Review for 10.1186/s12876-023-03085-8 (2023)

Title: Dual Metformin and SGLT2 Inhibitor Therapy Reduces Mortality and Liver
Complications in Cirrhotic Patients with Diabetes Mellitus
Version: 3 Date: 25 Sep 2023
Reviewer's report:
The authors propose an interesting question: to assess the association between SGLT2i use
in combination with other medications and clinical outcomes in persons with cirrhosis. They
used propensity score matching to support a causal effect. I have several concerns about the
methodology of the study that preclude me from being able to recommend it for publication.
Firstly, it is not clear what point in time served as the "index" date for patients selected from
TriNetX for this study. Is it at time of diagnosis with cirrhosis? Time of entry into TriNetX?
The authors also state that they followed patients for the events of interest until 5 years after
initiation of metformin or metformin+SGLTL2 initiation. What if patients initiated medications
before entering the cohort? Before developing cirrhosis? If someone started metformin in 2011
and developed cirrhosis in 2014, why only follow them for 1 year? In this type of observational
study, careful definition of start of follow up and cohort definition are essential to avoiding bias.
The question itself is interesting, but comparing monotherapy with metformin to combination
therapy with metformin + a second agent does not seem like a "fair" comparison, since
presumably these are different patient populations (controlled on metformin alone vs
uncontrolled and requiring a second anti-diabetic agent). Comparing to a different dual therapy
group would be more appropriate.
Based on the propensity score development, it appears as though patients could be on additional
anti-diabetic therapies beyond metformin and SGLT2i (the score matches on use of numerous
other anti-diabetic medications). So, I was left wondering if these patients are on metformin
monotherapy or dual metformin+SGLT2i or if they could also be on other medications.
It's not clear from reading the manuscript how hepatic decompensations were defined in the
database used, if that definition is validated in any way, or how NASH cirrhosis was defined. The
authors stratify by several demographic factors but do not provide justification for this stratified
analysis - is there a reason to believe that there is a statistical interaction between SGLT2i use
and sex, race on the outcome of interest? Furthermore, why were patients with CKD excluded
based on the concern that they may be less likely to be treated with metformin? If anything, CKD
and other comorbid conditions (namely CAD and CHF) could be incorporated into a propensity
score.
I would not emphasize the 5-year cumulative event rates in tables 2-4 so prominently, since time
to event data is much more relevant when dealing with competing events like decompensation
and death in the context of cirrhosis (see https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/
hep.27598).
The HRs observed are dramatic: a HR of 0.4 or 0.5 is a very strong measure of effect for
the association between a single antidiabetic therapy and outcomes such as mortality and
decompensation. We typically see much more modest effect sizes. This reinforces my concern
for significant bias in the study design.
I also suggest some editorial changes to the manuscript. There have been studies evaluating
metformin in cirrhosis (https://pubmed.ncbi.nlm.nih.gov/32798709/) and comparing metformin
+SGLTL2I to metformin+DPP4 in cirrhosis (see: https://pubmed.ncbi.nlm.nih.gov/34227216/),
and these should be reviewed and incorporated into the discussion of evidence. The introduction
has some repetitive, vague sentences and can be re-written for greater clarity. The language
should be patient-centered throughout the manuscript, using "patients with cirrhosis" or "patients
with diabetes" instead of "cirrhotic patients" or "T2DM patients". The title of the manuscript
and interpretation of results imply causal effect and the language should be adjusted to reflect
the observational nature of the design, which reflects an association.