Trelagliptin-induced polyarthritis with positive dechallenge: First reported case

INTRODUCTION

Type 2 diabetes mellitus (T2DM) imposes a substantial and growing global burden, with an estimated 589 million adults affected worldwide; India alone accounts for approximately 101 million of these cases, constituting the world’s second largest diabetic population.^[1] Dipeptidyl peptidase-4 (DPP-4) inhibitors, the “gliptins,” represent an important class of glucose-lowering agents prized for their insulin-independent, glucose-dependent mechanism of action, minimal hypoglycemia risk, and weight neutrality.^[2]

Trelagliptin is the world’s first once-weekly DPP-4 inhibitor, originally approved in Japan and more recently introduced in India, offering a pharmacokinetic profile that sustains DPP-4 inhibition exceeding 80% throughout the entire weekly dosing interval.^[3] Its long half-life (~51 h) and primarily renal excretion profile distinguish it from daily gliptins, and its once-weekly formulation offers a compelling adherence advantage, particularly in resource-constrained settings.^[3]

Despite their generally favorable tolerability, DPP-4 inhibitors carry a recognized musculoskeletal risk. In August 2015, the United States Food and Drug Administration (US FDA) issued a class-wide safety communication acknowledging severe and potentially disabling arthralgia as a reportable adverse effect requiring drug discontinuation if it develops.^[4] Subsequent case reports have implicated sitagliptin, linagliptin, vildagliptin, and teneligliptin in drug-induced inflammatory polyarthritis, suggesting a pharmacological class effect.^[5-9] However, no case of trelagliptin-associated polyarthritis has been published to date. The World Health Organization (WHO) VigiBase pharmacovigilance database, accessed in May 2026, records only six musculoskeletal and connective tissue adverse drug reactions attributed to trelagliptin globally: Back pain (n = 1), Immunoglobulin G4-related disease (n = 1), prolapsed intervertebral disc (n = 1), decreased mobility (n = 1), muscular weakness (n = 1), and seronegative arthritis (n = 1) - none classified as polyarthritis.^[10]

We report the first documented case of trelagliptin-induced polyarthritis, establishing a definite temporal link through positive dechallenge, and assess causality using the Naranjo Adverse Drug Reaction Probability Scale.^[11]

CASE REPORT

A 54-year-old male agricultural laborer of modest socioeconomic means presented to our outpatient medicine department with a 4-week history of polydipsia, polyuria, and unintentional weight loss of approximately 4 kg. He had no prior diagnosis of diabetes mellitus, rheumatological disease, or any autoimmune condition. Family history was negative for arthritis, connective tissue disorders, and diabetes. He was not receiving any prescription or over-the-counter medications. He did not consume alcohol and had no tobacco use. His body mass index was 24.1 kg/m².

Investigations confirmed T2DM: Fasting plasma glucose 232 mg/dL, 2-h postprandial glucose 374 mg/dL, and hemoglobin A1C 9.1%. General and systemic examination, including musculoskeletal assessment, was entirely unremarkable at baseline.

Given the patient’s limited financial resources and the challenge of daily medication adherence in a manual laborer with irregular working hours, once-weekly trelagliptin 100 mg was selected as an appropriate, cost-effective therapeutic option alongside metformin 500 mg twice daily and individualized lifestyle counseling. The patient was instructed to return promptly if any new symptoms emerged.

Eight days after initiating trelagliptin, the patient returned reporting acute-onset bilateral joint pain, swelling, and stiffness. The affected joints included both wrists, both knees, and both ankles. He described prolonged morning stiffness lasting approximately 75 mins. He associated the onset clearly with the days following his first trelagliptin dose, noting progressive worsening over the subsequent week. He denied any preceding infection, skin rash, ocular symptoms, oral ulcers, urethral discharge, or constitutional symptoms such as fever or significant malaise.

Physical examination revealed bilateral synovial thickening, periarticular warmth, and tenderness at the wrists, knees, and ankles, with moderately restricted range of motion in all affected joints. No subcutaneous nodules, tophi, skin rashes, nail changes, or lymphadenopathy were identified. Vital signs were stable.

Laboratory investigations demonstrated elevated inflammatory markers: C-reactive protein (CRP) 44 mg/L (reference <5 mg/L) and erythrocyte sedimentation rate (ESR) 71 mm/h (Westergren method; reference <20 mm/h). Complete blood count, renal function, hepatic function, and serum electrolytes were within normal limits. Serum uric acid was 4.5 mg/dL, excluding gout. Autoimmune serological panel, rheumatoid factor, anti-cyclic citrullinated peptide antibodies, antinuclear antibody, anti-double-stranded DNA (anti-dsDNA), and HLA-B27 were entirely negative; these investigations were performed at subsidized rates through the hospital’s welfare provisions for economically disadvantaged patients attending the outpatient department. Plain radiographs of the wrists, knees, and ankles demonstrated no erosions, joint space reduction, or periarticular demineralization.

Synovial fluid aspiration from the knee was declined by the patient owing to concerns regarding the additional procedural cost and time away from daily wage work.

The constellation of findings, acute symmetric seronegative polyarthritis with elevated acute-phase reactants, temporally coherent with trelagliptin initiation, negative autoimmune serology, non-erosive radiographs, and no alternative etiology, indicated trelagliptin as the causative agent. Trelagliptin was withdrawn immediately. Given the patient’s financial constraints, ibuprofen 400 mg three times daily (procured at minimal cost from the hospital pharmacy) was prescribed for 2 weeks for symptomatic relief. Metformin was continued, and glimepiride 1 mg once daily was added to maintain glycemic control in the interim.

Within 48 h of trelagliptin discontinuation, the patient reported meaningful improvement in joint pain and morning stiffness. By day 5, he was entirely asymptomatic with no residual joint swelling or tenderness on physical examination. Repeat inflammatory markers at day 14 confirmed full resolution (CRP 3.1 mg/L; ESR 18 mm/h). Fasting plasma glucose on follow-up was 164 mg/dL and postprandial glucose was 238 mg/dL on the revised regimen.

The patient was reviewed at 1 month and 2 months following trelagliptin cessation. He remained symptom-free with no recurrence of joint complaints at either visit, on metformin plus glimepiride. Given the patient’s clinical recovery, financial background, and his explicit disinclination to undergo a formal rechallenge, the decision was made not to reintroduce trelagliptin. The complete clinical timeline is summarized in Table 1.

Causality was formally assessed using the Naranjo Adverse Drug Reaction Probability Scale,^[11] yielding a score of 7, classifying the reaction as probable.

DISCUSSION

To the best of our knowledge, this is the first published case report of trelagliptin-induced polyarthritis. The case is characterized by acute-onset symmetric seronegative inflammatory arthritis in a temporally coherent relationship with trelagliptin initiation, complete resolution following dechallenge, and a Naranjo score of 7 (probable causality). The absence of rechallenge is an acknowledged limitation; however, the Naranjo criteria do not mandate rechallenge to achieve a probable classification, and the overall clinical picture is compelling. Likewise, synovial fluid analysis was not obtained; crystal arthropathy was considered but deemed unlikely on clinical and biochemical grounds. Metformin has no recognized association with inflammatory arthritis; no case reports of drug-induced synovitis are attributable to it in the literature, and it was continued unchanged throughout the episode without any effect on joint symptoms, further supporting trelagliptin as the causative agent.

The pharmacovigilance context is notable. The WHO VigiBase database records only six musculoskeletal adverse events for trelagliptin globally as of May 2026, with no prior case of polyarthritis.^[10] This is likely an underestimate, reflecting both the drug’s relatively recent introduction and well-recognized underreporting of adverse drug reactions in pharmacovigilance systems globally. The present case may therefore represent the first of many such reports as trelagliptin use expands across South and Southeast Asia.

The occurrence of polyarthritis with trelagliptin is consistent with the class-wide adverse effect profile of DPP-4 inhibitors. The US FDA’s 2015 class-wide safety communication explicitly acknowledged severe arthralgia with all approved DPP-4 inhibitors and recommended discontinuation if disabling joint pain develops.^[4] Subsequent case reports have documented inflammatory polyarthritis with sitagliptin,^[5,7] vildagliptin,^[6,7] linagliptin,^[8] and teneligliptin,^[9] spanning all three structural subclasses of DPP-4 inhibitors. This cross-class pattern argues that the musculoskeletal toxicity is a consequence of DPP-4 enzyme inhibition per se, rather than off-target effects of any individual molecule.

The proposed pathophysiological mechanisms are multifactorial. DPP-4 is constitutively expressed on activated T lymphocytes as the co-stimulatory receptor CD26; pharmacological inhibition may dysregulate lymphocyte co-stimulation and alter cytokine homeostasis, promoting elevated levels of pro-inflammatory mediators including interleukin-1β, interleukin-6, and tumour necrosis factor-α.^[12] In addition, DPP-4 shares structural homology with fibroblast activation protein (FAP); selective DPP-4 inhibition without equivalent suppression of FAP may disinhibit FAP-mediated cartilage invasion by synovial fibroblasts, compounded by upregulation of matrix metalloproteinases.^[13] Trelagliptin’s exceptionally long half-life (~51 h) and sustained DPP-4 inhibition throughout the weekly dosing cycle may theoretically prolong the duration of these immunomodulatory perturbations compared with daily gliptins, though comparative clinical data are not yet available.

The clinical phenotype in this case, symmetric seronegative polyarthritis with elevated acute-phase reactants but negative autoimmune serology and non-erosive radiographs, is entirely consistent with previously published DPP-4 inhibitor-induced arthritis cases.^[5-9] HLA-B27 negativity, combined with the absence of axial involvement, enthesitis, preceding infection, or extra-articular features, effectively excludes reactive arthritis and spondyloarthropathy; the symmetric peripheral large- and medium-joint distribution is also atypical for spondyloarthropathy. Drug-induced arthritis should be considered in any patient presenting with new inflammatory joint disease shortly after commencing a DPP-4 inhibitor, particularly when standard autoimmune serological workup is negative. The diagnostic approach should include detailed medication history, full autoimmune panel, serum uric acid, joint radiography, and ideally synovial fluid analysis to exclude infection and crystal arthropathy.

Several practical points deserve emphasis. First, patients of limited financial means, as in this case, present particular challenges: Procedural investigations such as synovial fluid aspiration and rechallenge under monitoring may be declined or inaccessible for economic reasons. Clinicians managing such patients should place proportionally greater weight on clinical and serological exclusion criteria. Second, trelagliptin’s once-weekly dosing means that by the time joint symptoms become prominent, a significant drug exposure has already accumulated; unlike daily gliptins, where a missed dose may provide incidental symptomatic relief (as reported in some cases), the once-weekly schedule offers no equivalent self-testing opportunity during the interval between doses. Third, given the class-wide nature of this adverse effect, substituting trelagliptin with another DPP-4 inhibitor is inadvisable; alternative antidiabetic agents, sulfonylureas, sodium-glucose cotransporter -2 inhibitors, or glucagon-like peptide-1 receptor agonists, should be considered. In resource-constrained patients, a sulfonylurea represents a particularly accessible option, as adopted in this case.

Characterizing this reaction by standard pharmacovigilance parameters: It is a Type B (idiosyncratic) reaction, as it is unpredictable from the drug’s primary pharmacodynamic action and not dose-dependent.^[14] The reaction was of moderate severity, causing functional joint impairment requiring anti-inflammatory therapy and drug withdrawal, but without end-organ damage or hospitalization. Onset was acute (within eight days of the 1^st weekly dose), and resolution was prompt (within five days of dechallenge), classifying it as acute. The absence of autoantibodies and the non-erosive radiological appearance suggest an immune-mediated but non-autoimmune mechanism, consistent with a pharmacologically driven rather than patient-specific hypersensitivity response.

CONCLUSION

Trelagliptin, the first once-weekly DPP-4 inhibitor, can cause acute seronegative polyarthritis as an adverse drug reaction, extending the class-wide musculoskeletal signal of DPP-4 inhibitors to this novel agent. Clinicians initiating trelagliptin should counsel patients about the possibility of new-onset joint pain, inquire specifically about musculoskeletal symptoms at follow-up visits, and discontinue trelagliptin promptly if inflammatory arthritis develops. Switching to an alternative DPP-4 inhibitor is not recommended; agents from a different therapeutic class should be used. Reporting such cases to national pharmacovigilance centers will be essential as trelagliptin use expands in India and other markets.