Copyright
©The Author(s) 2021.
World J Diabetes. Sep 15, 2021; 12(9): 1426-1441
Published online Sep 15, 2021. doi: 10.4239/wjd.v12.i9.1426
Published online Sep 15, 2021. doi: 10.4239/wjd.v12.i9.1426
Table 1 List of the keywords used for literature search
| No. | |
| 1 | Dipeptidyl peptidase 4 inhibitor |
| 2 | DPP-4 inhibitor |
| 3 | Gliptins |
| 4 | ‘Autoimmune disease’ |
| 5 | [1] and [4] |
| 6 | [2] and [4] |
| 7 | [3] and [4] |
| 8 | [2] and [3] and [4] |
| 9 | Inflammatory bowel disease |
| 10 | [1] and [9] |
| 11 | Arthritis |
| 12 | Arthralgia |
| 13 | ‘Rheumatoid arthritis’ |
| 14 | [1] and [11] |
| 15 | [1] and [12] |
| 16 | [1] and [13] |
Table 2 Summary of the studies that assessed risk of overall autoimmune diseases in dipeptidyl peptidase-4 inhibitor users
| Ref. | Population | Study design | Composite outcome | Individual autoimmune disease outcome |
| Kridin et al[36], 2018 | T2DM patients receiving DPP-4i (n = 283) vs matched controls (n = 5660) | Cross-sectional retrospective study using patient database | OR 1.44 (95%CI: 1.06–1.96) for any disease from the cluster of AD (Crohn’s disease, psoriasis, Hashimoto’s thyroiditis, MS, ulcerative colitis) | Crohn’s disease OR 3.56 (95%CI: 1.04–12.21). Psoriasis OR 2.12 (95%CI: 0.99–4.66). Hashimoto’s thyroiditis OR 1.38 (95%CI: 1.00–1.91). No difference in the following ADs: Addison’s disease, Arthropathy, Celiac disease, Idiopathic thrombocytopenic Purpura, Myasthenia gravis, Pernicious anaemia, RA, Sarcoidosis, Scleroderma, SLE |
| Noguchi et al[37], 2019 | Diabetes patients receiving DPP-4i and other antidiabetic drugs (n = 38887) | Adverse Drug Event Report database analysis | PRR 4.09 for overall autoimmune disease | Increased risk was noted in the following AD: RA, pemphigoid, autoimmune pancreatitis, and polymyalgia rheumatica |
| Chen et al[38], 2020 | T2DM patients (age ≥ 20 yr) receiving DPP-4i vs non-DPP-4i medications (n = 387099 in each group) | Retrospective cohort study using insurance claim data | HR 0.56 (95%CI: 0.53–0.60) for overall AD like RA, SLE, IBD, Sjogren syndrome, psoriasis and ankylosing spondylitis | RA: HR 0.56 (95%CI: 0.46–0.68). Psoriasis: HR 0.56 (95%CI: 0.52–0.61). Ankylosing spondylitis: HR 0.56 (95%CI: 0.50–0.63). SLE: HR 0.55 (95%CI: 0.35–0.88). IBD: HR 0.66 (95%CI: 0.11–3.95). Sjogren syndrome: HR 0.58 (95%CI: 0.46–0.75) |
| Kim et al[39], 2015 | T2DM patients (age ≥ 40 yr) started on DPP-4i as a part of combination therapy (n = 73928) vs non-DPP-4i combination therapy (n = 163062) | Cohort study using insurance claim data | HR 0.68 (95%CI: 0.52-0.89) for AD like RA, SLE, psoriasis, psoriatic arthritis, MS and IBD | RA: HR 0.66, (95%CI: 0.44-0.99). Other AD (excluding RA): HR 0.73 (95%CI: 0.51-1.03) |
| Seong et al[40], 2019 | New T2DM patients (age ≥ 18 yr) using DPP-4i (n = 497619) or non-DPP-4i (n = 643165) oral combination therapy | Active comparator new-user cohort study | aHR 0.82 (95%CI: 0.68–0.99) for AD like RA, IBD, MS and SLE | RA: aHR 0.67 (95%CI: 0.49–0.92). IBD: aHR 0.81 (95%CI: 0.61-1.08). SLE + MS: aHR 0.67 (95%CI: 0.37-1.19) |
Table 3 Summary of the pharmacovigilance and population-based studies reporting dipeptidyl peptidase-4 inhibitor induced bullous pemphigoid
| Ref. | Country | Population | Pooled odds ratio | Individual DPP-4i | Remarks |
| Reolid et al[55], 2020 | Spanish Pharmacovigilance System | Overall reported adverse events | NA | ROR: linagliptin 69.42 (95%CI: 21.17–227.57), saxagliptin 46.45 (6.26-344.25), vildagliptin 123.38 (95%CI: 68.72–221.15), sitagliptin 12.42 (95%CI: 3.89–39.63) | Vildagliptin was the DPP-4i that most frequently induced BP |
| García et al[56], 2016 | European pharmacovigilance database | Overall reported adverse events | NA | PRR: Vildagliptin 85.98 (95%CI: 70.98–104.15), sitagliptin 4.55 (95%CI: 3.32–6.24), saxagliptin 8.36 (95%CI: 3.14–22.28), linagliptin 24.32 (95%CI: 14.11–41.92) | Alogliptin was not associated with development of BP |
| Lee et al[57], 2019 | Korea (Retrospective, nationwide, population-based, case-control study) | 670 patients with diabetes with BP and 670 control patients with only diabetes | aOR, 1.58 (95%CI: 1.25-2.00) | Vildagliptin aOR 1.81 (95%CI: 1.31-2.50), sitagliptin aOR, 1.70 (95%CI: 1.19-2.43), linagliptin aOR 1.64 (95%CI: 1.15-2.33) | Male gender was associated with higher risk of development of BP |
| Carnovale et al[58], 2019 | World Health Organization global Individual Case Safety Reports database | Overall reported adverse events | ROR 179.48 (95%CI: 166.41–193.58) | Teneligliptin 975.04 (95%CI: 801.70–1185.87), sitagliptin 46.52 (95%CI: 40.57–53.36), vildagliptin 399.70 (95%CI: 362.26–441.02), linagliptin 143.23 (95%CI: 122.60–167.33) | The highest ROR was found for teneligliptin |
| Béné et al[59], 2016 | French Pharmacovigilance Database | Among 1297 spontaneous ADR reports, 42 were DPP-4i induced BP | ROR 67·5 (95%CI: 47.1-96.9) | Vildagliptin ROR 225·3 (95%CI: 148.9-340.9), sitagliptin ROR 17.0 (95%CI: 8.9-32.5), saxagliptin ROR 16.5 (95%CI: 2.3-119.1) | Vildagliptin had higher ROR |
| Varpuluoma et al[60], 2018 | Finland (Nationwide Registry Study) | 3397 BP cases and 12941 controls | aOR 2.13 (95%CI: 1.51–3.00) | aOR vildagliptin 8.66 (95%CI: 4.06-18.50), aOR sitagliptin 1.36 (95%CI: 0.93-1.99) | A significantly increased risk of BP after the use of vildagliptin |
| Hung et al[61], 2020 | Taiwan (Nationwide, population-based, cohort study) | 6340 patients with DM on DPP-4i and 25360 DM patients without DPP-4i | aHR 2.382 (95%CI: 1.163-4.883) | Vildagliptin aHR, 2.849 (95%CI: 1.893-4.215), saxagliptin aHR, 2.657 (95%CI: 1.770-3.934), sitagliptin aHR, 2.585 (95%CI: 1.723–3.829), linagliptin aHR, 2.360 (95%CI: 1.567–3.477), alogliptin aHR, 1.450 (95%CI: 0.965–2.152) | Vildagliptin was significantly associated with an increased risk of BP, and alogliptin was not associated with development of BP |
| Arai et al[49], 2018 | Japanese Adverse Drug Event Report database | 392 BP cases in DPP-4i user and 12811 without BP as control | ROR 87.56 (95%CI: 72.61–105.59) | ROR: alogliptin 8.02 (95%CI: 4.87–13.22), anagliptin 10.84 (95%CI: 3.46–33.96), sitagliptin 12.59 (95%CI: 9.86–16.06), trelagliptin 13.77 (95%CI: 3.40–55.85), saxagliptin 15.85 (95%CI: 5.87–42.79), linagliptin 28.96 (95%CI: 21.38–39.23), omarigliptin 43.79 (95%CI: 5.85–327.70), teneligliptin 58.52 (95%CI: 42.75–80.10), vildagliptin 105.33 (95%CI: 88.54–125.30) | The highest ROR was found with vildagliptin |
| MolinaGuarneros et al[70], 2020 | Spain (pharmacovigilance data) | Case/non-case analysis (1998 DPP-4i induced ADR where 45 were DPP-4i induced BP) | ROR 70.0 (47.1–104.1) | Vildagliptin 113.9 (95%CI: 73.4–177), linagliptin 55.2 (95%CI: 28.2–108.0), sitagliptin 9.1 (95%CI: 3.7–22.6), saxagliptin 27.4 (95%CI: 3.7–200.1) | Highest risk of BP with vildagliptin |
| Douros et al[80], 2019 | United Kingdom Clinical Practice Research Datalink | Cohort study among 168774 patients started on antidiabetic drugs | HR 2.21 (95%CI: 1.45-3.38) | Linagliptin HR 4.90 (95%CI: 2.68–8.96), vildagliptin HR 4.56 (95%CI: 1.42–14.64), saxagliptin HR 2.16 (95%CI: 0.86–5.46), sitagliptin HR 1.42 (95%CI: 0.79–2.53) | HRs for development of BP gradually increased with longer durations of DPP-4i use |
Table 4 Clinical characteristics of case-control studies reporting dipeptidyl peptidase-4 inhibitor-induced bullous pemphigoid
| Ref. | Type of the study | Population | Effect of gender | Latency period | Age | Outcome |
| Plaquevent et al[50], 2019 | Multicentre case-control study | Out of 1787 patients with BP, 108 subjects were gliptin users. Comparison with a large general population data base | NA | 14.8 mo (interquartile range 6.0-26.7 mo) | 77.9 ± 9.3 yr | No difference in outcome between gliptin withdrawal vs continued groups |
| Schaffer et al[51], 2017 | Retrospective case-control study | Patients with diabetes and BP (n = 23) compared with patients with only diabetes (n = 170) | NA | Range: 5-48 mo | 77.6 yr | Favourable outcome after gliptin withdrawal; however topical and systemic therapy were required in most of the cases |
| Béné et al[59], 2016 | Case/non case analysis from database | Patients with BP (n = 150) compared with other spontaneous adverse drug reactions | NA | 10 mo (range 8 d-37 mo) | 74 yr (range 45-91) | Favourable outcome in patients when DPP-4is were discontinued. Median time to improvement was 10 d ( interquartile range : 5-15 d) |
| Benzaquen et al[68], 2018 | Retrospective case-control study with 1:2 design | Patients with diabetes and BP (n = 61) compared with patients with only diabetes (n = 122) | Male aOR 4.36 (95%CI: 1.38-13.83), females 1.64 (95%CI: 0.53-5.11) | Median 8.2 mo (range 10 d to 3 yr) | 79.1 ± 7.0 yr | Favourable outcome when DPP-4is were discontinued |
| Kridin and Bergman[71], 2018 | Retrospective case-control study | Diabetes patients with BP (n = 82) vs age and gender matched control population with only diabetes (n = 328) | Male OR 4.46 (95%CI: 2.11-9.40), female OR 1.88 (95%CI: 0.92-3.86) | Median 10.4 mo (range 1.0-26.5 mo) | 79.1 ± 9.1 yr | Favourable outcome in gliptin withdrawal group |
Table 5 Emerging risk factors for development of dipeptidyl peptidase-4 inhibitor-induced bullous pemphigoid
| Risk factors | Possible risk/trigger factor1 |
| Older age (> 70 yr of age)[57,59,68] | Longer duration of DPP-4i use[64] |
| Male gender[64,71] | Patients with dementia[53,54] |
| Specific HLA like HLA-DQB1*03:01 (In Japanese population)[73] | Concomitant use of spironolactone[53] |
| Certain DPP-4i[63,64] (i.e. vildagliptin, linagliptin)2 | Chronic kidney disease[54,77] and haemodialysis[76] |
| Thermal Burn[75] |
- Citation: Roy A, Sahoo J, Narayanan N, Merugu C, Kamalanathan S, Naik D. Dipeptidyl peptidase-4 inhibitor-induced autoimmune diseases: Current evidence. World J Diabetes 2021; 12(9): 1426-1441
- URL: https://www.wjgnet.com/1948-9358/full/v12/i9/1426.htm
- DOI: https://dx.doi.org/10.4239/wjd.v12.i9.1426