Individual patient-level data combined with SUSTAIN 6 (once weekly injectable semaglutide versus placebo) and PIONEER 6 (oral semaglutide versus placebo) were collected to assess MACE and HF in patients with and without established CV disease and/or chronic kidney disease, prior MI or stroke, and prior HF. This post hoc analysis of both studies revealed that semaglutide had consistent effects on MACE across varying CV risk groups. This benefit was driven mainly by a significant reduction in all-cause stroke caused by semaglutide. No effect of semaglutide on MACE was observed in subjects with prior HF [15].

A pooled analysis of these data also revealed that semaglutide significantly slowed the rate of kidney function decline, irrespective of kidney function at baseline [16]. This finding has been convincingly reiterated by FLOW, a randomized controlled trial that has shown significant improvement in renal and cardiovascular outcomes in patients with established CKD [8].

This meta-analysis of all CVOTs conducted with oral and parenteral semaglutide to date revealed that the use of semaglutide as a molecule resulted in a significant 21% reduction in MACE, which was driven by reduction in CV death (HR 0.79, 95% CI 0.61–0.90).

In the past, several trials were terminated prematurely because the required number of events was accrued earlier than the estimated duration. These studies include the CARMELINA, CAROLINA, CREDENCE, EMPAREG, DECLARE TIMI-58, LEADER, SUSTAIN 6, PIONEER 6, REWIND, EXSCEL, ELIXA, DAPA-CKD, and EMPA-kidney trials [7, 11, 22–27]. The estimated duration of these studies and the required events were based on the CV risk in the population determined by published prevalence or cross-sectional studies. While earlier trials did not have dedicated RCTs at their disposal, studies such as the SOUL trial had 3 prior RCTs to refer to, as far as baseline CV risk estimation was concerned. In fact, both PIONEER 6 and SUSTAIN 6 were prematurely terminated, reflecting a lack of accurate estimation of the time needed to attain the required number of CV events.

With the availability of data from three CVOTs with semaglutide, this meta-analysis provides a platform for designing a mathematical model to predict the outcomes of the ongoing SOUL trial, a CVOT comparing oral semaglutide with placebo.

Because the placebo arms in all the CVOTs now reflect the background CV risk in the population, the study duration required to obtain the desired number of events can be estimated far more accurately based on power calculations.

The calculated duration of the SOUL trial was 5 years and 5 weeks based on a baseline annualized CV risk of 3.5%. However, using the background MACE rate in the population in the placebo arm of the PIONEER 6, SUSTAIN 6, and FLOW trials, the duration required to reach 1225 events can be accurately estimated to be 3.78 years.

The duration required to obtain the desired number of events can be estimated from previous CVOTs, and the number of probable events in the placebo and intervention arms can both be estimated while predicting the direction of the effect size (hazard ratio). This analysis predicts that the required number of events (1225) will have occurred after 3.78 years. This analysis also predicted that the estimated number of events (MACE) in the semaglutide and placebo groups would be 647 and 578, respectively.

This difference in events was significant at 0.05, indicating that we can expect superiority from the primary end point of the SOUL trial.

The annualized MACE rate in the pooled placebo arm was 5.66% (per our calculation), in contrast to the 3.5% reported in the SOUL trial. This difference explains why the trial will likely be terminated early, and a more objective background risk estimation needs to be performed (if available) compared to heterogeneous prevalence studies.

This mathematical prediction will be subject to scrutiny once the original SOUL trial has been published. However, once it is proven to be accurate, this mathematical prediction may be used to calculate not only the power but also the duration of such studies. In addition to making such RCTs more practical, they will significantly reduce the cost of conducting such expensive projects, providing relief for both industry and researchers.

The principal limitations are related to the fact that we analyzed means from the RCTs instead of individual patient-related data. The number of studies included in the present study was too low to conclusively assess heterogeneity. In addition, the annual CV event rate was assumed to be constant but may have been affected by the COVID-19 pandemic.

The main strength of this analysis is related to the pooling of the placebo CV event rates from the three trials, providing us with a robust backdrop to compare the intervention-related outcomes. Traditionally, the background event rates in the population are based on cross-sectional or prevalence studies. In addition, the selection of a conservative random effect model would increase the credibility of the outcomes.