Dhiren Patel, PharmD, CECES, BC-ADM: Dr Busch, you’ve had a front-row seat. You’re an investigator in the Dapa-CKD trial. You saw what happened there. You saw the final label. One of the things that was intriguing in looking at that was the indication. Unlike prior ones, it wasn’t based on a certain cutoff. You have anyone that’s at risk of progression. To me, that’s pretty much anyone, right? All of us are at risk of progression, so to speak. Help me understand how you’re understanding that indication and how you’re talking to your peers about that. Depending on what continuum you sit, you might not be seeing those patients until they’re more severe. The way it’s written, this therapy can be very valuable even for patients who are on the mild to moderate side. What was your reaction to it, and how are you disseminating this information to your peers and colleagues?
Robert Busch, MD: It’s a very generous label because with canagliflozin in CREDENCE, it was the study criteria, urine microalbumin over 300 mg/dL. Even though in this study, you had to have 200 mg/dL. The FDA was so impressed with the data and the 39% lowering of the composite end point for renal protection that they don’t have proteinuria in the label. As you mentioned, it’s who’s at risk for progression of kidney disease. It’s like beauty is in the eye of the beholder. If you think your patient is at risk, the GFR [glomerular filtration rate] could be higher than 60 or 70 mL/min, but they have proteinuria. Or they could have a GFR without proteinuria, but they’re at risk of getting worse. Those are the types of patients.
It’s a very generous label. You don’t just have to have diabetes. Even in a hypertensive patient who has some urine microalbumin present, whose GFR is in the 50s mL/min, that’s a patient who’s also at high risk to progress toward dialysis. That’s someone for whom you’d also want to slow down things, with not only a RAS blocker but going beyond that with dapagliflozin.
Dhiren Patel, PharmD, CECES, BC-ADM: Sure.
Muthiah Vaduganathan, MD, MPH: I agree 100%. Both CREDENCE and Dapa-CKD had average UACRs [urine albumin-to-creatinine ratio] of about 1000 mg/g, based on the relative cutoffs. The FDA labeling, the documents, and the discussion during the advisory committee reflected on the parallel experiences between DECLARE-TIMI58 and Dapa-CKD, where you have a continuum of low-risk patients with type 2 diabetes who are at risk for progression, and then more advanced patients with established albuminuric kidney disease. There’s no heterogeneity in treatment effects across that spectrum based on UACR. That was the rationale behind not including it in the label.
In practice, that removes a substantial barrier to use because albumin-creatinine ratios are often not measured. Sometimes there aren’t even structures in place to measure them. For instance, in a cardiology clinic, I could probably count the number of times we’ve measured UACR. It’s an extension beyond the trial, for sure, but it borrows on adjacent disease states and trials that have studied the exact same compound.
Transcript edited for clarity.