Title: Effect of Empagliflozin and Pioglitazone on Left Ventricular Function in Patients with
Type Two Diabetes and Nonalcoholic Fatty Liver Disease without Established Cardiovascular
Disease: A Randomized Single-blind Clinical Trial
Version: 1 Date: 08 Sep 2022
Reviewer's report:
- As liver fibrosis is only a secondary outcome, consider removing it from the title of the
manuscript.
- Table 1: Please remove decimals for age, as these are not clinically relevant
- Considering simplifying Table 1 by removing the “All patients” column and not using 2
decimals for all variables if not clinically relevant. One decimal (if any) should suffice in most
parameters.
- When presenting results (both in the abstract and manuscript), please start presenting the
primary outcome (i.e., GLS change after treatment). Only then move to secondary outcomes
(e.g., relationship between GLS and liver fibrosis). Was the primary outcome a within group
comparison? (i.e., two main comparisons, one for pioglitazone and one for empagliflozin?).
What was the consideration for multiple comparisons? (vs. the primary outcome was comparing
the GLS change in pioglitazone vs. empagliflozin).
- Ethical concern: as per flowchart in Appendix 2, 78 patients were randomized. Yet 5 were
excluded because they “did not sign an informed consent”... So, how did they get randomized in
the first place?! How were all the other procedures performed if they did not sign an informed
consent?! Was this retrospectively collected information?
- How do authors explain the significant change in LDL during the study? Were patients started
on statins during the run-in period?
- Please provide information regarding changes in diabetes and lipid medications 3 months
before randomization and during the study. Any data on changes in diet and/or exercise in
patients?
- For patients not completing follow-up, how was the data analyzed? You mention ITT, but it is
unclear what authors mean by that? How was missing data managed?
- Please describe adverse events under Results. Any severe AEs?
- RCTs with empagliflozin using MRI-PDFF have shown a significant reduction in liver fat,
but this improvement has been consistently lower than the reduction observed in liver fat with
pioglitazone. How do authors explain this difference in their study. Please comment in the
Discussion.
- Lack of control group. Due to the fact that pioglitazone and empagliflozin showed similar
changes in the primary outcome, it is possible that these changes were not related to the
medications, but other confounding factors. Please expand on this as a limitation in the
Discussion. The main conclusion of the study is that there were no differences in GLS when
pioglitazone and empagliflozin were compared. All other results are secondary.
- This is a relatively short study and changes in Fibroscan (LSM) could be in part related to
changes in CAP measurements (there are several reports showing some interaction between both
measurements). Please comment on this in the discussion.
- “Considering the double blind nature of this clinical trial, the result will be expected to
generalize in people with type two diabetes mellitus with NAFLD and without established
cardiovascular disease”. This statement is incorrect. The double-blind nature of the study is
unrelated to its external validity. Please change this sentence.
- GLS is a surrogate marker of LV function. Please discuss its limitations in the Discussions.
Also, I would suggest using terms like “GLS improved” instead of “LV function improved”.
Title: Effect of Empagliflozin and Pioglitazone on Left Ventricular Function in Patients with
Type Two Diabetes and Nonalcoholic Fatty Liver Disease without Established Cardiovascular
Disease: A Randomized Single-blind Clinical Trial
Version: 1 Date: 08 Sep 2022
Reviewer's report:
- As liver fibrosis is only a secondary outcome, consider removing it from the title of the
manuscript.
- Table 1: Please remove decimals for age, as these are not clinically relevant
- Considering simplifying Table 1 by removing the “All patients” column and not using 2
decimals for all variables if not clinically relevant. One decimal (if any) should suffice in most
parameters.
- When presenting results (both in the abstract and manuscript), please start presenting the
primary outcome (i.e., GLS change after treatment). Only then move to secondary outcomes
(e.g., relationship between GLS and liver fibrosis). Was the primary outcome a within group
comparison? (i.e., two main comparisons, one for pioglitazone and one for empagliflozin?).
What was the consideration for multiple comparisons? (vs. the primary outcome was comparing
the GLS change in pioglitazone vs. empagliflozin).
- Ethical concern: as per flowchart in Appendix 2, 78 patients were randomized. Yet 5 were
excluded because they “did not sign an informed consent”... So, how did they get randomized in
the first place?! How were all the other procedures performed if they did not sign an informed
consent?! Was this retrospectively collected information?
- How do authors explain the significant change in LDL during the study? Were patients started
on statins during the run-in period?
- Please provide information regarding changes in diabetes and lipid medications 3 months
before randomization and during the study. Any data on changes in diet and/or exercise in
patients?
- For patients not completing follow-up, how was the data analyzed? You mention ITT, but it is
unclear what authors mean by that? How was missing data managed?
- Please describe adverse events under Results. Any severe AEs?
- RCTs with empagliflozin using MRI-PDFF have shown a significant reduction in liver fat,
but this improvement has been consistently lower than the reduction observed in liver fat with
pioglitazone. How do authors explain this difference in their study. Please comment in the
Discussion.
- Lack of control group. Due to the fact that pioglitazone and empagliflozin showed similar
changes in the primary outcome, it is possible that these changes were not related to the
medications, but other confounding factors. Please expand on this as a limitation in the
Discussion. The main conclusion of the study is that there were no differences in GLS when
pioglitazone and empagliflozin were compared. All other results are secondary.
- This is a relatively short study and changes in Fibroscan (LSM) could be in part related to
changes in CAP measurements (there are several reports showing some interaction between both
measurements). Please comment on this in the discussion.
- “Considering the double blind nature of this clinical trial, the result will be expected to
generalize in people with type two diabetes mellitus with NAFLD and without established
cardiovascular disease”. This statement is incorrect. The double-blind nature of the study is
unrelated to its external validity. Please change this sentence.
- GLS is a surrogate marker of LV function. Please discuss its limitations in the Discussions.
Also, I would suggest using terms like “GLS improved” instead of “LV function improved”.
Please review this paper.
user
Title: Effect of Empagliflozin and Pioglitazone on Left Ventricular Function in Patients with
Type Two Diabetes and Nonalcoholic Fatty Liver Disease without Established Cardiovascular
Disease: A Randomized Single-blind Clinical Trial
Version: 1 Date: 08 Sep 2022
Reviewer's report:
- As liver fibrosis is only a secondary outcome, consider removing it from the title of the
manuscript.
- Table 1: Please remove decimals for age, as these are not clinically relevant
- Considering simplifying Table 1 by removing the “All patients” column and not using 2
decimals for all variables if not clinically relevant. One decimal (if any) should suffice in most
parameters.
- When presenting results (both in the abstract and manuscript), please start presenting the
primary outcome (i.e., GLS change after treatment). Only then move to secondary outcomes
(e.g., relationship between GLS and liver fibrosis). Was the primary outcome a within group
comparison? (i.e., two main comparisons, one for pioglitazone and one for empagliflozin?).
What was the consideration for multiple comparisons? (vs. the primary outcome was comparing
the GLS change in pioglitazone vs. empagliflozin).
- Ethical concern: as per flowchart in Appendix 2, 78 patients were randomized. Yet 5 were
excluded because they “did not sign an informed consent”... So, how did they get randomized in
the first place?! How were all the other procedures performed if they did not sign an informed
consent?! Was this retrospectively collected information?
- How do authors explain the significant change in LDL during the study? Were patients started
on statins during the run-in period?
- Please provide information regarding changes in diabetes and lipid medications 3 months
before randomization and during the study. Any data on changes in diet and/or exercise in
patients?
- For patients not completing follow-up, how was the data analyzed? You mention ITT, but it is
unclear what authors mean by that? How was missing data managed?
- Please describe adverse events under Results. Any severe AEs?
- RCTs with empagliflozin using MRI-PDFF have shown a significant reduction in liver fat,
but this improvement has been consistently lower than the reduction observed in liver fat with
pioglitazone. How do authors explain this difference in their study. Please comment in the
Discussion.
- Lack of control group. Due to the fact that pioglitazone and empagliflozin showed similar
changes in the primary outcome, it is possible that these changes were not related to the
medications, but other confounding factors. Please expand on this as a limitation in the
Discussion. The main conclusion of the study is that there were no differences in GLS when
pioglitazone and empagliflozin were compared. All other results are secondary.
- This is a relatively short study and changes in Fibroscan (LSM) could be in part related to
changes in CAP measurements (there are several reports showing some interaction between both
measurements). Please comment on this in the discussion.
- “Considering the double blind nature of this clinical trial, the result will be expected to
generalize in people with type two diabetes mellitus with NAFLD and without established
cardiovascular disease”. This statement is incorrect. The double-blind nature of the study is
unrelated to its external validity. Please change this sentence.
- GLS is a surrogate marker of LV function. Please discuss its limitations in the Discussions.
Also, I would suggest using terms like “GLS improved” instead of “LV function improved”.
assistant