title: Cardiovascular safety with linagliptin in patients with type 2 diabetes mellitus: a pre-specified, prospective, and adjudicated meta-analysis of a phase 3 programme.
abstract: BACKGROUND
  This study investigated the cardiovascular (CV) safety profile of the dipeptidyl peptidase (DPP)-4 inhibitor linagliptin versus comparator treatments.
  
  
  METHODS
  This was a pre-specified meta-analysis of CV events in linagliptin or comparator-treated patients with type 2 diabetes mellitus (T2DM) from eight Phase 3 studies. All suspected CV events were prospectively adjudicated by a blinded independent expert committee. The primary endpoint was a composite of CV death, stroke, myocardial infarction, and hospitalization for unstable angina. Three secondary composite endpoints derived from the adjudicated CV events were also pre-specified. Risk estimates were calculated using several statistical methods including Cox regression analysis.
  
  
  RESULTS
  Of 5239 treated patients (mean ± SD HbA1c 65 ± 10 mmol/mol [8.0 ± 0.9%], age 58 ± 10 years, BMI 29 ± 5 kg/m2), 3319 received linagliptin once daily (5 mg, 3159; 10 mg, 160) and 1920 received comparators (placebo, 977; glimepiride 1-4 mg, 781; voglibose 0.6 mg, 162). Cumulative exposure (patient-years) was 2060 for linagliptin and 1372 for comparators. Primary CV events occurred in 11 (0.3%) patients receiving linagliptin and 23 (1.2%) receiving comparators. The hazard ratio (HR) for the primary endpoint showed significantly lower risk with linagliptin than comparators (HR 0.34 [95% confidence interval (CI) 0.16-0.70]) as did estimates for all secondary endpoints (HR ranging from 0.34 to 0.55 [all upper 95% CIs < 1.0]).
  
  
  CONCLUSIONS
  These results from a large Phase 3 programme support the hypothesis that linagliptin may have CV benefits in patients with T2DM.
authors.affiliation: Boehringer Ingelheim, Asker, Norway. odd-erik.johansen@boehringer-ingelheim.com
authors.forename: Odd Erik
authors.initials: OE
authors.lastname: Johansen
authors.forename: Dietmar
authors.initials: D
authors.lastname: Neubacher
authors.forename: Maximilian
authors.initials: M
authors.lastname: von Eynatten
authors.forename: Sanjay
authors.initials: S
authors.lastname: Patel
authors.forename: Hans-Juergen
authors.initials: HJ
authors.lastname: Woerle
mesh_terms: D000368:Aged; D000789:Angina, Unstable / Q000209:etiology / Q000517:prevention & control; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000209:etiology / Q000401:mortality / Q000517:prevention & control*; D017326:Clinical Trials, Phase III as Topic; D048909:Diabetes Complications / Q000209:etiology / Q000401:mortality / Q000517:prevention & control*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000401:mortality; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D019317:Evidence-Based Medicine; D005260:Female; D006442:Glycated Hemoglobin / Q000378:metabolism; D006760:Hospitalization / Q000706:statistics & numerical data; D006801:Humans; D000069476:Linagliptin; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000209:etiology / Q000517:prevention & control; D061214:Patient Safety; D016016:Proportional Hazards Models; D011446:Prospective Studies; D011687:Purines / Q000009:adverse effects*; D011799:Quinazolines / Q000009:adverse effects*; D016032:Randomized Controlled Trials as Topic; D018570:Risk Assessment; D012307:Risk Factors; D020521:Stroke / Q000209:etiology / Q000517:prevention & control; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D006442:Glycated Hemoglobin; D000069476:Linagliptin; D011687:Purines; D011799:Quinazolines; C517652:hemoglobin A1c protein, human