In April 2021, dapagliflozin (Farxiga) received a new indication from the US Food and Drug Administration (FDA) for slowing progression of chronic kidney disease (CKD) in people without any other disorder — type 2 diabetes or heart failure — that qualified them for treatment with a sodium-glucose cotransporter 2 (SGLT2) inhibitor, the class that includes dapagliflozin.
Dapagliflozin became the first agent in a new drug class approved for treating people with isolated CKD since angiotensin-converting enzyme inhibitors and angiotensin receptor blockers became mainstays more than two decades ago.
But use of dapagliflozin for CKD alone in US practice has lagged despite compelling efficacy evidence from the DAPA-CKD trial. In this study, one third of the randomized 4094 participants did not have type 2 diabetes, and the superior efficacy of dapagliflozin compared with placebo was similar in both the diabetes and nondiabetes subgroups. (Most people with CKD without diabetes have hypertension.)
This underuse may soon end, in part owing to one recent and one imminent change in the landscape.
In September 2023, a second SGLT2 inhibitor, empagliflozin (Jardiance), received the identical indication on the basis of its performance in the EMPA-KIDNEY trial. In this study, somewhat more than half of the 6609 randomized participants did not have type 2 diabetes, and again the efficacy of SGLT2 inhibitor treatment significantly surpassed that of placebo in both those with and those without diabetes.
A pending new guideline from the influential organization Kidney Disease: Improving Global Outcomes (KDIGO), expected to be finalized by early 2024, calls in draft form for a 1A indication for SGLT2 inhibitors in selected people with isolated CKD.
'Gross Underuse' in US Practice
"Despite robust trial evidence and FDA approval of dapagliflozin for CKD there is gross underuse of SGLT2 inhibitors in the US," commented Tazeen H. Jafar, MD, a nephrologist and professor at Duke-NUS Graduate Medical School in Singapore.
Perhaps one third of US patients with isolated CKD who could potentially benefit from treatment with dapagliflozin have recently been receiving it, primarily from nephrologists, although no reported data yet document this uptake, said Donald A. Molony, MD, a nephrologist and professor at UTHealth Houston, Texas.
"I suspect [US] uptake is very low right now," with use primarily limited to nephrologists, agreed Ian de Boer, MD, professor, and director of the Kidney Research Institute at the University of Washington in Seattle.
SGLT2 inhibitors are "uncommonly" used, which is "certainly less than optimal," said Chi-yuan Hsu, MD, professor and chief of nephrology at the University of California, San Francisco.
"Most nephrologists have increased their prescription of SGLT2 inhibitors in people with CKD and without diabetes; however, widespread use is likely still limited by underdiagnosis of CKD that is secondary to a lack of albuminuria testing in the general population," said Diana Kwong, MD, a nephrologist at the University of California, San Francisco.
Jafar cites several factors that have held back dapagliflozin use in this population over the past 2.5 years:
Excessive concern over adverse effects;
Ongoing skepticism about the value of SGLT2 inhibitor treatment;
Poor CKD recognition;
Treatment inertia; and
High cost of SGLT2 inhibitor treatment, with a retail price tag of about $6000 annually, that often leads to coverage barriers such as required prior authorizations and high copays.
An Imminent KDIGO Guideline
Another key barrier, cited by de Boer, Molony, and others, has been lack of authoritative guidelines that clearly call for SGLT2 inhibitor treatment in patients with CKD but without diabetes or heart failure. This seems poised to soon change.
In July 2023, KDIGO released a draft version of a revised guideline for evaluating and managing people with CKD that contains what experts call the first formal recommendation for treating people with isolated CKD with an SGLT2 inhibitor.
For patients with clear proteinuria and a diminished estimated glomerular filtration rate (eGFR) that's not yet reached end-stage, SGLT2 inhibitor treatment gets the highest level and grade recommendation: 1A. The draft says:
Recommendation 3.6.2: We recommend treating adults with CKD and heart failure or eGFR ≥20 mL/min/1.73m 2 with a urine albumin-to-creatinine ratio ≥200 mg/g with an SGLT2 inhibitor (1A).
The guideline also gives a weaker, 2B recommendation to consider treating people with less proteinuria who are at the lower end of the eGFR spectrum, including many with stage 3b or stage 4 CKD:
Recommendation 3.6.3: We suggest treating adults with eGFR ≥20 to 45 mL/min/1.73 m 2 with urine albumin-to-creatinine ratio <200 mg/g with an SGLT2 inhibitor (2B).
"Guidelines are a critical step in the implementation process," said de Boer in an interview. "Having evidence from DAPA-CKD and EMPA-KIDNEY was the first step. Clear guidance from KDIGO, which we anticipate in early 2024, is a necessary next step." However, de Boer cautions that additional steps are also needed, including a more detailed analysis from EMPA-KIDNEY that examines the degree of benefit from empagliflozin treatment relative to a person's baseline level of albuminuria.
The pending KDIGO guideline will be especially important once finalized as the "the first clear treatment recommendation for people with CKD and without diabetes," noted Molony.
"Rollout of the KDIGO-CKD management guidelines should have a significant impact on uptake of SGLT2 inhibitors" for people with isolated CKD," agreed Kwong in an interview.
Choosing Among Dapa, Empa — and Cana
Although perhaps not as impactful, addition of empagliflozin as a second SGLT2 inhibitor with FDA endorsement for the isolated CKD indication should also spur uptake, Kwong added.
"Having a second agent from the SGLT2 inhibitor class with an indication for isolated CKD will likely boost use" of the class for these people in US practice, in part by giving clinicians a second option that may have better insurance coverage for some patients, she said.
Experts also agree that the exact agent used, dapagliflozin or empagliflozin, seems to make little difference. Patient access and affordability are by far the top criteria by which to choose between them.
"Whether dapagliflozin or empagliflozin is prescribed is based on affordability and accessibility," said Kwong.
"The benefit is presumably a class effect; cost is a big issue," said Hsu in an interview.
"The choice between these two agents depends on their availability in the formulary and the preferences of a patient's insurance company," said Jafar.
A third SGLT2 inhibitor, canagliflozin (Invokana), was the first SGLT2 inhibitor with clear evidence for slowing CKD progression as a primary endpoint in the CREDENCE trial, but this study included only people with type 2 diabetes and the label indications for canagliflozin remain exclusive to people with type 2 diabetes.
Experts say that although the CKD slowing from canagliflozin treatment in people without diabetes is very likely similar to the effect from dapagliflozin and empagliflozin, the added data for isolated CKD give dapagliflozin and empagliflozin a small edge.
"I'd have no problem treating a patient [with isolated CKD] with canagliflozin if that's what's available. It's certainly preferable to not treating with an SGLT2 inhibitor," said de Boer. "But I'd first reach for dapagliflozin or empagliflozin because of the evidence and the support of the labeled indication."
At this point, "there is more evidence supporting use of dapagliflozin and empagliflozin compared with canagliflozin; however, it is important to appreciate that these drugs have similar chemical structures, pharmacology, and physiologic effects, and all three showed similar benefit in patients with diabetes and CKD," said Jafar. "This suggests a potential class effect, although we need data for canagliflozin in nondiabetic CKD."
Jafar, Molony, Hsu, and Kwong had no relevant disclosures. De Boer has been a consultant to AstraZeneca and Boehringer Ingelheim.
Mitchel L. Zoler is a reporter with Medscape and MDedge based in the Philadelphia region. @mitchelzoler
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Cite this: Will Kidney Disease Patients Finally Receive New Drug Class? - Medscape - Oct 19, 2023.
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