INTRODUCTION
Cubital tunnel syndrome (CuTS), resulting from ulnar nerve compression at the elbow, is the second most common compressive neuropathy of the upper extremity, with an estimated annual incidence ranging from 25 to 30 per 100,000 persons [1,2]. This condition can cause substantial pain, sensory loss, and motor weakness in the hand, leading to functional impairment. Surgical cubital tunnel release (CuTR) is a common intervention used to decompress the ulnar nerve, alleviating symptoms and restoring function. While surgical decompression is often successful, a significant proportion of patients experience unsatisfactory outcomes, including recurrent symptoms. Negative outcomes have been reported in 10% of moderate compression cases following CuTR and in up to 35% of severe cases [3]. Revision surgery rates have been reported to be approximately 7%, with some studies indicating higher rates of up to 18% within 5 years [4,5].
Type 2 diabetes mellitus (T2DM) is a well-established risk factor for various peripheral neuropathies, including CuTS [6,7]. The prevalence of ulnar neuropathy at the elbow in diabetic patients has been reported to be around 2.1%, up to four times the rate in the general population. It is often more challenging to diagnose and manage CuTS in the context of underlying diabetic polyneuropathy compared to that in non-diabetic patients [7]. Patients with T2DM may experience a higher incidence and greater severity of ulnar neuropathy, potentially leading to less favorable outcomes after CuTR compared to non-diabetic individuals. Stirling et al. [8] found that, while patient satisfaction remained high, diabetic patients did not achieve the same level of functional improvement (as measured by shortened disabilities of the arm, shoulder and hand questionnaire [QuickDASH] scores) after CuTR as their non-diabetic counterparts.
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are a class of medications with rapidly growing popularity in the management of T2DM, with beneficial effects on blood pressure and cholesterol. In conjunction with or without first-line metformin, these drugs have more desirable properties than alternative forms of glycemic control, which can result in bodyweight increase (thiazolidinediones, sulfonylureas, and insulin), hypoglycemia (sulfonylureas, repaglinides, and insulin), or gastrointestinal side effects (metformin and alpha glucosidase inhibitors). Beyond primary effects on glycemic control and weight reduction, GLP-1RAs exhibit several pleiotropic properties that may be beneficial in the context of nerve injury and surgical recovery [9]. Preclinical studies have demonstrated neuroprotective properties, including the promotion of Schwann cell proliferation and migration, modulation of macrophage polarization toward the anti-inflammatory M2 phenotype, reduction of oxidative stress, and enhancement of axonal regeneration. These mechanisms suggest that GLP-1RAs limit fibrosis, reduce neuroinflammation, and promote nerve repair, potentially improving outcomes after peripheral nerve surgery [10-13]. Their adverse-effect profile is more frequent at higher doses, and most such effects are gastrointestinal in nature (nausea, vomiting, constipation or diarrhea) or involve hypoglycemic risk. Rare complications include gallbladder disease and pancreatitis, with absolute contraindications including a history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2, severe gastroparesis, and end-stage renal disease [9].
With the burden of CuTS and the challenges posed by T2DM in surgical recovery, the benefits of GLP-1RAs should be explored for influence on outcomes in type 2 diabetic patients undergoing CuTR. To date, there has been limited evidence on this specific interplay between GLP-1RAs and CuTR. As such, this study aims to compare short-term (90-day) and mid-term (2-year) postoperative outcomes between CuTR patients with T2DM who underwent surgery and were treated perioperatively with GLP-1RAs and those who did not receive such medication, using a large real-world database.
METHODS
All data within the TriNetX network are actively de-identified and in compliance with the Health Insurance Portability and Accountability Act and the General Data Protection Regulation. The TriNetX network has received a waiver of approval from the Western Institutional Review Board-Copernicus Group Institutional Review Board, as it is considered research on non-human subjects. Therefore, patient consent and additional institutional review board approval were not required for this study.
Study Design and Data Source
This retrospective cohort study utilized de-identified patient data from the Global TriNetX Research Network. TriNetX is a federated global health research network providing access in real-time to electronic health records (EHRs) from numerous healthcare organizations (HCOs), primarily in the United States, encompassing over 160 million unique patients. Data within TriNetX include demographics, diagnoses (International Classification of Diseases, 10th Revision, Clinical Modification [ICD-10-CM]), procedures (Current Procedural Terminology [CPT] codes), medications, and laboratory values. The TriNetX platform standardizes data and has been extensively used in clinical research for various purposes [14,15].
Patient Population and Cohort Identification
The TriNetX database was queried to identify adult patients (≥18 years) who underwent primary CuTR, defined by CPT code 64718 (Neuroplasty, ulnar nerve at elbow; with or without transposition), between January 1, 2015, and January 1, 2023, with a minimum 2-year follow-up period. All patients were required to have a diagnosis of T2DM, as defined by relevant ICD-10-CM codes.
Defined Cohorts
Experimental (GLP-1RA Users): Patients with T2DM who had at least one prescription for a GLP-1RA within 90 days prior to the CuTR procedure and whose prescription was active at the time of surgery and 2 years post-surgery. Control (GLP-1RA non-users): Patients with T2DM who did not have a prescription for a GLP-1RA recorded within 3 months prior to or during the index CuTR procedure. Patients were excluded if they had a diagnosis of type 1 diabetes mellitus, chronic pancreatitis, multiple endocrine neoplasia 2, history of long-term systemic steroid use, end-stage renal disease, or a prior ipsilateral CuTR procedure performed more than 6 months before the index surgery.
Propensity Score Matching
To minimize selection bias and confounding due to differences in baseline characteristics between the GLP-1RA user and non-user cohorts (control), 1:1 propensity score matching was performed using the built-in analytics of TriNetX. Propensity score was calculated using a regression model with covariates of age at index procedure, sex, race, ethnicity, body mass index (BMI), baseline glycated hemoglobin (HbA1c) values (within 1 year prior to surgery), baseline serum creatinine value (within 1 year prior to surgery), and pre-existing comorbidities and relevant prior procedures (e.g., history of other neuropathies, carpal tunnel release, diabetic complications) recorded within the year prior to the index CuTR. A caliper width of 0.1 standard deviation of the propensity score was used.
Outcome Measures
Postoperative outcomes were identified using ICD-10-CM and CPT codes recorded in the electronic medical records (EMRs). Short-term outcomes were assessed at 90 days post-CuTR and included major medical complications (myocardial infarction, stroke, deep vein thrombosis/pulmonary embolism, sepsis, gastroparesis), laboratory values (BMI, HbA1c, creatinine), and emergency department (ED) utilization.
Mid-term outcomes were assessed cumulatively up to 2 years post-CuTR and included the incidence of reoperation (defined as a subsequent ipsilateral CuTR or ulnar nerve transposition); ulnar nerve neuropathy (ICD-10-CM codes including G56.2 indicating ulnar nerve lesion); inpatient hospital admissions; laboratory values (BMI, HbA1c, creatinine); and other complications such as joint contracture, surgical site or other infections, falls, prolonged opioid use, and late-stage diabetic microvascular complications (neuropathy, nephropathy, retinopathy). We report both procedure-specific postoperative outcomes (reoperation/revision, surgical site infection, wound complications, readmission) and all-cause outcomes (ED visits, diabetic ketoacidosis, ICD-10-coded ulnar neuropathy) that occurred during follow-up. Secondary/exploratory outcomes were ICD-coded all-cause neuropathy encounters and ED visits within 90 days and 2 years, were not adjudicated for relatedness to the index CuTR, and do not imply symptom severity.
Statistical Analysis
Baseline characteristics of the matched cohorts were compared using standardized mean differences (SMDs), with an SMD less than 0.1 generally considered to indicate good balance. For outcome analysis, relative risks and risk differences with 95% CIs were calculated using TriNetX’s statistical tools. P-values were also generated, with P<0.05 considered statistically significant. All analyses were performed on the propensity score-matched cohorts.
RESULTS
Cohort Characteristics
The initial query identified 2,427 GLP-1RA users and 5,236 control-eligible patients. After 1:1 propensity score matching, a total of 1,766 pairs (n=3,532 patients) was included in the analysis. Baseline demographic and clinical characteristics were balanced between the GLP-1RA user and non-user cohorts after matching. The mean age of the matched cohort was about 60±11 years, with approximately 52% males. The mean baseline BMI was 35.5±7.5 kg/m² in the GLP-1RA group and 34.3±7.2 kg/m² in the control group. Baseline mean HbA1c was 7.4%±1.7% for GLP-1RA users and 6.9%±1.6% for controls. Other baseline comorbidities were also well balanced (Table 1).
After 1:1 propensity matching, these differences were markedly diminished, with SMDs less than 0.05 and P-values ≥0.05 for almost all covariates, indicating adequate baseline balance between exposure groups. There was significant difference in initial BMI and HbA1c among the two groups.
Ninety-Day Outcomes
At 90 days post-CuTR, the incidence of major medical complications (e.g., myocardial infarction, stroke, pulmonary embolism) was low and did not differ significantly between the GLP-1RA users and non-users. Surgical site infection rates were also similar. Patients in the GLP-1RA group had a substantially lower rate of ED visits. Euglycemic diabetic ketoacidosis occurred only in the control group (two events), yielding a significant absolute difference but an indeterminable risk ratio (Table 2).
Two-Year Outcomes
At 2 years post-CuTR, patients in the GLP-1RA group experienced significantly fewer reoperations for ulnar nerve decompression and had a lower incidence of ulnar nerve neuropathy. The GLP-1RA group also had fewer inpatient admissions over 2 years (Table 3). GLP-1 use was associated with fewer reoperations, a 7% absolute reduction in ulnar-nerve neuropathy, and lower inpatient admission rates. There were no significant differences in rates of surgical site infections or joint contracture. Interestingly, the incidence of diabetic neuropathy was slightly higher in the GLP-1RA group. Rates of diabetic nephropathy and retinopathy did not differ significantly between groups.
GLP-1RA+ patients started with higher HbA1c (7.48% vs. 6.93%) and BMI (35.6±0.18 kg/m² vs. 33.8±0.16 kg/m²) than matched controls. By 2 years, HbA1c in the treated group had decreased to 0.32%, whereas controls showed no change, narrowing the inter-group gap to approximately 0.2%. BMI likewise decreased by 1.1±0.2 kg/m² in GLP-1+ patients versus 0.3±0.2 kg/m² in controls. Serum creatinine transiently increased at 90 days but returned toward baseline in both cohorts (year 2 means 1.08±0.03 vs. 1.12±0.04 mg/dL), with no sustained difference (Fig. 1). Thus, perioperative GLP-1 therapy was linked to glycemic and weight improvements without renal compromise after CuTR.
DISCUSSION
This retrospective cohort study demonstrated that perioperative use of GLP-1RAs may be associated with improved all-cause postoperative outcomes among adult patients with T2DM undergoing primary CuTR compared to a cohort of GLP-1RA non-users. Specifically, GLP-1RA users experienced significantly lower rates of ED visits at 90 days and at 2 years, fewer revision surgeries, a reduced incidence of ulnar nerve neuropathy, and fewer inpatient admissions. These findings are intriguing, particularly as GLP-1RA users had, on average, higher baseline BMI and HbA1c levels even after propensity score matching and continued to show higher HbA1c values postoperatively. On the other hand, average BMI and HbA1c showed a sharper decrease among the GLP-1RA users. In addition, creatinine levels were lower initially but were not significantly different after 2 years.
The observed reductions in revision surgeries and ulnar neuropathy at 2 years in the GLP-1RA group were clinically significant. Persistent symptoms and the need for reoperation are major concerns after CuTR, contributing to patient morbidity and healthcare costs [3,5]. The literature currently reports up to 35% neuropathy and approximately 7% revision rates for CuTR. In the present matched-cohort analysis, neuropathy occurred in 23.4% of the GLP-1RA group and 30.4% of the control group. Similarly, revision surgery occurred in 5.2% of GLP-1RA patients versus 6.9% of controls. Our findings suggest that GLP-1RAs can mitigate neuropathy and revision rates in a diabetic population, a group typically considered at higher risk for poorer surgical outcomes [8,16]. The neuroprotective and regenerative properties attributed to GLP-1RAs offer a plausible biological basis for these improvements, collectively contributing to more favorable nerve healing and functional recovery after surgical decompression. Recent human studies, though mostly small in scale, have also suggested benefits of GLP-1RAs in reducing symptoms of diabetic peripheral neuropathy [17,18].
The lower rates of ED visits at 90 days and inpatient admissions at 2 years in the GLP-1RA group may reflect a better recovery trajectory, fewer complications, or improved general health status through systemic impacts, including weight management and cardiovascular benefits [9,19,20]. While major medical and surgical site complications were infrequent and similar between groups in the short term, the reduction in broader healthcare utilization metrics may be a significant finding, further supporting findings from prior studies [21].
Furthermore, diabetic neuropathy was more common at 2 years in the GLP-1RA group, while ulnar nerve neuropathy was less common. This may warrant deeper consideration, as it could be due to several factors, as follows: (1) ascertainment bias: Patients using GLP-1RAs may undergo more frequent and thorough diabetic screenings. (2) Progression of systemic diabetic neuropathy is more likely in a cohort with more severe T2DM at baseline. Alternatively, billing (based on ICD codes) may be more precise in these patients. (3) GLP-1RAs may positively influence the recovery of local ulnar nerve compression but may not halt or reverse the progression of all forms of generalized diabetic polyneuropathy within a 2-year timeframe. (4) The benefits are more significant for specific nerves undergoing acute damage or surgical intervention.
Prior studies have shown that T2DM is associated with poorer outcomes after CuTR, yet they did not evaluate the influence of GLP-1RA therapy. Our matched-cohort analysis addresses this gap, demonstrating that perioperative GLP-1RA use is linked to lower rates of neuropathy and revision surgery in diabetic patients undergoing CuTR. For example, Stirling et al. [8] found that diabetic patients had worse functional scores post-CuTR. Furthermore, Aschen et al. [22] found significant postoperative reductions in risk-adjusted readmission, wound dehiscence, and hematoma in T2DM patients. Our findings suggest that GLP-1RA therapy may modify this risk profile. Furthermore, while Smit et al. [5] identified factors like age and prior neuropathies as risks for revision CuTR, our study points to GLP-1RAs as a class of medication that may reduce such risks in a diabetic population.
This study has several limitations inherent to its retrospective design that utilizes aggregate EHR data. First, despite propensity score matching, unmeasured confounding variables may exist, including duration of diabetes, severity of neuropathy at presentation, specific surgical techniques, surgeon experience, patient adherence to GLP-1RA therapy, and other lifestyle factors. It should also be noted that some variables, although significant, are all-cause measures, contextualizing overall postoperative health status in the diabetic cohorts, and inform perioperative planning and should not be construed as caused by or prevented by CuTR. Such variables may assist orthopedic surgeons in risk stratification, site-of-service selection, and counseling (e.g., noting patients who might benefit from optimization or closer follow-up). We report these as secondary, all-cause outcomes and do not imply procedure-level causality. Second, reliance on diagnostic and procedural codes can lead to misclassification bias, although the codes for CuTR and T2DM were employed. Furthermore, as ulnar neuropathy or diabetic neuropathy can be a vast spectrum, it is challenging to assess granular details from billing codes alone. Large EHR networks lack CuTR-specific clinical outcomes such as QuickDASH, grip strength, or two-point discrimination. Because visit-level coding can reflect surveillance, problem-list carryover, or evaluation of nonoperative symptoms, neuropathy ICD codes should be interpreted cautiously and not equated with clinical failure. Third, TriNetX primarily consists of data from large HCOs in the US; the generalizability of findings to international health systems may be limited [23]. Finally, information on the specifics pertaining to GLP-1RA was not measured (i.e., type, dosage, and duration).
CONCLUSIONS
This large-scale PS-matched retrospective study compared cohorts of T2DM patients undergoing CuTR and whether perioperative use of GLP-1RAs was associated with measurable clinical outcomes. Despite presenting with a higher baseline HbA1c and BMI, patients treated with GLP-1RAs experienced fewer all-cause ED visits at 90 days, significantly lower rates of revision surgery, reduced incidence of all-cause ulnar neuropathy, and fewer all-cause inpatient admissions over a 2-year follow-up period compared to matched T2DM patients not receiving GLP-1RAs. These findings suggest that GLP-1RAs are consistent with hypothesized neuroprotective effects, as they may improve local nerve healing and the long-term inflammatory profile in diabetic patients undergoing CuTR, mitigating the risk of other post-surgical complications in this population. Further prospective research is warranted to confirm these observations and deduce the underlying mechanisms of such benefits; however, these real-world data support the decision to continue GLP-1RA therapy as a comprehensive management strategy for T2DM patients undergoing CuTR.
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