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. 2024 Feb 2;19(2):e0296662. doi: 10.1371/journal.pone.0296662

Association of hypoglycemic events with cognitive impairment in patients with type 2 diabetes mellitus: Protocol for a dose-response meta-analysis

Min Ye 1, Ai Hong Yuan 2,*, Qi Qi Yang 1, Qun Wei Li 1, Fei Yue Li 1, Yan Wei 1
Editor: Muhammad Shahzad Aslam3
PMCID: PMC10836671  PMID: 38306364

Abstract

Introduction

With an incidence rate as high as 46%-58%, hypoglycemia is a common complication of glycemic management among those suffering from type 2 diabetes mellitus(T2DM). According to preclinical research, hypoglycemia episodes may impair cognition by harming neurons. However, there is still controversy regarding the clinical evidence for the relationship between hypoglycemic events and the likelihood of cognitive impairment. Furthermore, little research has been done on the dose-response association between hypoglycemia incidents and the possibility of cognitive impairment. To address these knowledge gaps, the present research intends to update the comprehension of the association among hypoglycemic events and the risk of cognitive impairment and to clarify the correlation between dose and response by incorporating the most recent investigations.

Method and analysis

This work has developed a protocol for a systematic review and meta-analysis that will examine, via a well-organized assessment of several databases, the relationship between the incidence of hypoglycemia and the probability of cognitive impairment. Observational studies investigating the connection between hypoglycemia episodes and cognitive impairment will be included. The databases that will be searched are PubMed, Web of Science, the Chinese Biomedical Literature Database (CBM), Cochrane Library, Embase, the China National Knowledge (CNKI), Wan Fang, the Chinese Science and Technology Periodical Database (VIP), and Du Xiu. Literature from the establishment of each database to December 2023 will be included in the search. Two researchers will independently screen the studies that satisfy the requirements for both inclusion and exclusion. A third researcher will be asked to mediate any disputes. The methodological caliber of the studies included will be assessed utilizing the Newcastle-Ottawa Scale (NOS) or the Joanna Briggs Institute (JBI) critical appraisal method. With regard to GRADE, which stands for Grading of Recommendations, Assessment, Development, and Evaluation, the quality of the evidence will be evaluated. ROBIS Tool will be used to evaluate the risk of bias in the development of the systematic review. If the data is accessible, meta-analysis and dose-response curve analysis will be employed by Stata software. However, if the data does not allow for such analysis, a descriptive review will be performed.

Discussion and conclusion

Hypoglycemic episodes may raise the likelihood of cognitive impairment, according to earlier investigations. This study will update the relevant evidence and explore the dose-response connection between hypoglycemic episodes and cognitive impairment. The results of this review will have significant effects on decision-making by individuals with diabetes, healthcare providers, and government policy institutions.

Trial registration

Prospero registration number: CRD42023432352.

Introduction

Type 2 diabetes mellitus (T2DM) is a chronic metabolic condition marked by insulin resistance and enhancing loss of β-cell function [1]. It is one of the important subtypes of diabetes, accounting for more than 90% of the diabetic population. T2DM has a high incidence, numerous complications, and imposes a heavy medical burden [2–4]. The increasing number of people with T2DM has become a great pressure and challenge in the field of public health due to the development of an ageing society [5].

Cognitive dysfunction is one of the most common complications of T2DM [6]. Empirical research has shown that individuals experiencing T2DM have a 2–3 times higher risk of developing cognitive disorders such as vascular dementia and Alzheimer’s disease compared to healthy individuals [7, 8]. The overall incidence of mild cognitive dysfunction in T2DM patients is as high as 45% [9]. However, currently, there is no officially recognized effective treatment for cognitive impairment caused by T2DM worldwide. Investigating practical preventative measures for cognitive dysfunction caused by T2DM will therefore be particularly crucial.

Blood glucose control is the core goal of the clinical therapy strategy for individuals concerning T2DM, and iatrogenic hypoglycemia is a common complication in the process of blood glucose control in patients with T2DM, with an incidence rate as high as 46%-58% [10]. The immediate effect of hypoglycemia on cognitive ability is well known to be very significant, with typical manifestations including sluggish response, lethargy, coma, etc [11]. However, the long-term impairment and cumulative effect of hypoglycemic events on cognitive function, as well as the dose-response relationship, remain unknown. In animal models, it has been observed that recurrent hypoglycemic events seem to cause cumulative brain damage, which is strongly connected to the eventual development of chronic cognitive dysfunction [12–14]. In recent years, clinical investigations have been carried out to examine the connection between hypoglycemic events and subsequent cognitive impairment, but unfortunately, different investigations have shown almost opposite conclusions. Studies such as Wajd Alkabbani et al. [15–18] have suggested that hypoglycemia significantly increases the risk of cognitive impairment, whereas Tali Cukierman-Yaffe et al. [19–21] found that hypoglycemia does not impair cognitive function or increase the likelihood of cognitive dysfunction. Therefore, the connection between hypoglycemic events and cognitive impairment remains controversial.

In 2022, Maria Dolores Gomez-Guijarro’s team [22] executed a systematic review and meta-analysis of research publications on the connection between severe hypoglycemic incidents and dementia in individuals concerning T2DM. However, due to the lack of relevant research at the time and the high heterogeneity among the literature, they were only able to incorporate 7 pieces of suitable literature in the evaluation. Simultaneously, a substantial portion of the literature indicates a moderate susceptibility to bias, as acknowledged by the authors who emphasized the need for cautious interpretation of their findings. Consequently, there is an absence of dependable evidence-based outcomes to substantiate the impact of hypoglycemic events on cognitive competence in individuals concerning T2DM. This manuscript aims to establish a methodological structure (protocol) to explore the cumulative effect of frequency of hypoglycemic events on cognitive function and further explore the dose-response relationship through systematic review and meta-analysis, which aims to update the association between hypoglycemia and cognitive impairment by including the latest relevant studies. Through these objectives, this study will provide new insights and strong evidence for the development of clinical glycemic control programs and the improvement of cognitive impairment prevention strategies.

Methods and materials

Before undertaking this research, we duly registered the study protocol with the PROSPERO database (Registration number: CRD42023432352). The execution of this study will adhere to the procedure outlined in the Cochrane Handbook for Systematic Reviews of Interventions [23]. The reporting of this study will adhere to the guideline of Meta-analyses of Observational Studies in Epidemiology (MOOSE) [24], and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols statement (PRISMA-P) will be applied for all subsequent reporting [25]. The PRISMA-P checklist is shown in the S1 Appendix.

Search strategy

A thorough search will be undertaken across various databases including PubMed, Web of Science, CBM, Cochrane Library, Embase, CNKI, Wan Fang, Wei Pu, and Du Xiu, covering the period from inception to December 2023. The search will utilize Medical Subject Headings (MeSH) and free terms, such as ‘diabetes mellitus, type 2’, ‘noninsulin’, ‘noninsulin-dependent diabetes mellitus’, ‘type 2 diabetes’, ‘type 2 diabetes mellitus’, ‘type 2 diabetic’, ‘T2DM’, ‘DM’, ‘cognitive dysfunction’, ‘cognition disorders’, ‘cognitive disorder’, ‘dementia’, ‘cognitive decline’, ‘cognition disorder’, ‘cognitive deficit’, ‘cognitive impairment’, ‘executive function’, ‘cognitive function’, ‘memory’, ‘neurodegeneration’, ‘neurodegenerative disease’, ‘neurocognitive disorder’, ‘neuropsychiatric disorder’, ‘mental deterioration’, ‘dysmnesia’, ‘learning-memorizing ability’, ‘allomnesia’, ‘risk factor’, ‘predicted’, ‘predictor’, ‘risk’, ‘relat’, ‘associat’, ‘factor’, ‘reason’, ‘correlated’, ‘predictor’, ‘influen’, ‘inciden’, ‘relevan’, for comprehensive coverage. Furthermore, reference lists of relevant papers will be manually checked and records from relevant trial registries will be retrieved. The search strategy will finally be formulated based on the results of repeated pre-search to include relevant studies as comprehensively as possible. The search strategy is shown in S2 Appendix.

Eligibility criteria

Inclusion criteria

Studies meeting all the given requirements will be contained.

Type of studies

All observational research will be included, including cross-sectional studies, case-control studies, and cohort studies.

Type of participants

Individuals who have been medically diagnosed with type 2 diabetes and have been at least 18 years old are eligible to participate. Prior to enrollment and at the time of enrollment, every participant had normal cognitive function. The study has no restrictions on sex, race, duration of diabetes, or severity of diabetes among the participants.

Criteria for the assessment of hypoglycemia

The plasma glucose level was less than 3.9 mmol per liter [11], the patient showed symptoms such as palpitation and dizziness, and the diagnosis was established by a trained physician or a formal medical institution.

Criteria for the assessment of cognitive impairment

The International Classification of Diseases (ICD) of the World Health Organization, the Diagnostic and Statistical Manual of Mental Disorders (DSM) of the American Psychiatric Association, cognitive testing, or other nationally recognized diagnostic standards were utilized to make diagnoses [26–28]. A qualified medical professional or other recognized healthcare provider was responsible for the diagnosis. The sources of diagnoses were either medical claims archives or electronic case databases.

Contents of studies

Studies that explored the connection between hypoglycemia and the likelihood of cognitive dysfunction will be included. The included studies have to provide data on the connection between the two, such as odds ratio (OR), risk ratio (RR), hazard ratio (HR), and 95% confidence intervals (CI).

Exclusion criteria

Studies will be disqualified if they fulfill any of the specified criteria.

  1. Duplicate publication of the same study (studies that have more detailed and credible results, are more recent, or have a larger sample size will be selected);

  2. Studies for which full text or relevant data are not available;

  3. Studies with insufficient methodological detail or poor quality (e.g., high risk of bias, inadequate statistical analysis);

  4. Studies with comorbid conditions that could independently affect cognitive function (e.g., neurodegenerative diseases other than diabetes-related cognitive impairment);

  5. Studies where the dose or severity of hypoglycemic events is not clearly defined;

  6. Studies not published in English or Chinese;

  7. Studies with a duration that is too short to capture meaningful cognitive changes;

  8. Studies with significant heterogeneity in interventions or treatment protocols that may impact the ability to conduct a meaningful dose-response analysis.

Literature screening

The literature will be managed using EndNote software. Two reviewers will screen the literature independently. Duplicate literature will be eliminated first. Then, the title and abstract will be used to weed out the literature that does not support the research theme. After that, the other literature will next be carefully read in its entirety and evaluated in light of the inclusion and exclusion criteria. If there is a difference of opinion, a compromise will be decided after chatting with another reviewer. To present the findings of the research screening and selection procedure, we will use the PRISMA flowchart (S1 Fig).

Data extraction

The information that followed will be obtained independently by two researchers.

  1. General information of studies: the first author, year of publication, country and region, study type, and duration of follow-up;

  2. Participant characteristics: average age, physical activity levels, body mass index (BMI), sample size;

  3. Disease characteristics: diagnostic criteria for hypoglycemia, duration of hypoglycemia, degree of hypoglycemia (light, resolves with rest; medium, resolves with medicine; severe, resolves after receiving comprehensive hospital treatment), measurements of hypoglycemia, frequency of hypoglycemic events, duration of diabetes mellitus, measurements of diabetes mellitus, definition of cognitive impairment, measurements of cognitive impairment, types of cognitive impairment(it may consist of Alzheimer’s disease, vascular dementia, and other types.), and diagnostic criteria for cognitive impairment.

Evaluation of literature quality

The Newcastle-Ottawa Scale (NOS) and the Joanna Briggs Institute (JBI) critical assessment method will be used by two investigators to independently grade the methodological quality of the included studies. Case-control study’s primary evaluation criteria focus on subject selection (4 points), group comparability (2 points), and exposure factor measurement (3 points). Cohort study grading criteria include subject selection (4 points), group comparability (2 points), and outcome measurement (3 points). The quality of studies will be judged and categorized as ’High’, ’Medium’, or ’Low’ based on the scoring criteria. The total score for both evaluations is 9 points. Scores above six indicate high quality, scores of five indicate medium quality, and scores below five indicate low quality. Eight items are used in the JBI critical assessment method to evaluate the cross-sectional survey. The responses to each item include four answers: "yes", "no", "not clear" and "not applicable". If a cross-sectional study has a "yes" response of more than 70%, the study is considered high-quality literature. A response of 50% to 69% is considered moderate quality, while less than 50% is considered low-quality literature.

Data synthesis

If there are enough studies (at least 2) that define the exposure and the desired outcome similarly, meta-analysis will be carried out; if not, only descriptive analyses will be carried out. To conduct our statistical analysis, we will first use the DerSimonian-Laird method to generate the pooled RR and its 95% CI [29]. In cases where the literature does not provide the RR, we will employ specific formulas to convert OR and HR to RR [30–32]. To assess the heterogeneity of the literature, we will use the Chi-square test and I2 statistic. There will be four categories for heterogeneity: not important (0%-40%), moderate (30%-60%), substantial (50%-90%) and considerable (75%-100%). The fixed effect model will be applied for combined analysis if the I2 value is less than 50%. A random effect model will be applied when P < 0.1 or I2 > 50% [33, 34]. Regardless of whether statistically significant heterogeneity is found, if there is enough literature, we will investigate clinical heterogeneity by subgroup analysis and other workable analytical techniques. For the statistical analysis, we will use the STATA SE program, version 15 (StataCorp).

Subgroup analysis and meta-regression

We will conduct subgroup analysis to explore the sources of heterogeneity if there are enough subgroup studies [34]. Factors used for grouping may include age, sex, BMI, physical activity levels, duration of diabetes, the severity of diabetes, follow-up period, type of study, country of study, type of cognitive impairment, severity of hypoglycemia, frequency of hypoglycemia, and duration of hypoglycemia. Furthermore, we will perform meta-regression to look at how these factors affect the study’s final combined results when the number of relevant studies is more than ten.

Sensitivity analysis

The stability of the combined findings will be identified by carrying out the sensitivity analysis, in which a single study will be removed one at a time.

Dose-response curve analysis

If data are available, we will use dose-effect curve analyses to investigate the dose-response relationship between hypoglycemic events and the likelihood of cognitive impairment. The frequency of hypoglycemia, the severity of hypoglycemia, and the duration of hypoglycemia are examples of exposure variables, while the incidence of cognitive impairment is an example of an outcome measure.

Publication bias

The retrieval of literature may generally involve omittance, small sample studies, published bias, negative results, etc., depending on the research purpose. Any of these conditions may contribute to publication bias, which will have an impact on the accuracy of the meta-analysis results. Therefore, to minimize publication bias as much as feasible, we will not only develop a strict search strategy but also gather pertinent grey literature as comprehensively as possible. Moreover, publication bias will be investigated using Begg’s test and Egger’s test. When there are more than ten papers in the meta-analysis, the evaluation will be presented in the form of funnel plots. A P value of less than 0.05 will be considered to indicate publication bias [35].

Grading the quality of evidence

Using the GRADE approach, we will evaluate the strength of the evidence. Depending on the study design, bias risk, inconsistency, indirect evidence, imprecision, and publication bias, each outcome may receive a high, moderate, low, or extremely low evidence rating [36]. Evidence at a high level will result in "strong recommendation", evidence at a moderate level in "practice consideration", and evidence below a moderate level in "insufficient evidence to guide" [37]. One tool that is particularly suited for evaluating the risk of bias in systematic reviews is ROBIS. It can be used to evaluate the relationship between the practical issues that users address and the questions of systematic reviews, as well as the risk of bias in the creation and interpretation of the results of systematic reviews (including interventions, diagnosis, prognosis, and etiology) [38]. We will also utilize the ROBIS Tool to assess the systematic review’s risk of bias, based on the kind of research that will be included in it. It is expected that a more thorough evaluation of the systematic review’s evidence level will be possible due to the complementarity of the GRADE standard and the ROBIS tool.

Discussion

It has become widely accepted that T2DM and cognitive dysfunction are progressive diseases closely related to age, which have a high prevalence in older people and those of middle age [39, 40]. T2DM with cognitive dysfunction has undoubtedly gotten a lot of attention in the medical and health fields as a result of the emergence of a world that is becoming older and the expansion of persons with T2DM’s life expectancy globally. However, the relationship between hypoglycemic events, one of the typical complications of glycemic control in individuals suffering from T2DM, and cognitive impairment remains unclear [41]. This investigation seeks to explore the connection between hypoglycemic events and cognitive impairment, and further explore the effects of the severity, duration, and frequency of hypoglycemic events on cognitive impairment by subgroup analysis or meta-regression. We will refine and distinguish the types of cognitive dysfunction once we have sufficient data, in order to clarify the precise association between hypoglycemia and different types of cognitive dysfunction. The results of the study will facilitate the development of personalized glycemic control strategies for patients with different conditions of T2DM, and hopefully improve the prevention strategies for different types of cognitive dysfunction related to diabetes.

Many medical staff working on the clinical front line have observed that people with frequent hypoglycemic events seem to be more likely to develop cognitive impairment [42]. The association between hypoglycemia incidents and cognitive impairment in terms of dose-response hasn’t been explored, though. This is very disadvantageous for the elderly population, who frequently experience hypoglycemic events. On the one hand, they do not understand the long-term and cumulative damage of hypoglycemic events to cognitive function, and on the other hand, they lack awareness of the management of hypoglycemic events, which is also an important reason for the common occurrence of hypoglycemic events in the elderly [43]. Understanding the dose-response relationship between hypoglycemic events and cognitive dysfunction not only directly affects the elaboration of precise hypoglycemic regimens, but also provides decision-making guidance for relevant medical workers and government policy agencies. Most importantly, it will help to enhance the awareness of hypoglycemia prevention in patients with T2DM, thereby reducing the cumulative damage of cognitive function caused by hypoglycemia and preventing cognitive impairment.

Hypoglycemic episodes and cognitive impairment, of course, have a complex dose-response connection that might be altered by a wide range of lifestyle factors. According to studies, a healthy lifestyle that includes things like exercise, social interaction, napping, and eating a balanced diet is linked to a slower rate of memory loss [44, 45]. One of the major factors contributing to the development of cognitive impairment in diabetics is the pervasive inflammatory condition [46]. According to studies, leading a healthy lifestyle—which includes exercise in particular—protects the brain from inflammatory states like CRP and enhances cognitive function [47]. Exercise, however, may raise the risk of hypoglycemia in diabetes individuals using insulin or insulin secretagogues, according to previous research [48, 49]. Exercise-related hypoglycemia impairs cognitive performance by inhibiting the autonomic nervous system, neuroendocrine system, and metabolic defenses (also known as counter-regulatory responses) [50]. Consequently, exercise may have a bidirectional effect on the dose-response connection between hypoglycemia events and cognitive impairment. Future research should be planned to account for or adjust for these confounders because it is yet unknown how other lifestyle factors, such as food and sleep, may affect the study’s estimated effect size. Eventually, these initiatives should produce more thorough research findings and practical lifestyle guidelines or suggestions for reducing cognitive impairment in diabetics.

In conclusion, this study has the potential to address the evidence gap on the connection between hypoglycemic events and cognitive dysfunction in patients suffering from T2DM. It also has the potential to promote glycemic and cognitive management, benefiting the large population of those suffering from T2DM.

Strengths of the proposed meta-analysis

There is currently no specific treatment plan for diabetes-related cognitive impairment, despite its high frequency. There is debate over whether hypoglycemia episodes are a major factor in type 2 diabetes patients’ cognitive impairment. It is anticipated that carrying out this study protocol will give rise to an evidence-based foundation supporting the link between hypoglycemia episodes and cognitive decline. It will also investigate the dose-response association between hypoglycemia and cognitive impairment for the first time. It is anticipated that this protocol will offer helpful recommendations for blood glucose regulation and the prevention of cognitive impairment in patients with type 2 diabetes.

Limitations of the proposed meta-analysis

First of all, the utilization of different literature types in this study protocol, including case-control and cohort studies, may result in some heterogeneity. Second, bias may be produced and the degree of evidence may be lowered because it only comprised observational research. In addition, the study will just incorporate English and Chinese literature, which may limit the total amount of data that may be extracted. The systematic review report will discuss these as study limitations.

Supporting information

S1 Appendix. The PRISMA-P checklist.

(DOCX)

Click here for additional data file. (34KB, docx)
S2 Appendix. The search strategy for PubMed.

(DOCX)

Click here for additional data file. (12.8KB, docx)
S1 Fig. The PRISMA flow diagram of the study selection process.

(TIF)

Click here for additional data file. (472.3KB, tif)
S1 File

(XLSX)

Click here for additional data file. (14.4KB, xlsx)

Acknowledgments

The study’s idea and the manuscript’s revision involved input from all authors. We are appreciative to teacher Ling Cheng from the College of Humanities at the Anhui University of Chinese Medicine for editing this article’s language.

Abbreviations

T2DM

Type 2 diabetes mellitus

GRADE

Grading of Recommendations, Assessment, Development, and Evaluation

CBM

the Chinese Biomedical Literature Database

ROBIS

Risk of Bias in Systematic Reviews

CNKI

the China National Knowledge

VIP

the Chinese Science and Technology Periodical Database

NOS

the Newcastle-Ottawa Scale

JBI

the Joanna Briggs Institute

PROSPRO

Prospective register of systematic reviews

BMI

Body Mass Index

MOOSE

Meta-analyses of Observational Studies in Epidemiology

PRISMA-P

the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols statement

OR

odds ratio

RR

risk ratio

HR

hazard ratio

CI

confidence intervals

MeSH

Medical Subject Headings

Data Availability

Our paper belongs to the meta-analysis protocol, and this paper itself does not involve any data at present. In the process of formulating the protocol, we have pre-searched relevant databases and extracted partial data from relevant literature to ensure the feasibility of the research protocol. Since the relevant data have not been uploaded to public repositories, we will upload the pre-searched relevant data as Supporting Information files.

Funding Statement

This work was supported by the Natural Science Foundation of Anhui Province (Grant No.2108085MH308), the National Inheritance Studio of Famous and Veteran TCM Experts (Grant No. 8187151181) and the Fifth Batch of the National TCM Clinical Excellent Talents Training Program. AHY received funding from the above projects. The funders did not and will not have a role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Decision Letter 0

Muhammad Shahzad Aslam

27 Oct 2023

PONE-D-23-23141Association of hypoglycemic events with cognitive impairment in patients with type 2 diabetes mellitus: Protocol for a dose-response meta-analysisPLOS ONE

Dear Dr. Ye,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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Muhammad Shahzad Aslam, Ph.D.,M.Phil., Pharm-D

Academic Editor

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[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

Reviewer #4: Yes

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4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Dear authors,

I have reviewed your work and appreciate your meticulous work on this subject. Overall, your protocol seems well designed and comprehensive. The literature review and data extraction methods appear to be comprehensive and robust, appropriate to the purpose of the study.

I suggest you take into consideration my suggestions below:

1-You can further expand the keywords used for the literature search. (For example: neurodegeneration,neurodegenerative disease, neurocognitive disorder, neuropsychiatric disorder) This will help researchers screen for all relevant studies.

2-You can make the information used for data extraction more detailed. Definition of cognitive impairment, Cognitive impairment measurements, etc.

3-You can define the variables to be used for dose-response analysis in more detail.

I wish you a successful completion of your work.

Reviewer #2: This protocol details the methodology to be followed for a systematic review and meta-analysis on hypoglycemic events and cognitive impairment in patients with type 2 diabetes mellitus. Ye et al. present an interesting protocol, well-structured and with a methodologic plan of interest. This type of study is needed in this population, so the protocol is relevant.

However, there are several comments that should be noted and addressed:

a. Eligibility criteria. Detail inclusion criteria for exposure, such as definition for hypoglycemic events or assessment methods. Furthermore, specify criteria for outcome (cognitive impairment), i.e., assessment methods, definition, etc.

b. Line 96. Specify the type of observational studies to be included.

c. Line 97. “Individuals with a diagnosis of T2DM will be incorporated”. Will only studies that report medical diagnosis be included or could they be self-reported? Please specify. Also, will the participants included be adults? Please specify and indicate age range.

d. Line 103. Please delete criterion 1. This is a repeated criterion that has already been established as an inclusion criterion.

e. Line 131.

f. Line 153. Will a minimum number of studies be considered for meta-analysis? Will different meta-analyses be performed depending on the study design? Please detail.

g. Line 157. Provide the interpretation of I2 according to the percentages of heterogeneity and its respective reference.

h. Line 165. Will a minimum of studies be considered for meta-regression analyses? Consider Cochrane recommendations.

i. For subgroup and meta-regression analyses consider BMI status and physical activity levels. Also, add these variables for data extraction.

j. Lines 171-172. Please provide more detail on the possible dose-response curve analysis to be performed.

k. Lines 174-175. Will a minimum of studies be considered for publication bias? Consider Sterne et al. (2011) recommendations. Moreover, for the linear regression approach, what will be the p-value considered significant?

l. Lines 177-178. Specify the characteristics of the levels of evidence. Detail the levels of evidence possible to be graded according to GRADE. What does high, medium, low and very low mean?

m. I think it would be useful for the authors to discuss the potential role of exercise, sleep, and other lifestyle behaviors in the association between hypoglycemic events and cognitive decline in patients with type 2 diabetes mellitus. In this sense, manuscripts with an integrative and translational character should be included in the discussion, such as doi: https://doi.org/10.1186/s12902-019-0402-3; doi: https://doi.org/10.1586/eem.10.78; doi: https://doi.org/10.4093/dmj.2022.0007; doi: https://doi.org/10.1136/bmj-2022-072691; and doi: http://dx.doi.org/10.1136/bjsports-2022-106355

Reviewer #3: Comments to the authors

Abstract

• “The connection that exists between hypoglycemic occurrences and the likelihood of cognitive impairment will be investigated through an organized review of multiple databases.” It is better to include a sentence summarising the inclusion criteria: "Studies that ........ were included".

• “Both Chinese and English literature…” Remove this from the summary.

Introduction

• “…normal individuals” Change from normal to healthy

• “By constructing a diabetic rat model, Seok Joon Won…”. Better: "In animal models, it has been observed that..."

• “This investigation seeks to update the systematic review and meta-analysis by including the latest relevant studies”. Better “This systematic review and meta-analyses aimed to…”

Methods and materials

• If it is a meta-analysis of observational studies, the MOOSE guideline should also be included.

• “All observational studies published in Chinese or English will be included”. Why not include other languages? Even if authors only know English and Chinese, there are translation tools that allow studies in other languages to be included.

• “The study has no restrictions on sex, race, duration of diabetes, or severity of diabetes among the participants” But is the severity of diabetes going to be controlled in some way?

• “…likelihood of cognitive dysfunction will be included”. Is there a way to determine if there is cognitive disorder? It is important to establish this a priori before the study.

• Inclusion criteria – “Studies not published in Chinese or English” and “Participants with gestational diabetes”. Exclusion criteria are not the opposite of inclusion criteria. Exclusion criteria are those that exclude participants or studies from inclusion even though they meet the inclusion criteria.

• Search strategy – I suggest this section be placed before the eligibility criteria.

• Data extraction – “the primary author” ¿first author? “period of publication” ¿year of publication? “type of diabetes mellitus” Isn't it just type 2 diabetes mellitus? “type of cognitive impairment” The type of cognitive dysfunction that can be included needs to be defined beforehand.

• “Evaluation of literature quality (publication bias)” – First, how many authors did the publication bias assessment? Secondly, I do not recommend putting publication bias. Publication bias generally refers to the Egger test and the funnel plot for meta-analysis.

• Data synthesis – First, the authors should rate the heterogeneity, for example, as not important, moderate, substantial, and considerable. Second, the p-value of heterogeneity should be assessed. Third, why did you choose the value of 30% or more to do a random-effects meta-analysis? Why not 50%? Or why not if p is < 0.05? I suggest doing the random effects meta-analysis, studies with some heterogeneity in the population and its characteristics will be included, and fixed effects meta-analyses usually give narrower confidence intervals, which can be misleading in some contexts.

• Publication bias – And what p-value is used as a threshold to consider that there is publication bias?

• Grading the quality of evidence – It is proposed to explain it a little more (not much, but a little more, yes)

Reviewer #4: Congratulations to the authors. This is a well-written and constructed manuscript. I enjoyed learning about the study. I believe it is worthy of publication.

Some minor changes:

1. Abstract

- I suggest including the specific study design (systematic review and meta-analysis protocol).

- I recommend including both that this protocol will be adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols and the meta-analysis will be guided by the Cochrane Collaboration Handbook recommendations.

- Line 28: I suggest specifying the way in which the inconsistences will be solved.

2. Introduction

- Great

- Objective: The objective of this manuscript is not to explore the cumulative effect of the frequency of hypoglycemia events on cognitive function, but to establish the methodological structure (protocol) in order to explore, through systematic review and meta-analysis, the cumulative effect of the frequency of hypoglycemia events on cognitive function. Reconsider.

3. Methods and materials

- Line 89. The systematic review should also be adhered to the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) statement.

- Line 96. Could the author please state the reason for the exclusion of experimental studies?

- Line 156: It is suggested to indicate the range of heterogeneity based on I2 (not important, moderate, substantial, and considerable)

- Will the authors consider the corresponding p-value?

4. Discussion

- Line 190: The authors state that “This investigation seeks to explore the connection between hypoglycemic events and cognitive impairment”. However, they pretend to “clarify the precise association between hyperglycemia and different types of cognitive dysfunction”. Is this correct?

**********

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes: Carlos Pascual-Morena; Irene Martínez-García

Reviewer #4: No

**********

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PLoS One. 2024 Feb 2;19(2):e0296662. doi: 10.1371/journal.pone.0296662.r002

Author response to Decision Letter 0

6 Nov 2023

Response to journal's requirements

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming.

Ans: We appreciate you reminding us. We have made the necessary formatting adjustments in accordance with PLOS ONE style guidelines, and we trust that the manuscript now satisfies your criteria.

2.We note that the grant information you provided in the ‘Funding Information’ and ‘Financial Disclosure’ sections do not match. When you resubmit, please ensure that you provide the correct grant numbers for the awards you received for your study in the ‘Funding Information’ section.

Ans: We appreciate you reminding us. We have reviewed the funding information portion of the manuscript and determined that the data it contains is correct. We apologize for any trouble this has given you with your work and will be updating the incorrect information in the online submission form.

3.Your ethics statement should only appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please move it to the Methods section and delete it from any other section. Please ensure that your ethics statement is included in your manuscript, as the ethics statement entered into the online submission form will not be published alongside your manuscript.

Ans: We appreciate your proposal, and as per it, we have relocated the ethical statement to the manuscript methodology section and deleted it from its previous location.

 

Response to Reviewer 1's Comments

Firstly, we would like to express our sincere thanks for your constructive comments and positive response. The revised version of the manuscript has been significantly modified based on your comments. The revised parts are marked in red font. We hope you are satisfied with our revisions.

1. You can further expand the keywords used for the literature search. (For example: neurodegeneration, neurodegenerative disease, neurocognitive disorder, neuropsychiatric disorder) This will help researchers screen for all relevant studies.

Ans: We have broadened relevant search terms based on your suggestions to completely choose relevant papers, as shown in lines 100-115 and S2 Appendix.

2. You can make the information used for data extraction more detailed. Definition of cognitive impairment, Cognitive impairment measurements, etc.

Ans: Thanks to your advice, we have modified the required data extraction information, making our scheme more complete and practicable, as shown in lines 148-160.

3. You can define the variables to be used for dose-response analysis in more detail.

Ans: We specified possible variables for dose-response analysis based on your suggestions, such as frequency of hypoglycemia, severity of hypoglycemia, duration of hypoglycemia, and incidence of cognitive impairment, to provide a clearer picture of our study protocol. For more information, see lines 154-160 and 197-202.

 

Response to Reviewer 2's Comments

Firstly, we would like to express our sincere thanks for your constructive comments and positive response. The revised version of the manuscript has been significantly modified based on your comments. The revised parts are marked in red font. We hope you are satisfied with our revisions.

1.Eligibility criteria. Detail inclusion criteria for exposure, such as definition for hypoglycemic events or assessment methods. Furthermore, specify criteria for outcome (cognitive impairment), i.e., assessment methods, definition, etc.

Ans: Thanks for your valuable advice, we have added the assessment methods for hypoglycemic events and cognitive impairment in the inclusion criteria section according to your suggestion. See lines 123-131 for details.

2. Line 96. Specify the type of observational studies to be included.

Ans: We have clarified the study types of the included observational research, such as cross-sectional studies, case-control studies, cohort studies, and so on, in response to your recommendation. For more information, see lines 118-119 of the text.

3.Line 97. “Individuals with a diagnosis of T2DM will be incorporated”. Will only studies that report medical diagnosis be included or could they be self-reported? Please specify. Also, will the participants included be adults? Please specify and indicate age range.

Ans: Thank you for your extremely useful advice. We clarified the characteristics of subjects in related studies based on your ideas. To assure the scientific validity and rigor of the trial results, we demand that all subjects be medically diagnosed with type 2 diabetes and be adults, that is, above the age of 18. Details can be found in lines 120-121.

4.Line 103. Please delete criterion 1. This is a repeated criterion that has already been established as an inclusion criterion.

Ans: Thank you for your wise counsel. This is the result of our carelessness. We removed criterion 1 based on your advice.

5. Line 153. Will a minimum number of studies be considered for meta-analysis? Will different meta-analyses be performed depending on the study design? Please detail.

Ans: Thank you for your valuable advice and in accordance with the Cochrane Handbook for Systematic Reviews, we have stipulated that meta-analyses will be performed only if there are sufficient studies (≥2) with similar definitions of exposure and outcome of interest, and only descriptive analyses will be performed if the number of studies is insufficient. When the number of studies and relevant data are sufficiently rich, we will conduct subgroup analysis according to different study types, such as cross-sectional studies, case-control studies, cohort studies, etc. See lines 176-177 and 190 of the text for details.

6. Line 157. Provide the interpretation of I2 according to the percentages of heterogeneity and its respective reference.

Ans：We have updated the explanation of I2 for the proportion of heterogeneity and its respective reference, as you requested. Details can be found on lines 181-186.

7. Line 165. Will a minimum of studies be considered for meta-regression analyses? Consider Cochrane recommendations.

Ans: Thank you for your insightful advice. According to the Cochrane Handbook for Systematic Reviews of Interventions, the minimum number of studies for meta-regression analysis is ten. Look at lines 192-193.

8. For subgroup and meta-regression analyses consider BMI status and physical activity levels. Also, add these variables for data extraction.

Ans: Thank you for your helpful suggestions. We completely agree with your points of view and will include BMI status and physical activity levels in the data extraction, subgroup analysis, and meta-regression, making our study more valuable. For more information, see lines 152 and 189.

9. Lines 171-172. Please provide more detail on the possible dose-response curve analysis to be performed.

Ans: We have added possible exposure factors and outcome measures that may be utilized for dose-response analyses to the dose-response curve analysis section based on your recommendation. See lines 197-202 for more information.

10. Lines 174-175. Will a minimum of studies be considered for publication bias? Consider Sterne et al. (2011) recommendations. Moreover, for the linear regression approach, what will be the p-value considered significant?

Ans: Thank you for your advice. We concluded that the minimal number of literature with publication bias is ten based on your proposal and relevant literature. At the same time, a P value of less than 0.05 for Egger's regression asymmetry test is considered severe publication bias. For more information, see lines 203-206.

11. Lines 177-178. Specify the characteristics of the levels of evidence. Detail the levels of evidence possible to be graded according to GRADE. What does high, medium, low and very low mean?

Ans: We appreciate your recommendations, which helped us clarify the characteristics of the evidence level and further explain the GRADE evidence level. For more information, see lines 207-212.

12. I think it would be useful for the authors to discuss the potential role of exercise, sleep, and other lifestyle behaviors in the association between hypoglycemic events and cognitive decline in patients with type 2 diabetes mellitus. In this sense, manuscripts with an integrative and translational character should be included in the discussion, such as doi: https://doi.org/10.1186/s12902-019-0402-3; doi: https://doi.org/10.1586/eem.10.78; doi: https://doi.org/10.4093/dmj.2022.0007; doi: https://doi.org/10.1136/bmj-2022-072691; and doi: http://dx.doi.org/10.1136/bjsports-2022-106355

Ans: Thank you for your detailed constructing proposal. We read the appropriate literature thoroughly and gained greatly. Lifestyle influences the link between hypoglycemic occurrences and cognitive impairment, which has crucial implications for future studies in this area. We have added relevant content to the discussion section based on your recommendation. Details can be found in lines 245-261.

 

Response to Reviewer 3's Comments

Firstly, we would like to express our sincere thanks for your constructive comments and positive response. The revised version of the manuscript has been significantly modified based on your comments. The revised parts are marked in red font. We hope you are satisfied with our revisions.

1.“The connection that exists between hypoglycemic occurrences and the likelihood of cognitive impairment will be investigated through an organized review of multiple databases.” It is better to include a sentence summarising the inclusion criteria: "Studies that ........ were included".

Ans: Thank you for your proposal; we have provided the summary discourse of the literature inclusion criteria based on it. See lines 25-26.

2. “Both Chinese and English literature…” Remove this from the summary.

Ans: Thank you for your important advice; we have removed "Both Chinese and English literature..." following your recommendation.

3. “…normal individuals” Change from normal to healthy

Ans: We modified "normal" to "healthy" based on your advice. See line 56 for further information.

4. “By constructing a diabetic rat model, Seok Joon Won…”. Better: "In animal models, it has been observed that..."

Ans: Thank you for your helpful advice. We changed the sentence structure based on your ideas. For more information, see line 67.

5. “This investigation seeks to update the systematic review and meta-analysis by including the latest relevant studies”. Better “This systematic review and meta-analyses aimed to…”

Ans: Thank you for your valuable suggestions. We have revised the sentence structure according to your suggestions. See lines 85-89 for details.

6. If it is a meta-analysis of observational studies, the MOOSE guideline should also be included.

Ans: Thank you for your valuable suggestions, and as indicated in the methodology section, we will report our work in compliance with the MOOSE guidelines. Details can be found on lines 95-97.

7.“All observational studies published in Chinese or English will be included”. Why not include other languages? Even if authors only know English and Chinese, there are translation tools that allow studies in other languages to be included.

Ans: Thank you for your proposal; we studied it carefully and ultimately chose to incorporate as many literatures in diverse languages as feasible, resulting in more scientifically robust findings. As indicated in lines 102 and 119, we added the target retrieval database and made the required adjustments in the body section.

8. “The study has no restrictions on sex, race, duration of diabetes, or severity of diabetes among the participants” But is the severity of diabetes going to be controlled in some way?

Ans：Thank you for your beneficial suggestions; we also considered patient safety when preparing the manuscript. As a result, we required that relevant disorders be diagnosed by professional physicians or competent healthcare institutions, and that patients receive counsel and guidance from professional physicians throughout the trial. At the same time, because this meta-analysis is a secondary review of the original study's data, it does not raise ethical or patient safety concerns. We did not limit the severity of diabetes in order to include as many relevant research as possible. If the data allow, we will undertake subgroup analyses based on diabetes severity to investigate the effect of diabetes severity on the connection between hypoglycemia and cognitive impairment.

9. “…likelihood of cognitive dysfunction will be included”. Is there a way to determine if there is cognitive disorder? It is important to establish this a priori before the study.

Ans: This is a critical and serious issue. Before creating this meta-analysis protocol, we conducted a pre-search of individual databases, and the majority of studies investigating the association between hypoglycemia and cognitive impairment performed cognitive function tests before individuals were enrolled. Subjects with impaired cognition were screened out because they did not match the inclusion criteria for these investigations since hypoglycemia was specified as an exposure factor and cognitive impairment was set as an outcome measure. This study was a meta-analysis of the findings from these studies, and cognitive impairment should be mentioned as an outcome indicator and its diagnostic criteria in the inclusion criteria. This was an oversight in the manuscript's preparation, which is now detailed in the inclusion criteria you requested, as indicated in lines 126-131.

10. Inclusion criteria – “Studies not published in Chinese or English” and “Participants with gestational diabetes”. Exclusion criteria are not the opposite of inclusion criteria. Exclusion criteria are those that exclude participants or studies from inclusion even though they meet the inclusion criteria.

Ans：Thank you for the suggestions. We removed the above two improper exclusion criteria based on your feedback.

11. Search strategy – I suggest this section be placed before the eligibility criteria.

Ans：Thanks for your suggestion, we have adjusted the order of the relevant content according to your suggestion, see lines 100 and 116 for details.

12. Data extraction – “the primary author” ¿first author? “period of publication” ¿year of publication? “type of diabetes mellitus” Isn't it just type 2 diabetes mellitus? “type of cognitive impairment” The type of cognitive dysfunction that can be included needs to be defined beforehand.

Ans：Thank you for your advice. We regret for the manuscript's confusing and erroneous description, and we have edited, eliminated, and replaced the appropriate text based on your suggestions. For more information, see lines 150-160.

13. “Evaluation of literature quality (publication bias)” – First, how many authors did the publication bias assessment? Secondly, I do not recommend putting publication bias. Publication bias generally refers to the Egger test and the funnel plot for meta-analysis.

Ans: Thank you for your advice. As per your suggestion, we have clarified in the publication that the assessment of the quality of the literature was conducted by two investigators, and any disagreements were resolved by a third investigator. We have removed the inappropriate phrase "publication bias" according to your suggestion. See lines 161-164 for details.

14. Data synthesis – First, the authors should rate the heterogeneity, for example, as not important, moderate, substantial, and considerable. Second, the p-value of heterogeneity should be assessed. Third, why did you choose the value of 30% or more to do a random-effects meta-analysis? Why not 50%? Or why not if p is < 0.05? I suggest doing the random effects meta-analysis, studies with some heterogeneity in the population and its characteristics will be included, and fixed effects meta-analyses usually give narrower confidence intervals, which can be misleading in some contexts.

Ans：Thank you for your valuable suggestions, which helped us clarify the heterogeneity rating. Initially, I2≥30% was chosen for random effect model analysis in order to estimate the effect size more conservatively, however after reviewing your idea, we believe that the previous consideration is unnecessary and erroneous. From this point on, we use the random effects model when either P < 0.1 or I2 ≥ 50%. Details can be found on lines 181-186.

15. Publication bias – And what p-value is used as a threshold to consider that there is publication bias?

Ans: Thanks for your suggestion, we have clarified the threshold of P value in the main text, when a P value < 0.05 is considered to have significant publication bias. See lines 175-186 for details.

16. Grading the quality of evidence – It is proposed to explain it a little more (not much, but a little more, yes)

Ans：Thanks for your guidance, we have elaborated the grading of the quality of evidence. See lines 207-212 for details. 

Response to Reviewer 4's Comments

Firstly, we would like to express our sincere thanks for your constructive comments and positive response. The revised version of the manuscript has been significantly modified based on your comments. The revised parts are marked in red font. We hope you are satisfied with our revisions.

1.I suggest including the specific study design (systematic review and meta-analysis protocol).

Ans：We have added specific study designs to the abstract section as suggested by you. See line 23 for details.

2. I recommend including both that this protocol will be adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols and the meta-analysis will be guided by the Cochrane Collaboration Handbook recommendations.

Ans: We appreciate your insightful counsel, which we will take into consideration as we adhere to the Cochrane Collaboration Handbook recommendations and the preferred reporting items for the Systematic Reviews and Meta-analyses Protocols. We provide further details on this in the section on Methods and Materials, and in the Supplementary material, we include the updated PRISMA-P checklist. For details, see lines 92–99.

3. Line 28: I suggest specifying the way in which the inconsistences will be solved.

Ans: We appreciate your insightful counsel, and as per it, we have clarified that any discrepancies in the literature screening procedure were addressed by a different researcher. See line 33.

4.Objective: The objective of this manuscript is not to explore the cumulative effect of the frequency of hypoglycemia events on cognitive function, but to establish the methodological structure (protocol) in order to explore, through systematic review and meta-analysis, the cumulative effect of the frequency of hypoglycemia events on cognitive function. Reconsider.

Ans: Thank you for your constructive suggestions. We have revised the inappropriate expression according to your suggestions. See lines 86-89 for details.

5.Line 89. The systematic review should also be adhered to the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) statement.

Ans: Thank you for your valuable suggestions. We have modified the relevant content according to your suggestions, which makes our scheme look more rigorous. See lines 96-97 for details.

6. Line 96. Could the author please state the reason for the exclusion of experimental studies?

Ans: Thank you for your question. First of all, this study aims to explore the relationship between hypoglycemic events (exposure factors) and cognitive impairment (outcome measures) in the natural state, and does not involve exploring the role of artificial interventions such as treatment measures. Second, hypoglycemic events are highly harmful to the human body and have unpredictable characteristics, so it is almost impossible to recruit subjects with stable hypoglycemia for experimental research due to ethical considerations. The current experimental studies on the relationship between hypoglycemic events and cognitive impairment are almost based on the construction of hypoglycemic animal models. Finally, this meta-analysis needs to use data such as odds ratio (OR), risk ratio (RR), hazard ratio (HR), and 95% confidence intervals (CI), which are not available in experimental studies. Therefore, only observational studies were included in this study.

7.Line 156: It is suggested to indicate the range of heterogeneity based on I2 (not important, moderate, substantial, and considerable). Will the authors consider the corresponding p-value?

Ans： Thank you for your proposal. We used the range of I2 values to grade the heterogeneity in accordance with your suggestion and the Cochrane Handbook. We also took into consideration that a P value < 0.1 was deemed to be significant heterogeneity. We have meticulously edited and illustrated the primary content. For more information, see lines 181–186.

8. Line 190: The authors state that “This investigation seeks to explore the connection between hypoglycemic events and cognitive impairment”. However, they pretend to “clarify the precise association between hyperglycemia and different types of cognitive dysfunction”. Is this correct?

Ans：Thank you for your careful review and finding this spelling error. We are very sorry for our carelessness. According to your suggestion, we have modified the text. See line 227 for details.

Attachment

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Decision Letter 1

Muhammad Shahzad Aslam

23 Nov 2023

PONE-D-23-23141R1Association of hypoglycemic events with cognitive impairment in patients with type 2 diabetes mellitus: Protocol for a dose-response meta-analysisPLOS ONE

Dear Dr. Yuan,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

 Please submit your revised manuscript by Jan 07 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

  • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

  • A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

  • An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Muhammad Shahzad Aslam, Ph.D.,M.Phil., Pharm-D

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Dear authors

I have carefully considered your responses to my requests for revisions and am pleased to note that your changes have both broadened and deepened the study. The expansion of the keywords has made the literature search more comprehensive, while the elaboration of the data extraction information has significantly increased the transparency and credibility of the study. In addition, the more detailed definition of the variables to be used for the dose-response analysis strengthens the methodological integrity of the study and contributes to the interpretation of the results.

Thank you for your hard work and diligence in this process.

Reviewer #2: The authors adrressed satisfatorily all the commentts and the manuscript can now be accepted for publication

Reviewer #3: Comments to the authors

Most of the comments have been dealt with satisfactorily, but I still have a few issues that I feel should be addressed.

• “There will be four categories for heterogeneity: not important (0%-40%), moderate (30%-60%), substantial (50%-90%) and considerable (75%-90%). The fixed effect model will be applied for combined analysis if the I2 value is less than 50%. A random effect model will be applied when P < 0.1 or I2 > 50%[32, 33]. Subgroup analysis and other techniques will be used to investigate sources of clinical or methodological heterogeneity when I2 > 75%.” - I suggest that considerable is 75-100%. I also suggest including subgroup studies even if there is no detected statistically significant heterogeneity.

• Publication bias – Why is p < 0.10 not used to assume publication bias? It is the most commonly used value.

Reviewer #4: Congratulations to the authors. This is a well-written and constructed manuscript. I enjoyed learning about the study. I believe it is worthy of publication.

Some minor changes:

- Line 85: I propose to rephrase the objective. I suggest the following: "This manuscript aims to establish a methodological structure (protocol) to explore the cumulative effect of frequency of hypoglycemic events on cognitive function and further explore the dose-response relationship through systematic review and meta-analysis, which aims to update the association between hypoglycemia and cognitive impairment by including the latest relevant studies."

- Could the authors please cite the MOOSE statement?

**********

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If you choose “no”, your identity will remain anonymous but your review may still be made public.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes: Carlos Pascual-Morena; Irene Martínez-García

Reviewer #4: No

**********

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PLoS One. 2024 Feb 2;19(2):e0296662. doi: 10.1371/journal.pone.0296662.r004

Author response to Decision Letter 1

28 Nov 2023

Response to journal's requirements

1. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Ans: I appreciate your kind reminder. We have conducted a thorough investigation of each reference once more by your recommendation. To standardize the reference format, all references were downloaded from PubMed and entered into the Endnote program. There is no issue number for references 7, 12, 13, 14, 39, and 43, and there is no digital object identifier number for reference 47 since it is not included in the original journal. Simultaneously, we examined all the references and were happy to see that none of the withdrawn publications had been cited. Once again, I appreciate your thorough review. 

Response to Reviewer 3's Comments

Firstly, we would like to express our sincere thanks for your constructive comments and positive response. The revised version of the manuscript has been significantly modified based on your comments. The revised parts are marked in red font. We hope you are satisfied with our revisions.

1. “There will be four categories for heterogeneity: not important (0%-40%), moderate (30%-60%), substantial (50%-90%) and considerable (75%-90%). The fixed effect model will be applied for combined analysis if the I2 value is less than 50%. A random effect model will be applied when P < 0.1 or I2 > 50%[32, 33]. Subgroup analysis and other techniques will be used to investigate sources of clinical or methodological heterogeneity when I2 > 75%.” - I suggest that considerable is 75-100%. I also suggest including subgroup studies even if there is no detected statistically significant heterogeneity.

Ans: Regards for your insightful recommendations. About the I2 value classification, while there are currently a variety of versions, following a collaborative discussion among all authors, we consider your recommendations to be more feasible and scientifically sound, so we modify the considerable heterogeneity to 75–100% by your recommendations. We made adjustments for assertions that were not accurate. That is, regardless of whether statistically significant heterogeneity is found, subgroup analysis and other workable analytical techniques will be used to investigate clinical heterogeneity if there is enough literature. Details are shown in lines 182-187.

2. Publication bias – Why is p < 0.10 not used to assume publication bias? It is the most commonly used value.

Ans: We appreciate you informing us that two types of publication bias P-values are currently in use: 0.05 and 0.1. Since 0.1 is more rigorous and widely used, we have adjusted the P-value to 0.1 per your recommendation. For more information, see lines 206-207. 

Response to Reviewer 4's Comments

Firstly, we would like to express our sincere thanks for your constructive comments and positive response. The revised version of the manuscript has been significantly modified based on your comments. The revised parts are marked in red font. We hope you are satisfied with our revisions.

1. Line 85: I propose to rephrase the objective. I suggest the following: "This manuscript aims to establish a methodological structure (protocol) to explore the cumulative effect of frequency of hypoglycemic events on cognitive function and further explore the dose-response relationship through systematic review and meta-analysis, which aims to update the association between hypoglycemia and cognitive impairment by including the latest relevant studies.".

Ans: We appreciate your patient advice, and we have adapted the research purpose in light of your recommendations, which improves the overall quality and scientific appearance of our program. For information, see lines 85–89.

2. Could the authors please cite the MOOSE statement?

Ans: We appreciate you reminding us and apologize for this error. As per your recommendation, we have now included the pertinent references of the MOOSE statement. For information, see lines 96–97 and 356–359.

Attachment

Submitted filename: Response to Reviewers.docx

Click here for additional data file. (23.6KB, docx)

Decision Letter 2

Muhammad Shahzad Aslam

5 Dec 2023

PONE-D-23-23141R2Association of hypoglycemic events with cognitive impairment in patients with type 2 diabetes mellitus: Protocol for a dose-response meta-analysisPLOS ONE

Dear Dr. Yuan,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

1) The researcher can disagree with the comment given by reviewer.

For example, Reviewer stated that "2. Publication bias – Why is p < 0.10 not used to assume publication bias? It is the

most commonly used value.

Ans: We appreciate you informing us that two types of publication bias P-values are

currently in use: 0.05 and 0.1. Since 0.1 is more rigorous and widely used, we have

adjusted the P-value to 0.1 per your recommendation. For more information, see lines

206-207.

As an editor, suggest it to keep statistical significance in scientific research is p < 0.05. I have given my details below. Moreover, Please explain in detail the Publication bias. The current has no justification and explanation.

The commonly used threshold for statistical significance in scientific research is p < 0.05, which means that the observed results are unlikely to have occurred by chance alone. However, the use of p < 0.10 to assume publication bias is not a standard practice. The threshold of p < 0.05 is widely accepted in the scientific community and is considered a standard level of significance.

The rationale behind using a stricter threshold for publication bias assessment is to reduce the risk of false positives or Type I errors. Setting a more lenient threshold, such as p < 0.10, increases the likelihood of incorrectly concluding that there is publication bias when it may not actually be present.

When assessing publication bias, researchers often use various statistical tests and graphical methods, such as funnel plots, Egger's test, and Begg's test. These tools help evaluate whether there is a systematic relationship between study precision and effect size, which could indicate the presence of publication bias. 

2) Please Revisit the exclusion criteria. I am giving some suggestion. It is not mandatory to include all suggestion. yet your study exclusion criteria is important

Study Design:

Exclude studies that are not primary research articles (e.g., reviews, editorials, commentaries).

Exclude observational studies lacking a clear dose-response relationship or studies not reporting relevant data for a dose-response analysis.

Exclude studies with insufficient methodological detail or poor quality (e.g., high risk of bias, inadequate statistical analysis).

Population:

Exclude studies that focus exclusively on populations other than patients with type 2 diabetes mellitus.

Exclude studies with mixed populations where data on patients with type 2 diabetes cannot be extracted separately.

Exclude studies with comorbid conditions that could independently affect cognitive function (e.g., neurodegenerative diseases other than diabetes-related cognitive impairment).

Intervention/Exposure:

Exclude studies that do not report hypoglycemic events or provide insufficient information on the exposure.

Exclude studies where the dose or severity of hypoglycemic events is not clearly defined.

Exclude studies where the exposure assessment does not align with the objectives of the dose-response meta-analysis.

Outcome:

Exclude studies that do not report cognitive impairment as an outcome.

Exclude studies that use different definitions or measurements of cognitive impairment.

Exclude studies with insufficient data for the dose-response relationship or studies not reporting relevant effect measures.

Publication Characteristics:

Exclude studies published in languages other than those your team can review.

Exclude studies with incomplete or inaccessible data, and those without sufficient details to conduct a dose-response analysis.

Duration and Follow-up:

Exclude studies with a duration that is too short to capture meaningful cognitive changes.

Exclude studies with inadequate follow-up periods or those not reporting relevant follow-up data.

Publication Date:

Consider excluding older studies if there have been significant advancements in the understanding of diabetes-related cognitive impairment over time.

Intervention Heterogeneity:

Exclude studies with significant heterogeneity in interventions or treatment protocols that may impact the ability to conduct a meaningful dose-response analysis.

3) Please give two heading study strength and study limitation and explain in depth. 

4) The rational to use Grading the quality of evidence is not clear. Explain in depth. It is suggestion compare GRADE with AMSTAR 2 (A MeaSurement Tool to Assess systematic Reviews), AHRQ (Agency for Healthcare Research and Quality) Methods Guide and ROBIS (Risk of Bias in Systematic Reviews) Tool.

Please submit your revised manuscript by Jan 19 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

  • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

  • A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

  • An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Muhammad Shahzad Aslam, Ph.D.,M.Phil., Pharm-D

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments:

1) The researcher can disagree with the comment given by reviewer.

For example, Reviewer stated that "2. Publication bias – Why is p < 0.10 not used to assume publication bias? It is the

most commonly used value.

Ans: We appreciate you informing us that two types of publication bias P-values are

currently in use: 0.05 and 0.1. Since 0.1 is more rigorous and widely used, we have

adjusted the P-value to 0.1 per your recommendation. For more information, see lines

206-207. 

As an editor, suggest it to keep statistical significance in scientific research is p < 0.05. I have given my details below. Moreover, Please explain in detail the Publication bias. The current has no justification and explanation.

The commonly used threshold for statistical significance in scientific research is p < 0.05, which means that the observed results are unlikely to have occurred by chance alone. However, the use of p < 0.10 to assume publication bias is not a standard practice. The threshold of p < 0.05 is widely accepted in the scientific community and is considered a standard level of significance.

The rationale behind using a stricter threshold for publication bias assessment is to reduce the risk of false positives or Type I errors. Setting a more lenient threshold, such as p < 0.10, increases the likelihood of incorrectly concluding that there is publication bias when it may not actually be present.

When assessing publication bias, researchers often use various statistical tests and graphical methods, such as funnel plots, Egger's test, and Begg's test. These tools help evaluate whether there is a systematic relationship between study precision and effect size, which could indicate the presence of publication bias.

2) Please Revisit the exclusion criteria. I am giving some suggestion. It is not mandatory to include all suggestion. yet your study exclusion criteria is important

Study Design:

Exclude studies that are not primary research articles (e.g., reviews, editorials, commentaries).

Exclude observational studies lacking a clear dose-response relationship or studies not reporting relevant data for a dose-response analysis.

Exclude studies with insufficient methodological detail or poor quality (e.g., high risk of bias, inadequate statistical analysis).

Population:

Exclude studies that focus exclusively on populations other than patients with type 2 diabetes mellitus.

Exclude studies with mixed populations where data on patients with type 2 diabetes cannot be extracted separately.

Exclude studies with comorbid conditions that could independently affect cognitive function (e.g., neurodegenerative diseases other than diabetes-related cognitive impairment).

Intervention/Exposure:

Exclude studies that do not report hypoglycemic events or provide insufficient information on the exposure.

Exclude studies where the dose or severity of hypoglycemic events is not clearly defined.

Exclude studies where the exposure assessment does not align with the objectives of the dose-response meta-analysis.

Outcome:

Exclude studies that do not report cognitive impairment as an outcome.

Exclude studies that use different definitions or measurements of cognitive impairment.

Exclude studies with insufficient data for the dose-response relationship or studies not reporting relevant effect measures.

Publication Characteristics:

Exclude studies published in languages other than those your team can review.

Exclude studies with incomplete or inaccessible data, and those without sufficient details to conduct a dose-response analysis.

Duration and Follow-up:

Exclude studies with a duration that is too short to capture meaningful cognitive changes.

Exclude studies with inadequate follow-up periods or those not reporting relevant follow-up data.

Publication Date:

Consider excluding older studies if there have been significant advancements in the understanding of diabetes-related cognitive impairment over time.

Intervention Heterogeneity:

Exclude studies with significant heterogeneity in interventions or treatment protocols that may impact the ability to conduct a meaningful dose-response analysis.

3) Please give two heading study strength and study limitation and explain in depth.

4) The rational to use Grading the quality of evidence is not clear. Explain in depth. It is suggestion compare GRADE with AMSTAR 2 (A MeaSurement Tool to Assess systematic Reviews), AHRQ (Agency for Healthcare Research and Quality) Methods Guide and ROBIS (Risk of Bias in Systematic Reviews) Tool.

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PLoS One. 2024 Feb 2;19(2):e0296662. doi: 10.1371/journal.pone.0296662.r006

Author response to Decision Letter 2

14 Dec 2023

Response to journal's requirements

1. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Ans: I appreciate your kind reminder. We have conducted a thorough investigation of each reference once more by your recommendation. To standardize the reference format, all references were downloaded from PubMed and entered into the Endnote program. There is no issue number for references 7, 12, 13, 14, 38, 40, and 44, and there is no digital object identifier number for reference 48 since it is not included in the original journal. Simultaneously, we examined all the references and were happy to see that none of the withdrawn publications had been cited. Once again, I appreciate your thorough review. 

Response to Reviewer 3's Comments

Firstly, we would like to express our sincere thanks for your constructive comments and positive response. The revised version of the manuscript has been significantly modified based on your comments. The revised parts are marked in red font. We hope you are satisfied with our revisions.

1. “There will be four categories for heterogeneity: not important (0%-40%), moderate (30%-60%), substantial (50%-90%) and considerable (75%-90%). The fixed effect model will be applied for combined analysis if the I2 value is less than 50%. A random effect model will be applied when P < 0.1 or I2 > 50%[32, 33]. Subgroup analysis and other techniques will be used to investigate sources of clinical or methodological heterogeneity when I2 > 75%.” - I suggest that considerable is 75-100%. I also suggest including subgroup studies even if there is no detected statistically significant heterogeneity.

Ans: Regards for your insightful recommendations. About the I2 value classification, while there are currently a variety of versions, following a collaborative discussion among all authors, we consider your recommendations to be more feasible and scientifically sound, so we modify the considerable heterogeneity to 75–100% by your recommendations. We made adjustments for assertions that were not accurate. That is, regardless of whether statistically significant heterogeneity is found, subgroup analysis and other workable analytical techniques will be used to investigate clinical heterogeneity if there is enough literature. Details are shown in lines 192-197.

2. Publication bias – Why is p < 0.10 not used to assume publication bias? It is the most commonly used value.

Ans: We appreciate your suggestion, but regrettably, we would still like to use P < 0.05 as the standard for determining publication bias for the reasons listed below.

1. After searching across several databases for relevant meta-analyses, we discovered that the most widely used value for assessing publication bias remains 0.05, with only a tiny number of studies using 0.10.

2. The commonly used threshold for statistical significance in scientific research is P < 0.05, which means that the observed results are unlikely to have occurred by chance alone. However, the use of P < 0.10 to assume publication bias is not a standard practice. The threshold of P < 0.05 is widely accepted in the scientific community and is considered a standard level of significance.

3. The rationale behind using a stricter threshold for publication bias assessment is to reduce the risk of false positives or Type I errors. Setting a more lenient threshold, such as p < 0.10, increases the likelihood of incorrectly concluding that there is publication bias when it may not be present.

 

Response to Reviewer 4's Comments

Firstly, we would like to express our sincere thanks for your constructive comments and positive response. The revised version of the manuscript has been significantly modified based on your comments. The revised parts are marked in red font. We hope you are satisfied with our revisions.

1. Line 85: I propose to rephrase the objective. I suggest the following: "This manuscript aims to establish a methodological structure (protocol) to explore the cumulative effect of frequency of hypoglycemic events on cognitive function and further explore the dose-response relationship through systematic review and meta-analysis, which aims to update the association between hypoglycemia and cognitive impairment by including the latest relevant studies.".

Ans: We appreciate your patient advice, and we have adapted the research purpose in light of your recommendations, which improves the overall quality and scientific appearance of our program. For information, see lines 85–89.

2. Could the authors please cite the MOOSE statement?

Ans: We appreciate you reminding us and apologize for this error. As per your recommendation, we have now included the pertinent references of the MOOSE statement. For information, see lines 96–97 and 393–396.

Response to Editor's Comments

1. As an editor, suggest it to keep statistical significance in scientific research is p < 0.05. I have given my details below. Moreover, Please explain in detail the Publication bias. The current has no justification and explanation.

Ans: Dear editor, thank you for your advice. After consultation with all the authors, we decided to adopt your suggestion and retain a P value of less than 0.05 as the measure of publication bias. For the following reasons:

(1) Within the scientific world, the threshold of P<0.05 is commonly acknowledged as the conventional level of significance. We examined meta-analyses from several databases, and it was found that the majority of writers continued to use P< 0.05 as the standard for evaluating publication bias.

(2) The reviewers recommend a looser criterion of P < 0.10, which will boost the sensitivity of the detection of publication bias. However, it may also lead to an incorrect conclusion that publication bias may be present in the findings when it might not be. As a result, we eventually chose to keep P < 0.05 as our publishing bias metric.

(3) Furthermore, we have included the potential for publication bias in our study protocol in the text. There was an explanation of pertinent potential publishing bias in detail. Refer to lines 214–222.

2. Please Revisit the exclusion criteria. I am giving some suggestion. It is not mandatory to include all suggestion. yet your study exclusion criteria is important.

Ans: Thank you for your valuable advice, which is very important to us. We have appropriately supplemented the exclusion criteria according to your suggestion, which makes our study protocol more rigorous and complete. See lines 137-149 for details. However, we did not use all of these recommendations as exclusion criteria for the following reasons:

(1) The inclusion criteria refer to the basic conditions for enrollment, while the exclusion criteria should be other special conditions that do not meet the requirements of the trial based on the inclusion criteria, rather than the opposite of the inclusion criteria. Therefore, suggestions about the opposite of the inclusion criteria, such as “studies that focus exclusively on populations other than patients with type 2 diabetes mellitus”, “studies with mixed populations where data on patients with type 2 diabetes cannot be extracted separately”, “studies that do not report hypoglycemic events”, “studies that do not report cognitive impairment as an outcome”, “studies that use different definitions or measurements of cognitive impairment”, “studies that are not primary research articles (e.g., reviews, editorials, commentaries)”, and “studies not reporting relevant effect measures” will not be included in the exclusion criteria, because these studies would not have been considered for inclusion in the first place.

(2) Furthermore, as stated in the inclusion criteria, original studies can be included as long as they provide pertinent data for the dose-response relationship, and the dose-response relationship was established by a meta-analysis synthesizing data from multiple original studies. Therefore, "observational studies lacking a clear dose-response relationship" will not be considered an exclusion criterion. All initial research doesn't need to have been done with dose-response relationship calculations.

(3) The results of the literature pre-search indicate that there hasn't been any notable advancement in our understanding of diabetes-related cognitive impairment, and the inclusion criteria specify the methodologies used to measure cognitive impairment. As there is nearly no earlier research remaining after rigorous screening in accordance with the inclusion criteria, it is not required to consider omitting earlier research at this time.

3. Please give two heading study strength and study limitation and explain in depth.

Ans: We appreciate your proposal, and as stated in lines 290 to 305 of the text, we added both the strengths and limitations of this study protocol.

4. The rationale to use Grading the quality of evidence is not clear. Explain in depth. It is suggestion compare GRADE with AMSTAR 2 (A MeaSurement Tool to Assess systematic Reviews), AHRQ (Agency for Healthcare Research and Quality) Methods Guide and ROBIS (Risk of Bias in Systematic Reviews) Tool.

Ans: We appreciate your constructive guidance. We examined four different tools (GRADE, AMSTAR 2, AHRQ, and ROBIS) based on your recommendations. In the end, we chose to evaluate the quality of the evidence using two tools: GRADE and ROBIS (see lines 36–37 and 228–236). The following are the reasons.

(1) AMSTAR 2 applies to systematic reviews of randomized controlled trials, non-randomized intervention studies, or both. This study protocol will include observational studies to explore the relationship between exposure factors and outcome measures and does not involve intervention studies, so AMSTAR 2 is not suitable for this study protocol.

(2) AHRQ Methods Guide recommends the criteria for quality assessment of observational studies, which assesses the risk of bias from five domains: selection bias, performance bias, follow-up bias, measurement bias, and reporting bias. It can assess the risk of bias in different types of original studies included in the same systematic review but does not give recommendations on how to determine the overall risk of bias in the review. As for the original study, the NOS scale, which is more commonly used and convenient, is intended to be used in this study. The NOS scale is a good combination of the reality of case-control studies and cohort studies, which is more in line with this study protocol. Therefore, the AHRQ Methods Guide will not be used in this study.

(3) Unlike the AMSTAR 2 tool, which concentrates on evaluating the methodological quality of systematic reviews, ROBIS is committed to evaluating the risk of bias in the production of systematic reviews. ROBIS is suitable for our research protocol because it may be used for systematic reviews of many study types, such as prognostic, etiologic, interventional, and diagnostic test reviews.

(4) The GRADE criteria explicitly define the quality of evidence and the strength of recommendations, completely abandoning the practice of grading evidence based on the type of study design and instead considering the type of study design, methodological quality, consistency of results, and directness of evidence.

(5) The methodological quality of systematic reviews reflects only part of the risk of bias, so it seems more reasonable for reviewers to evaluate the quality of systematic reviews using different tools at the same time, complementing each other. For the final evaluation of the quality of the evidence, we therefore chose to employ the GRADE criteria and ROBIS, taking into account the specific circumstances of the study protocol.

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Decision Letter 3

Muhammad Shahzad Aslam

18 Dec 2023

Association of hypoglycemic events with cognitive impairment in patients with type 2 diabetes mellitus: Protocol for a dose-response meta-analysis

PONE-D-23-23141R3

Dear Dr. Yuan,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Kind regards,

Muhammad Shahzad Aslam, Ph.D.,M.Phil., Pharm-D

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Acceptance letter

Muhammad Shahzad Aslam

25 Jan 2024

PONE-D-23-23141R3

PLOS ONE

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Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Appendix. The PRISMA-P checklist.

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    Data Availability Statement

    Our paper belongs to the meta-analysis protocol, and this paper itself does not involve any data at present. In the process of formulating the protocol, we have pre-searched relevant databases and extracted partial data from relevant literature to ensure the feasibility of the research protocol. Since the relevant data have not been uploaded to public repositories, we will upload the pre-searched relevant data as Supporting Information files.

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