title: Comparative risk of major cardiovascular events associated with second-line antidiabetic treatments: a retrospective cohort study using UK primary care data linked to hospitalization and mortality records.
abstract: To examine the risk of major cardiovascular events associated with second-line diabetes therapies, in patients with type 2 diabetes, after adjusting for known cardiovascular risk factors.
  
  
  
  This was a retrospective cohort study of patients prescribed second-line regimens between 1998 and 2011 after first-line metformin. The UK Clinical Practice Research Datalink, with linked national hospitalization and mortality data, for the period up to December 2013, was used. Inverse probability of treatment-weighted time-varying Cox regression models was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for developing a major cardiovascular event (cardiovascular death, myocardial infarction, stroke, acute coronary syndrome, unstable angina, or coronary revascularization) associated with second-line therapies. Analyses adjusted for patient demographic characteristics, comorbidities, glycated haemoglobin, socio-economic status, ethnicity, smoking status and concurrent medications.
  
  
  
  A total of 10 118 initiators of a second-line add-on to metformin of either a sulphonylurea (n = 6740), dipeptidyl peptidase-4 (DPP-4) inhibitor (n = 1030) or thiazolidinedione (n = 2348) were identified. After a mean (standard deviation) of 2.4 (1.9) years of follow-up, 386, 36 and 95 major cardiovascular events occurred in sulphonylurea-, DPP-4 inhibitor- and thiazolidinedione-initiators, respectively. In comparison with the metformin-sulphonylurea regimen, adjusted HRs were 0.78 (95% CI 0.55; 1.11) for the metformin-DPP-4 inhibitor regimen and 0.68 (95% CI 0.54; 0.85) for the metformin-thiazolidinedione regimen.
  
  
  
  Thiazolidinedione add-on treatments to metformin were associated with lower risks of major cardiovascular disease or cardiovascular death compared with sulphonylurea add-on treatment to metformin. Lower, but non-statistically significant, risks were also found with DPP-4 inhibitor add-on therapies.
authors.affiliation: Centre for Pharmacoepidemiology and Drug Safety, Manchester Pharmacy School, University of Manchester, Manchester, UK.|Department of Pharmaceutics, Faculty of Pharmacy, University of Tripoli, Tripoli, Libya.
authors.forename: S S
authors.initials: SS
authors.lastname: Zghebi
authors.affiliation: Centre for Pharmacoepidemiology and Drug Safety, Manchester Pharmacy School, University of Manchester, Manchester, UK.
authors.forename: D T
authors.initials: DT
authors.lastname: Steinke
authors.affiliation: Endocrinology and Diabetes Research Group, Institute of Human Development, University of Manchester, Manchester, UK.|Manchester Diabetes Centre, Manchester Academic Health Science Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
authors.forename: M K
authors.initials: MK
authors.lastname: Rutter
authors.affiliation: Centre for Biostatistics, Institute of Population Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
authors.forename: R A
authors.initials: RA
authors.lastname: Emsley
authors.affiliation: Centre for Pharmacoepidemiology and Drug Safety, Manchester Pharmacy School, University of Manchester, Manchester, UK.
authors.forename: D M
authors.initials: DM
authors.lastname: Ashcroft
mesh_terms: D054058:Acute Coronary Syndrome / Q000453:epidemiology; 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*; D004359:Drug Therapy, Combination; D005260:Female; D006760:Hospitalization; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D016247:Information Storage and Retrieval; D008297:Male; D008687:Metformin / Q000627:therapeutic use*; D008875:Middle Aged; D009026:Mortality; D009203:Myocardial Infarction / Q000453:epidemiology; D009204:Myocardial Revascularization / Q000706:statistics & numerical data; D016016:Proportional Hazards Models; D065840:Protective Factors; D012189:Retrospective Studies; D012307:Risk Factors; D020521:Stroke / Q000453:epidemiology; D013453:Sulfonylurea Compounds / Q000627:therapeutic use*; D045162:Thiazolidinediones / Q000627:therapeutic use*; D006113:United Kingdom / Q000453:epidemiology
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D013453:Sulfonylurea Compounds; D045162:Thiazolidinediones; D008687:Metformin
keywords: DPP-4 inhibitor; cardiovascular disease; pharmaco-epidemiology; sulphonylureas; thiazolidinediones; type 2 diabetes