Table 1B:
Retrospective studies on glucose-lowering agents after kidney transplantation or SOT including kidney.
| Study | Study size | Organ | Primary results | Secondary results | Strength | Weakness |
|---|---|---|---|---|---|---|
| Insulin | ||||||
| Chandra et al. 2023 [82] | N = 23 (N = 10 treated with insulin isophane, N = 13 treated with insulin glargine) | Kidney | 12 episodes of hypoglycaemia in glargine-treated PTDM patients compared with 3 in isophane-treated PTDM patients (P = .056) | Significantly lower blood glucose and HbA1c in the glargine vs. isophane group. In the glargine group, 8 out of 12 hypoglycaemic episodes were nocturnal (1 out of 3 hypoglycaemic episodes were nocturnal in the isophane group) | First report on hypoglycaemia risk with various basal insulin regimens | Patient population predominantly male (87% males) and of relatively young age (average age <40 years in both groups) |
| Sulfonylureas | ||||||
| Tuerk et al. 2008 [83] | N = 47 gliquidone + 28 rosiglitazone (N = 75) | Kidney | Mean fasting blood glucose improved, success rate was similar in both groups | In 4 patients the dose of gliquidone therapy had to be reduced due to hypoglycaemia. Pretreatment with other antidiabetics was identified as a negative prognostic factor | First report on SUs in PTDM | Comparison against TZDs (rosiglitazone) with non-standard treatment goals may be somewhat unusual |
| Metformin | ||||||
| Kurian et al. 2008 [84] | N = 32 in the metformin and N = 46 in the thiazolidinedione group (pioglitazone, rosiglitazone) | Kidney | No significant difference in HbA1c before and after metformin therapy or thiazolidinedione therapy | No case of lactic acidosis in the metformin group. A slight decrease in eGFR was only significant in the preexisting DM group | Long observational period, first data on safety of metformin | The fact that no treatment effect was observed may not be meaningful in view of sample size and study design |
| Stephen et al. 2014 [60] | N = 46 914 (4609 with metformin, 42 305 non-metformin glucose-lowering agent | Kidney | Metformin claims were filled later and were associated with higher eGFR before the first claim | Metformin was associated with lower adjusted hazard for living and deceased donor allograft survival at 3 years. Metformin was associated with lower mortality | Sample size, outcome data | No clear distinction between DM and PTDM, bias by indication |
| Kwon et al. 2023 [59] | N = 1193 with metformin, N = 802 without | Kidney | Metformin reduced death-censored graft failure, no association with all-cause mortality | No association with BPAR, no confirmed case of lactic acidosis | Sample size, outcome data | Bias by indication |
| Thiazolidinediones | ||||||
| Pietruck et al. 2005 [85] | N = 22 (rosiglitazone) | Kidney | 73% had sufficient glycaemic control | Diabetologically comprehensive. Novelty at that time. Duration of follow-up | Sample size | |
| Luther and Baldwin 2004 [86] | N = 10 with DM2 and PTDM in KTR and LTR (pioglitazone) | Kidney | Mean HbA1c and mean total daily insulin dose was significantly lower after pioglitazone initiation. Mean serum creatinine levels did not change. Mean blood tacrolimus levels were lower in the pioglitazone group (no difference in dose-normalized tacrolimus blood levels) | Mean BMI increased after pioglitazone. Mean daily prednisolone dose decreased non- significantly. No significant fluid retention and no differences in mean serum lipid values after pioglitazone initiation | Emphasis on safety. Duration of follow-up | Study design itself, potential selection bias, sample size, similarity to study by Baldwin and Duffin |
| Kurian et al. 2008 [84] | N = 32 in the metformin and N = 46 in the thiazolidinedione group (pioglitazone, rosiglitazone) | Kidney | No significant difference in HbA1c before and after metformin therapy or thiazolidinedione therapy | No case of lactic acidosis in the metformin group. A slight decrease in eGFR was only significant in the preexisting DM group | Long observational period, first data on safety of metformin | The fact that no treatment effect was observed may not be meaningful in view of sample size and study design |
| Meglitinides | ||||||
| Türk et al. 2006 [87] | N = 44 (N = 23 repaglinide, N = 21 rosiglitazone) | Kidney | After 6 months, 14/23 patients showed successful repaglinide treatment (significant improvement of blood glucose concentrations and HbA1c <7%, no other medication needed) | No significant change in creatinine, cyclosporine A and tacrolimus levels. Similar success rate and HbA1c as in rosiglitazone group | First report on glinides in PTDM | Comparison of various subgroups with non-standard treatment goals |
| GLP-1 receptor agonists | ||||||
| Liou et al. 2018 [88] | N = 7 (liraglutide) | Kidney | Glycaemia improved incl. HbA1c | eGFR improved | Long treatment duration | Small sample size |
| Singh et al. 2019 [89] | N = 63 (dulaglutide) | Kidney, liver, heart | Weight loss | Reduction in insulin requirements | Relatively large cohort | Inhomogeneous cohort (multiple organs) |
| Thangavelu et al. 2020 [90] | N = 19 | Kidney, liver, heart | Stability of the tacrolimus level | Reduction in body weight, BMI and HbA1c | Relatively early study | Inhomogeneous cohort (multiple organs), small sample size |
| Singh et al. 2020 [91] | N = 63 (dulaglutide) N = 25 (liraglutide | Kidney, liver, heart | Weight loss | Reduction in insulin requirement | Relatively large cohort | Similar data as previous study |
| Vigara et al. 2022 [92] | N = 50 (semaglutide, liraglutide, duaglutide) | Kidney | Improvement in eGFR and reduction in proteinuria | Body weight reduction, improvement in HbA1c | Relatively large cohort | Exclusion criteria not clear |
| Sweiss et al. 2022 [93] | N = 118, 70% KTRs, 32% PTDM (liraglutide, dulaglutide, semaglutide, exenatide) | Kidney, lung, liver | Significant difference fasting blood glucose and HbA1c at baseline to 3- to 12-month nadir, weight loss | 7% nausea, 4% pancreatitis, 7% hypo- glycaemic events | Large cohort of SOT with GLP-1-RA treatment | Various transplanted organs and various GLP-1-RA |
| DPP4 inhibitors | ||||||
| Sanyal et al. 2013 [94] | N = 21 (linagliptin) | Kidney | Linaglitpin monotherapy was effective for glycaemic control in patients with NODAT | Insulin requirement in 2 patients, 1 hypoglycaemic episode | Early real-world data | Entirely descriptive |
| Boerner et al. 2014 [95] | N = 22 (sitagliptin) | Kidney | Diabetes control (defined by HbA1c) improved at 6 months and persisted at 12 months | Graft function (serum creatinine and eGFR) did not differ at month 12. No effect on liver transaminase levels and rare occurrence of transplant associated adverse events | Systematic follow-up | Entirely descriptive |
| Bae et al. 2016 [96] | N = 65 (vildagliptin, sitagliptin, linagliptin) | Kidney | HbA1c at 3 months significantly decreased from baseline in the linagliptin group compared with other DPP4i | Cyclosporin trough levels were increased in the sitagliptin group compared with the vildagliptin group | Various DPP4 inhibitors analysed | Superiority of one gliptine versus others is clinically implausible and not known in DM2, may have been dose-dependent |
| Guardado-Mednoza et al. 2019 [97] | N = 14 (linagliptin + basal (NPH) and lispro insulin) N = 14 basal (NPH) and lispro insulin | Kidney | Significant lower fasting plasma glucose levels in the linagliptin plus insulin group after 5 days and at 1 year | Lower insulin doses in the insulin plus linagliptin group and less severe hypoglycaemic events | Data from the early post-transplant period | Treatment duration unclear, therefore, follow-up data not meaningful |
| Sanyal et al. 2021 [98] | N = 95 any agent [all received linagliptin (alone or in combination)] | Kidney | NODAT patients achieved long-term glycaemic control and improved renal function | Most patients needed a combination therapy. Linagliptin was effective without producing hypoglycaemia | Manuscript describes a real-world outpatient scenario | Bias by indication |
| SGLT2is | ||||||
| Rajasekeran et al. 2017 [99] | N = 10 (6 KTRs, 4 SPKTs, PTDM and T2DM) (canagliflozin) | Kidney | Meaningful changes in various parameters (incl. HbA1c, weight, and blood pressure), but none of them significant | First study of SGLT2is in transplanted patients | Small sample size | |
| Attallah and Yassine 2019 [100] | N = 8 (empagliflozin) | Kidney | Increase in creatinine, decrease in HbA1c, body weight and urinary protein excretion | Meaningful HbA1c reduction shown for patients with excellent allograft function | Descriptive, small sample size | |
| AlKindi et al. 2020 [101] | N = 8 (empagliflozin, dapagliflozin) | Kidney | Decrease in HbA1c and body mass index, kidney function remained stable | Meaningful HbA1c reduction shown for patients with excellent allograft function | Descriptive, small sample size | |
| Song et al. 2021 [102] | N = 50 (empagliflozin, canagliflozin, dapagliflozin) | Kidney | Weight reduction | Improvement in hypomagnesemia, reduction in insulin requirement | Relatively large cohort | Low incidence of UTIs is difficult to interpret (more clarity would have been helpful) |
| Lim et al. 2022 [103] | N = 226 (empagliflozin, dapagliflozin) among N = 2083 (propensity score matching 1:3) | Kidney | Improvement in a composite outcome, consisting of all-cause mortality, death-censored graft failure, and serum creatinine doubling | Graft failure reduced (this item was also part of the composite outcome) | First study to describe hard outcome data in KTRs | Written like an RCT (misleading) |
| Lemke et al. 2022 [104] | N = 39 (canagliflozin, dapagliflozin) | Kidney | Decrease in HbA1c | Kidney function and tacrolimus levels not meaningfully altered | Honest discussion of therapy pros and cons | UTIs not clarified further |
Both tables contain studies from patients with disorders of the glucose metabolism that became known after transplantation (hyperglycaemia/PTDM/IGT). If studies were entirely conducted with patients who had type 2 diabetes before transplantation, they were not listed.
DM: diabetes mellitus; DM2: type 2 diabetes mellitus; NODAT: new-onset diabetes after transplantation; BMI: body mass index; GLP-1-RA: GLP-1 receptor agonist; DPP4i: DPP4 inhibitor; SU: sulfonylurea; TZDs: thiazolidinediones; BPAR: biopsy proved acute rejection.