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Effects of Dipeptidyl Peptidase-4 Inhibitors on Renal Outcomes in Patients with Type 2 Diabetes: a Systematic Review and Meta-Analysis

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Effects of Dipeptidyl Peptidase-4 Inhibitors on Renal Outcomes in Patients with Type 2 Diabetes: a Systematic Review and Meta-Analysis Original Endocrinol Metab 2019;34:80-92 https://doi.org/10.3803/EnM.2019.34.1.80 Article pISSN 2093-596X · eISSN 2093-5978 Effects of Dipeptidyl Peptidase-4 Inhibitors on Renal Outcomes in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis Jae Hyun Bae1,*, Sunhee Kim2,*, Eun-Gee Park2, Sin Gon Kim1, Seokyung Hahn3,4, Nam Hoon Kim1 1Department of Internal Medicine, Korea University College of Medicine; 2Interdisciplinary Program in Medical Informatics, Seoul National University College of Medicine; 3Division of Medical Statistics, Medical Research Collaborating Center, Seoul National University Hospital; 4Department of Medicine, Seoul National University College of Medicine, Seoul, Korea Background: To investigate the effects of dipeptidyl peptidase-4 (DPP-4) inhibitors on renal outcomes in patients with type 2 diabetes. Methods: MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched to identify randomized con- trolled trials (RCTs) of DPP-4 inhibitors from inception to September 2017. We selected eligible RCTs comparing DPP-4 inhibitors with placebo or other antidiabetic agents and reporting at least one renal outcome. A meta-analysis was conducted to calculate stan- dardized mean differences, weighted mean differences (WMDs), relative risks (RRs), and 95% confidence intervals (CIs) for each renal outcome. Results: We included 23 RCTs with 19 publications involving 41,359 patients. Overall changes in urine albumin-to-creatinine ratio were comparable between DPP-4 inhibitors and controls (P=0.150). However, DPP-4 inhibitors were associated with significantly lower risk of incident microalbuminuria (RR, 0.89; 95% CI, 0.80 to 0.98; P=0.022) and macroalbuminuria (RR, 0.77; 95% CI, 0.61 to 0.97; P=0.027), as well as higher rates of regression of albuminuria (RR, 1.22; 95% CI, 1.10 to 1.35; P<0.001) compared with controls. Although DPP-4 inhibitors were associated with small but significantly lower estimated glomerular filtration rate (WMD, −1.11 mL/min/1.73 m2; 95% CI, −1.78 to −0.44; P=0.001), there was no difference in the risk of end-stage renal disease between two groups (RR, 0.93; 95% CI, 0.76 to 1.14; P=0.475). Conclusion: DPP-4 inhibitors had beneficial renal effects mainly by reducing the risk of development or progression of albuminuria compared with placebo or other antidiabetic agents. Keywords: Albuminuria; Diabetes complications; Diabetes mellitus, type 2; Diabetic nephropathies; Dipeptidyl-peptidase IV inhib- itors; Glomerular filtration rate; Kidney failure, chronic; Meta-analysis; Systematic review Received: 14 December 2018, Revised: 3 February 2019, Copyright © 2019 Korean Endocrine Society Accepted: 26 February 2019 This is an Open Access article distributed under the terms of the Creative Com- Corresponding authors: Nam Hoon Kim mons Attribution Non-Commercial License (http://creativecommons.org/ Department of Internal Medicine, Korea University College of Medicine, licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribu- 73 Inchon-ro, Seongbuk-gu, Seoul 02841, Korea tion, and reproduction in any medium, provided the original work is properly Tel: +82-2-920-6268, Fax: +82-2-953-9355, E-mail: [email protected] cited. Seokyung Hahn Department of Medicine, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 03080, Korea Tel: +82-2-740-8911, Fax: +82-2-743-8361, E-mail: [email protected] *These authors contributed equally to this work. 80 www.e-enm.org DPP-4 Inhibitors and Renal Outcomes INTRODUCTION In the present study, we performed a systematic review and meta-analysis of RCTs to investigate the effects of DPP-4 inhib- Diabetic kidney disease (DKD) is one of the major microvascu- itors on individual renal outcomes including ESRD compared lar complications of type 2 diabetes and a leading cause of end- with placebo or other antidiabetic agents in patients with type 2 stage renal disease (ESRD) accounting for one-third of all pa- diabetes. tients initiating renal replacement therapy (RRT) worldwide [1,2]. DKD is clinically characterized by persistent albuminuria, METHODS progressive decline in renal function, and the development of ESRD [3]. In the development or progression of DKD, pro- We conducted the systematic review and meta-analysis based longed hyperglycemia plays a crucial role through an increase on a prespecified protocol developed by authors (Appendix 1) in intracellular glucose metabolism, advanced glycation end and reported the results according to the Preferred Reporting products, oxidative stress, and epigenetic reprogramming [4]. In Items for Systematic Review and Meta-Analysis (PRISMA) this regard, intensive glucose control has been proven to be ef- statement (Supplemental Table S1) [16]. fective in preventing or delaying the development and progres- sion of DKD [5,6]. However, the effects of individual antidia- Search strategy and study selection betic drugs on the kidney have been reported to be different [7]. We searched MEDLINE, Embase, and the Cochrane Central Dipeptidyl peptidase-4 (DPP-4) inhibitors are a class of anti- Register of Controlled Trials to identify relevant RCTs pub- diabetic agents that potentiate incretin action by reducing degra- lished in full-text articles from inception to September 2017 dation of glucagon-like peptide-1 and glucose-dependent insuli- with no restriction of language. The search terms used for DPP- notropic polypeptide [8]. DPP-4 inhibitors have been used safe- 4 inhibitors were DPP-4 inhibitor or DPP-4 inhibitor or alo- ly in patients with chronic kidney disease, but their effects on gliptin or anagliptin or evogliptin or gemigliptin or linagliptin or renal outcomes are uncertain. Preclinical studies suggested omarigliptin or saxagliptin or sitagliptin or teneligliptin or trela- pleiotropic effects of DPP-4 inhibition which might be benefi- gliptin or vildagliptin. cial to the kidney [8-10]. However, in clinical trials, the effects We included RCTs comparing DPP-4 inhibitors with placebo of DPP-4 inhibitors on DKD were inconsistent. In the Saxa- or other antidiabetic agents in patients with type 2 diabetes. The gliptin Assessment of Vascular Outcomes Recorded in Patients eligible studies were at least 12 weeks of study duration and re- with Diabetes Mellitus (SAVOR)-Thrombolysis in Myocardial ported one or more renal outcomes including changes in UACR Infarction (TIMI) 53 trial, saxagliptin significantly reduced or eGFR, and the development of microalbuminuria, macroal- urine albumin-to-creatinine ratio (UACR) without affecting re- buminuria, doubling of serum creatinine levels, renal failure, nal function [11]. On the other hand, in the Trial Evaluating ESRD, RRT, dialysis, or kidney transplantation. Pooled analysis Cardiovascular Outcomes with Sitagliptin (TECOS) trial, sita- for multiple RCTs was also included when it provided addition- gliptin showed a small but early decline in estimated glomerular al information on renal outcomes which had not been reported filtration rate (eGFR) which lasted for 48 months with no differ- in the original publications. After removing duplicate publica- ence in changes of UACR [12]. It also should be noted that in tions, we screened titles and abstracts, and thoroughly reviewed those studies renal outcomes were neither primary nor second- full-text articles according to inclusion and exclusion criteria. ary endpoints [13,14]. In a study to assess albuminuria-lowering effect as a key efficacy outcome, linagliptin did not have benefi- Data extraction cial effects on either albuminuria or renal function [15]. How- Two authors (S.K. and N.H.K.) independently extracted data ever, generalization of these results would be cautious in that from included studies according to the standardized protocol the study comprised patients with relatively early stage of DKD. (Appendix 1). Prespecified outcomes of interests were changes Indeed, in the SAVOR-TIMI 53 trial, the decrease in albumin- in UACR and eGFR, the development of microalbuminuria uria was greater in patients with lower eGFR [11]. Therefore, to (UACR >30 mg/g) and macroalbuminuria (UACR >300 mg/g), clarify the renal effects of DPP-4 inhibitors, additional method regression of albuminuria (defined as the development of nor- is needed to integrate the results and complement the limitations moalbuminuria from microalbuminuria or macroalbuminuria; of individual randomized controlled trials (RCTs), even if they development of microalbuminuria from macroalbuminuria), did not initially evaluate renal outcomes. and incident ESRD. Any discrepancies were resolved by con- Copyright © 2019 Korean Endocrine Society www.e-enm.org 81 Bae JH, et al. sensus among the authors (S.K., N.H.K., and S.H.). For contin- portant, moderate, substantial, and considerable heterogeneity, uous variables, mean changes from baseline and their standard respectively [19]. We used the funnel plot and Egger’s test to deviations were extracted from both intervention (DPP-4 inhibi- address reporting bias for the renal outcome with sufficient tors) and control (placebo or other antidiabetic agents) groups number of studies for the exploration [21,22]. In prespecified as summary measures. In a study which reported changes in subgroup analysis, we evaluated changes in UACR according to UACR according to eGFR categories [11], we extracted pooled sodium-glucose cotransporter 2 (SGLT2) inhibitors versus non- mean differences between groups. When only mean difference SGLT2 inhibitors in the control group. All
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