Patients with Sjögren disease and type 2 diabetes who take metformin show less severe clinical and pathological symptoms—including reduced lymphocytic infiltration in salivary glands—than those not taking the medication, according to a retrospective case-control study presented at the International Symposium on Sjögren’s Disease in Paris, France, Medscape reported.
Analysis in the Discovery Cohort
R. Hal Scofield, MD, a professor in the Arthritis and Clinical Immunology Research Program at the Oklahoma Medical Research Foundation in Oklahoma City, and his colleagues examined records for 459 patients at the foundation’s sicca assessment clinic. The initial analysis focused on 31 patients with both Sjögren disease and type 2 diabetes who were taking metformin. Researchers matched each of these individuals with four patients who had Sjögren disease but not diabetes, creating a comparison group of 124 people matched by age, sex, and race or ethnicity.
Patients taking metformin had a mean salivary gland focus score of 1.88, compared with 3.26 for the matched Sjögren group. Only 16% of the patients taking metformin recorded a focus score greater than 3, versus 40% of the matched control patients. Objective tests for eye dryness yielded similar differences. Patients taking metformin exhibited a 60% lower odds of a positive Schirmer test, 66% lower odds of a positive van Bijsterveld score, and 76% lower odds of a positive ocular staining score when compared against the matched Sjögren cohort.
External Validation in an Independent Cohort
To test these findings outside the Oklahoma center, researchers evaluated data from an independent cohort maintained by the National Institute of Dental and Craniofacial Research. This external group included 26 patients with Sjögren disease taking metformin and 394 patients with Sjögren disease and no diabetes who were not taking the drug. Biopsy focus scores and van Bijsterveld scores remained significantly lower in patients taking metformin across both the Oklahoma Medical Research Foundation and National Institute of Dental and Craniofacial Research groups. A subsequent meta-analysis combining data from both cohorts confirmed the association between metformin use and lower biopsy focus scores as well as lower van Bijsterveld scores.
Caution and Limitations From Independent Specialists
Teja M. Kapoor, MD, associate professor of medicine in rheumatology and director of the Columbia Sjögren’s Center at Columbia University Irving Medical Center in New York City, who was not involved in the study, described the results as an interesting and hypothesis-generating signal. However, Kapoor urged clinicians to interpret the data cautiously. She noted that the cross-sectional design means the study cannot establish whether patients experienced symptom improvement after starting metformin, nor does it clarify how long patients had taken the drug before undergoing biopsies and eye testing.
Additional analysis revealed several secondary outcomes that did not favor metformin use, including unstimulated salivary flow and specific glandular domain scores evaluated by the European Alliance of Associations for Rheumatology Sjögren’s Syndrome Disease Activity Index. A significantly higher percentage of patients taking metformin exhibited an elevated erythrocyte sedimentation rate compared with matched controls, an outcome the current data do not explain. Kapoor emphasized that randomized controlled trials are necessary before determining whether metformin can treat Sjögren disease or prevent its complications.
Common Questions About Metformin and Sjögren Disease
What biological mechanisms might explain metformin’s effect on Sjögren disease?
Scofield noted that metformin appears to downregulate the activity of the signal transducer and activator of transcription 4 protein, which modulates the immune system in an anti-inflammatory direction. The drug may also improve mitochondrial function to reduce inflammation and has demonstrated increased salivary production via calcium signaling in animal models. PMC research published separately also indicates that metformin activates AMP-activated kinase, which suppresses effector T cells and regulates B cell differentiation.
Should newly diagnosed patients with Sjögren disease immediately start taking metformin?
Both Scofield and Kapoor agreed that it is premature to recommend metformin for all patients with Sjögren disease. Scofield indicated he might lean toward prescribing metformin for a newly diagnosed Sjögren patient who also has diabetes, but both researchers stressed that definitive guidance requires prospective, randomized controlled trials.
How did the study control for the presence of diabetes in its comparisons?
Researchers used multiple comparison groups, including patients with Sjögren disease and diabetes who were not taking metformin, patients with diabetes and Sjögren regardless of metformin status, and patients with Sjögren without diabetes.
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