Title: Dual Metformin and SGLT2 Inhibitor Therapy Reduces Mortality and Liver
Complications in Cirrhotic Patients with Diabetes Mellitus
Version: 3 Date: 18 Sep 2023
Reviewer's report:
The authors present a very interesting analysis and well-written manuscript examining the risk
of mortality, liver decompensation events and hepatocellular carcinoma in patients on dual
metformin/SGLT2i therapy vs. metformin alone. The authors find a lower risk of these events
in patients on dual vs. mono therapy using propensity score matching.
I find these analyses and findings to be worthwhile for publication in BMC Gastroenterology,
however I have one main concern and a few minor comments that should be addressed prior
to publication:
1) My main concern relates to the grouping of hypoglycemia medications together, without
separating out GLP-1RA and pioglitazone. While the variable "other hypo meds" is included
in propensity score matching, this doesn't account for specific differences that may exist in
GLP-1RA use and pioglitazone between the two groups. This is important because both of these
medications have been shown to improve NAFLD/NASH , and because patients on SGLT2i
may be more likely to be prescribed GLP-1RA than those NOT on SGLT2i, given their joint
indication in ASCVD.  Furthermore, GLP-1RA reduce CV events, so it cannot be known
whether GLP-1RA use is actually driving a reduction in (CV) mortality vs. SGLT2i (or both).
This is a major limitation. Please include the proportion of GLP-1RA and pioglitazone use
between arms in Table 1, and re-run an analysis with matching for at least the GLP-1RA use.
2) Minor comments
- Page 7, line 18: CKD stages 3-4 are no longer a contraindication to SGLT2i based on guidelines,
however they may have been for a part of the study period examined. The exclusion is justified,
but please acknowledge somehow that this is no longer the case, so as to not mislead readers
- Recommend softening conclusion in abstract and in main paper to "may improve" or "may
benefit" - you cannot infer causation here, only association
- Consider switch to updated nomenclature: MASLD/MASH (Rinella ME, Lazarus JV, Ratziu
V, et al. A multi-society Delphi consensus statement on new fatty liver disease nomenclature.
Hepatology. 2023)
-Please switch language from "Hispanics" to "Hispanic patients" wherever this is listed.
- In addition to poor coding of NASH/NAFLD, another potential reason for why you are seeing
lower HR with SGLT2i in the "non-NASH" cohort is because there is still overlap between
metabolic liver disease (NAFLD) and other forms of liver disease. This is becoming increasingly
recognized (and very likely in a diabetes population), and could be another reason why a
potential benefit with SGLT2i is seen in seemingly "non NASH/NAFLD" groups.
Title: Dual Metformin and SGLT2 Inhibitor Therapy Reduces Mortality and Liver
Complications in Cirrhotic Patients with Diabetes Mellitus
Version: 3 Date: 18 Sep 2023
Reviewer's report:
The authors present a very interesting analysis and well-written manuscript examining the risk
of mortality, liver decompensation events and hepatocellular carcinoma in patients on dual
metformin/SGLT2i therapy vs. metformin alone. The authors find a lower risk of these events
in patients on dual vs. mono therapy using propensity score matching.
I find these analyses and findings to be worthwhile for publication in BMC Gastroenterology,
however I have one main concern and a few minor comments that should be addressed prior
to publication:
1) My main concern relates to the grouping of hypoglycemia medications together, without
separating out GLP-1RA and pioglitazone. While the variable "other hypo meds" is included
in propensity score matching, this doesn't account for specific differences that may exist in
GLP-1RA use and pioglitazone between the two groups. This is important because both of these
medications have been shown to improve NAFLD/NASH , and because patients on SGLT2i
may be more likely to be prescribed GLP-1RA than those NOT on SGLT2i, given their joint
indication in ASCVD.  Furthermore, GLP-1RA reduce CV events, so it cannot be known
whether GLP-1RA use is actually driving a reduction in (CV) mortality vs. SGLT2i (or both).
This is a major limitation. Please include the proportion of GLP-1RA and pioglitazone use
between arms in Table 1, and re-run an analysis with matching for at least the GLP-1RA use.
2) Minor comments
- Page 7, line 18: CKD stages 3-4 are no longer a contraindication to SGLT2i based on guidelines,
however they may have been for a part of the study period examined. The exclusion is justified,
but please acknowledge somehow that this is no longer the case, so as to not mislead readers
- Recommend softening conclusion in abstract and in main paper to "may improve" or "may
benefit" - you cannot infer causation here, only association
- Consider switch to updated nomenclature: MASLD/MASH (Rinella ME, Lazarus JV, Ratziu
V, et al. A multi-society Delphi consensus statement on new fatty liver disease nomenclature.
Hepatology. 2023)
-Please switch language from "Hispanics" to "Hispanic patients" wherever this is listed.
- In addition to poor coding of NASH/NAFLD, another potential reason for why you are seeing
lower HR with SGLT2i in the "non-NASH" cohort is because there is still overlap between
metabolic liver disease (NAFLD) and other forms of liver disease. This is becoming increasingly
recognized (and very likely in a diabetes population), and could be another reason why a
potential benefit with SGLT2i is seen in seemingly "non NASH/NAFLD" groups.
Please review this paper.
user
Title: Dual Metformin and SGLT2 Inhibitor Therapy Reduces Mortality and Liver
Complications in Cirrhotic Patients with Diabetes Mellitus
Version: 3 Date: 18 Sep 2023
Reviewer's report:
The authors present a very interesting analysis and well-written manuscript examining the risk
of mortality, liver decompensation events and hepatocellular carcinoma in patients on dual
metformin/SGLT2i therapy vs. metformin alone. The authors find a lower risk of these events
in patients on dual vs. mono therapy using propensity score matching.
I find these analyses and findings to be worthwhile for publication in BMC Gastroenterology,
however I have one main concern and a few minor comments that should be addressed prior
to publication:
1) My main concern relates to the grouping of hypoglycemia medications together, without
separating out GLP-1RA and pioglitazone. While the variable "other hypo meds" is included
in propensity score matching, this doesn't account for specific differences that may exist in
GLP-1RA use and pioglitazone between the two groups. This is important because both of these
medications have been shown to improve NAFLD/NASH , and because patients on SGLT2i
may be more likely to be prescribed GLP-1RA than those NOT on SGLT2i, given their joint
indication in ASCVD.  Furthermore, GLP-1RA reduce CV events, so it cannot be known
whether GLP-1RA use is actually driving a reduction in (CV) mortality vs. SGLT2i (or both).
This is a major limitation. Please include the proportion of GLP-1RA and pioglitazone use
between arms in Table 1, and re-run an analysis with matching for at least the GLP-1RA use.
2) Minor comments
- Page 7, line 18: CKD stages 3-4 are no longer a contraindication to SGLT2i based on guidelines,
however they may have been for a part of the study period examined. The exclusion is justified,
but please acknowledge somehow that this is no longer the case, so as to not mislead readers
- Recommend softening conclusion in abstract and in main paper to "may improve" or "may
benefit" - you cannot infer causation here, only association
- Consider switch to updated nomenclature: MASLD/MASH (Rinella ME, Lazarus JV, Ratziu
V, et al. A multi-society Delphi consensus statement on new fatty liver disease nomenclature.
Hepatology. 2023)
-Please switch language from "Hispanics" to "Hispanic patients" wherever this is listed.
- In addition to poor coding of NASH/NAFLD, another potential reason for why you are seeing
lower HR with SGLT2i in the "non-NASH" cohort is because there is still overlap between
metabolic liver disease (NAFLD) and other forms of liver disease. This is becoming increasingly
recognized (and very likely in a diabetes population), and could be another reason why a
potential benefit with SGLT2i is seen in seemingly "non NASH/NAFLD" groups.
assistant