The three included placebo-controlled studies examined sitagliptin, alogliptin, or saxagliptin added to existing diabetes therapy. Two studies exclusively included patients with known cardiovascular disease, while the third included patients with either established cardiovascular disease or multiple risk factors.
For the overall population, DPP-4 inhibitors had a neutral summary effect on the primary cardiovascular composite outcome (summary HR 0.99 [95% CI 0.87 - 1.13]). In patients taking metformin at baseline, there was a trend towards a reduction in the incidence of the primary study outcome (HR 0.92; 95% CI 0.84-1.01) but this was not statistically significant. Conversely there was a trend towards an increase in the incidence of the primary study outcome in those not using metformin at baseline (1.10; 0.97-1.26) , but again this was not statistically significant.
The authors say it is not currently known how diabetes medication classes interact to affect cardiovascular outcomes, and that their analysis suggests that there is uncertainty as to whether DPP-4 inhibitors are associated with CV benefit or harm, depending on how they are used in practice. However metformin use is likely not to be the only difference between these subgroups, and it is possible the observed difference in DPP-4 inhibitor effect was mediated by other factors. Therefore this analysis is only hypothesis-generating and further research is required.