title: Glucose-lowering agents for treating pre-existing and new-onset diabetes in kidney transplant recipients.
abstract: Kidney transplantation is the preferred form of kidney replacement therapy for patients with end-stage kidney disease (ESKD) and is often complicated by worsening or new-onset diabetes. Management of hyperglycaemia is important to reduce post-transplant and diabetes-related complications. The safety and efficacy of glucose-lowering agents after kidney transplantation is largely unknown.
  
  
  
  To evaluate the efficacy and safety of pharmacological interventions for lowering glucose levels in patients who have undergone kidney transplantation and have diabetes.
  
  
  
  We searched the Cochrane Kidney and Transplant Specialised Register to 15 April 2016 through contact with the Information Specialist using search terms relevant to this review. Studies contained in the Specialised Register are identified through search strategies specifically designed for CENTRAL, MEDLINE, and EMBASE; handsearching conference proceedings; and searching the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.
  
  
  
  All randomised controlled trials (RCTs), quasi-RCTs and cross-over studies examining head-to-head comparisons of active regimens of glucose-lowering therapy or active regimen compared with placebo/standard care in patients who have received a kidney transplant and have diabetes were eligible for inclusion.
  
  
  
  Two authors independently assessed study eligibility and quality and performed data extraction. Continuous outcomes were expressed as post-treatment mean differences (MD) or standardised mean difference (SMD). Adverse events were expressed as post-treatment absolute risk differences (RD). Dichotomous clinical outcomes were presented as risk ratios (RR) with 95% confidence intervals (CI).
  
  
  
  We included seven studies that involved a total of 399 kidney transplant recipients. All included studies had observed heterogeneity in the patient population, interventions and measured outcomes or missing data (which was unavailable despite correspondence with authors). Many studies had incompletely reported methodology preventing meta-analysis and leading to low confidence in treatment estimates.Three studies with 241 kidney transplant recipients examined the use of more intensive compared to less intensive insulin therapy in kidney transplant recipients with pre-existing type 1 or 2 diabetes. Evidence for the effects of more intensive compared to less intensive insulin therapy on transplant graft survival, HbA1c, fasting blood glucose, all cause mortality and adverse effects including hypoglycaemia was of very low quality. More intensive versus less intensive insulin therapy resulted in no difference in transplant or graft survival over three to five years in one study while another study showed that more intensive versus less intensive insulin therapy resulted in more rejection events over the three year follow-up (11 events in total; 9 in the more intensive group, P = 0.01). One study showed that more intensive insulin therapy resulted in a lower mean HbA1c (10 ± 0.8% versus 13 ± 0.9%) and lower fasting blood glucose (7.22 ± 0.5 mmol/L versus 13.44 ± 1.22 mmol/L) at 13 months compared with standard insulin therapy. Another study showed no difference between more intensive compared to less intensive insulin therapy on all-cause mortality over a five year follow-up period. All studies showed either an increased frequency of hypoglycaemia or severe hypoglycaemia episodes.Three studies with a total of 115 transplant recipients examined the use of DPP4 inhibitors for new-onset diabetes after transplantation. Evidence for the treatment effect of DPP4 inhibitors on transplant or graft survival, HbA1c and fasting blood glucose levels, all cause mortality, and adverse events including hypoglycaemia was of low quality. One study comparing vildagliptin to placebo and another comparing sitagliptin to placebo showed no difference in transplant or graft survival over two to four months of follow-up. One study comparing vildagliptin to placebo showed no significant change in estimated glomerular filtration rate from baseline (1.9 ± 10.3 mL/min/1.73 m2, P = 0.48 and 2.1 ± 6.1 mL/min/1.73 m2, P = 0.22) and no deaths, in either treatment group over three months of follow-up. One study comparing vildagliptin to placebo showed a lower HbA1c level (mean ± SD) (6.3 ± 0.5% versus versus 6.7 ± 0.6%, P = 0.03) and trend towards a greater lowering of fasting blood glucose (-0.91 ± -0.92 mmol/L versus vs -0.19 ± 1.16 mmol/L, P = 0.08) with vildagliptin. One study comparing sitagliptin to insulin glargine showed an equivalent lowering of HbA1c (-0.6 ± 0.5% versus -0.6 ± 0.6%, P = NS) and fasting blood glucose (4.92 ± 1.42 versus 4.76 ± 1.09 mmol/L, P = NS) with sitagliptin. For the outcome of hypoglycaemia, one study comparing vildagliptin to placebo reported no episodes of hypoglycaemia, one study comparing sitagliptin to insulin glargine reported fewer episodes of hypoglycaemia with sitagliptin (3/28 patients; 10.7% versus 5/28; 17.9%) and one cross-over study of sitagliptin and placebo reported two episodes of asymptomatic moderate hypoglycaemia (2 to 3.9 mmol/L) when sitagliptin was administered with glipizide. All three studies reported no drug interactions between DPP4 inhibitors and the immunosuppressive agents taken.Evidence for the treatment effect of pioglitazone for treating pre-existing diabetes was of low quality. One study with 62 transplant recipients compared the use of pioglitazone with insulin to insulin alone for treating pre-existing diabetes. Pioglitazone resulted in a lower HbA1c level (mean ± SD) (-1.21 ± 1.2 versus 0.39 ± 1%, P < 0.001) but had no effects on fasting blood glucose (6.58 ± 2.71 versus 7.28 ± 2.78 mmol/L, P = 0.14 ), and change in creatinine (3.54 ± 15.03 versus 10.61 ± 18.56 mmol/L, P = 0.53) and minimal adverse effects (no episodes of hypoglycaemia, three dropped out due to mild to moderate lower extremity oedema, cyclosporin levels were not affected).
  
  
  
  Evidence concerning the efficacy and safety of glucose-lowering agents for treating pre-existing and new-onset diabetes in kidney transplant recipients is limited. Existing studies examine more intensive versus less intensive insulin therapy, and the use of DPP4 inhibitors and pioglitazone. The safety and efficacy of more intensive compared to less intensive insulin therapy is very uncertain and the safety and efficacy of DPP4 inhibitors and pioglitazone is uncertain, due to data being limited and of poor quality. Additional RCTs are required to clarify the safety and efficacy of current glucose-lowering agents for kidney transplant recipients with diabetes.
authors.affiliation: Diabetes and Vascular Research Program, Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, Clayton, VIC, Australia.
authors.forename: Clement
authors.initials: C
authors.lastname: Lo
authors.affiliation: The George Institute for Global Health, The University of Sydney, Camperdown, NSW, Australia.
authors.forename: Min
authors.initials: M
authors.lastname: Jun
authors.affiliation: Department of Nephrology, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia, 4102.
authors.forename: Sunil V
authors.initials: SV
authors.lastname: Badve
authors.affiliation: Department of Renal Medicine, Auckland Hospital, Park Road, Grafton, Auckland, New Zealand.
authors.forename: Helen
authors.initials: H
authors.lastname: Pilmore
authors.affiliation: Renal and Metabolic Division, The George Institute for Global Health, The University of Sydney, Level 10, King George V Building, Royal Prince Alfred Hospital, Camperdown, NSW, Australia, 2050.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: White
authors.affiliation: Department of Nephrology, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia, 4102.
authors.forename: Carmel
authors.initials: C
authors.lastname: Hawley
authors.affiliation: Renal and Metabolic Division, The George Institute for Global Health, The University of Sydney, Level 10, King George V Building, Royal Prince Alfred Hospital, Camperdown, NSW, Australia, 2050.|Menzies School of Health Research, PO Box 41096, Casuarina, NT, Australia, 0811.
authors.forename: Alan
authors.initials: A
authors.lastname: Cass
authors.affiliation: Renal and Metabolic Division, The George Institute for Global Health, The University of Sydney, Level 10, King George V Building, Royal Prince Alfred Hospital, Camperdown, NSW, Australia, 2050.
authors.forename: Vlado
authors.initials: V
authors.lastname: Perkovic
authors.affiliation: Diabetes and Vascular Research Program, Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, Clayton, VIC, Australia.|The George Institute for Global Health, The University of Sydney, Camperdown, NSW, Australia.
authors.forename: Sophia
authors.initials: S
authors.lastname: Zoungas
mesh_terms: D000218:Adamantane / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000188:drug therapy*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D018819:Dipeptidyl Peptidase 4; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D005215:Fasting / Q000097:blood; D006442:Glycated Hemoglobin / Q000378:metabolism; D006085:Graft Survival / Q000187:drug effects; D006801:Humans; D007003:Hypoglycemia / Q000139:chemically induced; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D007328:Insulin / Q000009:adverse effects / Q000627:therapeutic use; D016030:Kidney Transplantation; D009570:Nitriles / Q000009:adverse effects / Q000627:therapeutic use; D000077205:Pioglitazone; D011759:Pyrrolidines / Q000009:adverse effects / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D000068900:Sitagliptin Phosphate / Q000009:adverse effects / Q000627:therapeutic use; D045162:Thiazolidinediones / Q000009:adverse effects / Q000627:therapeutic use; D000077597:Vildagliptin
chemical_list: D000218:Adamantane; D018819:Dipeptidyl Peptidase 4; D054873:Dipeptidyl-Peptidase IV Inhibitors; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D009570:Nitriles; D000077205:Pioglitazone; D011759:Pyrrolidines; D000068900:Sitagliptin Phosphate; D045162:Thiazolidinediones; D000077597:Vildagliptin; C517652:hemoglobin A1c protein, human; C042807:DPP4 protein, human