Comparative risk of major cardiovascular events associated with second-line antidiabetic treatments: a retrospective cohort study using UK primary care data linked to hospitalisation and mortality records

Aims
The cardiovascular benefits of second-line regimens after metformin are uncertain. The aim of this study was 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
A retrospective cohort study of patients prescribed second-line regimens between 1998 and 2011 following first-line metformin. The UK Clinical Practice Research Datalink (CPRD) with linked national hospitalisation and mortality data were used up to December 2013. Inverse probability of treatment weighted time-varying Cox regression models estimated HR and 95% confidence intervals (CI) 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, co-morbidities, glycated haemoglobin (HbA1c), 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 = 6,740), dipeptidyl peptidase-4 inhibitor (DPP-4i) (n = 1,030) or thiazolidinedione (n = 2,348) were identified. After a mean (SD) 2.4 (1.9) years of follow-up, 386, 36 and 95 major cardiovascular events occurred in sulphonylurea, DPP-4i and thiazolidinedione initiators, respectively. In comparison to the metformin-sulphonylurea regimen, adjusted HRs were 0.78 (95% CI 0.55; 1.11) for metformin-DPP-4i regimen and 0.68 (95% CI 0.54; 0.85) for metformin-thiazolidinedione regimen.
Conclusions
Thiazolidinedione add-on treatments to metformin were associated with lower risks for major cardiovascular disease or cardiovascular death compared to sulphonylurea combination with metformin. Lower, but non-statistically significant, risks were also found with DPP-4i add-on therapies.