THE POTENTIAL OF GLP-1 IN THE TREATMENT OF AUTOIMMUNE DISEASES: A REVIEW OF MECHANISMS AND CLINICAL DATA

Abstract

Introduction: Autoimmune diseases are a heterogeneous group of disorders characterized by dysregulated immune responses against self-antigens, leading to chronic inflammation and progressive organ damage. Despite advances in immunosuppressive and biologic therapies improving outcomes in conditions like systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and multiple sclerosis (MS), a subset of patients exhibit suboptimal responses or experience significant adverse effects. Additionally, access to certain biologic treatments may be limited by strict eligibility criteria. Metabolic comorbidities such as obesity, insulin resistance, and type 2 diabetes are prevalent in patients with autoimmune diseases and can exacerbate inflammation, accelerate organ damage, and diminish therapeutic efficacy. Glucagon-like peptide-1 receptor agonists (GLP-1RA), a class of drugs originally developed for type 2 diabetes and obesity, have demonstrated pleiotropic effects extending beyond glycemic control, including modulation of immune cell function, suppression of pro-inflammatory cytokine release, and improvement of endothelial function. These immunometabolic properties suggest that GLP-1RA could serve as promising adjunctive agents in managing autoimmune diseases, particularly in patients with coexisting metabolic disturbances.

Materials and Methods: The article was written based on scientific papers available on PubMed and Google Scholar

Key findings: Evidence gathered indicates that GLP-1 receptor agonists exert significant immunomodulatory and metabolic effects that may translate into clinical benefits across multiple autoimmune diseases. In psoriasis and psoriatic arthritis, where chronic Th1/Th17-driven inflammation often coexists with obesity and insulin resistance, GLP-1RA therapy has been associated with improvements in inflammatory markers and disease severity indices (such as PASI for skin lesions and DAPSA for joint disease), alongside substantial weight reduction and better glycemic control. Multiple sclerosis models and preliminary clinical observations suggest that GLP-1RA can attenuate neuroinflammation and promote neuroprotection: these agents reduce pathogenic Th1/Th17 cell activity, inhibit microglial activation, and may enhance remyelination processes, thereby potentially decreasing relapse rates and neurological damage. In systemic lupus erythematosus, a small retrospective analysis indicated that adjunctive GLP-1RA use led to significant weight loss and improved metabolic profiles without provoking new organ involvement or severe flares; notably, no acceleration of lupus disease activity was seen over short-term follow-up, aligning with GLP-1RA’s known cardiovascular and renal protective effects. (An isolated case of GLP-1RA–induced lupus has been reported, underscoring the need for vigilance.) In rheumatoid arthritis, in vitro studies on fibroblast-like synoviocytes demonstrated that GLP-1RA (e.g., lixisenatide, dulaglutide) can suppress the production of pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) and matrix-degrading enzymes (MMP-1, -3, -13) by inhibiting NF-κB and MAPK signaling pathways, thereby potentially protecting joint cartilage and bone. Early clinical studies and case series in RA patients (especially those with coexisting type 2 diabetes or obesity) reported reduced disease activity scores (DAS28), lower C-reactive protein and erythrocyte sedimentation rate levels, fewer swollen joints, and diminished morning stiffness during GLP-1RA treatment, along with the expected weight reduction and improved insulin sensitivity. In type 1 diabetes mellitus, which involves autoimmune β-cell destruction, adjunctive therapy with GLP-1RA (such as exenatide, liraglutide, or semaglutide) has shown promise in patients with residual β-cell function. These agents consistently reduced exogenous insulin requirements and facilitated modest improvements in glycemic control (including lower HbA1c and increased time-in-range on continuous glucose monitoring) while promoting weight loss. In honeymoon-phase or early type 1 diabetes mellitus GLP-1RA addition even enabled temporary insulin independence in a few cases. However, across these studies, gastrointestinal side effects were common, and a few instances of euglycemic ketosis were noted, indicating that careful patient selection and monitoring are necessary. Overall, the integration of GLP-1RA into the treatment of autoimmune diseases has yielded partial improvements in disease control and significant benefits in managing metabolic comorbidities, though these benefits are often contingent on disease severity and the presence of a metabolic-inflammatory phenotype. No evidence to date suggests that GLP-1RA can replace standard immunotherapies; rather, they function as complementary agents that address an often overlooked metabolic component of autoimmunity.

Conclusions: Autoimmune diseases remain a therapeutic challenge, as many patients achieve only incomplete remission and continue to endure disease-related damage and comorbidities under current treatment paradigms. Glucagon-like peptide-1 receptor agonists offer a novel, multidimensional approach that simultaneously targets metabolic dysregulation and immune aberrations. The current body of evidence indicates that GLP-1RA can confer additional clinical benefits – such as reducing systemic inflammation, improving disease activity metrics, aiding weight loss, and lowering cardiovascular risk – especially in patients whose autoimmune disease is compounded by obesity or insulin resistance. These agents represent a promising adjunct to existing therapies, potentially bridging a gap between metabolic syndrome management and immunomodulation in autoimmune care. However, their therapeutic impact appears to be partial and disease-specific, often providing symptomatic relief or slowing disease activity rather than inducing full remission. Limitations such as high relapse rates upon GLP-1RA discontinuation (noted in conditions like hidradenitis suppurativa and suggested by analogy in other diseases), the risk of side effects (gastrointestinal intolerance, rare immune reactions), and the absence of long-term safety data in autoimmune populations underscore that GLP-1RA are not a standalone solution. The complex interplay of immune and metabolic pathways in autoimmunity highlighted by these findings reinforces the need for further research. Well-designed, large-scale clinical trials are urgently needed to confirm the efficacy and safety of GLP-1RA across different autoimmune diseases, to determine optimal patient selection criteria, and to elucidate the mechanisms by which metabolic modulation can alter immune-driven disease courses. Such studies will pave the way for the development of more targeted and personalized treatment strategies, potentially solidifying the role of GLP-1RA as part of a multidimensional therapeutic approach to autoimmune disorders.