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Key Takeaways on Improving Renal and Cardiovascular Outcomes in Patients with CKD and T2D
Key Takeaways on Improving Renal and Cardiovascular Outcomes in Patients with CKD and T2D

Released: June 07, 2022

Expiration: June 06, 2023

George L. Bakris
George L. Bakris, MD
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Chronic kidney disease (CKD) is one of the most common complications of diabetes. In patients with type 2 diabetes (T2D), the presence of CKD increases the risks for progressive loss of renal function and cardiovascular (CV) morbidity and mortality. In this commentary, I will discuss important considerations for CKD screening, CV risk, and how to integrate the recently approved therapy, finerenone, into the management of patients with T2D and CKD.

CKD Screening in T2D

Proper screening for CKD is a 2-step process, not a 1-step process. Most clinicians will order tests for creatinine and estimated glomerular filtration rate (eGFR) and think they are done. But numerous guidelines recommend measuring spot urinary albumin-to-creatinine ratio (UACR) and eGFR at least annually. Taken together, these tests give you a picture of the state of kidney function at that time.

In my experience, 1 value is not sufficient to assess kidney function, especially if it is different from a previous value. Persistently abnormal values are necessary to conclude that kidney function has declined. Many clinicians make the mistake of seeing 1 value that is different from the previous and immediately conclude that the patient has worsening kidney function. But common causes such as relative dehydration can result in normal fluctuations. Too many patients are put on dialysis without having any protein spillage when simply rehydrating them may have improved their UACR. On the other hand, some patients are spilling 2-3 grams of protein while having relatively normal eGFR. That does not mean they have normal kidney function. So it is very important to assess both. As mentioned, numerous guidelines agree on this, including those from the American Diabetes Association (ADA), the Healthcare Effectiveness Data and Information Set (HEDIS), and the Kidney Disease Improving Global Outcomes (KDIGO).

CV Risks With CKD and T2D

When managing patients with T2D, it is important to understand the CV risks associated with kidney disease—defined as UACR >30 mg/g creatinine with eGFR <60 mL/min/1.73 m2. According to a massive 2004 analysis of more than 1 million individuals in the Kaiser Permanente Renal Registry, the risk of death and CV events increases as eGFR declines. An individual with eGFR of 40 mL/min/1.73 m2 has a 4-fold higher risk for all-cause mortality and an 11-fold higher risk for adverse CV events than someone with normal kidney function.

Clearly, kidney function and CV health are linked. You can't divorce them. So, if you are focusing on the kidney and ignoring CV events, you will run into trouble. Likewise, focusing on CV events by treating cholesterol and counseling on lifestyle modifications will not suffice. You need to treat the kidney disease as well, as outlined in the major diabetes guidelines.

Nonsteroidal MRAs

Recent findings from the phase III FIDELIO-DKD and FIGARO-DKD studies have demonstrated efficacy of the novel nonsteroidal mineralocorticoid receptor antagonist (MRA) finerenone in slowing progression of diabetic kidney disease. These studies enrolled more than 13,000 individuals with T2D and various levels of kidney disease, from microalbuminuria and eGFR in the 80s to people with 2-3 grams of protein in their urine and eGFR in the 30s. That entire spectrum of participants received CV and renal benefits from adding finerenone to maximally dosed RAAS inhibitors (note that fewer than 8% of participants were receiving sodium glucose cotransporter-2 [SGLT2] inhibitors or glucagon-like peptide-1 receptor agonists [GLP-1 RAs].)

Many people think of spironolactone when they think of an MRA, but finerenone is quite different: the chemistry is different, and the side effect profile is improved. Spironolactone does not have benefit in kidney disease primarily because of the risk of hyperkalemia. In contrast, in FIDELIO-DKD and FIGARO-DKD, the risk of serious hyperkalemia and hyperkalemia leading to discontinuation with finerenone was low (<2%). Moreover, finerenone is indicated for patients with eGFR as low as 25 mL/min/1.73 m2 and serum potassium levels ≤5 mEq/L.

Current guidelines from both the ADA and KDIGO advise that persons with T2D and CKD should receive an SGLT2 inhibitor because of the cardiorenal benefits. Additionally, those who either cannot tolerate an SGLT2 inhibitor or have evidence of additional cardiorenal risk should also receive a nonsteroidal MRA (finerenone) to reduce the risk of CV events and kidney disease progression.

Nephrologists have finally entered the era of “pillar-based” therapy for CKD. Just as heart failure specialists have 4 classes of drugs they must give for optimal benefits, nephrologists now have 3 drugs we can give to optimize renal and CV risk reduction; these include maximally tolerated doses of RAAS inhibitors (ACE inhibitors or ARBs), SGLT2 inhibitors, and nonsteroidal MRAs.

Who Should Start Finerenone?

Finerenone can be initiated in anyone with diabetes and CKD who is already receiving an ACE inhibitor or an ARB for hypertension and CKD protection. But don’t stop with those 2 drug classes; we know that adding an SGLT2 inhibitor provides cardiorenal protection beyond the need for glycemic control. SGLT2 inhibitors will help lower glucose if kidney function is good, but if the kidney function is not good, they still lower cardiorenal risk without further lowering glucose. Similarly, finerenone will not further lower glucose and has some—albeit small—effect on blood pressure-lowering if the blood pressure is well controlled, and a greater effect if uncontrolled. Of interest, another benefit of administering SGLT2 inhibitors alongside finerenone is a reduced risk of hyperkalemia.

We can no longer think of 1 drug, 1 outcome. Nor can we think of drugs that focus on risk factor reduction alone; we need to think of drugs that reduce cardiorenal risk independent of these traditional risk factors. We have progressed to drugs with unique mechanisms that have demonstrated improved outcomes across systems. Hence, our goal should be to have all 3 drug classes on board for individuals with diabetes and CKD. Even when glucose and blood pressure are controlled, we will see additional benefits from adding finerenone.

Sequencing Medicines

All of these drug classes are known to cause an initial drop in eGFR, so if you initiate them simultaneously, you risk a dramatic drop in eGFR. You also risk an increase in serum potassium. Instead, I suggest starting with maximumly tolerated doses of an ACE inhibitor or ARB, and after 1-2 weeks, start an SGLT2 inhibitor or finerenone. And after another week, start the drug not started earlier. That is how we pace the medicines in my practice, and we have consistent success.

Can Patients Safely Discontinue Treatment?

A common question I receive is, once a patient’s numbers have improved, can they discontinue any therapies?

Consider a pot of boiling water on the stove where the heat is on high. That is uncontrolled diabetes. Adding medication such as an ACE inhibitor or an ARB is like turning the heat down. Adding an SGLT2 inhibitor is further reducing the heat. Adding finerenone gets you to the lowest setting yet. But still, you have not turned the heat off. Nothing that we know of has been able to shut it off.

In medicine, surgeons are the only people who cure conditions. Other clinicians treat conditions. Kidney disease is not curable. Hypertension is not curable. Any disease that requires a medication to control it will require lifelong therapy. You may be able to modify the doses, but the therapy will be lifelong.

Your Thoughts?

Have you integrated finerenone into the management of patients with T2D and CKD? How often do you screen for CKD in persons with T2D? Join the discussion by posting a comment.