Validation of Hemoglobin A1c in Patients With Inflammatory Arthritis Treated With Sulfasalazine

Official title

How Can We Prevent the Underdiagnosis of Diabetes and the Undertreatment of Known Diabetes in Patients With Inflammatory Arthritis Treated With Sulfasalazine?

Overview

The purpose of this study is to examine whether the blood test Hemoglobin A1c (HbA1c) gives an accurate picture of blood glucose levels in patients with inflammatory arthritis who are treated with sulfasalazine. HbA1c is widely used to diagnose and monitor diabetes, but sulfasalazine can shorten red blood cell lifespan and thereby lower HbA1c values independently of actual glucose levels. This may lead to underdiagnosis of diabetes in patients who develop diabetes during sulfasalazine treatment, and to undertreatment in patients with known diabetes due to falsely reassuring HbA1c values. The study aims to answer two main questions: 1. How many patients treated with sulfasalazine have undiagnosed diabetes despite having HbA1c values below the diagnostic threshold? 2. Does HbA1c underestimate actual glucose levels when compared with continuous glucose monitoring (CGM) in patients with sulfasalazine-treated inflammatory arthritis, both in those with known diabetes and those that are not diagnosed with diabetes but have borderline HbA1c values (≥ 38 mmol/mol)?

Detailed description

HbA1c is widely used to diagnose diabetes and to monitor long-term glycaemic control. HbA1c reflects average blood glucose levels over approximately two months but can be influenced by factors unrelated to glucose, including changes in red blood cell lifespan. Sulfasalazine, a disease-modifying antirheumatic drug commonly used to treat inflammatory arthritis, is known to cause mild haemolysis in some patients, which can lower HbA1c values independently of actual glucose levels.

This effect may have important clinical consequences. In patients without diabetes at the start of sulfasalazine treatment, HbA1c values may remain below diagnostic thresholds even if diabetes develops over time, potentially delaying diagnosis. In patients with established diabetes, sulfasalazine-associated lowering of HbA1c may give a misleading impression of adequate glycaemic control, which may result in insufficient treatment intensification despite elevated true glucose levels. Together, these mechanisms may contribute to underdiagnosis and undertreatment of diabetes in patients receiving sulfasalazine.

CGM provides direct, sensor-based measurements of interstitial glucose levels and is not affected by red blood cell turnover. CGM therefore offers an opportunity to assess actual glycaemic exposure independently of HbA1c. However, prospective data comparing HbA1c with CGM-derived glucose measures in sulfasalazine-treated patients with inflammatory arthritis are lacking.

This study is a prospective observational investigation conducted in patients with inflammatory arthritis treated with sulfasalazine. Participants include both individuals with known diabetes and individuals without known diabetes who have HbA1c values in the borderline range. Each participant undergoes a single study phase in which blinded CGM is worn for up to 14 days, with blood sampling performed within the same time period. In participants without known diabetes, fasting plasma glucose measurements are used to evaluate the presence of previously unrecognised diabetes.

By comparing HbA1c values with CGM-derived average glucose levels, the study aims to evaluate whether HbA1c accurately reflects glycaemic status in sulfasalazine-treated patients. The results are expected to improve understanding of the limitations of HbA1c in this clinical context and to inform future strategies for diabetes diagnosis and monitoring in patients receiving sulfasalazine, including the potential need for alternative or supplementary glucose assessment methods.

Primary outcome measures

• Prevalence of undiagnosed diabetes mellitus [Time frame: Within 14-21 days]

Secondary outcome measures (1)

• Agreement between HbA1c and CGM-derived mean glucose in sulfasalazine-treated patients [Time frame: Within 14-21 days]

Eligibility criteria

Inclusion criteria

• Age ≥18 years
• Treatment with sulfasalazine for at least 2 months prior to inclusion
• Inflammatory arthritis diagnosis (Reumatoid Arthritis, Reaktive Arthritis, Axial spa, Psoriatic spondylitis, and Juvenil artrit)
• HbA1c ≥38 mmol/mol obtained at least 2 months after sulfasalazine initiation OR a diabetes mellitus diagnosis (Type 1 diabetes mellitus, Type 2 diabetes mellitus, Malnutrition-related diabetes mellitus, Other specified diabetes mellitus (andre specificerede former for diabetes), and Unspecified diabetes mellitus (uspecificeret diabetes))
• Can communicate in Danish
• Informed consent including permission to upload glucose data and study ID to the Libreview Platform.

Exclusion criteria

• Systemic treatment or local injections with glucocorticoids within the previous 2 months or planned within the following 4 weeks
• Clinical conditions interfering with the interpretation of HbA1c expect for sulfasalazine alterations in red cell lifespan (etc. Dapson treatment)
• Allergy towards the adhesive used in the CGM
• Considered ineligible for participating (e.g. patients without decision-making capacity, , malignancy, terminal illness, ect.)

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

Denmark · 1 center

• Medical Diagnostic Center — Silkeborg

Publications

• Infante M, Padilla N, Alejandro R, Caprio M, Della-Morte D, Fabbri A, Ricordi C. Diabetes-Modifying Antirheumatic Drugs: The Roles of DMARDs as Glucose-Lowering Agents. Medicina (Kaunas). 2022 Apr 21;58(5):571. doi: 10.3390/medicina58050571. PMID 35629988
• Farmacies sales of drugs. eSundhed.dk [Internet]. Available from: https://www.esundhed.dk/Emner/Laegemidler/Apotekernes-salg-af-laegemidler
• Lindhardsen J, Ahlehoff O, Gislason GH, Madsen OR, Olesen JB, Torp-Pedersen C, Hansen PR. The risk of myocardial infarction in rheumatoid arthritis and diabetes mellitus: a Danish nationwide cohort study. Ann Rheum Dis. 2011 Jun;70(6):929-34. doi: 10.1136/ard.2010.143396. Epub 2011 Mar 9. PMID 21389043
• Baghdadi LR, Woodman RJ, Shanahan EM, Mangoni AA. The impact of traditional cardiovascular risk factors on cardiovascular outcomes in patients with rheumatoid arthritis: a systematic review and meta-analysis. PLoS One. 2015 Feb 17;10(2):e0117952. doi: 10.1371/journal.pone.0117952. eCollection 2015. PMID 25689371
• N'Dow SMS, Donnelly LA, Pearson ER, Rena G. In a cohort of individuals with type 2 diabetes using the drug sulfasalazine, HbA1c lowering is associated with haematological changes. Diabet Med. 2021 Sep;38(9):e14463. doi: 10.1111/dme.14463. Epub 2020 Dec 8. PMID 33236391
• Mitchell K, Mukhopadhyay B. Drug-Induced Falsely Low A1C: Report of a Case Series From a Diabetes Clinic. Clin Diabetes. 2018 Jan;36(1):80-84. doi: 10.2337/cd17-0005. No abstract available. PMID 29382985
• Tack CJ, Wetzels JF. Decreased HbA1c levels due to sulfonamide-induced hemolysis in two IDDM patients. Diabetes Care. 1996 Jul;19(7):775-6. doi: 10.2337/diacare.19.7.775. PMID 8799639
• Danish Society of Rheumatology. Rheumatoid arthritis - national clinical guideline [Internet]. [cited 2025 Aug 20].

Identifiers

NCT: NCT07416656 · 1-10-72-190-25

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗