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: 4 Date: 12 Jul 2023
Reviewer's report:
"PEER REVIEWER ASSESSMENTS:
OBJECTIVE - Full research articles: is there a clear objective that addresses one or several
testable research questions? (Brief or other article types: is there a clear objective?)
No - there are minor issues
DESIGN - Is the current approach (including controls and analysis protocols) appropriate for
the objective?
No - there are minor issues
EXECUTION - Are the experiments and analyses performed with sufficient technical rigor to
allow confidence in the results?
No - there are minor issues
STATISTICS - Is the use of statistics in the manuscript appropriate?
Yes - appropriate statistical analyses have been used in the study
INTERPRETATION - Is the current interpretation/discussion of the results reasonable and not
overstated?
No - there are major issues
OVERALL MANUSCRIPT POTENTIAL - Has the author addressed your concerns sufficiently
for you to now recommend the work as a technically sound contribution? If not, can further
revisions be made to make the work technically sound?
Maybe - with major revisions
PEER REVIEWER COMMENTS:
GENERAL COMMENTS: The authors conducted 24-week clinical trial investigating the
effect of pioglitazone and empagliflozin on GLS in people with T2DM and NAFLD without
established atherosclerotic cardiovascular disease. They also investigated liver steatosis and
fibrosis using transient elastography in these patients. The conclusion is that empagliflozin and
pioglitazone improve GLS, liver fibrosis, and steatosis in patients with T2DM with NAFLD and
without established ASCVD. The authors responded adequately on the previous comments of
the reviewers.
REQUESTED REVISIONS:
There are still some points that need to be discussed:
1. In the abstract is written:” Global longitudinal strain (GLS) is an indicator of myocardial
strain”. GLS is not indicator of strain, but LV mechanics or LV function. Please change this.
2. I would recommend to mention secondary endpoint in the background (abstract section)
because more than half of the results (as well as conclusion) are devoted to liver changes that
are not mentioned as aim of this study.
3. In the introduction is written: “Global longitudinal strain (GLS) is one of the most sensitive
and accurate echocardiographic measures for assessing cardiac geometry”. This is not true, GLS
is not parameter of cardiac geometry, but LV function or even more accurate LV mechanics
(deformation). Please change this.
4. Sentence about the prediction of GLS in HF patients from the introduction should be excluded,
as this is not the topic of your article.
5. “More significant negative numbers indicate improvement in myocardial function”? This is
correct, but written in a very incomprehensible way. I would strongly suggest to ask cardiologist
(echocardiography specialist, if possible) to read this article again, as it seems that article is
written by non-cardiologist and in some parts in incorrectly written and discussed.
6. The number of included patients is very limited for two-arm trial. Please acknowledge this
in the limitations.
7. You keep repeating “people with T2DM”. This should be rephrased into “patients”.
8. Did you standardize antidiabetic therapy before trial period?
9. Descriptions of kits used for laboratory analyses are not necessary in the methodology section.
10. “Images were obtained from the peak of the R wave to the three subsequent cardiac cycles.”
Echocardiographic machines do not make clips from peak of R wave. This is not correct. This
can be only our decision in post-processing. Please correct this.
11. Please change “trans-apical” into “apical” images.
12. How did you calculate GLS at the end? Did you calculate GLS as the average of 3 apical
views in 3 cycles? Did you use formula or use the value that software provided? The formula
that you provided is theoretical and it has not been used in clinical practice for GLS assessment.
Echocardiographic software is providing value, you are not calculating anything.
13. “Endocardial border tracing and global longitudinal ventricular strain calculation were done
on two separate occasions. It included the average of these two measurements in the final
analyses.” What does this mean? Please ask echocardiographer to write again segments related
with echocardiographic examination.
14. The description of LV diastolic function should be in the separate paragraph, after description
of GLS assessment.
15. Normal value that you cited for GLS is not correct and it is not from the guidelines. Normal
values is considered >18% in absolute value.
16. You did not describe the evaluation of LVEF. Please add this.
17. Please provide LA volume if available, instead of LA area.
18. Please change “phone visits” into “remote visits via phone”.
19. There are too many secondary endpoints. I would concentrate on GLS as primary and
hepatic parameters as secondary. Many parameters of LV diastolic function should be omitted
as secondary endpoints.
20. How do you explain the lack of the association between the improvement of GLS and the
changes in the LSM? Is there some correlation between GLS improvement with HbA1c or some
other hepatic parameter?
21. LVEF should be described as the whole number, without decimal numbers.
22. BMI significantly reduced in empagliflozin group after 24 weeks, which may be one of the
confounding factors of GLS improvement. Please discuss this.
23. The GLS difference of 0.5% between groups did not reach statistical significance probably
due to small sample size, but it is not clinically irrelevant.
24. Conclusion is not informative. Please elaborate your results in this section in a better way.
25. The whole manuscript would benefit largely from English language editing."
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: 4 Date: 12 Jul 2023
Reviewer's report:
"PEER REVIEWER ASSESSMENTS:
OBJECTIVE - Full research articles: is there a clear objective that addresses one or several
testable research questions? (Brief or other article types: is there a clear objective?)
No - there are minor issues
DESIGN - Is the current approach (including controls and analysis protocols) appropriate for
the objective?
No - there are minor issues
EXECUTION - Are the experiments and analyses performed with sufficient technical rigor to
allow confidence in the results?
No - there are minor issues
STATISTICS - Is the use of statistics in the manuscript appropriate?
Yes - appropriate statistical analyses have been used in the study
INTERPRETATION - Is the current interpretation/discussion of the results reasonable and not
overstated?
No - there are major issues
OVERALL MANUSCRIPT POTENTIAL - Has the author addressed your concerns sufficiently
for you to now recommend the work as a technically sound contribution? If not, can further
revisions be made to make the work technically sound?
Maybe - with major revisions
PEER REVIEWER COMMENTS:
GENERAL COMMENTS: The authors conducted 24-week clinical trial investigating the
effect of pioglitazone and empagliflozin on GLS in people with T2DM and NAFLD without
established atherosclerotic cardiovascular disease. They also investigated liver steatosis and
fibrosis using transient elastography in these patients. The conclusion is that empagliflozin and
pioglitazone improve GLS, liver fibrosis, and steatosis in patients with T2DM with NAFLD and
without established ASCVD. The authors responded adequately on the previous comments of
the reviewers.
REQUESTED REVISIONS:
There are still some points that need to be discussed:
1. In the abstract is written:” Global longitudinal strain (GLS) is an indicator of myocardial
strain”. GLS is not indicator of strain, but LV mechanics or LV function. Please change this.
2. I would recommend to mention secondary endpoint in the background (abstract section)
because more than half of the results (as well as conclusion) are devoted to liver changes that
are not mentioned as aim of this study.
3. In the introduction is written: “Global longitudinal strain (GLS) is one of the most sensitive
and accurate echocardiographic measures for assessing cardiac geometry”. This is not true, GLS
is not parameter of cardiac geometry, but LV function or even more accurate LV mechanics
(deformation). Please change this.
4. Sentence about the prediction of GLS in HF patients from the introduction should be excluded,
as this is not the topic of your article.
5. “More significant negative numbers indicate improvement in myocardial function”? This is
correct, but written in a very incomprehensible way. I would strongly suggest to ask cardiologist
(echocardiography specialist, if possible) to read this article again, as it seems that article is
written by non-cardiologist and in some parts in incorrectly written and discussed.
6. The number of included patients is very limited for two-arm trial. Please acknowledge this
in the limitations.
7. You keep repeating “people with T2DM”. This should be rephrased into “patients”.
8. Did you standardize antidiabetic therapy before trial period?
9. Descriptions of kits used for laboratory analyses are not necessary in the methodology section.
10. “Images were obtained from the peak of the R wave to the three subsequent cardiac cycles.”
Echocardiographic machines do not make clips from peak of R wave. This is not correct. This
can be only our decision in post-processing. Please correct this.
11. Please change “trans-apical” into “apical” images.
12. How did you calculate GLS at the end? Did you calculate GLS as the average of 3 apical
views in 3 cycles? Did you use formula or use the value that software provided? The formula
that you provided is theoretical and it has not been used in clinical practice for GLS assessment.
Echocardiographic software is providing value, you are not calculating anything.
13. “Endocardial border tracing and global longitudinal ventricular strain calculation were done
on two separate occasions. It included the average of these two measurements in the final
analyses.” What does this mean? Please ask echocardiographer to write again segments related
with echocardiographic examination.
14. The description of LV diastolic function should be in the separate paragraph, after description
of GLS assessment.
15. Normal value that you cited for GLS is not correct and it is not from the guidelines. Normal
values is considered >18% in absolute value.
16. You did not describe the evaluation of LVEF. Please add this.
17. Please provide LA volume if available, instead of LA area.
18. Please change “phone visits” into “remote visits via phone”.
19. There are too many secondary endpoints. I would concentrate on GLS as primary and
hepatic parameters as secondary. Many parameters of LV diastolic function should be omitted
as secondary endpoints.
20. How do you explain the lack of the association between the improvement of GLS and the
changes in the LSM? Is there some correlation between GLS improvement with HbA1c or some
other hepatic parameter?
21. LVEF should be described as the whole number, without decimal numbers.
22. BMI significantly reduced in empagliflozin group after 24 weeks, which may be one of the
confounding factors of GLS improvement. Please discuss this.
23. The GLS difference of 0.5% between groups did not reach statistical significance probably
due to small sample size, but it is not clinically irrelevant.
24. Conclusion is not informative. Please elaborate your results in this section in a better way.
25. The whole manuscript would benefit largely from English language editing."
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: 4 Date: 12 Jul 2023
Reviewer's report:
"PEER REVIEWER ASSESSMENTS:
OBJECTIVE - Full research articles: is there a clear objective that addresses one or several
testable research questions? (Brief or other article types: is there a clear objective?)
No - there are minor issues
DESIGN - Is the current approach (including controls and analysis protocols) appropriate for
the objective?
No - there are minor issues
EXECUTION - Are the experiments and analyses performed with sufficient technical rigor to
allow confidence in the results?
No - there are minor issues
STATISTICS - Is the use of statistics in the manuscript appropriate?
Yes - appropriate statistical analyses have been used in the study
INTERPRETATION - Is the current interpretation/discussion of the results reasonable and not
overstated?
No - there are major issues
OVERALL MANUSCRIPT POTENTIAL - Has the author addressed your concerns sufficiently
for you to now recommend the work as a technically sound contribution? If not, can further
revisions be made to make the work technically sound?
Maybe - with major revisions
PEER REVIEWER COMMENTS:
GENERAL COMMENTS: The authors conducted 24-week clinical trial investigating the
effect of pioglitazone and empagliflozin on GLS in people with T2DM and NAFLD without
established atherosclerotic cardiovascular disease. They also investigated liver steatosis and
fibrosis using transient elastography in these patients. The conclusion is that empagliflozin and
pioglitazone improve GLS, liver fibrosis, and steatosis in patients with T2DM with NAFLD and
without established ASCVD. The authors responded adequately on the previous comments of
the reviewers.
REQUESTED REVISIONS:
There are still some points that need to be discussed:
1. In the abstract is written:” Global longitudinal strain (GLS) is an indicator of myocardial
strain”. GLS is not indicator of strain, but LV mechanics or LV function. Please change this.
2. I would recommend to mention secondary endpoint in the background (abstract section)
because more than half of the results (as well as conclusion) are devoted to liver changes that
are not mentioned as aim of this study.
3. In the introduction is written: “Global longitudinal strain (GLS) is one of the most sensitive
and accurate echocardiographic measures for assessing cardiac geometry”. This is not true, GLS
is not parameter of cardiac geometry, but LV function or even more accurate LV mechanics
(deformation). Please change this.
4. Sentence about the prediction of GLS in HF patients from the introduction should be excluded,
as this is not the topic of your article.
5. “More significant negative numbers indicate improvement in myocardial function”? This is
correct, but written in a very incomprehensible way. I would strongly suggest to ask cardiologist
(echocardiography specialist, if possible) to read this article again, as it seems that article is
written by non-cardiologist and in some parts in incorrectly written and discussed.
6. The number of included patients is very limited for two-arm trial. Please acknowledge this
in the limitations.
7. You keep repeating “people with T2DM”. This should be rephrased into “patients”.
8. Did you standardize antidiabetic therapy before trial period?
9. Descriptions of kits used for laboratory analyses are not necessary in the methodology section.
10. “Images were obtained from the peak of the R wave to the three subsequent cardiac cycles.”
Echocardiographic machines do not make clips from peak of R wave. This is not correct. This
can be only our decision in post-processing. Please correct this.
11. Please change “trans-apical” into “apical” images.
12. How did you calculate GLS at the end? Did you calculate GLS as the average of 3 apical
views in 3 cycles? Did you use formula or use the value that software provided? The formula
that you provided is theoretical and it has not been used in clinical practice for GLS assessment.
Echocardiographic software is providing value, you are not calculating anything.
13. “Endocardial border tracing and global longitudinal ventricular strain calculation were done
on two separate occasions. It included the average of these two measurements in the final
analyses.” What does this mean? Please ask echocardiographer to write again segments related
with echocardiographic examination.
14. The description of LV diastolic function should be in the separate paragraph, after description
of GLS assessment.
15. Normal value that you cited for GLS is not correct and it is not from the guidelines. Normal
values is considered >18% in absolute value.
16. You did not describe the evaluation of LVEF. Please add this.
17. Please provide LA volume if available, instead of LA area.
18. Please change “phone visits” into “remote visits via phone”.
19. There are too many secondary endpoints. I would concentrate on GLS as primary and
hepatic parameters as secondary. Many parameters of LV diastolic function should be omitted
as secondary endpoints.
20. How do you explain the lack of the association between the improvement of GLS and the
changes in the LSM? Is there some correlation between GLS improvement with HbA1c or some
other hepatic parameter?
21. LVEF should be described as the whole number, without decimal numbers.
22. BMI significantly reduced in empagliflozin group after 24 weeks, which may be one of the
confounding factors of GLS improvement. Please discuss this.
23. The GLS difference of 0.5% between groups did not reach statistical significance probably
due to small sample size, but it is not clinically irrelevant.
24. Conclusion is not informative. Please elaborate your results in this section in a better way.
25. The whole manuscript would benefit largely from English language editing."
assistant