Background

Novel oral antidiabetic drugs have shown relative benefits for both type 2 diabetes (T2DM)-related and cardiovascular outcomes in major Cardiovascular Outcome Trials (CVOTs), however time-dependent absolute treatment effects of these drugs have thus far been unknown; we thus aimed to perform a meta-analysis of digitalized individual patient data from CVOTs.

Methods

CVOTs evaluating dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists and sodium glucose transporter 2 (SGLT2) inhibitors against Placebo were identified; those with time-to-event information in Kaplan-Meier plots for cardiovascular mortality (CM) and/or hospitalization for heart failure (HHF) endpoints were included. Individual patient outcomes were digitalized from Kaplan-Meier plots using WebPlotDigitizer v4.2; Weibull regression models were fitted to estimate survival functions and compute time-dependent numbers-needed-to-treat (NNT). Random-effects inverse-variance meta-analysis was performed for monthly time-points to achieve Meta-NNT.

Results

Sixteen CVOTs reported original time-to-event information for at least one of the two outcomes, 14 of which in primary T2DM, two in primary heart failure populations. Outcome data digitalization quality and Weibull model correspondence to original data was excellent. Thirteen studies with 4,997 events from 96,860 observations were meta-analyzed for CM; at the median follow-up time of 30 months, Meta-NNTs were 178 (95% CI: 64 to ꚙ to -223) for DPP-4 inhibitors, 261 (95% CI: 158 to 745) for GLP-1 receptor agonists and 118 (95% CI: 68 to 435) for SGLT2 inhibitors. Ten studies with 4,065 events from 96,128 observations were meta-analyzed for HHF; at the median follow-up time of 29 months, estimated Meta-NNTs were -644 (95% CI: 229 to ꚙ to -134) for DPP-4 inhibitors, 441 (95% CI: 184 to ꚙ to -1100) for GLP-1 receptor agonists and 126 (95% CI: 91 to 208) for SGLT2 inhibitors. SGLT2 inhibitors were especially effective in primary heart failure populations (Meta-NNT 25 (95% CI: 19 to 39)) compared to primary T2DM populations (Meta-NNT 233 (95% CI: 167 to 385)) at 16 months of follow-up.

Conclusion

We found time-dependent absolute treatment benefits of GLP-1 receptor agonists and SGLT2 inhibitors on cardiovascular mortality and hospitalization for heart failure, for which SGLT2 inhibitors were especially effective in primary heart failure populations.