title: Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes and moderate or severe renal impairment: observations from the SAVOR-TIMI 53 Trial.
abstract: OBJECTIVE
  The glycemic management of patients with type 2 diabetes mellitus (T2DM) and renal impairment is challenging, with few treatment options. We investigated the effect of saxagliptin in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR)-Thrombolysis in Myocardial Infarction (TIMI) 53 trial according to baseline renal function.
  
  
  METHODS
  Patients with T2DM at risk for cardiovascular events were stratified as having normal or mildly impaired renal function (estimated glomerular filtration rate [eGFR] >50 mL/min/1.73 m(2); n = 13,916), moderate renal impairment (eGFR 30-50 mL/min/1.73 m(2); n = 2,240), or severe renal impairment (eGFR <30 mL/min/1.73 m(2); n = 336) and randomized to receive saxagliptin or placebo. The primary end point was cardiovascular death, myocardial infarction, or ischemic stroke.
  
  
  RESULTS
  After a median duration of 2 years, saxagliptin neither increased nor decreased the risk of the primary and secondary composite end points compared with placebo, irrespective of renal function (all P for interactions ≥ 0.19). Overall, the risk of hospitalization for heart failure among the three eGFR groups of patients was 2.2% (referent), 7.4% (adjusted hazard ratio [HR] 2.38 [95% CI 1.95-2.91], P < 0.001), and 13.0% (adjusted HR 4.59 [95% CI 3.28-6.28], P < 0.001), respectively. The relative risk of hospitalization for heart failure with saxagliptin was similar (P for interaction = 0.43) in patients with eGFR >50 mL/min/1.73 m(2) (HR 1.23 [95% CI 0.99-1.55]), eGFR 30-50 mL/min/1.73 m(2) (HR 1.46 [95% CI 1.07-2.00]), and in patients with eGFR <30 (HR 0.94 [95% CI 0.52-1.71]). Patients with renal impairment achieved reductions in microalbuminuria with saxagliptin (P = 0.041) that were similar to those of the overall trial population.
  
  
  CONCLUSIONS
  Saxagliptin did not affect the risk of ischemic cardiovascular events, increased the risk of heart failure hospitalization, and reduced progressive albuminuria, irrespective of baseline renal function.
authors.affiliation: Cardiovascular Division, Women's College Hospital, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Jacob A
authors.initials: JA
authors.lastname: Udell
authors.affiliation: TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
authors.forename: Deepak L
authors.initials: DL
authors.lastname: Bhatt
authors.affiliation: TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
authors.forename: Eugene
authors.initials: E
authors.lastname: Braunwald
authors.affiliation: TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Cavender
authors.affiliation: Diabetes Unit, Division of Internal Medicine, Hadassah Hebrew University Hospital, Jerusalem, Israel.
authors.forename: Ofri
authors.initials: O
authors.lastname: Mosenzon
authors.affiliation: Département Hospitalo-Universitaire-Fibrosis Inflammation Remodelling, INSERM U-1148, Université Paris-Diderot, and Hôpital Bichat, AP-HP, Paris, France Imperial College, Royal Brompton Hospital, London, U.K.
authors.forename: Ph Gabriel
authors.initials: PG
authors.lastname: Steg
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Jaime A
authors.initials: JA
authors.lastname: Davidson
authors.affiliation: Heart Institute (InCor), University of São Paulo Medical School, São Paulo, Brazil.
authors.forename: Jose C
authors.initials: JC
authors.lastname: Nicolau
authors.affiliation: Cardiovascular Division, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Ramon
authors.initials: R
authors.lastname: Corbalan
authors.affiliation: AstraZeneca Research and Development, Wilmington, DE.
authors.forename: Boaz
authors.initials: B
authors.lastname: Hirshberg
authors.affiliation: Bristol-Myers Squibb, Princeton, NJ.
authors.forename: Robert
authors.initials: R
authors.lastname: Frederich
authors.affiliation: TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
authors.forename: KyungAh
authors.initials: K
authors.lastname: Im
authors.affiliation: TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
authors.forename: Amarachi A
authors.initials: AA
authors.lastname: Umez-Eronini
authors.affiliation: TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
authors.forename: Ping
authors.initials: P
authors.lastname: He
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Darren K
authors.initials: DK
authors.lastname: McGuire
authors.affiliation: Division of Endocrinology and Metabolism, Keenan Research Centre in the Li Ka Shing Knowledge Institute of St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: Leiter
authors.affiliation: Diabetes Unit, Division of Internal Medicine, Hadassah Hebrew University Hospital, Jerusalem, Israel.
authors.forename: Itamar
authors.initials: I
authors.lastname: Raz
authors.affiliation: TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA bscirica@partners.org.
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Scirica
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000368:Aged; D002318:Cardiovascular Diseases / Q000175:diagnosis / Q000453:epidemiology*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy* / Q000453:epidemiology*; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000453:epidemiology; D004151:Dipeptides / Q000627:therapeutic use*; D005260:Female; D006333:Heart Failure / Q000150:complications / Q000453:epidemiology; D006760:Hospitalization / Q000706:statistics & numerical data; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000150:complications / Q000453:epidemiology; D051437:Renal Insufficiency / Q000188:drug therapy* / Q000453:epidemiology / Q000209:etiology; D012720:Severity of Illness Index; D020521:Stroke / Q000150:complications / Q000453:epidemiology; D016896:Treatment Outcome
chemical_list: D004151:Dipeptides; C502994:saxagliptin; D000218:Adamantane