Efficacy of glucagon‐like peptide‐1 receptor analogues in kidney transplant recipients with diabetes: A single‐centre retrospective study

Pre- and post-transplant diabetes mellitus (PTDM) are common amongst kidney transplant recipients (KTR); around 10%–30% of this population (depending on definition) have the condition.1 Diabetes in KTRs is associated with higher rates of graft loss and overall mortality.2 Furthermore, diabetes management in KTRs can be challenging due to the effect of immunosuppression, particularly in the early post-transplant period.3 In the acute phase immediately post-transplant, insulin is commonly required, and if kidney function allows, metformin should be considered first-line oral therapy.1 Glucagon-like peptide-1 receptor analogues (GLP-1RAs) are widely used in the management of Type 2 diabetes (T2D) in the general diabetes population due to their potent effects on glucose, weight reduction and potential benefits on the cardiovascular and renal indices.4 Evidence for their use in PTDM is growing. This study aimed to assess the efficacy and safety profile of GLP-1RAs in KTRs from a single centre. GLP-1RA therapy was used according the NICE guidance on their use in Type 2 diabetes (i.e. BMI >30 kg/m2 or 27.5 kg/m2 in non-White ethnicity and glycated haemoglobin (HbA1c) >58 mmol/mol 7.5%). A retrospective analysis was conducted on a cohort of KTRs with a known diagnosis of diabetes (either pre-existing diabetes or PTDM) in our centre. The transplant database was searched, and data were extracted from the electronic medical records over the preceding 5 years. Patients who had minimal follow-up data were excluded from this study. Details of age, sex, ethnicity, weight, glucose control and kidney function were obtained on each patient. Details regarding the GLP-1RA therapy were also recorded, including the agent, dose and duration of treatment. Data collected at baseline (before the initiation of treatment) and at 3-, 6- and 12- month follow-up included HbA1c, weight, body mass index (BMI) urine protein creatinine ratio (PCR), creatinine and estimated glomerular filtration rate (eGFR). Statistical analysis was performed using GraphPad Prism version 10.2.2 (341). Data normality were assessed using the Shapiro–Wilk test. Parametric data were described using mean ± standard deviation and non-parametric data represented with median and interquartile range (IQR). For each parameter, the change in measurements for each follow-up was calculated in comparison to baseline, and these results analysed using a one-sample t-test. Results were considered to be statistically significant if p < 0.05. Adverse effects of GLP-1RAs in the cohort were uncommon. Four patients (4.2%), however, stopped therapy due to gastrointestinal side effects. Of the remaining 91 patients included (44% women, mean age 55.7 ± 10.7 years), 45 received semaglutide, 29 dulaglutide, 9 tirzepatide and 8 liraglutide. Median treatment duration was 17 months (IQR 10–27.5). Table 1 summarizes clinical outcomes. Significant reductions in weight and BMI were observed across the entire cohort at all timepoints (p < 0.05). Sub-analysis revealed that dulaglutide was the only agent associated with consistent weight loss at every assessment. Glycaemic control improved significantly, with the cohort achieving a mean HbA1c reduction of 6 mmol/mol at 12 months (p = 0.0003). Individually, significant 12-month HbA1c reductions were noted for dulaglutide (p = 0.0007) and tirzepatide (p = 0.04). While a statistical increase in creatinine was noted at 12 months (p = 0.0023), the mean difference of 4 umol/L was not clinically significant, and eGFR remained stable throughout the study. Urine PCR did not change during the study period. −3.00 −8.25 to 2.25 (n = 72) p = 0.052 −4.50 −15.00 to 6.00 (n = 82) p = 0.0083 −6.00 −13.00 to 4.00 (n = 85) p = 0.0003 −4.00 −8.00 to 4.00 (n = 33) p = 0.43 −2.00 −10.25 to 8.00 (n = 40) p = 0.28 −2.00 −9.00 to 5.50 (n = 43) p = 0.14 −3.00 −11.00 to 3.50 (n = 6) p = 0.37 −15.00 −22.00 to 3.00 (n = 7) p = 0.35 −8.50 −21.00 to 8.50 (n = 8) p = 0.39 −3.50 −9.75 to 1.25 (n = 24) p = 0.09 −7.00 −15.25 to 3.25 (n = 28) p = 0.04 −8.00 −14.25 to 2.25 (n = 28) p = 0.0007 −2.00 −7.00 to 2.00 (n = 9) p = 0.47 −10.00 −17.50 to −2.00 (n = 7) p = 0.20 −10.50 −14.00 to −6.25 (n = 5) p = 0.04 −1.80 −3.60 to 0.95 (n = 55) p = 0.0019 −1.35 −5.10 to 1.55 (n = 60) p = 0.0025 −2.00 −8.50 to 1.00 (n = 67) p < 0.0001 −0.45 −3.00 to 1.25 (n = 28) p = 0.15 −0.7 −2.93 to 2.28 (n = 32) p = 0.44 0.00 −3.00 to 1.50 (n = 33) p = 0.30 −3.60 −4.40 to −2.80 (n = 2) p = 0.30 −8.10 −10.60 to 4.00 (n = 5) p = 0.27 −8.60 −11.35 to −2.55 (n = 7) p = 31 −2.00 −3.80 to −0.50 (n = 17) p = 0.049 −2.20 −9.00 to 0.70 (n = 17) p = 0.0087 −4.10 −10.60 to 0.00 (n = 21) p = 0.001 −1.80 −4.13 to 0.93 (n = 8) p = 0.13 −2.85 −8.70 to 0.90 (n = 6) p = 0.15 −2.90 −6.30 to −1.10 (n = 7) p = 0.06 −0.60 −1.43 to 0.40 (n = 55) p = 0.0057 −0.50 −2.25 to 0.40 (n = 60) p = 0.0015 −0.75 −3.10 to 0.33 (n = 67) p = 0.0016 0.00 −1.20 to 0.70 (n = 28) p = 0.31 −0.10 −1.05 to 0.73 (n = 32) p = 0.37 −0.20 −1.10 to 0.50 (n = 33) p = 0.20 −1.40 −1.55 to −1.25 (n = 2) p = 0.13 −3.40 −3.50 to 1.30 (n = 5) p = 0.29 −3.10 −4.20 to −0.98 (n = 7) p = 0.05 −0.70 −1.40 to −0.20 (n = 17) p = 0.046 −0.90 −2.90 to 0.20 (n = 17) p = 0.0061 −2.30 −4.05 to −0.15 (n = 21) p = 0.023 −0.30 −1.3 to 0.33 (n = 8) p = 0.18 −1.05 −2.70 to 0.38 (n = 6) p = 0.16 −1.20 −2.28 to −0.28 (n = 7) p = 0.069 0 −3 to 4 (n = 85) p = 0.75 −1 −4 to 5 (n = 87) p = 0.42 −1 −6 to 4 (n = 89) p = 0.11 0.00 −3.75 to 2.00 (n = 42) p = 0.87 −0.50 −4.25 to 5.00 (n = 44) p = 0.45 −1.00 −5.00 to 4.00 (n = 44) p = 0.31 2.00 −1.00 to 3.50 (n = 7) p = 0.28 3.00 −2.00 to 4.50 (n = 7) p = 0.96 −5.00 −6.25 to 1.25 (n = 8) p = 0.25 0.00 −4.50 to 2.50 (n = 27) p = 0.37 −2.00 −4.00 to 4.00 (n = 29) p = 0.38 −3.00 −8.00 to 5.00 (n = 29) p = 0.11 2.00 −1.00 to 9.00 (n = 9) p = 0.06 −1.00 −4.00 to 8.00 (n = 7) p = 0.51 2.00 −1.50 to 8.25 (n = 8) p = 0.22 −2 −9 to 9 (n = 85) p = 0.07 3 −9 to 16 (n = 86) p = 0.06 4 −7 to 27 (n = 89) p = 0.0023 −1.00 −7.00 to 7.75 (n = 42) p = 0.18 2.00 −8.50 to 13.50 (n = 43) p = 0.18 3.00 −6.50 to 19.25 (n = 44) p = 0.03 −7.00 −32.00 to 10.50 (n = 7) p = 0.81 −15.00 −33.50 to 27.00 (n = 7) p = 0.63 10.00 −6.25 to 42.50 (n = 8) p = 0.24 0.00 −8.50 to 16.50 (n = 27) p = 0.15 5.00 −8.00 to 16.00 (n = 29) p = 0.04 13.00 −7.00 to 31.00 (n = 29) p = 0.04 −6.00 −13.00 to 3.00 (n = 9) p = 0.93 7.00 −18.50 to 13.00 (n = 7) p = 0.60 4.00 −12.75 to 11.25 (n = 8) p = 0.89 −2 −20 to 34 (n = 85) p = 0.63 −5 −24 to 43 (n = 87) p = 0.41 −5 −26 to 45 (n = 89) p = 0.15 −3 −22 to 21 (n = 42) p = 0.89 −2 −13 to 22 (n = 44) p = 0.34 −6 −15 to 62 (n = 44) p = 0.33 −2 −12 to 15 (n = 7) p = 0.27 −4 −14 to 28 (n = 7) p = 0.37 −5 −34 to 67 (n = 8) p = 0.23 −1 −16 to 25 (n = 27) p = 0.24 −2 −28 to 52 (n = 29) p = 0.51 −3 −14 to 59 (n = 29) p = 0.31 −2 −19 to 29 (n = 9) p = 0.16 −1 −32 to 68 (n = 7) p = 0.24 −2 −15 to 81 (n = 8) p = 0.29 We present a single-centre retrospective study of metabolic outcomes following GLP-1RA therapy in KTRs with diabetes. GLP-1RAs are increasingly used in people with T2D and obesity to optimise glycaemic control and reduce weight. The results from this study showed that these benefits are applicable to KTRs. Our findings are consistent with that of the current literature. A retrospective study of 19 patients showed a significant decrease of HbA1c from baseline at 12 months 0.75%, 95% CI 1.55, p = 0.05,5 and a further retrospective study of 31 patients showed a significant decrease at 13–18 months with semaglutide treatment 7.4% ± 1.0%, p < 0.001.6 We also found that there was a significant reduction in weight and BMI with dulaglutide. This is supported by a large USA-based retrospective registry cohort study (n = 18,016),7 and a single-centre retrospective study (n = 63),8 which both found a significant decrease of weight and BMI from dulaglutide treatment. Whilst this study found a statistically significant difference in the creatinine levels at 12-months compared to baseline, the overall mean difference of 4 umol/l is clinically insignificant. This is consistent with other studies which found stable renal function following GLP-1RA therapy.9, 10 Our study is limited by its retrospective design and incomplete follow-up data. Semaglutide is now licenced for use down to end stage kidney disease in the US (although not yet in Europe). Our findings contribute to the expanding body of evidence supporting the use of GLP-1RAs in KTRs with diabetes. Future research should include well-designed randomised controlled trials in this population, as well as pharmacokinetic and pharmacodynamic studies to determine whether the observed benefits represent a class effect or vary among individual agents. The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.