title: Cardiovascular safety for once-weekly dulaglutide in type 2 diabetes: a pre-specified meta-analysis of prospectively adjudicated cardiovascular events.
abstract: BACKGROUND
  Patients with type 2 diabetes (T2D) have a substantial increased risk for cardiovascular (CV) disease and associated mortality than those without diabetes. Dulaglutide is a once-weekly glucagon-like peptide-1 receptor agonist that is approved for treatment of T2D.
  
  
  METHODS
  This meta-analysis evaluates the CV risk in patients with T2D treated with dulaglutide in 9 randomized safety and efficacy trials. Mean (median) treatment duration was 333 (358) days. Reported CV events were independently adjudicated by a treatment-blinded clinical endpoint committee. The primary measure was a 4-component major adverse CV event (4-component MACE) composite endpoint of death due to CV causes, nonfatal myocardial infarction (MI), nonfatal stroke, or hospitalization for unstable angina. Additional pre-specified endpoints included adjudicated coronary revascularizations, hospitalization for heart failure, and all-cause mortality. A Cox proportional hazards regression model (stratified by study) was used to estimate the hazard ratio (HR) and confidence interval (CI). Tests of treatment effects for the primary endpoint were conducted at a 2-sided alpha level of 0.0198 and a corresponding 98.02 % CI was calculated. Statistical heterogeneity between the strata (studies) was tested by including in the Cox model an interaction term between treatment and strata.
  
  
  RESULTS
  The analysis included 6010 randomized patients [dulaglutide: 3885; comparator therapy (active or placebo): 2125]; cumulative exposure to dulaglutide or comparator therapy was 3941 and 2223 patient-years, respectively. The demographic and baseline CV disease characteristics were similar across groups. Twenty-six (0.67 %) patients in the dulaglutide group versus 25 (1.18 %) in the comparator group experienced a primary 4-component MACE (HR 0.57; adjusted 98.02 % CI 0.30, 1.10). Results for the 3-component MACE (composite endpoint of death due to CV causes, nonfatal MI or stroke), 6-component MACE (composite endpoint of death due to CV causes, nonfatal MI or stroke, hospitalization for unstable angina or heart failure, or coronary revascularizations) and all-cause mortality were consistent with the primary analysis (HR < 1.0 for all).
  
  
  CONCLUSIONS
  These results suggest that dulaglutide does not increase the risk of major CV events in T2D patients. The ongoing CV outcomes study, Researching CV Events with a Weekly Incretin in Diabetes (REWIND), will further assess CV safety of dulaglutide.
authors.affiliation: Tulane University SOM, 1430 Tulane Avenue, #8548, New Orleans, LA, 70112, USA. kferdina@tulane.edu.
authors.forename: Keith C
authors.initials: KC
authors.lastname: Ferdinand
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, 46285, USA. botros_fady_t@lilly.com.
authors.forename: Fady T
authors.initials: FT
authors.lastname: Botros
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, 46285, USA. charles.atisso@lilly.com.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Atisso
authors.affiliation: Cardiac Safety Research Consortium, Stanford University School of Medicine, 719 Carolina St., San Francisco, CA, 94107, USA. Psager@Stanford.edu.
authors.forename: Philip T
authors.initials: PT
authors.lastname: Sager
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000175:diagnosis / Q000209:etiology* / Q000401:mortality; D017326:Clinical Trials, Phase III as Topic; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality; D004334:Drug Administration Schedule; D005260:Female; D000067757:Glucagon-Like Peptide-1 Receptor / Q000378:metabolism; D004763:Glucagon-Like Peptides / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D007141:Immunoglobulin Fc Fragments / Q000008:administration & dosage* / Q000009:adverse effects; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D011446:Prospective Studies; D065840:Protective Factors; D016032:Randomized Controlled Trials as Topic; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000009:adverse effects; D018570:Risk Assessment; D012307:Risk Factors; D016896:Treatment Outcome; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D007141:Immunoglobulin Fc Fragments; D011993:Recombinant Fusion Proteins; D004763:Glucagon-Like Peptides; C555680:dulaglutide; D000097789:Glucagon-Like Peptide-1 Receptor Agonists