Dipeptidyl peptidase-4 inhibitor-induced autoimmune diseases: Current evidence

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)

AD: Autoimmune disease; aHR: Adjusted hazard ratio; CI: Confidence interval; DPP-4i: Dipeptidyl peptidase-4 inhibitor; HR: Hazard ratio; IBD: Inflammatory bowel disease; MS: Multiple sclerosis; OR: Odds ratio; PRR: Proportional reporting ratio; RA: Rheumatoid arthritis; SLE: Systemic lupus erythematosus; T2DM: Type 2 diabetes mellitus.