Are Newer Diabetes Drug Classes Ready for Prime Time in CV Prevention?

Two groundbreaking drug classes, the sodium glucose co-transporter 2 (SGLT2) inhibitors and the glucagon-like peptide-1 (GLP-1) receptor agonists, are ready for much bigger roles in primary prevention of cardiovascular (CV) events, according to Mikhail Kosiborod, MD, a leading cardiologist and diabetes expert who is vice president of research at Saint Luke's Health System.

Not so fast, countered Darren K. McGuire, MD, MHSc, a professor at UT Southwestern who directs the Parkland Hospital outpatient cardiology clinic. Both classes, he said, have mixed records in preventing major cardiovascular events, such as heart attacks or strokes, although they have other benefits.

Kosiborod led off the light-hearted debate, “Primary Cardiovascular Prevention with SGLT2 Inhibitors or GLP-1 Receptor Agonists: Are We Ready for Prime Time?” that took place Monday during the 80th American Diabetes Association Scientific Sessions, being held in virtual format. Kosiborod and McGuire, longtime collaborators and friends, admittedly built their presentations around what they thought the other might say.

To start, Kosiborod framed 3 arguments typically used against the 2 classes and sought to knock each one down: (1) there isn’t enough evidence for primary prevention; (2) event rates are too low, so the number needed to treat is too high to justify broader use; and (3) the drugs are not cost-effective for patients in primary prevention.

“We absolutely are ready for prime time in primary prevention,” he said.

Kosiborod pointed not only to results from cardiovascular outcomes trials, but also to recent FDA labels to build his case on the evidence. Of note, he said when it comes to preventing the progression of heart failure and chronic kidney disease, he said, “This is where these medications really shine.”

As for preventing future events, he used a modeling approach to assert that SGLT2 inhibitors, treating 340 million people worldwide with type 2 diabetes who have no established CV disease could prevent 6.8 million episodes of heart failure hospitalization and 12.5 million cases of decline from chronic kidney disease. Treating this population with GLP-1 receptor agonists, he argued, could prevent 1.3 million heart attacks, 1.5 million strokes, and 1 million cases of peripheral artery disease.

This, Kosiborod said, should eliminate the argument that “the juice is not worth the squeeze.”

McGuire then stepped back to ask what is meant by “primary prevention,” and noted that much of the evidence used in the guidelines comes from CV outcomes trials that revolve around atherosclerosis, “but of course, there’s lots of other cardiovascular diseases.”

Most of the trials, he argued, involved patients who had risk factors. “These were not primary prevention patients,” McGuire said, but instead were patients who had type 2 diabetes but had not yet developed CVD.

McGuire agreed that the SGLT2 inhibitor class has shown effectiveness preventing heart failure hospitalization and renal decline, but said the drugs have a mixed record in preventing major cardiovascular events. The GLP-1 receptor agonist class, meanwhile, is murkier: Some drugs in this powerful injectable class have shown they can prevent cardiovascular events, but some haven’t, and renal outcomes are mixed.

The cost of some drugs, especially in the GLP-1 class, is sufficiently high that McGuire argued widespread use among patients with lower levels of CV risk would mean millions in new health care spending to prevent very few events. Kosiborod disagreed with some of McGuire’s cost estimates, saying that they were based on list prices for drugs, not what people actually pay once insurers have negotiated discounts.

McGuire agreed that evaluating the effectiveness of both classes demands a broader view beyond the focus on major cardiovascular events. He also seemed disappointed that Kosiborod, who led the CVD-REAL trial, had not made his arguments with real-world evidence. With a slide that had been photoshopped to depict Kosiborod riding on a bear, McGuire said he would “poke the bear,” and offer the argument that in other areas of medicine:

“There are times when you wouldn’t use a drug that’s proven to treat a disease to prevent a disease. And there’s always some possibility, there’s also possibility that there’s a risk treatment interaction that you have to have a certain level of morbidity before you can reverse that with these agents,” McGuire said.

In his rebuttal, Kosiborod pushed back against the cost-effectiveness argument, particularly the idea of waiting until these medications are available in generic formulations.

“Are you waiting for somebody to have a mild stroke, heart failure, kidney disease? Or are you waiting for interventions to become more cost effective?” he asked. As it is, Kosiborod argued, it takes years for therapies to work their way into clinical practice once evidence emerges. “So we cannot wait until these medications go generic, because we’re talking about years and years afterward before we actually make progress.”