Abstract
Rationale: Diabetes is a critical risk factor for cardiovascular disease and chronic kidney disease (CKD). Type 2 diabetes increases all-cause and cardiovascular death and impairs health-related quality of life. More than a third of people with type 2 diabetes develop kidney failure, requiring treatment with dialysis or kidney transplantation. People with CKD and type 2 diabetes have a substantially higher risk of premature cardiovascular complications. Dipeptidyl peptidase 4 (DPP-4) inhibitors are glucose-lowering agents that achieve glucose control in people with type 2 diabetes and may prevent poor kidney and cardiovascular outcomes for people with CKD and type 2 diabetes. However, new trials are emerging rapidly, and continuous evidence synthesis is essential to summarising cumulative evidence.
Objectives: This review aims to assess the benefits and harms of DPP-4 inhibitors in people with CKD and type 2 diabetes.
Search methods: We searched the Cochrane Kidney and Transplant Register of Studies up to 25 March 2025 using a search strategy designed by an Information Specialist. Studies in the Register are continually identified through regular searches of CENTRAL, MEDLINE, Embase, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.
Eligibility criteria: Randomised controlled studies (RCTs) were eligible if they compared treatment with a DPP-4 inhibitor against placebo, standard medical care (including usual other glucose-lowering agents or no treatment), or another glucose-lowering agent in people with CKD and type 2 diabetes. We included all CKD categories (from 1 to 5), including people treated with dialysis. People with type 1 diabetes and kidney transplant recipients were excluded.
Outcomes: The critical review outcomes were cardiovascular death and hypoglycaemia requiring third-party assistance. The key important outcomes included 3- and 4-point major cardiovascular events (MACE), nonfatal myocardial infarction, nonfatal stroke, and kidney failure.
Risk of bias: The risk of bias version 2 tool was used to assess the studies.
Synthesis methods: Three review authors independently extracted data and assessed the study risk of bias. Treatment estimates were summarised using random effects meta-analysis and expressed as relative risk (RR) or mean difference (MD), with corresponding 95% confidence interval (CI). Evidence certainty was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.
Included studies: Fifty-nine studies involving 27,893 participants were included. DPP-4 inhibitors with or without other background treatments were compared to placebo, standard medical care, sodium-glucose cotransport 2 inhibitors, glucagon-like peptide-1 receptor agonists, sulfonylurea, other DPP-4 inhibitors, insulin, or alpha-glucosidase inhibitors. There were no studies evaluating treatment in children. We contacted 10 authors from primary studies to retrieve additional information, but no further data were added to this review.
Synthesis of results: Compared to placebo or standard medical care, DPP-4 inhibitors may have little or no effect on the risk of cardiovascular death (RR 0.96, 95% CI 0.82 to 1.14; 6 studies, 7568 participants; low-certainty evidence) and hypoglycaemia requiring third-party assistance in people with all CKD categories (RR 0.97, 95% CI 0.76 to 1.25; I² = 0%; 10 studies, 8994 participants; low-certainty evidence). DPP-4 inhibitors probably have little or no effect on 3-point MACE compared with placebo (RR 1.03, 95% CI 0.91 to 1.17; 1 study, 6979 participants; moderate-certainty evidence). DPP-4 inhibitors had uncertain effects on the risk of 4-point MACE compared with placebo (RR 0.74, 95% CI 0.29 to 1.88; 1 study, 133 participants; very low-certainty evidence), nonfatal myocardial infarction compared with placebo in people with CKD categories 3-5, including those on dialysis (RR 1.91, 95% CI 0.36 to 10.08; 1 study, 133 participants; very-low-certainty evidence), or nonfatal stroke compared with placebo (RR 0.96, 95% CI 0.06 to 14.97; 1 study, 133 participants; very-low-certainty evidence). Compared to placebo or standard medical care, DPP-4 inhibitors probably have little or no effect on kidney failure in people with all CKD categories (RR 1.09, 95% CI 0.78 to 1.53; I² = 0%; 3 studies, 7472 participants; moderate-certainty evidence). The effects of DPP-4 inhibitors compared to other glucose-lowering agents were uncertain. No studies evaluated treatment on the clinical outcomes of life participation, lactic acidosis, blindness, diabetic ketoacidosis, peritoneal dialysis infection, or peritoneal dialysis failure. The overall risk of bias was assessed as low or very low for most included studies.
Authors' conclusions: DPP-4 inhibitors had an uncertain effect on the risks of cardiovascular death and hypoglycaemia requiring third-party assistance in people with CKD and type 2 diabetes when compared with placebo or standard medical care, whilst the effects on other glucose-lowering agents were uncertain. Despite the large number of studies, there is little evidence that DPP-4 inhibitors prevent key adverse clinical outcomes for people who have CKD and type 2 diabetes. Future well-designed and adequately powered RCTs can provide better information about the effects of DPP-4 inhibitors on key patient-reported outcomes and cost to better inform decision-making and clinical practice in this setting.