Efficacy and safety of glucagon-like peptide-1 receptor agonist liraglutide in new-onset diabetes after kidney transplantation: An open-label, parallel-group, randomized controlled trial

To the Editor: The incidence of new-onset diabetes after kidney transplantation (NODAKT) can be as high as 30% within the first year following transplantation.[1] Numerous studies have demonstrated that NODAKT is associated with an elevated risk of infection, atherosclerotic cardiovascular disease, and chronic graft dysfunction.[2,3] However, the management of NODAKT continues to pose a significant clinical challenge at this time. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have exhibited potent glucose-lowering and weight-reducing effects. Furthermore, they confer well-documented cardiovascular and renal protective benefits, with a minimal risk of hypoglycemia.[4] However, the safety and efficacy of GLP-1 RAs in managing NODAKT remain underexplored. This study aimed to compare the efficacy of liraglutide and metformin in improving glycemic control, reducing cardiovascular risk factors, and protecting graft function in NODAKT patients. In addition, the safety profiles of both treatments were also evaluated. This study was an open-label, parallel-group, randomized controlled trial with blinded endpoint assessment. Participants were recruited from the kidney transplant outpatient department of Beijing Chaoyang Hospital, Capital Medical University. This study was conducted by the ethical principles outlined in the Declaration of Helsinki and was prospectively registered at chictr.org.cn (ChiCTR2300078600). Approval was obtained from the Ethics Committee of Beijing Chao-yang Hospital, Capital Medical University (No. 2022-ke-475). Written informed consent was obtained from all participants before their involvement in the study. The inclusion and exclusion criteria are detailed in the Supplementary Methods, https://links.lww.com/CM9/C670. In the liraglutide group, the initial dose of liraglutide was 0.6 mg/day administered via subcutaneous injection. After 1 week, based on the patient’s gastrointestinal tolerance, the dose could be escalated to 1.8 mg/day and maintained for a total duration of 26 weeks. In the metformin group, the initial dose of metformin was set at 0.5 g twice daily. The dosage could be escalated to 1.0 g twice daily based on the patient’s gastrointestinal tolerance and maintained for 26 weeks as well [Supplementary Figure 1, https://links.lww.com/CM9/C670]. The primary endpoint was the change in glycated hemoglobin (HbA1c) from baseline to 26 weeks. Secondary efficacy endpoints comprised the following: (1) changes from baseline in fasting plasma glucose (FPG), 2-hour postprandial plasma glucose (2hPG), fasting insulin (FINS), homeostasis model assessment of β-cell function (HOMA-β) and insulin resistance (HOMA-IR), waist circumference, body weight, blood pressure, plasma homocysteine concentrations, lipid profiles, urinary albumin/creatinine ratio (UACR), and estimated glomerular filtration rate (eGFR); (2) the proportion of patients reaching the HbA1c target (<7.0% [53 mmol/mol]) after 26 weeks. The safety assessment focused on the incidence, duration, and severity of adverse events, primarily comprising gastrointestinal adverse events and hypoglycemia. The method for calculating the sample size is detailed in Supplementary Methods, https://links.lww.com/CM9/C670. Continuous variables following a normal distribution were presented as mean ± standard deviation, while those not normally distributed were reported as medians (interquartile ranges). For comparisons of continuous variables at the baseline level between the two groups, a two-sided Student’s t-test was used for normally distributed data, whereas the Mann–Whitney U test was used for non-normally distributed data. Categorical variables were summarized as n (%) and compared using Pearson’s chi-squared test or Fisher’s exact test, as appropriate. An analysis of covariance model was used to evaluate the changes in continuous efficacy variables after 26 weeks of treatment. The superiority of glycemic control with liraglutide was established if the lower limit of the two-sided 95% confidence interval (CI) for the difference in least square (LS) mean (metformin − liraglutide) was >0, while noninferiority was confirmed if this lower limit was greater than −0.4%. A logistic regression model was used to evaluate the difference in HbA1c target achievement rates between the two groups. Further details are provided in Supplementary Methods, https://links.lww.com/CM9/C670. A total of 205 patients who developed NODAKT were screened between October 2022 and March 2024. Ultimately, 58 patients in the liraglutide group and 59 patients in the metformin group completed all scheduled follow-ups [Supplementary Figure 2, https://links.lww.com/CM9/C670]. Demographic characteristics were generally well-balanced between the two groups. Baseline levels of HbA1c, plasma glucose, FINS, HOMA-β, HOMA-IR, lipid profiles, and renal function-related indicators were also well-balanced and comparable between the groups [Supplementary Table 1, https://links.lww.com/CM9/C670]. After 26 weeks of intervention, LS mean HbA1c (95% CI) decreased by 1.44% (1.38%, 1.49%) with liraglutide, and by 1.00% (0.95%, 1.05%) with metformin [Figure 1A, B]. The ratio of the reduction in HbA1c levels between the metformin group and the liraglutide group was 0.69 (95% CI: 0.64, 0.76). Glycemic control was superior in the liraglutide group compared with that in the metformin group (difference in LS mean [95% CI]: 0.43% [0.35%, 0.52%], P <0.001). As for other indicators of glycemic control, the LS mean (95% CI) change from baseline in FPG was −2.05 (−2.10, −1.99) mmol/L in the liraglutide group and −1.33 (−1.37, −1.28) mmol/L in the metformin group [Figure 1C, D]. Liraglutide demonstrated superior efficacy in reducing FPG (P <0.001). For 2hPG, the LS mean (95% CI) change was −2.93 (−2.97, −2.89) mmol/L in the liraglutide group and −2.09 (−2.12, −2.05) mmol/L in the metformin group [Figure 1E, F]. Consequently, liraglutide was also more effective than metformin in reducing 2hPG (P <0.001). In addition, HOMA-IR decreased by 1.81 (95% CI: 1.64, 1.97) in the liraglutide group and by 1.18 (95% CI: 0.91, 1.45) in the metformin group, with a more significant reduction in the liraglutide group (P = 0.007) [Supplementary Table 2, https://links.lww.com/CM9/C670]. The proportion of patients reaching the HbA1c target was significantly higher in the liraglutide group compared with the metformin group (79.3% [46/58] vs. 40.7% [24/59], P <0.001) [Figure 1G].Figure 1: Comparison of glycemic efficacy between liraglutide and metformin in kidney transplant recipients with new-onset diabetes after transplantation. (A) Least squares (LSs) mean change in HbA1c for the modified intent-to-treat population; (B) HbA1c change over time; (C) LS mean change in FPG; (D) FPG change over time; (E) LS mean change in 2hPG; (F) 2hPG change over time; (G) Percentage of kidney transplant recipients reaching HbA1c target (<7.0% [53 mmol/mol]). Error bars in A, C, and E are 95% confidence interval; Error bars in B, D, and F are standard deviation. 2hPG: 2-hour postprandial plasma glucose; FPG: Fasting plasma glucose; HbA1c: Glycated hemoglo­bin; KT: Kidney transplant.The liraglutide group experienced a weight loss of 4.15 kg (95% CI: 3.59, 4.71), whereas the metformin group had a weight loss of 1.82 kg (95% CI: 1.17, 2.48) [Supplementary Table 2, https://links.lww.com/CM9/C670]. The difference in weight loss between the two groups was statistically significant (P <0.001), with liraglutide demonstrating superior efficacy compared with metformin. In the liraglutide group, systolic blood pressure was reduced by 6.32 mmHg (95% CI: 5.92, 6.71), a significantly greater reduction compared with the metformin group (P <0.001) [Supplementary Table 2, https://links.lww.com/CM9/C670]. Regarding lipid parameters, in the liraglutide group, low-density lipoprotein-cholesterol decreased by 0.47 mmol/L (95% CI: 0.42, 0.52) and triglycerides decreased by 0.39 mmol/L (95% CI: 0.37, 0.42), both of which were significantly greater than those in the metformin group (P = 0.004 and P = 0.031, respectively). The UACR decreased in both groups compared with baseline (LS mean [95% CI]: −13.43 [−13.92, −12.94] mg/g and −3.74 [−4.43, −3.06] mg/g, respectively) [Supplementary Table 2, https://links.lww.com/CM9/C670]. The reduction in UACR was significantly greater in the liraglutide group (P <0.001). For the eGFR, the increase was 5.76 (95% CI: 4.38, 7.15) mL·min−1·1.73 m−2 in the liraglutide group and 1.25 (95% CI: 0.17, 2.33) mL·min−1·1.73 m−2 in the metformin group. The increase in eGFR was significantly more pronounced in the liraglutide group (P = 0.002) [Supplementary Table 2, https://links.lww.com/CM9/C670]. The main adverse events included hypoglycemia, nausea, diarrhea, vomiting, dyspepsia, dizziness, and headache [Supplementary Table 3, https://links.lww.com/CM9/C670]. Gastrointestinal disorders were the most frequently reported adverse events in both groups. Specifically, the most common adverse events reported were nausea (22.4% [13/58]) and dyspepsia (15.5% [9/58]) in the liraglutide group, both significantly higher than in the metformin group (P = 0.037 and P = 0.008, respectively). The incidence of diarrhea and vomiting was higher in the liraglutide group, although the differences between the two groups were not statistically significant (P = 0.163 and P = 0.053, respectively). The duration of gastrointestinal adverse events in both groups did not exceed 3 days, and the events were categorized as mild. Following dose adjustment, these adverse reactions gradually resolved. There was no significant difference in hypoglycemia incidence between the groups (P = 0.679), with no severe hypoglycemic events reported. All adverse events were transient, primarily occurring during the dose-adjustment phase (the first 8 weeks) and gradually diminishing after dose stabilization. No severe adverse events were observed in either group. Furthermore, there were no significant fluctuations in the plasma concentrations of immunosuppressive agents between the two groups, and no substantial modifications to the immunosuppressive regimens were made. Throughout this study, no participants experienced any of the following events: mortality, graft dysfunction, transplant kidney biopsy, rejection episodes, infectious complications, or hospital readmissions. This study provides compelling evidence that liraglutide, a GLP-1 RA, might outperform metformin in managing NODAKT. Specifically, liraglutide demonstrates superior efficacy in glycemic control, weight management, cardiovascular risk factors mitigation, and graft function protection. The predominant adverse events associated with liraglutide treatment in patients who developed NODAKT were gastrointestinal disorders. Compared with metformin, liraglutide was found to cause a higher incidence of nausea and dyspepsia, consistent with observations in patients with general type 2 diabetes.[5] Nonetheless, the gastrointestinal adverse events predominantly occurred during the initial phase of liraglutide administration and were characterized as mild in severity with a transient duration. Overall, liraglutide demonstrates safety in patients with NODAKT. This study has the following limitations: (1) the single-center study design limited the generalizability of the findings; (2) blinding was not feasible due to varying administration methods, potentially introducing subjective diagnostic suspicion bias; (3) the assessment of glucose metabolism, cardiovascular risk factors, and graft function was not sufficiently comprehensive, and future studies should incorporate additional efficacy indicators to further validate these results. In conclusion, GLP-1 RA liraglutide appears to be a more effective therapeutic option for NODAKT. Compared with metformin, liraglutide might offer superior benefits in glycemic control, weight loss, cardiovascular risk factor mitigation, and graft function protection. Although liraglutide treatment is generally safe, clinicians should remain vigilant regarding the increased incidence of gastrointestinal adverse events. Further evaluation through multicenter, large-sample clinical trials is warranted to comprehensively assess the long-term efficacy and safety of GLP-1 RAs in managing NODAKT. Funding This work was supported by grants from the Beijing Municipal Science and Technology Commission (No. Z221100007422029), Clinical Research Incubation Project of Beijing Chao-yang Hospital, Capital Medical University (No. CYFH202203), National Natural Science Foundation of China (No. 82370752), Capital’s Funds for Health Improvement and Research (No. 2024-1Y-002), and Capital Health Research and Development of General Practice (No. 2023-2Y-007). Conflicts of interest None.