DocTalk Podcast: Canagliflozin's Approval and SGLT2 Inhibitors with Dr. Bakris

With the recent approval of canagliflozin(Invokana) for the treatment of diabetic kidney disease, the treatment became the first in nearly 2 decades to receive approval for that specific condition.

Approval of canagliflozin is based on the results of the phase 3 CREDENCE trial. Trial results demonstrated the oral therapy was associated with a 30% reduction in risk to progression of end-stage kidney disease, doubling of serum creatinine, and renal or cardiovascular death among patients with CKD and type 2 diabetes, compared to placebo.

The double-blind study, which included 4401 patients, showed the drug—along with standard care—was associated with a 32% reduction in end-stage kidney disease alone (HR, 0.68; (95% CI, 0.54 — 0.86; P = .0015). Canagliflozin also reduced risk of cardiovascular death and hospitalization for heart failure by 31% (HR, 0.69; 95% CI, 0.57 — 0.83; P = .0001) and major cardiovascular events (MACE) by 20% (HR, 0.80; 95% CI, 0.67 — 0.95; P = .0121).

Additionally, there were fewer reported adverse events and serious adverse events among the treatment arm, with no statistically significant difference in incidence of amputations or adjudicated fractures.

With studies like CREDENCE and DAPA-HF, which showed the potential for dapagliflozin for the treatment of heart failure, continuing the showcase the versatility of SGLT2 inhibitors, they also leave many with questions about the potential mechanisms behind these treatments. As more and more data supporting their use for conditions, the questions and curiosity surrounding SGLT2 inhibitors also continues to grow.

For a better look at the recent approval of canagliflozin, the mechanism behind it, and where clinicians could expect canagliflozin to fit into their treatment regimens, MD Magazine® sat down with George Bakris, MD, professor of medicine and director of the American Heart Association Hypertension Center at the University of Chicago Medicine, for the latest episode of the DocTalk Podcast.

MD Mag: Hello, and welcome to the DocTalk Podcast. I'm Patrick Campbell, Associate Editor with MD Magazine. I'll be your host for this edition of the DocTalk Podcast as we discuss the recent approval of canagliflozin with Dr. George Bakris.

Dr. Bakris, welcome to the DocTalk Podcast. If you could just give our listeners a little bit of background on who you are and your involvement with canagliflozin—then, we can dive into our discussion.

Bakris: I'm Dr. George Bakris, I'm a professor of medicine and director of the American Heart Association Hypertension Center at the University of Chicago Medicine. I was involved in the CREDENCE trial in terms of development of the protocol and I was on the steering committee of the study and actually was a recruitment site.

MD Mag: Now, I guess we can just dive into the question. So, I think the first thing is: what does this approval mean from a physician-centered standpoint?

Bakris: Well, I think it actually makes life easier if the physicians are willing to accept this. It basically is one drug that will control sugar, it's one drug that will preserve kidney function, it's one drug that will actually aid in blood pressure management, and it's not associated with some of the effects of some of the other drugs that would be prescribed in this setting, including hyperkalemia and acute kidney injury.

So, it's really kind of a multipurpose compound that has multiple mechanisms, many of which are still being explored. I think for the practicing physician, it gives them license to prescribe this drug even more than metformin because with metformin you have to adjust dose when the GFR falls to below 45. Here, there's no dosage adjustment needed and you can prescribe it above a GFR 30 and you can keep using it below 30. So it's really kind of a no brainer, to be honest with you.

MD Mag: From a patient centered standpoint, what does this mean? Is this sort of a cure all for them or is this more of an add-on therapy?

Bakris: So, this is not a cure all by any means, but it is an adjunct of medicine to already what is considered standard of care. What I mean by that is, if you add this medicine—if you add the SGLT2 canagliflozin— to the armamentarium of what the patient should already be on, including ACEs or ARBs, and other glucose lowering medications, lipid-lowering medications, you're going to further delay decline in kidney function by 58%, you're going to reduce the risk of heart failure substantially, and, fundamentally, you're going to improve glycemic control, especially in people with estimated GFRs above 45. The beauty of this label is you can certainly use this drug, even in people below a GFR of 45.

You should not think of this as a glucose-lowering medication. In fact, you should think about this as a cardio-renal risk reducing agent that happens to have glucose-lowering as a side effect. That's actually, the way this drug works. It's really got anti-inflammatory properties—we really don't know the full mechanism of how this drug is working.

So, it's very important to understand, from a patient standpoint, they're getting additional benefit that they may not realize on multiple fronts, including blood pressure, including glucose for many, and even some uric acid lowering, etc. None of this specific stuff is in the label for those specific risk factors, however, that benefit is there. So, I think the patients should view it as kind of a multipurpose pill that is helping longevity and, primarily, reducing morbidity. There's no greater morbidity then going on to dialysis and there's no greater morbidity and being put in the hospital for heart failure. And clearly, the canagliflozin clearly prevented the death or reduced the risk.

MD Mag: Okay, now, I'm glad you touched a bit on the mechanism for canagliflozin in that last answer. What does it say about canagliflozin and sort of the versatility or the robustness of it, that it became the first drug approved to treat diabetic kidney disease in two decades?

Bakris: Well, the truth is, it's the first drug that was actually studied in people with intense kidney disease. There are now two other studies following, but the results of those won't be available for at least a year, if not longer. So, that's part of it, but I think when we sat down to actually start talking about this, and I'm talking about in 2012. We speculated that mechanistically this drug could have benefits on the kidney because it would have hemodynamic effects. We had no idea about what has recently been found with this class of drugs and it turns out, it's an explosion of activity.

Many people think this drug is a mild diuretic, and it causes glycemic loss. Well, that's true when you're GFR is 75 to 80. But when your GFR a fire is 30, that is not true. You're not losing glucose in the urine, you're not getting a reduction in GFR, you're not getting the hemodynamic effects that were described, when it's higher up. So, then, how can it possibly work? and actually help predict the kidney? Well, it turns out that there's recent studies and I when I say recently, I mean, these are just published literally within the last year to year-and-a-half and there's a panoply of them.

One is that they block the kidneys ability to generate angiotensinogen, which is the precursor to the renin-angiotensin system. Now, some people have interpreted that as this is like an ACE for an arm that couldn't be farther from the truth. This works at a cellular level, to blocking angiotensinogen production, independent of ACEs and ARBs, and that's only seen in diabetes.

So, is that an explanation? Well, we just had data to suggest that in non-diabetics from the DAPA-heart failure study, that may not be a mechanism because you're getting a benefit in non-diabetic patients as well. Now that's one.

There's another mechanism really relating to the NLRP3, and RP3 inflammasome. The inflammasome is something that's in cells, it's kind of a shark within the cell. It cleans up a lot of inflammatory things and the SGLT2s actually potentiate this is actually speculated to be one of the potential mechanisms, along with facilitating ketone use in the heart for reducing heart failure risk. There's actually data suggesting the adipose site, which in obese individuals with diabetes, is a very inflammatory organ, and the SGLT2 actually quells some of the inflammatory cytokines that come out of that. There's more, I mean, we could spend the whole time talking about that.

This is just the beginning of understanding what these drugs can do. The other thing is people think SGLT2 s are only in the kidney and they're nowhere else. Well, it turns out, much to the chagrin of many, that cells have the ability to actually synthesize the transporter. It's been found in cancer cells. It's been found in glioblastoma, pancreatic cancer, lung cancer, prostate cancer. So, clearly, if the cell needs it. It's there. People say there's no SGLT2s in the heart. Well, in the normal heart, that's true. But is anyone looked at a failing heart? No. So, we don't know if it's there.

We really are just scratching the surface mechanistically and just assume these drugs are just dumping glucose in the urine and we're done. That turns out to be a very naive interpretation of what these drugs can do.

MD Mag: That really leads well into my last question for you, as you touched on canagliflozin and SGLT2 inhibitors have a ton of uses and we're finding more and more about them—it seems like—with each and every study. What do you think is next or could we see any potential other indications coming down the road?

Bakris: Well, I don't see it being developed as an antihypertensive that actually was proposed years ago, and nobody went there. I don't see it being proposed as a drug to aid in prevention of gout. And so, what else can you do? I think, really, if I had to say something, I think you have enough now, to make it standard of care. I'm not at liberty to discuss with you the upcoming 2020 ADA guidelines, but I can tell you, they're going to be a little different than what you currently have.

I think within the next year to year and a half, this class of drugs is going to be mandated like the ACEs and the ARBs to be standard of care in people with diabetes and have high risk for cardiovascular and kidney disease because of the overwhelming benefits. We're going to have the DAPA-CKD trial coming out the end of next year. I can't imagine that's not going to be positive.

So, the data is literally just going to be piling up. It'll just be overwhelming. If you're not using these agents, it's going to be troubling. In fact, I can tell you, there's a couple of trials coming out next year. One is the FIDELIO trial, which is in kidney disease, but looking at a nonsteroidal mineralocorticoid receptor antagonist and that's 5300 patients and of those 5300 patients, about 8% are on SGLT2s. We've already planned—because I'm the principal investigator. We've already planned and analysis of that subgroup to see if there's additive benefit, with a mineralocorticoid on top of the SGLT2. So, we're kind of treating it as if it makes standard of care.

So, I don't think there's any question that there's not going be anything new necessarily—We've got heart failure now, we've got kidney disease, and prevention of dialysis. We've got reduction of cardiovascular risk. How much more do you want? I mean, that's the pretty much the Full Monty, as far as I'm concerned.

MD Mag: Okay, that was about it on my questions. Was there anything else you wanted to add that we might not have touched on?

Bakris: I think the only thing I would say is conceptually. When the ACE inhibitors and ARBs first came out, they were easy, because they were blood pressure lowering drugs and, by the way, the bandwagon went crazy. All right. The problem here is these are perceived as glucose-lowering drugs. So, if I'm not lowering glucose, why am I giving the drugs? You cannot think like that. If you do, the people with advanced kidney disease are going to miss a huge opportunity of benefit that they're not going to get because you are not lowering glucose—and that's a huge mistake.

These drugs need to be understood as glucose-lowering agents if your kidneys are good enough; however, in people that have lower GFRs, they don't have increased risk of side effects, and, at the same time, they're slowing kidney disease progression by mechanisms that are postulated now, but we don't fully understand, but it's not the diuretic effect that people think it is, because it doesn't have that effect at that level of GFR.

Yet, you're still getting protection of slowing kidney disease progression and, in fact, I will invite people listening to this—if they hear it in time—to come to the American Society of Nephrology in Washington, DC in early November, I will be presenting data in the subgroup of people with GFRs below 30 and I will tell you without telling you the results. It's not surprising what the benefits are.

MD Mag: All right, that was it on my questions. Thank you again for joining us today, Dr. Bakris.

Bakris: Thank you for having me. I appreciate it.

MD Mag: Alright, that's it for this edition of the Doc Talk podcast. For the latest in diabetes and nephrology Be sure to head to MDmag.com