Supplementary Material for: Dipeptidyl Peptidase-4 Inhibitors in Chronic Kidney Disease: A Systematic Review of Randomized Clinical Trials

<p><b><i>Background:</i></b> Chronic kidney disease (CKD) is common in patients with type 2 diabetes mellitus (T2DM) and limits therapeutic options. Dipeptidyl peptidase-4 (DPP-4) inhibitors represent a novel class of oral glucose-lowering agents and are known to be safe and effective in the general population. <b><i>Methods:</i></b> We searched Cochrane, EMBASE, and PubMed from the time of their inception until March 2015. We included randomized controlled trials analyzing the efficacy (change in hemoglobin A1C [HbA1C]) and safety of DPP-4 agents in individuals with reduced kidney function (estimated glomerular filtration rate <60 mL/min/1.73 m<sup>2</sup>). We extracted study characteristics, participants' baseline characteristics, and safety outcomes from eligible studies. We performed a random effects meta-analysis to summarize the change in HbA1C and the relative risk of cardiovascular events in patients with T2DM and CKD. We also collected data on hypoglycemia, other serious adverse events, and mortality. <b><i>Results:</i></b> We reviewed 12 studies with 4,403 patients with CKD and 239 on dialysis, finding a mean weighted decline in HbA1C of -0.48 (95% CI -0.61 to -0.35) with DPP-4 inhibitor therapy compared to placebo. DPP-4 inhibitors did not result in any additional adverse events, hypoglycemic episodes, or increased mortality. Restricting to studies with low risk of bias did not alter these findings. <b><i>Conclusions:</i></b> DPP-4 inhibitors can lower HbA1C without increasing the risk of cardiovascular or other major adverse events in patients with CKD. Few studies reported critical adverse events such as heart failure and hypersensitivity. If compared with other oral antiglycemic drugs, the effect of DPP-4 inhibitors is limited; however, their low risk of hypoglycemia may favor their use in patients with CKD. <b><i>Summary:</i></b> This systematic review of DPP-4 inhibitors in CKD suggests that they reduce HbA1C by about 0.5%. Furthermore, there was not any increase in the risk for significant adverse events. More research is needed to determine the safety and efficacy of DPP-4 inhibitors in CKD.</p>