Steve Nissen, MD: The Next Generation of SGLT-2 Trials

Since the US Food and Drug Administration (FDA) began requiring cardiovascular outcome data for diabetes trials, the design and intent of cardiovascular-related therapy studies have shifted. Now, clinicians are gifted with critical treatment information across multiple conditions in tens of thousands of observed patients.

But what the field needs now is head-to-head data. In an interview with MD Magazine® while at the American College of Cardiology (ACC) 2019 Annual Scientific Sessions in New Orleans, LA, Steve Nissen, MD, chairman of the Department of Cardiovascular Medicine at the Cleveland Clinic, made the case for comprehensive trials comparing sodium glucose co-transporter 2 therapies.

MD Mag: How does the prevalence of cardiovascular disease and its comorbidities influence standards for clinical research?

Nissen: I'm really pleased to look back at this. We made this proposal, and the FDA acted in December 2000. By 2011, there were 115,000 patients in large trials looking at outcomes with diabetes. If you go back and look at the previous 40 years, there were a few hundred patients in well-designed outcome trials looking at different effects of different drugs. It just wasn't anything. So, we've completely changed the paradigm now over the last decade.

When comparative trials begin for SGLT-2 inhibitors, what will be the most important outcome or metrics?

We need to do something now. The next generation of trials needs to be designed. It will be hard for industry to do it, but it has to be done. We need more head-to-head trials. If you have given metformin—which everybody agrees is what you ought to do to begin with—and you want to do something else for cardio protection, do you give an SGLT-2 inhibitor, do you give a GLP-1 agonist? We need head-to-head trials comparing different strategies—not just, Is a drug better than placebo," but "Is drug A better than drug B."

And that's comparative efficacy trials. Those trials tend to be large, long-term, complex, and costly, but the payoff for patients and for doctors is that both the physician and the patient will learn what works the best. Industry doesn't like head-to-head trials because they're risky, but that's where the evidence comes from. And we had the courage to do that with statins.

We did some head-to-head trials, we found out that more intensive LDL-lowering produced better benefits. The famous PROVE-IT trial was a very aggressive dose of atorvastatin versus pravastatin, and the more intensive therapy showed better results. We're going to have to do that now in the diabetes space. Why is it worth it? Because this is the epidemic of the decade.

The number of people with type 2 diabetes now is huge, and 70% of them are still dying of cardiovascular diseases. And we've got to figure it out, because there's a lot of people that it's going to affect.