Skin-Related Adverse Reactions Induced by Oral Antidiabetic Drugs—A Review of Literature and Case Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Congratulations to the authors for this interesting review about the safety of oral antidiabetic drugs that pointed out another crucial issue related to this type of drugs!

However, in general, to help the reader in founding the information rapidly a re-organization of sections is required and to improve the quality of this review, additional information/evidence are needed.

- Please, where available insert the information about the time to onset of CADRs for all the drugs.

- line 59 page 2 Please modify the following title in "Pathophysiology of skin-related disorders in diabetes"

- line 79 page 2 Please insert as title " 3. Oral antidiabetic drugs" and then the single drug or drug classes will follow as subheading, so for instance metformin will become 3.1 metformin.

In addition, please modify the title "3. Metformin" into "3.1 Metformin: pharmacotherapy and case reports of CADRs "

- line 110 page 4 It would be usefull to improve completness and quality of evidence by adding a subsection entitled "3.1.1 Real world evidence of metformin related CADRs ", where you provide evidence from population based studies (observational retrospective or prospective studies) and/or and disproportional analyses on spontaneous reporting systems. 

- lines 111 -154 pages 5-6 As done for metformin, please modify the title into "3.2 Sulphonylureas: pharmacotherapy and case reports of CADRs " and add another subsection about real world evidence "3.2.1 Real world evidence of Sulphonylureas related CADRs".

- lines 155-193 pages 6-7 As above, please modify the title into "3.3 Sodium-glucose cotransporter 2 inhibitors : pharmacotherapy and case reports of CADRs " and add another subsection about real world evidence "3.3.1 Real world evidence of Sodium-glucose cotransporter 2 inhibitors  related CADRs".

-  lines 162-164 page 6 Please move this evidence in the subsection that will be created, i.e. 3.3.1 subsection

- lines 194-256 pages 7-11 As above, please modify the title into "3.4 Dipeptidylpeptidase-4 inhibitors: pharmacotherapy and case reports of CADRs " and add another subsection about real world evidence "3.4.1 Real world evidence of Dipeptidylpeptidase-4 inhibitors related CADRs".

- lines 229-233 page 8 Please move into the subsection 3.4.1 that will be created and improve information there.

- lines 234-235 page 8 If these metanalysis included observational studies they will be moved to the subsection 3.4.1 also, and improve information there.

- lines 257-265 page 11 As above, please modify the title into "3.5 Semaglutide: pharmacotherapy and case reports of CADRs " and add another subsection about real world evidence "3.5.1 Real world evidence of Semaglutide related CADRs".

- page 12 The same changes are required for Thiazolidinediones, Meglitinides, and Alpha -glucosidase inhibitors

- lines 295-297 page 12 This evidence will be moved into the appropriate subsection that will be created and more information will be provided.

 

Author Response

POINT-BY-POINT RESPONSE TO REVIEWER 1

We would like to thank the Reviewer for the statement” “interesting review about the safety of oral antidiabetic drugs that pointed out another crucial issue related to this type of drugs.” We would also like to thank for all insightful suggestions and comments. We have revised the manuscript following the Reviewer’s remarks.

COMMENT: Please, where available insert the information about the time to onset of CADRs for all the drugs

RESPONSE: We added the times of onset of symptoms in the presented case reports (if indicated by the authors) in an additional column of tables or in the following fragments:

“A case of bullous pemphigoid associated with semaglutide was reported, which manifested as crusted erosions of the breast and lower back after 1 month of therapy [164]. In addition, there is a case report of itchy palmar erythema 17 hours after the administration of the drug [165].”

“A case report of hypersensitivity to pioglitazone has been reported, which manifested as pruritus and rash, that appeared after 2 months of therapy [168].”

“Repaglinide hypersensitivity case report is available in the literature [171]. The clinical manifestation was a maculopapular rash on the face, neck, and upper chest, which appeared after 5 days of therapy.”

“Among CADRs, a case of acarbose-induced generalized erythema multiforme was reported [173]. The patient presented with erythematous plaques with vesicles on almost the entire body after 13 days of therapy.”

COMMENTS:

line 59 page 2 Please modify the following title in "Pathophysiology of skin-related disorders in diabetes"

line 79 page 2 Please insert as title " 3. Oral antidiabetic drugs" and then the single drug or drug classes will follow as subheading, so for instance metformin will become 3.1 metformin.

In addition, please modify the title "3. Metformin" into "3.1 Metformin: pharmacotherapy and case reports of CADRs- line 110 page 4

lines 111 -154 pages 5-6 As done for metformin, please modify the title into "3.2 Sulphonylureas: pharmacotherapy and case reports of CADRs " and add another subsection about real world evidence "3.2.1 Real world evidence of Sulphonylureas related CADRs".

lines 155-193 pages 6-7 As above, please modify the title into "3.3 Sodium-glucose cotransporter 2 inhibitors : pharmacotherapy and case reports of CADRs " and add another subsection about real world evidence "3.3.1 Real world evidence of Sodium-glucose cotransporter 2 inhibitors  related CADRs".

lines 194-256 pages 7-11 As above, please modify the title into "3.4 Dipeptidylpeptidase-4 inhibitors: pharmacotherapy and case reports of CADRs " and add another subsection about real world evidence "3.4.1 Real world evidence of Dipeptidylpeptidase-4 inhibitors related CADRs".

lines 257-265 page 11 As above, please modify the title into "3.5 Semaglutide: pharmacotherapy and case reports of CADRs " and add another subsection about real world evidence "3.5.1 Real world evidence of Semaglutide related CADRs".

page 12 The same changes are required for Thiazolidinediones, Meglitinides, and Alpha -glucosidase inhibitors

RESPONSE: We have revised the manuscript in accordance with the reviewer's comments.

 

COMMENTS:

It would be usefull to improve completness and quality of evidence by adding a subsection entitled "3.1.1 Real world evidence of metformin related CADRs ", where you provide evidence from population based studies (observational retrospective or prospective studies) and/or and disproportional analyses on spontaneous reporting systems.

lines 111 -154 pages 5-6 As done for metformin, please modify the title into "3.2 Sulphonylureas: pharmacotherapy and case reports of CADRs " and add another subsection about real world evidence "3.2.1 Real world evidence of Sulphonylureas related CADRs".

lines 155-193 pages 6-7 As above, please modify the title into "3.3 Sodium-glucose cotransporter 2 inhibitors : pharmacotherapy and case reports of CADRs " and add another subsection about real world evidence "3.3.1 Real world evidence of Sodium-glucose cotransporter 2 inhibitors  related CADRs".

lines 162-164 page 6 Please move this evidence in the subsection that will be created, i.e. 3.3.1 subsection

lines 194-256 pages 7-11 As above, please modify the title into "3.4 Dipeptidylpeptidase-4 inhibitors: pharmacotherapy and case reports of CADRs " and add another subsection about real world evidence "3.4.1 Real world evidence of Dipeptidylpeptidase-4 inhibitors related CADRs".

lines 229-233 page 8 Please move into the subsection 3.4.1 that will be created and improve information there.

lines 234-235 page 8 If these metanalysis included observational studies they will be moved to the subsection 3.4.1 also, and improve information there.

lines 257-265 page 11 As above, please modify the title into "3.5 Semaglutide: pharmacotherapy and case reports of CADRs " and add another subsection about real world evidence "3.5.1 Real world evidence of Semaglutide related CADRs".

page 12 The same changes are required for Thiazolidinediones, Meglitinides, and Alpha -glucosidase inhibitors

lines 295-297 page 12 This evidence will be moved into the appropriate subsection that will be created and more information will be provided.

RESPONSE: For most drug groups, population-based studies and/or disproportionate analyses on spontaneous reporting systems were not available, so we introduced subsections " Real world data of [group/drug name] related CADRs " where we presented data from the FAERS and the EudraVigilance. For SGLT-2is, DPP-4-is and AGIs, we moved information from observational studies into these subsections.

“3.1.1. Real world data of Metformin related CADRs

The FDA adverse reporting system (FAERS) lists 8712 cases of skin and subcutaneous tissue disorders related to metformin use. The largest number of cases included: pruritus (1495), rash (1209), hyperhidrosis (1057), and urticaria (734) [48]. EudraVigilance notes 3624 cases of skin and subcutaneous tissue disorders [49].”

“3.2.1. Real world data of Sulphonylureas related CADRs

The FAERS reports 4073 cases of skin and subcutaneous tissue disorders associated with the use of second-generation sulfonylureas: 24 for gliquidone, 816 for gliclazide, 929 for glimepiride, 995 for glipizide, and 1309 for glyburide (glibenclamide). The most commonly reported CADRs include: rash, pruritus, and dermatitis [48]. The EudraVigilance lists 1923 cases of skin and subcutaneous tissue disorders: 21 for gliquidone, 162 for glipizide, 380 for glyburide (glibenclamide), 659 for gliclazide, and 701 for glimepiride [49].”

“3.3.1. Real world data of Sodium-glucose cotransporter 2 inhibitors related CADRs

The disproportionality analysis conducted by Raschi et al. [11] showed a higher frequency of reported skin-related side effects associated with SGLT-2is administration, which was unexpected as it did not emerge from preapproval randomized clinical trials. The FAERS notes 6123 cases of skin and subcutaneous tissue disorders linked to the use of SGLT-2is: 1 for bexaglifloxin, 2 for ipragliflozin, 4 for sotagliflozin, 1203 for dapagliflozin, 1956 for empagliflozin, and 2957 for canagliflozin. Among the most commonly reported CADRs are: diabetic foot, skin ulcer, rash, pruritus, and angioedema [48]. The EudraVigilance holds 5638 records of skin and subcutaneous tissue disorders: 19 for ertugliflozin, 1677 for dapagliflozin, 1884 for empagliflozin, and 2058 for canagliflozin [49].”

“3.4.1. Real world data of Dipeptidylpeptidase-4 inhibitors related CADRs

The FAERS reports 3024 cases of skin and subcutaneous tissue disorders arising after DPP-4-is use: 8 for anagliptin, 41 for tenegliptin, 66 for saxagliptin, 97 for alogliptin, 332 for sitagliptin, 703 for vildagliptin, and 1777 for linagliptin. The most commonly reported CADR is pemphigoid - 970 cases [48]. The EudraVigilance lists 6419 cases of skin and subcutaneous tissue disorders: 283 for saxagliptin, 342 for alogliptin, 1603 for linagliptin, 1720 for vildagliptin, and 2471 for sitagliptin [49].

The relationship between gliptins and BP, as well as the clinicopathological and immunological features of GABP, have been widely studied. The following reports con-firm the increased risk of BP in gliptins-treated patients:

• a Swiss case-controlled study by Schaffer et al. [156];
• a French/Swiss case-controlled study by Benzaquen et al. [121];
• a French case-controlled study by Plaquevent et al. [122];
• an Israeli case-controlled study by Kridin and Bergman [123];
• a Korean case-controlled study by Lee et al. [124];
• a Greek prospective observational study by Lambadiari et al. [157];
• a case–noncase study in the French Pharmacovigilance Database by Béné et al.[158];
• a Finnish nationwide Registry Study by Varpuluoma et al. [125];
• a large population-based study in the UK by Douros et al. [159];
• a meta-analysis by Phan et al. [160];
• a meta-analysis by Yang et al. [161].”

“3.5.1. Real world data of Semaglutide related CADRs

In the case of sameglutide, 2513 cases of adverse skin and subcutaneous tissue disorders were reported in the FAERS and 1425 in the EudraVigilance [48,49]. The following CADRs had the largest number of reports: rash, pruritus, alopecia, and hyperhidrosis [48].”

“3.6.1. Real world data of Thiazolidinediones related CADRs

The FAERS reporting system records 183, and the the EudraVigilance 679 cases of skin and subcutaneous tissue disorders in response to pioglitazone (respectively 145 and 38) and rosiglitazone (respectively 393 and 286) [48,49].”

“3.7.1. Real world data of Meglitinides related CADRs

The FAERS notes 634 cases of skin and subcutaneous tissue disorders linked to the use of meglitinides: 8 for mitiglinide, 124 for nateglinide, and 502 for repaglinide [48]. The EudraVigilance lists 425 cases of skin and subcutaneous tissue disorders: 14 for mitiglinide, 84 for nateglinide, and 327 for repaglinide [49].”

“3.7.1. Real world data of Alpha -glucosidase inhibitors related CADRs

The FAERS reports 541 cases of skin and subcutaneous tissue disorders arising after AGIs use: 71 for voglibose, 74 for miglitol, and 396 for acarbose. Among the most commonly reported CADRs are hyperhidrosis and pruritus. Voglibose has had 11 cases of Stevens–Johnson syndrome [48]. The EudraVigilance lists 508 cases of skin and subcutaneous tissue disorders: 57 for voglibose, 58 for miglitol, and 393 for acarbose [49].

In addition, a population-based study by Huang et al. [174] found that AGIs use and discontinuation may be associated with an increased risk of psoriatic disease. The data source was the 1999-2013 Taiwanese Longitudinal Cohort of Diabetes Patients Database. It was considered the data of patients who used the following AGIs: acarbose and miglitol.”

 

 

 

Reviewer 2 Report

Comments and Suggestions for Authors

I read with interest the paper titled "Skin Related Adverse Reactions Induced by Oral Antidiabetic Drugs - A Review of Literature and Case Reports". 

 

1. Why you choose those particular cases do develop in the paper? Anything related with their prevalence in the databases consulted? From a rapid consultation of EudraVigilance, there are others most common ADRs related to each drug specified. Otherwise, you should justify why choose those "cases", instead of others.  

 

2. Adverse events reported in the tables should be assessed for causality, to be considered ADRs. If yes, please provide the level of causality in a Naranjo or WHO scale (definitive, propable, possible, unlikely). Please provide information on the tool used to assess caulasity. Otherwise, you cannot state that those are ADRs and this is a major drawback. 

 

3. The Fournier's gangrene is not classified as a skin disorder, so it doesnt aling with you title or objective (that I suggest to change). 

Accordingly to the MedDRA 25.1, the SOCs related to Fornier's gangrene are:

10021881 - Infections and infestations

10028395 - Musculoskeletal and connective tissue disorders

10038604 - Reproductive system and breast disorders

 

Despite of understanding the connection, the adverse drug reaction is cannot be described inside the group of "skin and subcutanous disorders". 

 

 

Author Response

POINT-BY-POINT RESPONSE TO REVIEWER 2

 

We are very glad that the reviewer read with interest our review. We would like to thank the Reviewer for all insightful suggestions and comments. We have revised the manuscript following the Reviewer’s remarks.

 

COMMENT: Why you choose those particular cases do develop in the paper? Anything related with their prevalence in the databases consulted? From a rapid consultation of EudraVigilance, there are others most common ADRs related to each drug specified. Otherwise, you should justify why choose those "cases", instead of others. 

 

RESPONSE: In reference to the Reviewer’s comment, we added the following fragment in the introduction:

 

„According to the recommendations, the risk of adverse events, mainly hypoglycemia, volume depletion, and pancreatitis, among others, should be taken into account during the choice of antidiabetic drugs [9]. However, it should be noted that all drugs can induce hypersensitivity reactions, which manifest as skin lesions, among others. Oral antidiabetic drugs can cause skin reactions ranging from mild, such as erythema, to severe, such as toxic epidermal necrolysis [8,10]. Besides hypersensitivity reactions, skin lesions may result from the mechanism of action of the drug, cross-reactions, or induction of other conditions that can lead to skin disorders. The current guidelines indicate that the new drugs that have been approved for therapy in recent years are first- and second-line drugs [9]. The safety of their use is still under evaluation, and post-marketing studies indicate a significantly higher risk of cutaneous side effects with some drug classes [11].”

 

8. Feingold, K.R. Oral and Injectable (Non-Insulin) Pharmacological Agents for the Treatment of Type 2 Diabetes. In Endotext [Internet]; MDText.com, Inc.: South Dartmouth (MA), USA 2022. Available online: https://www.ncbi.nlm.nih.gov/books/NBK279141/ (accessed on 15 Janury 2024)
9. Davies, M.J.; Aroda, V.R.; Collins, B.S.; Gabbay, R.A.; Green, J.; Maruthur, N.M.; Rosas, S.E.; Del Prato, S.; Mathieu, C.; Mingrone, G.; Rossing, P.; Tankova, T.; Tsapas, A.; Buse, J.B. Management of hyperglycaemia in type 2 diabetes, 2022. a consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 2022, 65 (12), 1925–1966. doi: 10.1007/s00125-022-05787-2.
10. Dermatology and Diabetes; Cohen Sabban, E. N., Puchulu, F. M., Cusi, K., Eds.; Springer: Cham, Switzerland,
11. Raschi, E.; Parisotto, M.; Forcesi, E.; La Placa, M.; Marchesini, G.; De Ponti, F.; Poluzzi, E. Adverse events with sodium-glucose co-transporter-2 inhibitors: a global analysis of international spontaneous reporting systems. Metab. Cardiovasc. Dis. NMCD 2017, 27 (12), 1098–1107. doi: 10.1016/j.numecd.2017.10.008.

 

COMMENT: Adverse events reported in the tables should be assessed for causality, to be considered ADRs. If yes, please provide the level of causality in a Naranjo or WHO scale (definitive, propable, possible, unlikely). Please provide information on the tool used to assess caulasity. Otherwise, you cannot state that those are ADRs and this is a major drawback.

 

RESPONSE: We added the level of causality in the presented case reports (if indicated by the authors) in an additional column of tables and we provided information on the tool used to assess caulasity. In the case of sulfonylureas and SGLT-2is, only a few studies reported the level of causality, so we introduced this information in the following fragments:

 

„The Naranjo probability scale was applied in the studies by Ben Salem et al. [59] and Al-Badawi et al. [60] to verify whether there was a causal relationship between the observed CADR and the sulfonylurea used. In both cases, a probable association was found. Ozuguz et al. [61] obtained a positive patch test result for gliclazide.”

 

„In a study by Nagano et al. [91], the Naranjo probability scale indicated a probable relationship between Fornier's gangrene and empagliflozin.”

 

COMMENT: The Fournier's gangrene is not classified as a skin disorder, so it doesnt aling with you title or objective (that I suggest to change).

Accordingly to the MedDRA 25.1, the SOCs related to Fornier's gangrene are:

10021881 - Infections and infestations

10028395 - Musculoskeletal and connective tissue disorders

10038604 - Reproductive system and breast disorders

 

Despite of understanding the connection, the adverse drug reaction is cannot be described inside the group of "skin and subcutanous disorders".

 

RESPONSE: In reference to the Reviewer’s comment, we modified the following sentences in the abstract and conclusions, and added the following sentence about the aim:

 

(Abstract) „Particular attention was paid to specific dermatological conditions such as dipeptidylpeptidase 4 inhibitor-associated bullous pemphigoid or Fournier's gangrene associated with sodium-glucose cotransporter 2 inhibitors therapy”

 

(Conclusions) „Advanced age may increase the risk of dermatological conditions related to new antidia-betic drugs approved for treatment in recent years, such as dipeptidylpeptidase-4 inhibitor-associated bullous pemphigoid or Fournier's gangrene associated with sodium-glucose cotransporter 2 inhibitors”

 

(Aim) „This review presents CADRs to oral antidiabetic drugs taking into account available studies and case reports. We have presented a wide range of skin lesions, also taking into ac-count conditions induced by oral antidiabetic drugs, which manifest as skin reactions, among other symptoms.”

 

 

Reviewer 3 Report

Comments and Suggestions for Authors

This review entitled “Skin Related Adverse Reactions Induced by Oral Antidiabetic Drugs - A Review of Literature and Case Reports” deals with a topic of the highest relevance. The review generally focuses on the most important aspects relating to skin reactions, and the inclusion of case reports effectively illustrates the real-life occurrence of these reactions. However, there are some aspects that need to be improved:

 

·         Line 46: "According to the recommendations, the risk of adverse events, mainly hypoglycemia…” - The authors should use "adverse drug reaction" instead of "adverse event" If the event is suspected to be caused by a drug, it should be labelled as an adverse drug reaction..

 

·         Line 74: "It is estimated that 30% of diabetic patients have skin symptoms" - The authors should add a reference at the end of this sentence.

 

·         Readers often skim an article before reading it in detail. Therefore, I advise authors to avoid using acronyms in the subtitles. I suggest writing out the acronym CADRs in all subtitles.

 

·         Line 133: "The first generation sulfonylureas, i.e., chlorpropamide and tolbutamide, are not currently used" - The authors should provide a reference at the end of this sentence.

 

·         The authors should provide a brief explanation of the Naranjo Adverse Drug Reaction Probability Scale and the Karch and Lasagna Scale, as people not working in the field of pharmacovigilance may not understand the meaning and importance of these scales.

 

·         The conclusion needs to be revised. While the review highlights the skin reactions associated with oral hypoglycaemic agents, the analysis of the case reports is not sufficient to claim that these reactions are more associated with advanced age. Furthermore, there are several case reports where causality was considered possible, meaning that other factors leading to the reaction were not ruled out.

Comments on the Quality of English Language

Moderate editing of English language required

Author Response

POINT-BY-POINT RESPONSE TO REVIEWER 3

We would like to thank the Reviewer for the statement that our review “deals with a topic of the highest relevance”. We would also like to thank for all insightful suggestions and comments. We have revised the manuscript following the Reviewer’s remarks.

COMMENTS:

Line 46: "According to the recommendations, the risk of adverse events, mainly hypoglycemia…” - The authors should use "adverse drug reaction" instead of "adverse event" If the event is suspected to be caused by a drug, it should be labelled as an adverse drug reaction.

Line 74: "It is estimated that 30% of diabetic patients have skin symptoms" - The authors should add a reference at the end of this sentence.

Readers often skim an article before reading it in detail. Therefore, I advise authors to avoid using acronyms in the subtitles. I suggest writing out the acronym CADRs in all subtitles.

Line 133: "The first generation sulfonylureas, i.e., chlorpropamide and tolbutamide, are not currently used" - The authors should provide a reference at the end of this sentence.

RESPONSE: We have revised the manuscript in accordance with the reviewer's comments.

COMMENT: The authors should provide a brief explanation of the Naranjo Adverse Drug Reaction Probability Scale and the Karch and Lasagna Scale, as people not working in the field of pharmacovigilance may not understand the meaning and importance of these scales.

RESPONSE: In reference to the Reviewer’s comment, we added the following fragment in the methods:

„In the case reports shown, we presented the results of the assessment of the causality of adverse drug reactions, taking into account the following methods [175-177]:

• the Naranjo Adverse Drug Reaction Probability Scale - a questionnaire consisting of 10 questions with “yes”, “no”, and “unknown” answers is used. The score is the sum of the values assigned to each item. Based on the score, the causality is assessed as definite, probable, possible, or doubtful.
• the Karch and Lasagna Scale - it consists of 3 tables with a number of closed ques-tions, which should be answered dichotomously. Causality is classified as definite, probable, possible, conditional, or unlikely.
• the Kramer´s Scale - it consists of 56 questions and is based on a comprehensive evaluation of all evidence available, including the patient's history and laboratory tests. It classifies causality as certain, probable, possible, or unlikely.
• the WHO-UMC System for Standardised Case Causality Assessment - it is catego-rized into 6 groups based on 4 criteria: temporal relationship, absence of other competing causes, laboratory findings, and de-challenge and re-challenge. Causality is classified as certain, probable/likely, possible, unlikely, conditional/unclassified, or un-assessable/unclassifiable.”

 

175. Marante, K.B. The Challenges of Adverse Drug Reaction Evaluation. J. Pharmacovigil. 2018, 6, 1-4. doi:4172/2329-6887.1000260.
176. Manjhi, P.K.; Singh, M.P.; Kumar, M. Causality, severity, preventability and predictability assessments scales for adverse drug reactions: a review. Cureus 2024, 16 (5), e59975. doi:10.7759/cureus.59975.
177. Kumar, A.P.; Bhoopathi, D.; Sunkara, H.; Chalasani, H. An overview of various scales used in causality assessment of adverse drug reactions. J. Pharm. Sci. 2020, 12, 1-5. doi:10.22159/ijpps.2020v12i5.37209.

 

COMMENT:  The conclusion needs to be revised. While the review highlights the skin reactions associated with oral hypoglycaemic agents, the analysis of the case reports is not sufficient to claim that these reactions are more associated with advanced age. Furthermore, there are several case reports where causality was considered possible, meaning that other factors leading to the reaction were not ruled out.

RESPONSE: We have revised the conclusions in accordance with the Reviewer's suggestions:

“This review shows that oral hypoglycemic agents that are first- or second-line drugs cause various CADRs. Among others, the widely used sulfonylureas may cause skin lesions due to cross-reactions with other sulfonamide derivatives used, e.g. in the treatment of hypertension. The use of new antidiabetic drugs approved for treatment in recent years, such as dipeptidylpeptidase-4 inhibitors and sodium-glucose cotransporter 2 inhibitors, is associated with an increased risk of dermatological conditions related to the mechanisms of action of these drugs. Inhibition of dipeptidylpeptidase-4 activity may lead to the onset of bullous pemphigoid, and induction of glucosuria by sodium-glucose cotransporter 2 inhibitors may promote the development of Fournier's gangrene.

Management of adverse drug reactions primarily involves discontinuing the drug. Therefore, it is important to be aware of the clinical manifestations of CADRs induced by oral antidiabetic drugs to properly diagnose the skin lesion and avoid the use of additional drugs. This is significant in medical practice, as diabetes occurs mainly in the elderly, who show a high risk of a prescribing cascade.”

 

Reviewer 4 Report

Comments and Suggestions for Authors

The manuscript entitled Skin Related Adverse Reactions Induced by Oral Antidiabetic Drugs - A Review of Literature and Case Reports proposed by Kowalska J. and Wrześniok D. is a review of CADRs induced by oral antidiabetic drugs, considering their dermatological manifestations and possible pathomechanism.

The recognition of a skin lesion resulting from an adverse drug reaction is important in clinical practice for the management of patients’ therapy, especially for the treatment of T2DM.  

This manuscript makes significant contributions by linking user interest data with pharmacovigilance. It is well structured, and the introduction presents current and relevant data. The conclusions are related to the findings of the study. 

Please consider the following recommendations:

Regarding the articles related to Case Reports, I suggest you provide information regarding the scientific platforms you used, the keywords you provided and the inclusion and exclusion criteria for the articles you cited. 

Subsection 3.1.1, 3.2.1, 3.3.1, 3.4.1, 3.5.1., 3.7.1. and 3.8.1 – Please insert the exact dates you used in order to extract the data from the databases. 

Line 363 – Please modify subsection 3.7.1 to 3.8.1.

Author Response

POINT-BY-POINT RESPONSE TO REVIEWER 4

 

We would like to thank the Reviewer for the statement that our review “makes significant contributions by linking user interest data with pharmacovigilance”. We would also like to thank for all insightful suggestions and comments. We have revised the manuscript following the Reviewer’s remarks.

 

COMMENT: Regarding the articles related to Case Reports, I suggest you provide information regarding the scientific platforms you used, the keywords you provided and the inclusion and exclusion criteria for the articles you cited.

 

RESPONSE: In reference to the Reviewer’s comment, we added the following fragment in the methods:

„This review compiles case reports following electronic searches conducted between October and December 2023 in PubMed and Google Scholar databases. No time limitations were imposed. The following queries were used for Pubmed: (i) (metformin) AND (skin); (ii) (chlorpropamide OR tolbutamide OR gliclazide OR gliquidone OR glipizide OR glibenclamide OR glyburide OR glimepiride) AND (skin); (iii) (canagliflozin OR dapagliflozin OR empagliflozin OR ertugliflozin OR bexaglifloxin OR ipragliflozin OR sotagliflozin) AND (skin); (iv) (alogliptin OR anagliptin OR linagliptin OR saxagliptin OR sitagliptin OR teneligliptin OR vildagliptin) AND (skin); (v) (semaglutide) AND (skin); (vi) (pioglitazone OR rosiglitazone) AND (skin); (vii) (repaglinide OR mitiglinide OR nateglinide) AND (skin); (viii) (acarbose OR voglibose OR miglitol) AND (skin). Searching Google, the query paired the word "skin" with the name of the drug. In particular, articles readily available in English, both original and translated, were included, and others were excluded. We retained articles that met the following criteria: 1) the authors suggested the possibility of an association between the induction of a skin-related effect and the use of the antidiabetic drug; 2) the clinical symptoms observed in the patient were presented. We discarded papers that were not a case report or case series.”

 

COMMENT: Subsection 3.1.1, 3.2.1, 3.3.1, 3.4.1, 3.5.1., 3.7.1. and 3.8.1 – Please insert the exact dates you used in order to extract the data from the databases.

 

RESPONSE: We did not impose limits on the range of years for the FAERS and EudraVigilance database searching, and we presented all available reports of skin and subcutaneous tissue disorders linked to the use of oral antidiabetic drugs. In reference to the Reviewer’s comment, we added the following sentence in the methods:

„Data from FAERS and EudraVigilance databases indicate the total number of available reports while searching these databases for the preparation of the review (May 2024).”

 

COMMENT: Line 363 – Please modify subsection 3.7.1 to 3.8.1..

 

RESPONSE: We thank the Reviewer for pointing this out. We have corrected the subsection number.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Congratulations to the authors for this work, the revisions have contributed to elevate the quality of evidence provided. The manuscript can be now accepted for publication.

Author Response

I would like to thank for positive comments.

Reviewer 2 Report

Comments and Suggestions for Authors

No further comments to be added to my previous revision. 

Author Response

I would like to thank for comments.