Thank you for the opportunity to speak today. My name is Dr. Stephanie Fox-Rawlings from the National Center for Health Research. Our center analyzes scientific and medical data to provide objective health information to patients, providers, and policy makers. We do not accept funding from drug and medical device companies, so I have no conflicts of interest.
Two of the major questions being addressed today relate to whether the LEADER trial provides sufficient evidence that Victoza 1) does not increase cardiovascular risk and 2) is protective against this risk.
Let’s start with the second question, since it is easier. To say it lowers risk, Victoza would need to demonstrate both a statistical and clinical improvement over placebo. In addition, the trial that provides support needs to be generalizable to the population of patients that are likely to consider using the product.
In the LEADER trial, Victoza shows a small improvement but it is not clear that this reduction in risk is clinically relevant. The incidence of a cardiovascular event was reduced from 3.9 events per 100 patient years to 3.4 events.
Even more important, the time to MACE is worse for Victoza among the U.S. patients than for patients for other countries. Since the FDA is a U.S. agency, it needs evidence that Victoza decreases the risk of MACE in U.S. patients. Improvement of risk needs to be established in a future study of U.S. patients.
Let’s go back to the first question: has the sponsor demonstrated that Victoza does not increase cardiovascular risk? In the LEADER trial, the drug did not worsen the time to the first MACE or increase the number of events compared to placebo. In fact, the hazard ratio for time to first MACE was statistically better than placebo overall – but it was worse for the U.S. patients. Even in the U.S., the hazard ratio was not statistically different for the drug and placebo. Therefore, at least within the confines of this trial, the drug does not increase risk and may reduce risk.
I want to quickly summarize concerns about the LEADER trial and why we aren’t fully confident of the results.
While the LEADER trial included over 9000 patients who were exposed for at least 3.5 years and was well controlled, it isn’t clear that this single trial is generalizable to all U.S. patients with type 2 diabetes mellitus and a high risk for cardiovascular events.
#1: The differences are small, which may not be replicated in another trial.
#2: There were more than twice the number of MACE than predicted. This could suggest that there was something different about the patients that may not represent patients with type 2 diabetes with high cardiovascular risks.
#3: Patients in the U.S. stopped taking both the placebo and drug to a greater extent and more quickly than patients in other countries. Why? What were the differences between the U.S. and the other countries that caused this discontinuation rate? Were the differences in adverse events in the U.S. compared to elsewhere? Were there other reasons that U.S. patients were not compliant? The differences in the number of patients stopping treatment may have contributed to the fact that in the U.S. the time to first MACE was better for patients on the placebo rather than the drug. But it is impossible to know for sure.
In summary, there are questions relating the LEADER trial that raises questions about its generalizability. With only one study, however large, we don’t even know if the results would be replicated. The LEADER study suggests that the drug does not significantly increase cardiovascular risk. However, the sponsor has not demonstrated that it reduces cardiovascular risk, especially not for U.S. patients whose BMI, diet, and exercise habits might be quite different from those in other countries.