Abstract
Background
Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are increasingly used for diabetes and obesity, but their safety and clinical impact after lung transplantation (LTx) are unclear.
Methods
We performed a single-center retrospective cohort study of adults undergoing primary LTx from 2018 to 2024. GLP-1 RA exposure was defined as either active treatment at the time of transplantation and/or GLP-1 RA use within the first 90 postoperative days. We compared early postoperative complications (including primary graft dysfunction grade 3 (PGD3), acute kidney injury, and respiratory infection), chronic lung allograft dysfunction (CLAD)-free survival, and overall survival according to GLP-1 RA use, using multivariable logistic regression and Cox models adjusted for key clinical covariates.
Results
Forty-two recipients received GLP-1 RA for obesity or diabetes and typically initiated months before LTx. Potential GLP-1 RA-related complications after lung transplant occurred in 4 patients (9.5%); therapy was discontinued in 3 patients (7.1%). Compared with non-users, GLP-1 RA recipients had higher body mass index and more diabetes, but pre-LTx GLP-1 RA use was not independently associated with PGD3 or other early complications. GLP-1 RA use within 90 days after LTx was not associated with postoperative aspiration or respiratory infection. In time-to-event analyses, GLP-1 RA use within 90 days was not associated with CLAD-free survival or overall survival.
Conclusions
In this small, retrospective cohort with limited GLP-1 RA exposure, GLP-1 RA use before and early after transplantation was not associated with worse early or late outcomes, including CLAD and mortality, and was generally well tolerated. These results are reassuring but should be interpreted cautiously; prospective studies in larger cohorts are needed to confirm safety and to define optimal patient selection and timing.
Keywords: Lung transplantation, Glucagon-like peptide-1 receptor agonist, Primary graft dysfunction, Chronic lung allograft dysfunction, Survival
Background
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are widely used for the treatment of type 2 diabetes mellitus and, more recently, for obesity management.1, 2 Beyond their glucose-lowering effects, GLP-1 RAs have demonstrated cardiovascular and renal benefits in large randomized clinical trials, including reductions in major adverse cardiovascular events, progression of kidney disease, and all-cause mortality in adults with type 2 diabetes at high cardiovascular or renal risk, such as those with established atherosclerotic cardiovascular disease or chronic kidney disease.3, 4, 5, 6 These data and contemporary guideline recommendations from the American Diabetes Association and ESC/EASD) suggest that GLP-1 RA will be used increasingly in patients with obesity, diabetes, and cardiovascular disease, conditions that are common among lung transplant candidates, and therefore the number of patients receiving GLP-1 RA therapy at the time of lung transplantation is expected to grow.7, 8, 9
Lung transplant recipients represent a particularly vulnerable population in whom the potential benefits of GLP-1 RAs must be weighed against unique perioperative risks. Many candidates have end-stage lung disease with frailty, sarcopenia, or pre-existing malnutrition and may be at risk for further weight loss or poor oral intake.10, 11, 12, 13 At the same time, GLP-1 RAs are increasingly used intentionally to promote weight loss in obese lung transplant candidates, as higher body mass index (BMI) has been associated with an increased risk of primary graft dysfunction and mortality after lung transplantation.14 In addition, GLP-1 RAs delay gastric emptying and are associated with gastrointestinal adverse effects such as nausea, vomiting, and decreased appetite, which might increase the risk of aspiration or interfere with perioperative nutritional support.15, 16, 17 For these reasons, GLP-1 RAs are recommended to be withheld temporarily or used with caution around the time of major surgery, and these concerns may make clinicians hesitant to prescribe them in the lung transplant setting despite their potential cardiometabolic advantages.18
Evidence regarding the safety and clinical impact of GLP-1 RAs in solid organ transplantation remains limited and has historically focused on kidney and liver transplant recipients.19, 20, 21, 22, 23, 24 More recently, small single-center series in lung transplant recipients also suggest that GLP-1 RAs can improve metabolic control and promote modest weight loss without clear major safety signals, although discontinuation due to gastrointestinal adverse effects is relatively common and benefits for lung allograft function have not been demonstrated.25, 26 In particular, it is unknown whether GLP-1 RA therapy around the time of lung transplantation influences early postoperative complications—such as primary graft dysfunction (PGD), acute kidney injury (AKI), or respiratory infection—or long-term outcomes such as chronic lung allograft dysfunction (CLAD) and overall survival.
In this context, we investigated the impact of GLP-1 RA use among lung transplant recipients to evaluate the association between GLP-1 RA exposure and clinical outcomes. We hypothesized that although GLP-1 RAs might be used selectively in patients with higher BMI or diabetes, their use would not be associated with an increased risk of perioperative complications or worse long-term survival or CLAD-free survival. To test this hypothesis, we retrospectively analyzed a contemporary cohort of lung transplant recipients, comparing baseline characteristics, early postoperative events, and long-term outcomes according to pre-transplant GLP-1 RA use and ongoing GLP-1 RA therapy at 90 days after transplantation.
Materials and methods
Study design and population
This was a retrospective cohort study of consecutive adult patients (≥18 years) who underwent lung transplantation at a single tertiary care center between January 2018 and May 2024. Clinical data were obtained from the electronic medical record and the institutional lung transplant database at Northwestern Memorial Hospital (Chicago, Illinois, USA). Multi-organ transplants and redo lung transplant procedures were excluded; only primary isolated lung transplants were included in the analytic cohort. The study protocol was approved by the Institutional Review Board of Northwestern University (STU00212120). The requirement for informed consent for data collection and analysis was waived because of the retrospective nature of the study. All transplants were performed according to institutional protocols, United States regulations, the Declaration of Helsinki, and the principles of the Declaration of Istanbul on Organ Trafficking and Transplant Tourism; no organs were procured from prisoners or other unethical sources. Peri-operative and post-operative management at our center has been described previously.27, 28, 29, 30, 31, 32 Detailed definitions of all study variables and complications are provided in the Supplemental Materials. Exposure groups were defined a priori according to the timing of GLP-1 RA therapy: (1) pre-transplant GLP-1 RA use and (2) GLP-1 RA initiation within 90 days after transplantation. Median follow-up time (reverse Kaplan-Meier) was 1.98 years (IQR 1.51-3.02) in the GLP-1 RA group and 3.18 years (IQR 1.89-4.56) in the non-GLP-1 RA group.
GLP-1 RA exposure and GLP-1 RA-related complications
As summarized above, exposure groups were defined based on the timing of GLP-1 RA therapy. Use of GLP-1 RA was ascertained from medication reconciliation records, pharmacy data, and treating physician documentation. Pre-LTx GLP-1 RA use was defined as active treatment with any GLP-1 RA at the time of lung transplantation. For these patients, we calculated the interval from GLP-1 RA initiation to transplantation (months). New GLP-1 RA use after LTx was defined as de novo initiation of a GLP-1 RA after transplantation, and the interval from LTx to GLP-1 RA initiation (days) was recorded. GLP-1 RA use within 90 days was defined as documented ongoing therapy during the early post-transplant period with continued use through postoperative day 90, based on medication reconciliation records and pharmacy data, irrespective of whether therapy was initiated before or after transplantation. This definition was intended to capture sustained early post-transplant exposure rather than isolated dosing. At our center, GLP-1 receptor agonists were not routinely discontinued prior to lung transplantation. Perioperative management was individualized by the transplant and anesthesia teams with standard perioperative fasting and aspiration risk mitigation as clinically indicated. Postoperatively, GLP-1 RAs were initiated or resumed after patients were clinically stable and able to tolerate oral intake, per routine clinical practice.
The specific GLP-1 RA used (e.g., semaglutide, dulaglutide, liraglutide, tirzepatide) and the primary indication for therapy (diabetes vs obesity/weight loss) were abstracted from the prescribing documentation. All GLP-1 receptor agonist use in this cohort consisted of injectable formulations; oral semaglutide was not used. Potential GLP-1 RA-related complications were defined a priori as gastrointestinal (GI) symptoms—nausea, vomiting, diarrhea, or decreased appetite—or aspiration events that the treating team considered at least possibly attributable to GLP-1 RA therapy. For patients who received GLP-1 RA after LTx, discontinuation of therapy and the reason for discontinuation (adverse event vs other causes) were recorded, and time from LTx to GLP-1 RA discontinuation (months) was calculated among those who stopped treatment. Complication categories were not considered mutually exclusive, and individual patients could contribute to more than 1 category.
Statistical analysis
Continuous variables are presented as medians with interquartile ranges (IQR), and categorical variables as counts with percentages. Baseline characteristics were compared according to (1) pre-transplant GLP-1 RA use (active therapy at the time of transplantation) and (2) GLP-1 RA use within 90 days (documented ongoing therapy through postoperative day 90, not a day-90 “snapshot”). Groups were compared using the Mann-Whitney U test; categorical variables were compared using the χ² test or Fisher’s exact test, as appropriate.
Short-term postoperative outcomes of interest included primary graft dysfunction grade 3 (PGD3), AKI, respiratory infection, other major complications, ICU and hospital length of stay, post-transplant ventilator days, and 90-day mortality. The association between pre-transplant GLP-1 RA use and PGD3 was evaluated using logistic regression. To reduce overfitting, the multivariable PGD3 model was prespecified as a parsimonious “core” model including age, ECMO bridge, dialysis, ischemic time, and pre-transplant GLP-1 RA exposure. Similarly, risk factors for respiratory infection were examined using logistic regression; the multivariable model included age, sex, BMI, smoking history, diabetes, CKD, ECMO bridge, bilateral versus single lung transplantation, operative time, peri-operative packed red blood cell transfusion, and GLP-1 RA use within 90 days. To address potential immunologic confounding, we additionally incorporated available immunologic covariates (PRA positivity, DSA positivity, desensitization, and post-discharge rejection [ACR/AMR]) in updated infection analyses and reported an exploratory post-transplant–adjusted sensitivity model in the Supplement. Odds ratios (ORs) with 95% confidence intervals (CIs) were reported.
Long-term outcomes were overall survival and CLAD-free survival. Time-to-event outcomes were analyzed using Kaplan-Meier methods and compared between exposure groups with the log-rank test. To mitigate immortal-time bias for “GLP-1 RA use within 90 days,” CLAD-free survival and overall survival were evaluated using a 90-day landmark approach (restricted to patients alive at postoperative day 90). For CLAD-free survival, patients were censored at last follow-up or death without CLAD. Cox proportional hazards models were used to identify factors associated with overall survival and CLAD-free survival. Primary multivariable Cox models used forced entry of prespecified clinically relevant baseline/perioperative covariates (age, sex, BMI, CKD, ECMO bridge, and bilateral versus single lung transplantation) and GLP-1 RA exposure; for CLAD models, key early post-transplant variables (AKI and PGD3) were included a priori. Because several post-transplant complications may lie on the causal pathway to mortality, these variables were not included in the primary overall survival model; instead, we conducted exploratory sensitivity analyses additionally adjusting for post-transplant events and downstream complications (including bowel ischemia, AKI, ICU length of stay, CLAD, and respiratory infection), reported in a Supplemental Table. Hazard ratios (HRs) with 95% CIs were reported.
The proportional hazards assumption was assessed using Schoenfeld residuals; when visual inspection suggested potential non-proportionality, we performed a restricted mean survival time sensitivity analysis (truncated at 5 years) to confirm the robustness of inferences. All tests were 2-sided, and a p value <0.05 was considered statistically significant; p values are reported to 3 decimal places (values of p = 0.050 were not considered statistically significant). Statistical analyses were performed using R (R Foundation for Statistical Computing, Vienna, Austria).
Results
Use of GLP-1 RA and related complications
A total of 460 lung transplant recipients were screened, and 443 patients met the inclusion criteria for analysis (Figure 1). A total of 42 patients received GLP-1 RA during the study period (Table 1). Most were already treated with GLP-1 RA before lung transplantation (37/42, 88%), with a median interval of 15 months [4-28.5] between GLP-1 RA initiation and transplantation. In the remaining 5 patients (12%), GLP-1 RA therapy was newly started after transplantation at a median of 15 days [11-23.5] post-LTx. The indication for GLP-1 RA was diabetes in 16 patients (38%) and obesity or weight loss in 26 (62%). Potential GLP-1 RA-related complications were infrequent, occurring in 4 patients (9.5%), all of whom experienced gastrointestinal symptoms; 1 patient (2.4%) also had an aspiration event considered at least possibly related to GLP-1 RA therapy. GLP-1 RA was discontinued in 3 patients (7.1%), all due to adverse events, with a median of 34 months [8-55] from lung transplantation to treatment discontinuation.
Figure 1.
Study cohort and GLP-1 exposure groups. Flow diagram of isolated primary lung transplant recipients between January 2018 and August 2024 (n = 461). Multi-organ transplants (n = 9) and re-do lung transplants (n = 9) were excluded. The entire cohort was used for short-term outcome analyses, comparing recipients with pre-operative GLP-1 use (n = 37) versus no pre-operative GLP-1 use (n = 406). For long-term outcome analyses, we further restricted the cohort to 90-day survivors (n = 446) and compared recipients with GLP-1 use within 90 days after transplantation (n = 40) versus those without GLP-1 use within 90 days (n = 388). A total of 42 patients had GLP-1 RA exposure at transplantation or within 90 days post-transplant (37 pre-transplant users and 5 post-transplant initiators). Two of these patients died within 90 days; therefore, 40 patients were on GLP-1 RA therapy at the 90-day time point among day-90 survivors.
Table 1.
Use of GLP-1 Receptor Agonists and GLP-1-Related Complications+A1:B50A36A1:B49A1:B49
| Variable | |
|---|---|
| GLP-1 exposure | |
| Patients with GLP-1 RA exposure at LTx or ≤90 days post-LTx | 42 |
| Pre-LTx GLP-1 use | 37 (88%) |
| Months from GLP-1 initiation to LTx | 15 [4-28.5] |
| De novo GLP-1 RA initiation after LTx | 5 (12%) |
| Days from LTx to GLP-1 initiation | 15 [11-23.5] |
| Indication - Diabetes | 16 (38%) |
| Indication - Obesity/weight loss | 26 (62%) |
| Death in 90 days after LTx | 3 (7.1%) |
| Type of GLP-1 agent | |
| Semaglutide | 21 (50.0%) |
| 0.25 mg/week SC | 13 (61.9%) |
| 0.5 mg/week SC | 4 (19.0%) |
| 1.0 mg/week SC | 2 (9.5%) |
| 2.0 mg/week SC | 2 (9.5%) |
| Dulaglutide | 4 (9.5%) |
| 1.5 mg/week SC | 2 (50.0%) |
| 0.75 mg/week SC | 2 (50.0%) |
| Liraglutide | 14 (33%) |
| 0.6 mg/daily SC | 7 (5.0%) |
| 1.2 mg/daily SC | 2 (28.6%) |
| 3.0 mg/daily SC | 5 (71.4%) |
| Tirzepatide | 3 (7.1%) |
| 5 mg/week SC | 1 (33.3%) |
| 10 mg/week SC | 2 (66.6%) |
| Complications possibly related to GLP-1 | |
| Any complication | 4 (9.5%) |
| Gastrointestinal symptoms | 4 (9.5%) |
| Aspiration | 1 (2.4%) |
| Discontinuation | |
| GLP-1 discontinued (any cause) | 3 (7.1%) |
| Discontinued due to adverse event | 3 (7.1%) |
| Months from LTx to GLP-1 discontinuation | 34 [8-55] |
Abbreviations: GLP-1, glucagon-like peptide-1; LTx, lung transplantation; GI, gastrointestinal.
Data are presented as n (%) or median IQR. Percentages are calculated among the 42 patients treated with GLP-1 receptor agonists. “Months from GLP-1 initiation to LTx” was calculated among patients who received GLP-1 before transplantation. “Days from LTx to GLP-1 initiation” and “Months from LTx to GLP-1 discontinuation” were calculated among patients who started or discontinued GLP-1 after LTx, respectively. Oral semaglutide was not used in the cohort. Complications “possibly related to GLP-1″ were defined as GI symptoms (nausea, vomiting, diarrhea, or decreased appetite) or aspiration events that the treating team considered at least potentially attributable to GLP-1 therapy. Complication categories are not mutually exclusive; the same patient may be counted in more than 1 row. Dose categories for each agent reflect the maintenance dose documented at the index timepoint (at lung transplantation for pre-LTx users, or the dose recorded within 90 days post-LTx for de novo initiators).
Baseline and perioperative characteristics
Baseline characteristics according to GLP-1 RA exposure are shown in Table 2. Compared with patients not receiving GLP-1 RA at the time of transplantation, those with pre-LTx GLP-1 RA use had substantially higher BMI and body surface area (BSA) and were more likely to have diabetes (54% vs 29%). Age, smoking history, hypertension, chronic kidney disease (CKD), dialysis dependence, waiting list duration, and use of pre-transplant extracorporeal membrane oxygenation (ECMO) were otherwise similar between groups. Lung disease etiology was broadly comparable, although interstitial lung disease was somewhat more frequent among GLP-1 RA users. Pre-LTx GLP-1 RA use was also associated with slightly shorter operative time and lower intra-operative packed red blood cells (pRBC) transfusion requirements, while the frequency of bilateral lung transplantation, use of intra-operative veno-arterial (VA)-ECMO, and other laboratory values were comparable. When patients were stratified by GLP-1 RA use at postoperative day 90, a similar pattern was observed: those with ongoing GLP-1 RA therapy had higher BMI and BSA and a higher prevalence of diabetes than patients not on GLP-1 RA, whereas age, sex distribution, comorbidities, lung disease etiology, pre-transplant support, laboratory measurements, and most intra-operative variables were largely similar between the 2 groups.
Table 2.
Characteristics of Patients
| Pre-LTx GLP-1 use |
GLP-1 use within 90 days after LTx |
||||||
|---|---|---|---|---|---|---|---|
| Variable | All patients (n = 443) | No (n = 406) | Yes (n = 37) | p value | No (n = 388) | Yes (n = 40) | p value |
| Pre-operative characteristics | |||||||
| Age, years | 63 [54-68] | 63 [54-68] | 63 [56-68] | 0.77 | 63 [54-68] | 62 [54-68] | 0.78 |
| Sex | 0.10 | 0.03 | |||||
| Male | 249 (56%) | 233 (57%) | 16 (43%) | 224 (58%) | 16 (40%) | ||
| Female | 194 (44%) | 173 (43%) | 21 (57%) | 164 (42%) | 24 (60%) | ||
| BMI, kg/m2 | 26.5 [22.2-29.5] | 25.8 [22.0-28.8] | 31.7 [30.5-32.5] | <0.001 | 25.7 [21.9-28.7] | 31.4 [29.5-32.4] | <0.001 |
| BSA, m2 | 1.87 [1.70-2.05] | 1.86 [1.68-2.02] | 2.06 [1.86-2.21] | <0.001 | 1.85 [1.68-2.02] | 2.03 [1.87-2.22] | <0.001 |
| Smoking history | 225 (51%) | 205 (50%) | 20 (54%) | 0.68 | 197 (51%) | 20 (50%) | 0.93 |
| Hypertension | 255 (58%) | 229 (56%) | 26 (70%) | 0.10 | 221 (57%) | 26 (65%) | 0.33 |
| Diabetes | 136 (31%) | 116 (29%) | 20 (54%) | 0.001 | 111 (29%) | 19 (48%) | 0.01 |
| CKD | 42 (9.5%) | 37 (9.1%) | 5 (14%) | 0.38 | 37 (9.5%) | 5 (13%) | 0.57 |
| Dialysis | 22 (5.0%) | 21 (5.2%) | 1 (2.7%) | >0.999 | 19 (4.9%) | 1 (2.5%) | 0.71 |
| Waiting list duration, days | 10 [5-33] | 10 [5-34] | 9 [5-19] | 0.74 | 10 [5-34] | 9 [5-24] | 0.64 |
| ECMO bridge | 46 (10%) | 44 (11%) | 2 (5.4%) | 0.41 | 42 (11%) | 3 (7.5%) | 0.79 |
| Etiology | 0.053 | 0.21 | |||||
| ARDS | 46 (10%) | 45 (11%) | 1 (2.7%) | 43 (11%) | 3 (7.5%) | ||
| COPD | 87 (20%) | 84 (21%) | 3 (8.1%) | 82 (21%) | 4 (10%) | ||
| ILD | 213 (48%) | 188 (46%) | 25 (68%) | 177 (46%) | 24 (60%) | ||
| PAH | 44 (9.9%) | 39 (9.6%) | 5 (14%) | 48 (12%) | 3 (7.5%) | ||
| Others | 53 (12%) | 50 (12%) | 3 (8.1%) | 38 (9.8%) | 6 (15%) | ||
| Laboratory | |||||||
| Hemoglobin, g/dL | 11.90 [10.10-13.50] | 11.80 [10.00-13.50] | 12.30 [10.80-13.40] | 0.23 | 11.85 [9.95-13.50] | 12.10 [10.60-13.45] | 0.40 |
| Platelets, 1,000/mm3 | 238 [190-297] | 238 [189-297] | 237 [195-291] | 0.83 | 238 [190-296] | 233 [189-291] | 0.57 |
| Creatinine, mg/dL | 0.78 [0.61-0.93] | 0.77 [0.61-0.92] | 0.82 [0.68-1.03] | 0.11 | 0.77 [0.61-0.92] | 0.80 [0.65-0.98] | 0.38 |
| INR | 1.00 [1.00-1.10] | 1.00 [1.00-1.10] | 1.00 [1.00-1.10] | 0.27 | 1.00 [1.00-1.10] | 1.00 [1.00-1.10] | 0.46 |
| PTT, seconds | 30.6 [28.1-33.6] | 30.6 [28.1-33.5] | 31.2 [28.4-34.2] | 0.57 | 30.5 [28.1-33.5] | 31.2 [27.9-34.2] | 0.52 |
| Intra-operative outcomes | |||||||
| Bilateral lung transplant | 277 (63%) | 255 (63%) | 22 (59%) | 0.69 | 247 (64%) | 23 (58%) | 0.44 |
| Operative time (hours) | 5.53 [4.31-7.30] | 5.62 [4.40-7.40] | 5.08 [3.80-6.23] | 0.02 | 5.59 [4.35-7.40] | 5.21 [3.99-6.23] | 0.08 |
| Intra-op blood transfusion | |||||||
| pRBC, unit | 0.00 [0.00-2.00] | 1.00 [0.00-3.00] | 0.00 [0.00-0.00] | 0.001 | 0.50 [0.00-2.00] | 0.00 [0.00-0.50] | 0.003 |
| FFP, unit | 0.00 [0.00-0.00] | 0.00 [0.00-0.00] | 0.00 [0.00-0.00] | 0.14 | 0.00 [0.00-0.00] | 0.00 [0.00-0.00] | 0.20 |
| Plt, unit | 0.00 [0.00-0.00] | 0.00 [0.00-0.00] | 0.00 [0.00-0.00] | 0.08 | 0.00 [0.00-0.00] | 0.00 [0.00-0.00] | 0.13 |
| VA ECMO use | 268 (60%) | 248 (61%) | 20 (54%) | 0.40 | 235 (61%) | 20 (50%) | 0.20 |
Abbreviations: ARDS, acute respiratory distress syndrome; BMI, body mass index; BSA, body surface area; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; ECMO, extracorporeal membrane oxygenation; eGFR, estimated glomerular filtration rate; FFP, fresh frozen plasma; GLP-1, Glucagon-like peptide-1 receptor agonist; HbA1c, glycated hemoglobin; ILD, interstitial lung disease; INR, international normalized ratio; PAH, pulmonary arterial hypertension; pRBC, packed red blood cells; PTT, partial thromboplastin time.
Values are presented as median [IQR] for continuous variables and n (%) for categorical variables. Pre-LTx GLP-1 use indicates treatment with any GLP-1 at the time of lung transplantation. GLP1 use within 90 days indicates ongoing GLP1 therapy at postoperative day 90.
BMI changes after transplantation
Among recipients treated with GLP-1 receptor agonists, BMI trajectories were evaluated according to timing of exposure (continued through transplantation [“GLP1 in LTx”] vs initiated within 90 days after transplantation [“GLP1 in 90 days”]) (Supplemental Figure S1). At baseline, median BMI was 31.70 kg/m² (IQR 30.46-32.47, n = 37) in the GLP1 in LTx group and 29.72 kg/m² (IQR 29.56-30.66, n = 5) in the GLP1 in 90 days group (p = 0.200). At POD90, median BMI was 29.55 kg/m² (IQR 28.38-30.65, n = 36) vs 29.52 kg/m² (IQR 28.08-30.36, n = 5; p = 0.873). At POD365, median BMI was 30.25 kg/m² (IQR 28.72-33.08, n = 33) vs 31.37 kg/m² (IQR 28.76-32.32, n = 5; p = 0.730). When expressed as change from baseline, the median ΔBMI at POD90 was −1.48 kg/m² (IQR −2.85 to 0.21) in the GLP1 in LTx group and −0.04 kg/m² (IQR −2.58 to 0.64) in the GLP1 in 90 days group (p = 0.618). At POD365, median ΔBMI was −0.90 kg/m² (IQR −3.01 to 1.28) vs −0.66 kg/m² (IQR −0.96 to 2.76; p = 0.364), with substantial inter-individual variability in both groups.
Renal function trajectories in recipients with pre-transplant CKD
In recipients with pre-transplant CKD, eGFR was evaluated at baseline (pre-transplant) and at 1, 3, 6, and 12 months after transplantation (Supplemental Figure S2). In this CKD subset (n = 42), 5 recipients received GLP-1 receptor agonists through transplantation (“GLP1 in LTx”), whereas 37 recipients received no GLP-1 therapy; notably, there were no recipients classified as “GLP1 in 90 days” within the CKD subset. Median baseline eGFR was 63.4 (IQR 53.9-73.0) mL/min/1.73 m² in the GLP1 in LTx group versus 86.1 (IQR 63.5-95.1) mL/min/1.73 m² in the No GLP1 group (p = 0.21), and absolute eGFR values did not differ significantly between groups at any post-transplant timepoint (all p ≥ 0.278). When expressed as change from baseline, ΔeGFR at 1, 3, and 6 months was similar between groups (p = 0.415, 0.278, and 0.414, respectively). At 12 months, the GLP1 in LTx group demonstrated a smaller median decline in eGFR (−13.0 [IQR −21.4 to 3.2] vs −49.3 [IQR −61.1 to −30.9] mL/min/1.73 m² p = 0.03); however, this difference did not remain significant after multiple-comparison adjustment (BH-adjusted p = 0.12) and was limited by the small number of GLP-1–treated recipients with 12-month data (n = 3).
Early postoperative complications and clinical course
Postoperative complications and early clinical course according to pre-transplant GLP-1 RA exposure are summarized in Table 3. The overall incidences of major thromboembolic or ischemic events did not differ significantly between patients with and without pre-LTx GLP-1 RA use, including cerebrovascular accident, bowel ischemia, digital ischemia, deep vein thrombosis, and pulmonary embolism. Rates of postoperative ECMO support, AKI, and hemodialysis after discharge were also comparable. Similarly, the proportion of patients who developed PGD grade 3, intensive care unit (ICU) length of stay, duration of post-transplant mechanical ventilation, total hospital stay, 90-day mortality, and postoperative respiratory infections were not significantly different between those with and without pre-LTx GLP-1 RA therapy.
Table 3.
Postoperative Complications and Clinical Course According to Pre-transplant GLP-1 Use
| Pre-LTx GLP-1 use |
||||
|---|---|---|---|---|
| Variable | All patients (n = 443) | No (n = 406) | Yes (n = 37) | p value |
| Post-operative outcomes | ||||
| CVA | 15 (3.4%) | 13 (3.2%) | 2 (5.4%) | 0.36 |
| Bowel ischemia | 6 (1.4%) | 6 (1.5%) | 0 (0%) | >0.999 |
| Digital ischemia | 8 (1.8%) | 7 (1.7%) | 1 (2.7%) | 0.51 |
| DVT | 230 (52%) | 210 (52%) | 20 (54%) | 0.86 |
| PE | 62 (14%) | 57 (14%) | 5 (14%) | >0.999 |
| Postoperative ECMO use | 57 (13%) | 53 (13%) | 4 (11%) | >0.999 |
| AKI | 207 (47%) | 187 (46%) | 20 (54%) | 0.39 |
| Hemodialysis after discharge | 58 (13%) | 54 (13%) | 4 (11%) | 0.80 |
| PGD grade 3 | 58 (13%) | 52 (13%) | 6 (16%) | 0.61 |
| ICU stay, days | 7 [4-15] | 7 [4-15] | 6 [4-12] | 0.27 |
| Post transplant ventilator days | 2 [1-3] | 2 [1-3] | 2 [1-3] | 0.85 |
| Hospital stay, days | 17 [12-31] | 17 [12-31] | 15 [13-31] | 0.67 |
| 90-days mortality | 15 (3.4%) | 13 (3.2%) | 2 (5.4%) | 0.36 |
| Respiratory infection | 205 (46%) | 192 (47%) | 13 (35%) | 0.17 |
Abbreviations: AKI, acute kidney injury; CVA, cerebrovascular accident; DVT, deep vein thrombosis; ECMO, extracorporeal membrane oxygenation; GLP-1, Glucagon-like peptide-1 receptor agonist; HD, hemodialysis; LTx, lung transplantation; PE, pulmonary embolism; PGD, primary graft dysfunction.
Values are presented as median [IQR] for continuous variables and n (%) for categorical variables. P values were calculated using the Mann-Whitney U test for continuous variables and Fisher’s exact test for categorical variables.
Predictors of PGD grade 3
Factors associated with the development of PGD grade 3 are summarized in Table 4. On univariable analysis, younger age, preoperative dialysis, the need for ECMO bridge to transplantation, lower hemoglobin, higher creatinine, higher international normalized ratio (INR) and partial thromboplastin time, longer operative time, greater intraoperative transfusion of pRBC, fresh frozen plasma (FFP), and platelets, and use of VA ECMO were each associated with increased odds of PGD grade 3. In the multivariable logistic regression model adjusting for age, dialysis, ECMO bridge, GLP-1 RA use, and ischemic time, ECMO bridge and dialysis remained independently associated with PGD grade 3, whereas pre-transplant GLP-1 RA use was not (OR 1.83, 95% CI 0.64-4.57; p = 0.22).
Table 4.
Univariate and Multivariate Logistic Regression Analysis to Predict PGD Grade 3
| Univariate |
Multivariate |
|||||
|---|---|---|---|---|---|---|
| Variable | OR | 95% CI | p value | OR | 95% CI | p value |
| Pre-operative characteristics | ||||||
| Age, years | 0.98 | 0.96-1.00 | 0.02 | 0.99 | 0.97-1.02 | 0.64 |
| Sex: Female (vs Male) | 0.75 | 0.43-1.31 | 0.31 | |||
| BMI, kg/m2 | 1.04 | 0.98-1.11 | 0.17 | |||
| BSA, m2 | 1.66 | 0.54-5.07 | 0.37 | |||
| Smoking history | 0.89 | 0.51-1.55 | 0.68 | |||
| Hypertension | 0.89 | 0.51-1.57 | 0.69 | |||
| Diabetes | 0.93 | 0.49-1.67 | 0.81 | |||
| CKD | 1.65 | 0.68-3.61 | 0.23 | |||
| Dialysis | 6.48 | 2.61-15.8 | <0.001 | 5.09 | 1.89-13.3 | <0.001 |
| Waiting list duration, days | 1.00 | 1.0-1.01 | 0.71 | |||
| ECMO bridge | 6.46 | 3.27-12.7 | <0.001 | 5.76 | 2.65-12.5 | <0.001 |
| GLP-1 use | 1.32 | 0.48-3.11 | 0.56 | 1.84 | 0.64-4.57 | 0.22 |
| Etiology | ||||||
| ILD | 0.85 | 0.38-2.11 | 0.71 | |||
| COPD | 0.42 | 0.13-1.27 | 0.13 | |||
| PAH | 0.41 | 0.09-1.53 | 0.21 | |||
| ARDS | 2.22 | 0.84-6.18 | 0.12 | |||
| Laboratory | ||||||
| Hemoglobin, g/dL | 0.87 | 0.78-0.98 | 0.02 | |||
| Platelets, 1,000/mm3 | 1.00 | 0.99-1.00 | 0.11 | |||
| Creatinine, mg/dL | 2.35 | 1.11-5.77 | 0.04 | |||
| INR | 3.36 | 1.00-11.94 | 0.046 | |||
| PTT, seconds | 1.02 | 1.00-1.04 | 0.03 | |||
| Intra-operative outcomes | ||||||
| Bilateral lung transplant | 1.39 | 0.78-2.56 | 0.28 | |||
| Operative time (hours) | 1.25 | 1.09-1.43 | 0.001 | |||
| Ischemic time (hours) | 0.97 | 0.87-1.05 | 0.48 | 0.93 | 0.83-1.03 | 0.19 |
| Intra-op blood transfusion | ||||||
| pRBC, unit | 1.15 | 1.09-1.22 | <0.001 | |||
| FFP, unit | 1.22 | 1.11-1.35 | <0.001 | |||
| Plt, unit | 1.48 | 1.24-1.80 | <0.001 | |||
| VA ECMO use | 2.04 | 1.12-3.91 | 0.02 | |||
Abbreviations: ARDS, acute respiratory distress syndrome; BMI, body mass index; BSA, body surface area; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; ECMO, extracorporeal membrane oxygenation; eGFR, estimated glomerular filtration rate; FFP, fresh frozen plasma; GLP-1, Glucagon-like peptide-1 receptor agonist; HbA1c, glycated hemoglobin; ILD, interstitial lung disease; INR, international normalized ratio; PAH, pulmonary arterial hypertension; pRBC, packed red blood cells; PTT, partial thromboplastin time.
Predictors of postoperative respiratory infection
Postoperative respiratory infection occurred in 205 patients during follow-up (Table 5). On univariable analysis, female sex, absence of smoking history, pre-operative dialysis, higher INR, longer operative time, and greater intraoperative transfusion (pRBC and FFP) were associated with respiratory infection, whereas GLP-1 RA use at transplantation (GLP1 in LTx) was not. In the multivariable model including clinically relevant pre-/intra-operative and immunologic factors (Table 5), smoking history remained associated with lower odds of respiratory infection (adjusted OR 0.51, 95% CI 0.27-0.93; p = 0.03), while DSA positivity was associated with higher odds (adjusted OR 6.49, 95% CI 1.52-36.4; p = 0.02). GLP-1 RA use at transplantation was not independently associated with respiratory infection (adjusted OR 0.91, 95% CI 0.33-2.39; p = 0.86). In an exploratory model additionally adjusting for selected post-transplant factors (Supplemental Table S1), results were consistent, and GLP-1 RA use remained non-significant (adjusted OR 0.88, 95% CI 0.29-2.48; p = 0.817).
Table 5.
Univariate and Multivariate Logistic Regression Analysis to Predict Respiratory Infection
| Univariate |
Multivariate |
|||||
|---|---|---|---|---|---|---|
| Variable | OR | 95% CI | p value | OR | 95% CI | p value |
| Pre-operative characteristics | ||||||
| Age, years | 0.99 | 0.97, 1.01 | 0.19 | 1.02 | 0.99, 1.04 | 0.23 |
| Sex: Female (vs Male) | 1.61 | 1.10, 2.36 | 0.01 | 1.76 | 0.94, 3.34 | 0.08 |
| BMI, kg/m2 | 0.97 | 0.93, 1.01 | 0.15 | 0.97 | 0.90, 1.04 | 0.34 |
| BSA, m2 | 0.65 | 0.30, 1.39 | 0.27 | |||
| Smoking history | 0.60 | 0.41, 0.87 | 0.01 | 0.51 | 0.27, 0.93 | 0.03 |
| Hypertension | 0.89 | 0.61, 1.31 | 0.56 | |||
| Diabetes | 1.09 | 0.73, 1.64 | 0.67 | 1.19 | 0.61, 2.29 | 0.61 |
| CKD | 0.77 | 0.40, 1.46 | 0.43 | 0.43 | 0.14, 1.14 | 0.11 |
| Dialysis | 2.61 | 1.08, 6.94 | 0.04 | |||
| Waiting list duration, days | 1.00 | 1.00, 1.01 | 0.55 | |||
| ECMO bridge | 1.58 | 0.86, 2.96 | 0.14 | 0.57 | 0.10, 2.62 | 0.48 |
| GLP-1 use | 0.60 | 0.29, 1.20 | 0.16 | 0.91 | 0.33, 2.39 | 0.86 |
| Etiology | ||||||
| ILD | 1.27 | 0.69, 2.36 | 0.44 | |||
| COPD | 1.26 | 0.63, 2.52 | 0.52 | |||
| PAH | 0.59 | 0.25, 1.37 | 0.22 | |||
| ARDS | 2.19 | 0.99, 4.97 | 0.06 | |||
| Laboratory | ||||||
| Hemoglobin, g/dL | 0.94 | 0.87, 1.02 | 0.13 | |||
| Platelets, 1,000/mm3 | 1.00 | 1.00, 1.00 | 0.47 | |||
| Creatinine, mg/dL | 0.81 | 0.42, 1.48 | 0.51 | |||
| INR | 4.33 | 1.39, 15.7 | 0.02 | |||
| PTT, seconds | 0.99 | 0.97, 1.01 | 0.38 | |||
| PRA positive | 1.06 | 0.72, 1.55 | 0.77 | 0.49 | 0.22, 1.03 | 0.07 |
| DSA positive | 1.43 | 0.83, 2.50 | 0.20 | 6.49 | 1.52, 36.4 | 0.02 |
| Desensitization protocol | 0.66 | 0.31, 1.32 | 0.25 | 0.25 | 0.05, 1.01 | 0.07 |
| Intra-operative outcomes | ||||||
| Bilateral lung transplant | 0.86 | 0.58, 1.27 | 0.45 | 1.13 | 0.48, 2.68 | 0.78 |
| Operative time (hours) | 1.21 | 1.10, 1.34 | <0.001 | 0.97 | 0.71, 1.32 | 0.83 |
| Intra-op blood transfusion | ||||||
| pRBC, unit | 1.06 | 1.01, 1.12 | 0.02 | 1.12 | 0.95, 1.33 | 0.18 |
| FFP, unit | 1.12 | 1.02, 1.23 | 0.02 | |||
| Plt, unit | 1.12 | 0.97, 1.32 | 0.14 | |||
| VA ECMO use | 1.08 | 0.74, 1.58 | 0.70 | |||
| Post-operative outcomes | ||||||
| GLP-1 use within 90 days | 0.62 | 0.31, 1.18 | 0.15 | |||
| CVA | 0.77 | 0.25, 2.16 | 0.62 | |||
| Bowel Ischemia | 1.16 | 0.21, 6.35 | 0.85 | |||
| Digital Ischemia | 1.16 | 0.27, 4.98 | 0.83 | |||
| DVT | 1.98 | 1.36, 2.90 | <0.001 | |||
| PE | 1.38 | 0.81, 2.38 | 0.24 | |||
| Postoperative ECMO use | 1.34 | 0.77, 2.35 | 0.30 | |||
| AKI | 1.21 | 0.83, 1.76 | 0.32 | |||
| Hemodialysis after discharge | 2.72 | 1.54, 4.98 | <0.001 | |||
| PGD grade 3 | 0.8 | 0.45, 1.39 | 0.42 | |||
| ICU stay, days | 1.01 | 1.00, 1.02 | 0.02 | |||
| Post transplant ventilator days | 1 | 0.99, 1.02 | 0.43 | |||
| Hospital stay, days | 1.01 | 1.00, 1.02 | 0.01 | |||
| ACR | 2.24 | 1.43, 3.56 | <0.001 | |||
| AMR | 2.03 | 0.88, 4.93 | 0.10 | |||
Abbreviations: ARDS, acute respiratory distress syndrome; BMI, body mass index; BSA, body surface area; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; ECMO, extracorporeal membrane oxygenation; eGFR, estimated glomerular filtration rate; FFP, fresh frozen plasma; GLP-1, Glucagon-like peptide-1 receptor agonist; HbA1c, glycated hemoglobin; ILD, interstitial lung disease; INR, international normalized ratio; PAH, pulmonary arterial hypertension; pRBC, packed red blood cells; PTT, partial thromboplastin time.
Association of GLP-1 RA use with CLAD-free survival
Among 90-day survivors, median follow-up was 2.4 years (IQR 1.49-4.10) in recipients without GLP-1 RA use (n = 401) and 1.84 years (IQR 1.44-2.37) in those with GLP-1 RA use within 90 days (n = 42). During follow-up, 66 patients developed CLAD (60 in the no GLP-1 group and 6 in the GLP-1 group). Among those who developed CLAD, the median time to CLAD was 587 days (IQR 400-996) in the no GLP-1 group and 424 days (IQR 330-794) in the GLP-1 group (Supplemental Table S2). In univariable Cox analyses, AMR and postoperative respiratory infection were associated with an increased hazard of CLAD, whereas postoperative AKI was associated with a lower hazard. In the multivariable Cox model including age, sex, BMI, ECMO bridge, transplant laterality, and pre-transplant GLP-1 RA use, GLP-1 RA use was not associated with CLAD (adjusted HR 1.23, 95% CI 0.47-3.25; p = 0.67), while older age was associated with a modestly lower hazard of CLAD (adjusted HR 0.97 per year, 95% CI 0.95-0.99; p = 0.01). In an exploratory model additionally incorporating post-transplant factors (any rejection [ACR/AMR] and any infection [CMV/respiratory]), GLP-1 RA use again was not associated with CLAD (adjusted HR 1.51, 95% CI 0.57-3.99; p = 0.41), and neither rejection nor infection reached statistical significance (Supplemental Table S3). Kaplan-Meier curves stratified by GLP-1 RA use showed no clear separation in CLAD-free survival between groups (Supplemental Figure S3).
Association of GLP-1 RA use with overall survival
Among patients alive at day 90 after lung transplantation (n = 428), 113 deaths (26.4%) occurred during follow-up. The median follow-up time from transplantation was 857 days (2.35 years; IQR 553-1408.8 days [1.51-3.86 years]; range 96-2810 days). Among decedents, the median time to death was 475 days (1.30 years; IQR 293-841 days [0.80-2.30 years]; range 96-2162 days). Kaplan-Meier curves stratified by GLP-1 RA use within 90 days of lung transplantation showed no apparent difference in overall survival between patients with and without ongoing GLP-1 RA therapy (Figure 2). Consistent with these visual findings, neither pre-transplant GLP-1 RA exposure nor GLP-1 RA use within 90 days after LTx was significantly associated with mortality on Cox regression (Table 6). In the multivariable model, pre-existing CKD was independently associated with an increased risk of death, whereas bilateral lung transplantation was associated with improved survival. GLP-1 RA use within 90 days after LTx was not associated with mortality (HR 1.56, 95% CI 0.79-3.05; p = 0.20). In an exploratory sensitivity model that additionally adjusted for early post-transplant events and downstream complications (bowel ischemia, AKI, ICU stay, CLAD, and respiratory infection), the point estimate for GLP-1 RA use within 90 days was higher but remained statistically non-significant (HR 1.91, 95% CI 0.97-3.77; p = 0.06; Supplemental Table S4).
Figure 2.
Overall survival according to early GLP-1 use. Kaplan–Meier curves for overall survival after lung transplantation stratified by GLP-1 receptor agonist use within 90 days after transplantation. The salmon line shows recipients without GLP-1 use (n = 388), and the blue line shows recipients with GLP-1 use within 90 days (n = 40). Tick marks indicate censored observations. There was no significant difference in overall survival between the 2 groups (log-rank p = 0.26). Numbers at risk at each time point are shown below the x-axis.
Table 6.
Univariate and Multivariate Cox Regression Analysis to Predict Overall Survival
| Univariate |
Multivariate |
|||||
|---|---|---|---|---|---|---|
| Variable | HR | 95% CI | p value | HR | 95% CI | p value |
| Pre-operative characteristics | ||||||
| Age, years | 1.01 | 0.99-1.02 | 0.42 | 1.00 | 0.98-1.02 | 0.77 |
| Sex: Female (vs Male) | 0.76 | 0.53-1.11 | 0.15 | 0.72 | 0.49-1.05 | 0.09 |
| BMI, kg/m2 | 0.99 | 0.95-1.04 | 0.76 | 0.97 | 0.93-1.01 | 0.18 |
| BSA, m2 | 0.68 | 0.31-1.48 | 0.33 | |||
| Smoking history | 1.2 | 0.83-1.74 | 0.34 | |||
| Hypertension | 1.18 | 0.81-1.71 | 0.40 | |||
| Diabetes | 1.34 | 0.91-1.96 | 0.14 | 1.32 | 0.89-1.96 | 0.17 |
| CKD | 2.17 | 1.29-3.65 | 0.003 | 2.05 | 1.21-3.48 | 0.007 |
| Dialysis | 3.2 | 1.75-5.82 | <0.001 | |||
| Waiting list duration, days | 1 | 1.00-1.00 | 0.88 | |||
| ECMO bridge | 1.08 | 0.61-1.93 | 0.80 | 1.49 | 0.78-2.82 | 0.23 |
| GLP-1 use | 1.53 | 0.80-2.94 | 0.203 | |||
| Etiology | ||||||
| ILD | 1.32 | 0.69-2.54 | 0.41 | |||
| COPD | 1.79 | 0.89-3.60 | 0.10 | |||
| PAH | 0.96 | 0.40-2.32 | 0.92 | |||
| ARDS | 1.03 | 0.44-2.38 | 0.95 | |||
| Laboratory | ||||||
| Hemoglobin, g/dL | 0.98 | 0.91-1.06 | 0.68 | |||
| Platelets, 1,000/mm3 | 1 | 1.00-1.00 | 0.68 | |||
| Creatinine, mg/dL | 2.12 | 1.31-3.43 | 0.002 | |||
| INR | 0.48 | 0.14-1.72 | 0.26 | |||
| PTT, seconds | 0.98 | 0.94-1.01 | 0.13 | |||
| Intra-operative outcomes | ||||||
| Bilateral lung transplant | 0.62 | 0.43-0.89 | 0.01 | 0.61 | 0.40-0.93 | 0.02 |
| Operative time (hours) | 0.98 | 0.89-1.07 | 0.63 | |||
| Intra-op blood transfusion | ||||||
| pRBC, unit | 1 | 0.96-1.05 | 0.88 | |||
| FFP, unit | 1.02 | 0.95-1.09 | 0.67 | |||
| Plt, unit | 1.08 | 0.95-1.23 | 0.25 | |||
| VA ECMO use | 0.8 | 0.55-1.16 | 0.23 | |||
| Post-operative outcomes | ||||||
| GLP-1 use within 90 days | 1.43 | 0.76-2.67 | 0.26 | 1.56 | 0.79-3.05 | 0.20 |
| CVA | 2.06 | 0.76-5.60 | 0.16 | |||
| Bowel Ischemia | 7.03 | 2.22-22.3 | <0.001 | |||
| Digital Ischemia | 3.09 | 0.98-9.75 | 0.05 | |||
| DVT | 2.24 | 1.49-3.36 | <0.001 | |||
| PE | 1.7 | 1.08-2.66 | 0.02 | |||
| Postoperative ECMO use | 1.94 | 1.18-3.18 | 0.009 | |||
| AKI | 2.01 | 1.38-2.92 | <0.001 | |||
| Hemodialysis after discharge | 6.53 | 4.40-9.67 | <0.001 | |||
| PGD grade 3 | 2.13 | 1.33-3.43 | 0.002 | |||
| ICU stay, days | 1.01 | 1.01-1.02 | <0.001 | |||
| Post transplant ventilator days | 1.01 | 1.00-1.02 | 0.004 | |||
| Hospital stay, days | 1.01 | 1.01-1.02 | <0.001 | |||
| CLAD | 1.55 | 1.02, 2.36 | 0.04 | |||
| Respiratory infection | 1.91 | 1.29, 2.81 | 0.001 | |||
Abbreviations: AKI, acute kidney injury; ARDS, acute respiratory distress syndrome; BMI, body mass index; BSA, body surface area; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; CVA, cerebrovascular accident; DVT, deep vein thrombosis; ECMO, extracorporeal membrane oxygenation, ECMO, extracorporeal membrane oxygenation; eGFR, estimated glomerular filtration rate; FFP, fresh frozen plasma; GLP-1, Glucagon-like peptide-1 receptor agonist; HbA1c, glycated hemoglobin; HD, hemodialysis; HR, hazard ratio; ILD, interstitial lung disease; INR, international normalized ratio; LTx, lung transplantation; PAH, pulmonary arterial hypertension; PE, pulmonary embolism; PGD, primary graft dysfunction; pRBC, packed red blood cells; PTT, partial thromboplastin time.
Discussion
In this single-center retrospective cohort of contemporary lung transplant recipients, both of pre and post lung transplant use of GLP-1 RA was common among patients with obesity and/or diabetes but was not associated with an increased risk of early postoperative complications, CLAD, or death. GLP-1 RA therapy was generally well tolerated, with relatively few treatment-limiting adverse events and only 1 aspiration event deemed at least possibly related to GLP-1 RA use. These findings suggest that, in carefully selected recipients, GLP-1 RA can be used perioperative period of lung transplantation without increase risk of short- or long-term clinical outcomes.
Our study adds to a growing body of literature examining GLP-1 RA in the lung transplant population. Prior work in solid organ transplantation has focused primarily on metabolic endpoints in kidney and liver transplant recipients, demonstrating improvements in glycemic control and weight without obvious detrimental effects on graft function, but with relatively short follow-up and limited characterization of hard clinical outcomes.33 More recently, Fishman and colleagues reported on 59 lung transplant recipients treated with GLP-1 RA at a single center, describing modest weight loss, high rates of gastrointestinal adverse effects, and frequent treatment discontinuation, but without systematic evaluation of perioperative complications or long-term outcomes such as CLAD or survival.26 January et al similarly observed that GLP-1 RA therapy after lung transplantation was associated with weight loss and improved glycemic control but did not demonstrate clear benefits for allograft function.25 In contrast to these primarily metabolic evaluations, our analysis was specifically designed to examine the clinical impact whether GLP-1 RA exposure before and early after transplantation was associated with PGD, AKI, respiratory infection, CLAD-free survival, and overall survival.
Perioperative safety is a central concern when considering GLP-1 RA in lung transplant candidates and recipients. Contemporary perioperative consensus statements recommend temporary withholding of GLP-1 RA therapy before major surgery owing to delayed gastric emptying and the risk of nausea, vomiting, and aspiration.18 Particularly after lung transplant, aspiration is both common and frequently clinically occult. In our prior single-center cohort of 118 lung transplant recipients who underwent instrumental swallow evaluation, 59% demonstrated pathological airway invasion, and more than half of aspiration events were silent, with lower BMI and markers of frailty associated with airway invasion.34 These observations highlight that lung transplant recipients already face a substantial baseline risk of aspiration, amplifying concern about additional delays in gastric emptying from perioperative GLP-1 RA use.
These concerns may be magnified in lung transplant recipients, who frequently have frailty, sarcopenia, and pre-existing malnutrition. In our cohort, however, pre-transplant GLP-1 RA use was not associated with PGD grade 3, AKI, thromboembolic events, or early mortality, even after adjustment for established risk factors including ECMO bridge and perioperative transfusion. GLP-1 RA use within the first 90 days after lung transplantation also was not independently associated with postoperative respiratory infection. Although the small number of GLP-1 RA-related adverse events (4/42; 9.5%) in our series precludes definitive safety conclusions, these findings provide reassuring real-world data that GLP-1 RA therapy does not appear to substantially worsen early postoperative outcomes.
We also observed no significant association between GLP-1 RA exposure and longer-term outcomes, including CLAD-free survival and overall survival. Kaplan-Meier curves for CLAD and death showed substantial overlap between GLP-1 RA users and non-users, and GLP-1 RA use did not emerge as an independent predictor in multivariable Cox models. Because GLP-1 RA delay gastric emptying and can increase nausea, vomiting, and aspiration risk, we initially hypothesized that their use might predispose lung transplant recipients to CLAD through chronic microaspiration. However, aspiration and microaspiration were not directly assessed in this study (e.g., by swallow evaluation, aspiration events, or biomarker-based measures). Therefore, while we did not observe an association between GLP-1 RA exposure and CLAD in this cohort, we cannot determine whether GLP-1 RA use altered aspiration risk; future studies incorporating aspiration-specific outcomes are warranted.
Our study has several important clinical implications. First, clinicians may consider continuing or re-initiating GLP-1 RA in selected lung transplant recipients with obesity or diabetes, particularly in the subacute and chronic postoperative phases, while closely monitoring for gastrointestinal adverse effects and aspiration risk.26, 33 Second, in this cohort, GLP-1 RA exposure before or early after transplantation was not associated with worse long-term outcomes, including CLAD-free survival and overall survival. These findings may provide reassurance for clinicians and patients when GLP-1 RA therapy is otherwise clinically indicated, and they do not support a blanket policy of routine discontinuation or universal avoidance after lung transplantation. Nonetheless, given the retrospective design and the absence of direct assessment of dysphagia/aspiration-related outcomes, treatment decisions should remain individualized. Further prospective studies are needed to define optimal patient selection, timing, dosing strategies, and to systematically evaluate gastrointestinal and aspiration-related safety endpoints in lung transplant recipients.
Several limitations should be acknowledged. The retrospective single-center design is subject to selection bias and unmeasured confounding. Patients prescribed GLP-1 RA likely differed from non-users in ways that we could not fully capture, including detailed measures of body composition, frailty, insulin resistance, and provider-level preferences. Exposure to GLP-1 RA therapy was heterogeneous with respect to specific agents, dosing, duration, and perioperative interruption, and we did not systematically evaluate metabolic outcomes such as weight trajectories or glycated hemoglobin, which may mediate long-term benefits. Aspiration events and gastrointestinal symptoms were ascertained from clinical documentation and may have been under-reported or misattributed. Similarly, postoperative respiratory infections were abstracted using a pragmatic composite definition and were not consistently subclassified into bacterial, fungal, and viral etiologies due to variability in documentation and microbiologic attribution. Because these infection subtypes may carry different risks for subsequent CLAD, this limitation may have introduced outcome misclassification and precluded pathogen-specific analyses. In addition, the GLP-1 RA-treated subgroup was small, which reduced statistical power and yielded wider CIs. Therefore, null findings should not be interpreted as definitive evidence of no effect (risk of type II error), and any borderline associations observed in exploratory models may represent chance findings in the setting of multiple comparisons and residual confounding (risk of type I error). Finally, although our follow-up was sufficient to capture early CLAD and mortality events, longer observation will be required to fully understand the impact of GLP-1 RA therapy on late-onset CLAD phenotypes and very long-term survival.
Conclusion
In this contemporary single-center cohort, including a relatively small number of GLP-1 RA-exposed recipients, we observed no signal that GLP-1 RA use was associated with higher rates of PGD, AKI, respiratory infection, CLAD, or death. These findings complement prior metabolic-focused reports and are generally reassuring regarding short- and intermediate-term safety in carefully selected lung transplant recipients. However, given the limited sample size and observational design, modest harms or benefits may have been missed, and larger prospective studies with granular metabolic and immunologic phenotyping are needed to confirm these findings and to clarify whether GLP-1 RA therapy can modify long-term allograft outcomes.
Financial support
The authors have no financial relationships or conflicts of interest to disclose related to the content of this manuscript.
Data Availability
The data that support the findings of this study are available from the corresponding author upon reasonable request but are not publicly available due to institutional privacy policies.
Conflicts of Interest statement
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
The authors thank Elena Susan for English proofreading.
Footnotes
Supplementary data associated with this article can be found in the online version at doi:10.1016/j.jhlto.2026.100513.
Appendix A. Supplementary material
Supplementary material
.
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplementary material
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request but are not publicly available due to institutional privacy policies.