Heart Failure, Saxagliptin, and Diabetes Mellitus: Observations from the SAVOR-TIMI 53 Randomized Trial

Abstract

iabetes mellitus (DM) adds incremental risk of the development and subsequent exacerbation of heart failure even after adjusting for common risk factors, such as ischemic heart disease and hypertension.1 Although incompletely understood, cardiac metabolic dysregulation of glycolysis and fatty acid oxidation observed in the heart of patients with Background-Diabetes mellitus and heart failure frequently coexist. However, few diabetes mellitus trials have prospectively evaluated and adjudicated heart failure as an end point. Methods and Results-A total of 16 492 patients with type 2 diabetes mellitus and a history of, or at risk of, cardiovascular events were randomized to saxagliptin or placebo (mean follow-up, 2.1 years). The primary end point was the composite of cardiovascular death, myocardial infarction, or ischemic stroke. Hospitalization for heart failure was a predefined component of the secondary end point. Baseline N-terminal pro B-type natriuretic peptide was measured in 12 301 patients. More patients treated with saxagliptin (289, 3.5%) were hospitalized for heart failure compared with placebo (228, 2.8%; hazard ratio, 1.27; 95% confidence intercal, 1.07-1.51; P=0.007). Corresponding rates at 12 months were 1.9% versus 1.3% (hazard ratio, 1.46; 95% confidence interval, 1.15-1.88; P=0.002), with no significant difference thereafter (time-varying interaction, P=0.017). Subjects at greatest risk of hospitalization for heart failure had previous heart failure, an estimated glomerular filtration rate ≤60 mL/min, or elevated baseline levels of N-terminal pro B-type natriuretic peptide. There was no evidence of heterogeneity between N-terminal pro B-type natriuretic peptide and saxagliptin (P for interaction=0.46), although the absolute risk excess for heart failure with saxagliptin was greatest in the highest N-terminal pro B-type natriuretic peptide quartile (2.1%). Even in patients at high risk of hospitalization for heart failure, the risk of the primary and secondary end points were similar between treatment groups. Conclusions-In the context of balanced primary and secondary end points, saxagliptin treatment was associated with an increased risk or hospitalization for heart failure. This increase in risk was highest among patients with elevated levels of natriuretic peptides, previous heart failure, or chronic kidney disease. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01107886.

GLP-1 receptor agonists and heart failure in diabetes

“…In EXAMINE, alogliptin had no effect on the composite events of cardiovascular death and hospital admission for HF on post-hoc analysis (HR: 1.00, 95% CI: 0.82-1.21), and the results did not differ by baseline BNP concentration [49]. In SAVOR -TIMI 53, the increased risk of hospitalization for HF was highest among patients with elevated levels of natriuretic peptides, previous HF or chronic kidney disease [50].…”

“…Indeed, these meta-analyses of RCTs with GLP-1RAs may be compared with those of RCTs with DPP-4 inhibitors [9,10], which showed that DPP-4 inhibitors were not associated with any increased risk of HF-related hospitalizations [10] except for saxagliptin [9], mainly because of the results of the SAVOR -TIMI 53 trial [7].…”

“…Unfortunately, no measurements of pro-BNP levels were available in the LEADER trial [24], and this key information was also missing in the ELIXA [47] and SUSTAIN-6 [48]. However, such measurements were included in two trials of DPP-4 inhibitors: the EXAMINE with alogliptin [49]; and SAVOR -TIMI 53 with saxagliptin [50]. In EXAMINE, alogliptin had no effect on the composite events of cardiovascular death and hospital admission for HF on post-hoc analysis (HR: 1.00, 95% CI: 0.82-1.21), and the results did not differ by baseline BNP concentration [49].…”

“…HF is of major interest as it is the one cardiovascular outcome for which the risk has unequivocally been shown to be increased by some glucose-lowering therapies, particularly thiazolidinediones (glitazones) [4,5], whereas metformin appears to be safe [6]. Recently, some concerns have also been raised with the dipeptidyl peptidase (DPP)-4 inhibitor saxagliptin, following the publication of the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR) -Thrombolysis in Myocardial Infarction (TIMI) 53 trial [7], a finding that casts some suspicion on the entire incretin-based pharmacological class [8][9][10]. In contrast, a marked, significant reduction in hospitalizations for HF has been reported with the sodium -glucose cotransporter type 2 (SGLT2) inhibitor empagliflozin in the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) [11,12].…”

“…During recent years following the request of the US Food and Drug Administration (FDA), special attention has been focused on their cardiovascular effects [15][16][17][18], and greater concerns surfaced after the report of a higher incidence of hospitalization for HF with the DPP-4 inhibitor saxagliptin [7,8].…”