Pioglitazone Is Associated with Lower Major Adverse Cardiovascular and Cerebrovascular Events than DPP4-Inhibitors in Diabetic Patients with End-Stage Renal Disease: A Taiwan Nationwide Cohort Study, 2006-2016

Abstract

While pioglitazone reduces insulin resistance and hepatic gluconeogenesis effectively in patients with type 2 diabetes mellitus (T2DM), these benefits remained controversial in patients with end stage renal disease (ESRD). We compared major adverse cardiac cerebrovascular events (MACCEs) and mortality (overall, infection-related, and MACCE-related) of pioglitazone to that of dipeptidyl peptidase 4 inhibitors (DPP4-inhibitors) in patients with T2DM and ESRD. From Taiwan's national health insurance research database (NHIRD), 647 pioglitazone users and 6080 DPP4-inhibitors users between 1 April 2006 and 31 December 2016 were followed from the 91th date after the ESRD certification until the study outcomes, independently; withdraw from the NHI program, death, or 31 December 2017, whichever came first. After weighting, risks of MACCEs (10.48% vs. 12.62% per person-years, hazard ratio (HR): 0.85, 95% (CI): 0.729-0.985) and all-cause mortality (12.86% vs. 13.22% per person-years, (HR): 0.88, 95% (CI): 0.771-0.995) are significantly lower in pioglitazone group. Subgroup analysis found lower MACCEs risk in the pioglitazone users without insulin therapy (6.44% vs. 10.04% (HR): 0.59, 95% (CI): 0.42-0.82) and lower MACCEs related death (2.76% vs. 3.84% (HR): 0.61, 95% (CI): 0.40-0.95) in the pioglitazone group with dyslipidemia, when comparing with DPP4-inhibitors users. Pioglitazone is associated with lower all-cause mortality and MACCEs in diabetic patients with ESRD, compared to DPP4-inhibitors. These benefits were even more significant in the non-insulin users and patients with dyslipidemia.

Keywords: DPP4-inhibitor; ESRD; Pioglitazone; cardiovascular outcome; mortality.

Figure 1

Flow chart of study patient enrollment. DM, diabetes mellitus; DPP4-inhibitor, Dipeptidyl peptidase 4 inhibitor; ESRD, end stage renal disease; MACCEs, major adverse cardiac cerebrovascular events.

Figure 2

Kaplan–Meier curve of cumulative incidence for primary and secondary outcomes after propensity score stabilize weighting (PSSW). (a) Major adverse cardiac cerebrovascular events; (b) All-cause mortality; (c) Infection related death; (d) Major adverse cardiac cerebrovascular events (MACCEs) related death. DPP4-inhibitors, dipeptidyl-peptidase 4 inhibitors.

Figure 3

Forest plot of subgroup analysis for primary and secondary outcomes. (a) Major adverse cardiac cerebrovascular events; (b) All-cause mortality; (c) Infection related death; (d) Major adverse cardiac cerebrovascular events (MACCEs) related death. AF, atrial fibrillation; CCI, Charlson’s cormobidity index; CI, confidence interval; CTD, connective tissue disease; DPP4i, dipeptidyl-peptidase 4 inhibitors; HR, hazard ratio; MI, myocardial infarction; PAD, peripheral artery disease.