title: Angiotensin-Converting Enzyme Inhibitor Use and Major Cardiovascular Outcomes in Type 2 Diabetes Mellitus Treated With the Dipeptidyl Peptidase 4 Inhibitor Alogliptin.
abstract: Activation of the sympathetic nervous system when there is dipeptidyl peptidase 4 inhibition in the presence of high-dose angiotensin-converting enzyme (ACE) inhibition has led to concerns of potential increases in cardiovascular events when the 2 classes of drugs are coadministered. We evaluated cardiovascular outcomes from the EXAMINE (Examination of Cardiovascular Outcomes With Alogliptin versus Standard of Care) trial according to ACE inhibitor use. Patients with type 2 diabetes mellitus and a recent acute coronary syndrome were randomly assigned to receive the dipeptidyl peptidase 4 inhibitor alogliptin or placebo added to existing antihyperglycemic and cardiovascular prophylactic therapies. Risks of adjudicated cardiovascular death, nonfatal myocardial infarction and stroke, and hospitalized heart failure were analyzed using a Cox proportional hazards model in patients according to ACE inhibitor use and dose. There were 3323 (62%) EXAMINE patients treated with an ACE inhibitor (1681 on alogliptin and 1642 on placebo). The composite rates of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke were comparable for alogliptin and placebo with ACE inhibitor (11.4% versus 11.8%; hazard ratio, 0.97; 95% confidence interval, 0.79-1.19; P=0.76) and without ACE inhibitor use (11.2% versus 11.9%; hazard ratio, 0.94; 95% confidence interval, 0.73-1.21; P=0.62). Composite rates for cardiovascular death and heart failure in patients on ACE inhibitor occurred in 6.8% of patients on alogliptin versus 7.2% on placebo (hazard ratio, 0.93; 95% confidence interval, 0.72-1.2; P=0.57). There were no differences for these end points nor for blood pressure or heart rate in patients on higher doses of ACE inhibitor. Cardiovascular outcomes were similar for alogliptin and placebo in patients with type 2 diabetes mellitus and coronary disease treated with ACE inhibitors.
authors.affiliation: From the Calhoun Cardiology Center, University of Connecticut School of Medicine, Farmington (W.B.W.); Takeda Development Center Americas, Inc, Deerfield, IL (C.A.W., S.K.); University of Chicago Medicine, IL (G.L.B.); International Diabetes Center, Park-Nicollet Clinic, Minneapolis, MN (R.M.B.); Brigham and Women's Hospital, Harvard Medical School, Boston, MA (C.P.C.); Memphis Veterans Affairs Medical Center, University of Tennessee College of Medicine (W.C.C.); University of Sheffield, United Kingdom (S.K.H.); Harvard School of Public Health, Boston, MA (C.R.M.); Cleveland Clinic Foundation, OH (S.E.N.); and Université de Lorraine, Nancy, France (F.Z.). wwhite@uchc.edu.
authors.forename: William B
authors.initials: WB
authors.lastname: White
authors.affiliation: From the Calhoun Cardiology Center, University of Connecticut School of Medicine, Farmington (W.B.W.); Takeda Development Center Americas, Inc, Deerfield, IL (C.A.W., S.K.); University of Chicago Medicine, IL (G.L.B.); International Diabetes Center, Park-Nicollet Clinic, Minneapolis, MN (R.M.B.); Brigham and Women's Hospital, Harvard Medical School, Boston, MA (C.P.C.); Memphis Veterans Affairs Medical Center, University of Tennessee College of Medicine (W.C.C.); University of Sheffield, United Kingdom (S.K.H.); Harvard School of Public Health, Boston, MA (C.R.M.); Cleveland Clinic Foundation, OH (S.E.N.); and Université de Lorraine, Nancy, France (F.Z.).
authors.forename: Craig A
authors.initials: CA
authors.lastname: Wilson
authors.affiliation: From the Calhoun Cardiology Center, University of Connecticut School of Medicine, Farmington (W.B.W.); Takeda Development Center Americas, Inc, Deerfield, IL (C.A.W., S.K.); University of Chicago Medicine, IL (G.L.B.); International Diabetes Center, Park-Nicollet Clinic, Minneapolis, MN (R.M.B.); Brigham and Women's Hospital, Harvard Medical School, Boston, MA (C.P.C.); Memphis Veterans Affairs Medical Center, University of Tennessee College of Medicine (W.C.C.); University of Sheffield, United Kingdom (S.K.H.); Harvard School of Public Health, Boston, MA (C.R.M.); Cleveland Clinic Foundation, OH (S.E.N.); and Université de Lorraine, Nancy, France (F.Z.).
authors.forename: George L
authors.initials: GL
authors.lastname: Bakris
authors.affiliation: From the Calhoun Cardiology Center, University of Connecticut School of Medicine, Farmington (W.B.W.); Takeda Development Center Americas, Inc, Deerfield, IL (C.A.W., S.K.); University of Chicago Medicine, IL (G.L.B.); International Diabetes Center, Park-Nicollet Clinic, Minneapolis, MN (R.M.B.); Brigham and Women's Hospital, Harvard Medical School, Boston, MA (C.P.C.); Memphis Veterans Affairs Medical Center, University of Tennessee College of Medicine (W.C.C.); University of Sheffield, United Kingdom (S.K.H.); Harvard School of Public Health, Boston, MA (C.R.M.); Cleveland Clinic Foundation, OH (S.E.N.); and Université de Lorraine, Nancy, France (F.Z.).
authors.forename: Richard M
authors.initials: RM
authors.lastname: Bergenstal
authors.affiliation: From the Calhoun Cardiology Center, University of Connecticut School of Medicine, Farmington (W.B.W.); Takeda Development Center Americas, Inc, Deerfield, IL (C.A.W., S.K.); University of Chicago Medicine, IL (G.L.B.); International Diabetes Center, Park-Nicollet Clinic, Minneapolis, MN (R.M.B.); Brigham and Women's Hospital, Harvard Medical School, Boston, MA (C.P.C.); Memphis Veterans Affairs Medical Center, University of Tennessee College of Medicine (W.C.C.); University of Sheffield, United Kingdom (S.K.H.); Harvard School of Public Health, Boston, MA (C.R.M.); Cleveland Clinic Foundation, OH (S.E.N.); and Université de Lorraine, Nancy, France (F.Z.).
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Cannon
authors.affiliation: From the Calhoun Cardiology Center, University of Connecticut School of Medicine, Farmington (W.B.W.); Takeda Development Center Americas, Inc, Deerfield, IL (C.A.W., S.K.); University of Chicago Medicine, IL (G.L.B.); International Diabetes Center, Park-Nicollet Clinic, Minneapolis, MN (R.M.B.); Brigham and Women's Hospital, Harvard Medical School, Boston, MA (C.P.C.); Memphis Veterans Affairs Medical Center, University of Tennessee College of Medicine (W.C.C.); University of Sheffield, United Kingdom (S.K.H.); Harvard School of Public Health, Boston, MA (C.R.M.); Cleveland Clinic Foundation, OH (S.E.N.); and Université de Lorraine, Nancy, France (F.Z.).
authors.forename: William C
authors.initials: WC
authors.lastname: Cushman
authors.affiliation: From the Calhoun Cardiology Center, University of Connecticut School of Medicine, Farmington (W.B.W.); Takeda Development Center Americas, Inc, Deerfield, IL (C.A.W., S.K.); University of Chicago Medicine, IL (G.L.B.); International Diabetes Center, Park-Nicollet Clinic, Minneapolis, MN (R.M.B.); Brigham and Women's Hospital, Harvard Medical School, Boston, MA (C.P.C.); Memphis Veterans Affairs Medical Center, University of Tennessee College of Medicine (W.C.C.); University of Sheffield, United Kingdom (S.K.H.); Harvard School of Public Health, Boston, MA (C.R.M.); Cleveland Clinic Foundation, OH (S.E.N.); and Université de Lorraine, Nancy, France (F.Z.).
authors.forename: Simon K
authors.initials: SK
authors.lastname: Heller
authors.affiliation: From the Calhoun Cardiology Center, University of Connecticut School of Medicine, Farmington (W.B.W.); Takeda Development Center Americas, Inc, Deerfield, IL (C.A.W., S.K.); University of Chicago Medicine, IL (G.L.B.); International Diabetes Center, Park-Nicollet Clinic, Minneapolis, MN (R.M.B.); Brigham and Women's Hospital, Harvard Medical School, Boston, MA (C.P.C.); Memphis Veterans Affairs Medical Center, University of Tennessee College of Medicine (W.C.C.); University of Sheffield, United Kingdom (S.K.H.); Harvard School of Public Health, Boston, MA (C.R.M.); Cleveland Clinic Foundation, OH (S.E.N.); and Université de Lorraine, Nancy, France (F.Z.).
authors.forename: Cyrus R
authors.initials: CR
authors.lastname: Mehta
authors.affiliation: From the Calhoun Cardiology Center, University of Connecticut School of Medicine, Farmington (W.B.W.); Takeda Development Center Americas, Inc, Deerfield, IL (C.A.W., S.K.); University of Chicago Medicine, IL (G.L.B.); International Diabetes Center, Park-Nicollet Clinic, Minneapolis, MN (R.M.B.); Brigham and Women's Hospital, Harvard Medical School, Boston, MA (C.P.C.); Memphis Veterans Affairs Medical Center, University of Tennessee College of Medicine (W.C.C.); University of Sheffield, United Kingdom (S.K.H.); Harvard School of Public Health, Boston, MA (C.R.M.); Cleveland Clinic Foundation, OH (S.E.N.); and Université de Lorraine, Nancy, France (F.Z.).
authors.forename: Steven E
authors.initials: SE
authors.lastname: Nissen
authors.affiliation: From the Calhoun Cardiology Center, University of Connecticut School of Medicine, Farmington (W.B.W.); Takeda Development Center Americas, Inc, Deerfield, IL (C.A.W., S.K.); University of Chicago Medicine, IL (G.L.B.); International Diabetes Center, Park-Nicollet Clinic, Minneapolis, MN (R.M.B.); Brigham and Women's Hospital, Harvard Medical School, Boston, MA (C.P.C.); Memphis Veterans Affairs Medical Center, University of Tennessee College of Medicine (W.C.C.); University of Sheffield, United Kingdom (S.K.H.); Harvard School of Public Health, Boston, MA (C.R.M.); Cleveland Clinic Foundation, OH (S.E.N.); and Université de Lorraine, Nancy, France (F.Z.).
authors.forename: Faiez
authors.initials: F
authors.lastname: Zannad
authors.affiliation: From the Calhoun Cardiology Center, University of Connecticut School of Medicine, Farmington (W.B.W.); Takeda Development Center Americas, Inc, Deerfield, IL (C.A.W., S.K.); University of Chicago Medicine, IL (G.L.B.); International Diabetes Center, Park-Nicollet Clinic, Minneapolis, MN (R.M.B.); Brigham and Women's Hospital, Harvard Medical School, Boston, MA (C.P.C.); Memphis Veterans Affairs Medical Center, University of Tennessee College of Medicine (W.C.C.); University of Sheffield, United Kingdom (S.K.H.); Harvard School of Public Health, Boston, MA (C.R.M.); Cleveland Clinic Foundation, OH (S.E.N.); and Université de Lorraine, Nancy, France (F.Z.).
authors.forename: Stuart
authors.initials: S
authors.lastname: Kupfer
mesh_terms: D054058:Acute Coronary Syndrome / Q000401:mortality / Q000503:physiopathology*; D000368:Aged; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D016001:Confidence Intervals; D003924:Diabetes Mellitus, Type 2 / Q000175:diagnosis / Q000188:drug therapy*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D010880:Piperidines / Q000627:therapeutic use*; D011379:Prognosis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012016:Reference Values; D018570:Risk Assessment; D015996:Survival Rate; D016896:Treatment Outcome; D014498:Uracil / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D010880:Piperidines; D014498:Uracil; C520853:alogliptin
keywords: alogliptin; angiotensin II; angiotensin-converting enzyme inhibitors dipeptidyl dipeptidase 4 inhibitors; heart rate; type 2 diabetes mellitus