Risk of Cardiovascular Disease According to the Precedence Relationship Between Hypertension and Diabetes Mellitus

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

 Title: Risk of cardiovascular disease according to the precedence relationship between hypertension and diabetes mellitus.

Abstract:

• Keywords should be in lowercase, unless they include proper nouns, abbreviations, or specific terms that require capitalization.

Introduction:

• Introduction is a bit short, adding details about the pathogenesis of the condition can help strengthen it.
• Please check the following sentence for grammatical error. Most epidemiological studies treat HTN and DM as separate independent variables regardless of their order of acquisition, but the pathophysiological mechanisms might be not the same between those who develop HTN first and those who develop DM first. Line 57
• Please check the following sentence for grammatical error. However, relevant research of this complex relationship is lacking. Line 61

Methodology:

• Methodology seems to be clear and concise.
• Please check the following sentence for grammatical error. Patients who were diagnosed with MI (n = 42,440) or ischemic stroke (n = 49,734) were excluded, as were those with missing data (n = 23,144). Therefore, data from 914,338 individuals were included in the analyses. Line 75.
• Please check the following sentence for grammatical error. The durations of HTN and DM were the times from initial drug prescription to the date of health examination. Line 82

Results:

• The results are well-articulated, and the use of tables enhances clarity and comprehension.

Discussion:

• Please check the following sentence for grammatical error. Blood pressure, obesity, and cholesterol profile, risk factors for CVD, were consid-174 ered to be better controlled in the DM→HTN group, probably because DM patients might 175 be more tightly controlled than HTN patients due to the strict DM guidelines. Line 174
• Please check the following sentence for grammatical error. One possible inference is that the DM→HTN group and HTN→DM group differ in insulin resistance duration. Line 179

Conclusion:

• Conclusion seems to be well written. It explains about the current status and the futuristic aspect.

Comments for author File: Comments.pdf

Comments on the Quality of English Language

• Please check the following sentence for grammatical error. Most epidemiological studies treat HTN and DM as separate independent variables regardless of their order of acquisition, but the pathophysiological mechanisms might be not the same between those who develop HTN first and those who develop DM first. Line 57
• Please check the following sentence for grammatical error. However, relevant research of this complex relationship is lacking. Line 61
• Please check the following sentence for grammatical error. Patients who were diagnosed with MI (n = 42,440) or ischemic stroke (n = 49,734) were excluded, as were those with missing data (n = 23,144). Therefore, data from 914,338 individuals were included in the analyses. Line 75.
• Please check the following sentence for grammatical error. The durations of HTN and DM were the times from initial drug prescription to the date of health examination. Line 82
• Please check the following sentence for grammatical error. Blood pressure, obesity, and cholesterol profile, risk factors for CVD, were consid-174 ered to be better controlled in the DM→HTN group, probably because DM patients might 175 be more tightly controlled than HTN patients due to the strict DM guidelines. Line 174
• Please check the following sentence for grammatical error. One possible inference is that the DM→HTN group and HTN→DM group differ in insulin resistance duration. Line 179

Author Response

Comment #1. Keywords should be in lowercase, unless they include proper nouns, abbreviations, or specific terms that require capitalization.

Response: We changed keywords to be in lowercase. Thanks for the thoughtful comments.

Comment #2. Introduction is a bit short, adding details about the pathogenesis of the condition can help strengthen it.

Response: We appreciate the reviewer’s suggestion. We added more detailed pathophysiological pathways to increase reader understanding of hypertension and diabetes mellitus. All mechanisms of hemodynamic and glycolipid metabolism are affected by increased levels of blood pressure and plasma glucose.

[Introduction] (page 2, paragraph 1, line 43)

Hypertension (HTN) and diabetes mellitus (DM) are risk factors for cardiovascular disease (CVD) and are prevalent comorbidities.[1] These conditions have common lifestyle factors and share pathophysiologic pathways such as the renin-angiotensin-aldosterone system (RAAS), inflammation, oxidative stress, and insulin resistance.[2] For example, the local RAAS stimulates vascular inflammation and oxidative stress, which leads to endothelial dysfunction and vascular injury. Increased RAAS activities may cause insulin resistance, which triggers increased production of reactive oxygen species (ROS) and induces free fatty acids, resulting in endothelial dysfunction and atherogenesis.[2] These pathways lead to increased levels of blood pressure and plasma glucose by changing hemodynamic and glycolipid metabolism and interact with one another, possibly leading to the creation of a vicious cycle. HTN and DM may develop sequentially and often coexist[3].

[Reference]

1. Sowers JR, Epstein M, Frohlich ED. Diabetes, hypertension, and cardiovascular disease: an update. Hypertension. 2001;37(4):1053-9.
2. Cheung BM, Li C. Diabetes and hypertension: is there a common metabolic pathway? Curr Atheroscler Rep. 2012;14(2):160-6.
3. Yildiz M, Esenboğa K, Oktay AA. Hypertension and diabetes mellitus: highlights of a complex relationship. Current Opinion in Cardiology. 2020;35(4):397-404.

 

Comment #3. Please check the following sentence for grammatical errors. Line 57, 61, 75, 82, 174, and 179.

Response: We edited the sentences for grammatical errors with the English editing service as the reviewer suggested. We appreciate your insightful comments.

Reviewer 2 Report

Comments and Suggestions for Authors

Very interesting manuscript. However, I have specific observations.
Although plagiarism was not detected, the similarity percentage should be lowered (now 32%), by rewording some sentences. See the similarity report on the platform.
The approach is innovative and very interesting. It was truly interesting to read the manuscript's approach and its results. I only have one basic observation: Those who start with DM have a higher risk of heart attack, but I wonder if this has to do with the sequence or order of onset of DM and hypertension, or if it's simply because diabetes alone carries a higher cardiovascular risk than hypertension, and what is being observed is the risk due to a longer progression of DM. Please clearly mention if the time of disease progression was included as an intervening variable in any model, so we can answer this question or discuss this point.
Whatever the reason, the finding that those who start with DM before hypertension have a higher risk is already a relevant result and should be considered in clinical practice.

Author Response

 

Comment #1. Very interesting manuscript. However, I have specific observations. Although plagiarism was not detected, the similarity percentage should be lowered (now 32%), by rewording some sentences. See the similarity report on the platform.

Response: We rephrased sentences from previous research and lowered the similarity percentage by under 30%. Excluding the methods and material section, the similarity percentage is lowered by under 25%. Thank you for the insightful comments.

 

Comment #2. The approach is innovative and very interesting. It was truly interesting to read the manuscript's approach and its results. I only have one basic observation: Those who start with DM have a higher risk of heart attack, but I wonder if this has to do with the sequence or order of onset of DM and hypertension, or if it's simply because diabetes alone carries a higher cardiovascular risk than hypertension, and what is being observed is the risk due to a longer progression of DM. Please clearly mention if the time of disease progression was included as an intervening variable in any model, so we can answer this question or discuss this point. Whatever the reason, the finding that those who start with DM before hypertension have a higher risk is already a relevant result and should be considered in clinical practice.

Response: We appreciate your insightful comments. To determine the reason for the higher risk of CVD in the DM-HTN group than the HTN-DM group, whether it is because of the sequence of development of DM or because of the longer progression of DM, we performed an exploratory analysis by further adjusting for durations of HTN and DM (Model 4). Significant association remained. This finding suggests that the durations of HTN and DM at least partially explain the risk difference between two groups. A future well-structured investigation could unveil the underlying mechanism in the precedence relationship between HTN and DM.

 

Reviewer 3 Report

Comments and Suggestions for Authors

This is a very intereesting analysis of the two subgroups of patiens with DM and hypertension  in the context of risk factors. Authors have elucidated the two possible scenarios of pathogenesis and proposed the  differenciation between the two groups DM-HTN and HTN-DM.  What I see at first view from the study there are obviously potential ethnic differences when comparing with European  population and other populations, looking at BMI and also authors considered the relatively early age diabetes prevalence in Korean population. This limitation should be added in Abstract, not only in Limitations paragraph.

In lines 240-244  there is: ... unlike dyslipidemia, CKD had a greater interactions  in patients with CKD than those without CKD in both MI and ischemic stroke development." Please, re-arrange this sentence in Discussion and similar corresponding statement in the Abstarct , as there is some grammar mistake and plese make the sentence more clear and easy to read.

Then:

"Therefore, in CKD patients, the marked increased risk of MI and stroke in the DM→HTN  group is appropriate." Please, exchange  the  expression "appropriate" to "as predicted," or "expected" or in another way as this one word used is not appropriate here .

 

In Discussion section, Lines 200-211 HTN-DM group could be better evaluated. Please, comment on different possible pathogenetic mechanisms of complications including vascualr stiffness, endothelial dysfunction and other potential ones typically connected with hypertension complictaions.

Author Response

 

Comment #1. This is a very interesting analysis of the two subgroups of patients with DM and hypertension in the context of risk factors. Authors have elucidated the two possible scenarios of pathogenesis and proposed the differentiation between the two groups, DM-HTN and HTN-DM. What I see at first view from the study there are potential ethnic differences when comparing with European population and other populations, looking at BMI and also authors considered the relatively early age diabetes prevalence in Korean population. This limitation should be added in Abstract, not only in Limitations paragraph.

Response: We added the generalization limitation of Asian patients as they develop diabetes mellitus at an earlier age than other races and are characterized by early beta-cell dysfunction with insulin resistance in the Abstract. Thank you for the suggestions.

 

Comment #2. In lines 240-244, there is: ... unlike dyslipidemia, CKD had a greater interactions in patients with CKD than those without CKD in both MI and ischemic stroke development." Please, re-arrange this sentence in Discussion and similar corresponding statement in the Abstract as there is some grammar mistake and please make the sentence more clear and easy to read.

Then: "Therefore, in CKD patients, the marked increased risk of MI and stroke in the DM→HTN group is appropriate." Please, exchange the expression "appropriate" to "as predicted," or "expected" or in another way as this one word used is not appropriate here.

 

Comment #3. In Discussion section, Lines 200-211 HTN-DM group could be better evaluated. Please, comment on different possible pathogenic mechanisms of complications including vascular stiffness, endothelial dysfunction and other potential ones typically connected with hypertension complications.

Response: We appreciate your thoughtful comments. We added the possible pathogenic mechanisms of hypertension-related complications. For example, hypertension impairs the vasodilation of skeletal muscle due to an increased response to vasoconstrictor stimulation. This results in vasoconstriction and may contribute to the genesis of vascular structural changes and increase the number of fast-twitch fibers, fostering the development of insulin resistance. Changes in endothelial permeability and decreased peripheral blood flow due to hypertension may limit insulin delivery and promote insulin resistance, which impair glucose uptake. In addition, systemic vascular resistance accompanied by oxidative stress and inflammation activates signaling molecules such as nuclear factor–kappa B (NF-ĸB) and other mediators of stress-sensitive pathways such as interleukin-1, 6 and tumor necrosis factor-alpha (TNF-α). All of these molecules can affect glucose and lipid metabolism, increase insulin resistance, and lead to the development of diabetes. [Cho NH et al, 2015] The physical stress on the arterial wall caused by initial HTN results in deterioration and acceleration of atherosclerosis, particularly affecting coronary and cerebral vessels.

[Reference]

1. Cho, N. H. et al. High Blood Pressure and Its Association With Incident Diabetes Over 10 years in the Korean Genome and Epidemiology Study (KoGES). Diabetes Care 38, 1333-1338 2015). https://doi.org:10.2337/dc14-1931