Journal of

Clinical Medicine

Review
Chronic Kidney Disease in the Older Adult Patient
with Diabetes
Raja Ravender, Maria-Eleni Roumelioti, Darren W. Schmidt, Mark L. Unruh and Christos Argyropoulos *

Division of Nephrology, Department of Internal Medicine, University of New Mexico School of Medicine,
MSC 04-2785, Albuquerque, NM 87131, USA; [email protected] (R.R.);
[email protected] (M.-E.R.); [email protected] (D.W.S.); [email protected] (M.L.U.)
* Correspondence: [email protected]

Abstract: Diabetes mellitus (DM) and chronic kidney disease (CKD) are common in middle aged and
older adult individuals. DM may accelerate the aging process, and the age-related declines in the
estimated glomerular filtration rate (eGFR) can pose a challenge to diagnosing diabetic kidney disease
(DKD) using standard diagnostic criteria especially with the absence of severe albuminuria among
older adults. In the presence of CKD and DM, older adult patients may need multidisciplinary care
due to susceptibility to various health issues, e.g., cognitive decline, auditory or visual impairment,
various comorbidities, complex medical regimens, and increased sensitivity to medication adverse
effects. As a result, it can be challenging to apply recent therapeutic advancements for the general
population to older adults. We review the evidence that the benefits from these newer therapies
apply equally to older and younger patients with CKD and diabetes type 2 and propose a compre-
hensive management. This framework will address nonpharmacological measures and pharmacolog-
ical management with renin angiotensin system inhibitors (RASi), sodium glucose co-transporter
2 inhibitors (SGLT2i), non-steroidal mineralocorticoids receptor antagonists (MRAs), and glucagon
like peptide 1 receptor agonists (GLP1-RAs).

Keywords: diabetes; chronic kidney disease; treatment; elderly; geriatric; dialysis; SGLT2 inhibitors;
GLP1 receptor agonists; non-steroidal mineralocorticoid antagonists

Citation: Ravender, R.; Roumelioti,

M.-E.; Schmidt, D.W.; Unruh, M.L.;
Argyropoulos, C. Chronic Kidney 1. Introduction
Disease in the Older Adult Patient
Diabetes mellitus (DM) and chronic kidney disease (CKD) pose substantial challenges
with Diabetes. J. Clin. Med. 2024, 13,
for older adult patients. In this review we aim to clarify emerging terminology, challenges in
348. https://doi.org/10.3390/
the diagnosis of CKD in older adult patients with diabetes, and a comprehensive approach
jcm13020348
to the management of such patients based on the current guidelines and emerging clinical
Academic Editor: Giuseppe Vezzoli trial data. Historically known as diabetic nephropathy (DN), CKD attributed to DM is often
referred to as diabetic kidney disease (DKD) and is the major cause of CKD and end-stage
Received: 6 October 2023
Revised: 27 December 2023
kidney disease (ESKD) in those over 60 years old [1]. Furthermore, a third of new ESKD
Accepted: 4 January 2024
cases in those over 75 years old are attributed to DKD, almost systematically without a
Published: 8 January 2024 histologic diagnosis. For those individuals the more encompassing term is diabetes in
CKD [2], a term that extends the classical definition of DKD [3] to reflect the complex
and often multifactorial pathogenesis of CKD in individuals with diabetes. This form of
CKD is increasingly not associated with proteinuria [4–7], and conversely, the presence of
Copyright: © 2024 by the authors. proteinuria or CKD in an older adult patient with DM is not always due to DN or DKD.
Licensee MDPI, Basel, Switzerland. Since none of the randomized controlled trials that led to therapeutic breakthroughs in this
This article is an open access article condition required a histological diagnosis for enrollment, the more general term more
distributed under the terms and accurately reflects the population of patients studied in the trials and thus the evidence. In
conditions of the Creative Commons this review, we will use these terms interchangeably, noting that the more general term that
Attribution (CC BY) license (https:// aligns with the clinical trial enrollment criteria may be used with increasing frequency in
creativecommons.org/licenses/by/
the future.
4.0/).

J. Clin. Med. 2024, 13, 348. https://doi.org/10.3390/jcm13020348 https://www.mdpi.com/journal/jcm

J. Clin. Med. 2024, 13, 348 2 of 20

Providing care in older individuals with DM and CKD is challenging because of the
substantial comorbidity burden and the co-existence of physical and mental conditions
such as dementia [8]. Multidisciplinary medical management may be required due to these
concomitant conditions, and the application of emerging evidence-based therapies should
neither be reflexively applied nor arbitrarily withheld.
While guidelines have incorporated fixed, age-independent referral criteria to nephrol-
ogy, older patients may benefit less from nephrology referral than younger individuals [9],
while the likelihood of regression, i.e., a spontaneous improvement in kidney filtration,
often exceeds the likelihood of progression [10]. This creates challenges in translating
interventions that are often tested in populations with some degree of proteinuria to those
patients with (near-) normoalbuminuria. However, recent advancements in DKD therapy
are applicable to both older and younger patients and confer broad cardiovascular benefits
(e.g., on cardiovascular disease or heart failure) that may be particularly applicable to older
patients with multiple comorbidities. Furthermore, these newer therapies are extremely
easy to apply and can be used in a pillars of therapy approach by either primary care
providers or specialists, offering unique opportunities to improve the outlook of older
patients with DKD. In this review, we will focus predominantly on agents that exert cardio-
vascular and kidney benefits in individuals with CKD and DM, i.e., SGLT2i, GLP1-RAs, and
MRAs, omitting agents such as the dipeptidyl peptidase 4 inhibitors whose cardiovascular
and kidney safety has been demonstrated in randomized clinical trials but that are cur-
rently not indicated to reduce the high cardiovascular and kidney risk in patients with DM
and CKD.

2. Definition, Epidemiology, and Burden of Diabetes in Older Adult Patients

with CKD
CKD is defined as either a persistent estimated GFR < 60 mL/min/1.73 m2 and/or
evidence of kidney damage (most commonly albuminuria). Based on this definition and
using NHANES data, an estimated 14% of the adult population has CKD; however, the
prevalence of persistently decreased eGFR was ~29% in those 65 years old and older [11,12].
The epidemiology of CKD seems to vary with age, in that CKD determined by low eGFR
alone (<60) is more common in older adults than in younger populations. Furthermore, the
association of low eGFR with mortality and ESKD in older adults, while still present, is less
pronounced in older individuals [13].
ESKD among patients with type II DM [4] is considered a problem of pandemic
dimensions [14], because of the increasing rates of DM and obesity, which will further
increase the prevalence of CKD and eventually the need for dialysis and kidney transplant.
Sequential analyses of the National Health and Nutrition Examination Survey (NHANES
analysis; 2003–2004 vs. 2013–2014) showed that the estimated frequency of DM increased
by 9 million, affecting 30.2 (13%) million US adults [4]. The 2020 updated National Diabetes
Statistics that examined data from 2013 to 2018 suggests very little improvement in this
figure [15]. According to the same report the prevalences of diagnosed and total DM among
people over the age of 65 in the United States were 21.4% and 26.8%, respectively. These
worrisome trends are not US specific; the International Diabetes Federation Atlas [16]
projects an increasing trend of DM up to 2045. The NHANES analyses also showed very
little change in the prevalence of CKD in patients with diabetes as defined by a persistent
urine albumin-to-creatinine ratio of ≥30 mg/g or a persistent eGFR of <60 mL/min per
1.73 m2 , from 28.4% (1988 to 1994) to 26.2% (2009 to 2014) [11]. Data from the CURE-CKD
registry, which collects electronic health data from two health care systems in the western
US, provide a slight contrast to these trends. Based on this registry, the overall prevalence
of CKD has trended down slightly among those with DM overall and noticeably in the
oldest population when comparing 2015-2016, 2017–2018, and 2019–2020 [17].
The higher rates of DM pose a significant threat to the falling incidence rates of ESKD
observed in recent years [18]. While improvements in the overall standards of care could
reduce the risk of a single individual to experience worsening of their kidney function to the
J. Clin. Med. 2024, 13, 348 3 of 20

point they need dialysis or kidney transplant, the overall number of patients needing renal
replacement therapy may increase if more patients develop DM. Analyses in NHANES [4]
and in non-US cohorts [19] suggest that this epidemiological trend may be particularly
relevant for older patients since those older than 65 years old are 35% more likely to manifest
albuminuria than those younger than 65 (32.3% vs. 23.9%, NHANES estimate). Prior to
the COVID19 pandemic, these trends were expected to lead to a rising prevalence in ESKD
from 2015 to 2030 [20]. African Americans, Hispanic Americans, and American Indians [4],
may exhibit even higher rates of CKD and DM in CKD [21], and these disparities carry
over to self-management of DM among older Medicare beneficiaries [22].

3. Pathophysiology of CKD in DM and DKD among Older Adults

The natural aging process in the kidney shares histopathologic findings, e.g., sclerosis,
mesangial matrix expansion, tubular and glomerular basement thickening, and interstitial
atrophy and fibrosis [23], with those observed in DKD (Table 1), suggesting shared but
not identical pathophysiology. Representative images from such lesions may be found
in the American Journal of Kidney Disease Atlas of Renal Pathology [24] or from the
PathologyOutlines.Com [25] atlas.

Table 1. Lesions by histologic compartment in the 2010 Pathologic Classification of Diabetic Kidney
Disease [26].

Glomerulus Arterioles Mesangium 2 Tubulo-Interstitium

Tubular
Diffuse intra-capillary Subintimal Mesangial matrix
atrophy/interstitial
glomerulosclerosis hyaline deposits expansion
space expansion
Nodular Capillary walls,
Tubular basement
(Kimmelstein Bowman capsules Mesangiolysis
membrane thickening
Wilson) (capsular drops) 1
Mesangial cell
Glomerulosclerosis Interstitial fibrosis
proliferation
1 Capsular drops may be observed in a small percentage (~5%) of patients without diabetes [26] but are considered
in general specific for DKD [27]. 2 Mesangial lesions correlate with loss of eGFR albuminuria and hypertension [28].

Hyperfiltration is thought to precede the functional loss of nephrons in DN; however,

in “normal aging” this loss [29] is not accompanied by a rise in single-nephron GFR [30,31].
Genetic studies have shown that loci linked to albuminuria in aging mice and diabetic
people are partially overlapping [32]. Accelerated senescence in tubular cells (primarily)
and podocytes (secondarily) has been shown in kidney biopsies from patients with DN
and type II DM [33]. Furthermore, these senescent cells secrete a variety of mediators
(e.g., proinflammatory cytokines and complement component and pro-fibrotic factors) that
drive glomerulosclerosis, podocyte hypertrophy, mesangial changes, and tubulointerstitial
fibrosis observed in DKD [34]. Advanced glycosylation end products (AGEs) and the RAGE
(cell surface receptor of AGEs) accumulate in both diabetic and senescent kidneys [35],
where they promote oxidation and inflammation [36,37], thus increasing the likelihood of
age- and diabetic-related CKD [38]. A recent review of the molecular pathways underlying
the progression of DKD in older adults [39] revealed a complex interplay between oxidative
stress, inflammation, and hyperglycemia.
The final common pathway linking inflammation and tissue fibrosis in CKD may be
mediated through the aberrant activation of the mineralocorticoid receptor, an observation
that is more than eighty years old [40]. Mineralocorticoid receptor activation links tissue
injury, oxidative stress, inflammation, arterial hypertension, and end organ damage of the
heart, blood vessels, and the kidneys [41–43].
While kidney biopsies are typically obtained not to diagnose DKD or DN but to exclude
other non-diabetic forms of kidney injury, if diabetic lesions are obtained, they should
be staged in both the glomerular and the vascular/tubulointerstitial compartments [26].
Due to the shared histology and pathophysiology the cause of the lesions observed in
 tissue injury, oxidative stress, inflammation, arterial hypertension, and end organ damage
of the heart, blood vessels, and the kidneys [41–43].
While kidney biopsies are typically obtained not to diagnose DKD or DN but to ex-
clude other non-diabetic forms of kidney injury, if diabetic lesions are obtained, they
J. Clin. Med. 2024, 13, 348 should be staged in both the glomerular and the vascular/tubulointerstitial compartments 4 of 20
[26]. Due to the shared histology and pathophysiology the cause of the lesions observed
in biopsies of patients with DM cannot be unequivocally assigned to the latter. For exam-
ple, renalofartery
biopsies stenosis
patients with and
DM secondary kidney ischemia
cannot be unequivocally [44] may
assigned tolead to intrarenal
the latter. arte-
For example,
rial hyalinosis [45]. While efferent arteriolar hyalinosis is typically associated
renal artery stenosis and secondary kidney ischemia [44] may lead to intrarenal arterial with a dia-
betic kidney lesion, afferent arteriolar hyalinosis may be observed in hypertensive
hyalinosis [45]. While efferent arteriolar hyalinosis is typically associated with a diabetic
nephropathy.
kidney lesion, Normoalbuminuric kidney disease
afferent arteriolar hyalinosis may be inobserved
the settinginofhypertensive
DM is becoming a more
nephropathy.
common clinical phenotype;
Normoalbuminuric it mayinbe
kidney disease theassociated
setting of with
DM isnon-glomerular
becoming a more lesions [46,47]
common or
clinical
the successful
phenotype; use of
it may beantiproteinuric
associated withtherapies such as inhibitors
non-glomerular of the
lesions [46,47] orrenin angiotensin
the successful use
system [4,48–50].
of antiproteinuric therapies such as inhibitors of the renin angiotensin system [4,48–50].

4. Diagnosis of CKD in
4. in Older
Older Patients
PatientswithwithDMDM
The diagnostic criteria
criteria for
for CKD
CKD do do not
notvary
varyby bychange,
change,i.e.,i.e.,either
eitheraadepressed
depressedeGFR eGFR
or an
or an elevated
elevated index of of protein
protein excretion
excretion inin the
the urine
urine(usually
(usuallymeasured
measuredasasthe theratio
ratioofof
urinary albumin
urinary albumin to urinary
urinary creatinine
creatinineon onaaspot
spoturine
urinespecimen)
specimen)asasaamarker markerofofkidney
kidney
damage should
damage shouldbe bedemonstrated
demonstrated forfor
thethe
diagnosis
diagnosis andand
staging of CKD.
staging In caring
of CKD. for indi-
In caring for
vidual patients, the potential for an age-related loss of kidney function
individual patients, the potential for an age-related loss of kidney function should also be should also be
considered as
considered asaapotential
potentialcause
causeofofa reduced
a reduced eGFR
eGFR value
value in in
thethe absence
absence of albuminuria.
of albuminuria. One
One cohort
cohort studystudy was conducted
was conducted in Canada
in Canada with awith a considerable
considerable representation
representation of indi-
of individuals
viduals
≥ 65 years >65oldyears
and old and compared
compared the implications
the implications of age-adapted
of age-adapted vs. fixed vs.eGFRfixed
on eGFR on
the 5-year
the 5-year
risk of renal risk of renal
failure andfailure
death.and Theydeath. They identified
identified a similaradifference
similar difference in theabsolute
in the 5-year 5-year
absolute
risk risk offailure
of kidney kidney failureamong
(0.12%) (0.12%)individuals
among individuals
65 years65 andyears
olderand older
who had who had anof
an eGFR
eGFR of
45–60 45–60 mL/min/1.73
mL/min/1.73 at baseline
at baseline and no and no detectable
detectable proteinuria
proteinuria compared
compared withwith non-
non-CKD
CKD patients [51]. Proposals for an age-adapted definition of CKD
patients [51]. Proposals for an age-adapted definition of CKD [52], by adopting a threshold [52], by adopting a
threshold of <45 2
mL/min/1.73 m 2 instead of <60 mL/min/1.73 2 m
of <45 mL/min/1.73 m instead of <60 mL/min/1.73 m , have been proposed (Figure 1), 2, have been proposed (Fig-

ure at
but 1),the
butpresent
at the time,
present
the time, the guidelines
guidelines endorse onlyendorse onlyage-independent
the fixed the fixed age-independent
threshold of
threshold
60 mL/min/1.73 m2 (Figure m
of 60 mL/min/1.73 1).2 (Figure 1).

Figure 1.
Figure 1. Age-adapted
Age-adapted definition
definitionof ofCKD
CKDbased
basedononeGFR
eGFRrisk
riskcategories
categoriesaccording
accordingtotopatient s age.
patient’s age.
Risk categories were defined in re-analyses of the CKD Prognosis Consortium data using
Risk categories were defined in re-analyses of the CKD Prognosis Consortium data using mortality mortality
as the outcome. These analyses suggest the need for a higher eGFR threshold for the diagnosis of
as the outcome. These analyses suggest the need for a higher eGFR threshold for the diagnosis of
CKD in younger individuals (<75 instead of <60 mL/min/1.73 m2)2and a lower eGFR value in older
CKD in younger individuals (<75 instead of <60 mL/min/1.73 m ) and a lower eGFR value in older
individuals [52,53]. Figure 1 summarizes these proposals using the color-coding system in the cur-
individuals
rent KDOQI[52,53]. Figure
guidelines. In1this
summarizes these
color-coding proposals
scheme, the using
lowestthe color-coding
category of risksystem in theby
is indicated current
the
KDOQI guidelines.
green color, and theIn this color-coding
highest scheme, the
risk with increasing lowest
shades category of risk is indicated by the green
of red.
color, and the highest risk with increasing shades of red.
Albuminuria is never a manifestation of “normal aging”, and its presence signifies
Albuminuria
an elevated risk foris never a manifestation
the progression of “normal
of CKD, aging”,
endothelial and its presence
dysfunction, need forsignifies
dialysis,an
elevated risk for the progression of CKD, endothelial dysfunction, need for dialysis, and
cardiovascular morbidity and mortality [54–56]. For the older individual with DM, who
is at risk for other forms of kidney disease (e.g., vasculitis), the initial diagnostic step is
to exclude a non-diabetic kidney lesion. In particular, if the diagnosis of CKD predates
the diagnosis of DM or occurs within a short period of time (5–10 years), then the risk for
another kidney disorder is particularly high [57].
The initial workup should not differ for older and younger patients and includes a
urinalysis, urine albumin to creatinine ratio (UACR), an eGFR, a complete blood count,
and a basic metabolic profile that incorporates measurements of sodium, potassium, bi-
J. Clin. Med. 2024, 13, 348 5 of 20

carbonate, calcium, and phosphorus [2,3]. Serological tests as per the guidance of the US
National Institute for Diabetes, Digestive and Kidney Diseases include tests for chronic
hepatitis B and C, antinuclear antibodies, rheumatoid factor, complement levels (C3/C4),
serum and urine protein electrophoresis, and a free light chain assay. A kidney ultrasound
is also part of the workup and can be used to diagnose bona fide urinary outflow ob-
struction (e.g., hydronephrosis) or subtler forms of bladder dysfunction (e.g., an elevated
postvoid residual urinary volume in the bladder). If a patient with DM has typical and
advanced retinopathy [58–61], albuminuria, and a negative serologic evaluation, most clini-
cians would not proceed to obtain a kidney biopsy. In the older patient, vascular disease
(e.g., due to atherosclerosis, hypertension, and RAS) [44,62] may also be present, and such
conditions may be used to diagnose the patient with cardiovascular disease and target
them for high-intensity therapy to reduce cardiovascular risk. At the time of this writing, a
precise histological diagnosis of DKD is not required to initiate therapies such as inhibitors
of the renin angiotensin system or sodium glucose co-transporter 2 inhibitors, whose spec-
trum of indications includes both diabetic and non-diabetic kidney lesions. However, a
missed glomerular diagnosis does not allow the initiation of specific therapy that may
preserve kidney function or prevent damage to other organs (e.g., due to vasculitis). Since
the histology cannot be predicted from clinical criteria [63] and a definitively higher risk of
bleeding is not seen in older adults [64–66], it may be reasonable to apply the same “atypical
feature” [67–70] criteria for pursuing a kidney biopsy as in the young (Table 2). Of note,
there is no specific eGFR cutoff for a kidney biopsy; rather, the procedure is pursued when
the patient is considered at risk for a non-diabetic kidney lesion (e.g., an active urinary
sediment with hematuria or casts) or when there is accelerated kidney functional decline,
which merits ruling out other diagnoses (such as rapidly progressing glomerulonephritis
or vasculitis).

Table 2. Features atypical of diabetic kidney disease: when to consider additional or alternative
pathology and biopsy.

Features Developing on Presentation

Features on Presentation
or Follow-Up
Absence of retinopathy Rapid decline in eGFR (>5 mL/min/1.73 m2 /year)
Albuminuria <5 years or >25 years ↓ eGFR by more than 30% after initiation
after the diagnosis of type 1 diabetes of an inhibitor of the renin angiotensin system
Active urine sediment or serologies Acute kidney injury (unexplained/sustained)
Sudden/acute worsening of albuminuria
Hematuria/nephritic syndrome
(unexplained/sustained)

5. Treatment Considerations
The general approach to treating CKD in DM in older adults is not different from the
one applied to younger individuals, although the elements should be highly individualized
to account for other medical problems and comorbidities with advancing age. When
approaching any patient with CKD, the overarching aim is to control the risks of both
cardiovascular disease and kidney disease progression as most patients are more likely to
experience a cardiovascular event than to need dialysis [71,72]. The components of this
approach include lifestyle changes (smoking cessation and a healthy lifestyle that includes
exercise preferably longer than 150 min weekly), a reduction in sodium intake (to less than
2 g every day) and avoiding extreme protein intakes (e.g., 0.8 gm/kg/d is a reasonable goal),
and active pharmaceutical interventions to control blood pressure, glycemia, atherosclerotic
cardiovascular risk, and specific antiproteinuric and antifibrotic therapies [2,3,72].
J. Clin. Med. 2024, 13, 348 6 of 20

5.1. Non-Pharmaceutical Interventions and Goals of Therapy

5.1.1. Exercise
An individualized, planned, and supervised combination of aerobic and resistance
training is considered the most effective way to control glycemia [73]. Contraindications
to exercise stem from specific comorbidities (e.g., proliferative retinopathy, aneurysms, or
severe autonomic insufficiency with propensity for hypoglycemia) and are often temporary
in nature (e.g., during an acute exacerbation of ischemia, heart failure, or hypertensive event
and periods of poor glycemic control with propensity to hypoglycemia) [74]. Tailoring the
prescription of exercise program to the functional capacity limitations of the individual can
be achieved through the Vivifrail multicomponent exercise program [75].

5.1.2. Dietary Considerations

Sodium restriction to less than 2 g a day improves hypertension and the efficacy of
antihypertensive medications. When the dietary intake of fresh vegetables is poor, increasing
levels of sodium intake have been associated with an increased incidence of diabetic retinal
disease [76]. A DASH diet can improve hypertension control but can lead to hyperkalemic
episodes in individuals with hyporeninemic hypoaldosteronism. Current American Diabetes
Association (ADA) guidelines suggest limiting protein intake to 0.8–1.0 g/kg/day in those
with DM and CKD. Nevertheless, studies on dietary protein restriction have failed to show a
clear benefit in reducing the progression of DKD [62,77,78]. One should be aware that this
target conflicts with that in the guideline for older adults that recommend a target protein
intake of 1–1.2 g/kg to prevent malnutrition and sarcopenia in old age [79]. The benefit
(progression of CKD) to risk (developing protein-energy wasting) should be carefully bal-
anced when prescribing low-protein diets in older adults with advanced CKD. This balanc-
ing act should consider the presence of pre-existing malnutrition, the rate of progression of
CKD, the CKD stage, and the presence of comorbidities/anticipated life expectancy, which
would shift the focus toward quality rather than quantity of life and dialysis avoidance. An
approach that attempts to reconcile guidelines and prioritize goals distinguishes between
“nutritional-geriatric” priorities (age is the dominant factor) vs. “renal” priority (when the
patient’s goal would be to avoid dialysis at any cost), emphasizing that these priorities may
shift during periods of critical illness [80]. Implementing nutritional therapies should be
performed in a stepwise manner: first, a nutritional assessment with a validated tool should
take place, and if the patient screens positive for protein-energy malnutrition, a formal
assessment with the Subjective Global Assessment (SGA) should be performed; second,
an ongoing evaluation of muscle mass and function during the implementation of dietary
restrictions to detect early development of sarcopenia and protein-energy malnutrition that
would limit the continuation of such diets should follow [80].

5.1.3. Blood Pressure, Lipid, and Glycemia Control in Older Adults with CKD in DM
The ADA standards of care in the DM [81] framework consider blood pressure,
glycemic control, and lipids together, and this integrative, comprehensive approach pro-
vides a solid base to approach the older individual with CKD in DM (Table 3). This
framework acknowledges that tight glycemic control comes with higher risks [82–86] in
such individuals due to a non-robust physiologic response to hypoglycemia and greater
hypoglycemia unawareness. That framework progressively de-escalates the aggressiveness
of goal-directed therapy as the number of pre-existing conditions (those severe enough to re-
quire medication or lifestyle management) advance to end-stage chronic illness. The blood
pressure targets that the ADA proposes differ from those in the KDIGO guidelines [87],
which are heavily influenced by the SPRINT trial [88]. However, even the KDIGO guide-
lines point out that the benefits of tight blood pressure control are less certain in those
with DM and advanced (stages 4 and 5) CKD and the very old (individuals older than
90). Hence, for older patients with DM and CKD who find themselves at the intersection
of these groups, shared decision making and individualized goal setting that minimizes
J. Clin. Med. 2024, 13, 348 7 of 20

the side effects of therapy and their effect on quality of life should take precedence over a
“one-size-fits-all” blood pressure target.

Table 3. Targets of anti-hypertensive, glycemic, and lipid therapy in the older patient with CKD
in diabetes.

Healthy Complex Very Complex

At least three coexisting chronic
Long-term care facility resident or
Few coexisting chronic illnesses or
end-stage chronic illnesses or
Patient characteristics illnesses and 2+ instrumental ADL
moderate-to-severe cognitive
Health status intact cognitive and impairments or
impairment or
functional status mild-to-moderate cognitive
2+ ADL impairments
impairment
Intermediate remaining life
expectancy, high treatment Limited remaining life expectancy
Rationale Longer remaining life expectancy
burden, hypoglycemia makes benefit uncertain
vulnerability, fall risk
Do not rely on HbA1C; glucose
<7.0–7.5% <8.0% control decisions should be based
HbA1c
(53–58 mmol/mol) (64 mmol/mol) on avoiding hypoglycemia and
symptomatic hyperglycemia.
80–130 mg/dL 90–150 mg/dL 100–180 mg/dL
Fasting/pre-prandial glucose
(4.4–7.2 mmol/L) (5.0–8.3 mmol/L) (5.6–10.0 mmol/L)
100–180 mg/dL 110–200 mg/dL
Bedtime glucose 80–180 mg/dL (4.4–10.0 mmol/L)
(5.6–10.0 mmol/L) (6.1–11.1 mmol/L)
Blood pressure <140/90 mmHg <140/90 mmHg <150/90 mmHg
Statin unless contraindicated Statin unless contraindicated Consider likelihood of benefit
Lipid target
or not tolerated or not tolerated with statin
Coexisting chronic illnesses: arthritis, cancer, heart failure, depression, emphysema, falls, hypertension, inconti-
nence, stage 3 or worse CKD, myocardial infarction, and stroke. End-stage chronic illness, such as stage 3–4 heart
failure or oxygen-dependent lung disease, dialysis-dependent ESKD, or uncontrolled metastatic malignancy.
ADL: activities of daily living. Definitions of older adults vary somewhat in the literature, and a clear distinction
between older adults ≥65 years of age as opposed to someone ≥90 years is often made. It may be prudent to
view individuals ≥90 years as more complex, even if they are otherwise healthy.

When statins are used for primary and secondary prevention, a benefit can be un-
equivocally expected for those individuals whose life expectancy exceeds the time frames
(2–6 years) of the clinical trials [89]. Equivalently, one may use the average time to benefit
for a therapy, which for statins was 2.5 years [90], and treat individuals whose expected
survival exceeds this time frame. Many advanced age individuals with CKD stage 3a–5
would benefit according to this criterion, and this is the reason the KDIGO clinical prac-
tice guidelines [91] recommend the use of a statin or a statin/ezetimibe in patients older
than 50 years old. These recommendations are largely based on the SHARP trial [92] that
randomized participants with CKD (mean eGFR of 27 mL/min/1.73 m2 , N = 9270) to
receive simvastatin 20 mg plus ezetimibe 10 mg daily or a placebo. Statin plus ezetimibe
therapy reduced the primary outcome of major atherosclerotic event (coronary death, my-
ocardial infarction, need for revascularization, or non-hemorrhagic stroke) by 17% (95% CI:
0.06–0.26) but without delaying dialysis.

5.2. Pharmaceutical Interventions to Reduce Cardiorenal Risk in Older Patients with CKD in DM
At the present time, multiple agents have established a track record in reducing the
adverse cardiovascular and renal effects of chronic kidney disease in DM/DKD. These
agents target various structural elements in the kidney (Figure 2) while also having sys-
temic sites of actions (e.g., inhibitors of the renin angiotensin system and mineralocor-
ticoid antagonists also target the heart and the blood vessels, while the actions of the
glucagon like peptides appear to be multisystemic and likely include both kidney and
vascular targets).
 adverse cardiovascular and renal effects of chronic kidney disease in DM/DKD. These
agents target various structural elements in the kidney (Figure 2) while also having sys-
temic sites of actions (e.g., inhibitors of the renin angiotensin system and mineralocorti-
coid antagonists also target the heart and the blood vessels, while the actions of the glu-
cagon like peptides appear to be multisystemic and likely include both kidney and vascu-
J. Clin. Med. 2024, 13, 348 lar targets). 8 of 20

Mechanismsofofaction
Figure2.2.Mechanisms
Figure actionofofkey
keypharmacologic
pharmacologicinterventions
interventionsforforCKDCKD in
in DM.
DM. Figure
Figure created
created by
Biorender. RASi: Renin Angiotensin System inhibitors (Section 5.2.1) Examples of
by Biorender. RASi: Renin Angiotensin System inhibitors (Section 5.2.1) Examples of commerciallycommercially avail-
able agents
available andand
agents brand names
brand namesin these classes
in these include
classes GLP1-RAs
include GLP1-RAs (dulaglutide
(dulaglutide(Trulicity), liraglutide
(Trulicity), lirag-
lutide (Victoza/Saxenda),
(Victoza/Saxenda), and semaglutide
and semaglutide (Ozempic/Rybelsus/Wegony)),
(Ozempic/Rybelsus/Wegony)), GLP1-RAs
GLP1-RAs /GIPRA/GIPRA (tir-
(tirzepatide
zepatide (Zepbound/Mounjaro),
(Zepbound/Mounjaro), discussed discussed
at Sectionat 5.2.4,
Section 5.2.4, mineralocorticoid
mineralocorticoid receptor antagonists
receptor antagonists (finerenone
(finerenone
(Kerendia))(Kerendia))
discussed discussed
at Section at Section
5.2.3, 5.2.3,
SGLT2i SGLT2i (bexagliflozin
(bexagliflozin (Brenzavvy)),(Brenzavvy)), canagliflozin
canagliflozin (Invokana),
(Invokana),
dapagliflozin (Farxiga/Forgixa), empagliflozin (Jardiance), and ertugliflozin (Steglatro)(Steglatro)
dapagliflozin (Farxiga/Forgixa), empagliflozin (Jardiance), and ertugliflozin discussed at
discussed at Section 5.2.2.
Section 5.2.2.

5.2.1. Inhibitors of the Renin Angiotensin System

Inhibitors of the renin angiotensin system (RASi) were established in the treatment of
DKD by the pivotal trials IDNT [93] and RENAAL [94]. IDNT and RENAAL established
that the benefits of RASi are maximized when the dose is maximized and identified residual
albuminuria as a marker of increased cardiovascular and kidney disease risk [95,96] and a
criterion for adding additional agents and/or enrolling patients in trials of investigational
agents to retard the progression of kidney disease. In a recent analysis these agents were
underutilized: 17% of patients with DM initiated these agents [97] within 12 months of
diagnosis of CKD [98]; eventually, these agents are only used in ~60% of eligible patients
but without any racial disparities in utilization [99]. The British Clinical Diabetologists
and the UK Renal Association guidelines about the management of ACEi and ARBs in
patients with DM and CKD [100], which do not explicitly apply to older individuals, are
summarized below:
1. Kidney function and potassium levels should be checked within 7 to 10 days
after initiation.
2. Up to 30% of eGFR decline may be tolerated.
J. Clin. Med. 2024, 13, 348 9 of 20

3. Drops in kidney function of more than 30% should prompt investigation for RAS,
sepsis, volume depletion, or concomitant medications, e.g., NSAIDs.
4. If an alternative explanation for a marked decline in renal function cannot be inferred,
the dose of the RASi may be reduced.
5. Potassium binders (Patiromer and sodium zirconium cyclosilicate) may be used
to reduce the serum potassium if it rises over 5 mEq/L and allow the RASi to
be continued.
6. Combination therapy with ACEi, direct renin inhibitor, and ARBs should not be used,
since multiple clinical trials have shown greater risks of hypotension, hyperkalemia,
and acute renal injury with these combinations [101].
7. In advanced (stage 4 and 5) CKD, discontinuation [102] of the RASi was associated
with a lower risk for hyperkalemia (HR, 0.65; 95% CI, 0.54–0.79) but a higher risk of
death (HR, 1.39, 95% CI 1.20–1.60) and a higher risk of progression to ESKD (HR 1.19,
95% CI: 0.86–1.65). The STOP-ACEi [103,104] RCT examined the benefits vs. harm of
stopping the RASi in patients with advanced CKD (eGFR was ~18 mL/min/1.73 m2 at
baseline). There was no difference in the eGFR (primary outcome) at 3 years between
participants older than 65 years (−0.32, 95% CI −2.72–2.09 mL/min/1.73 m2 ) and
those younger than 65 years (−0.32, 95%CI −2.92–2.28 mL/min/1.73 m2 ). ESKD
occurred in 128 patients (62%) among those who discontinued the RASi and in
115 patients (56%) who continued them (HR, 1.28; 95% CI, 0.99 to 1.65). There were
similar numbers of cardiovascular events (108 vs. 88) and deaths (20 vs. 22) in the
two arms.
As noted above, RASi offer significant benefits to patients with DM and CKD; how-
ever, caution needs to be exercised with declining renal function particularly to avoid
severe hyperkalemia. Overall, RASi remain one of the primary interventions in diabetic
nephropathy to prevent the progression of CKD. An approximate 5-year risk reduction
for ESKD of 30% with use of RASi is a useful rule of thumb, although specific benefits in
patient subsets may vary [105].

5.2.2. Sodium Glucose Co-Transporter 2 Inhibitors

SGLT2is are small molecules that act on the luminal side in the proximal tubule of the
kidney and inhibit the SGLT2 transporter. In meta-analyses of treatment naïve patients and
patients treated with metformin, SGLT2is reduced HbA1c by −0.81 to −1.02% and by −0.57
to −0.63%, respectively [106]. The glucosuric effect of this category of antidiabetic agents
depends on the total eGFR, and they become less efficacious in reducing HbA1c when
eGFR drops below 60 mL/min/1.73 m [107,108]. Nevertheless, according to Brenner’s
hypothesis, hyperfiltering nephrons exist at all levels of kidney dysfunction, and SGLT2is
continue to alleviate kidney hyperfiltration in diabetic patients with low GFRs.
The cardiovascular safety trials for empagliflozin (EMPA-REG OUTCOME) [109,110],
canagliflozin (integrated CANVAS program consisting of two clinical trials, CANVAS and
CANVAR-R) [111–113], dapagliflozin (DECLARE-TIMI-58), and ertugliflozin (VERTIS-
CV) [107,111] hinted at the combined cardiorenal benefit of SGLT2i. In these, SGLT2i
reduced major adverse cardiovascular events (MACEs: cardiovascular death, non-fatal
myocardial infarction, or stroke) in the case of the empagliflozin, and canagliflozin trials
were non-inferior in the dapagliflozin and ertugliflozin trials. All drugs reduced heart
failure hospitalizations in these trials. When the composite kidney-specific outcome of
progression to dialysis dependency/need for kidney transplantation and declines in eGFR
was harmonized across the four trials [107], SGLT2is were associated with renal benefits.
Heart-failure-specific trials have included patients with reduced (dapagliflozin, DAPA-
HF [114], and empaglifozin EMPEROR-REDUCED [115]) and preserved (dapagliflozin,
DELIVER [116], and empagliflozin EMPEROR-PRESERVED [117]) ejection fractions. Trials
with primary kidney-specific outcomes include the CREDENCE trial (canagliflozin) [118]
in DKD, DAPA-CKD (dapagliflozin) [119], and EMPA-KIDNEY (empagliflozin) [120]. The
latter two trials included patients with both diabetic and non-diabetic forms of CKD. All
J. Clin. Med. 2024, 13, 348 10 of 20

SGLT2i kidney outcome trials included patients who manifested residual, moderate to
severe albuminuria while on the standard of therapy for kidney disease, i.e., a maximum
tolerated dose of an ACEi or an ARB. Across all trials, the SGLT2i were associated with
biphasic effects on the eGFR, with an acute dip of between 2 and 5 mL/min/1.73 m2 during
the first month [121–123] followed by stabilization thereafter, while the participants in the
placebo group experienced a faster decline in kidney function.
A previous random effect meta-analysis that modeled heterogeneity in these trials [124]
by one of the authors has demonstrated that the beneficial effects of SGLT2i are a class
effect. Other meta-analyses have shown that the benefits of these drugs do not vary by
participant age [125,126]. In Figure 3 we summarize the age by subgroup results in the
cardiovascular, heart failure, and kidney outcomes in the SGLT2i trials to date. Taken as
a class, the interactions with age are not statistically significant (p = 0.294, Wald p-value),
i.e., the benefits of the SGLT2i do not vary by age. Furthermore, there was no evidence
of heterogeneity by drug type (p = 0.62, ANOVA test comparing a model adjusting for
drug, outcome, age group vs. model adjusting for outcome, age group). SGLT2is are in
general safe drugs, but reported side effects such as diabetic ketoacidosis and lower limb
amputations appear to be barriers in prescribing them. A meta-analysis [127] has quantified
the risks and benefits of SGLT2i in patients with and without DM: the number needed to
treat to prevent one death (120) or one kidney disease progression event (48) dominated the
number needed to harm for the development of one lower limb amputation (309) or diabetic
ketoacidosis event (636). For most patients, SGLT2i would accrue a 3- to 10-fold larger
benefit than risk depending on the specific pair of outcomes considered [127]. Of
J. Clin. Med. 2024, 13, x FOR PEER REVIEW 11 note,
of 21
acute kidney injury (AKI) is reduced by 23% (RR 0.77, 95% CI 0.70–0.84) under an SGLT2i.
A framework for managing the risks of the SGLT2i was put forward in a roundtable
discussion involving representatives from cardiology, endocrinology, and nephrology
(Table 4).

Figure 3. SGLT2i and clinical outcomes in older vs. younger individuals (hazard ratio and 95%
Figure 3. SGLT2i and clinical outcomes in older vs. younger individuals (hazard ratio and 95% con-
confidence intervals). CRC: cardiorenal composite (CREDENCE: death from renal or cardiovascular
fidence intervals). CRC: cardiorenal composite (CREDENCE: death from renal or cardiovascular2
causes, doubling of serum creatinine, or kidney failure defined as eGFR < 15 mL/min/1.73 m ,
causes, doubling of serum creatinine, or kidney failure defined as eGFR < 15 mL/min/1.73 m2, need
need for dialysis
for dialysis or transplant,
or transplant, DAPA-CKD:
DAPA-CKD: death death from or
from renal renal or cardiovascular
cardiovascular causes,causes,
declinedecline
of >50%of
>50%
of the of the from
eGFR eGFRbaseline
from baseline and failure,
and kidney kidney defined
failure, as
defined as dialysis,
need for need fortransplant,
dialysis, transplant,
or sustainedor
sustained eGFR
eGFR to less thanto15
less than 15 mL/min/1.73
mL/min/1.73 m2 , EMPA-KIDNEY:
m2, EMPA-KIDNEY: death from cardiovascular
death from cardiovascular cases
cases or progres-
sion
or of kidney of
progression disease
kidney defined
diseaseasdefined
ESKD, assustained decrease decrease
ESKD, sustained in eGFR <10 mL/min/1.73
in eGFR m2 ,
m2, decrease
<10 mL/min/1.73
of eGFR >40%
decrease from
of eGFR baseline,
>40% death from
from baseline, kidney
death fromrenal
kidneycauses),
renal HHF: hospitalization
causes), for heartfor
HHF: hospitalization failure,
heart
MACE: major adverse cardiovascular events (composite of cardiovascular death, non-fatal
failure, MACE: major adverse cardiovascular events (composite of cardiovascular death, non-fatal myocar-
dial infarction, or stroke). Diamonds show predictions for a random effects model adjusting for
myocardial infarction, or stroke). Diamonds show predictions for a random effects model adjusting
drug, outcome, and age subgroup, and whiskers and boxes show the observed hazard ratios and
for drug, outcome, and age subgroup, and whiskers and boxes show the observed hazard ratios and
95% confidence intervals in the source trial data.
95% confidence intervals in the source trial data.
Table 4. Adverse events associated with SGLT-2i and proposed preventative measures.

Adverse Events At Risk Preventive Measures

Adequate perineal hygiene
Optimal diabetes care
J. Clin. Med. 2024, 13, 348 11 of 20

Table 4. Adverse events associated with SGLT-2i and proposed preventative measures.

Adverse Events At Risk Preventive Measures

Adequate perineal hygiene
Optimal diabetes care
Women,
Genitourinary infections Antifungals
uncircumcised men
Avoid SGLT-2is in patients with history of severe,
recurrent infections
Maintain insulin; ≤20% reduction in insulin dosage
if necessary
Discontinue SGLT-2i temporarily in acute illness
Insulin deficiency, ketogenic diet, alcohol
Diabetic ketoacidosis or surgery
abuse, acute illness, surgery
Avoid SGLT-2is in patients with history of DKA
Discontinue SGLT-2i if patient is not eating or has
vomiting and/or diarrhea
Reassess SGLT-2i regimen
Frequently assess renal function, especially in
Acute kidney injury eGFR dip ≥30%, volume depletion
patients with baseline eGFR <60 mL/min/1.73 m2
Discontinue SGLT-2i temporarily in acute illness
eGFR <60 mL/min/1.73 m2 , old age, Reduce diuretic or hypotension-inducing agent use
Volume depletion concomitant diuretic, prior volume Inform patients to maintain adequate oral hydration
depletion, hypotension, SBP <110 mm Hg Discontinue SGLT-2i temporarily in AKI
Reduce insulin ≤20% or SU ≤50% if
HbA1c <7.0%–8.0%
Hypoglycemia Concomitant insulin or SU, old age Discontinue SU if HbA1c <8.0% in older patients
Gradually reduce SU if HbA1c <8.0% in
younger patients
Monitor at-risk patients for new pain, skin
History of amputation, peripheral
Amputation ulcerations, or infections
vascular disease, neuropathy, foot ulcers
Inform patients about proper foot care
Hyperkalemia No concern
The data in this table were adapted from Figure 3 from [128] under the Creative Commons Attribution
(CC BY) license.

5.2.3. Mineralocorticoid Antagonists

The use of mineralocorticoid receptor antagonists (MRAs) in CKD with DM is predi-
cated on their anti-inflammatory and anti-fibrotic effects on the heart, blood vessels, and
kidneys. The benefits of steroidal MRAs (e.g., eplerenone and spironolactone) were sum-
marized by the Cochrane group [129] and included reductions in systolic blood pressure
by ~5 mmHg (95% CI −8.22 to −1.75 mmHg) and protein excretion by ~0.5 g per day
(95% CI −0.2 to −0.82 g/day) but had uncertain effects on kidney failure, cardiovascular,
and total mortality. In this meta-analysis of mostly spironolactone studies, the risks for
gynecomastia and hyperkalemia were increased with the use of spironolactone.
Non-steroidal MRAs such as finerenone, esaxerenone, and apararenone offer a balanced
antagonism in the kidney and the heart, thus reducing the risk of hyperkalemia [43,130].
Phase 2 clinical trials with esaxerenone [131] and apararenone [132] in DKD show that these
agents may reduce proteinuria by 40–60% when added on RASi. At the time of this writing the
only commercially available non-steroidal MRA for CKD in DM is finerenone. The approval
of finerenone was based on two large randomized controlled trials, FIDELIO-DKD [133]
and FIGARO-DKD [134], and a pre-specified patient-level meta-analysis of these two trials
(FIDELITY) [135], which provided the data for the effects of this drug on cardiovascular and
kidney-specific outcomes. Both these studies followed a similar design, i.e., they enrolled
patients with CKD in type II DM who had some degree of residual albuminuria despite
being on a maximum tolerated dose of RASi. FIGARO-DKD recruited patients with better
preserved kidney function (UACR > 300 mg/g with eGFR > 60 mL/min/1.73 m2 or UACR
in 30–300 mg/g and eGFR in 25–90 mL/min/1.73 m2 ), while FIDELIO-DKD recruited
patients with more advanced CKD (UACR > 300 mg/g and eGFR 25–75 mL/min/1.73 m2
or UACR in 30–300 mg/g and eGFR 25–60 mL/min/1.73 m2 ). The primary outcome of
J. Clin. Med. 2024, 13, 348 12 of 20

FIDELIO-DKD was a composite of kidney failure (need of dialysis and transplant) and a
sustained decrease in the eGFR by 40% relative to the baseline and death from renal causes.
The primary outcome for FIGARO-DKD was a composite of cardiovascular death, non-fatal
myocardial infarction and stroke, and hospitalization for heart failure (MACE/HHF). The
primary outcome of FIGARO-DKD was a secondary outcome of FIDELIO-DKD and vice
versa, enabling the joint examination of the effects of finerenone on the cardiorenal risk in
patients with DKD in FIDELITY. Finerenone was equally effective in younger (<65 years
old) and older (≥65 years old) patients (Table 5). None of the differences were statistically
significant at the 0.05 level.

Table 5. Finerenone and clinical outcomes in older vs. younger individuals (hazard ratio and 95%
confidence intervals).

Effect in Younger Effect in Older

Clinical Trial Outcome
Patients Patients
0.90 0.85
FIGARO-DKD MACE/HHF 2
0.74–1.10 0.72–1.00
0.72 0.92
FIGARO-DKD 1 CR 3
0.52–0.99 0.61-1.38
0.85 0.79
FIDELIO-DKD CR
0.72–1.01 0.67–0.94
1 The subgroup analysis was presented in a follow-up publication [136] and used a sustained reduction of
eGFR > 57%, rather than the 40% used in the primary analysis of the FIGARO-DKD study. 2 HHF: hospitalization
for heart failure, MACE: major adverse cardiovascular events (composite of cardiovascular death, non-fatal
myocardial infarction, or stroke). 3 CR: composite renal outcome.

5.2.4. GLP1 and Dual GLP1/GIP1 Receptor Agonists

GLP1 and the dual receptor agonists of the GLP1/GIP receptors are a class of
antiglycemic agents with broad cardiometabolic effects and emerging kidney and car-
diovascular benefits. These drugs activate the receptors of the endogenous incretins,
glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide (GIP). Simi-
lar to SGLT2is, GLP1-RAs were initially introduced to reduce glycemia with a minimal
risk for hypoglycemia, while also reducing weight. Specific GLP1-RAs (liraglutide and
semaglutide) have been approved as anti-obesity medications even in patients without
DM. Dual agonists are associated with more pronounced weight loss [137] and an en-
hanced antiglycemic effect relative to insulin or pure GLP1-RAs in the SURPASS clinical
trial [138–141]. Triple antagonists (GLP1/GIP1 and glucagon receptor antagonists) are
also entering the therapeutic arena [142], but the dedicated cardiovascular and kidney
benefit trials have not been reported yet, and the agents are not available yet for clinical
use. Certain GLP1 classes (dulaglutide, liraglutide, and semaglutide) have been shown
to reduce cardiovascular disease and thus are indicated in the ADA standards of care
for DM [143] for the management of patients with atherosclerotic cardiovascular disease
(ASCVD) or with high-risk indicators of ASCVD. In a recent meta-analysis [126], GLP1-RAs
in adults older than 65 years old were associated with a 15.3% (OR 0.85, 95% CI 0.79 to
0.91) reduction in MACE events, similar to the 16% (OR 0.84, 95% CI 0.70 to 1.01) benefit
seen in younger adults. Hence, GLP1-RAs are equally beneficial in older and younger
adults with type II DM for the management of their cardiovascular disease. To date, the
clinical benefits of GLP1-RAs and GLP1/GIP RA on kidney outcomes have been limited to
surrogate markers of kidney function loss (eGFR slope) and markers of kidney damage
(UACR) often examined as explorations of kidney-specific outcomes [144–147] in their
cardiovascular safety and primary efficacy trials. A recent meta-analysis [148] examined
the effects of GLP1-RAs on cardiovascular (MACE) and two kidney outcomes: a kidney
composite consisting of development of macroalbuminuria, doubling of serum creatinine
or at least a 40% decline in eGFR, kidney replacement therapy, or death due to kidney
disease, and worsening of kidney function, defined as either doubling of serum creatinine
or at least a 40% decline in eGFR. GLP1-RAs reduced MACE by 14% (HR 0.86, 95% CI
J. Clin. Med. 2024, 13, 348 13 of 20

0.80–0.93, p < 0.0001), with no evidence of interaction by age (p = 0.78 comparing effects
in individuals younger than 65 vs. those older than 65). Age-stratified kidney outcomes
were unavailable in this paper; however, overall, GLP1-RAs were associated with a favor-
able effect on the composite kidney outcome (21%reduction (HR 0.79 [95% CI 0.73–0.87];
p < 0.0001)), with a favorable trend for the worsening kidney function outcome (14% reduc-
tion (HR 0.86 [95% CI 0.72–1.02])). In REWIND [144], one of the few GLP1-RAs trials to
report a kidney-specific outcome by age, individuals older than 66 years had an HR of 0.79
(95% CI 0.69–0.90) that was not statistically different (p-value for the interaction 0.17) from
that of individuals younger than 66 (HR: 0.90, 95% CI: 0.79–1.02). The kidney outcome in
REWIND was a composite of the development of incident macroalbuminuria (300 mg/gm
of creatinine) and a sustained (>30% in two consecutive measurements) decrease in eGFR
from the baseline or new kidney replacement therapy, i.e., a broad outcome that consid-
ered both the development of worsening kidney damage (UACR elevation) and function
(decreased eGFR/need for dialysis), as in the SGLT2i and MRA trials. In SURPASS-4 [145],
the placebo-corrected difference in the eGFR slope did not differ in older (≥65 years old)
and younger individuals: 2.4 (1.5–3.3) vs. 2.1 (95% CI 1.2–2.9) ml/min/1.73 m2 /year,
p for interaction = 0.67. Additionally, the least squares change from the baseline over the
placebo was −38.5% (95% CI: −43.6% to −26.2%) vs. −28.5% (95% CI: −36.4% to −19.7%),
p for interaction = 0.80. Hence, similarly to SGLT2i and non-steroidal MRA, the beneficial
effects of GLP1 and GLP1/GIP receptor agonists are observed across the adult age span.
Tirzepatide (GLP1/GIPRA) and Retartrutide (GLP1/GIP/GlucagonRA) are examined in
ongoing trials to assess their impacts on renal function in overweight patients with and
without DM (NCT05936151 and NCT05536804).

6. Conclusions
CKD in older patients with DM is associated with both cardiovascular risks and
kidney progression risks. The pathophysiology is complex, and the spectrum of CKD is
not limited to typical DN but may also include additional vascular insults superimposed
on a senescence molecular phenotype. Care of the older patient with CKD in DM requires
a multidisciplinary, holistic approach that considers cardiovascular risk, comorbidities,
and life expectancy in addition to the risk of kidney disease progression. The effects of
emerging standard of care pharmaceutical interventions (e.g., SLGT2 inhibitors, MRAs,
and GLP1-RAs /dual GLP1/GIP RA antagonists) to reduce the risk of cardiovascular and
kidney risk are observed in both younger and older individuals. Hence, there should be no
age discrimination in prescribing these newer agents for older individuals as the trials to
date suggest that older individuals will derive benefit from such therapies. Finally, meta-
analyses [149,150] and actuarial re-analyses of outcomes trial data [151] suggest that the
combination of SGLT2i/ GLP1-RAs and SGLT2i/MRA/ GLP1-RAs will be associated with
improved glucometabolic control and cardiovascular/dialysis-free and overall survival.
Considering the high risk for cardiovascular death and the detrimental effects of dialysis
upon the quality and quantity of life among older adults, strong consideration should be
given to combination therapies with these classes of agents.

Author Contributions: Conceptualization, C.A. and M.-E.R.; writing—original draft preparation,

C.A. and M.-E.R.; writing—review and editing, R.R., M.L.U., D.W.S., C.A. and M.-E.R.; visualization,
C.A.; project administration, C.A. All authors have read and agreed to the published version of
the manuscript.
Funding: This research received no external funding.
Data Availability Statement: Data are contained within the article.
Conflicts of Interest: C.A. has received consultant fees from Bayer (manufacturer of finerenone
Hanover, NJ, USA).
J. Clin. Med. 2024, 13, 348 14 of 20

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