Cutaneous Adverse Effects of Dipeptidyl Peptidase‑4 Inhibitors (Gliptins): A Systematic Review and Meta‑analysis with Emphasis on Bullous Pemphigoid

Dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors), commonly known as gliptins, are well-established glucose-lowering agents used in the management of type 2 diabetes mellitus. Their widespread use is driven by convenient oral administration, weight neutrality, and low intrinsic risk of hypoglycemia. Consequently, gliptins are frequently prescribed to elderly patients and individuals with multiple comorbidities, populations that are inherently vulnerable to adverse drug reactions.

Beyond their role in incretin metabolism, DPP-4, also known as CD26, is a multifunctional transmembrane glycoprotein expressed on keratinocytes, fibroblasts, endothelial cells, and a wide range of immune cells. It plays an important role in immune regulation, T cell activation, and chemokine processing. Therefore, pharmacological inhibition of DPP-4 has the potential to disrupt cutaneous immune homeostasis and alter inflammatory pathways within the skin.

Over the past decade, bullous pemphigoid (BP) has emerged as the most consistent and clinically significant cutaneous adverse drug reaction associated with exposure to gliptins. Multiple population-based cohort studies, case-control analyses, and pharmacovigilance reports from diverse geographic regions have demonstrated an increased incidence of BP in DPP-4 inhibitor users. Drug-specific differences, particularly a stronger association with vildagliptin, have been repeatedly observed, suggesting heterogeneity within the class.

In addition to BP, a spectrum of other cutaneous adverse effects, including pruritus, eczematous eruptions, urticaria, angioedema, photosensitivity, and rare severe reactions, have been reported, although these events are less well quantified at the population level. Given the expanding use of gliptins and the potential for delayed recognition of drug-induced BP, a comprehensive synthesis of the original evidence is clinically relevant.

This systematic review and meta-analysis aimed to synthesize original studies evaluating the cutaneous adverse effects of DPP-4 inhibitors and quantitatively estimate the association between gliptin exposure and bullous pemphigoid, with an emphasis on epidemiological consistency, drug-specific signals, and clinical implications.

Thirty original studies were included in the qualitative synthesis, including population-based cohorts, case-control designs, and pharmacovigilance analyses. Five population-level studies contributed to the adjusted estimates of the quantitative meta-analysis.

Additional synthesis suggested a higher relative risk among elderly patients (>65 years) and among male patients in some Asian cohorts, while sex differences were less pronounced in European datasets. Time-to-event analyses suggested risk accrual after approximately 3–12 months of continuous exposure, supporting a delayed autoimmune mechanism.

Table 1. Characteristics of key population-level studies evaluating bullous pemphigoid risk with DPP-4 inhibitors

Table 1 summarizes the principal population-level observational studies that form the epidemiological evidence base for the association between DPP-4 inhibitor exposure and bullous pemphigoid. Despite differences in study design and data sources, a consistent increase in BP risk was observed across regions and methodologies. Studies employing validated outcome definitions and active comparator designs strengthen causal inference and support the robustness of the observed association.

Table 2. Drug-wise bullous pemphigoid (BP) signal: consistency across datasets

Table 2 presents a qualitative, drug-specific synthesis of the risk of bullous pemphigoid associated with individual DPP-4 inhibitors. Vildagliptin demonstrated the most consistent and reproducible association with BP, whereas other agents showed weaker or region-dependent signals, supporting heterogeneity within the gliptin class.

Figure 2. Forest plot of bullous pemphigoid risk with DPP-4 inhibitor exposure

Figure 2 depicts a forest plot summarizing the adjusted relative risk estimates for bullous pemphigoid associated with exposure to dipeptidyl peptidase-4 inhibitors, derived from population-based cohort and case-control studies. Individual study estimates are shown as point estimates with corresponding 95% confidence intervals plotted on a logarithmic scale. The vertical dashed line represents a null effect. The pooled estimate, calculated using a random-effects model, demonstrated a significantly increased risk of bullous pemphigoid among gliptin users (pooled adjusted RR 2.26, 95% CI 1.62–3.15). Moderate between-study heterogeneity was observed (I² = 66.3%), likely reflecting differences in the study design, comparator selection, and population characteristics. Despite this heterogeneity, the direction of effect across studies was consistent, supporting a robust association between DPP-4 inhibitor exposure and bullous pemphigoid incidence.

Table 3. Subgroup patterns observed in original studies evaluating gliptin-associated bullous pemphigoid

Table 3 summarizes the consistent subgroup-level patterns reported in the original epidemiological studies evaluating gliptin-associated bullous pemphigoid. Elderly patients and those exposed to vildagliptin demonstrated the most reproducible increase in relative risk, while sex-specific associations have been predominantly described in Asian populations. Prolonged exposure appears to amplify this risk, supporting a delayed autoimmune mechanism. These findings represent a qualitative synthesis of subgroup observations and should not be interpreted as the results of a pooled subgroup meta-analysis.

Figure 3. Drug-wise relative risk trend for bullous pemphigoid among DPP-4 inhibitors

Figure 3 illustrates the relative magnitude of bullous pemphigoid risk associated with individual DPP-4 inhibitors based on adjusted effect estimates reported in original epidemiological studies. The bar graph depicts the approximate central tendencies of the reported relative risks for each agent and is intended for visual comparison rather than a pooled drug-wise meta-analysis. Vildagliptin demonstrated the highest and most consistent risk signal, followed by linagliptin, whereas sitagliptin and saxagliptin showed comparatively lower relative risks. These findings highlight the heterogeneity within the gliptin class and support drug-specific differences in autoimmune risk, potentially related to pharmacodynamic properties and tissue selectivity.

Table 4. Other cutaneous adverse drug reactions (CADRs) reported with gliptins: frequency patterns and plausible mechanisms

Table 4 summarizes the nonbullous pemphigoid cutaneous adverse drug reactions reported in association with DPP‑4 inhibitor therapy. Unlike bullous pemphigoid, these reactions are infrequently captured in population-level studies and are primarily derived from pharmacovigilance reports and individual case descriptions. The proposed mechanisms reflect the broader immunomodulatory role of DPP‑4/CD26 inhibition in the skin, including its effects on cytokine signaling, mast cell activation, and photo reactivity. Although rare, the recognition of these adverse reactions is important for the comprehensive dermatological assessment of patients receiving gliptins.

The BP signal associated with DPP‑4 inhibitors is reproducible in pharmacovigilance and population-based studies. The pooled effect suggests an approximate doubling of the BP risk, while the absolute risk remains low. Heterogeneity likely reflects differences in comparator choice, exposure ascertainment, outcome validation, and regional prescription patterns. Drug-specific differences have been repeatedly observed, with vildagliptin showing the most consistent signal [1–6,8].

Mechanistically, DPP‑4/CD26 inhibition may influence chemokine processing and immune regulation, potentially facilitating the loss of tolerance to BP180 (collagen XVII) and promoting Th2‑eosinophilic responses typical of BP. Several original clinical studies have described phenotypic differences in DPP4i‑associated BP, including reduced erythema and altered autoantibody profiles, particularly in Asian cohorts [14,15].

Nonbullous CADRs are less well quantified at the population level. Most evidence comes from case reports or pharmacovigilance studies. Nevertheless, photosensitivity to sitagliptin has been clinically described [10], and its photo reactivity has been experimentally explored [9]. Lichenoid eruptions attributed to sitagliptin have been reported [12], and severe idiosyncratic reactions, such as DRESS, have been documented [13].

Clinically, new pruritus or blistering in older patients with diabetes should prompt a review of DPP‑4 inhibitor exposure. Where BP is confirmed, interdisciplinary consideration of gliptin withdrawal is reasonable, in addition to standard dermatologic therapy.

In addition to epidemiological consistency, several temporal and clinical observations support a causal relationship between DPP‑4 inhibitor exposure and bullous pemphigoid. Multiple cohort studies have demonstrated a latency period ranging from several months to over one year after drug initiation, consistent with the gradual loss of immune tolerance. Although limited, rechallenge data further strengthen causality, with recurrence of the disease following re‑exposure reported in isolated but well‑documented cases.

The observed drug-specific heterogeneity likely reflects differences in molecular selectivity for DPP‑4 versus related enzymes such as DPP‑8 and DPP‑9, tissue penetration, and off-target immunologic effects. Vildagliptin, which shows lower selectivity and higher tissue affinity, consistently demonstrated the strongest association with BP across registries and pharmacovigilance databases. This suggests that subtle pharmacodynamic differences within the class may translate into clinically meaningful variations in autoimmune risk.

From a dermatological perspective, DPP‑4 inhibitor–associated BP may present with atypical features, including less erythema, non‑inflammatory blisters, and lower titers of BP180 NC16A antibodies in some populations. Such features may delay diagnosis, underscoring the importance of a detailed drug history in elderly diabetic patients presenting with pruritus or blistering. Early recognition and timely withdrawal of the offending agent may reduce disease severity and treatment burden.

Finally, although nonbullous cutaneous adverse reactions are relatively uncommon, their occurrence highlights the broader immunomodulatory role of DPP‑4 inhibition in skin biology. These reactions may represent a spectrum of immune dysregulation rather than isolated phenomena, reinforcing the need for continued post-marketing surveillance and mechanistic research.

Limitations

Observational designs are subject to confounding factors and misclassification. Not all datasets used active comparators, and residual confounding by indication may have persisted. Only studies reporting compatible adjusted estimates were pooled in the meta‑analysis.

Original evidence supports an association between DPP‑4 inhibitors and bullous pemphigoid, with the strongest and most consistent signal observed for vildagliptin. Other cutaneous adverse effects are less common and are mostly supported by case-level or pharmacovigilance evidence. Recognition of this association can aid in early diagnosis, appropriate drug review, and coordinated care.

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