Heart failure, saxagliptin, and diabetes mellitus: Observations from the SAVOR-TIMI 53 randomized trial

Benjamin M. Scirica, Eugene Braunwald, Itamar Raz, Matthew A. Cavender, David A. Morrow, Petr Jarolim, Jacob A. Udell, Ofri Mosenzon, Kyungah Im, Amarachi A. Umez-Eronini, Pia S. Pollack, Boaz Hirshberg, Robert Frederich, Basil S. Lewis, Darren K McGuire, Jaime Davidson, Ph Gabriel Steg, Deepak L. Bhatt

Research output: Contribution to journalArticle

368 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1579-1588
Number of pages10
JournalCirculation
Volume130
Issue number18
DOIs
StatePublished - 2014

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Diabetes Mellitus
Heart Failure
Brain Natriuretic Peptide
Hospitalization
Placebos
saxagliptin
Natriuretic Peptides
Glomerular Filtration Rate
Chronic Renal Insufficiency
Type 2 Diabetes Mellitus
Stroke
Myocardial Infarction
Confidence Intervals
Therapeutics

Keywords

  • Diabetes mellitus
  • Heart failure
  • Saxagliptin

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine
  • Medicine(all)

Cite this

Scirica, B. M., Braunwald, E., Raz, I., Cavender, M. A., Morrow, D. A., Jarolim, P., ... Bhatt, D. L. (2014). Heart failure, saxagliptin, and diabetes mellitus: Observations from the SAVOR-TIMI 53 randomized trial. Circulation, 130(18), 1579-1588. https://doi.org/10.1161/CIRCULATIONAHA.114.010389

Heart failure, saxagliptin, and diabetes mellitus : Observations from the SAVOR-TIMI 53 randomized trial. / Scirica, Benjamin M.; Braunwald, Eugene; Raz, Itamar; Cavender, Matthew A.; Morrow, David A.; Jarolim, Petr; Udell, Jacob A.; Mosenzon, Ofri; Im, Kyungah; Umez-Eronini, Amarachi A.; Pollack, Pia S.; Hirshberg, Boaz; Frederich, Robert; Lewis, Basil S.; McGuire, Darren K; Davidson, Jaime; Steg, Ph Gabriel; Bhatt, Deepak L.

In: Circulation, Vol. 130, No. 18, 2014, p. 1579-1588.

Research output: Contribution to journalArticle

Scirica, BM, Braunwald, E, Raz, I, Cavender, MA, Morrow, DA, Jarolim, P, Udell, JA, Mosenzon, O, Im, K, Umez-Eronini, AA, Pollack, PS, Hirshberg, B, Frederich, R, Lewis, BS, McGuire, DK, Davidson, J, Steg, PG & Bhatt, DL 2014, 'Heart failure, saxagliptin, and diabetes mellitus: Observations from the SAVOR-TIMI 53 randomized trial', Circulation, vol. 130, no. 18, pp. 1579-1588. https://doi.org/10.1161/CIRCULATIONAHA.114.010389
Scirica, Benjamin M. ; Braunwald, Eugene ; Raz, Itamar ; Cavender, Matthew A. ; Morrow, David A. ; Jarolim, Petr ; Udell, Jacob A. ; Mosenzon, Ofri ; Im, Kyungah ; Umez-Eronini, Amarachi A. ; Pollack, Pia S. ; Hirshberg, Boaz ; Frederich, Robert ; Lewis, Basil S. ; McGuire, Darren K ; Davidson, Jaime ; Steg, Ph Gabriel ; Bhatt, Deepak L. / Heart failure, saxagliptin, and diabetes mellitus : Observations from the SAVOR-TIMI 53 randomized trial. In: Circulation. 2014 ; Vol. 130, No. 18. pp. 1579-1588.
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T2 - Observations from the SAVOR-TIMI 53 randomized trial

AU - Scirica, Benjamin M.

AU - Braunwald, Eugene

AU - Raz, Itamar

AU - Cavender, Matthew A.

AU - Morrow, David A.

AU - Jarolim, Petr

AU - Udell, Jacob A.

AU - Mosenzon, Ofri

AU - Im, Kyungah

AU - Umez-Eronini, Amarachi A.

AU - Pollack, Pia S.

AU - Hirshberg, Boaz

AU - Frederich, Robert

AU - Lewis, Basil S.

AU - McGuire, Darren K

AU - Davidson, Jaime

AU - Steg, Ph Gabriel

AU - Bhatt, Deepak L.

PY - 2014

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N2 - 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.

AB - 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.

KW - Diabetes mellitus

KW - Heart failure

KW - Saxagliptin

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