title: Cardiovascular safety of linagliptin in type 2 diabetes: a comprehensive patient-level pooled analysis of prospectively adjudicated cardiovascular events.
abstract: BACKGROUND
  The cardiovascular (CV) safety of linagliptin was evaluated in subjects with type 2 diabetes (T2DM).
  
  
  METHODS
  Pre-specified patient-level pooled analysis of all available double-blind, randomized, controlled trials, ≥ 12 weeks' duration (19 trials, 9459 subjects) of linagliptin versus placebo/active treatment. Primary end point: composite of prospectively adjudicated CV death, non-fatal myocardial infarction, non-fatal stroke, and hospitalization for unstable angina (4P-MACE). Hospitalization for congestive heart failure (CHF) was also evaluated; adjudication of CHF was introduced during the phase 3 program (8 trials; 3314 subjects). 4P-MACE was assessed in placebo-controlled trials (subgroup of 18 trials; 7746 subjects). Investigator-reported events suggestive of CHF from 24 placebo-controlled trials (including trials <12 weeks' duration, 8778 subjects) were also analyzed.
  
  
  RESULTS
  5847 patients received linagliptin (5 mg: 5687, 10 mg: 160) and 3612 comparator (glimepiride: 775, voglibose: 162, placebo: 2675); cumulative exposure, 4421.3 and 3254.7 patient-years, respectively. 4P-MACE incidence rates: 13.4 per 1000 patient-years, linagliptin (60 events), 18.9, total comparators (62 events); overall hazard ratio (HR), 0.78 (95% confidence interval [CI], 0.55-1.12). HR for adjudicated hospitalization for CHF (n = 21): 1.04 (0.43-2.47). For placebo-controlled trials, 4P-MACE incidence rates: 14.9 per 1000 patient-years, linagliptin (43 events), 16.4, total comparators (29 events); overall HR, 1.09 (95% CI, 0.68-1.75). Occurrence of investigator-reported events suggestive of CHF was low for linagliptin- (26 events, 0.5%; serious: 16 events, 0.3%) and placebo-treated (8 events, 0.2%; serious: 6 events, 0.2%) patients.
  
  
  CONCLUSIONS
  Linagliptin is not associated with increased CV risk versus pooled active comparators or placebo in patients with T2DM.
authors.affiliation: Dallas Diabetes and Endocrine Center at Medical City, Dallas, TX, USA. juliorosenstock@dallasdiabetes.com.
authors.forename: Julio
authors.initials: J
authors.lastname: Rosenstock
authors.affiliation: Department of Internal Medicine I, University Hospital Aachen, Aachen, Germany. nmarx@ukaachen.de.
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Marx
authors.affiliation: Boehringer Ingelheim, Biberach, Germany. dietmar.neubacher@boehringer-ingelheim.com.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Neubacher
authors.affiliation: Boehringer Ingelheim, Ingelheim, Germany. thomas.seck@boehringer-ingelheim.com.
authors.forename: Thomas
authors.initials: T
authors.lastname: Seck
authors.affiliation: Boehringer Ingelheim, Bracknell, Berkshire, UK. sanjay.patel@boehringer-ingelheim.com.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Patel
authors.affiliation: Boehringer Ingelheim, Ingelheim, Germany. hans-juergen.woerle@boehringer-ingelheim.com.
authors.forename: Hans-Juergen
authors.initials: HJ
authors.lastname: Woerle
authors.affiliation: Boehringer Ingelheim, Drengsrudbekken 8, 1373 Asker, Oslo, Norway. odd_erik.johansen@boehringer-ingelheim.com.
authors.forename: Odd Erik
authors.initials: OE
authors.lastname: Johansen
mesh_terms: D000368:Aged; D000789:Angina, Unstable / Q000453:epidemiology*; D002318:Cardiovascular Diseases / Q000453:epidemiology / Q000401:mortality*; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000627:therapeutic use*; D005260:Female; D006333:Heart Failure / Q000453:epidemiology*; D006760:Hospitalization / Q000706:statistics & numerical data; D006801:Humans; D015994:Incidence; D000069476:Linagliptin / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000453:epidemiology*; D016016:Proportional Hazards Models; D011446:Prospective Studies; D016032:Randomized Controlled Trials as Topic; D012307:Risk Factors; D020521:Stroke / Q000453:epidemiology*
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D000069476:Linagliptin