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

Type 2 diabetes (T2DM) is a chronic metabolic disease with a steadily increasing prevalence worldwide. Diabetes affects the function of many organs, including the skin. Pharmacotherapy for T2DM is mainly based on oral hypoglycemic drugs. The therapeutic strategy is chosen taking into account the individual patient’s characteristics, among other comorbidities. Antidiabetic drugs can induce cutaneous adverse reactions (CADRs) ranging in severity from mild erythema to serious disorders such as DRESS or Stevens–Johnson syndrome. CADRs can result from hypersensitivity to the drug but can also be related to the mechanism of action of the drug or cross-reactivity with drugs of similar structure. This paper reviews CADRs induced by oral antidiabetic drugs, considering their dermatological manifestations and possible pathomechanisms. 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 inhibitor therapy. Knowledge of the dermatological manifestations of CADRs is important in clinical practice. Recognition of a skin lesion resulting from an adverse drug reaction allows for appropriate management, which in this case is primarily related to drug discontinuation. This is particularly important in the treatment of T2DM since this disease has a high prevalence in the elderly, who are at higher risk of adverse drug reactions.


Introduction
Diabetes mellitus is a very serious health problem worldwide.The current global prevalence is estimated at 6.1%.The most prevalent diabetes type is type 2 (T2DM), which accounts for about 96% of the total incidence of diabetes [1,2].T2DM was earlier known as insulin-independent diabetes mellitus or adult-onset diabetes because it most frequently occurs in people over the age of 45 and is characterized by a lack of insulin requirements to prevent ketoacidosis [3][4][5].T2DM is caused by a combination of genetic factors and lifestyle.A major lifestyle risk factor is a high body mass index (BMI).Obesity has been found to account for about 55% of T2DM cases [2,6].
According to the recommendations, the risk of adverse drug reactions, 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 the 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].
Diabetes is particularly common in people aged 65 and older in all countries, with a prevalence in this demographic group of over 20% worldwide [2].In the elderly, polypharmacotherapy is often used due to the presence of comorbidities.In a high percentage of patients with T2DM, there is a need to use cardiological and antihyperlipidemic drugs.
Elderly patients are at higher risk of adverse drug reactions.In addition, this group of patients has an increased risk of the prescribing cascade, which is the administration of drugs to treat the adverse reactions of drugs already in use [7].
It is important to know the extent of cutaneous adverse drug reactions (CADRs) to antidiabetic drugs because diabetes is prevalent in the elderly, who are at greater risk of side effects of therapy.It is also relevant because diabetic patients have a high risk of developing skin disorders due to the pathomechanism of the disease [12].This review presents CADRs for oral antidiabetic drugs, taking into account available studies and case reports.We have presented a wide range of skin lesions, also taking into account conditions induced by oral antidiabetic drugs, which manifest as skin reactions, among other symptoms.

Pathophysiology of Skin-Related Disorders in Diabetes
The skin in diabetes undergoes pathological processes, whose severity is proportional to the duration of hyperglycemia [12].It is estimated that 30% of diabetic patients have skin symptoms [10].Cutaneous complications are associated with microangiopathy, neuropathy, and immune response changes, which are in turn due to biochemical alterations such as hyperglycemia, insulin deficiency, and non-enzymatic glycation (NEG) [10].Insulin is essential for skin cell proliferation, differentiation, migration, metabolism, and apoptosis.Therefore, insulin deficiency leads to relevant skin abnormalities associated with, for example, impaired wound healing [13].Enhanced NEG under hyperglycemic conditions decreases stiffness and reduces the elasticity of the skin due to collagen modification.In addition, NEG leads to an increase in oxidative stress and the induction of inflammation, both of which affect skin cell dysfunction [14].Among others, suppression of proliferation and migration of keratinocytes and fibroblasts occurs [15,16].Under hyperglycemic conditions, the physiological function of fibroblasts is impaired, leading to reduced secretion of extracellular matrix components.This results in decreased elasticity of the skin and causes it to become dry and thin [14,16].Skin problems associated with T2DM include yellow nails, acrochordons, diabetic dermopathy, acanthosis nigricans, acquired perforating dermatosis, calciphylaxis, and eruptive xanthoma [17].Skin complications of long-term diabetes also include infections, both bacterial and fungal [10,17,18].

Metformin: Pharmacotherapy and Case Reports of Cutaneous Adverse Reactions
Metformin is a biguanide derivative that lowers blood glucose levels via multiple pathways.A drug reduces glucose absorption in the intestines and stomach and enhances insulin-dependent glucose uptake into skeletal muscle.In addition, it inhibits glycogenolysis and gluconeogenesis in the liver [19,20].
Metformin is a widely-used drug.It is recommended as a first-line treatment for T2DM according to the joint guidelines of the American Diabetes Association and the European Association for the Study of Diabetes [9].In addition, metformin is recommended for the prevention of diabetes in patients aged < 60 years with a BMI ≥ 35 kg/m 2 and women with a gestational diabetes history [21,22].It is also used to reduce insulin resistance in patients with type 1 diabetes and overweight/obesity and to treat metabolic abnormalities associated with polycystic ovary syndrome [22,23].
This drug has a generally good safety profile and rarely causes CADRs.Metformininduced skin lesions are immune-mediated reactions [24].CADRs to metformin include, among others, erythema multiforme [25], lichen planus [26], rosacea-like facial rash [27], bullous pemphigoid [28], and psoriasiform drug eruption [29].There are some reports in the literature of metformin-induced photosensitivity with the symptoms of erythematous, eczematous [30], or blistering lesions in sun-exposed areas [31].Other skin adverse reactions caused by metformin are leukocytoclastic vasculitis and fixed-drug eruptions.Tables 1 and 2 summarize the reported cases of these CADRs.
The most serious metformin-induced CADR that has been reported is a drug rash with eosinophilia and systemic symptoms syndrome known as DRESS syndrome.The patient presented with generalized pruritus, rash, lymphadenopathy, and eosinophilia [32].
Long-term metformin therapy can lead to the onset of vitamin B 12 deficiency, which, besides hematological or neurological disorders, can manifest as hyperpigmented lesions on the knees, lateral surfaces of the legs, the dorsum of the hands and feet, fingers, as well as skin folds [33,34].

Real-World Data on Metformin-Related Cutaneous Adverse Reactions
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].

Sulphonylureas: Pharmacotherapy and Case Reports of Cutaneous Adverse Reactions
Sulfonylureas are derivatives of sulfonamides, which are divided into two generations.The first-generation sulfonylureas, i.e., chlorpropamide and tolbutamide, are not currently used [50].In contrast, the second-generation sulfonylureas, which include gliclazide, gliquidone, glipizide, glibenclamide (glyburide), and glimepiride, are among the most frequently used oral antidiabetic drugs [50].This drug group is recommended when metformin is intolerant, contraindicated, or ineffective [51,52].Sulfonylureas are also prescribed as an add-on to metformin to improve glycemic control [53].
The main mechanism of sulfonylureas is to trigger insulin release from the pancreatic β cells by binding to the sulfonylurea receptor.The drugs inhibit ATP-sensitive potassium channels, which leads to blockage of potassium ion efflux and depolarization of the cell membrane.As a result, the calcium channels open and the intracellular calcium concentration increases, which enhances insulin secretion [10,[53][54][55].
CADRs occur in about 1% of patients using sulfonylureas [54].First-generation drugs induced the following skin reactions: maculopapular exanthema, phototoxic and photoallergic reactions, pruritus, urticaria, erythema nodosum, fixed erythema, erythema multiforme, toxic epidermal necrolysis, and Lyell's syndrome [10,56].Moreover, chlorpropamidealcohol flushing (CPAF) has been reported to occur in 10-30% of patients using the drug [10].CPAF manifests as facial erythema after consuming a small amount of alcohol.It has been suggested that CPAF is an autosomal dominant inherited trait and that it has prognostic significance-patients with a positive CPAF test have a lower risk of developing vascular complications [57,58].
Second-generation sulfonylureas also induce skin reactions.In Table 3, case reports of CADRs induced by these drugs are summarized.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 in vitro and in vivo studies, the phototoxic potential of the following second-generation sulfonylureas has been demonstrated: glipizide, glibenclamide, and gliquiudone [62,63].
CADRs to sulfonylureas may result from cross-reactivity with other sulfonamide derivatives.Sulfonamides are associated with a high risk of allergic reactions.Sulfonamide metabolites act as haptens and bind to proteins, and the formed complexes, after being bound to MHC class I or II molecules, are presented to T lymphocytes.Sulfonylureas can trigger an allergic response similar to sulfonamides due to their structural similarity [64,65].The following cases of cross-reactions between sulfonamide derivatives have been reported:

•
Petechial eruptions after the use of hydrochlorothiazide in a patient diagnosed with tolbutamide allergy [66]; • Leukocytoclastic vasculitis after gliburide use in a patient with a history of sulfamethoxazole-trimethoprim allergy [67]; • Erythema multiforme occurring after the use of celecoxib as well as glyburide [68]; • Fatal toxic epidermal necrolysis probably associated with glimepiride in a patient with sulfamethoxazole-trimethoprim hypersensitivity [69].

Sodium-Glucose Cotransporter 2 Inhibitors: Pharmacotherapy and Case Reports of Cutaneous Adverse Reactions
Sodium-glucose cotransporter 2 inhibitors are recommended as second-line treatment after metformin for T2DM patients with atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease [9].SGLT-2is include canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, bexaglifloxin, ipragliflozin, and sotagliflozin [78].These drugs act by inhibiting paired sodium and glucose reuptake in the renal proximal tubule and thus supporting urinary excretion of glucose and sodium [78,79].
CADRs usually appear within 2 weeks of SGLT-2is administration and include, among others, severe generalized rash, urticaria, erythema, drug eruption, and eczema [80,81].In addition, a case of bullous pemphigoid during treatment with ipragliflozin [82], generalized intense pruritus caused by canagliflozin [83], and a fixed drug eruption induced by dapagliflozin [84] were reported.In reports by Yabe et al. [81] and Sakaeda et al. [85], ipraglifrozin, within SGLT-2is, was associated with the highest incidence of skin and subcutaneous tissue disorders.A significant risk of ipraglifrozin-induced CADRs may result from the interaction of the drug with melanin, a pigment occurring in the skin.A 3-D in silico docking simulation showed that ipragliflozin can bind to melanin, and analysis of the drug's skin tissue distribution in rats showed that ipragliflozin was retained in skin tissue [85].Studies by Yokote et al. [86] and Maegawa et al. [87] found that female patients and those older than age 65 have a higher risk of skin complications during ipragliflozin treatment.
Ma et al. [88] showed that SGLT-2 significantly increased the risk of psoriasis in patients with diabetes and renal diseases.
SGLT-2 increases the risk of urinary tract infections due to their mechanism of action.The drugs induce glucosuria, and increased glucose concentration in the urine creates a rich medium for bacteria and fungi [80,89].It is estimated that 5-10% of women with T2DM receiving SGLT-2is experience genital fungal infections.Many genitourinary infections are mild to moderate and are readily treated.However, there is a risk of developing severe urosepsis or potentially life-threatening Fournier's gangrene [11,89].Fournier's gangrene is necrotizing fasciitis of the perineum.Clinical manifestations include persistent severe perianal or genital pain, blistering, redness, ecchymosis, skin necrosis, and extensive swelling [90,91].It has not yet been determined whether SGLT-2 itself causes Fournier's gangrene or whether a subgroup of patients receiving those antidiabetic drugs are at risk.The following conditions are considered to be risk factors: advanced age, obesity, smoking, and alcohol abuse [78,92,93].Table 4 summarizes cases of Fournier's gangrene in patients using SGLT-2is.In a study by Nagano et al. [91], the Naranjo probability scale indicated a probable relationship between Fornier's gangrene and empagliflozin.

Real-World Data on Sodium-Glucose Cotransporter 2 Inhibitors-Related Cutaneous Adverse Reactions
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].

Dipeptidylpeptidase-4 Inhibitors: Pharmacotherapy and Case Reports of Cutaneous Adverse Reactions
Dipeptidylpeptidase-4 inhibitors, also known as gliptins, are a class of oral antidiabetic drugs that include alogliptin, anagliptin, linagliptin, saxagliptin, sitagliptin, teneligliptin, and vildagliptin.Gliptins are recommended as second-line treatment when metformin is contraindicated or intolerant and in patients without high-risk or diagnosed cardiovascular disease (as SGLT-2is are preferred in this patient subgroup) [104][105][106].Gliptins, by inhibiting the enzyme dipeptidylpeptidase-4, prevent the degradation of the incretin hormone (glucagon-like peptide 1), which has a role in controlling post-meal glycemic levels.Incretin promotes insulin secretion from β cells in a glucose-dependent manner and suppresses glucagon release from α cells [107][108][109].
It has been reported that vildagliptin is the DPP-4-i that most frequently induces the onset of BP [121][122][123][124][125]. A higher risk of GABP has been shown to occur in elderly patients and those with dementia [126,127].The latency between the beginning of gliptin treatment and the onset of BP symptoms varied widely across studies and ranged from 8 days to 6.5 years [128].Several Asian studies have shown that patients with GABP exhibit a noninflammatory phenotype characterized by less eosinophilia infiltration than observed in typical BP [129][130][131].In contrast, European studies did not confirm significant differences between GABP and typical BP [122,132,133].
The pathomechanism of GABP remains largely unclear.It seems significant that DPP-4 is involved in many biological processes, is expressed as a cell surface protein by various cells, including T lymphocytes, macrophages, fibroblasts, and keratinocytes, and is also found in body fluids [113,134].Among others, DPP-4 is a cell-surface plasminogen receptor that is responsible for the transformation of plasminogen into plasmin.Plasmin cleaves collagen XVII, which plays a crucial role in the maintenance of stable adhesion of the epidermis to the dermis.It is supposed that DPP-4 suppression modifies the ability of plasmin to cleave collagen XVII and could affect the formation of new epitopes for BP autoantibodies.In addition, DPP-4 inhibition is also thought to increase the activity of proinflammatory chemokines such as CCL11/eotaxin, enhancing the activation of eosinophils in the skin and bullae formation [119,128,135].Real-World Data on Dipeptidylpeptidase-4 Inhibitors-Related Cutaneous Adverse Reactions The FAERS reports 3024 cases of skin and subcutaneous tissue disorders arising after DPP-4-is use: eight for anagliptin, forty-one for teneligliptin, sixty-six for saxagliptin, ninety-seven for alogliptin, three hundred and two for sitagliptin, seven hundred and three for vildagliptin, and one thousand seven hundred and seven 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 confirm the increased risk of BP in gliptin-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].

Semaglutide: Pharmacotherapy and Case Reports of Cutaneous Adverse Reactions
Semaglutide is the first oral glucagon-like peptide 1 receptor agonist approved for the treatment of T2DM.It is recommended as a first-or second-line therapy [162].Semaglutide, as administered subcutaneously, is also approved for the treatment of overweight and obesity [163].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 h after the administration of the drug [165].

Real-World Data on Semaglutide-Related Cutaneous Adverse Reactions
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].

Thiazolidinediones: Pharmacotherapy and Case Reports of Cutaneous Adverse Reactions
Thiazolidinediones decrease insulin resistance by activating the gamma isoform of the peroxisome proliferator-activated receptor, which regulates the transcription of genes involved in glucose and lipid metabolism.Thiazolidinediones, which include pioglitazone and rosiglitazone, are recommended as third-line or second-line drugs if first-and secondline antidiabetic drugs are not effective [166,167].CADRs in thiazolidinedione therapy are primarily related to hypersensitivity reactions.A case report of hypersensitivity to pioglitazone has been reported, which manifested as pruritus and rash and appeared after 2 months of therapy [168].

Real-World Data onon Thiazolidinediones-Related Cutaneous Adverse Reactions
The FAERS reporting system records 183, and the EudraVigilance dtabase records 679 cases of skin and subcutaneous tissue disorders in response to pioglitazone (respectively 145 and 38) and rosiglitazone (respectively 393 and 286) [48,49].

Meglitinides: Pharmacotherapy and Case Reports of Cutaneous Adverse Reactions
Meglitinides are a group of oral antidiabetic drugs preferred in patients with chronic or end-stage renal disease.They stimulate the production of endogenous insulin in the pancreas.The Meglitinides group comprises repaglinide, mitiglinide, and nateglinide [169,170].Reported CADRs to the meglitinide therapy include rash, pruritus, and pemphigoid [24].A 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.

Real-World Data onon Meglitinides-Related Cutaneous Adverse Reactions
The FAERS notes 634 cases of skin and subcutaneous tissue disorders linked to the use of meglitinides: eight for mitiglinide, one hundred and twenty-four for nateglinide, and five hundred and two for repaglinide [48].The EudraVigilance lists four hundred and twenty-five cases of skin and subcutaneous tissue disorders: fourteen for mitiglinide, eighty-four for nateglinide, and three hundred and twenty-seven for repaglinide [49].

Alpha-Glucosidase Inhibitors: Pharmacotherapy and Case Reports of Cutaneous Adverse Reactions
Alpha-glucosidase inhibitors are used in the treatment of T2DM and glucose intolerance.They are particularly useful for patients who cannot use sulfonylurea derivatives and metformin because of the risk of hypoglycemia or lactate acidosis.AGIs include acarbose, voglibose, and miglitol.AGIs inhibit the absorption of carbohydrates from the small intestine.They competitively inhibit enzymes, including alpha-glucosidase, which is responsible for converting complex, non-absorbable carbohydrates into simple, absorbable carbohydrates [169,172].
The most commonly used drug among the AGIs is acarbose [172].Acarbose is poorly absorbed from the gut and has low bioavailability, so it rarely causes adverse reactions [169,173].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.

Real-World Data onon Alpha-Glucosidase Inhibitors-Related Cutaneous Adverse Reactions
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 acarbose49.
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.

Methods
This review compiles case reports following electronic searches conducted between October and December 2023 in the 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 case reports or case series.
Data from the FAERS and EudraVigilance databases indicate the total number of available reports while searching these databases for the preparation of the review (May 2024).
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][176][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 three tables with a number of closed questions, 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 six groups based on four 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 unassessable/unclassifiable.

Conclusions
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.

Table 3 .
Case reports of cutaneous adverse reactions induced by second-generation sulfonylureas.
NA = Not available.
NA = Not available.

Table 5 .
Cont.Not available; a The Naranjo Adverse Drug Reaction Probability Scale; b The Karch and Lasagna Scale; c The WHO-UMC System for Standardised Case Causality Assessment.