Nine studies were included in meta-analyses (n=84,287 patients calculated from the Table 1; n=101,733 reported in the text). There were six retrospective cohort studies, two prospective cohort studies, and one nested case-control study. The sample sizes of studies ranged from 910 to 39,721. The mean follow-up duration ranged from 2.1 to 7.7 years.
The combination therapy of metformin plus sulfonylurea was significantly associated with an increased risk of the composite end point of cardiovascular hospitalizations or cardiovascular mortality (RR 1.43, 95% CI 1.10 to 1.85; five studies, seven comparisons) compared with control therapies.
No significant differences were found between the two groups in terms of all-cause mortality (RR 1.19, 95% 0.88 to1.62; seven studies, ten comparisons) or cardiovascular mortality (RR1.29, 95%0.73 to 2.27; four studies, six comparisons).
Significant heterogeneity was observed for all these outcomes (p value less than or equal to 0.001).
Sensitivity analyses did not significantly alter most of the outcomes. However, when excluding one study (by Johnson et al), there was a significant increased risk of cardiovascular mortality associated with combination therapy of metformin and sulfonylureas (RR 1.63, 95% CI 1.11 to 2.39). Results of subgroup analyses were also reported.
There was no evidence for publication bias.