It’s been a decade since U.S. and European regulatory agencies began requiring cardiovascular outcomes assessment as an extension of all clinical trials involving diabetes medications. The requirement has added significant cost and burden to registration programs, and some researchers and clinicians have asked whether the requirement provides adequate “bang for the buck.”
A pair of experts debated that question during the Friday afternoon session Cardiovascular Outcomes Trials (CVOTs) in Diabetes—Shall We Continue or Change Course?
Darren K. McGuire, MD, MHSc, Professor in the Department of Internal Medicine at the University of Texas Southwestern Medical Center and Director of the Parkland Hospital and Health System Outpatient Cardiology Clinics, advocated for a CVOT change of course. Steven P. Marso, MD, Medical Director of Cardiovascular Services at HCA Midwest Health, made the counter argument, saying that cardiovascular outcomes trials are worth the expense for the knowledge gained.
“To date, we’ve studied some 200,000 patients and we now have a handful of clinical trials that have not only demonstrated cardiovascular safety, but also cardiovascular superiority of SGLT2 [sodium glucose cotransporter 2] and GLP-1 [glucagon-like peptide-1] agents, landmark findings that would not have been possible prior to the issuance of the Food and Drug Administration guidance in 2008,” Dr. Marso said.
Another important thing that has been discovered, Dr. Marso said, is that not all drugs in the same class are equal.
“We have evidence, especially regarding the GLP-1 agents, that there appears to be enhanced cardiovascular benefits for some agents but not others,” he said. “If you look at lixisenatide versus liraglutide and semaglutide, for example, those cardiovascular outcomes look very different, so there’s clearly not a class effect for all of these diabetes medications.”
Dr. Marso said that results of the EMPA-REG OUTCOME clinical trial were also profound, as empagliflozin significantly decreased the rate of cardiovascular mortality and hospitalization for congestive heart failure among high-risk patients with type 2 diabetes.
“These trials are needed just to clarify whether or not next-in-class drugs are going to be beneficial,” he said. “Moving forward, I think we’ve set the stage now to do nothing but properly sized cardiovascular outcome trials. The designs may be subtly different and the comparison groups will most certainly be different, but there’s no way we’re going to go back to small, underpowered clinical studies.”
While Dr. McGuire agreed that the larger trials are needed, he said improving upon present value both medically and economically requires changes in study approaches and an expanded focus of the questions researchers are asking.
“The reality is, when the FDA and the European Medicines Agency flipped the switch in 2008, it increased the scope of the development programs by about 70-fold, now requiring about 15,000 patient-years of exposure to establish at a minimum CV safety and to get ultimate approval of these medications for use in the clinical space,” Dr. McGuire said. “That’s a very expensive proposition, especially when you consider that when the outcomes from the first few of these trials were reported, they all pretty much showed neutrality against placebo. They proved safety but did not prove any incremental efficacy, and a lot of people began to challenge whether this was the right way to do things.”
Fast forward to today, he said, and although there are now some trials proving superiority for cardiovascular outcomes of various therapies, there continue to be questions as to whether there are more appropriately focused and cost-efficient ways to design and conduct these studies.
“A change in course is definitely needed,” Dr. McGuire said. “I would not argue that we need to completely abandon the present strategies, but we might fine tune them to get even more informative results and more value from these trials than we have to date.”
One proposal for fine tuning future study designs that’s gaining traction is to consider heart failure outcomes either in the primary analysis of the composite of CV outcomes, or as a co-primary outcome with simultaneous analysis of the atherosclerotic vascular disease outcomes and, at a similar priority, heart failure outcomes.
“Additionally, in the large scale trials of novel therapies, it would be really attractive to piggyback onto them some factorial randomization so we can analyze some of the older therapies,” Dr. McGuire said. “Metformin, for example, remains the number one recommended pharmacologic therapy for patients with type 2 diabetes and, while it appears to be a very safe medication, it’s incremental benefit with regard to cardiovascular disease remains unknown. These mega trials give us a chance that we may never have otherwise to rigorously test the cardiovascular effects of metformin versus placebo and other legacy agents.”