Diabetes mellitus (DM) is a complication after kidney transplantation (KT), with a prevalence of approximately 40%. In addition, 10–20% of non-diabetic KT recipients develop post-transplant diabetes mellitus (PTDM). Both pre-existing DM and PTDM are associated with higher mortality of the recipient and affects negatively renal graft survival,1–3 owing to which there is a need to modify risk factors in this population.

Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are a class of anti-diabetic drugs that have demonstrated cardiovascular and renal benefits; they reduce proteinuria and slow the decline of glomerular filtration rate (eGFR).4,5 They also promote weight loss, since they delay gastric emptying and promote satiety. Furthermore, they carry a lower risk of hypoglycemia as they induce glucose-dependent insulin secretion.4,5 Their metabolism does not involve cytochrome P450 enzymes or transporter-mediated drug–drug interactions. Nonetheless, it is suggested that their role in gastric emptying could affect the absorption of certain drugs.4,5

However, experience with GLP-1 RAs in KT is limited.6–11 We have previously reported the results of our experience with a small group of KT recipients.12 The present study aims to analyze treatment results with GLP-1 RAs in a larger cohort with longer follow-ups to evaluate the effectiveness and safety of these drugs in diabetic KT recipients.

This was a multicentre retrospective cohort study of KT recipients with pre-existing DM or PTDM who commenced treatment with subcutaneously administered GLP-1 RAs between February 2016 and July 2022. The prescription criteria were based on recommendations from the American Diabetes Association.13 The use of GLP-1 RAs was preferred over sodium-glucose cotransporter type 2 inhibitors (SGLT2i) in subjects with obesity (body mass index [BMI] >30 kg/m2). The three hospitals that conducted follow-ups on KT recipients in the province of Cadiz participated (Puerta del Mar, Jerez de la Frontera and Puerto Real Hospitals). In all subjects prescribed a GLP-1 RA, monthly check-ups were performed until the maximum tolerated dose of the drug was reached, to monitor immunosuppressant levels and identify adverse effects. Subsequently, the check-ups were spaced out according to the needs of each subject and time post-KT. All subjects included had a minimum follow-up of six months after starting the drug. Given the efficacy of these drugs shown by other groups, we did not propose a control group and we started treatment in those subjects in whom it was considered that GLP-1 RAs could provide special benefits, such as obese diabetic subjects.

Clinical and analytical data were collected at baseline, and at 6 and 12 months after treatment initiation. The eGFR was measured using the Modification of Diet in Renal Disease (MDRD) equation.14 Proteinuria was quantified using the albumin/creatinine ratio (ACR) in a first-morning urine sample. Blood pressure (BP) was measured by a nurse using an oscillometric device (Welch Allyn Spot Vital Signs LXi, Soma Technology Inc., USA) with the subject seated, before entering the doctor's office and at least five minutes after arrival. BP was calculated as an average of three measurements taken five minutes apart. We documented episodes of acute rejection (AR), development of de novo donor-specific antibodies (dnDSA) and occurrence of adverse effects. dnDSA were requested prospectively annually in all subjects or before any episode of renal function deterioration. We collected type and dose of GLP-1 RAs and other anti-diabetic, lipid-lowering, anti-hypertensive and immunosuppressive drugs; as well as tacrolimus trough levels, dose and C/D ratio (pre-dose tacrolimus blood levels [ng/mL]/daily dose of tacrolimus [mg]) in each period analyzed.

During the study period, 96 subjects started treatment with GLP-1 RA. Baseline characteristics are shown in Table 1. The majority were male (56.2%) with a mean age of 61.6 ± 9.7 years. In total, 53 subjects (55.2%) had pre-existing DM, and the rest developed PTDM. Semaglutide was the most prescribed GLP-1 RA (66.7%), followed by liraglutide (20.8%) and dulaglutide (12.5%). Some 52 subjects (54.2%) reached the maximum recommended dose of the drug. Finally, 84 KT recipients reached a minimum follow-up of six months after the start of treatment and, of these, 61 completed 12 months of follow-up (Fig. 1). The study variables compared at six and 12 months are shown in Table 2 and Fig. 2. The analysis of the main variables was also performed by comparing the three types of GLP-1 RA (semaglutide, liraglutide, and dulaglutide) that our subjects received, with no significant differences observed between them being in any of the variables analyzed (Table 3).

Figure 1.

Flowchart of the subjects included in the study.

KT: kidney transplant; GLP-1 RA: glucagon-like peptide-1 receptor agonists; GI: gastrointestinal; HD: hemodialysis.

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Figure 2.

Changes in weight, HbA1c, albuminuria and glomerular filtration rate at 6 and 12 months after initiation of GLP-1 RA.

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We present the results of the largest series reported to date of KT recipients with pre-existing DM or PTDM who received treatment with GLP-1 RAs. In addition, we show data on tacrolimus levels and doses, incidence of acute rejection and potential development of dnDSA during follow-up. These drugs were well tolerated by our subjects, without alterations in immunosuppressive therapy and with improvement in metabolic control and anthropometric parameters. It also observed positive effects on blood pressure control and on parameters of renal function that may offer significant benefits to diabetic KT recipients.

Similar to the efficacy observed in the general diabetic population, in our patients we noticed a significant improvement in glycaemic control, with a decrease in HbA1c levels.4,5 It is important to note that the insulin dose was reduced and there was no change in most anti-diabetic drugs.

GLP-1 RAs can cause gastrointestinal adverse effects that could alter the absorption of immunosuppressive medication and promote renal graft dysfunction. However, several studies point to a potential nephroprotective role of this pharmacological group in other populations, induced by different factors: improvement of hyperglycemia, overweight and insulin resistance, systemic and glomerular hypertension, dyslipidemia, sodium retention, inflammation and renal hypoxia.15,16 In our series, renal function remained stable, in line with that reported in other series of KT recipients.8–10 Therefore, our data appear to confirm the notion that, with appropriate monitoring, GLP-1 RAs are safe drugs regarding graft function.

It was also observed a reduction in body weight and BMI similar to that described in the general population.5,15 This effect has been explained by the delay in gastric emptying and satiety caused by this group of anti-diabetics.4,5

The prevalence of obesity in the KT recipient population is high. This is associated with the development of PTDM, arterial hypertension and dyslipidemia, increasing the risk of death and graft failure.17 In our series we also observed a significant decrease in albuminuria, like in the non-KT population, which is not previously described in other experiences in KT recipients. Albuminuria is also a predictor of mortality and worsening of CKD in KT recipients.18 It has been suggested that body weight influences the development of albuminuria in KT, similarly to that reported in non-KT recipients.18 Our results show a significant decrease in weight, which could explain this decrease in the ACR observed in our subjects. The number of patients treated with SGLT2i at one year was higher, which may also have influenced these findings. Nonetheless, we cannot rule out the direct beneficial effects of GLP-1 RAs on albuminuria, which will need to be the focus of future studies.

Several clinical trials have reported improvement in systolic blood pressure with GLP-1 RAs in non-KT populations.19,20 This may be due to weight loss and the natriuretic and vasodilative effects of these groups of drugs.21,22 However, such findings have not been evaluated or described in the KT population. In our series, we observed an improvement in systolic blood pressure. However, the increase in the number of subjects treated with calcium antagonists at one year of follow-up may have contributed to the improvement in blood pressure control.

In addition, dyslipidemia is a frequent complication after KT and is a risk factor for the development of cardiovascular disease and graft loss.23 Furthermore, most immunosuppressive drugs used in transplantation have a detrimental effect on the lipid profile.24 These alterations have not been adequately analyzed in the previously published series of KT recipients treated with GLP-1 RAs.6–11 In our series, we observed a significant reduction in total cholesterol and LDLc, and it is interesting to note that there were no differences in the number of subjects who received statins or in the dose of those drugs. All this suggests that the benefits derived from GLP-1 RA treatment may help to improve the lipid profile of KT recipients and, consequently, cardiovascular control.

The GLP-1 RAs are eliminated by proteolytic degradation and their metabolism does not involve cytochrome P450 enzymes or transporter-mediated drug interactions.4 Therefore, the probability of interaction with immunosuppressive drugs is low. There is, however, some concern that GLP-1 RAs may affect the absorption of immunosuppressive drugs owing to their role in slowing gastric emptying.4,5 To date, data on tacrolimus doses and levels have been published on a small number of KT recipients treated with GLP-1 RAs.6,8–11 In our study, with a significant number of subjects, trough levels, doses and tacrolimus C/D ratio did not change significantly during follow-up, allowing confidence regarding the safety of immunosuppressive treatment. Furthermore, we observed no episodes of AR, development of dnDSA or an increase in the number of biopsies performed, which also provides safety data about this group of anti-diabetics.

The side effects of GLP-1 RAs are mainly gastrointestinal. Their incidence in clinical trials in the non-KT population ranges between 10% and 50%.21,25 In our series, these adverse effects were not greater than in the general population and they are similar to those reported in other studies in the KT population.6–11 In one of our subjects, GLP-1 RA was discontinued eight months into treatment following a diagnosis of pancreatic adenocarcinoma. In the early years of GLP-1 RA use it was suggested, an increased risk of pancreatitis and pancreatic tumors related to the use of these anti-diabetics.26 However, large clinical trials and other subsequent studies did not confirm this finding accordingly, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) concluded that a causal relationship between these drugs and the development of pancreatitis or pancreatic cancer could not be established.27–31

Our study has several limitations. This was an observational, retrospective, real-life study, without a control group, with the limitations inherent to this design. It would have been interesting to have a comparison arm, but these drugs were prescribed for diabetics with obesity and it was not possible to have a control group with similar characteristics, therefore the results should be considered with caution. Although larger than other series, the number of subjects remains small. No data are available on the adherence to GLP-1 RA treatment, but all subject-reported drug discontinuations were collected. Moreover, conclusions cannot be drawn regarding the influence of these drugs on the dose and levels of everolimus or ciclosporin due to the scarcity of subjects in our series taking these immunosuppressants.

In conclusion, GLP-1 RAs appear to be an option for the management of DM in KT recipients. Our results suggest that they are safe and that they do not appear to alter tacrolimus trough levels or induce episodes of AR or development of dnDSA, with renal function remaining stable. Improvement of metabolic control, weight and blood pressure are of great relevance in this population. For all these reasons, prospective, controlled and randomized studies are warranted to advance our knowledge of the effects of these agents in KT recipients.

This study received no specific funding from public, private or non-profit organizations.

The authors declare that they have no conflicts of interest.