Dermatology: Practical and Conceptual Commentary | Dermatol Pract Concept. 2023;13(1):e2023063 1 Treatment of Diabetes in Bullous Pemphigoid Patients: Where Do We Stand? Maria Inês Alexandre1, Pedro Miguel Garrido2, Paulo Filipe2,3,4 1 Endocrinology Department, Hospital de Santa Maria, Centro Hospitalar Universitário de Lisboa Norte, Lisbon, Portugal 2 Dermatology Department, Hospital de Santa Maria, Centro Hospitalar Universitário de Lisboa Norte, Lisbon, Portugal 3 University Dermatology Clinic, Faculty of Medicine, University of Lisbon, Lisbon, Portugal 4 Dermatology Research Unit, Instituto de Medicina Molecular, University of Lisbon, Lisbon, Portugal Citation: Alexandre MI, Garrido PM, Filipe P. Treatment of diabetes in bullous pemphigoid patients: where do we stand? Dermatol Pract Concept. 2023;13(1):e2023063. DOI: https://doi.org/10.5826/dpc.1301a63 Accepted: April 13, 2022; Published: January 2023 Copyright: ©2023 Alexandre et al. This is an open-access article distributed under the terms of the Creative Commons Attribution- NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. Funding: None. Competing Interests: None. Authorship: All authors have contributed significantly to this publication. Corresponding Author: Maria Inês Alexandre, Serviço de Endocrinologia, Hospital de Santa Maria, Centro Hospitalar Universitário de Lisboa Norte, 1649-028 Lisboa, Portugal. Phone: 00351 21 780 5000; E-mail: mariaines.f.alexandre@gmail.com Bullous pemphigoid (BP) affects predominantly elderly pa- tients, and the disease incidence rises exponentially with age. A high prevalence of diabetes mellitus (DM) in patients with BP has been noticed, ranging from 20 to 30% [1]. The treatment of BP patients is challenging and should be carefully assessed bearing in mind their multiple comorbid- ities. Corticosteroids are the mainstay of treatment for BP. However, their systemic use is limited in diabetic patients by the risk of acute hyperglycemic complications. This is par- ticularly concerning given the age group of BP patients and the chronicity of treatment. Adjunctive therapy with immu- nosuppressants such as azathioprine, mycophenolate mofetil or methotrexate may also be needed [2]. Also, novel targeted therapeutic approaches such as omalizumab and dupilumab have been reported as effective alternatives, but their use in BP is still off-label [3]. Several population-based studies supported an increased risk of developing BP in diabetic patients treated with dipep- tidyl peptidase-4 inhibitors (DPP4i). A recent meta-analysis showed that the odds ratio (OR) for BP among patients re- ceiving any DPP4i ranged from 1.27 to 3.45 [4]. The exact pathogenesis of how DPP4i might induce BP remains largely unclear and it is not known if the suspension of DPP4i can revert this immunological process. However, the clinical out- come appears to be better if DPP4i is discontinued. A presumed association between BP and glucagon-like peptide-1 (GLP-1) receptor agonists has also been reported [5]. The underlying mechanism is unclear, however since DPP4i and GLP-1 receptor agonists both rely on enhancing the activ- ity of the incretin hormone GLP-1, a common effect between these two classes of antidiabetic drugs should be sought. Although more robust studies are required, we suggest that this association is taken into account when selecting the most appropriate medication for BP patients. Other widely used antidiabetic drugs like second-generation sulfonylureas and metformin seem safer options, but their use can be limited by the patient’s comor- bidities [6]. The sodium–glucose cotransporter (SGLT)2 in- hibitors also seem like good alternatives. These drugs do not increase the risk of hypoglycemia, have low rates of adverse effects and may be continued in patients with moderate renal impairment. Overall, they can be used in selected BP patients. 2 Commentary | Dermatol Pract Concept. 2023;13(1):e2023063 In many cases, insulin is the most suitable choice, partic- ularly for inpatients on corticosteroids. Morning basal insu- lin may closely fit the glucose excursion induced by a single dose of morning corticosteroid. The initial dose and titration should take into account the patient’s weight and dose of corticosteroid. Dairy adjustments are frequently necessary and often difficult to predict. Based on the previous data, a treatment algorithm for BP patients with type 2 DM is proposed in Fig. 1. In conclusion, it is decisive that we view BP patients beyond a single-disease framework and treat them in the context of multi-morbidities. Diabetes management in these patients can be particularly troublesome and, to date, there are no orienting guidelines on this matter. Endocrinologists should be aware of BP as a challenging problem in patients with DM and collabo- ration with dermatologists is essential for good outcomes. References 1. Chai ZT, Tan C, MeiQi Liau M, et al. Diabetes mellitus and hy- perglycemic complications in bullous pemphigoid. J Am Acad Dermatol. 2020 May;82(5):1234-1237. 2. Di Lernia V, Casanova DM, Goldust M, Ricci C. Pemphigus Vul- garis and Bullous Pemphigoid: Update on Diagnosis and Treat- ment. Dermatol Pract Concept. 2020 Jun 29;10(3):e2020050. 3. Garrido PM, Alexandre MI, Travassos AR, Filipe P. Dipeptidyl-peptidase IV inhibitor-associated bullous pemphigoid Type 2 DM with BP Consider discontinuation of DPP4i, if present If patient is treated with systemic corticosteroids Consider referral to an endocrinologist if glycemia is persistently above 200 mg/dL Insulin- treated patients Non-insulin- treated patients Morning basal insulin 0,2 U/kg/day (Ex: glargin/NPH) Increase basal insulin 2U every 2-3 days if glycemia before dinner is above 180 mg/dL After discharge, return to oral antidiabetic drugs if possible (see outpatient care scheme); evaluate need to maintain basal insulin Pre-prandial rapid/short action insulin according to glycemia (Ex: <140 mg/dL: OU; 140-200mg/dL: 2U; 201-250mg/dL: 4U; 251-300mg/dL: 6U; 301-350mg/dL: 8U; 351-400mg/dL: 10U; 401-450mg/dL: 12U; ≥451mg/dL: 14U) Switch to basal morning administration and consider increase dose in 10-20%. If ambulatory dose is not known start at 0,3-0,4 U/kg/day Increase basal insulin 2U every 2-3 days if glycemia before dinner is above 180 mg/dL Check glycemia at admission and every 4 hours Inpatient care Outpatient care Advise to check glycemia before every meal Optimize metformin dose if tolerated and patient’s eGFR>30 mL/min/1.72m2 Consider adding SGLT2i (adjustments may be needed for renal impairment; see drug information) Sulfonylureas (later generation) also an option; higher risk of hypoglycemia Avoid DPP4i combination/mono therapy Caution with GLP1a Morning basal insulin may be needed if glycemia is above 180 mg/dL before dinner Figure 1. Proposed treatment algorithm for bullous pemphigoid patients with type 2 diabetes mellitus treated with corticosteroids. BP, bullous pemphigoid; DM, diabetes mellitus; DPP4i, dipeptidyl peptidase-4 inhibitor; eGFR, estimated glomerular filtration rate; GLP1a, glucagon-like peptide 1 receptor agonist; SGLT2i, sodium–glucose cotransporter 2 inhibitor. Commentary | Dermatol Pract Concept. 2023;13(1):e2023063 3 efficiently treated with omalizumab. Dermatol Ther. 2020 Nov;33(6):e14160. 4. Kridin K, Cohen AD. Dipeptidyl-peptidase IV inhibitor-associated bullous pemphigoid: A systematic review and meta-analysis. J Am Acad Dermatol. 2021 Aug;85(2):501-503. 5. Burruss CP, Jones JM, Burruss JB. Semaglutide-associated bul- lous pemphigoid. JAAD Case Rep. 2021 Aug 5;15:107-109. 6. Lee H, Chung HJ, Pawar A, Patorno E, Kim DH. Evaluation of Risk of Bullous Pemphigoid With Initiation of Dipeptidyl Peptidase-4 Inhibitor vs Second-generation Sulfonylurea. JAMA Dermatol. 2020 Oct 1;156(10):1107-1114.