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. 2021 Feb 11;16(2):e0246463. doi: 10.1371/journal.pone.0246463

Efficacy and safety of diazoxide for treating hyperinsulinemic hypoglycemia: A systematic review and meta-analysis

Xiaohong Chen 1,*,#, Lifang Feng 1,#, Hui Yao 1, Luhong Yang 1, Yuan Qin 1
Editor: Cho Naing2
PMCID: PMC7877589  PMID: 33571197

Abstract

Diazoxide is the first-line drug for treating hyperinsulinism and the only pharmacological agent approved for hyperinsulinism by the Federal Drug Administration. This systemic review and meta-analysis aimed to investigate the efficacy and safety of diazoxide for treating hyperinsulinemic hypoglycemia (HH). The meta-analysis of the efficacy and safety of diazoxide in treating HH was performed by searching relevant studies in the PubMed, Embase, and Cochrane databases. The findings were summarized, and the pooled effect size and its 95% confidence interval (CI) were calculated. A total of 6 cohort studies, involving 1142 participants, met the inclusion criteria. Among the cohort studies, the pooled estimate of the response rate of diazoxide therapy was 71% (95% CI 50%–93%, Pheterogeneity< 0.001, I2 = 98.3%, Peffect< 0.001). The common side effects were hypertrichosis (45%), fluid retention (20%), gastrointestinal reaction (13%), edema (11%), and neutropenia (9%). Other adverse events included pulmonary hypertension (2%) and thrombocytopenia (2%). This meta-analysis suggested that diazoxide was potentially useful in HH management; however, it had some side effects, which needed careful monitoring. Furthermore, well-designed large-scale studies, such as randomized controlled trials, might be necessary in the future to obtain more evidence.

Introduction

Hyperinsulinemic hypoglycemia (HH) describes the condition and effects of low blood glucose caused by excessive insulin. Many cases are reported in childhood as a congenital disorder [1]. Congenital hyperinsulinemia (CHI) is the most common and serious cause of persistent hypoglycemia in newborns and children. It occurs between 1:2500 and 50,000 live births [2]. CHI is characterized by excessive secretion of insulin by pancreatic B cells, which is the most common cause of persistent hypoglycemia in infancy [2]. CHI is a heterogeneous disease in clinical manifestations, imaging, histology, and genetics. So far, mutations in more than 10 different genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, HK1, CACNA1D, FOXA2, UCP2, SLC16A1, HNF4A, HNF1A, PMM2, and PGM1) have been reported in the genetic etiology of CHI [36]. CHI has three main histological types: focal, diffuse, and atypical [7,8].

Diazoxide is the first choice for treating CHI. It is a nondiuretic benzothiadiazine originally formulated as a peripheral vasodilator to reduce severe hypertension by smooth muscle relaxation [9]. It was first used to treat CHI in the 1960s [10] and has been the primary treatment since then. Diazoxide is the only drug approved for this indication in the United States, Canada, the United Kingdom, the European Union, China, Australasia, and Japan, [11]. Diazoxide acts by binding to the sulfonylurea receptor-1 subunit in the ATP-sensitive K+ (KATP) channel, causing the channel to open and increase its permeability to potassium ions. This results in the excessive polarization of beta cells, followed by the inhibition of Ca2+-dependent insulin secretion [12].

Several clinical studies investigated the efficacy and safety of diazoxide for treating CHI [1318]. However, the results remain ambiguous. Meissner et al. [13] reported that 47/114 (41.2%) patients responded to diazoxide. Hu et al. [14] found that 36/44 (81.8%) patients were responsive to diazoxide treatment. This meta-analysis based on six cohort studies was conducted and aimed to investigate the efficacy and safety of diazoxide for treating CHI.

Materials and methods

The present meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines [19].

Search strategy

The PubMed, Embase, and Cochrane databases were searched for studies published up to January 2021, using the following terms: ‘‘hyperinsulinemic hypoglycemia,” ‘‘Congenital hyperinsulinism,” ‘‘hypoglycemia,” ‘‘neonates,” ‘‘infants,” ‘‘children,” and ‘‘diazoxide” with all possible combinations. The search strategy for the Embase database was included in the supplementary document in S1 Table. Using these parameters, all eligible studies were filtered out, and their reference lists were viewed for more available studies.

Study selection

The inclusion criteria were as follows: (1) cohort studies focusing on the efficacy and safety of diazoxide in treating HH; (2) studies reporting clinical outcomes such as response rates and complications; (3) studies available with the full text; and (4) if more than one study was published using the same case series, selection of the study with the largest sample size. The exclusion criteria were as follows: (1) experimental studies of animal models or cell lines; (2) similar studies involving repetition of patients; and (3) abstract or inappropriate types of publications, such as reviews, guides, or case reports. The selection had no language restrictions. Two investigators independently assessed the eligibility of each study and resolved any differences through discussion.

Data extraction and quality assessment

Two investigators (Xiaohong Chen and Lifang Feng) independently extracted all available data from the included studies based on the description provided by the authors of these studies. Subsequently, any differences were resolved through discussions with the third author. The following information was extracted from all relevant studies: first author, year of publication, country, sex, mean age, number of patients, follow-up time, and assessment results. The quality of the cohort study was assessed using the 9-star Newcastle–Ottawa Scale [20]. High-quality studies were defined as a study with more than 7 stars [20].

Statistical analysis

The meta-analysis was conducted using Stata 12 (Stata-Corp, TX, USA). A meta-analysis of cohort studies based on the random-effects model was conducted to evaluate the clinical response rate (patients responsive to diazoxide/all patients treated with diazoxide) and complications using effect size (response or incidence rate) and its corresponding 95% confidence interval (CI). The heterogeneity of the studies was assessed using Cochran’s Q test and quantified using the I2 statistic (considered high heterogeneity for I2 > 50%) [21,22]. Publication bias was evaluated by the visual inspection of the symmetry of the funnel plot and assessment of Begg’s and Egger’s tests [23]. The trim-and-fill analysis was applied in the case of any publication bias [24].

Results

Study selection

The electronic search identified 348 studies. Three additional studies were found by hand searching from the reference lists of other review studies. According to the inclusion criteria, 227 studies remained after removing the duplicates. Subsequently, 193 irrelevant studies were excluded. Of the remaining 34 studies, 15 were letters, reviews, and meta-analyses, and hence excluded. The remaining 19 studies were systematically reviewed and qualified for full-text reading. After full-text reading, five studies not focusing on children, three lacking usable data, and five case reports were excluded. Finally, 6 studies involving 1142 patients were included in the present meta-analysis [1318]. The flow chart of the selection of studies and reasons for exclusion is presented in Fig 1.

Fig 1. Flow diagram of study identification.

Fig 1

Characteristics of the studies

The main characteristics of the eligible studies are shown in Table 1. Six cohort studies were included in the meta-analysis. The studies were performed in 4 countries (Germany, China, Japan, and the United States), and the study size ranged from 44 to 384 patients. The patients’ age ranged from 1 day to 17 years. The methodological quality of cohort studies included in the meta-analysis is shown in Table 2. The quality of the cohort studies included in the meta-analysis was generally high: two studies had seven stars, three studies had six stars, and one study had five stars.

Table 1. Characteristics of the studies included in this meta-analysis.

Authors/Year of publication Country Male (%) Age Birth Weight (g) Diazoxide (mg/(kg · day)] Number of patients Study design Follow-up Outcomes assessed
Meissner/2003 [12] Germany 52.6 1 D−17 Y 3670 15 114 Retrospective cohort 6.6Y Respond to diazoxide
Hu/2012 [13] China 68.2 1 D−2 Y 2200−5100 5−15 44 Retrospective cohort NA Respond to diazoxide, Fluid retention, Gastrointestinal reaction, Hypertrichosis
Wang/2017 [14] China 55.1 NA 1900−5800 NA 140 Retrospective case NA Respond to diazoxide
Fukutomi/2018 [15] Japan 61.2 0 M−15 Y NA 0.3−17.4 384 Special survey 7Y Respond to diazoxide, Pulmonary hypertension, Edema, Thrombocytopenia, Fluid retention, Gastrointestinal reaction, Hypertrichosis
Herrera/2018 [16] USA 56.3 8−161 D 2350−3700 10−15 295 Retrospective cohort NA Neuthropenia, Pulmonary hypertension, Edema, Thrombocytopenia
Thornton/2019 [17] USA 58.8 1 D−17 Y 580−6600 2−12 165 Retrospective cohort NA Respond to diazoxide, Neuthropenia, Pulmonary hypertension

D: Day; Y: Year; NA: Not available.

Table 2. Methodological quality of observational studies included in the meta-analysis1.

First author Representativeness of the exposed cohort Selection of the unexposed cohort Ascertainment of exposure Outcome of interest not present at the start of the study Control for important factor or additional factor Outcome assessment Follow-up long enough for outcomes to occur Adequacy of the follow-up of cohorts Total quality scores
Meissner/2003 [12] 6
Hu/2012 [13] 6
Wang/2017 [14] 5
Fukutomi/2018 [15] 7
Herrera/2018 [16] 7
Thornton/2019 [17] 6

1 A study could be awarded a maximum of one star for each item except for the item Control for important factor or additional factor.

Quantitative synthesis

Response to diazoxide

The response to diazoxide in patients with congenital hyperinsulinism (CHI) depends on the mutational status. Typically patients with focal CHI or patients with homozygous or compound heterozygous mutations in the K-ATP channel do not respond to diazoxide. Five studies provided outcomes regarding the response to diazoxide in patients with HH and were included in the meta-analysis. Significant evidence of heterogeneity was found among the studies (Pheterogeneity < 0.001, I2 = 98.3%); therefore, a random-effects model of analysis was used. The pooled proportion of patients who were responsive to diazoxide was 71% (95% CI = 50%–93%, Peffect < 0.001) (Fig 2).

Fig 2. Effect of diazoxide on patients with hyperinsulinemic hypoglycemia.

Fig 2

Edema

Two studies provided outcomes regarding edema in patients with HH and were included in the meta-analysis. Significant evidence of heterogeneity among the studies was found (Pheterogeneity < 0.001, I2 = 95.1%, Peffect < 0.001); therefore, a random-effects model of analysis was used. The pooled proportion of patients who had edema was 11% (95% CI = 0–22) (Fig 3A).

Fig 3. Safety of diazoxide in patients with hyperinsulinemic hypoglycemia.

Fig 3

(A) Edema; (B) fluid retention; (C) gastrointestinal reaction; (D) hypertrichosis; (E) neutropenia; (F) pulmonary hypertension; and (G) thrombocytopenia.

Fluid retention

Two studies provided outcomes regarding fluid retention in patients with HH and were included in the meta-analysis. Significant evidence of heterogeneity among the studies was found (Pheterogeneity < 0.001, I2 = 96.5%, Peffect = 0.008); therefore, a random-effects model of analysis was used. The pooled proportion of patients who had fluid retention was 20% (95% CI = –18 to 59) (Fig 3B).

Gastrointestinal reaction

Two studies provided outcomes regarding gastrointestinal reaction in patients with HH and were included in the meta-analysis. Significant evidence of heterogeneity among the studies was found (Pheterogeneity < 0.001, I2 = 93.5%, Peffect = 0.045); therefore, a random-effects model of analysis was used. The pooled proportion of patients who had gastrointestinal reaction was 13% (95% CI = –13 to 39) (Fig 3C).

Hypertrichosis

Two studies provided outcomes regarding hypertrichosis in patients with HH and were included in the meta-analysis. Significant evidence of heterogeneity among the studies was found (Pheterogeneity<0.001, I2 = 99.3%, Peffect< 0.001); therefore, a random-effects model of analysis was used. The pooled proportion of patients who had hypertrichosis was 45% (95% CI = –27 to 117) (Fig 3D).

Neutropenia

Two studies provided outcomes regarding neutropenia in patients with HH and were included in the meta-analysis. Significant evidence of heterogeneity among the studies was found (Pheterogeneity < 0.001, I2 = 92.1%, Peffect = 0.005); therefore, a random-effects model of analysis was used. The pooled proportion of patients who had neutropenia was 9% (95% CI = 0–19) (Fig 3E).

Pulmonary hypertension

Three studies provided outcomes regarding pulmonary hypertension in patients with HH and were included in the meta-analysis. Significant evidence of heterogeneity among the studies was found (Pheterogeneity = 0.013, I2 = 76.8%, Peffect = 0.005); therefore, a random-effects model of analysis was used. The pooled proportion of patients who had pulmonary hypertension was 2% (95% CI = 0–4) (Fig 3F).

Thrombocytopenia

Two studies provided outcomes regarding thrombocytopenia in patients with HH and were included in the meta-analysis. Significant evidence of heterogeneity among the studies was found (Pheterogeneity = 0.013, I2 = 83.7%, Peffect < 0.008); therefore, a random-effects model of analysis was used. The pooled proportion of patients who had thrombocytopenia was 2% (95% CI = –1 to 5) (Fig 3G).

Publication bias

Funnel plot and Begg’s and Egger’s tests were performed to assess publication bias among the studies. The shapes of the funnel plots showed obvious evidence of asymmetry (Fig 4), and the P value of Egger’s test confirmed the existence of publication bias for the response to diazoxide (Begg’s test P = 0.462; Egger’s test P = 0.045). The trim-and-fill method showed no need for additional studies (Fig 5).

Fig 4. Funnel plot of diazoxide responsiveness for testing publication bias.

Fig 4

Each point represents a separate study for the indicated association.

Fig 5. Filled funnel plot of diazoxide responsiveness using the trim-and-fill method.

Fig 5

Discussion

This systematic review and meta-analysis evaluated the efficacy and safety of diazoxide for patients with HH. Six cohort studies involving 1142 patients were included. This meta-analysis was novel in evaluating the efficacy and safety of diazoxide for patients with HH. The meta-analysis showed that diazoxide was potentially useful in HH management; however, it had some side effects needing careful monitoring. Better-designed randomized controlled trials are still required to confirm the findings.

Diazoxide is the first-line drug for hyperinsulinemia and the only drug approved by the Federal Drug Administration. Its use has increased over the years, including patients with various genetic forms of hyperinsulinemia or perinatal stress hyperinsulinemia as well as infants of mothers with diabetes who have received this treatment more than ever before [25]. In 1964, diazoxide was first reported as an effective treatment for leucine-sensitive hypoglycemia [26]. Subsequently, several studies reported its effectiveness in treating metastatic or inoperable insulinomas [27,28]. Diazoxide is usually effective in children with complete KATP channels, but it is ineffective if the KATP channels are malformed due to ABCC8/KCNJ11 mutation. However, the exception is that children with ABCC8 mutation respond to diazoxide, indicating that cellular adaptation and redundancy in the standard KATP channel model determine the pathophysiology of CHI [29]. In this study, 71% (646/831) of patients responded to diazoxide treatment. Besides, about 25% of children with CHI were partially or completely unresponsive to diazoxide [30]. Other drugs, such as octreotide, may be required for the second-line treatment in such children [31].

The most common side effect is mild-to-severe hypertrichosis, which is thought to depend on the dose for each patient [18]. In this study, the most common adverse drug reaction was hypertrichosis (45%). For older children, body hair can be troublesome, and they may choose to use other drugs to avoid this complication. In theory, local KATP channel blockers, such as toluene butylamine, may reduce hair growth, but this indication has not been systematically assessed [32]. The retention of sodium and fluorine is a common side effect of diazoxide (18%) [17]. All patients taking diazoxide should be carefully monitored for weight, electrolytes and edema, and cardiopulmonary function, especially when starting or increasing doses. The simultaneous use of diuretics, such as chlorothiazide, can reduce urinary retention. In 2015, the US Food and Drug Administration issued a drug safety statement because 11 infants treated with nitrous oxide developed pulmonary hypertension (PH) [33]. It is believed that about 2.4% of all children treated with diazoxide have PH [17,18,34]. These data were consistent with the results of the present study (2%). A recent study published by Herrera et al. [17] employed all patients with a formal diagnosis of hyperinsulinemia. Their study included perinatal stress−induced hyperinsulinemia and showed that 2.4% of patients developed PH after starting the use of sodium diazoxide. They believed that PH is more likely to occur in preterm and low-birth-weight infants.

At the same time, some limitations of this meta-analysis should be emphasized. First, meta-analyses may be biased when literature searches fail to identify all relevant trials or subjectively apply selection criteria for including trials. To minimize these risks, thorough searches in multiple bibliographic databases were conducted, and clear criteria were used for research selection, data abstraction, and data analysis. Second, all the studies included in the present meta-analysis were observational. Observational studies are susceptible to selection bias and confusion, leading to the underestimation or overestimation of the actual effects of the intervention. Finally, some studies had small sample sizes, thus reducing the statistical power.

Conclusions

In summary, the results demonstrated that diazoxide had a potential role in treating HH; however, it had some side effects needing careful monitoring. Furthermore, well-designed large-scale studies, such as randomized controlled trials, might be necessary in the future to obtain more evidence.

Supporting information

S1 Checklist. PRISMA 2009 checklist.

(DOC)

S1 Table. Search strategies for Embase.

(DOC)

S1 Data

(ZIP)

Data Availability

All relevant data are within the manuscript and its Supporting Information files.

Funding Statement

The authors received no specific funding for this work.

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Cho Naing

2 Nov 2020

PONE-D-20-17226

Efficacy and safety of diazoxide for treating hyperinsulinemic hypoglycemia: a systematic review and meta-analysis

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Upon re-submitting your revised manuscript, please upload your study’s minimal underlying data set as either Supporting Information files or to a stable, public repository and include the relevant URLs, DOIs, or accession numbers within your revised cover letter. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. Any potentially identifying patient information must be fully anonymized.

Important: If there are ethical or legal restrictions to sharing your data publicly, please explain these restrictions in detail. Please see our guidelines for more information on what we consider unacceptable restrictions to publicly sharing data: http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. Note that it is not acceptable for the authors to be the sole named individuals responsible for ensuring data access.

We will update your Data Availability statement to reflect the information you provide in your cover letter.

4. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information.

5. PLOS requires an ORCID iD for the corresponding author in Editorial Manager on papers submitted after December 6th, 2016. Please ensure that you have an ORCID iD and that it is validated in Editorial Manager. To do this, go to ‘Update my Information’ (in the upper left-hand corner of the main menu), and click on the Fetch/Validate link next to the ORCID field. This will take you to the ORCID site and allow you to create a new iD or authenticate a pre-existing iD in Editorial Manager. Please see the following video for instructions on linking an ORCID iD to your Editorial Manager account: https://www.youtube.com/watch?v=_xcclfuvtxQ

Additional Editor Comments (if provided):

This is an interesting research area. The authors can improve the quality of their manuscript.

Introduction

The authors need to state the objective in the last paragraph, although it has been described in the Abstract

Methods

The authors need to improve this section.

Study selection

It will be informative to provide more details of search strategy used for Embase in appendix.

Study selections

The authors have indicated clinical studies as an inclusion criteria.

However, it has indicated in the abstract that cohort studies are included.

The quality assessment use was the NOS checklist. Hence, the included studies were observational type, rather than clinical studies. Please, provide what type of observational studies....... Only cohort or/ and case-control designs.

In Table 1, please add 1 more column for study design.

Data extraction

Please, indicate the initials of two authors who had done study selection/data extraction

Statistical analysis

It is essential to describe the outcome measurement ( e.g OR or RR and its 95%CI).

To be more informative, please define the response rate (e.g what is numerator/ denominator, etc)

Reference

In addition to #21 (Lu et al).......... It will be better to refer Higgins et al 2019 ( available from the Cochrane Library website)

.

Thank you

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

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). 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

**********

4. 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

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Overall, the manuscript was well written, and presented adequate study methodology, results and discussion.

Some minor clarifications are required on the following.

Discussion

Para 2, Line 2: “Its use has increased… having more babies than ever before.” – This statement is unclear.

Para 2, Line 9: “However, the exception is that children with ABCC8 mutation respond to diazoxide, indicating cellular adaptation and red blood cells”- The statement regarding red blood is unclear

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2021 Feb 11;16(2):e0246463. doi: 10.1371/journal.pone.0246463.r002

Author response to Decision Letter 0


9 Dec 2020

Dear editor,

On behalf of all co-authors, we would like to express our great appreciation to you and the reviewers for your positive, constructive and insightful comments on our manuscript entitled “Efficacy and safety of diazoxide for treating hyperinsulinemic hypoglycemia: a systematic review and meta-analysis”. These comments and suggestions are really helpful in improving the quality of our manuscript. Accordingly, we have revised the manuscript. In addition, point-by-point responses to the editor’s and reviewers’ comments are listed below.

We, again, thank you and the reviewers for your constructive comments and hope that the revision is acceptable for publication in your journal.

We are looking forward to hearing from you soon.

Sincerely,

Point-by-point responses to the editor’s comments:

Important Comments:

Comment 1: Introduction The authors need to state the objective in the last paragraph, although it has been described in the Abstract.

Response: We thank you for this kind reminding. Accordingly, we have added it to Introduction in the newly revised version.

Comment 2: Study selection It will be informative to provide more details of search strategy used for Embase in appendix.

Response: As suggested, we have added it in the newly revised version (Table S1).

Comment 3: The authors have indicated clinical studies as an inclusion criteria. However, it has indicated in the abstract that cohort studies are included. The quality assessment use was the NOS checklist. Hence, the included studies were observational type, rather than clinical studies. Please, provide what type of observational studies....... Only cohort or/ and case-control designs. In Table 1, please add 1 more column for study design.

Response: Thanks for this kind suggestion, we have added it to Table 1 in the newly revised version.

Comment 4: Data extraction Please, indicate the initials of two authors who had done study selection/data extraction.

Response: Thanks for this kind suggestion, we have added them in the newly revised version.

Comment 5: Statistical analysis It is essential to describe the outcome measurement ( e.g OR or RR and its 95%CI). To be more informative, please define the response rate (e.g what is numerator/ denominator, etc).

Response: Thanks for this kind suggestion, we have added them to Statistical analysis in the newly revised version.

Comment 6: Reference. In addition to #21 (Lu et al).......... It will be better to refer Higgins et al 2019 (available from the Cochrane Library website).

Response: Thanks for this kind suggestion, we have added it to Reference in the newly revised version.

Point-by-point responses to the reviewer’s comments:

Reviewer #1:

Important Comments:

Comment 1: Overall, the manuscript was well written, and presented adequate study methodology, results and discussion. Some minor clarifications are required on the following.

Response: It is pleasing to have acknowledged our diligence in completed this manuscript. We appreciate the reviewer’s kindly comments.

Comment 2: Discussion Para 2, Line 2: “Its use has increased… having more babies than ever before.” – This statement is unclear.

Response: Thanks for this kind suggestion, we have rewritten them in the newly revised version.

Comment 3: Para 2, Line 9: “However, the exception is that children with ABCC8 mutation respond to diazoxide, indicating cellular adaptation and red blood cells”- The statement regarding red blood is unclear.

Response: Thanks for this kind suggestion, we have rewritten them in the newly revised version.

Attachment

Submitted filename: Response Letter.doc

Decision Letter 1

Cho Naing

14 Dec 2020

PONE-D-20-17226R1

Efficacy and safety of diazoxide for treating hyperinsulinemic hypoglycemia: a systematic review and meta-analysis

PLOS ONE

Dear Dr. Chen,

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 28 2021 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: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Cho Naing, MBBS, PhD, FRCP

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

The current analysis was based on six cohort studies.

In the Background, six clinical studies. Please make a correction.

The inclusion criteria were as follows: (1) clinical studies focusing on ..................... This was incorrect. The authors have selected only cohort studies. No clinical studies. Plese update this. selection criteria. I have already highlighted this point in initial comments.

The authors still need substantial improvements in grammar/language throughout the text

Examples,

In abstrct

The meta-analysis of the efficacy and safety of diazoxidein treating HH was performed by searching the PubMed, Embase, ..............

Two missing words "relevant studies" between searching the and PubMed,

A total of 6studies, ................... It should be presented 'a total of six cohort studies'.,

Among the cohort studies, the pooled estimate of patients who were diazoxide responsive was 71% (95% CI 50%–93%.................. Please rephrase this sentence by adding pool estimates of what outcome.

In Text

A meta-analysis of cohorts based on the random-effects............................ It should describe 'cohort studies, instead of cohorts. .

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

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2021 Feb 11;16(2):e0246463. doi: 10.1371/journal.pone.0246463.r004

Author response to Decision Letter 1


30 Dec 2020

Dear editor,

On behalf of all co-authors, we would like to express our great appreciation to you for your positive and constructive comments on our manuscript entitled “Efficacy and safety of diazoxide for treating hyperinsulinemic hypoglycemia: a systematic review and meta-analysis”. These comments and suggestions are really helpful in improving the quality of our manuscript. Accordingly, we have revised the manuscript. In addition, point-by-point responses to the editor’s comments are listed below.

We hope that the revision is acceptable for publication in your journal.

We are looking forward to hearing from you soon.

Sincerely,

Point-by-point responses to the editor’s comments:

Important Comments:

Comment 1: The current analysis was based on six cohort studies. In the Background, six clinical studies. Please make a correction.

Response: Accordingly, we have corrected it in the newly revised version.

Comment 2: The inclusion criteria were as follows: (1) clinical studies focusing on ..................... This was incorrect. The authors have selected only cohort studies. No clinical studies. Plese update this. selection criteria. I have already highlighted this point in initial comments.

Response: Accordingly, we have corrected it in the newly revised version.

Comment 3: The authors still need substantial improvements in grammar/language throughout the text.

Examples,

In abstract

The meta-analysis of the efficacy and safety of diazoxidein treating HH was performed by searching the PubMed, Embase, ..............

Two missing words "relevant studies" between searching the and PubMed,

A total of 6studies, ................... It should be presented 'a total of six cohort studies'.,

Among the cohort studies, the pooled estimate of patients who were diazoxide responsive was 71% (95% CI 50%–93%.................. Please rephrase this sentence by adding pool estimates of what outcome.

In Text

A meta-analysis of cohorts based on the random-effects............................ It should describe 'cohort studies, instead of cohorts. .

Response: Accordingly, we have carefully proofread the manuscript and corrected the spelling and grammatical errors in the revised manuscript.

Attachment

Submitted filename: Response to Reviewers.doc

Decision Letter 2

Cho Naing

6 Jan 2021

PONE-D-20-17226R2

Efficacy and safety of diazoxide for treating hyperinsulinemic hypoglycemia: a systematic review and meta-analysis

PLOS ONE

Dear Dr. Chen,

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 Feb 20 2021 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: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Cho Naing, MBBS, PhD, FRCP

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

The authors have addressed almost all comments provided.

1) It is necessary to include your revised text in your reply to the comments.

2) The authors have to update literature search whether there may be additional published studies after your initial search in 2019. This is crucially important in this field as the evidence must be based on comprehensive review of all eligible studies.

Thank you

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

Reviewers' comments:

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2021 Feb 11;16(2):e0246463. doi: 10.1371/journal.pone.0246463.r006

Author response to Decision Letter 2


18 Jan 2021

Dear editor,

On behalf of all co-authors, we would like to express our great appreciation to you for your positive and constructive comments on our manuscript titled “Efficacy and safety of diazoxide for treating hyperinsulinemic hypoglycemia: a systematic review and meta-analysis.” These comments and suggestions are really helpful in improving the quality of our manuscript. Accordingly, we have revised the manuscript. In addition, point-by-point responses to the editor’s comments are listed below.

We hope that the revision is acceptable for publication in your journal.

We look forward to hearing from you soon.

Sincerely,

Point-by-point responses to the editor’s comments:

Important Comments:

Comment 1: The current analysis was based on six cohort studies. In the Background, six clinical studies. Please make a correction.

Response: Thank you for the comments. We have corrected it in the revised version.

Revised text: “This meta-analysis based on six cohort studies was conducted and aimed to investigate the efficacy and safety of diazoxide for treating CHI.”

Comment 2: The inclusion criteria were as follows: (1) clinical studies focusing on ..................... This was incorrect. The authors have selected only cohort studies. No clinical studies. Please update this. selection criteria. I have already highlighted this point in initial comments.

Response: Thank you for the comments. We have corrected it in the revised version.

Revised text: “Cohort studies focusing on the efficacy and safety of diazoxide in treating HH.”

Comment 3: The authors still need substantial improvements in grammar/language throughout the text.

Examples,

In abstract

The meta-analysis of the efficacy and safety of diazoxidein treating HH was performed by searching the PubMed, Embase, ..............

Two missing words "relevant studies" between searching the and PubMed,

A total of 6studies, ................... It should be presented 'a total of six cohort studies'.,

Among the cohort studies, the pooled estimate of patients who were diazoxide responsive was 71% (95% CI 50%–93%.................. Please rephrase this sentence by adding pool estimates of what outcome.

In Text

A meta-analysis of cohorts based on the random-effects............................ It should describe 'cohort studies, instead of cohorts. .

Response: Thank you for the suggestion. We have carefully proofread the manuscript and corrected the spelling and grammatical errors in the revised manuscript.

Revised text: “The meta-analysis of the efficacy and safety of diazoxide in treating HH was performed by searching relevant studies in the PubMed, Embase, and Cochrane databases.”

“A total of 6 cohort studies, involving 1142 participants, met the inclusion criteria.”

“Among the cohort studies, the pooled estimate of the response rate of diazoxide therapy was 71%.”

“A meta-analysis of cohort studies based on the random-effects model was conducted to evaluate the clinical response rate.”

Comment 4: The authors have to update literature search whether there may be additional published studies after your initial search in 2019. This is crucially important in this field as the evidence must be based on comprehensive review of all eligible studies.

Response: Thank you for the suggestion. The literature search has been updated up to January 2021.

Revised text: “The PubMed, Embase, and Cochrane databases were searched for studies published up to January 2021.”

“The electronic search identified 348 studies. Three additional studies were found by hand searching from the reference lists of other review studies. According to the inclusion criteria, 227 studies remained after removing the duplicates. Subsequently, 193 irrelevant studies were excluded. Of the remaining 34 studies, 15 were letters, reviews, and meta-analyses, and hence excluded. The remaining studies were systematically reviewed, and 19 were qualified for full-text reading. After full-text reading, five studies not focusing on children, three lacking usable data, and five case reports were excluded.” (Figure 1)

Attachment

Submitted filename: Response to Reviewers.doc

Decision Letter 3

Cho Naing

20 Jan 2021

Efficacy and safety of diazoxide for treating hyperinsulinemic hypoglycemia: a systematic review and meta-analysis

PONE-D-20-17226R3

Dear Dr. Chen,

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.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Cho Naing, MBBS, PhD, FRCP

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

The authors have addressed the comments. Thank you

Reviewers' comments:

Acceptance letter

Cho Naing

2 Feb 2021

PONE-D-20-17226R3

Efficacy and safety of diazoxide for treating hyperinsulinemic hypoglycemia: a systematic review and meta-analysis

Dear Dr. Chen:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Professor Cho Naing

Academic Editor

PLOS ONE

Associated Data

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

    Supplementary Materials

    S1 Checklist. PRISMA 2009 checklist.

    (DOC)

    S1 Table. Search strategies for Embase.

    (DOC)

    S1 Data

    (ZIP)

    Attachment

    Submitted filename: Response Letter.doc

    Attachment

    Submitted filename: Response to Reviewers.doc

    Attachment

    Submitted filename: Response to Reviewers.doc

    Data Availability Statement

    All relevant data are within the manuscript and its Supporting Information files.


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