Glucose-lowering agents for treating pre-existing and new-onset diabetes in kidney transplant recipients

What is the issue?

Kidney transplantation is often complicated by worsening or new-onset diabetes. The safety and effectiveness of drugs used to lower glucose in this setting is largely unknown.

What did we do?

We evaluated the effectiveness and safety of glucose-lowering drugs in people with diabetes who have received a kidney transplant by searching the Cochrane Kidney and Transplant Specialised Register. We updated our original review by including all randomised controlled and cross-over studies examining this question to 16 January 2020.

What did we find?

We included ten studies (including three additional studies) with a total of 603 randomised people receiving kidney transplants. Four studies compared more intensive to less intensive insulin therapy; two studies compared dipeptidyl peptidase-4 (DPP-4) inhibitors to placebo; one study compared DPP-4 inhibitors to insulin glargine; one study compared sodium glucose co-transporter 2 (SGLT2) inhibitors to placebo; and two studies compared glitazones plus insulin to insulin therapy alone. From these studies, the effects of more compared to less intensive insulin treatment on kidney transplant survival, blood glucose control, death, and treatment side-effects including hypoglycaemia, are not well understood. Based on one study, DPP-4 inhibitors may improve blood glucose control without affecting kidney function markers. The rate of side-effects of DPP-4 inhibitors compared to placebo or insulin is also not well understood. Based on one study, SGLT2 inhibitors probably do not affect kidney transplant survival, but may improve long-term blood glucose control without affecting long-term kidney function. SGLT2 inhibitors probably do not cause low sugar levels and have little or no effect on people stopping the medication. However, in the study, people who stop SGLT2 inhibitors had urinary tract infections. Glitazones and insulin may not have an effect on blood glucose control or side-effects compared to insulin alone. The effects of using DPP-4 inhibitors compared to placebo or insulin, or glitazones and insulin compared to insulin alone, on survival of the kidney transplant and death is also unclear.

Conclusion

Contemporary evidence concerning glucose-lowering treatment for diabetes in people who have received kidney transplants is limited. Larger, higher quality studies are needed to evaluate the safety and effectiveness of current glucose lowering treatments.

Authors' conclusions: 

The efficacy and safety of glucose-lowering agents in the treatment of pre-existing and new-onset diabetes in kidney transplant recipients is questionable. Evidence from existing studies examining the effect of intensive insulin therapy, DPP-4 inhibitors, SGLT inhibitors and glitazones is mostly of low to very low certainty. Appropriately blinded, larger, and higher quality RCTs are needed to evaluate and compare the safety and efficacy of contemporary glucose-lowering agents in the kidney transplant population.

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Background: 

Kidney transplantation is the preferred management for patients with end-stage kidney disease (ESKD). However, it is often complicated by worsening or new-onset diabetes. The safety and efficacy of glucose-lowering agents after kidney transplantation is largely unknown. This is an update of a review first published in 2017.

Objectives: 

To evaluate the efficacy and safety of glucose-lowering agents for treating pre-existing and new onset diabetes in people who have undergone kidney transplantation.

Search strategy: 

We searched the Cochrane Kidney and Transplant Register of Studies up to 16 January 2020 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.

Selection criteria: 

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.

Data collection and analysis: 

Four 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).

Main results: 

Ten studies (21 records, 603 randomised participants) were included - three additional studies (five records) since our last review. Four studies compared more intensive versus less intensive insulin therapy; two studies compared dipeptidyl peptidase-4 (DPP-4) inhibitors to placebo; one study compared DPP-4 inhibitors to insulin glargine; one study compared sodium glucose co-transporter 2 (SGLT2) inhibitors to placebo; and two studies compared glitazones and insulin to insulin therapy alone. The majority of studies had an unclear to a high risk of bias. There were no studies examining the effects of biguanides, glinides, GLP-1 agonists, or sulphonylureas.

Compared to less intensive insulin therapy, it is unclear if more intensive insulin therapy has an effect on transplant or graft survival (4 studies, 301 participants: RR 1.12, 95% CI 0.32 to 3.94; I2 = 49%; very low certainty evidence), delayed graft function (2 studies, 153 participants: RR 0.63, 0.42 to 0.93; I2 = 0%; very low certainty evidence), HbA1c (1 study, 16 participants; very low certainty evidence), fasting blood glucose (1 study, 24 participants; very low certainty evidence), kidney function markers (1 study, 26 participants; very low certainty evidence), death (any cause) (3 studies, 208 participants" RR 0.68, 0.29 to 1.58; I2 = 0%; very low certainty evidence), hypoglycaemia (4 studies, 301 participants; very low certainty evidence) and medication discontinuation due to adverse effects (1 study, 60 participants; very low certainty evidence).

Compared to placebo, it is unclear whether DPP-4 inhibitors have an effect on hypoglycaemia and medication discontinuation (2 studies, 51 participants; very low certainty evidence). However, DPP-4 inhibitors may reduce HbA1c and fasting blood glucose but not kidney function markers (1 study, 32 participants; low certainty evidence).

Compared to insulin glargine, it is unclear if DPP-4 inhibitors have an effect on HbA1c, fasting blood glucose, hypoglycaemia or discontinuation due to adverse events (1 study, 45 participants; very low certainty evidence).

Compared to placebo, SGLT2 inhibitors probably do not affect kidney graft survival (1 study, 44 participants; moderate certainty evidence), but may reduce HbA1c without affecting fasting blood glucose and eGFR long-term (1 study, 44 participants, low certainty evidence). SGLT2 inhibitors probably do not increase hypoglycaemia, and probably have little or no effect on medication discontinuation due to adverse events. However, all participants discontinuing SGLT2 inhibitors had urinary tract infections (1 study, 44 participants, moderate certainty evidence).

Compared to insulin therapy alone, it is unclear if glitazones added to insulin have an effect on HbA1c or kidney function markers (1 study, 62 participants; very low certainty evidence). However, glitazones may make little or no difference to fasting blood glucose (2 studies, 120 participants; low certainty evidence), and medication discontinuation due to adverse events (1 study, 62 participants; low certainty evidence).

No studies of DPP-4 inhibitors, or glitazones reported effects on transplant or graft survival, delayed graft function or death (any cause).

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