Abstract
Background/Aim: Emerging evidence suggests that sodium-glucose co-transporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) may offer neuroprotective effects. This study aimed to compare the risk of new-onset fibromyalgia between diabetic patients starting SGLT2i versus those using GLP-1RA.
Patients and Methods: A target trial emulation was conducted using the TriNetX Global Collaborative Network. Adult patients with type 2 diabetes mellitus starting use of SGLT2i or GLP-1RA were included, excluding those with prior fibromyalgia or psychiatric disorders. Propensity score-matching (1:1) was applied to demographics, comorbidities, laboratory data, and co-medications. The primary outcome was incidence of fibromyalgia. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated.
Results: After matching, 297,937 patients per group were analyzed. During follow-up, fibromyalgia occurred in 6,963 (2.3%) of SGLT2i users and 7,855 (2.6%) of GLP-1RA users. SGLT2i use was associated with significantly lower fibromyalgia risk (HR=0.896, 95% CI=0.867-0.925). Findings remained robust in sensitivity analyses, including in 1-year (HR=0.884, 95% CI=0.855-0.914), 3-year (HR=0.880, 95% CI=0.850-0.912), and 5-year (HR=0.889, 95% CI=0.860-0.918) follow-up.
Conclusion: In this large real-world cohort, SGLT2i use in diabetic patients was associated with a significantly reduced risk of fibromyalgia compared to GLP-1RA.
Introduction
Fibromyalgia is a prevalent but controversial condition that affects approximately 2-4% of the world’s population, with a higher incidence among women (1). It is one of the most widespread musculoskeletal disorders, after lower back pain and osteoarthritis (2, 3). Fibromyalgia is diagnosed based on a detailed clinical history focusing on chronic and diffuse musculoskeletal pain, sleep problems, extreme exhaustion, and cognitive dysfunction, combined with the systematic elimination of other underlying organic diseases (1, 3). The most common diagnostic criteria are the 1990 and 2010 American College of Rheumatology criteria (4, 5), and the estimated prevalence of fibromyalgia varies with these criteria (2, 6). Because of its pathophysiology, fibromyalgia syndrome has been a topic of much debate and despite considerable research, all features of its risk factors and pathogenesis are not completely understood but neurogenic inflammation, peripheral sensitization and central sensitization are considered as major contributors (1, 7, 8).
Type 2 diabetes mellitus (T2DM) is a major cardiovascular and metabolic disorder globally, with macrovascular and microvascular complications including neuropathy and inflammation (9). More specifically, approximately 60% of diabetic patients develop chronic pain, which often manifests in the form of neuropathic pain (9, 10). A recent systematic review and meta-analysis suggested that the prevalence of fibromyalgia in the general population is 1.78% and can be as high as 14.80% among patients with T2DM (6). This suggests that a possible underlying link between the two conditions warrants further investigation. Given the increasing prevalence of T2DM and the growing burden of fibromyalgia, it is critical to identify effective strategies to prevent or delay the onset of fibromyalgia in patients with T2DM is of vital importance (6, 11, 12).
In the past decade, two new classes of antidiabetic medications have emerged, sodium-glucose cotransporter 2 inhibitors (SGLT2i) and receptor agonists of the glucagon-like peptide-1 receptor (GLP-1RA) due to their pronounced cardiovascular and renal benefits independent of glycemic improvement (13, 14). These agents are often indicated for use in patients with prevalent comorbidities such as obesity, atherosclerotic cardiovascular disease, and chronic kidney disease (15). Emerging evidence suggests that both drug types may possess neuroprotective properties, particularly in neurodegenerative disorders (16-18).
Studies in animals have shown that most GLP-1RAs can penetrate the blood-brain barrier to exert direct neurophysiological effects (18, 19). Neuroprotective effects are characterized by the proliferation of neural progenitor cells, cognitive improvement, reduced deposition of amyloid-β plaques in the brain, and mitigation of neuroinflammatory response (20). Moreover, GLP-1RAs have been reported to protect neurons from cell death induced by excitotoxicity, oxidative stress, and hypoxia (21, 22).
Inhibitors of SGLT2 have a putative protective effect against diabetic peripheral neuropathy and in immune regulation (23, 24). Empagliflozin, one SGLT2i, has been shown to increase energy availability in mononeuropathy by promoting phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and counteracting active pathways that regulate pain sensitivity, including mitogen-activated protein kinase p38 and extraneous signal-regulated kinase (ERK1/2) (25, 26). Furthermore, inhibitors of SGLT2 exhibit antioxidant and anti-inflammatory properties, suppress pro-inflammatory cytokines, polarize macrophages to the M2 phenotype, and inhibit the activation of the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 1 (STAT1) and NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome (26, 27). They also improve cerebrovascular endothelial function and reduce neurovascular remodeling, thus maintaining blood-brain barrier integrity (19).
However, there is limited knowledge about the possible risk of fibromyalgia with the use of SGLT2i and GLP-1RA. To bridge this knowledge gap, we performed a nationwide population-based cohort analysis to determine the effects of SGLT2i and GLP-1RA on the risk of fibromyalgia in patients with T2DM.
Patients and Methods
Data were obtained from the TriNetX research network. This database collects de-identified laboratory data, diagnoses, procedures, socioeconomic status, lifestyles, and genomic information from patients in the collaborative health institutions. TriNetX research network has been widely used in real-world epidemiological research (28, 29). For this study, we applied the Global Collaborative Network, a subset of TriNetX comprising records from more than 100 healthcare organizations across the world. Disease diagnosis was based on the International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) (30). Medication data were classified by Anatomical Therapeutic Chemical codes (31). Both coding systems are integrated into the TriNetX platform and detailed in Table I. This study was approved by the Institutional Review Board of Chung Shan Medical University Hospital (CS1-25003) and no direct interaction or intervention with human participants was involved in this study.
Definition of diseases, interventions and covariates of this study.
This study emulated the conditions of a randomized controlled trial through the propensity score-matching (PSM) process and following a target trial framework with observation data. The comparison between the target and emulated trials are presented in Table II. The study enrollment period was between January 01, 2015, to December 31, 2021. We defined the cohort index date as the prescription of SGLT2i or GLP-1RA and being diagnosed of diabetes, with the record of visiting healthcare institutions. Eligible participants involved adult patients aged ≥18 years with underlying T2DM (ICD-10-CM codes E11). Exclusion criteria included patients with previous neoplasm, end-stage kidney disease, depressive episodes, anxiety, dissociative, stress-related, somatoform, and other nonpsychotic mental disorders or fibromyalgia before or on the index date. Two treatment groups were allocated. The SGLT2i group comprised users of SGLT2i without prior GLP-1RA use before or on the index date. Similarly, the GLP-1RA group included users of GLP-1RA, and those who had prior SGLT2i use were excluded. The primary outcome was defined as incident fibromyalgia, classified as ICD-10-CM code M79.7. The follow-up period began at the point of treatment assignment and concluded upon the earliest occurrence of fibromyalgia.
Description and comparison of the target trial and the emulated trial using real-world data.
The primary analysis focused on measuring the outcomes based on the group assignment at the beginning of the study. Sensitivity analysis applying different wash-out periods (1 or 2 months) and follow-up periods (1, 3, and 5 years) were also applied. Stratification analysis was performed on subgroups by sex and age to assess the risk of new-onset fibromyalgia of the two treatment groups.
Propensity score-matching of 1:1 (shown in Table III) was utilized to construct a study population where the probability of being assigned to a specific treatment would be evenly distributed between and similar for the groups. Covariates in the analysis included age at index, sex, race, body mass index, comorbidities (including cardiovascular comorbidities, autoimmune comorbidities), co-medication use (acetaminophen, nonsteroidal anti-inflammatory drugs, triptans), smoking status, alcoholism and substance use, medical utilization status and socioeconomic status (problems related to housing and economic circumstances, persons with potential health hazards related to socioeconomic and psychosocial circumstances). The standardized mean difference was set to 0.1 to assess the covariate balance. A standardized mean difference greater than 0.1 was considered indicative of a significant difference between the groups. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to estimate the fibromyalgia risk. All statistical analysis was based on the analytic function of the TriNetX network.
Baseline characteristics of patients with type 2 diabetes mellitus using sodium-glucose cotransporter 2 inhibitor (SGLT2i) and glucagon-like peptide-1 receptor agonist (GLP-1RA), before and after propensity score-matching.
Results
Characteristics of the patient cohort. A total of 356,141 patients in the SGLT2i and 367,820 patients in the GLP-1RA groups met the inclusion criteria after applying the exclusion criteria. After PSM, both groups comprised 297,937 patients each.
Before PSM, the mean age of the patients in the SGLT2i group was 59.4±12.1 years compared to 57.2±12.8 years in the GLP-1RA group. The proportion of female patients was 56.4% and 46.3%, respectively. Furthermore, comorbidities such as being overweight/obese, ischemic heart disease, and heart failure, as well as co-medications such as selective serotonin reuptake inhibitors, insulin, and analogs, were imbalanced between the two groups.
After PSM, the baseline characteristics of the SGLT2i and GLP-1RA groups became more homogeneous, with all significant mean difference for the variables except body mass index being <0.1 (Table III). In both cohorts, approximately 44% of the patients were women. Most of the patients were White, comprising 59.1% of the SGLT2i group and 58.7% of the GLP-1RA group.
Outcomes. The incidence of new-onset fibromyalgia was 6,963 cases (2.3%) in the SGLT2i group and 7,855 cases (2.6%) in the GLP-1RA group (Figure 1). Patients in the SGLT2i group showed a significantly lower risk of developing fibromyalgia compared to those in the GLP-1RA group, with a HR of 0.896 (95% CI=0.867-0.925).
Risk of fibromyalgia in users of sodium-glucose cotransporter 2 inhibitor (SGLT2i) versus users of glucagon-like peptide-1 receptor agonist (GLP-1RA). CI: Confidence interval; HR: hazard ratio.
In the original dataset, use of SGLT2i showed an even greater risk reduction (HR=0.710, 95% CI=0.689-0.731). The reduced risk of fibromyalgia in the SGLT2i group compared to the GLP-1RA group remained consistent in all follow-up periods. As shown in Figure 1, the HR for new-onset fibromyalgia in the SGLT2i group was 0.884 (95% CI=0.855-0.914) at 1 year, 0.880 (95% CI=0.850-0.912) at 3 years, and 0.889 (95% CI=0.860-0.918) at 5 years.
When stratified by different washout periods, the HR for SGLT2i users in a 1-month wash-out window was 0.885 (95% CI=0.856-0.915), and for a 2-month washout window, the HR was 0.884 (95% CI=0.855-0.914), while comparing with GLP1-RA users. These findings suggest that variations in the washout periods had minimal impact on the results.
Stratified analysis results. Table IV summarizes the stratified analysis of the risk of fibromyalgia after PSM, comparing SGLT2i and GLP-1RA groups by sex and age. In all subgroups, the SGLT2i group demonstrated a potential protective effect, with a consistently lower risk of fibromyalgia compared to the GLP-1RA group.
Age and sex stratification of fibromyalgia risk in 5-year follow-up of patients using sodium-glucose cotransporter 2 inhibitor (SGLT2i) and glucagon-like peptide-1 receptor agonist (GLP-1RA).
Among male patients, the HR for fibromyalgia was 0.911 (95% CI=0.836-0.992), while for female patients, it was 0.900 (95% CI=0.865-0.935). Similarly, the protective effect was slightly more pronounced in older patients. For patients aged 18 to 64 years, the HR was 0.911 (95% CI=0.872-0.952), while for those aged ≥65 years, the HR was 0.865 (95% CI=0.823-0.910).
Discussion
This target trial emulation study used a large-scale global electronic health record database to evaluate the impact of SGLT2i and GLP-1RA on the risk of fibromyalgia in patients with T2DM. The results showed that the risk of fibromyalgia was significantly lower among patients using a SGLT2i than among those receiving a GLP-1RA. The primary results were supported by sensitivity and subgroup analyses that reinforce the robustness of the observed associations. Furthermore, these results suggest that the use of SGLT2i may serve to manage the range of underlying pathophysiological processes involved in fibromyalgia beyond glycemic control.
The high prevalence of fibromyalgia among patients with T2DM may be related to chronic hyperglycemia-mediated neuropathology, systemic inflammation, immune dysregulation, endocrine disorders, and psychological health status (13, 32). The pathophysiological mechanism of fibromyalgia is complicated, but studies indicate an association between excessive oxidative stress and immersion inflammatory response related to T2DM with severe fibromyalgia (3, 33). Furthermore, metabolic syndrome and obesity, along with intestinal microbiota dysbiosis, potentially represent overlapping pathogenic pathways linking T2DM and fibromyalgia, ultimately driving immune system activation (34, 35). Neuroprotective effects of SGLT2i and GLP-1RA in animal models, especially in the treatment of diabetic peripheral neuropathy (25, 36). However, direct comparative studies that analyze their impact on fibromyalgia risk are scarce. The differences in fibromyalgia risk between patients treated with SGLT2i and those treated with GLP-1RA observed in our study may be attributed to their different pharmacological mechanisms, including modulation of inflammatory pathways, neuroprotection, and metabolic regulation.
Fibromyalgia has a pathophysiological basis that includes central and peripheral sensitization, resulting in reduced pain tolerance and increased neuronal excitability (3, 33). Peripheral sensitization is largely determined by chronic inflammation, oxidative stress, and metabolic dysregulation, which jointly modify nociceptive transmission and neuroplasticity (3). Inhibitors of SGLT2 have been shown to affect these pathophysiological processes through several mechanisms, potentially preventing the development of fibromyalgia in patients with T2DM.
Firstly, inhibitors of SGLT2 activate AMPK, a master regulator of energy metabolism that exerts protective actions against oxidative stress (25, 37). AMPK activation has been established to inhibit both the p38 mitogen-activated protein kinase and the ERK1/2 signaling pathways, which play a pivotal role in mediating chronic pain and neuroinflammation (37). SGLT2i may blunt the activation of these inflammatory cascades, reducing neuronal hypersensitivity, ultimately resulting in increased pain thresholds and attenuation of nociceptive amplification (38, 39). inhibitors of SGLT2 also improve macrophage switching from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype and inhibit the activity of nuclear factor kappa B p65 (40). This in turn inhibits the secretion of pro-inflammatory cytokines such as interleukin-1β (IL1β), tumor necrosis factor-α, and IL6, which contributes to chronic inflammation of the nervous system and the exacerbation of pathological pain perception (40, 41).
Second, inhibitors of SGLT2 can also influence fibromyalgia pathophysiology by modulating the mammalian target of rapamycin (mTOR) signaling pathway, which is a key regulator of autophagy and neuronal homeostasis (42, 43). Inhibition of mTOR upregulates activation of two key autophagic molecules, UNC-51-like kinase 1 and BECLIN1, which enhances the autophagic process, leading to neuronal repair and synaptic remodeling (44). This mechanism may promote better neuroplasticity and neuronal stability, reducing the maladaptive changes associated with chronic pain states in fibromyalgia (26).
Furthermore, the use of SGLT2i can have neuroprotective effects through the regulation of matrix metalloproteinases (MMPs), which are important in neuroinflammation and neurodegeneration (45). SGLT2i directly regulates the miR-21-reversion inducing cysteine rich protein with kazal motifs (RECK) axis to inhibit the expression of MMP2 and MMP9 (45, 46). Overactivation of MMPs has been associated with neurodegenerative processes and neuronal damage, triggering persistent pain signaling (47, 48). Inhibitors of SGLT2 may mitigate neuroinflammation, prevent neurovascular injury, and ultimately prevent the potentiation of pathways promoting pain signaling pathways underling fibromyalgia through up-regulation of the endogenous MMP inhibitor RECK (39, 45).
These pathways cumulatively play a role in dampening chronic neuroinflammation and peripheral sensitization, which may explain the reduced incidence of fibromyalgia seen among users of SGLT2i in patients with T2DM in this study.
Fibromyalgia is closely associated with anxiety, depression, and sleep disturbances (3, 33, 49). Inhibitors of SGLT2 significantly improve quality of life in patients with T2DM, including physical function, emotional role, vitality, mental health, pain, and general perception of health (50). Studies have indicated that SGLT2is can modulate the tryptophan-kynurenine pathway, increasing serotonin synthesis, thus improving mood and emotional well-being in patients with fibromyalgia (51-53). Furthermore, SGLT2i use may promote neuroplasticity through modulation of the mTOR signaling pathway, further improving emotional and cognitive function while reducing pain perception (53). Furthermore, a Mendelian randomization analysis demonstrated an inverse association between SGLT2i use and insomnia, as well as a positive association with a prolonged duration of sleep (54). These findings underscore the multifactorial benefits of SGLT2i beyond glycemic control.
Recent studies have shown that GLP-1Rs are widely distributed throughout the central nervous system, including the hippocampus, cerebral cortex, hypothalamus, spinal cord, and cerebellum (21). Several studies have indicated that GLP-1RA can exert beneficial potential effects on the brain through multiple mechanisms, such as modulating neuroinflammation and promoting cell survival (21). In vitro studies have also found that GLP-1RAs can protect neurons from glutamate-induced cell necrosis, Fe2+, and hypoxia (55). Furthermore, animal experiments have demonstrated that intrathecal injection of GLP-1RA can effectively alleviate formalin-induced peripheral nerve injury, as well as cancer and diabetes-related pain, without causing serious adverse reactions (56, 57). Wu et al. elucidated that after exenatide stimulation of GLP-1Rs in microglia, the cyclic adenosine monophosphate, protein kinase A, p38 beta mitogen-activated protein kinase, and cAMP response element-binding protein signaling pathways can be activated, thereby promoting the expression of IL10 (58-60). The IL10 receptor/signal transducer and activator of transcription-3 signaling pathway is subsequently activated autocrinally within microglia, promoting the expression and release of β-endorphin, which acts on μ-opioid receptors of neurons, producing analgesia and neuroprotection (59, 60).
The present investigation has a strength in that a target trial emulation framework was implemented to approximate the salient features of randomized controlled trials, thereby bolstering the capacity for causal inference within the observational study design. However, some limitations must be acknowledged. Firstly, this was a retrospective study, and potential residual confounders, including lifestyle, dietary habits, and stress levels of patients can influence the risk of fibromyalgia. Secondly, the limitations in directly assessing adherence to medication use in the database require future prospective studies to validate the findings of the present study. Thirdly, this study primarily examined patients with T2DM who were confirmed to have diabetes through tests, allowing future studies to consider the extended effect of SGLT2i in patients with non-diabetic fibromyalgia. Lastly, occupational risk factors were not available in the data acquired through the TriNetX platform.
In conclusion, these findings reveal that patients treated with SGLT2i have a significantly lower risk of developing fibromyalgia than those treated with GLP-1RA. These findings are of clinical relevance in the selection of antidiabetic medications and open new avenues for future fibromyalgia treatment strategies. Further studies should explore the potential therapeutic applications of SGLT2i in fibromyalgia and evaluate long-term safety and efficacy. Furthermore, exploring the combination therapy of SGLT2i and GLP-1RA might reveal synergistic effects that could provide broader therapeutic benefits to patients at risk of fibromyalgia.
Footnotes
Authors’ Contributions
All the Authors were involved in drafting or revising the article and approved the submitted version. Study conception and design: Jhang YS, Lu HY, Lin CY, Lee CY, Su YJ, Chang HC, Chen SJ and Gau SY. Data acquisition: Jhang YS and Gau SY. Data analysis and demonstration: Jhang YS and Gau SY. Original draft preparation: Jhang YS, Lu HY, Lin CY, Lee CY, Su YJ, Chang HC, Chen SJ and Gau SY.
Data Sharing Statement
Data in this study were retrieved from TriNetX Research Network. All data available in the database were administrated by the TriNetX platform. Detailed information can be retrieved at the official website of the research network (https://trinetx.com).
Conflicts of Interest
All Authors declare that no potential conflicts of interest exist.
Funding
This study was funded by Chung Shan Medical University Hospital (CSH-2025-A-013).
Artificial Intelligence (AI) Disclosure
During the preparation of this manuscript, a large language model (ChatGPT 4o, OpenAI) was used solely for language editing and stylistic improvements in select paragraphs. No sections involving the generation, analysis, or interpretation of research data were produced by generative AI. All scientific content was created and verified by the authors. Furthermore, no figures or visual data were generated or modified using generative AI or machine learning-based image enhancement tools.
- Received June 19, 2025.
- Revision received July 10, 2025.
- Accepted July 17, 2025.
- Copyright © 2026 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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