INCRETIN BASED THERAPIES IN DIABETIC KIDNEY TRANSPLANT RECIPIENTS: A SYSTEMATIC REVIEW AND META-ANALYSIS

Abstract Background and Aims Diabetes mellitus (DM) is the major cause of ESRD. New-onset DM after transplantation (NODAT) frequently occurs and increases the risk of infection and mortality. Kidney transplant recipients (KTR) with pre-existing risk factors for DMt2 are more prone to develop NODAT. An intriguing novel concept is the use of the incretin-based therapies including dipeptidyl peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 receptor agonists (GLP-1-RAs) and Sodium-glucose co-transporter-2 inhibitors (SGLT2i) in solid organ transplantation. This class of antidiabetic therapy is not yet established in KTR. Our aim was to examine the efficacy and safety of incretin-based therapies in DM or NODAT in KTR. Method We searched without language restrictions for all publications on Kidney/Renal Transplantation and DPP-4i, GLP-1-RAs and SGLT-2i using electronic databases including Medline, Embase, Cochrane, PubMed. We hand-search the reference lists of every relevant study for additional publications. Further searches were done by reviewing abstract and review articles. We included every study (retrospective/prospective) that used these classes of antidiabetics as treatment of NODAT or DMt2 in KTR. All the primary and secondary outcomes were calculated as mean ± sd. Heterogeneity was assessed with Cochrane’s Q statistics and quantified using the I stat, which indicated the proportion of variability across studies that was due to heterogeneity. We used the DerSimonian-Laird estimator for tau^2. Meta-regression was used to assess the effect of different antidiabetics on the primary and secondary outcomes. We assumed a priori the presence of heterogeneity and we used the model of random effects in all analyses. We assessed publication bias using the Begg-Mazumdar test and to nullify the estimated bias the trim-and-fill method, where it was necessary. A p-value < 0.05 was considered statistical significant. Results On the 1512 references screened, 16 studies were included in the final analysis. In total, 310 individuals were analyzed with a mean age of 55.98 ± 8.81 years, similar between studies. In 10 of them, participants were diagnosed with NODAT, whereas in all other trials were DMt2 or NODAT. In 8 studies participants received DPP-4i, in 6 SGLT-2i i and in rest 2 GLP-1-RAs. All included KTR were stable and transplanted over 6 months. The mean follow-up of all trials included was 22,03±14.95 weeks. Glycemic control reduces HbA1c (10 studies, MD=-0.38 %, I=45%). The MD of HbA1c for the DPP-4i group was -0.3741 and for the SGLT-2i group was -0.4596 mg/dl. Within every group of each different category of drugs, there was homogeneity (QM, p-value>0.05) and it was explained the most of the variance of the previous meta-analysis (QE= 15.76). The Begg-Mazumdar test showed that publication bias was not present (p> 0.05). Nine trials reported the difference of FPG and 5 of PPG before and after the administration of antidiabetics. The common MD estimator with a random effect model was – 25.76 for FPG and – 6.61 for PPG with a high grade of heterogeneity for both. Seven trials reported the change of body mass index (BMI) and body weight (BW) before and after the administration of this class of antidiabetics. The BW reduction, where reported, was significant in KTR on SGLT1i or DPP-4i whereas BMI wasn’t significantly reduced in this group, possible due to statistical artifact. The majority of the studies showed that GFR and hepatic biochemical parameters, didn’t change during therapy (DPP-4i, GLP-1-RAs, SGLT-2i). Conclusion Evidence concerning the efficacy of incretins in diabetes on KTR is limited. SGLT2i and DPP-4i are efficacious for glucose-lowering. The safety profile based on renal and hepatic function is indicative for the use of this class of antidiabetics in this population. More high-quality studies are required to help guide therapeutic choice for antidiabetics in KTR.