Dipeptidyl Peptidase-4 Inhibitor Alarms: Is Heart Failure Caused by a Class Effect?

Corresponding author: Yong-ho Lee Division of Endocrinology and Metabolism, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Korea E-mail: [email protected] Since the rosiglitazone controversy aroused in 2007 [1], US Food and Drug Administration and most other regulatory agencies have requested to perform cardiovascular safety assessments for upcoming antidiabetic medications [2]. Dipeptidyl peptidase-4 (DPP4) inhibitors belong to a new class of oral antidiabetic drugs which can ameliorate hyperglycemia by increasing endogenous concentration of glucagon-like peptide-1, a gut-derived hormone that stimulates insulin secretion and delays gastric emptying. However, despite its popularity in the diabetes market, the cardiovascular safety of DPP4 inhibitors has not been investigated following the two large, randomized, placebo-controlled trials (RCTs), saxagliptin assessment of vascular outcomes recorded in patients with diabetes mellitus-thrombolysis in myocardial infarction (SAVOR-TIMI 53) [3] with saxagliptin and Examination of Cardiovascular Outcomes with Alogliptin vs. Standard of Care (EXAMINE) [4] with alogliptin, which recently published the results of cardiovascular outcomes in 2013. Unexpectedly, SAVOR-TIMI 53 showed that the rate of hospital admission for heart failure was significantly increased by 27% in subjects treated with saxagliptin, while EXAMINE did not report any outcome related to heart failure. A subsequent paper based on EXAMINE trial reported that alogliptin was not associated with the increased risk of heart failure outcomes, such as hospital admission for heart failure, compared with placebo group [5]. However, both studies observed that hospital admission for heart failure occurred more frequently in subjects treated with saxagliptin or alogliptin who had no history of this disease condition (SAVOR-TIMI 53: hazard ratio [HR], 1.30, 95% confidence interval [CI], 1.03 to 1.65; EXAMINE: HR, 1.76, 95% CI, 1.07 to 2.90). According to the additional report from SAVOR-TIMI 53, the high-risk patients for heart failure hospitalization were those who had a prior history of heart failure, elevated baseline levels of N-terminal pro-brain natriuretic peptide, or chronic kidney disease [6]. To date, several studies demonstrated conflicting results regarding the safety of DPP4 inhibitors on heart failure. A nested case-control study based on a large insurance claimed that the database from United States showed that sitagliptin was associated with heart failure admissions in patients recently diagnosed with heart failure (adjusted odds ratio [OR], 1.84; 95% CI, 1.16 to 2.92; P=0.01) [7]. A propensity-matched analysis using Taiwan National Health Insurance research database with a total of 16,576 subjects reported that sitagliptin users were hospitalized for heart failure more frequently than patients that were never exposed to a DPP4 inhibitor (HR, 1.21; 95% CI, 1.04 to 1.42; P=0.017) [8]. In this study, patients with the highest adherence to sitagliptin had the greatest risk of developing heart failure (HR, 2.56; 95% CI, 2.10 to 3.12) compared with never users. In addition, similar findings were derived from a recent meta-analysis of 82 randomized controlled clinical trials with various DPP4 inhibitors treated for at least 24 weeks. The overall risk of acute heart failure was significantly elevated in the DPP4 inhibitor group compared with placebo/active comparators (n=69,615; Mantel-Haenszel OR, 1.19; 95% CI, 1.03 to 1.37; P=0.015) [9]. In Vildagliptin in VentricuEditorial Others