Glycative Stress, Glycated Hemoglobin, and Atherogenic Dyslipidemia in Patients with Hyperlipidemia
Round 1
Reviewer 1 Report
This is an interesting and well-written study exploring glycative stress, glycated hemoglobin, and atherogenic dyslipidemia in patients with hyperlipidemia. However, I have some remarks:
1. Authors should explain what means “chronic kidney disease with creatinine levels ≥ 3” in Materials and Methods.
2. The authors stated that they excluded subjects with nephrotic syndrome and chronic kidney disease. Chronic kidney disease was defined as a glomerular filtration rate < 60 ml/min according to CKD-EPI, MDRD or some other formula? Also, chronic kidney disease includes patients with proteinuria in the below nephrotic syndrome range as well. There is a strong relationship between dyslipidemia and albuminuria even in those with preserved glomerular filtration rate so information about the range of albuminuria/proteinuria of studied subjects would be useful.
3. What is the Authors explanation that almost 70% of participants are males?
4. What about those subjects with diabetes treated with insulin therapy? Insulin therapy activates lipid metabolism via up-regulating CETP and shows anti-atherogenic effects by increasing HDL and decreasing LDL cholesterol subfractions in a short time period.
5. What is Authors’ explanation that subjects with established diabetes have significantly lower LDL cholesterol levels (without therapy!) compared to those with normal glucose tolerance although have doubled higher hypertension prevalence (Table 2)? It does not make sense. In addition, HDL cholesterol is lower and triglycerides are higher in DM, as expected. The Authors should check those results.
6. Waist-to-hip ratio is a much better metabolic parameter compared to BMI in patients with metabolic syndrome. For example, in the IGT group, the BMI of the two subgroups was similar. The WHR will probably be different.
Author Response
Thank you for kind and valuable advice.
Several correction and discussion have been documented.
Point 1:
Authors should explain what means “chronic kidney disease with creatinine levels ≥ 3” in Materials and Methods.
Response 1:
The unit has been added as “mg/dL”. We view “chronic kidney disease with creatinine levels ≥ 3 mg/dL” as advanced CKD. Additional explanation has been added to the manuscript:
“We adopted several exclusion criteria in our study to eliminate confounders. CKD is associated with dyslipidemia, largely due to increased triglyceride levels, decreased HDL-C and varying levels of LDL-C, attributed by complicated metabolic interference [17]. Usually, CKD is defined as an estimated glomerular filtration rate < 60 ml/min, which could be derived from simplified Modification of Diet in Renal Disease (MDRD) equation. In our study, CKD patients with creatinine level ≥ 3 mg/dL were excluded, to minimize the confounding factors. ”
Point 2:
The authors stated that they excluded subjects with nephrotic syndrome and chronic kidney disease. Chronic kidney disease was defined as a glomerular filtration rate < 60 ml/min according to CKD-EPI, MDRD or some other formula? Also, chronic kidney disease includes patients with proteinuria in the below nephrotic syndrome range as well. There is a strong relationship between dyslipidemia and albuminuria even in those with preserved glomerular filtration rate so information about the range of albuminuria/proteinuria of studied subjects would be useful.
Response 2:
Thank you for kindly reminding about the definition. We define CKD as eGFR < 60 ml/min according to MDRD equation. Additional explanation is added, as Response 1.
As for proteinuroia below nephrotic range, unfortunately we did not recruit related data. It could be quite valuable in further analysis. However, since we have excluded those with high risks of confoudning, we sincerely consider the study population representative.
Point 3:
What is the Authors explanation that almost 70% of participants are males?
Response 3:
We consecutively recruit patients from out-patient clinic of dyslipidemia, and the unbalanced gender distribution reflects the patient composition. Limitation is added:
“There are several nonnegligible limitations in this study. …… Second, we consecutively recruits patients from out-patient clinic of dyslipidemia and unbalanced gender distribution is noted. Since we adopted several exclusion criteria, our results could not be generalized to other patient groups. ”
Point 4:
What about those subjects with diabetes treated with insulin therapy? Insulin therapy activates lipid metabolism via up-regulating CETP and shows anti-atherogenic effects by increasing HDL and decreasing LDL cholesterol subfractions in a short time period.
Response 4:
Insulin therapy is considered to influence lipid metabolism and patients with insulin therapy were excluded. In Taiwan, patients were usually reluctant to initiate insulin, and OHA remained the major policy of DM treatment. Exclusion of patients with insulin therapy seem to have few influence on study population.
Point 5:
What is Authors’ explanation that subjects with established diabetes have significantly lower LDL cholesterol levels (without therapy!) compared to those with normal glucose tolerance although have doubled higher hypertension prevalence (Table 2)? It does not make sense. In addition, HDL cholesterol is lower and triglycerides are higher in DM, as expected. The Authors should check those results.
Response 5:
Thank you for reminding the study results. We have checked the data and the results seemed compatible. In patients with DM, variable LDL level could be noted, possibly due to lipid metabolism and profile conversion. Additional explanation is added to the manuscript:
“We also observed, in Table 2, that patients with DM live with lower LDL in contrast of significantly higher VLDL and TG. Previous evidence have shown the complicated conversion of variable lipid profiles, and lipid metabolism with LDL, VLDL and sdLDL all play important roles in atherosclerosis [23]. The results indicates that LDL alone may not be representative enough when it comes to atherosclerosis.”
Point 6:
Waist-to-hip ratio is a much better metabolic parameter compared to BMI in patients with metabolic syndrome. For example, in the IGT group, the BMI of the two subgroups was similar. The WHR will probably be different.
Response 6:
WHR is quite important in metabolic syndrome. However, we use BMI as common and useful parameters in this study. As advice from reviewer, maybe further analysis of WHR will provided more information. We will take it into consideration in the future.
Sincerely
Author Response File: 
Author Response.docx
Reviewer 2 Report
Well-written manuscript with thorough planning and execution of study. Tables excellent. Discussion very good.
3 comments:
1) please explain abbreviation CV (coefficient of variation.
2) Cite and discuss this relevant paper: Yoon, S. R., Lee, J. H., Na, G. Y., Seo, Y. J., Han, S., Shin, M. J., & Kim, O. Y. (2015). Glycated Hemoglobin is a Better Predictor than Fasting Glucose for Cardiometabolic Risk in Non-diabetic Korean Women. Clinical nutrition research, 4(2), 97–103. https://doi.org/10.7762/cnr.2015.4.2.97
3) Did you measure CRP? If not, address why not. Also, did you measure ApoB? Please discuss ApoB as predictor of CV risk in DM.
Author Response
Than you for kind and valuable advice.
Several correction and discussion have been made.
Point 1:
please explain abbreviation CV (coefficient of variation.
Response 1:
Thank you for reminding. Explanation for abbreviation is added.
Point 2:
Cite and discuss this relevant paper: Yoon, S. R., Lee, J. H., Na, G. Y., Seo, Y. J., Han, S., Shin, M. J., & Kim, O. Y. (2015). Glycated Hemoglobin is a Better Predictor than Fasting Glucose for Cardiometabolic Risk in Non-diabetic Korean Women. Clinical nutrition research, 4(2), 97–103. https://doi.org/10.7762/cnr.2015.4.2.97
Response 2:
We added this study in the discussion:
“A previous study in Korea had raised the importance of glycated hemoglobin as a predictor for cardiometabolic risk in non-diabetic women, which demonstrated better performance than fasting glucose [10]. However, related evidence derived from large-scale research in Taiwan is scarce. “
Point 3:
Did you measure CRP? If not, address why not. Also, did you measure ApoB? Please discuss ApoB as predictor of CV risk in DM.
Response 3:
We focused on lipid profiles and did not measure CRP. If further study is conducted for evaluation of CV risk and outcome, we will take it into consideration.
As for ApoB, unfortunately we did not measure it directly. However, ApoB containing lipids, such as LDL and VLDL, are measured and demonstrated significance in our study. We sincerely consider the results representative.
Sincerely
