The past decade has seen a meteoric rise in the popularity of glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) in the United States. The US Food and Drug Administration (FDA) first approved the GLP-1RA liraglutide in 2014 to treat type 2 diabetes (T2D), followed by the approval of semaglutide in 2021 to manage individuals with obesity or overweight with at least 1 weight-related comorbidity.¹

Around 1 million new individuals began using GLP-1s in the US between 2011 and 2023. Over this period, researchers reported a decreasing trend in the percentage of new individuals using GLP-1s for T2D and an increasing trend among those with obesity or related conditions who did not have T2D.¹ Between 2019 and 2023, the use of GLP-1s for obesity or overweight in the absence of T2D rose by more than 700%.²

Off-label use of GLP-1s for conditions other than the designated FDA-approved indications also rose from 0.21% in 2019 to 0.37% in 2023.¹ This trend suggests that weight-loss medications may have an impact beyond obesity and diabetes.

The Intersection of Obesity and Rheumatic Disease

Obesity increases the risk of developing many chronic health conditions, including rheumatic and musculoskeletal diseases (RMDs). An estimated 7 out of 10 adults with RMDs live with overweight or obesity. While obesity is a risk factor for developing RMDs, it also worsens disease activity, pain, and fatigue and impairs treatment response, resulting in declining quality of life and physical function.³

While they are not curative, weight loss medications may represent a future paradigm shift in managing inflammation and improving outcomes and quality of life among patients with rheumatic diseases.

The association between obesity and rheumatic disease begs the question: Do weight loss medications such as GLP-1s carry the potential to modify disease activity, boost treatment responsiveness, and improve quality of life among individuals with RMDs?

Pathophysiological Implications of Obesity

Excess adipose tissue promotes systemic inflammation and insulin resistance that can progress to T2D, increases blood pressure and biomechanical stress on the cardiovascular system, and can alter hemodynamics in such a way that accelerates progression to chronic kidney disease or heart failure.³

Other biomechanical ramifications of obesity include increased joint stress, loading, and pain, as well as reduced activity tolerance. Consequently, affected persons are less likely to lose weight by exercising, thus accelerating development of osteoarthritis (OA).³ Limited adherence and reduced access impact the effectiveness of traditional approaches to weight loss among this patient population, such as lifestyle modifications through exercise programs and bariatric surgery.

Endothelial cells and perivascular mesenchymal stromal cells promote local inflammation of adipose tissues. Inflamed adipose tissues release inflammatory mediators — such as tumor necrosis factor (TNF) and interleukin 6 (IL-6) — which promote the transition from local to systemic inflammation by stimulating the recruitment and activation of proinflammatory immune cells such as macrophages, neutrophils, natural killer cells, and cytotoxic CD8+ T cells. Activated immune cells also release proinflammatory cytokines such as interferon gamma (IFN-γ) and interleukin 1-beta (IL-1β), which in turn perpetuate a vicious proinflammatory cycle. Thus, innate biological immune responses trigger chronic inflammation of adipose tissue.⁴

Metabolic inflammation — also termed meta-inflammation⁵ or metaflammation⁶ — describes the chronic, low-grade, systemic inflammation associated with obesity-driven metabolic dysfunction. The enhanced macrophage activity associated with obesity has been posited to play an underlying role in the pathogenesis of meta-inflammation.⁵ Autoimmune processes have been linked to altered metabolic functioning of immune cells and dysregulation of the immune response, promoting damage to healthy tissues, inflammation, and the development of autoimmune conditions.⁷

Effects of Obesity on Treatment Responsiveness

Obesity also has implications for the effectiveness of disease-modifying biologics used to treat several RMDs, including rheumatoid arthritis (RA), psoriatic arthritis, or axial spondyloarthritis. According to a systematic review of the literature published by Gialouri et al in 2023, obesity and higher body mass index (BMI) negatively affected response to treatment with biologic disease-modifying antirheumatic drugs (DMARDs), particularly reducing the efficacy of TNF inhibitors used to treat all forms of inflammatory arthritis.⁸

Based on their research, the study the authors concluded, “Weight/BMI should be considered in the treatment plan of [patients with inflammatory arthritis], with its effects being more pronounced for TNF-inhibitors compared to other [biologic/targeted-synthetic] DMARDs.”⁸

Potential Benefits of Weight Loss Medications for Rheumatic Diseases

Results of in-vitro research studies have suggested that GLP-1s can inhibit the inflammatory response and the modulate the immune response via suppression of inflammatory cytokines such as IFN-γ, IL-1β, IL-6, and TNF-β. In-vivo murine studies have shown that semaglutide reduces plasma concentrations of proinflammatory cytokines, which in turn decreases recruitment and activation of immune cells that promote systemic inflammation.⁹

Results of a murine study by Wu et al showed that the GLP-1RA exendin-4 significantly improved glucose uptake, formation of type 1 skeletal muscle fibers, and mitochondrial respiration. These findings suggest that GLP-1RAs may be beneficial in regulating skeletal muscle remodeling and may help to improve exercise endurance via activation of the GLP-1 receptor (GLP-1R) /AMP-activated protein kinase signaling pathway.¹⁰

Most preliminary studies on GLP-1RAs in rheumatic diseases have been conducted among individuals with OA, RA, and certain connective tissue diseases such as lupus and Sjögren syndrome.¹²

Osteoarthritis

Targeting the GLP-1/GLP-1R axis may be particularly beneficial for individuals with OA. Glucagon-like peptide-1 receptors are expressed in chondrocytes, macrophages, and adipocytes, as well as in cells involved in bone destruction and renewal including osteoblasts, osteocytes, osteoclasts, and bone marrow stem cells.¹¹ Glucagon-like peptide-1 receptor agonists decrease sclerostin (an inhibitor of bone formation) and bone resorption while increasing bone formation and the ratio of osteoprotegerin to receptor activator of nuclear factor kappa-B ligand.¹²

Glucagon-like peptide-1 receptor agonists bind to GLP-1 receptors, resulting in inhibition of cytokine secretion into the synovial fluid, which decreases local inflammation and indirectly inhibits the nuclear factor-kappa B pathway. This allows for macrophage phenotypes to switch from pro- (M1) to anti- (M2) inflammatory. Decreased local joint inflammation may help to reduce OA-related pain sensitivity.¹¹  

Glucagon-like peptide-1 analogues can also mediate OA nociceptive pain by binding to GLP-1Rs located on dorsal root ganglion neuron endings in the affected joint’s synovium. Decreased local inflammation can also have downstream effects that reduce multiple OA-associated processes such as oxidative stress, secretion of degradative mediators, and impairment or destruction of joint cells via apoptosis or senescence.¹¹ Specifically, GLP-1RAs decrease type 2 collagen degradation and downregulate production of matrix degrading enzymes.¹²

Zhu et al conducted a prospective, multicenter study involving 1807 adults aged at least 45 years with knee OA and comorbid T2D. Of these patients, 233 received GLP-1RAs while the remaining 1574 did not. The researchers reported that the GLP-1RA cohort demonstrated increased weight loss, lower incidence of knee surgery, and lower velocity of cartilage loss in the medial tibiofemoral joint compared with the non-GLP-1RA cohort. The GLP-1RA cohort also had statistically significant decreases in Western Ontario and McMaster Universities Osteoarthritis Index total and pain subscale scores compared with baseline measurements. These findings indicated that GLP-1RAs may effectively modify disease-related processes among individuals with OA.¹³

Rheumatoid Arthritis

Glucagon-like peptide-1 receptor agonists also may produce similar beneficial effects among individuals with RA, including decreased synovial inflammation, decreased production and secretion of proinflammatory cytokines, and decreased joint damage.¹⁴

The use of GLP-1RAs has been shown to reduce RA disease activity and pain levels, as well as improve cardiovascular risk profiles among this patient population. In a retrospective review by Kellner et al, patients with RA who received GLP-1RA treatment achieved significantly greater reductions in body weight, total and low-density lipoprotein cholesterol, triglycerides, erythrocyte sedimentation rate, glycosylated hemoglobin, and C-reactive protein when compared against an untreated group with RA. However, gastrointestinal adverse effects led to discontinuation of GLP-1RAs among almost one-third of patients.¹⁵

Lupus

Preliminary retrospective studies among individuals with systemic lupus erythematosus have suggested that GLP-1RAs may decrease BMI without triggering flares.¹⁶ Treatment may also decrease the risk for mortality and acute myocardial infarction among patients with lupus nephritis, as well as reduce the progression of chronic kidney disease.¹⁷

Sjögren Syndrome

Glucagon-like peptide-1 receptor agonists may protect glandular epithelial tissue among individuals with Sjögren syndrome via inhibition of apoptosis, immune cell infiltration, and lysosomal dysfunction.¹²

Potential Adverse Effects of GLP-1RAs

The most frequently reported adverse effects of GLP-1RAs are gastrointestinal complaints: nausea, vomiting, diarrhea, constipation, and abdominal discomfort due to delayed gastric emptying and modulation of central appetite. Gastrointestinal side effects are usually dose-dependent and often decrease over time.¹²

Other concerning side effects include worsening of diabetic retinopathy, tachycardia, and hypoglycemia, with the latter especially of concern among individuals receiving treatment with insulin and sulfonylureas. Potential associations between GLP-1RAs and acute pancreatitis, thyroid C-cell hyperplasia, and medullary thyroid carcinoma are also worrisome and may prompt contraindication of GLP-1RA use among individuals with certain personal or family medical histories.¹² 

Another valid concern related to the long-term use of GLP-1RAs is the potential loss of skeletal muscle mass, which may worsen existing sarcopenia, cachexia, or frailty among older individuals or those with specific chronic conditions. Monitoring body composition among individuals taking GLP-1RAs and countering these side effects with structured exercise, nutritional programs, or other medications can help preserve muscular integrity and physical function.¹⁸

Promising, But Cautious Optimism

While they are not curative, weight loss medications may represent a future paradigm shift in managing inflammation and improving outcomes and quality of life among patients with rheumatic diseases. Rigorous, high-quality research and multidisciplinary collaboration are essential for defining their true role and safety/efficacy profiles in each specific disease.