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.

AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.