Updates in the Management of Chronic Kidney Disease and Type 2 Diabetes - Episode 11

Chronic Kidney Disease: Treatment Landscape

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Therapies used to help treat patients who have chronic kidney disease and type 2 diabetes.

Neil B. Minkoff, MD: Let me pull this back a little, because I want to touch on a couple of things Dr Bakris said earlier. One is the primary care doctor being underwhelmed by the treatment paradigm. And earlier, you said something like, “I already put them on an ACE [angiotensin-converting enzyme inhibitor], I’m done.” Maybe you could talk a little about blood pressure management, ACEs and ARBs [angiotensin receptor blockers] and so on, and why the primary care doctors are underwhelmed compared with what you know.

George L. Bakris, MD: What I meant by underwhelmed is that when you tell them, they know that. And because they know that, they think there’s got to be something more than that because they’re already addressing that. So if you’ve got nothing more, we’ve got nothing else to say. This is what I meant by underwhelmed.

As far as ACEs and ARBs go, they’ve been the cornerstone of kidney protection for the last 2 decades. They’re well established and well accepted today. They’ve evolved going back to 2000 or 2001. There’s no question that they have to be the mainstay of therapy, but not just that and you’re done. You can’t just be on ACE or an ARB. You have to be on properly dosed ACEs or ARBs. If you’re on half doses or quarter doses, that doesn’t count. That hasn’t been shown to protect anybody, anywhere. You need to be on the doses used in the clinical trials, which were the maximal doses for the most part. Sometimes they were reduced a little, but they have to be maximally dosed. I can’t tell you the number of people I get referred to me on 5 mg of lisinopril, and the comment is, “Well, they’re on an ACE.” Not really. Or 25 mg of losartan. “You think you’re doing something, really? OK.”

There’s this lack of awareness and the thought that all drugs need to be slowly titrated for adverse effects. That’s not true when it comes to ARBs because they’re dosed independently of adverse effects. They are the best tolerated class of drugs. The FDA says this. There’s a lack of penetration of proper education to physicians.

Neil B. Minkoff, MD: But now hypertension is, as we’ve discussed, only 1 of the boxes we need to check, right? Dr Wright, I know you’re very active in community medicine. What are the different strategies you use around glycemic control with your patients? How do you ramp that up?

Eugene Wright Jr., MD: It’s tough, because so much of glycemic control is behavior. We have medications to help people with that, but so much of it relies on their behavior. This is where one of the resources that we’re starting to utilize more is the concept of motivational interviewing, understanding what’s important to the patient and helping them understand the value of changing their behavior, if just a little, to relieve some of the burden of the long-term complications.

Many patients feel that glycemic control isn’t a big deal. “I take a pill, I take a shot, I can eat what I want.” We have to disconnect that from them and explain that it’s work. And we have to understand, as we listen to patients, that it’s hard work for many of them. We have to take little steps with them in terms of glycemic control. If they come in with an A1C [glycated hemoglobin] of 12% or 15%, and move it to 10%, we should celebrate.

Neil B. Minkoff, MD: Yes, that’s a big deal.

Eugene Wright Jr., MD: We don’t celebrate by eating ice cream, but we celebrate that and try to reinforce that behavior to get them down over time.

Neil B. Minkoff, MD: Maybe I shouldn’t assume, but I’m assuming that metformin would be one of the building blocks of how you do this. But as the treatment for type 2 diabetes has progressed over time, we have SGLT2 inhibitors and GLP-1 inhibitors. How do you make use of those and tailor them to your patients?

Eugene Wright Jr., MD: That’s a great point because with the explosion of new therapies, there’s been an explosion of confusion over how to use them in the primary care community.

Neil B. Minkoff, MD: Yes, that would be me.

Eugene Wright Jr., MD: We should be talking to the patient, listening to the patient with the idea of understanding as opposed to responding to them, and understanding what motivates them. If weight loss is a key factor for them, I can get that with GLP-1 inhibitors. And if they can see some self-efficacy and some benefit from that, their adherence goes up because they’ve got something that’s driving them.

If we talk about heart failure or kidney disease, and we can help show them where an SGLT2 inhibitor or other therapies can help with that, that’s a reason for them to continue on that. Metformin is foundational therapy. The ADA [American Diabetes Association] algorithm now helps us stratify at an earliest point, irrespective of their A1C, whether they have high cardiovascular risk, ASCVD [atherosclerotic cardiovascular disease], heart failure, or high renal risk for CKD [chronic kidney disease], and it helps direct our therapy. It’s guideline-directed therapy.

Neil B. Minkoff, MD: Let me pull Dr Agarwal in here. You mentioned earlier the disconnect you have with folks about starting spironolactone. Spironolactone isn’t the only mineralocorticoid receptor agonist [MRA], but it’s something that people have been thinking about or starting to use for a long time. But I understand that many clinicians have the struggle that you just mentioned, which is they start it, somebody else stops it, they start it again, and so on. When do you use an MRA? And which MRAs beyond spironolactone might you be using?

Rajiv Agarwal, MD: The story I mentioned was about an MRA in a patient with preserved kidney function, who has a little proteinuria. I was consulted for taking care of hypertension. In that situation, it’s a level 1a indication if the patient has HFrEF [heart failure with reduced ejection fraction], which is a very different situation than the typical patient I might see in the clinic. Once the potassium is higher, for example, if you look at the European Society of Cardiology guidelines, they say, “If your GFR [glomerular filtration rate] is less than 45 mL/min, potassium more than 4.5 mEq/L, then use with caution.” If you look at the eplerenone label, for example, if you have diabetes and any microalbuminuria, or creatinine clearance less than 50 mL/min, it’s contraindicated. So for the majority of the patients who have significant kidney disease, these drugs are dangerous.

To give you a bit of a historical perspective, spironolactone was approved by the FDA in 1960, and it’s a drug where you take a few doses and it never really leaves your body. It’s almost like giving somebody radium or strontium. It sticks in their bones. In fact, when you look at metabolites of spironolactone 3 weeks after stopping the drug, you can still detect them in the urine. It’s because spironolactone is a prodrug. It’s metabolized to canrenone and 7alpha-thiomethyl spironolactone, and the latter has a half-life of 1 week, or 168 hours.

We have made substantial advances in the design of these molecules that you can have MR [mineralocorticoid receptor] antagonism, yet you have a drug with a 2- to 3-hour half-life and no active metabolites, compared with 1 week half-life after stopping the drug and having several metabolites. You’re not dealing with radium that’s sticking to your bones anymore, but something that goes in and out very quickly. And before you take the next pill, 8 to 12 half-lives have elapsed, so you almost have no drug remaining in your body.

These are drugs that have just been approved. For example, finerenone was approved on July 9th by the FDA for the treatment of type 2 diabetes and chronic kidney disease for the prevention of cardiovascular and kidney disease. It’s yet to hit the clinic, but it’s approved and an exciting new development for people with kidney disease.

Transcript edited for clarity.