European Review for Medical and Pharmacological Sciences 2018; 22: 3502-3514 Efficacy and safety of dipeptidyl peptidase-4 inhibitors in the treatment of type 2 diabetes mellitus patients with moderate to severe renal impairment: a meta-analysis Y. CHEN1,2, K. MEN3, X.-F. LI4, J. LI4, M. LIU2, Z.-Q. FAN1 1Department of Endocrinology, The Second Hospital of Tianjin Medical University, Tianjin, China 2Department of Endocrinology and Metabolism, The General Hospital of Tianjin Medical University, Tianjin, China 3Department of Clinical Laboratory, The Second Hospital of Tianjin Medical University, Tianjin, China 4Department of Endocrinology, Shanxi Provincial People’s Hospital, Xian, China Yu Chen and Kun Men are co-first authors Abstract. – OBJECTIVE: Dipeptidyl pepti- CONCLUSIONS: DPP-4 inhibitors significantly dase-4 (DPP-4) inhibitors are a new class of oral an- lowered HbA1c levels in T2DM patients with mod- tidiabetic agents for type 2 diabetes mellitus erate to severe RI. And the treatment of DPP-4 in- (T2DM) patients. However, the effects and safety of hibitors did not increase the risk of hypoglycemia DPP-4 inhibitors in T2DM patients with renal im- and adverse events. Considering the potential lim- pairment (RI) remain controversial. Therefore, we itations in this meta-analysis, more large-scale, conducted this meta-analysis to assess the effica- well-conducted RCTs are needed to identify our cy and safety of DPP-4 inhibitors in T2DM patients findings. with moderate to severe RI. MATERIALS AND METHODS: The PubMed, Key Words Embase, and Web of Science database were Type 2 diabetes mellitus, Dipeptidyl peptidase-4 in- searched for published randomized controlled tri- hibitor, Renal impairment, Meta-analysis. als (RCTs), which compared DPP-4 inhibitors with placebo or a control regimen. A fixed-model effect or random-effect model was used to assess the effects of DPP-4 inhibitors on T2DM patients with RI. Subgroup analysis or meta-regression analy- Introduction sis were performed to explore the potential sourc- es of heterogeneity among the included studies. Type 2 diabetes mellitus (T2DM) is the lead- RESULTS: 13 RCTs with a total of 2,940 patients ing cause of chronic kidney disease (CKD)1. were included in this meta-analysis. Compared with other treatments, DPP-4 inhibitors were as- Moderate to severe renal impairment (RI), which sociated with a greater change in HbA1c level defined as an estimated glomerular filtration rate (weight mean difference (WMD)=-0.50, 95%CI: (GFR) below 60 mL/min/1.73 m2, occurred in -0.61, -0.39; p<0.001), and a higher response rate 20-30% of patients2,3. Patients at this advantage of patients achieving the HbA1c goal of <7% (risk of RI is difficult to manage because of the high ratio (RR)=1.38, 95%CI: 1.12, 1.70; p=0.002). Sub- prevalence of co-morbidities, increased risk of group analysis suggested that the reduced HbA1c hypoglycemia4, and reduced drug elimination was observed in all types of DPP-4 inhibitors, and 5 in patients with moderate or severe RI, but not in rate . Insulin therapy combined with oral antihy- those with end-stage renal disease. DPP-4 inhibi- perglycemic drugs (OADs) is frequently used in tors did not significantly lower the FPG level patients with T2DM when their glycemic control (WMD=-0.36, 95%CI: -0.92, 0.20; p=0.204), and deteriorates3. However, commonly used OADs this was seen in all types of DPP-4 inhibitors ex- are either contraindicated or should be used at cept gemigliptin, which showed a significant re- reduced doses in individuals with RI3. Important- duction in FPG level. The prevalence of adverse ly, patients with T2DM and RI have an increased events (RR=0.98, 95%CI: 0.94, 1.02; p=0.256) in risk of hypoglycemia, which is commonly due the two groups was not significantly different, and 6 DPP-4 inhibitors did not induce a higher rate of hy- to decreased clearance of insulinotropic agents . poglycemia (RR=1.31, 95%CI: 0.97, 1.77; p=0.075). Moreover, most OADs are affected by kidney 3502 Corresponding Author: Xiao-Feng Li, MD; e-mail: [email protected] Efficacy and safety of dipeptidyl peptidase-4 inhibitors function and should, therefore, be either or used OR (“dipeptidyl peptidase 4”[MeSH Terms] OR at reduced doses in patients with CKD5,7. Conse- “dipeptidyl peptidase 4”[All Fields] OR (“dipep- quently, additional treatment options suitable for tidyl”[All Fields] AND “peptidase”[All Fields] patients with T2DM and CKD and which have a AND “iv”[All Fields]) OR “dipeptidyl pepti- low risk of hypoglycemia are needed. dase iv”[All Fields])) AND (“renal insufficien- Dipeptidyl peptidase-4 (DPP-4) inhibitors are cy”[MeSH Terms] OR (“renal”[All Fields] AND relatively new oral hypoglycemic drugs. They could “insufficiency”[All Fields]) OR “renal insuffi- modulate fasting plasma glucose, postprandial glu- ciency”[All Fields] OR (“renal”[All Fields] AND cose, and HbA1c levels by decreasing the inacti- “impairment”[All Fields]) OR “renal impair- vation of incretins such as glucagon-like peptide 1 ment”[All Fields]). The searches were limited to and glucose-dependent insulinotropic polypeptide human subjects, and no language restriction was to stimulate the release of insulin in a glucose-de- imposed. We did not include abstracts or meeting pendent manner8,9. These agents include sitagliptin, proceedings. In addition, we also searched the vildagliptin, saxagliptin, and linagliptin. For pa- reference lists of the included studies and reviews tients with T2DM and CKD, these agents are suit- to identify other potentially eligible papers that able since they show good tolerability, low risk of we may leave out of our primary search. hypoglycemia, and neutral effect on body effect. Two systematic reviews and meta-analysis10,11 Study Selection regarding the DPP-4 inhibitors on reducing We included full-text publications when the HbA1c level have been published. Both of them following inclusion criteria were met: (1) study showed that DPP-4 inhibitors were effective at design: RCT; (2) study population: patients diag- lowering HbA1c in T2DM patients with moder- nosed with T2DM and had RI; (3) intervention: ate or severe RI. However, one was only based on DPP-4 inhibitors; (4) comparison: placebo, or five randomized controlled trials (RCTs) and in- other glucose-lowering medications; (5) outcome cluded relatively small sample size10, and another measures: change from baseline in HbA1c, re- included half of the studies published in the form sponder rates: achieving an HbA1c of <7%, fast- of conferences abstracts, clinical trials registries, ing plasma glucose (FPG), adverse events; (6) company websites, and FDA and EMA websites, sample size: more than 50. without access to the full-data11. Moreover, the roles of different type of DPP-4 inhibitors on var- Data Extraction ious CKD stages have not been well established. Two independent investigators extracted the Recently, several relevant RCTs regarding DPP-4 following information from each trial: first au- inhibitors on reducing the HbA1c level have been thor’s name, year of publication, country of or- published. These reports were well-performed igin, sample size in each group, patients’ char- RCTs and included an additional more than 1,356 acteristics, methods of randomization and blind, patients. We, therefore, conducted this updated duration of follow-up, the change from baseline in meta-analysis of 13 RCTs to evaluate the efficacy HbA1c, FPG, prevalence of adverse events. When and safety of DPP-4 inhibitors for T2DM patients the same population appeared in several publi- with moderate or severe RI. cations, we only included the most informative study to avoid duplication of information. Any discrepancies were resolved by discussion and Materials and Methods consensus. Search Strategy Risk of Bias and Evidence This meta-analysis was conducted in accor- of Grade Assessment dance with the Preferred Reporting Items for Sys- The risk of bias in RCTs was assessed using tematic Reviews and meta-analysis (PRISMA) the method recommended by Cochrane Collab- criteria12. Two independent investigators searched oration13. The scale consists of seven items de- the literature collected in PubMed, Embase, and scribing random sequence generation; allocation Web of Science up to April 12, 2017. Electronical concealment; blinding of participants and person- search was performed using the following search nel; blinding of outcome assessment; incomplete algorithm: (“diabetes mellitus, type 2”[MeSH outcome data; selective reporting and other bias13. Terms] OR “type 2 diabetes mellitus”[All Fields]) Each study was classified as “high”, “unclear”, or AND (DPP-4[All Fields] OR dppiv[All Fields] “low” risk of bias13. 3503 Y. Chen, K. Men, X.-F. Li, J. Li, M. Liu, Z.-Q. Fan The quality of evidence for outcome measures was evaluated using the Grading of Recommen- dations Assessment, Development and Evaluation (GRADE) approach14. Through reviewing the in- consistency, indirectness, imprecision, and publi- cation bias, each outcome was regarded as very low, low, moderate, or high quality14. A summary table was constructed using the GRADE profiler (GRADE pro, version 3.6). Statistical Analysis We calculated weight mean difference (WMD) with 95% confidence intervals (95%CIs) for continuous outcomes, and risk ratio (RR) with 95%CIs for dichotomous outcomes. Before the data were pooled, we used the Cochrane Q chi-square test and I2 statistic to test the het- erogeneity across studies, in which p-value less than 0.1 or I2>50% indicated significant hetero- geneity15. A random-effects model (DerSimoni- an-Laird method)16 was used to pool data when significant heterogeneity was identified; other- wise, a fixed-effects model (Mantel-Haenszel method)17 was used. We also conducted sensi- tivity analysis, meta-regression, and subgroup analysis based on types of DPP-4 inhibitors, and severity of RI to explore the potential sources Figure 1.