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Abstract

Background

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly prescribed for obesity and type 2 diabetes mellitus (T2DM). While their metabolic benefits are well-established, their impact on postoperative outcomes following total joint arthroplasty (TJA) remains controversial. This study aimed to systematically evaluate the association between GLP-1 RA use and postoperative outcomes in patients undergoing total hip (THA), knee (TKA), or shoulder arthroplasty (TSA).

Methods

We conducted a PRISMA-compliant systematic review and meta-analysis across PubMed, Embase, Web of Science, and Scopus through April 24, 2025. Eligible retrospective cohort studies compared adults undergoing TJA with and without preoperative GLP-1 RA exposure. Primary outcomes were 90-day readmission and all-cause revision. Pooled odds ratios (ORs) and standardized mean differences (SMDs) were calculated under random-effects models. Subgroup analysis based on the type of arthroplasty was conducted where applicable.

Results

Fourteen studies (total sample size of 365,154; including 62,117 (17.01%) GLP-1 consumers, and 303,037 (82.98%) control cases) met the inclusion criteria (All studies included primary TJA cases). GLP-1 RA use was associated with lower 90-day readmission (OR = 0.86, 95% CI: 0.74-0.99, p = 0.033) and reduced sepsis incidence (OR = 0.63, 95% CI: 0.46–0.88, p = 0.006). No significant differences were observed for all-cause revision, thromboembolic events, and other medical and surgical complications. Length of stay was marginally shorter in GLP-1 users (SMD = −0.09, p = 0.048). Subgroup analyses showed the strongest sepsis reduction in TSA.

Conclusion

GLP-1 RA use before TJA is associated with reduced readmission and sepsis risk without increasing surgical or thromboembolic complications. These findings support the potential perioperative benefits of GLP-1 RAs, warranting prospective trials to confirm causality and define optimal perioperative strategies for high-risk arthroplasty patients.

Keywords

glucagon-like peptide-1 receptor agonists total joint arthroplasty postoperative complications readmission rates

Introduction

The intersection of metabolic health and musculoskeletal outcomes has garnered increasing attention with the widespread use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs), originally developed for type 2 diabetes mellitus (T2DM) and now widely adopted for obesity management.^1,2 Total joint arthroplasty (TJA) has become one of the most frequently performed elective procedures worldwide, with its use steadily rising in response to demographic aging and lifestyle changes. ³ Within this context, the most common procedures are total knee arthroplasty (TKA), total hip arthroplasty (THA), and total shoulder arthroplasty (TSA), which together account for the majority of joint replacements performed.

Recent studies suggest that GLP-1 RAs may influence joint health and arthroplasty outcomes through both systemic and local mechanisms. Their weight-reducing properties may alleviate mechanical stress on joints, potentially delaying OA progression or improving postoperative recovery.⁴ In addition, preclinical research indicates anti-inflammatory and bone-modulating effects that could impact cartilage integrity and implant survivorship. However, still, inconsistency remains regarding clinical findings, as it has been shown that in lower extremity OA populations, GLP-1 RA use has been associated with reduced rates of THA and TKA and improved postoperative outcomes, including lower rates of medical complications and readmissions.⁵ Conversely, data from non-OA cohorts and upper extremity arthroplasty studies report increased OA incidence, elevated surgical risk, and higher revision rates, suggesting joint-specific or weight-independent effects.⁶ As the global use of GLP-1 RAs, such as Semaglutide and Liraglutide, is expected to surpass 30 million users by 2025, clarifying their role in arthroplasty outcomes is both timely and necessary. The apparent paradox in existing literature underscores the need for a systematic evaluation.⁷ This warrants an updated systematic review and meta-analysis focusing on how the use of GLP-1 receptor agonists can affect postoperative outcomes following THA, TKA, and TSA.

This meta-analysis aims to synthesize evidence on the impact of GLP-1 RAs across different types of arthroplasty. We evaluate their influence on a comprehensive range of postoperative outcomes, including 90-day readmission, all-cause mortality, deep vein thrombosis (DVT), pulmonary thromboembolism (PTE), renal complications, cardiac complications, pneumonia, wound complications, periprosthetic joint infection (PJI), aseptic loosening, all-cause revision surgery, cerebrovascular accidents (CVA), urinary and gastrointestinal (GI) complications, and sepsis. Subgroup analyses are performed based on the type of arthroplasty to explore potential differences in the effects of GLP-1 RAs across surgical contexts. By integrating data from over 2 million patients from recent cohort studies and clinical trials, our goal is to inform perioperative risk management and enhance shared decision-making in metabolic and orthopedic care.

Materials and methods

This meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) 2020 guidelines⁸ and has been registered in PROSPERO under code CRD420251126822. This study aimed to assess postoperative outcomes in patients undergoing total joint arthroplasty (TJA), comparing those who had a history of GLP-1 RAs consumption to those who had not. The analysis included data from patients undergoing THA, TKA, and TSA and was stratified by arthroplasty type where applicable.

Search strategy

Eligible studies were identified based on a comprehensive and systematic literature review focused on GLP-1 usage in patients undergoing THA, TSA, or TKA. A systematic search was conducted across four electronic databases, including PubMed, Embase, Web of Science, and Scopus, from inception to April 24, 2025. The search strategy included terms such as “GLP-1 receptor agonists,” “total joint arthroplasty”, “total hip arthroplasty”, “total knee arthroplasty”, and “total shoulder arthroplasty” along with relevant synonyms, combined using Boolean operators (AND, OR) within the title and abstract fields. Peer-reviewed studies were included if they reported outcomes of interest with a clear comparison between patients treated with GLP-1 RAs and those who did not receive such therapy prior to surgery. Reference lists of all included studies were manually screened to identify additional eligible publications. The complete search strategies used for each database are provided in Supplemental Table S1.

Eligibility criteria

Studies were eligible for inclusion if they adhered to the PECO framework. The population consisted of adult patients who underwent TJA. The exposure group included patients who received GLP-1 RAs prior to surgery. The comparison group consisted of patients who underwent TJA without receiving GLP-1 RAs.

The primary outcomes of interest included 90-day readmission and all-cause revision incidence. The secondary outcome included (DVT, PTE, GI complications, CVA, renal complications, cardiac complications, sepsis, pneumonia, wound complications, urinary complications, PJI, and length of hospital stay (LOS). Studies were excluded if they lacked outcome data, did not include a comparison group, or failed to distinguish GLP-1 exposure status. Furthermore, review articles and qualitative studies, as well as letters and book chapters, were excluded.

Study selection

The search results were imported into the Rayyan software for screening and selection. Duplicate records were removed, and two independent reviewers (Y.M. and A.M.A) screened the titles and abstracts of retrieved studies to identify those eligible for full-text review. Full-text articles were then independently reviewed by the same reviewers to determine final inclusion based on the predefined eligibility criteria. Any disagreements during the screening or selection process were resolved through discussion or adjudication by a third reviewer (F.S.).

Data extraction

Data were extracted by two independent reviewers (R.J. and T.P.) using a standardized data extraction form. The extracted information included the study author, year of publication, type of arthroplasty, number of patients in the GLP-1 and control groups, number of events for each outcome, and relevant statistical measures such as means and standard deviations for continuous variables, or event counts for binary outcomes. Any discrepancies between the reviewers were resolved through discussion or, when necessary, by a third reviewer (A.M.A.).

Quality assessment

To evaluate the risk of bias in the included non-randomized studies, we used the Risk Of Bias In Non-randomized Studies - of Interventions (ROBINS-I) tool, which is specifically designed for assessing the methodological quality of observational studies. This tool assesses seven domains of potential bias, including confounding, selection of participants, classification of interventions, deviations from intended interventions, missing data, measurement of outcomes, and selection of reported results. Each study was independently assessed by two reviewers (A.M.A. and R.J.), and any disagreements were resolved through discussion or consultation with a third reviewer (F.S.). The overall risk of bias for each study was categorized as low, moderate, serious, or critical, based on the ROBINS-I guidelines.⁹

Statistical analysis

All statistical analyses were performed using R software (version 4.4.2) and the ‘meta’ package. For dichotomous outcomes, odds ratios (ORs) and their 95% confidence intervals were calculated using the inverse variance method under a random-effects model. For continuous outcomes, standardized mean differences (SMDs) were calculated. Heterogeneity was assessed using the I² statistic, with values above 30% considered indicative of substantial heterogeneity. Tau² and its 95% confidence intervals were also reported. Subgroup analyses were conducted based on the type of arthroplasty (THA, TKA, and TSA). Sensitivity analyses using leave-one-out procedures were performed to evaluate the robustness of pooled estimates. Publication bias was assessed visually with funnel plots and tested using Harbord’s regression test. A continuity correction of 0.5 was applied for studies with zero events in one or both groups. A p-value of <0.05 was considered statistically significant for all tests.

Results

Study selection

Following a systematic search of electronic databases and omitting duplicates, we identified 83 identical records. The records were then subjected to title/abstract screening, after which 24 articles were identified to be relevant for full-text review. After full-text review, 14 papers^10–23 were considered eligible to be included in this systematic review and meta-analysis (All studies included primary TJA patients) (Figure 1).

Figure 1.

PRISMA flowchart.

Baseline characteristics and quality assessments

A total of 365,154 TJA cases (59.4% female) were included in our meta-analysis, of which 62,117 (17.01%) were GLP-1 consumers, and 303,037 (82.98%) were control patients.

Based on the available data, 60.8% of the study population underwent TKA, 31.2% were THA cases, and 7.9% were TSA cases. In all the included studies, only primary TJA patients were included.

All included studies were retrospective cohort studies and were conducted in the USA. Considering the utilized dataset, eight studies used the PearlDiver database, two used the TriNetX database, two used the IBM MarketScan databases, and two were based on single-center databases.

A detailed representation of each of the included studies’ baseline characteristics (comprising the type of GLP-1 agents and the reason for prescription) is presented in Table 1.

Table 1.

Baseline characteristics of the included studies.

Author(Year)	Country	Study design	Data Source/Database	Type of TJA Surgery	Cause of GLP-1 RAsprescription	GLP-1 RAs which prescribed	Sample Size (Total)	Sample size (Knee)	Sample size (Hip)	Sample size (Shoulder)	GLP-1 RA Users (Total)	GLP-1 RA Users (Knee)	GLP-1 RA Users (Hip)	GLP-1 RA Users (Shoulder)	Gender ( Male %)	Follow-up Duration
Verhey et al., (2025)	USA	Retrospective cohort	PearlDiver mariner (2010–2022)	THA	Weight loss (not diabetic)	Liraglutide, Semaglutide, Dulaglutide, Exenatide, lixisenatide	10,690	NA	10,690	NA	5345	NA	5345	NA	31%	2 years
Magruder et al., (2023)	USA	Retrospective cohort	PearlDiver database (2010–2021)	TKA	T2DM	Semaglutide	41,575	41,575	NA	NA	7051	7051	NA	NA	38%	2 years
Magruder et al., (2024)	USA	Retrospective cohort	PearlDiver database (2010–2021)	THA	T2DM	Semaglutide	9465	NA	9465	NA	1653	NA	1653	NA	52.40%	2 years
Magaldi et al., (2024)	USA	Retrospective cohort	Single center/June (2016–Dec 2022)	THA	NS	Dulaglutide, Exenatide, Liraglutide, Semaglutide	192	NA	192	NA	66	NA	66	NA	58%	12 months
Kim et al., (2024)	USA	Retrospective cohort	PearlDiver mariner database (2010–2022)	THA	Weight management in morbid obesity (BMI ≥ 40)	Exenatide, Semaglutide, Dulaglutide, Liraglutide (Tirzepatide was excluded)	771 (treatment), 3084 (control), 3084 (severe obesity)	NA	771 (treatment), 3084 (control), 3084 (severe obesity)	NA	771	NA	771	NA	48%	2 years
Katzman et al., (2025)	USA	Retrospective cohort	Urban, academic health system, (2012–2023)	TKA	NS	Semaglutide, Liraglutide, Dulaglutide, Exenatide, Tirzepatide, Lixisenatide, Albiglutide	9515	9515	NA	NA	865	865	NA	NA	33.70%	A mean of 2.2 years in the GLP-1 group and 2.9 years in the control group
Heo et al., (2024)	USA	Retrospective cohort	IBM MarketScan commercial claims and encounters and medicare supplemental and coordination of benefit databases (2016-2021)	TKA	T2DM	Unspecified (study includes all GLP-1 RAs)	4776	4776	NA	NA	2388	2388	NA	NA	43%	1 year
Buddhiraju et al., (2024)	USA	Retrospective cohort	TriNetX database (May 2005 – December 2023)	THA, TKA	NS	Semaglutide, Liraglutide, Dulaglutide, Exenatide, Lixisenatide	6278	4190	2088	NA	3139	2095	1044	NA	43%	90 days
Baum et al., (2024)	USA	Retrospective cohort	PearlDiver Mariner (2010–2022)	THA, TKA	NS	Adlyxin, Bydureon, Byetta, Ozempic, Rybelsus, Saxenda, Trulicity, Victoza, Wegovy	233,686	150,099	83,587	NA	2543	1876	667	NA	NR	4 months
Kim et al., (2025)	USA	Retrospective cohort	PearlDiver mariner (January 2010 – October 2022)	TKA	NS	Exenatide, Semaglutide Dulaglutide, Liraglutide (Tirzepatide was excluded)	90 days: 11899; 2 years: 7062	90 days: 11899; 2 years: 7062	NA	NA	2975	2975	NA	NA	33%	2 years
Heo et al., (2024)	USA	Retrospective cohort	IBM MarketScan databases (2016–2021)	THA	T2DM	Various GLP-1 RAs (not specified)	4060	NA	4060	NA	812	NA	812	NA	58%	1 year
Elsabbagh et al., (2025)	USA	Retrospective cohort	PearlDiver mariner (2010–2022)	TSA	T2DM	Dulaglutide, Exenatide, Liraglutide, Lixisenatide, Semaglutide	23,711	NA	NA	23,711	5010	NA	NA	5010	45%	2 years
Lawand et al., (2025)	USA	Retrospective cohort	TriNetX (2010–2023)	TSA	NS	Semaglutide, Liraglutide	2518	NA	NA	2518	1259	NA	NA	1259	39.70%	2 years
Seddio et al., (2024)	USA	Retrospective cohort	PearlDiver mariner (2010– 2022)	TSA	T2DM	Semaglutide	2934	NA	NA	2934	632	NA	NA	632	45.20%	90 days

Abbreviations: BMI: Body Mass Index, GLP-1: Glucagon-Like Peptide-1, GLP-1 RA: Glucagon-Like Peptide-1 Receptor Agonist, IBM: International Business Machines, TJA: Total Joint Arthroplasty, THA: Total Hip Arthroplasty, TKA: Total Knee Arthroplasty, TSA: Total Shoulder Arthroplasty, U.S.: United States, T2DM: Type 2 diabetes mellitus, NS: Not specified, NR: Not reported, NA: Not applicable/ Not available.

All studies were assessed based on ROBINS-1, of which 12 showed low risk of bias and two^15,20 showed moderate risk of bias. No significant publication bias was observed for any of the investigated outcomes. Table S1 presents each study’s ROBINS-I risk of bias assessment across the seven domains.

Meta-analyses

Primary outcomes

Our meta-analysis unveiled a significantly lower rate of 90-day readmission: (OR = 0.85; 95% CI: [0.74-0.98]; P = 0.03; I² = 73.6%) in GLP-1 group, while no considerable difference was shown in terms of all-cause Revision: (OR = 0.92; 95% CI: [0.83–1.02]; p = 0.13; I² = 20.2%) (Figures 2 and 3).

Figure 2.

Forest plot of 90-day readmission rate comparison between GLP-1 group and control group undergoing TJA (OR with 95% CI).

Figure 3.

Forest plot of all-cause revision rate comparison between GLP-1 group and control group undergoing TJA (OR with 95% CI).

Leave-one-out analysis showed a notably higher rate of all-cause revision (OR = 0.90; 95% CI: [0.82–0.98]) after removing the Kim et al.¹⁴ study (Figure S1). For 90-day readmission, leave-one-out analysis showed that after removing five studies,^{14,16,19,21,23} readmission became comparable between groups of patients while still showing a trend toward a lower readmission rate in the GLP-1 group (Figuer S2).

Secondary outcomes

Medical complications

Our meta-analysis demonstrated a significantly lower rate of postoperative sepsis (OR = 0.63; 95% CI: [0.45–0.87]; p = 0.005; I² = 63.6%) in GLP-1 consumers (Figure 4). However there were no significant difference between the two groups in terms of DVT (OR = 1.10; 95% CI: [0.86–1.40]; p = 0.41; I² = 57.2%), PTE (OR = 1.05; 95% CI: [0.71–1.57]; p = 0.77; I² = 62.7%), GI complications (OR = 0.95; 95% CI: [0.86–1.04]; p = 0.31; I² = 64.9%), CVA (OR = 1.10; 95% CI: [0.77–1.57]; p = 0.58; I² = 66.7%), renal complications (OR = 0.95; 95% CI: [0.76–1.18]; p = 0.66; I² = 79.3%), urinary complications (OR = 0.80; 95% CI: [0.59–1.09]; p = 0.16; I² = 85.0%), pneumonia (OR = 0.97; 95% CI: [0.67–1.39]; p = 0.87; I² = 88.0%), and cardiac complications (OR = 1.12; 95% CI: [0.63–2.01]; p = 0.68; I² = 76.6%) (Figure S3–S10).

Figure 4.

Forest plot of sepsis rate comparison between GLP-1 group and control group undergoing TJA (OR with 95% CI).

By conducting sensitivity analysis, the results for all outcomes remained consistent (Figure S11–S18) except for sepsis, which was comparable between the two groups after removal of three of the included studies,^10,12,22 however, a trend toward a lower rate of sepsis in the GLP-1 group was still demonstrated (Figure S19).

Surgical complications and hospitalization-related outcomes

Based on our meta-analysis, the GLP-1 and control group were comprable in terms of PJI (OR = 0.92; 95% CI: [0.74–1.15]; p = 0.51; I² = 67.9%), wound complications: (OR = 0.90; 95% CI: [0.78–1.04]; p = 0.15; I² = 32.9%), and aseptic loosening (OR = 1.17; 95% CI: [0.84–1.62]; p = 0.34; I² = 37.6%) (Figure S20–S22). However, LOS was notably lower in GLP-1 patients (SMD = −0.09; 95% CI: [−0.18 to −0.0008]; p = 0.04; I² = 84.6%) (Figure 5).

Figure 5.

Forest plot of LOS comparison between GLP-1 group and control group undergoing TJA (OR with 95% CI).

While the meta-analysis results for PJI and aseptic loosening remained consistent after leave-one-out analysis, it was shown that wound complication was notably lower in the GLP-1 group after omitting Verhey et al. study.²² In addition, LOS was statistically comparable between the two groups following the removal of three of the included studies^12,14,18 (Figure S23–S26).

Figure 6 summarizes the meta-analysis results for all the investigated outcomes.

Figure 6.

Summary of all outcomes meta-analysis.

Functional outcome

Magaldi et al.²⁰ study on 192 THA patients, including 66 GLP-1 consumers, showed no significant difference between the two groups of patients in terms of Hip Osteoarthritis Outcome Score for Joint Replacement (HOOS-JR) at none of the preoperative, 6-week, 6-month, and 12-month follow-up timepoints. None of the other included studies compared functional outcomes between GLP-1 and control groups.

Subgroup analysis based on the type of arthroplasty

Subgroup analysis based on the region of arthroplasty (hip, knee, shoulder) demonstrated no significant between group difference for none of the investigated outcomes except for sepsis (between-group p-value = 0.0478). Table 2 comprehensively shows the effect size and heterogeneity in each subgroup as well as between-group difference p-values across all outcomes.

Table 2.

Summary of subgroup analysis based on type of arthroplasty.

Outcome	Subgroup	OR/SMD	95% CI	I²	Between-group p-value
DVT	Hip	0.89	[0.64–1.24]	33.6%	0.23
	Knee	1.05	[0.75–1.47]	60.7%
	Shoulder	1.87	[0.84–4.15]	74.8%
PTE	Hip	1.06	[0.31–3.57]	77.1%	0.78
	Knee	0.83	[0.62-1.12]	0.0%
	Shoulder	1.08	[0.49–2.38]	70.6%
GI complications	Hip	1.20	[0.36–3.99]	74.6%	0.41
GI complications	Knee	0.56	[0.14–2.22]	71.1%
Cerebrovascular accidents	Hip	0.54	[0.08–3.70]	67.0%	0.61
	Knee	0.94	[0.39–2.26]	79.2%
	Shoulder	1.36	[0.65–2.85]	82.7%
Renal complications	Hip	0.84	[0.70–1.01]	3.0%	0.07
	Knee	1.12	[0.95–1.31]	42.8%
	Shoulder	0.86	[0.21–3.38]	95.7%
Cardiac complications	Hip	0.84	[0.13–5.43]	73.7%	0.59
	Knee	1.47	[1.14–1.89]	0.0%
	Shoulder	0.89	[0.29–2.75]	87.5%
Sepsis	Hip	0.37	[0.03–4.64]	69.3%	0.04
	Knee	0.01	[0.00–0.31]	—
	Shoulder	0.63	[0.46–0.86]	3.5%
Wound complications	Hip	0.86	[0.65–1.13]	52.3%	0.69
	Knee	0.95	[0.80–1.13]	0.0%
	Shoulder	0.70	[0.29–1.69]	75.3%
Pneumonia	Hip	1.10	[0.82–1.47]	0.0%	0.90
	Knee	1.06	[0.61–1.83]	90.7%
	Shoulder	0.83	[0.25–2.76]	94.4%
Urinary complications	Hip	0.89	[0.69–1.15]	0.0%	0.65
	Knee	0.92	[0.79–1.08]	0.0%
	Shoulder	0.57	[0.21–1.57]	97.0%
90-day readmission	Hip	0.81	[0.69–0.96]	40.7%	0.21
	Knee	0.77	[0.61–0.97]	72.4%
	Shoulder	1.11	[0.78–1.58]	77.1%
All-cause revision	Hip	0.81	[0.63–1.05]	29.2%	0.38
	Knee	0.94	[0.79–1.12]	20.1%
	Shoulder	1.02	[0.84–1.24]	—
PJI	Hip	0.84	[0.58–1.24]	66.9%	0.58
	Knee	0.95	[0.67–1.34]	82.0%
	Shoulder	1.22	[0.68–2.20]	—
Length of stay	Hip	−0.02	[−0.48 – 0.42]	88.5%	0.79
	Knee	−0.08	[−0.15 – 0.01]	69.1%
	Shoulder	−0.05	[−0.09 – 0.02]	—

Discussion

To the best of our knowledge, this is the first meta-analysis to evaluate the impact of GLP-1 RAs on outcomes following arthroplasty. The results suggest a potentially protective role for GLP-1 therapy in the postoperative setting, particularly in reducing 90-day readmission rates and the incidence of sepsis. While most other outcomes did not achieve statistical significance, several demonstrated a decreasing trend. Notably, patients receiving GLP-1 therapy exhibited lower rates of postoperative complications, outcomes that are key determinants of surgical morbidity and long-term implant success. Furthermore, no significant differences were observed in thromboembolic events (including DVT, PTE, and cerebrovascular accidents), nor cardiovascular, renal, gastrointestinal, and urinary complications, or aseptic loosening.

The observed reductions in readmission are consistent with findings from a broad body of studies examining the effects of GLP-1 RAs in surgical populations, which have reported decreased hospitalization rates. A large retrospective cohort study involving over 74,000 surgical procedures in diabetic patients reported that those with an active perioperative GLP-1 RA prescription had a 12% lower risk of 30-day readmission.²⁴ Similarly, in morbidly obese individuals (BMI ≥40) undergoing TKA, GLP-1 RA use was linked to a 47% decrease in 90-day readmissions compared to non-users.¹⁴ Likewise, a multicenter retrospective study involving diabetic patients undergoing spinal fusion found that those treated with GLP-1 receptor agonists had significantly lower rates of hospital readmissions.²⁵ However, some studies initially reported an increased rate of emergency department visits beyond 90 days among patients who underwent TKA.²⁶ Nevertheless, their subsequent findings aligned with ours and with other studies, indicating that the number of hospital readmissions during this period was significantly lower among individuals treated with GLP-1 RAs compared to non-users.^16,23

GLP-1 RAs improve glycemic control, a critical factor in reducing postoperative infections and enhancing wound healing, which are major contributors to hospital readmission.^27,28 Additionally, by suppressing pro-inflammatory cytokines (such as IL-6 and TNF-α), these agents may help attenuate the systemic inflammatory response following major surgery, thereby further reducing the risk of complications that commonly lead to readmission.²⁹ The associated weight loss may also contribute to better surgical outcomes by reducing physiological stress and facilitating early postoperative mobilization, which may help decrease readmission rates.

Differences in the timing of GLP-1 RA initiation (especially when started after discharge) may postpone their clinical benefits, which could explain higher rates of early healthcare visits in some studies. In addition, patients receiving GLP-1 RAs often have more complex health conditions, leading to closer follow-up and precautionary visits that may be misclassified as complications. Because these medications are expensive, they are more commonly prescribed to individuals with greater socioeconomic advantages, healthier lifestyles, and better access to care,^30–32 all of which are linked to improved recovery and lower readmission risk. Variations in hospital protocols, follow-up practices, and reporting standards may also contribute to inconsistent findings across studies.

Surgical complications are critical endpoints in evaluating outcomes following TJA, particularly in patients with metabolic comorbidities such as obesity and type 2 diabetes. This analysis included a range of arthroplasty procedures (TKA, THA, and TSA) and focused on four key postoperative outcomes: revision, PJI, wound complications, and aseptic loosening, which represent clinically significant concerns in orthopedic practice. Our findings align with several previous studies that have found no statistically significant effect of GLP-1RA use on these postoperative complications,^{12,17–19,33} although a few studies have reported significant associations. Among these, only a limited number of studies reported significant reductions associated with GLP-1RA use. A decrease in revision was noted in a single study²¹ within the THA subgroup, whereas investigations involving TKA and TSA did not reveal meaningful differences. For PJI, reductions were observed in select THA and TKA cohort studies,^21,23 though findings were inconsistent across studies. A significant decrease in wound complications was reported solely in a TSA subgroup treated with Semaglutide,³⁴ with no notable effects in THA or TKA. No study demonstrated a significant reduction in aseptic loosening, and overall findings for this outcome remained inconclusive. Although GLP-1RA use was not significantly associated with reductions in the aforementioned complication rates, it also did not increase the risk, and the observed trends across multiple outcomes consistently favored lower complication rates, indicating a potentially beneficial effect in specific surgical settings. These findings may reflect variations based on patient-specific risk factors and characteristics, underscoring the need for further research to identify which patients would benefit most from perioperative GLP-1RA use.

Several interrelated factors may explain the lack of significant findings in studies examining these outcomes. First, the use of retrospective administrative databases likely introduced inconsistencies in coding accuracy and exposure classification, thereby diminishing internal validity. Moreover, the limited follow-up durations in several studies may have precluded the capture of late-onset outcomes, such as aseptic loosening, which typically manifest over extended periods post-arthroplasty. Procedural heterogeneity across TKA, THA, and TSA, with differing anatomical complexity, soft tissue manipulation, and baseline complication profiles, further complicated the detection of pooled effects. Additionally, some cohorts included surgeries conducted before the widespread adoption of drugs such as Semaglutide, potentially underestimating the clinical benefits associated with GLP-1RA use.

Another key factor is the multifactorial nature of outcomes like aseptic loosening and PJI, where mechanical stress, immune dysfunction, and systemic inflammation interact in complex ways.^35–37 These overlapping etiologies may have obscured the specific contribution of GLP-1RAs. Infrequent events such as aseptic loosening also limited statistical power, while heterogeneity in medication dosing, duration, and formulation reduced consistency across studies. Given the high cost of GLP-1RAs and limited insurance coverage, individuals receiving these therapies often belong to higher socioeconomic levels.^38,39 As a result, comparisons with patients not using GLP-1RAs may be confounded by differences in baseline health status, nutritional habits, lifestyle factors, and access to higher-quality care. Consequently, the improved outcomes observed in some studies may not be solely attributable to the pharmacological effects of GLP-1RAs, but also to these underlying socioeconomic advantages. Despite these limitations, the absence of increased complications among GLP-1RA users, along with several directionally favorable trends, supports the rationale for future prospective trials targeting high-risk subgroups with extended follow-up.

Among the postoperative medical complications assessed, sepsis showed a significant reduction in patients receiving GLP-1 RAs, while the incidence of pneumonia and urinary tract infections remained unchanged, supporting the potential anti-infective properties of these agents. This finding is supported by a growing body of clinical evidence indicating that GLP-1 RAs possess notable anti-inflammatory and immunomodulatory properties.^40,41 Some studies have shown that agents such as liraglutide and dulaglutide suppress key pro-inflammatory cytokines, including TNF-α, IL-6, and IL-1β^40,42,43; inhibit NF-κB signaling pathways⁴⁴; and mitigate septic injury and endothelial dysfunction.⁴⁵ Clinical evidence further supports these insights, and our findings are consistent with those reported in previous studies.^23,34 A cohort study involving more than 300,000 adults with type 2 diabetes found that GLP-1 RA use was associated with a significantly lower risk of sepsis, pneumonia, and urinary tract infections compared to non-users.⁴⁶ However, findings from perioperative settings remain inconclusive. In a retrospective study, Aschen et al. reported that GLP-1 RA use was significantly associated with reduced risks of wound dehiscence and hematoma; however, no significant difference was observed in infection rates among surgical patients.²⁴ Similarly, Rashid et al. reported no statistically significant differences in the incidence of sepsis, pneumonia, or surgical site infections between GLP-1 RA users and non-users in an analysis of nearly 140,000 patients undergoing major surgical procedures.⁴⁷

The observed discrepancies in postoperative infection outcomes associated with GLP-1 RA use likely arise from key clinical and methodological variations across studies. The postoperative protective effects of GLP-1 RAs may be more pronounced in high-risk individuals, such as those with poorly controlled diabetes or morbid obesity,¹⁹ particularly when these agents are used consistently over an extended period.^48,49 In contrast, studies involving non-diabetic populations or limited perioperative exposure may not fully capture the systemic benefits of GLP-1RAs. Comparative interpretation is further complicated by heterogeneity in surgical procedures (e.g., hip vs knee arthroplasty), variability in baseline comorbidities, and inconsistent perioperative care protocols. Thus, conflicting findings across studies may not indicate a true absence of efficacy but rather reflect a complex interplay of patient selection, dosing duration, and outcome definitions that obscure potential benefits in specific subgroups. Supporting this, our subgroup analysis indicated that the protective effect of GLP-1RAs against sepsis varies by surgical site, with the greatest benefit observed in shoulder procedures. This site-specific response may be attributed to differences in operative complexity, anatomical structure, and infection risk. For example, shoulder surgeries generally involve less soft tissue thickness, leading to reduced tissue disruption⁵⁰ and shorter operative durations compared to hip or knee arthroplasty.^51,52 These factors may contribute to a lower systemic inflammatory response, which not only reduces the risk of complications such as sepsis but also enhances the therapeutic efficacy of GLP-1RAs. Moreover, variations in vascularization, local immune environments, and postoperative mobility, along with individual patient factors such as metabolic profile, may modulate the observed outcomes.

Our findings demonstrated no significant association between GLP-1 RA use and thromboembolic events (including DVT and PTE), cardiovascular or cerebrovascular complications, or renal dysfunction, with no observed increase in the incidence of these potentially life-threatening outcomes. These findings are supported by major randomized clinical trials such as SUSTAIN 6, PIONEER 6, and LEADER, which confirmed the cardiovascular safety of GLP-1 receptor agonists. These studies demonstrated that GLP-1 RAs significantly reduced major adverse cardiovascular events, including non-fatal myocardial infarction and cardiovascular death in patients with type 2 diabetes, or at minimum reinforced this drug class’s neutral or favorable cardiovascular profile.^53–55

This meta-analysis provides one of the earliest comprehensive evaluations of GLP-1 RAs in orthopedic surgery, with notable strengths including a large sample size and consistent trends across key outcomes. However, limitations must be acknowledged. Most included studies were retrospective and relied on administrative databases, which are prone to coding errors and outcome misclassification. Given the reliance on large national databases, a degree of study overlap cannot be entirely excluded and should be recognized as a potential limitation, although this is unlikely to materially influence the overall results. Variability in surgical protocols, follow-up durations, and GLP-1 RA regimens (type, dose, timing) may have affected comparability. The lack of granular clinical data, such as glycemic control, medication adherence, and thromboprophylaxis strategies, limits the ability to make appropriate adjustments for confounding. Additionally, potential socioeconomic disparities and the inclusion of cases before widespread adoption of some agents, such as semaglutide, may have influenced the findings. Importantly, all included procedures were primary arthroplasties; thus, the concern regarding the inclusion of revision cases does not apply and cannot account for the observed heterogeneity. Moreover, recent evidence suggests that the interval between discontinuation of GLP-1 RAs and surgery may significantly impact postoperative outcomes; however, this information was inconsistently reported in the included studies and therefore could not be systematically evaluated in the present analysis. Future research should prioritize adequately powered, diabetes-stratified analyses to provide more definitive evidence. Despite these limitations, the overall direction of the results supports further prospective studies in high-risk surgical populations. In addition, we conducted a comprehensive series of leave-one-out sensitivity analyses and subgroup analyses to assess the potential influence of confounding factors and to evaluate the consistency and robustness of the findings derived from this meta-analysis.

Conclusion

This meta-analysis provides one of the earliest comprehensive evaluations of the effects of GLP-1 RAs on arthroplasty and postoperative medical outcomes. The use of GLP-1 RAs was associated with non-inferior outcomes compared with non-users, with observed trends toward lower readmission rates and sepsis, and without evidence of increased thromboembolic, cardiovascular, or renal complications. These findings indicate that GLP-1 RA therapy is not detrimental in the perioperative setting and may offer potential benefits; however, the variations across studies likely reflect differences in regimens, patient characteristics, and the nature of data capture. Accordingly, the results should be interpreted with caution, as they do not establish GLP-1 RAs as superior in this context. Future prospective studies with standardized protocols are needed to define the patient populations most likely to benefit and to clarify the role of GLP-1 RAs in optimizing surgical outcomes.

Supplemental Material

Supplemental Material - Impact of glucagon-like peptide-1 receptor agonists on postoperative complications after total joint arthroplasty: A systematic review and meta-analysis

Supplemental Material for Impact of glucagon-like peptide-1 receptor agonists on postoperative complications after total joint arthroplasty: A systematic review and meta-analysis by Yashar Mashayekhi, Amir-Mohammad Asgari, Mohammad-Taha Pahlevan-Fallahy, Mohammad Amin Karimi, Ronak Jalali, Farhad Shaker in Journal of Orthopaedic Surgery

Footnotes

ORCID iDs

Yashar Mashayekhi

Amir-Mohammad Asgari

Mohammad-Taha Pahlevan-Fallahy

Mohammad Amin Karimi

Ronak Jalali

Farhad Shaker

Authors’ contributions

Y.M.: Conceptualization, Writing-original draft, Investigation, Methodology, Project administration

AM.A.: Conceptualization, Writing-original draft, Investigation, Methodology, MT.PF.: Formal analysis, Software validation, Investigation. M.A.K.: Methodology, Data extraction, Writing-original draft. R.J.: Conceptualization, Investigation, Data curation, Writing-original draft, Writing-review & editing. F.S.: Data curation, validation, Supervision, Methodology, Writing-original draft, Writing-review & editing.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

PROSPERO registration

This meta-analysis has been registered in PROSPERO under code CRD420251126822.

Supplemental Material

Supplemental material for this article is available online.

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