Impact of perioperative GLP-1 agonist use on pseudarthrosis rates following single-level anterior cervical discectomy and fusion: a propensity-matched cohort study

Introduction

Anterior cervical discectomy and fusion (ACDF) is a very common surgical intervention for cervical spine pathology, with over 150,000 procedures performed annually in the United States (1). The success of this procedure has been well-documented since its introduction by Smith-Robinson and Cloward in the 1950s (2-4). Despite technological advances in surgical technique and instrumentation over recent decades, pseudarthrosis, defined as failure to achieve solid bony fusion by 1 year postoperatively (5), continues to present a significant clinical challenge. In cervical fusion procedures, reported pseudarthrosis rates vary between 0% and 25% (6), with increased risk in multi-level procedures (7). Failed fusion can result in persistent neck pain, recurrent neurological symptoms, hardware failure, and the need for revision surgery, leading to diminished quality of life and substantial healthcare costs (8).

The cervical spine presents unique anatomical and physiological considerations that influence fusion outcomes. The distinctive vascular anatomy of the cervical vertebrae, combined with the biomechanical stresses of head and neck movement (9), creates a complex environment for bone healing. Multiple risk factors for cervical pseudarthrosis have been identified, including diabetes, smoking, osteoporosis, and poor glycemic control (10). Of particular importance is the role of microvascular disease, which can significantly impair the healing process by compromising blood supply to the fusion site. Recent research has demonstrated that diabetes-associated microvascular complications can lead to decreased bone formation and impaired osseointegration in cervical fusion procedures (11,12).

Glucagon-like peptide-1 (GLP-1) receptor agonists, initially developed for diabetes management, have recently gained attention for their potential effects beyond glycemic control. These agents have demonstrated significant improvements in vascular endothelial function and have been shown to reduce microvascular disease complications (13). Furthermore, research has identified GLP-1 receptors on osteoblastic precursor cells, with studies suggesting that GLP-1 agonists may enhance cellular viability and bone formation (14). While the impact of traditional metabolic risk factors such as diabetes and obesity on cervical fusion outcomes (15,16) has been extensively studied the potential influence of GLP-1 agonists on pseudarthrosis rates remains unexplored. Given the critical role of vascular health and bone metabolism in successful cervical fusion (17), understanding the relationship between GLP-1 agonist use and fusion outcomes could have significant clinical implications. This study aims to be the first to investigate the association between perioperative GLP-1 agonist use and pseudarthrosis rates following ACDF using a large national patient database. We hypothesize that perioperative GLP-1 receptor agonist use would reduce pseudarthrosis rates after ACDF. We present this article in accordance with the STROBE reporting checklist (available at https://jss.amegroups.com/article/view/10.21037/jss-25-142/rc) (18).

Methods

Data source

Our investigation leveraged the TriNetX platform, an aggregated electronic health records (EHRs) platform encompassing clinical information from 92 major healthcare institutions, predominantly large-scale academic medical centers. We executed our data extraction on November 14, 2024, using the TriNetX infrastructure. Permission is not needed for the use of data from TriNetX.

Ethical approval

The TriNetX platform provides de-identified patient information in compliance with Health Insurance Portability and Accountability Act (HIPAA) Privacy Rule Section §164.514(a), specifically meeting de-identification standards. Expert determination guidelines updated in December 2020 waived the need for institutional review board approval. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Patient selection

Single-level ACDFs performed between October 15, 2010, and October 15, 2022, were identified using Current Procedural Terminology (CPT) code [22551]. Lumbar and thoracic arthrodesis, multilevel ACDFs, Fusions above C2, and arthrodeses for spinal deformities were excluded using CPT codes [22633, 22630, 22632, 22610, 22590, 22634, 22600, 22595, 1004109, 22614, 1004093, 22548, 22552] and International Classification of Diseases, Tenth revision, Procedure Coding System (ICD-10 PCS) codes (0SG00JJ, 0SG03KJ, 0SG037J, 0SG00KJ, 0SG007J, 0SG00AJ). The index event was defined as the day of the single-level ACDF.

A total of 30,488 patients who underwent ACDFs were identified and grouped into cohorts based on GLP-1 agonist usage. The GLP-1 use cohort comprised patients prescribed GLP-1 agonists within 6 months before or after the date of surgery. This perioperative window was selected to capture patients actively using GLP-1 agonists during the critical bone healing period following ACDF, as the initial fusion process predominantly occurs within the first 3–6 months postoperatively, with continued remodeling extending to 1 year (18). The inclusion of the 6-month preoperative period ensures capture of patients with established GLP-1 agonist therapy at the time of surgery, while the 6-month postoperative period accounts for new prescriptions initiated in the immediate perioperative period that would still influence the bone healing cascade. GLP-1 agonist use was identified using RxNorm concept unique identifiers for dulaglutide [1551291], exenatide [60548], liraglutide [475968], lixisenatide [1440051], semaglutide [1991302], and tirzepatide [2601723].

Outcomes of interest

The primary outcome was pseudarthrosis, defined as International Classification of Diseases, Tenth revision (ICD-10) code M96.0. Outcomes were measured at 6 months, 1 year, and 2 years postoperatively between cohorts that did and did not receive GLP-1 agonists.

Statistical analysis

We conducted all analyses within the TriNetX environment. Descriptive statistics included means with standard deviations for continuous measures and counts with percentages for categorical measures. Between-group comparisons employed independent sample t-tests for continuous data and chi-square analyses for categorical data.

We performed 1:1 greedy nearest neighbor propensity score matching (PSM) to create balanced cohorts. The propensity model incorporated age, race, sex, ethnicity, body mass index (BMI), hemoglobin A1c (HbA1c), and comorbidity presence (diabetes, hypertension, nicotine dependence, osteoporosis). Age was modeled continuously. Race, sex, ethnicity, nicotine dependence, diabetes, hypertension, and osteoporosis were binary variables. BMI was categorized as (0–18.49 kg/m², 18.5–24.9 kg/m², 25–29.9 kg/m², 30–34.9 kg/m², 35+ kg/m²) (19). HbA1c categories were (<5.7%, 5.7–<6.5%, ≥6.5%) (20). Our matching algorithm utilized 0.1 pooled SD calipers for propensity scores. We calculated standardized mean differences (SMDs) to evaluate covariate balance, with SMD ≤0.1 indicating adequate matching. Outcomes were analyzed using odds ratios (ORs) with 95% confidence intervals (CIs). Statistical significance was defined as P<0.05.

BMI and HbA1c values were required for propensity matching inclusion; patients lacking these laboratory values were excluded from the matched analysis.

Results

Study population and matching

Among 28,133 total patients receiving ACDF procedures, 555 had documented GLP-1 agonist prescriptions within 6 months of surgery, while 27,578 had no GLP-1 agonist exposure at any timepoint. After PSM, we achieved balanced cohorts of 546 patients in each group (Figure 1).

Figure 1 Flowchart depicting patient selection in TriNetX database. ACDF, anterior cervical discectomy and fusion; GLP-1, glucagon-like peptide 1; PSM, propensity score matching.

Demographics of GLP-1 agonist-exposed cohort

The GLP-1 agonist-exposed cohort was 51% female with mean age of 56.5±10.5 years. Racial composition included 61.3% White and 14.2% Black or African American patients. Mean BMI was 35.3±7.9 kg/m² with mean HbA1c of 7.4±1.7%.

Demographics of non-exposed cohort

The non-GLP-1 agonist cohort was 44.1% female with mean age of 53.7±13.3 years. Racial distribution was 69.4% White and 9.8% Black or African American. Mean BMI was 29.4±6.5 kg/m² with mean HbA1c of 6.0±1.5% (Table 1).

Pseudarthrosis outcomes

Patients receiving GLP-1 agonists demonstrated significantly reduced pseudarthrosis odds at 6 months (OR: 0.60, 95% CI: 0.42–0.87), 1 year (OR: 0.65, 95% CI: 0.46–0.94), and 2 years (OR: 0.62, 95% CI: 0.44–0.86) postoperatively compared to non-GLP-1 agonist patients (Table 2).

Discussion

While recent evidence suggests GLP-1 agonists improve fusion outcomes in lumbar procedures (21), the cervical spine presents distinct anatomical and biomechanical considerations that necessitate independent investigation. Furthermore, the increasing prevalence of ACDF (22) highlights the importance of understanding the interplay between comorbidities, medications, and fusion outcomes, with the goal of preventing revision surgeries and improving outcomes. In our analysis, we observed that the use of GLP-1 agonists significantly decreased the rates of pseudarthrosis after ACDF at 6 months, 1 year, and 2 years postoperatively.

Understanding the molecular basis of GLP-1 agonist activity provides insight into their potential effects on cervical fusion outcomes. These compounds achieve their therapeutic effects through interaction with the GLP-1 receptor, which belongs to the class B G-protein-coupled receptor family (23). The widespread distribution of GLP-1 expression throughout the body, from pancreatic endocrine cells to vascular tissues, neural structures, and the gastrointestinal system, underlies its diverse physiological effects (24). When GLP-1 receptors are activated, they initiate a cascade of metabolic responses, including enhanced insulin secretion, preservation of pancreatic B-cell function, and suppression of glucagon production (25). Beyond these primary effects, GLP-1 agonists influence gastrointestinal motility and appetite regulation, leading to significant weight management benefits (26). These physiologic changes can be significant for cervical fusion procedures, where clinical evidence has established strong associations between elevated HbA1c, diabetes, increased BMI, and suboptimal surgical outcomes (27-29). Notably, our findings were statistically significant, while PSM for both BMI and HbA1c allowed us to isolate the impact of GLP-1 agonists independent of their metabolic effects. This statistical robustness suggests that the beneficial effects of GLP-1 agonists on pseudarthrosis rates likely extend beyond their established role in glycemic control and weight management.

One of the key factors mediating the success of spinal fusion procedures is healthy bone remodeling. Emerging evidence suggests that GLP-1 agonists play a significant role in bone metabolism. Recent molecular studies have revealed complex interactions between these medications and skeletal homeostasis. Of particular interest, experimental research examining liraglutide’s impact on bone density has demonstrated promising osteogenic properties through multiple cellular pathways (30). The medication engages in activating osteoblast proliferation through the Wnt and p-AMPK/PGC1α cascades, while concurrently regulating bone resorption via modulation of the OPG/RANKL/RANK pathway (30). These molecular mechanisms appear to be a class effect among GLP-1 agonists, with both liraglutide and exenatide demonstrating positive effects on bone formation in preclinical models (31-33). Exenatide was also found to downregulate sclerostin expression (34,35), a protein that normally inhibits bone formation and is frequently elevated in diabetic patients. In the context of cervical fusion, these molecular interactions may be especially significant given the unique biomechanical environment of the cervical spine. The ability of GLP-1 agonists to enhance bone formation while simultaneously regulating resorption could create optimal conditions for successful fusion in the cervical region, where the balance between bone formation and remodeling is crucial.

Multiple major clinical trials have examined how GLP-1 agonists affect cardiovascular function in type 2 diabetic populations. From eight pivotal outcome studies, five revealed meaningful decreases in composite cardiovascular endpoints encompassing cardiovascular mortality, myocardial infarction without fatality, and non-fatal cerebrovascular events (36). The trials showing cardiovascular benefit, LEADER (37), SUSTAIN-6 (38), Harmony Outcomes (39), REWIND (40), and AMPLITUDE-O (41), demonstrated variable magnitudes of protective effects, whereas ELIXA (42), EXSCEL (43), and FREEDOM (44) showed no significant cardiovascular benefit. The documented cardiovascular improvements, particularly the reduction in acute vascular events, indicate that GLP-1 agonists may beneficially affect vascular health through mechanisms independent of blood glucose regulation. This observation aligns with our findings of improved cervical fusion outcomes among patients using these medications. We propose that the vascular protective effects of GLP-1 agonists may extend to the microvasculature of the cervical spine, potentially optimizing the local environment for successful bone fusion.

Another vital component to successful cervical fusion is proper blood flow and vascularization. Research has demonstrated that GLP-1 agonists significantly enhance endothelium-dependent vasodilation through multiple mechanisms. Studies in both animal models and human subjects have shown that GLP-1 agonists improve microvascular recruitment and blood flow through endothelial nitric oxide synthase (eNOS) activation, mediated by protein kinase A signaling pathways (45-47). In human umbilical vein endothelial cells, it was shown that GLP-1 promotes angiogenesis in a dose-dependent manner (48). At the cellular level, exenatide exhibits vasculoprotective effects through increased nitric oxide production and decreased reactive oxygen species production in endothelial cells (49).

Demographic trends indicate a progressive increase in the age of patients seeking ACDF intervention (1,22). The implications of this aging patient population are significant, as advanced age brings substantial changes to vascular physiology that extend beyond traditional cardiovascular risk factors such as atherosclerosis and dyslipidemia. Of concern is the age-associated accumulation of calcium within arterial walls (50). Furthermore, aging tissues demonstrate reduced metabolic activity, manifested through diminished oxygen utilization in bone tissue and reduced vascular conductance (51). These age-related vascular changes, especially arterial calcification, contribute to reduced blood flow to bone, which is crucial for proper healing in spinal fusion surgeries (52). In vitro research has demonstrated these medications’ capacity to regulate vascular smooth muscle cell dynamics, specifically inhibiting pathological proliferation and migration while reducing vascular calcification processes (53). GLP-1 agonists have also been found to suppress calcification of aortic valve interstitial cells in vitro (54). Animal models have yielded promising results as well. Exenatide reduced atherosclerotic lesions in apolipoprotein E (ApoE) deficient mice, which is a model specifically designed to study accelerated atherosclerosis (55). Translation to human studies has further validated these findings, with clinical research demonstrating that GLP-1 agonists enhance flow-mediated vasodilation in the brachial arteries (56).

While our PSM approach controlled for key demographic and metabolic variables including age, sex, race, ethnicity, BMI, HbA1c, diabetes status, hypertension, nicotine dependence, and osteoporosis, the potential for residual confounding from unmeasured variables must be acknowledged. Several factors that may influence pseudarthrosis rates were not captured in our analysis. Specific surgical technique variations, including graft material selection (autograft versus allograft), the use and type of anterior cervical plating systems, and surgeon experience, could potentially impact fusion outcomes. Patient-specific factors such as preoperative nutritional status (particularly vitamin D and calcium levels), bone mineral density beyond clinical osteoporosis diagnosis, activity levels, and postoperative rehabilitation protocols may also serve as confounders. Additionally, concurrent medications that could affect bone metabolism, including bisphosphonates, corticosteroids, proton pump inhibitors, and anticoagulants, were not controlled for in our matching algorithm. The indication for GLP-1 agonist prescription (diabetes management versus weight loss) and the specific dosing regimens may also represent important unmeasured confounders that could influence both metabolic profiles and fusion outcomes. Future prospective studies with detailed capture of these variables would help clarify the independent effect of GLP-1 agonists on cervical fusion success.

Our findings regarding GLP-1 agonists and cervical fusion outcomes suggest multiple promising directions for future investigation. The establishment of definitive causal relationships requires prospective randomized controlled trials specifically designed for ACDF procedures. These studies should incorporate careful patient stratification based on key clinical variables, including glycemic control status, BMI, and age demographics, to identify which populations might derive maximal benefit from GLP-1 agonist therapy in the context of cervical fusion. Understanding the underlying biological mechanisms warrants dedicated laboratory investigation. Particular emphasis should be placed on examining the impact of GLP-1 agonists on the unique vascular patterns and bone healing characteristics of the cervical spine. Such research should include detailed analysis of molecular pathways specific to cervical bone formation and remodeling, as well as investigation of local microvascular responses in cervical fusion models. The distinct biomechanical environment of the cervical spine necessitates focused examination of how GLP-1 agonists might influence healing under the specific mechanical stresses encountered in this region. The durability of cervical fusion and potential long-term effects of GLP-1 agonist therapy require extended follow-up studies. These investigations should assess not only fusion stability but also evaluate the medication’s impact on adjacent segment health and overall cervical spine function over time. Such longitudinal data would provide valuable insights into the sustained benefits and any potential long-term considerations of GLP-1 agonist use in cervical fusion patients.

Limitations

This investigation has several notable methodological limitations that warrant discussion. The primary limitation stems from our reliance on ICD-10 coding for pseudarthrosis identification in cervical fusion cases. Given the variability in diagnostic criteria among surgeons, this approach may result in inconsistent reporting. To address this concern, we attempted a secondary analysis examining revision surgery rates using CPT code 22830 (revision anterior cervical fusion); however, the limited number of revision cases (fewer than 10 patients in each cohort) prevented meaningful statistical analysis. The use of diagnostic coding alone presents challenges, as it may encompass various clinical scenarios ranging from patient-reported symptoms to radiographic evidence of failed fusion or mechanical instability requiring surgical intervention.

A second significant limitation involves medication adherence data in EHRs. Recent research on GLP-1 agonist usage patterns indicates substantial variation in long-term medication compliance, with overall 1-year persistence rates of approximately 32%. Notably, adherence differs significantly by medication type, with semaglutide showing higher persistence (47.1%) compared to other agents such as liraglutide (19.2%) (57). This variability in adherence could impact the interpretation of our results.

The retrospective design introduces additional limitations regarding potential confounding factors. Despite database limitations, we could not control for several important variables, including specific surgical technique variations and postoperative management protocols. While these factors are unlikely to systematically differ between study groups, their potential impact on fusion outcomes cannot be completely discounted.

Conclusions

This investigation demonstrates that patients receiving GLP-1 agonists in the perioperative period (within 6 months before or after surgery) experienced significantly reduced rates of pseudarthrosis following ACDF at 6 months, 1 year, and 2 years postoperatively. The persistence of these findings after PSM for HbA1c and BMI suggests that GLP-1 agonists may influence cervical fusion outcomes through mechanisms beyond their established metabolic effects. While these results suggest a promising role for GLP-1 agonists in cervical fusion procedures, they must be interpreted within the context of our study’s methodological limitations. Validation through prospective randomized controlled trials is essential, particularly focusing on the specific challenges and considerations unique to cervical fusion. If confirmed, these findings could significantly impact perioperative management strategies for cervical fusion patients, especially those with metabolic comorbidities such as diabetes or obesity.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jss.amegroups.com/article/view/10.21037/jss-25-142/rc

Data Sharing Statement: Available at https://jss.amegroups.com/article/view/10.21037/jss-25-142/dss

Peer Review File: Available at https://jss.amegroups.com/article/view/10.21037/jss-25-142/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jss.amegroups.com/article/view/10.21037/jss-25-142/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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