Lee RA, Jiang Y, Reuter C, Watkins R, Szempruch K, Gerber DA, Desai CS, DeCherney GS, Barritt AS 4th. The impact of post-transplant diabetes mellitus on liver transplant outcomes. Clin Transplant. 2019 Jun;33(6):e13554. doi: 10.1111/ctr.13554. Epub 2019 Apr 23. PMID: 30927288; PMCID: PMC6995642.

2.Rossi MR, Mazzali M and de Sousa MV (2024) Post-transplant diabetes mellitus: risk factors and outcomes in a 5-year follow-up. Front. Clin. Diabetes Healthc. 5:1336896. doi: 10.3389/fcdhc.2024.1336896

3.Kanbay M, Copur S, Topçu AU, et al. An update review of post-transplant diabetes mellitus: Concept, risk factors, clinical implications and management. Diabetes Obes Metab. 2024; 1-15. doi:10.1111/dom.15575