Dr Maddux: Originally developed to treat diabetes SGLT2 inhibitors are potentially groundbreaking and slowing the progression of chronic kidney disease. Recent studies indicate SGLT2 inhibitors hold promise for slowing CKD progression, and for reducing cardiovascular complications. Today's guest, Dr. Michael Anger of Fresenius Medical Care's Global Medical Office, discusses how this underused class of drugs has the potential, if used earlier in the course of chronic kidney disease, to improve overall patient health. Welcome, Mike. Thanks for joining me.
Dr Michael Anger: Thanks, Frank. Good to be here.
Dr Maddux: Let's start. Just tell me a little bit about what this sodium glucose co-transporter inhibitor is. What are these things?
Dr Michael Anger: These are proteins that are predominantly located in the proximal convoluted tubule. Their main job is to reabsorb glucose. So, glucose gets filtered in the kidney and the proximal tubule and gets reabsorbed. 90% of it gets reabsorbed in the proximal tubule, and these proteins modulate that. And Typically, we have a renal threshold of about 180 milligrams per deciliter. Which means when glucose in the blood reaches that level, up to that level, these proteins help reabsorb that completely into the blood, and when that blood level exceeds that it spills into the urine.
Dr Maddux: We know from studies, and I'll ask you to give us a little hint on why did these things slow CKD progression? And these inhibitor drugs are really groundbreaking, potentially for our patients with advancing kidney disease.
Dr Michael Anger: They truly are. It's interesting, because when the drugs first came out, they were designed to treat diabetes. It's a great protein to target for diabetes, because if you can block the reabsorption of glucose and spill it out in the urine, it simply helps to control blood sugars. In the early studies, there were some requirements by the agencies to show the safety from a cardiovascular standpoint of the use of these drugs, and they were, indeed, shown to be beneficial in terms of cardiovascular outcomes. Incidentally, they also noted some slowing of the progression of kidney disease. And that led to a series of studies that further underscored the benefits in chronic kidney disease.
Dr Maddu: What do you think the mechanism might be for the cardiovascular impact? Is it the fact that the diabetes control is different? Or do you think it's some other independent effect with regard to these better cardiovascular outcomes that we see.
Dr Michael Anger: I think it's less likely diabetes control. The studies have demonstrated that the better outcomes are either with or without better glucose management. It seems that this class of drugs seems to improve certainly in the kidney, renal hypoxia, and it improves mitochondrial function and probably in cardiac tissue. That's where a major factor of the benefit is.
Dr Maddux: How well utilized in our patients are these drugs today?
Dr Michael Anger: Unfortunately, not very well utilized. Despite numerous studies that have shown tremendous impact of these drugs in terms of outcomes, both from a renal standpoint and cardiovascular standpoint, they seem to be underutilized, probably just because of lack of familiarity with all the benefits, especially in non-diabetes conditions. In fact, a recent publication and Kidney 360 locally looked at over 72,000 patients in the Brigham MassGeneral system with chronic kidney disease, and in that population, only 6% with diabetes were prescribed SGLT2 inhibitors. And only .3% without diabetes were prescribed those drugs.
Dr Maddux: What do you think we should do? How do we begin to socialize and change the nature of how nephrologists look at this particular class of drugs, which they may think is an endocrinologist drug to use, but, in fact, isn't?
Dr Michael Anger: It's a great question. I think that it's getting nephrologist and other healthcare providers more familiar with the benefits of these drugs and the importance and the significant improvement in outcomes that can occur. It's educational programs like this, that will educate healthcare providers out there and hopefully get them to prescribe it more often.
Dr Maddux: Where do you think is the greatest benefit for patients with advancing kidney disease? Because we know the drugs are used in earlier stages of kidney disease, is it the slowing progression of kidney disease? Or is it the cardiovascular benefit? What do you think?
Dr Michael Anger: I think it's a little of both. We certainly would like to improve both, and the studies have suggested that both benefit. So, I think it would be used for both purposes.
Dr Maddux: Describe for folks just so we can ground ourselves, when's the best time to initiate these drugs? When are we finding that their impact is going to be greatest in patients, and how do you recommend getting started?
Dr Michael Anger: Well, certainly earlier is better. KDIGO recommends the use of this class of drugs in any patient with chronic kidney disease and in any patient with albuminuria with or without diabetes. So, earlier in the course, is certainly better. Later in the course, the current recommendations are not lower than a GFR of 30, with the exception of dapagliflozin, which can be used down to a GFR of 25. I think those limits are there solely because the studies haven't looked at more advanced kidney disease.
Dr Maddux: There are a couple of drugs on the market for this today. You want to just sort of run us through the pantheon of what's available today and whether there are any distinctions between those drugs?
Dr Michael Anger: Sure. There's canagliflozin which is one of the earlier ones. It got a bad rap because in the early cardiovascular study called CANVAS, they noted an increase incidence of amputations which hadn't proven so in future studies. There's dapagliflozin which has the characteristic of having been trialed in patients with GFR is a little bit lower down to 25. And there's empagliflozin. Outside the US, there's sotagliflozin which actually is both an SGLT2 and SGLT1 inhibitor.
Dr Maddux: How long do you think it will take for us to see the full benefit of these drugs? In sort of populations of patients that we see? Is there impact something that's seen in the first six months and over a period of years? What do you think the response should be that physicians should expect?
Dr Michael Anger: I think it's going to probably be over a few years. I think that the reason for that is in studies like Creedence, which was canagliflozin and DAPA CKD, which was dapagliflozin. Both those trials were stopped at about two and a half years because the benefits were so profound. I think that may be a time when we see it. One of the challenges with this entire class of drugs that might be a problem is that, early on, many patients actually have an increase in their creatine because of volume depletion.
Dr Maddux: How well are the drugs tolerated and talk a little bit about other side effects than what you just described?
Dr Michael Anger: In general, they're pretty well tolerated. As with any medication, there are some side effects urinary tract infections, some yeast infections, and rarer but more serious, you can see diabetic ketoacidosis and Fournier's gangrene. And as I mentioned, in the early studies with canagliflozin, and some amputation increase, but not seen with the others.
Dr Maddux: How do you think in our population, we need to begin to socialize and address some of the impact we need to work not only with physicians, but also our social workers, dietitians, patient groups. It seems to me trying to make this more routine is one of the things that might actually improve some of these pretty poor levels of utilization that we see today.
Dr Michael Anger: I agree. I would expand that list and include policymakers, insurance companies. These are very expensive drugs, and currently there are no generic options. I think that as we see the tremendous benefits that they offer, all of these parties can come together and perhaps make these more affordable, more readily available for patients to use.
Dr Maddux: We talk a lot about precision medicine and the development of precisely treating a particular mechanism of injury, but these drugs tend to now be indicated pretty broadly in the population of people with CKD. Do you think we'll get to a time where the drugs have a more specific use because they have an impact on a particular type of injury that's occurring to the kidney?
Dr Michael Anger: I think that's hard to predict right now. Initially, they were thought to be beneficial solely in diabetes. The studies have now shown that in non-diabetic chronic kidney disease, they're quite beneficial. I think that their benefits are more broad. Now, we may find some specific reasons that they may be used in certain disease states, but overall, I think it will have pretty wide impact.
Dr Maddux: CKD patients, as they progress, lose their opportunity for these drugs to be able to be used or affected because of the limits of where the studies have been today and in safe use of the drugs. Just remind us, the EGFR and your impression of the changes to how we calculate EGFR and what the impact will be on the number of patients because of the elimination of sort of race in the equation.
Dr Michael Anger: Well, currently, the limits recommended as far as initiation of drugs are down to a EGFR 30 or 25, with the one drug dappogalflozin. I think that that will be critical as we look at potential changes in calculations, as far as race impact on the equations. And whether or not it will be a problem in initiating these drugs in some patients who might otherwise fall out of the qualifying range if their GFR is too low. I do suspect that as time goes on, we will see the use of these become more liberal to lower levels of GFR.
Dr Maddux: Any other drug drug interactions or interactions with other types of drugs that are frequently used in our patients, whether they are blood pressure drugs or cardiovascular related drugs?
Dr Michael Anger: Not so much drug to drug interactions, but they do cause a naturecess, and they can cause some volume depletion. So, they need to be used with caution with diuretics. And because they do have the potential to lower blood sugars when they're used with diabetes medicines like insulin, there is some risk of hypoglycemia. Then rarely and again, maybe because canagliflozin has been out the longest, there are some drug interactions, where drugs like phenytoin and rifampin can increase the elimination of canagliflozin and canagliflozin can raise digoxin levels.
Dr Maddux: You mentioned earlier, these are expensive drugs. What do we see as the range of costs for patients, and are insurers actually covering these drugs, given the benefits that they can see?
Dr Michael Anger: I don't know.
Dr Maddux: I don't know. Either. We have to find that out.
Dr Michael Anger: Yes.
Dr Maddux: Interesting thought that SGLT2 to specifically hear you mentioned, one of the drugs also inhibits SGLT1, you want to talk to us just a little bit about that.
Dr Michael Anger: SGLT1 is predominantly located in the intestine and plays a role in the absorption of glucose in the GI tract. So, the one drug that's available, but not in the US, is sotagliflozin, and it inhibits both. So SGLT2 is predominantly in the proximal convoluted tubule; SGLT1 is predominantly in the testand a little bit in the kidney. And by blocking SGLT1, it impairs glucose absorption.
Dr Maddux: You've been involved in our discussions around genomics and genetics and so forth. Any thoughts over time about whether we will identify certain populations of patients that might actually do better on this kind of drug or potentially the combination drug of SGLT1 and SGLT2?
Dr Michael Anger: I think that that's a possibility as we explore whole new areas with genomics. We're learning new things about other diseases that, as you mentioned earlier, can help us truly practice precision medicine. I think we may see some specifics like that.
Dr Maddux: Any final thoughts about SGLT2s? What would you recommend to our colleagues, as they begin thinking about their practice patterns and so forth.
Dr Michael Anger: I think that their use needs to become more commonplace almost as common as ACE inhibitors or angiotensin receptor blockers, and should be thought of at the same time and used in combination with those drugs because that combination really seems to provide the greatest benefit both from a kidney standpoint and a cardiovascular standpoint.
Dr Maddux: I'm here today talking with Dr. Mike Anger, about SGLT2 inhibitors and the fact that they can really positively impact the outcomes of our patients with advancing kidney disease. So, Mike, thanks so much for being here.
Dr Michael Anger: Thanks for having me, Frank.