Research Article: Risk of cardiovascular events associated with dipeptidyl peptidase-4 inhibitors in patients with diabetes with and without chronic kidney disease: A nationwide cohort study

Date Published: May 21, 2019

Publisher: Public Library of Science

Author(s): Tzu-Lan Huang, Fei-Yuan Hsiao, Chih-Kang Chiang, Li-Jiuan Shen, Chih-Fen Huang, Vivekanand Jha.

http://doi.org/10.1371/journal.pone.0215248

Abstract

Cardiovascular events associated with oral hypoglycemic agents (OHAs) have raised significant safety concerns. This study assessed the association between dipeptidyl peptidase-4 inhibitors (DPP-4i) and the risk of cardiovascular events in patients with type 2 diabetes mellitus with or without chronic kidney disease (CKD).

A retrospective cohort study using Taiwan’s National Health Insurance Research Database.

Our study included patients with type 2 diabetes who received OHAs between March 1, 2009, and December 31, 2012. All eligible subjects were classified into CKD and non-CKD cohorts and further categorized as the DPP-4i and non-DPP-4i users in each cohort.

The DPP-4i and non-DPP-4i groups were matched 1:1 by propensity score to attenuate potential selection bias. Propensity score was estimated by logistic regression, using demographics, co-medications, comorbidities. and adapted diabetic complication severity index at baseline.

Outcomes of interest included a composite endpoint of ischemic stroke, myocardial infarction, cardiovascular death (major adverse cardiac events [MACE]), and hospitalization for heart failure (hHF). COX proportional hazard models were applied to examine the association between DPP-4i and outcomes of interest.

We identified 37,641 and 87,604 patients with type 2 diabetes with and without CKD, respectively. After propensity score matching, 8,213 pairs of CKD patients and 12,313 pairs of non-CKD patients were included for analysis. In the CKD cohort, DPP-4i were associated with a 25% increased risk of hHF (DPP-4i vs. non-DPP-4i incidence/1,000 person-years: 15.0 vs. 9.9, HR = 1.25; 95% CI 1.01–1.54, p = 0.037) but not with the risk of MACE (HR = 0.89, p = 0.144). In the non-CKD cohort, DPP-4i were associated with a lower risk of MACE (DPP-4i vs. non-DPP-4i incidence/1,000 person-years: 9.8 vs. 12.6 HR = 0.73; 95% CI 0.61–0.87, p = 0.0007), but not the risk of hHF (HR = 1.09, p = 0.631).

DPP-4i were found to be associated with decreased risk of MACE in the non-CKD cohort in our study. However, DPP-4i were associated with increased risk of hHF in the CKD cohort. DPP-4i in the CKD cohort should be used cautiously.

Partial Text

Oral antidiabetic-agents-associated cardiovascular events have raised serious concerns since the debates about such risks among thiazolidinedione users that have arisen in the past decades[1]. As a result, the U.S. Food and Drug Administration /European Medical Association have requested cardiovascular safety trials with emerging antidiabetic agents, including Dipeptidyl peptidase-4 inhibitors (DPP-4i).

Between March 1, 2009, and December 31, 2012, we identified 8,213 pairs of CKD patients and 12,313 pairs of non-CKD patients after propensity-score matching. Baseline demographics were similar between the two user groups in both cohorts after matching (Table 1, Fig 1). Median follow-up for HF was 567 days (Q1-Q3: 176–1190) and 611 (Q1-Q3: 202–1298) days in the CKD and the non-CKD cohort, respectively. For MACE, the median follow-up was 553 days (Q1-Q3: 170–1161) and 600 (Q1-Q3: 196–1273) days in the CKD and the non-CKD cohort, respectively.

To the best of our knowledge, our study is the first to examine the association between DPP-4i and cardiovascular events in patients with type 2 diabetes with or without CKD. Compared to the non-DPP-4i users, DPP-4 significantly increased 25% risk of hHF in CKD patients. This is consistent with the SAVOR-TIMI-53 trial, which shows a 27% increased risk of hHF associated with saxagliptin use, regardless of kidney disease status[2]. Udell et al. stratified patients according to kidney function in their post hoc analysis and found that increased risk of hHF is seen only in patients with moderately impaired renal function (30 ml/min/1.73 m2 < estimated glomerular filtration rate [eGFR] <50 ml/min/1.73 m2), but not the normal-to-mildly impaired and the severely impaired renal function group (eGFR <30 ml/min/1.73 m2) [23]. Their results are similar to those of our study, since the increased risk is seen only in the CKD cohort but not the non-CKD cohort or dialysis subgroup. However, we have to bear in mind that the number of patients in the most severely impaired renal function group is small in both our study (i.e., dialysis subgroup) and the post hoc analysis. Another difference between our study and the post hoc analysis is that our patients were predominately sitagliptin users. For patients with type 2 diabetes without CKD, we found that DPP-4i exposure is associated with a lower risk of MACE and ischemic stroke. However, DPP-4i are associated with a higher risk of hHF in patients with type 2 diabetes with CKD. DPP-4i in the CKD cohort should be used cautiously. Future studies with more comprehensive hospital-based cohorts with more detailed patient data are warranted.   Source: http://doi.org/10.1371/journal.pone.0215248

 

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