COMMENTARY

The Path to Progress: worldwide, responsible for up to

50% of end-stage renal disease.
Glucagon-like Peptide 1 Furthermore, CKD and diabetes
have an independent and additive
Agonists, Individualized effect on cardiovascular (CV) risk
Care, and Overcoming and mortality. The Kidney Disease:
Improving Global Outcomes
Goal-Directed Medical (KDIGO) risk classification uses
Therapy Barriers in Diabetes albuminuria and estimated
glomerular filtration rate to cate-
and CKD gorize risk of progression to kid-
ney failure, CV events, and death.
Sophia L. Ambruso1,2 and Matthew R. Weir3 However, developments in dia-
1
Renal Division, Aurora, VA Eastern Colorado Health Care System, Aurora, Colorado, USA; betes and CKD management are
2
Department of Medicine, University of Colorado, Aurora, Colorado, USA; and 3Depart- reshaping the therapeutic land-
ment of Medicine, University of Maryland, Baltimore, Maryland, USA scape with the emergence of so-
dium glucose cotransporter 2
Kidney Int Rep (2024) -, -–-; https://doi.org/10.1016/j.ekir.2024.05.027 inhibitors (SGLT2i), nonsteroidal
Published by Elsevier Inc. on behalf of the International Society of Nephrology. This is mineralocorticoid receptor antago-
an open access article under the CC BY-NC-ND license (http://creativecommons.org/ nists such as finerenone, and now
licenses/by-nc-nd/4.0/). GLP-1RAs, which are in addition
See [article type, i.e., Clinical Research] on Page xxx. to the age-old renin angiotensin
aldosterone inhibitors. Random-
ized controlled trials examining
he origin of glucagon-like pep- transcription, and inhibits
T tide 1 (GLP-1) agonists (GLP-
1RA) can be traced back to a shy, un-
glucagon release. In the stomach,
it inhibits gastric emptying
GLP-1RA CV outcomes revealed
improvement in CV disease in pa-
tients with type 2 diabetes and
assuming, slow-moving reptile thereby reducing appetite. In the high CV risk. Although these trials
found within the southwestern re- brain, GLP-1 promote satiety and were not powered for kidney out-
gions of the United States. In 1990, demonstrates neuroprotective ef- comes, the accumulating data and
an endocrinologist named John fects. Interestingly, GLP-1 is multiple pooled analyses provide
Eng from the veterans’ administra- rapidly degraded within minutes compelling data that GLP-1RAs
tion center in Bronx, NY, isolated whereas exendin-4 evades GLP-1 provide protective kidney func-
exendin-4 from the venomous saliva regulatory mechanisms, with a tion benefits. The long-anticipated
of the famed Gila monster. Exendin- substantially longer half-life FLOW randomized controlled trial
4 is an incretin hormone that stimu- compared to its human counter- published in NEJM evaluating
lates insulin production during pe- part. And the rest is history, the once weekly subcutaneous sem-
riods of high glucose loads in the potential diabetes and weight loss aglutide versus placebo in diabetic
Gila monster, known to consume benefits of a long-acting GLP-like kidney disease reported a 24% risk
only 3 to 4 meals per year. therapy were clear. Following the reduction of the primary compos-
Exendin-4 is molecularly similar 2005 release of the first US Food ite end point of kidney failure,
to mammalian GLP-1 and can and Drug Administration- persistent $50% reduction in
bind to GLP-1 receptors imparting approved GLP-1RA exenatide for estimated glomerular filtration
similar physiologic responses. As the treatment of type 2 diabetes, rate, or death from kidney or CV;
an incretin hormone, GLP-1 stimu- the GLP-1RAs drug industry expe- finally removing any doubts that
lates glucose-dependent insulin rienced exponential growth, GLP-1RA has kidney protective
secretion, promotes insulin gene releasing a myriad of GLP-1RA for- benefits.1
mulations, administration routes, The SUSTAIN 6 randomized
Correspondence: Sophia L. Ambruso, duration of action, and indications controlled trial published in 2016
Renal Division, VA Eastern Colorado bringing us to the current day. considered CV outcomes with once
Health Care System, 1700 N Wheeling St.
Aurora, Colorado 80045, USA. E-mail: Diabetes is the leading cause of weekly subcutaneous semaglutide
[email protected] chronic kidney disease (CKD) compared with placebo in patients
Kidney International Reports (2024) -, -–- 1
COMMENTARY SL Ambruso and MR Weir: Individualizing GLP-1RA Care and Overcoming GDMT Barriers

with type 2 diabetes. In addition to The 2024 KDIGO clinical practice is multifaceted. Frequently cited
positive primary end point CV guidelines for patients with CKD barriers include limited kidney
outcomes, secondary outcomes and diabetes lists the following as disease education among patients
revealed reduced risk of new or recommended goal-directed medical and providers, low CKD aware-
worsening nephropathy.2 In a post therapy (GDMT): metformin and ness, clinical inertia, poly-
hoc analysis published in Kidney SGLT2i, followed by nonsteroidal pharmacy, cost, disparities in
International Reports, Tuttle et al.3 mineralocorticoid receptor antago- underserved populations, lack of
sought to assess treatment effects nists in those with persistent albu- public policy on health equity, and
of once weekly semaglutide versus minuria >30 mg/g despite other fragmented care.8 Surmounting
placebo on kidney outcomes by standard-of-care therapies, and these barriers will take a coordi-
KDIGO risk category and on GLP-1RA in those not achieving nated effort between health sys-
changes in KDIGO risk category, individualized glycemic targets tems and communities,
using the SUSTAIN 6 trial patient despite standard-of-care therapies interdisciplinary care; and local,
cohorts. The values were pooled (1B evidence).5 Populations that fall national, and global initiatives
by treatment and stratified into 4 within the high and very high risk aimed to educate and create CKD
subgroups by KDIGO risk cate- KDIGO categories are associated awareness.
gory, which included low risk, with the highest burden of disease, At the level of the provider,
moderate risk, high risk, and very have the greatest risk of disease patients often receive fragmented
high risk. The results revealed that progression, and seem to benefit the care caused by the siloed care
regardless of CKD severity, once greatest with rapid implementation models found in many health care
weekly semaglutide participants of GDMT. Incorporating standard- delivery systems, where providers
experienced a positive treatment of-care interventions such as GLP- practice independent of one
effect in the composite kidney end 1RA does not only reduce progres- another. In the setting of advanced
point. Importantly, the greatest sion of kidney disease; they reduce diabetic kidney disease, where
benefit was observed at the highest risk of CV progression and death. primary care physicians, nephrol-
risk categories. A similar trend was Utilizing KDIGO risk categories in ogists, cardiologists, and other
observed in estimated glomerular patient care enable practitioners to specialists provide overlapping
filtration rate slope, which individualize CKD risk assessment, care, providers can fall victim to
revealed a smaller decline in the prioritizing those with greatest “stay in your lane” mentalities.
semaglutide cohort, which was need and urgency in GDMT This is a form of clinical inertia
numerically smaller in the highest implementation. whereby crucial GDMT such as
risk categories. Participants Unfortunately, the known benefit SGLT2i and GLP-1RA can be
receiving semaglutide were more of GLP-1RA and other GDMT in delayed. In any disease with
likely to move to a lower KDIGO CKD and diabetes has not translated increasing complexity, clinical
risk category and less likely to into widespread implementation of inertia is magnified. We call it a
move to a higher KDIGO risk these practices. A cross-sectional “medical complexity care conun-
category. As expected, changes in study in the veterans’ health drum” when increased disease
urine albumin-to-creatinine ratio administration between 2019 and complexity and comorbid condi-
were the primary drivers for 2020 revealed that 10.7% and 7.7% tions necessitate an increased
regression of KDIGO risk category of patients were prescribed an number of involved specialists.
in both semaglutide and placebo SGLT2i or a GLP-1RA, respec- With increased complexity, pri-
groups. However, uniquely iden- tively.6 Data from the centers for mary care physician and specialist
tified, change in estimated disease control and prevention show care responsibility overlap
glomerular filtration rate was the that older adults, women, and non- whereby everyone, or no one is
main driver for progression of Hispanic White patients are more responsible, and deferral of patient
KDIGO category in both semaglu- likely to be prescribed SGLT2i, management decisions is common.
tide and placebo groups. A post hoc GLP-1RA, or DPP-4 inhibitor In addition, increased subspecialist
analyses SGTL2i EMPA-REG compared to other ages, male visit frequency competes with time
OUTCOME randomized controlled gender, and race/ethnicities; how- and motivation to attend primary
trial demonstrated similar wide- ever, they were still only prescribed care physician visits. The sum ef-
spread renal protective benefits in 21.3%, 17.8%, and 20.4% of fect is a greater number of physi-
across KDIGO risk categories with those cohorts, respectively.7 cians involved in patient care;
the greatest benefit observed in the Reasons for the lackluster however, an overall reduction in
higher risk cohorts.4 adoption of these important GDMT coordinated care whereby patient
2 Kidney International Reports (2024) -, -–-
SL Ambruso and MR Weir: Individualizing GLP-1RA Care and Overcoming GDMT Barriers COMMENTARY

Figure 1. The medical complexity care conundrum is a phenomenon observed with increasing disease complexity, which results in a pro-
portional increase in the number of physicians (primary care physician and specialists) providing patient care. Competing appointment time,
siloed medical care, and “stay in your lane” mentalities result in fragmented care and clinical inertia whereby delays in care decisions, reduced
care coordination, and a loss of patient ownership occurs.

ownership is not claimed Vitor, NovoNordisk, and Boehringer 5. Floege J, Jayne DRW, Sanders JSF,
(Figure 1). Using the example of Ingelheimer. Tesar V, Rovin BH. Corrigendum to
“KDIGO 2024 Clinical Practice Guide-
diabetes management in diabetic
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Kidney International Reports (2024) -, -–- 3