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Combination therapy for kidney

disease in people with diabetes
mellitus
Daniël H. van Raalte1,2,3 , Petter Bjornstad4, David Z. I. Cherney 5, Ian H. de Boer6, Paola Fioretto 7, Daniel Gordin8,9,10,
Frederik Persson 11, Sylvia E. Rosas 10, Peter Rossing 11, Jennifer A. Schaub 12, Katherine Tuttle 13,14,15,
Sushrut S. Waikar 16 & Hiddo J. L. Heerspink 17,18
Abstract Sections

Diabetic kidney disease (DKD), defined as co-existing diabetes and Introduction

chronic kidney disease in the absence of other clear causes of kidney Epidemiology of DKD
injury, occurs in approximately 20–40% of patients with diabetes Multifactorial pathophysiology
mellitus. As the global prevalence of diabetes has increased, DKD of DKD
has become highly prevalent and a leading cause of kidney failure, Kidney-protective therapies
accelerated cardiovascular disease, premature mortality and global Non-pharmacological
health care expenditure. Multiple pathophysiological mechanisms approaches to DKD
contribute to DKD, and single lifestyle or pharmacological interventions Combination therapies
have shown limited efficacy at preserving kidney function. For nearly
Clinical guidelines
two decades, renin–angiotensin system inhibitors were the only
Personalized medicine for DKD
available kidney-protective drugs. However, several new drug classes,
including sodium glucose cotransporter-2 inhibitors, a non-steroidal Conclusions and future
perspectives
mineralocorticoid antagonist and a selective endothelin receptor
antagonist, have now been demonstrated to improve kidney outcomes
in people with type 2 diabetes mellitus. In addition, emerging preclinical
and clinical evidence of the kidney-protective effects of glucagon-like-
peptide-1 receptor agonists has led to the prospective testing of these
agents for DKD. Research and clinical efforts are geared towards using
therapies with potentially complementary efficacy in combination
to safely halt kidney disease progression. As more kidney-protective
drugs become available, the outlook for people living with DKD should
improve in the next few decades.

A full list of affiliations appears at the end of the paper. e-mail: d.vanraalte@amsterdamumc.nl

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Key points
•• Diabetic kidney disease (DKD) is associated with substantial
morbidity and cardiovascular mortality, and for nearly two decades,
the only kidney-protective treatment for DKD was renin–angiotensin
system blockade.
•• Positive kidney outcome data have now been reported for SGLT2
inhibitors, the mineralocorticoid antagonist finerenone and endothelin
receptor antagonists.
•• GLP1 receptor agonists have been shown to have beneficial effects
on surrogate kidney end points, and a kidney outcomes trial is
underway.
•• The advent of novel kidney-protective drugs provides new
therapeutic options for people living with diabetes and kidney disease
but increases the complexity of treatment decisions for caregivers.
•• Combining drugs may enhance their kidney protective efficacy and
could potentially reduce the risk of adverse effects that are associated
with specific drug classes.
•• An important goal for the future pharmacological management
of DKD is to individualize treatment with optimal drug combinations
based on the underlying pathophysiology and guided by tissue or
serum biomarkers.
Introduction
The prevalence of chronic kidney disease (CKD) that can be attrib-
uted to diabetes mellitus, termed diabetic kidney disease (DKD), has
increased dramatically in parallel with an increase in the global preva-
lence of type 2 diabetes mellitus (T2DM) in the past 4 decades1–4. In
addition to hyperglycaemia, comorbid conditions such as obesity,
hypertension, atherosclerosis, dyslipidaemia and insulin resistance
contribute to kidney damage, making DKD a heterogeneous disorder.
Yearly screening by measuring serum creatinine concentrations and
urinary albumin excretion is recommended for all patients with T2DM
to facilitate diagnosis of DKD in the early stages and enable initiation
of appropriate therapies. Strict control of glycaemia reduces the risk of
developing DKD5, and blood pressure control attenuates progression
of DKD6. For the past 30 years, blockers of the renin–angiotensin sys-
tem (RAS) have been the cornerstone of therapy for DKD7–9. However,
residual risk of kidney failure remains high in patients treated with RAS
inhibitors, indicating a large unmet medical need.
In the past 20 years, several approaches that were developed to
reduce the DKD burden were unsuccessful. For example, dual RAS block-
ade using combination treatment with an angiotensin converter enzyme
(ACE) inhibitor and an angiotensin receptor blocker (ARB) (VA-nephron
trial)10 and direct renin inhibition using aliskiren in combination with ACE
inhibitor or ARB therapy (ALTITUDE trial)11 did not improve kidney out-
comes and were associated with adverse events such as hyperkalaemia
and acute kidney injury (AKI). Similarly, treatment with the endothelin
receptor antagonist avosentan (ASCEND trial)12 or bardoxolone methyl,
which reduces tissue oxidative stress (BEACON trial)13, did not reduce
the incidence of kidney failure, and both drugs were associated with an
increased incidence of congestive heart failure. Finally, treatment with
Nature Reviews Nephrology
sulodexide, which is a mixture of glycosaminoglycan polysaccharide
components of the endothelial glycocalyx (Sun-MACRO trial)14, did not
slow kidney function decline in people with DKD.
The results of large placebo-controlled trials of novel drug classes
ended this period of failure. Improved kidney outcomes in patients with
CKD with and without diabetes have been demonstrated with sodium
glucose cotransporter-2 (SGLT2) inhibitors (CREDENCE (canagliflozin),
DAPA-CKD (dapagliflozin) and EMPA-KIDNEY (empagliflozin) trials)15–17,
the non-steroidal mineralocorticoid antagonist (MRA) finerenone
(FIDELIO-DKD trial)18 and the selective endothelin receptor antagonist
(ERA) atrasentan (SONAR trial)19. Although these findings were met
with great enthusiasm, the number of kidney events observed during
treatment with these novel drugs remains high. Given the multifactorial
causes of DKD, the heterogeneity of the observed histological lesions
and the differing mechanisms of action of the novel pharmacological
agents, combination therapies could offer additional benefits.
In this Review, we examine the evidence for the efficacy and safety
of combination treatment to reduce DKD progression, based on mecha-
nistic and clinical outcome data in people with T2DM, and highlight
ongoing trials that are employing combination therapies. We also
extend these data to other causes of CKD and discuss considerations
for people with type 1 diabetes mellitus (T1DM). Finally, we discuss
current guidelines for the management of CKD and DKD and suggest
that a personalized medicine approach may help to select the right
drugs for the right patient at the right time.
Epidemiology of DKD
The International Diabetes Federation estimates that 537 million adults
worldwide had diabetes in 2021 and that this figure will increase to
784 million by 2045 (ref. 20). This epidemic is largely attributable
to an increased prevalence of T2DM, driven by increasingly sedentary
lifestyles and obesity, as well as an increased incidence of T1DM21. CKD,
defined as a persistently reduced estimated glomerular filtration rate
(eGFR) and/or albuminuria, affects about 30–40% of people with diabe-
tes over their lifetimes1–4. Globally, approximately 850 million people
were estimated to have CKD in 2017, including 3.9 million people who
received dialysis or kidney transplantation owing to kidney failure, for
which the leading cause is diabetes22.
Increased awareness of the public health impact of diabetes has led
to improved diabetes case-finding in clinical practice as well as mod-
est improvements in the control of glycaemia and other intermediate
targets related to diabetes complications, such as blood pressure and
lipids3. Nonetheless, the prevalence of CKD among people with dia-
betes has remained stable1,3, and temporal trends in the incidence of
kidney failure have been variably reported as decreasing, increasing or
unchanged23–27. As the population prevalence of diabetes has increased
in the past 30 years, the absolute prevalence of CKD and incidence of
kidney failure attributable to diabetes have also increased3,28. Moreo-
ver, CKD is associated with markedly increased risks of other diabetes
complications, such as heart failure and atherosclerotic cardiovascular
disease (CVD)29,30. Among people with diabetes, CKD is associated with a
loss of life expectancy of approximately 5 years27, and kidney failure with
a loss of life expectancy of 9–31 years, depending on age at diagnosis31.
Together, these data highlight an urgent need for new approaches to
preventing and treating CKD among people with diabetes.
Multifactorial pathophysiology of DKD
The pathophysiology of DKD is complex, particularly in people with
T2DM (Fig. 1). In T1DM, diabetic glomerulopathy, with the typical
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constellation of thickening of the glomerular basement membrane,
mesangial expansion, mesangial nodule formation, and afferent
and efferent glomerular arteriolar hyalinosis, is the predominant
hyperglycaemia-induced kidney lesion. By contrast, the lesions that
underlie kidney dysfunction in T2DM are much more diverse32,33. Kid-
ney biopsy studies have demonstrated that only 30–50% of patients
with T2DM and DKD have classic diabetic glomerulopathy and many
individuals have ‘atypical patterns of diabetic kidney lesions’, char-
acterized by severe tubulointerstitial and/or arteriolar and vascular
abnormalities in the presence of mild or absent glomerular lesions33.
IgA nephropathy was a common finding in individuals whose histo-
logical features were not consistent with diabetic nephropathy. These
additional pathological changes, isolated or superimposed on classic
diabetic glomerulopathy lesions, may be driven by comorbid condi-
tions that are present in many people with T2DM, including ageing,
obesity, hypertension, dyslipidaemia, atherosclerosis and insulin resist-
ance, all of which have been linked to DKD progression34. Changes in
glomerular haemodynamic function (characterized by whole-kidney
or single nephron hyperfiltration) and activation of pro-inflammatory
and pro-fibrotic factors also have important roles in inducing kidney
damage, and proteinuria may further drive kidney fibrosis in people
with DKD. This heterogeneity in kidney insults underlies the differ-
ing clinical phenotypes of DKD, with approximately 30% of patients
presenting without albuminuria35.
The heterogeneity of DKD has potentially important prog-
nostic consequences. In the early stages of DKD, GFR loss was
more strongly associated with diabetic glomerulopathy than with
tubulointerstitial lesions36. We hypothesize that patients with clas-
sic glomerular lesions are more likely to benefit from agents that
affect renal haemodynamic function, whereas those with more
advanced tubule-interstitial lesions are more likely to benefit from
anti-inflammatory and antifibrotic agents. Reversal of diabetic kid-
ney lesions is possible as demonstrated by a study in patients with
T1DM that showed regression of glomerular and tubulointerstitial
lesions and preservation of eGFR following long-term normoglycae-
mia obtained with pancreas transplantation37. Thus, given the mixed
lesions in T2DM and novel drugs that target different pathological
pathways, a precision medicine approach using combination thera-
pies may enable more effective targeting of kidney lesions and hence
improve clinical outcomes.
Kidney-protective therapies
A number of drugs have shown kidney-protective effects in people with
DKD in large clinical trials, including RAS blockers, SGLT2 inhibitors,
the mineralocorticoid receptor antagonist finerenone and ERAs. Stud-
ies with surrogate kidney end points suggest that GLP1R agonists may
also be kidney protective, but the results of large CKD trials of these
drugs are not yet available.
Renin–angiotensin–aldosterone blockers
RAS inhibition using ACE inhibitors or ARBs remains the cornerstone
of treatment to reduce the risk of kidney failure in people with DKD.
Clinical trial evidence of the kidney-protective properties of RAS
inhibitors in proteinuric DKD dates back more than 30 years (Table 1).

Hypertension GLP1R agonist ↑ RAS activity RAAS • Atherosclerosis GLP1R agonist

MRA inhibitor • Microvascular disease SGLT2 inhibitor
RAAS inhibitor
SGLT2 inhibitor
High sodium intake

Glomerulosclerosis • Fibrosis • Capillary rarefaction

• Inflammation • Intima-media thickening
Extracellular SGLT2
volume expansion inhibitor

Development and ↓ Perfusion GLP1R agonist

SGLT2 inhibitor
progression of DKD
↑ Creatinine
Dyslipidemia ↑ UACR
Dysmetabolism
Kidney hypoxia
GLP1R
agonist
SGLT2
Tubulo-interstitial Diabetic inhibitor ↑ O2 consumption
lesions glomerulopalhy Insulin resistance

Fibrosis RAAS inhibitor Inflammation GLP1R agonist AGE RAAS inhibitor Hyperfiltration Obesity
MRA SGLT2 inhibitor SGLT2 inhibitor
ERA MRA
ERA GLP1R agonist

Hyperglycemia GLP1R agonist

SGLT2 inhibitor

Fig. 1 | The pathophysiology of diabetic kidney disease. Established kidney target these risk factors and pathways. Inflammation may also be driven by a lack
risk factors including hypertension, obesity and hyperglycaemia induce kidney of kidney protective factors such as Klotho (not shown)151, which may be partly
tissue damage via various mechanisms, resulting in unfavourable kidney restored by SGLT2 inhibition152.
outcomes. Kidney-protective drugs have differing mechanisms of action that

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Table 1 | Large cardiovascular outcome trials of kidney-protective therapies

Study (year) Intervention Population (n) Primary outcome Result (HR [95% CI]) Ref.

Renin–angiotensin–aldosterone system inhibitors

Captopril (1993) Captopril Insulin-dependent Doubling of baseline serum creatinine to 0.48 [0.16–0.69] 7
(ACE inhibitor) diabetes, DKD (409) >177 μmol/l
IDNT (2001) Irbesartan (ARB) T2DM, DKD (1,715) Composite of doubling of baseline serum 0.80 [0.66–0.97] versus 8
creatinine, onset of kidney failure and death placebo; 0.77 [0.63–0.93]
from any cause versus amlodipine
RENAAL (2001) Losartan (ARB) T2DM, DKD (1,513) Composite of doubling of baseline serum 0.84 [0.72–0.98] 9
creatinine, onset of kidney failure and death
from any cause
Sodium glucose cotransporter-2 inhibitors
CREDENCE (2019) Canagliflozin T2DM, DKD (4,401) Composite of doubling of baseline serum 0.70 [0.59–0.82] 15
creatinine, onset of kidney failure and death
from renal or cardiovascular disease
DAPA-CKD (2020) Dapagliflozin T2DM, non-diabetic Composite of 50% reduction in eGFR, 0.61 [0.51–0.72] 16
CKD (4,304) onset of kidney failure and death from
renal or cardiovascular causes
EMPA-KIDNEY (2023) Empagliflozin T2DM, non-diabetic Composite of 40% reduction in eGFR, onset 0.72 [0.64–0.82] 17
CKD (6,609) of kidney failure, death from renal causes and
death from cardiovascular causes
Mineralocorticoid antagonist
FIDELIO-DKD (2020) Finerenone T2DM, DKD (5,734) Composite of 40% reduction in eGFR, onset 0.82 [0.73–0.93] 18
of kidney failure and death from renal causes
Endothelin receptor antagonist
SONAR (2019) Atrasentan T2DM, DKD (2,648) 40% reduction in eGFR or onset of kidney 0.65 [0.49–0.88] 19
failure including renal death
ACE, angiotensin converter enzyme; ARB, angiotensin receptor blocker; CI, confidence interval; CKD, chronic kidney disease; DKD, diabetic kidney disease; eGFR, estimated glomerular
filtration rate; HR, hazard ratio; T2DM, type 2 diabetes mellitus.

In 1993, a placebo-controlled multicentre trial7 in 409 individuals with
T1DM, diabetic retinopathy, proteinuria >0.5 g per day and serum
creatinine <2.5 mg/dl (<221 μmol/l), demonstrated a 50% reduction
in the risk of death, dialysis, or kidney transplantation with capto-
pril therapy independent of blood pressure changes. In addition, the
IDNT trial8, which included 1,715 individuals with T2DM, proteinuria
>0.9 g per day and median serum creatinine 1.7 mg/dl (150 μmol/l),
reported a 20% and 23% reduction in the relative risk of doubling
of serum creatinine, kidney failure or serum creatinine >6.0 mg/dl
(530 μmol/l) in those who were randomly assigned to irbesartan com-
pared with those in the amlodipine and placebo groups, respectively.
Furthermore, the RENAAL trial in 1,513 participants with T2DM, urine
albumin‐to‐creatinine ratio (UACR) ≥300 mg/g or proteinuria ≥0.5 g
per day and serum creatinine 1.3–3.0 mg/dl (115–265 μmol/l) showed
a 16% reduction in the risk of doubling of serum creatinine and kidney
failure in those randomly assigned to losartan versus placebo9.
RAS inhibitors have been shown to have blood pressure-independent
kidney-protective effects via inducing dilation of the efferent arteriole,
which results in lowering of intraglomerular pressure38,39. Intraglo-
merular hypertension and hyperfiltration are hallmarks of DKD and
angiotensin-II is a potent pro-inflammatory cytokine that triggers kidney
inflammation. To what extent this inflammation is prevented by RAS inhi-
bition is uncertain, which could in part explain the residual kidney risk
of DKD progression in people with diabetes40,41. The adverse effects that
have been observed with RAS inhibitors are fairly mild, with hypoten-
sion, dizziness and mild hyperkalaemia the most commonly reported,
whereas ACE inhibitors may induce a dry cough42.
Sodium glucose cotransporter-2 inhibitors
SGLT2 inhibitors lower glycaemia by inducing glucosuria and were ini-
tially developed to reduce HbA1c levels in people with T2DM43. However,
they also exert a variety of physiological effects that underlie kidney
and cardiovascular protection in clinical trials independent of improve-
ments in glycaemia44 (Table 1). SGLT2 inhibitors induce transient natriu-
resis, reduce effective circulating volume and lower blood pressure.
They also activate tubuloglomerular feedback, resulting in lowering
of intraglomerular pressure by efferent vasodilation in people with
normal or reduced kidney function45 and by afferent vasoconstriction
in those with T1DM and whole-kidney hyperfiltration46. SGLT2 inhibi-
tors also reduce the levels of pro-inflammatory cytokines such as IL-6,
TNF receptor 2 and high-sensitivity C-reactive protein41 and have sup-
pressive effects on fibrosis, kidney and systemic metabolism, hypoxia
and ischaemia-related pathways47. A meta-analysis of 13 randomized,
placebo-controlled, clinical trials involving 90,413 participants, showed
that in addition to reducing the risk of cardiovascular death or hospi-
talization for heart failure, SGLT2 inhibitor treatment reduced the risk
of a kidney composite end point (sustained decrease in eGFR ≥50%
from baseline, kidney failure (sustained eGFR <15 ml/min per 1.73 m²)
or death from kidney failure) by 37% (CI 42–31%), with similar effects
reported in those with and without diabetes, and across different CKD
aetiologies and baseline eGFR levels48.
Use of SGLT2 inhibitors is associated with an increased risk of
genital mycotic infections, which are usually non-serious and ame-
nable to non-prescription topical treatments. They also increase the
risk of euglycaemic diabetic ketoacidosis, but these events are very

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rare in patients with T2DM (absolute risk ~0.2 per 1,000 patient years
versus placebo)48. SGLT2 inhibitors may cause volume depletion and
hypotension, but unlike other pharmacological agents with diuretic
activity, they are not associated with electrolyte abnormalities and have
been shown to reduce the risk of clinically significant hyperkalaemia
by 15–20%49.
Mineralocorticoid receptor antagonists
Overactivation of the mineralocorticoid receptor in individuals with
T2DM leads to increases in reactive oxygen species, inflammation
and fibrosis. The MRA spironolactone has been shown to reduce
proteinuria and blood pressure in patients with DKD and CKD, but
increase the risk of hyperkalaemia and hormonal adverse effects such
as gynecomastia50,51. Finerenone is a novel, selective, non-steroidal MRA
that has similar activity in the heart and the kidneys52,53.
The FIDELIO-DKD trial, which enrolled individuals with CKD
and T2DM on maximum tolerated RAS inhibitor therapy, reported
that treatment with finerenone reduced the risk of CKD progression
(a composite of kidney failure, sustained decrease in eGFR of ≥40%
from baseline or death from kidney disease) compared with placebo
during a median follow-up of 2.6 years18. In this study, 17.8% of par-
ticipants in the finerenone group compared with 21.1% of those in the
placebo group (hazard ratio 0.82; 95% CI 0.73 to 0.93) met the primary
end point (Table 1). The FIDELITY pooled analysis of data from the
FIDELIO-DKD and FIGARO-DKD trials, which enrolled 13,026 individuals
with T2DM and CKD, reported that at a median follow-up of 3.0 years,
the c
­ omposite kidney outcome (kidney failure, sustained decrease in
eGFR of ≥57% from baseline over ≥4 weeks or death from kidney disease)
occurred in 360 patients in the finerenone group (5.5%) compared with
465 of those in the placebo group (7.1%) (HR 0.77; 95% CI 0.67–0.88)54.
In addition to the kidney benefits, finerenone treatment also improved
cardiovascular outcomes. The most problematic adverse effect of
finerenone treatment is hyperkalaemia. The FIDELITY analysis reported
that hyperkalaemia leading to permanent treatment discontinuation
occurred more frequently in the finerenone group than in the placebo
group (1.7% versus 0.6%), even though patients with serum potassium
≥4.8 mM at the screening visit were excluded. In the FIDELIO-DKD trial,
hyperkalaemia of any level occurred in nearly 20% of participants in
the finerenone group compared with 10% in the placebo group trial55.
Importantly, treatment with SGLT2 inhibitors was associated with a
lower frequency of hyperkalaemia in this trial.
Another non-steroidal MRA with high MRA specificity, esaxer­
enone, is in development. In the ESAX-DN study, which included
455 patients with T2DM and UACR 45 to <300 mg/g who were treated
with RAS inhibitors, esaxerenone markedly reduced microalbuminuria
compared with placebo56. A cardiovascular or kidney outcome trial of
this drug has not yet been conducted.
Endothelin receptor antagonists
The levels of endothelin-1 (ET-1), a vasoconstrictive factor that is
­produced in the kidney by glomerular epithelial cells, mesangial
cells and medullary collecting duct cells, are increased in people with
CKD and DKD57. ET-1 binds to endothelin-1 receptor (ETA), which is
localized on the afferent and efferent arterioles of the glomerulus,
podocytes, mesangial cells, vasa recta and arcuate arteries, and
endothelin receptor type B (ETB), which is mainly expressed in the
collecting system57. Activation of ETA causes arteriolar vasoconstric-
tion, podocyte dysfunction, cell proliferation, matrix accumulation and
inflammation, whereas ETB activation induces natriuresis and diuresis.
Nature Reviews Nephrology
Given the detrimental consequences of ETA activation, ET-1 blockade
by ERAs has been pursued as a potential therapy for CKD and DKD57. In
animal and human studies, ERAs reduced albuminuria but were associ-
ated with adverse effects of fluid overload and congestive heart failure
owing to ETB receptor blockade. This finding led to the development of
selective ERAs that target ETA alone. However, adverse effects remain
an issue as these selective ERAs do still have an effect on ETB58.
The largest kidney outcome study of a selective ERA to date is
the SONAR trial of atrasentan19. This trial had a unique design with an
active run-in period that was used to select participants with a UACR
decrease of ≥30% and no substantial fluid retention for inclusion in the
double-blind treatment phase. During a median follow-up of 2.2 years,
a 35% (CI 12%–51%) reduction in the primary composite kidney end point
(doubling of serum creatinine, kidney failure or death from kidney
disease) (Table 1) was observed in the atrasentan group compared
with the placebo group. Despite the exclusion of participants who were
prone to developing fluid-related adverse effects during the active
run-in period, fluid retention, anaemia and hospitalization for heart
failure (3.5% versus 2.6%) were more common in the atrasentan group19.
Other selective ERAs including darusentan59 and avosentan (ASCEND
study)12 have also been shown to have beneficial effects on surrogate
kidney end points such as albuminuria. However, the development of
these drugs was halted owing to safety issues related to fluid retention.
Glucagon-like peptide-1 receptor agonists
Glucagon-like peptide 1 (GLP1) is a gut-derived incretin hormone that
is produced following meal ingestion. Native GLP1 and GLP1 receptor
(GLP1R) agonists lower blood glucose by stimulating insulin secretion
and suppressing glucagon release. They also lower blood pressure and
induce weight loss secondary to the slowing of gastric emptying and the
triggering of satiety through actions on the central nervous system60,61.
In large cardiovascular outcome trials, GLP1R agonists reduced
CVD and cardiovascular mortality, including in participants with
DKD62. Kidney disease outcomes were major secondary outcomes
in these trials63,64. Among participants with T2DM and eGFR 30 to
<60 ml/min/1.73 m2, treatment with GLP1R agonists reduced albu-
minuria and slowed annual eGFR decline to a level that was predic-
tive of t-e prevention of kidney failure (>0.75 ml/min/1.73 m 2 per
year compared with placebo)64. In studies that included participants
with DKD (eGFR <60 ml/min/1.73 m2), the kidney protective effects
seemed to be more pronounced among those with higher levels of
eGFR at baseline65.
The results of mediation analyses of clinical trial data suggest that
changes in glucose levels, blood pressure and body weight only explain
10–25% of the observed kidney benefits of GLP1R agonists, indicating
that direct actions of GLP-1 receptor agonists on the kidney have a
dominant effect66,67. In experimental studies, GLP1R agonists reduced
immune cell activity and the release of pro-inflammatory cytokines,
suggesting a potential kidney-protective mechanism68,69. GLP-1 recep-
tor agonists have also been shown to stimulate natriuresis and diuresis
in experimental models70, healthy volunteers71 and individuals with
overweight72 or diabetes73. As tubules lack a GLP1 receptor, inhibition of
the sodium hydrogen exchanger-3 has been proposed as a mechanism
of GLP1-induced natriuresis73.
Given the emerging body of preclinical and clinical evidence for
beneficial kidney effects of GLP1R agonists, these drugs are now being
prospectively tested in people with DKD. The FLOW study is investigating
the effects of semaglutide on hard kidney outcomes in 3,534 partici­
pants with eGFR 25–75 ml/min/1.73 m2 and UACR 300–5,000 mg/g74.
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In addition, the REMODEL trial is using MRI of the kidney and analysis of
kidney biopsy samples with the aim of identifying the molecular, struc-
tural and functional actions of GLP1 receptor agonists in participants
with DKD75.
Non-pharmacological approaches to DKD
Lifestyle interventions are a fundamental component of the care of
people with diabetes and CKD. Although high-quality randomized
clinical trials on lifestyle measures in this population are scant, advice
regarding lifestyle should be reinforced at each clinical opportunity
during intensification of pharmacological treatment.
In people with CKD, low dietary sodium intake (<2 g or 90 mmol
per day) is recommended to control extracellular fluid status and
blood pressure, which are often increased in these salt-sensitive
individuals76–78. Low sodium intake is also associated with a lower inci-
dence of cardiovascular events in the general population and could
benefit people with diabetes and CKD. Moreover, reduced sodium
intake enhances the blood pressure-lowering effects of RAS inhibitors79.
An ongoing study is assessing the effect of daily sodium intake on blood
pressure, kidney function and kidney physiology in patients with T2DM
who are receiving SGLT2 inhibitor therapy (DESIGN trial80). However,
whether a low-sodium diet reduces DKD progression and the optimal
sodium intake during the different phases of CKD and DKD is uncer-
tain. Low protein intake may also prevent kidney function decline81,
potentially by reducing intraglomerular pressure82.
The prevalence of overweight and obesity is increased among
individuals with T2DM and kidney disease compared with the general
population. The LOOK AHEAD trial demonstrated a beneficial effect of
weight loss induced by calorie restriction and physical activity on the
risk of developing CKD, as demonstrated by reductions in UACR and
eGFR83. Similarly, metabolic weight loss surgery was shown to protect
against CKD in individuals with and without T2DM, as reflected by
reductions in UACR and eGFR, stressing the importance of weight man-
agement as part of lifestyle treatment84. Frequent physical activity is
associated with improved quality of life and a reduction in the incidence
of CVD in people with CKD85–87. However, exercise-based interventions
are understudied in this population. The ongoing ACTIDIANE study88
will provide data on the effects of exercise on kidney function in people
with T2DM. The Kidney Disease: Improving Global Outcomes guideline
recommends a cumulative weekly duration of ≥150 min of physical
activity for people with CKD78. Last, smoking cessation is advised for
patients with all stages of diabetes and CKD78.
Combination therapies
Despite the availability of several drugs with kidney-protective efficacy,
the large number of end points reached in the active treatment arms
of the published trials clearly indicate that the number of individuals
at risk remains high. Thus, a crucial question to address is whether
combinations of these agents have increased kidney protective effi-
cacy compared with the respective monotherapies. Given the differ-
ing mechanisms of action of the available drugs (Fig. 1 and Table 1),
an additional benefit of combination therapies is plausible. Another
important consideration, particularly for patients with CKD who are
at risk of polypharmacy, is whether different kidney-protective drugs
can be combined safely without inducing harmful interactions. On
the other hand, the adverse effects that are associated with particular
drug classes could potentially be mitigated by combination treatment
with other drug classes. Understanding interactions between the vari-
ous drug classes is also important because some of these classes have
Nature Reviews Nephrology
additional actions, including reducing hyperglycaemia and blood
pressure. Combinations of these drugs will therefore be encountered
frequently in clinical practice. Information regarding the effects of
combination therapies can be deduced from animal models and post
hoc analyses of large trials. In addition, small mechanistic studies and
trials that have been specifically designed to assess the kidney effects
of combination therapies have begun to emerge.
Preclinical studies
As multiple pathways in various kidney cell types are perturbed in
DKD89–93, use of combination therapies with the aim of achieving syner-
gistic benefit makes sense from a molecular perspective. In addition to
deepening our understanding of the molecular impact of combination
therapies, preclinical studies provide information regarding perturbed
pathways in DKD that are not ameliorated with therapy, highlighting
opportunities for drug development.
The effects of combination therapies using ACE inhibitors, thiazo-
lidinedione (TZD, which activates PPARγ and increases insulin sensitiv-
ity) and SGLT2 inhibitors were investigated using single-nucleus RNA
sequencing in a mouse model of advanced DKD (db/db mice with unine-
phrectomy and kidney renin overexpression)94. Although DKD induced
transcriptional changes in all kidney cell types, the most prominently
impacted were parietal epithelial cells, principal cells and endothelial
cells. The monotherapies preferentially rescued perturbed transcripts
in different cell types; TZD rescued about 40% of perturbed transcripts in
the thick ascending limb (TAL) and principal cells, whereas SGLT2
inhibitors rescued approximately 25% of perturbed transcripts in the
TAL. Overall, the percentage of rescued genes was lower in podocytes,
juxtaglomerular apparatus and macula densa than in the TAL, which
may reflect lower cell numbers in these populations. Combination
therapy with ACE inhibitors and TZD rescued about 30% of transcripts
in injured proximal tubule cells and 40% of those in the TAL, whereas
combination therapy with ACE inhibitors and SGLT2 inhibitors rescued
30% of transcripts in injured proximal tubule cells and 20% of those in
the TAL. The effects of combination therapies on the proximal tubule
were particularly pronounced, including a reduction in the number
of proximal tubule cells in an injured state, which was not seen with
monotherapies. Moreover, ligand-receptor analysis, which predicts
interactions between different cell types, suggested that combina-
tion regimens normalized signalling between glomerular endothelial
cells and podocytes. As diabetes-induced changes differ between DKD
stages and murine models95,96, careful research is needed to character-
ize how transcriptional changes reverse diabetes-induced perturba-
tions throughout all stages of the disease. Caution is also warranted
as transcriptional changes in diabetic murine models do not always
closely align with those that occur in human DKD95. Aligning transcrip-
tome data from human kidney biopsy studies with that from murine
models holds great promise in identifying shared ­transcriptional
changes in human and mouse DKD95.
Other drug combinations have also been tested in preclinical
studies. For example, in hypertensive renin-transgenic rats, finerenone
combined with the SGLT2 inhibitor empagliflozin conferred greater
reductions in proteinuria and histopathological kidney lesions than
either agent alone97. Moreover, in db/db mice, combined treatment
with the RAS inhibitor ramipril, empagliflozin and the ERA atrasentan
showed greater efficacy in preserving podocyte number and activat-
ing the protective intrarenal ACE2–Ang–Mas pathway than any of
the therapies alone98. Together these data suggest that combination
therapies may offer additional benefits compared with monotherapies.
Review article
Human studies
RAS blockers and SGLT2 inhibitors. As outlined above, both RAS
inhibitors and SGLT2 inhibitors reduce glomerular hypertension
and hyperfiltration. RAS inhibitors induce vasodilation of the effer-
ent arteriole by blocking the endothelial actions of angiotensin II,
whereas SGLT2 inhibitors induce vasodilation of the efferent arteri-
ole secondary to activation of tubular glomerular feedback. These
similar glomerular haemodynamic actions could suggest reduced
efficacy when the drugs are used in combination38,39. However, post
hoc analyses of large outcome trials showed that the kidney-protective
effects of SGLT2 inhibitors did not differ by RAS inhibitor background
therapy. A meta-analysis of trials of SGLT2 inhibitors in patients with
T2DM reported hazard ratios for the composite kidney end point
versus placebo of 0.52 (95% CI 0.37–0.74) and 0.65 (95% CI 0.30–1.39)
for participants who did and did not receive RAS inhibitors, respec-
tively; the P value for interaction was not significant99. However, as
RAS inhibitors are standard of care for T2DM, <20% of the participants
were not receiving this therapy, limiting the strength of the analysis.
Furthermore, bias by indication is an issue, as participants who were
prescribed RAS blockers likely differed from those who did not receive
RAS blockade and could for example have experienced faster kidney
disease progression.
Combination therapy with RAS inhibitors and SGLT2 inhibi-
tors has also been investigated in mechanistic double-blind trials in
participants with T1D1 (ref. 100) and T2DM39. The BETWEEN study
in young adults with T1DM (age 26 ± 4 years; BMI 26 ± 4 kg/m2; eGFR
120 ± 16 ml/min/1.73 m2) reported that empagliflozin–ramipril reduced
iohexol-measured GFR by 8 ml/min/1.73 m2 compared with placebo–
ramipril, suggesting a reduction in intraglomerular pressure, and
lowered urinary 8-isoprostane levels, suggesting a decrease in kidney
oxidative stress100. Empagliflozin–ramipril also reduced systolic blood
pressure by 4 mmHg, diastolic blood pressure by 3 mmHg and total
peripheral resistance compared with placebo–ramipril, indicating an
improvement in systemic haemodynamic function100.
The RECOLAR crossover trial in participants with T2DM (age
66 ± 6 years; BMI 31 ± 3 kg/m2; eGFR 90 ± 12 ml/min/1.73 m2), reported
that combination therapy with empagliflozin (10 mg) and losartan
(50 mg once daily) reduced iohexol-measured GFR by 10.9 ml/min,
3.7 ml/min and 3.4 ml/min and systolic blood pressure by 15 mmHg,
7 mmHg and 3 mmHg compared with placebo, empagliflozin mono-
therapy and losartan monotherapy, respectively39. These data indicate
a clear additive effect of SGLT2 inhibitor and RAS inhibitor combina-
tion therapy on markers of systemic and glomerular haemodynamic
function that underlie kidney benefits.
Combination therapy with drugs that induce reductions in glo-
merular pressure could result in kidney hypoperfusion, particularly
under conditions of illness with low fluid intake, potentially increas-
ing the risk of AKI. Indeed, cases of AKI have been reported in patients
who were receiving SGLT2 inhibitors and RAS blockers101. The risk of
AKI in people using RAS inhibitors is poorly investigated. However,
a meta-analysis of data from SGLT2 inhibitor trials (in which 80% of
participants received maximal tolerable doses of RAS inhibitors) sug-
gested that these therapies reduce AKI risk48. This analysis found that
allocation to SGLT2 inhibitor versus placebo reduced the risk of AKI
in patients with T2DM (HR 0.79, 95% CI 0.72–0.88; 1,622 events) and in
those without diabetes (HR 0.77, 95% CI 0.70–0.88; 2,010 events). As
AKI was not a primary or secondary end point in the SGLT2 inhibitor tri-
als, the results of ongoing dedicated trials are needed to confirm these
data102. From a mechanistic perspective, SGLT2 inhibitors or combined
Nature Reviews Nephrology
therapy with SGLT2 inhibitors and RAS inhibitors might protect against
AKI by lowering GFR, leading to reduced kidney oxygen consumption
while maintaining perfusion39,103.
The observation that SGLT2 inhibitors, likely in response to
ongoing osmotic diuresis owing to glucosuria, activate the renin–
angiotensin–aldosterone system (RAAS), resulting in increased con-
centrations of renin, angiotensin and aldosterone45, initially caused
concern because chronic RAAS activation is known to be harmful for
the heart and kidneys. However, the results of clinical trials of SGLT2
inhibitors have alleviated these worries. A potential explanation
for SGLT2 inhibitor-induced cardiovascular and kidney protection
despite increased RAAS activity is that combined SGLT2 inhibitor
and RAS inhibitor treatment activates alternative, non-classic RAAS
pathways such as angiotensin 1–7 and Mas104, which are associated with
anti-fibrotic and anti-inflammatory effects40.
SGLT2 inhibitors and GLP1R agonists. Early studies such as DURA-
TION-8 in patients with T2DM, showed that combination treatment
with SGLT2 inhibitors and GLP1 receptor agonists had greater benefi-
cial effects on blood glucose levels, body weight and blood pressure
in people with diabetes than either therapy alone105. These additive
effects on kidney risk factors can be partially attributed to the distinct
mechanisms of action of these drugs.
A low percentage of participants in the GLP1R agonist trials
used SGLT2 inhibitors. The AMPLITUDE-O trial, which investigated
the cardiovascular and renal effects of efpeglenatide, had the larg-
est percentage of SGLT2 inhibitor users (15%)106. The effects of efpe-
glenatide versus placebo on the kidney composite outcome were not
modulated by SGLT2 inhibitor treatment (HR 0.70, 95% CI 0.59–0.83,
and HR 0.52, 95% CI 0.33–0.83 for non-users and users, respectively;
P for interaction > 0.2)107. By contrast, the results of mechanistic
clinical trials suggest additive kidney protection with SGLT2 inhibi-
tors and GLP1R agonists. In the DECADE study, 20 participants with
DKD and albuminuria completed three 6-week treatment periods,
during which dapagliflozin 10 mg daily, exenatide long-acting release
(LAR) 2 mg weekly and both drugs combined were given in a random
order108. Combined dapagliflozin–exenatide LAR treatment resulted in
a greater decrease in UACR (26%) than dapagliflozin (22%) or exenatide
LAR (8%) monotherapy. In the DECREASE randomized double-blind
placebo-controlled trial in patients with T2DM and obesity, combina-
tion therapy with exenatide twice daily and dapagliflozin 10 mg daily
resulted in a greater reduction in UACR at 16 weeks (40%), than mono-
therapy with dapagliflozin (18%) or exenatide (16%). The dapagliflozin–
exenatide group also showed a greater initial drop in cystatin C eGFR
from baseline (−10.4 ml/min/1.73 m2) than the monotherapy groups109.
A larger initial drop in eGFR and UACR is generally associated with more
favourable kidney outcomes over time.
Another trial used multiparametric MRI to investigate the kid-
ney effects of combination therapy with a SGLT2 inhibitor and a GLP1
receptor agonist in participants with T2DM. This study found that the
SGLT2 inhibitor but not the GLP1 receptor agonist reduced medullary
kidney oxygenation, whereas the GLP1 receptor agonist but not the
SGLT2 inhibitor reduced kidney perfusion110. The combination therapy
reduced both medullary kidney oxygenation and kidney perfusion.
The safety profiles in the combination therapy groups of these stud-
ies were similar to their profiles as individual drugs. Thus, these studies
indicate that SGLT2 inhibitor-GLP1 receptor agonist combination thera-
pies may have additive kidney protection. This finding is supported
by real-world data showing that SGLT2 inhibitor and GLP1 receptor
Review article
agonist combination therapy was associated with a reduction in major
cardiac and cerebrovascular events and heart failure compared with
other glucose-lowering drugs111. Whether this benefit extends to kidney
outcomes remains to be investigated.
Combination therapies with MRAs. The interaction between finer-
enone and other kidney-protective drugs has been investigated only
a little. Owing to the timing of the FIDELIO-DKD and FIGARO-DKD tri-
als of finerenone, the number of participants who were using SGLT2
inhibitors and/or GLP-1 receptor agonists was fairly low (877 (6.7%) and
944 (7.2%), respectively), limiting the potential for robust subgroup
analyses18,112. In the FIDELITY pooled analysis of these trials, finerenone
treatment versus placebo was associated with similar improvements in
kidney outcomes in non-users and users of SGLT2 inhibitors (HR 0.80,
95% CI 0.69–0.92 in non-users and HR 0.42, 95% CI 0.16–1.08 in users
at baseline; P interaction > 0.1)113. Similarly, no interaction was found
for the effect of finerenone on kidney end points in those who received
a GLP1R agonist at baseline or at any point during the trial (HR 0.82,
95% CI 0.45–1.48 with GLP1R agonist and HR 0.77, 95% CI 0.67–0.89
without GLP1R agonist); however, a trend towards increased UACR
reduction with finerenone was observed in those using GLP1R agonists
versus non-users114.
A dedicated crossover study (ROTATE-3) has been conducted with
the steroidal MRA eplerenone and the SGLT2 inhibitor dapagliflozin. In
this study, 46 participants with CKD who were receiving the maximum
tolerable dose of RAS inhibitors were treated with eplerenone 50 mg,
dapagliflozin 10 mg or their combination in a random order. The com-
bination treatment resulted in a greater reduction in UACR (53%) than
eplerenone (33%) or dapagliflozin (34%) monotherapy, indicating an
additive effect115.
As discussed above, the main limitation for the use of MRAs, includ-
ing finerenone, is hyperkalaemia. A meta-analysis of six randomized
trials of SGLT2 inhibitors reported that these therapies reduced the risk
of clinically significant hyperkalaemia in participants with T2DM and
high cardiovascular risk or CKD49. Moreover, in the ROTATE-3 study, dapa-
gliflozin partly attenuated the eplerenone-induced increase in serum
potassium levels115. It is interesting to speculate that SGLT2 inhibitors
may increase the kidney-protective efficacy of MRAs while also increas-
ing their potential use by mitigating hyperkalaemia. This hypothesis is
currently being investigated in the phase II CONFIDENCE trial116.
Combination therapies with ERAs. Although the SONAR trial showed
kidney benefits of atrasentan, this drug is not currently used in the clinic
owing to adverse effects of anaemia, fluid overload and hospitalization
Glossary
Diabetes case-finding between two variables or conditions by
A systematic approach to identifying including a mediation variable.
patients with a disease. Active screening
for hyperglycaemia has increased the Steno Type 1 Risk Engine
detection of diabetes in the general A risk calculator that estimates
population. the 10-year risk of fatal or non-fatal
cardiovascular disease in patients with
Mediation analyses type 1 diabetes mellitus. The calculator
Statistical models that seek to explain a incorporates clinical and biochemical
mechanism that underlies a relationship risk parameters.
Nature Reviews Nephrology
for heart failure19. Combination therapy with SGLT2 inhibitors, which
increase red blood cell mass, induce diuresis and lower heart failure
hospitalization, could potentially ameliorate these adverse effects.
A post hoc analysis of the SONAR trial showed that among individuals
who were randomly assigned to atrasentan, those who were using
SGLT2 inhibitors experienced a greater reduction in UACR at 6 weeks
(55%) than those who received the ERA alone (38%)117. Participants
who received combination therapy also showed greater decreases
in body weight, a marker of fluid retention and B-type natriuretic
peptide, a biomarker of fluid congestion, than those who received
atrasentan alone.
The efficacy and safety of combination therapy with the ERA
zibotentan and the SGLT2 inhibitor dapagliflozin are currently being
investigated in the ZENITH-CKD study118 and the mechanistic ZODIAC
trial119, both of which include patients with and without diabetes. Con-
current SGLT2 inhibitor therapy could reduce ETB blockade-induced
fluid overload and drive the risk–benefit balance of zibotentan in a
more favourable direction.
Combination therapies in T1DM. Little evidence is currently available
to inform the use of combinations of kidney-protective therapies in
patients with T1DM. Studies of empagliflozin (EASE)120, dapagliflo-
zin (DEPICT)121 and the dual SGLT1 and SGLT2 inhibitor sotagliflozin
(InTandem)122–124 in patients with T1DM have focused primarily on
glucose management. However, post hoc analyses of the InTandem-1
and -2 (ref. 125) and the EASE-2 and -3 studies126 reported short-term
changes in eGFR and UACR similar to those seen in patients with T2DM.
The InTandem post hoc analysis reported that in participants with
baseline UACR ≥30 mg/g, sotagliflozin 200 mg and 400 mg reduced
UACR by 24% and 18%, respectively, versus placebo125. The EASE post
hoc analysis reported that in participants with baseline UACR ≥30 mg/g,
26 weeks of treatment with empagliflozin 10 mg (n = 71) and 25 mg
(n = 77), reduced UACR by 16% and 30%, respectively, versus placebo
(n = 65)126. A modelling analysis using data from the DEPICT studies and
the Steno Type 1 Risk Engine, found that the addition of SGLT2 inhibitor
to standard of care for patients with T1DM could lead to a reduction in
the relative risk of developing kidney failure over 5 years of 5.3% in the
whole cohort and 7.6% in a subgroup with UACR >30 mg/g127. To date,
studies of GLP1R agonists in participants with T1DM have investigated
the effects on HbA1c, insulin dose and tolerability, but not on kidney
disease parameters.
Combination therapies in non-diabetic CKD. The DAPA-CKD trial17 of
dapagliflozin added to standard care, including the maximal tolerated
dose of RAS inhibitor, was the first large SGLT2 inhibitor trial to include
participants with non-diabetic CKD, comprising about one-third of the
study population of 4,304 participants. In these non-diabetic partici-
pants, dapagliflozin treatment resulted in a relative risk reduction in
the primary composite outcome (50% reduction in eGFR, kidney failure,
cardiovascular or renal death) of 50%128. The EMPA-KIDNEY trial15 also
included participants with non-diabetic kidney disease (54% of the
study population), including 1,669 patients with glomerular disease,
and confirmed the DAPA-CKD results. A subsequent meta-analysis
reported that in patients with non-diabetic CKD who were receiving
standard care, treatment with an SGLT2 inhibitor was associated with
a 31% reduction in the relative risk of progression of kidney disease48.
Participants who received SGLT2 inhibitors had an annual eGFR decline
of 1.6 ml/min/1.73 m2 compared with a mean decline in the placebo
group of 2.4 ml/min/1.73 m2.
Review article
GLP1R agonists could potentially also have protective effects in
non-diabetic CKD but no conclusive studies in this population are avail-
able. The ongoing SELECT study in patients with obesity129 will evaluate
the effect of oral semaglutide on kidney outcomes as a secondary end
point. Several smaller studies in participants with obesity-related
kidney disease are planned or in progress, including the SMART trial,
which is investigating the effects of higher-dose semaglutide (2.4 mg
once weekly) on UACR, iohexol-GFR and blood pressure130. Whether
the kidney protective effects of non-steroidal MRA finerenone also
extend to non-diabetic CKD will be studied in the FIND-CKD trial131.
Clinical guidelines
Providing guidance on the management of CKD and DKD was fairly
straightforward when RAS inhibitors were the only treatment option,
but these drugs were not very effective in halting disease progression.
Newer guidelines have incorporated the growing evidence of proven
kidney and cardiovascular protective benefits of multiple agents in
people with CKD and made recommendations on their combinations.
A 2022 consensus report by the American Diabetes Association and
the European Association for the Study of Diabetes recommended
use of SGLT2 inhibitors for patients with T2DM and CKD, preferably in
combination with GLP1R agonists if further glucose control is needed,
because of the CVD benefit of these agonists in this population132.
The 2022 Kidney Disease: Improving Global Outcomes guide-
line for diabetes management in CKD described a more comprehen-
sive approach for all individuals with T2DM and CKD with first-line
treatment comprising RAS inhibitors and SGLT2 inhibitors for kidney
protection with a statin and with metformin if needed for additional
glucose lowering133. They suggest the addition of a non-steroidal-MRA
with proven kidney or cardiovascular benefit for those with residual
albuminuria (≥30 mg/g) despite use of the maximum tolerated dose of
RAS inhibitor and of GLP1R agonists for additional glycaemic control
and CVD benefits. ERAs have not been approved for use in patients with
T2DM and CKD and are not recommended for use in this population
owing to their adverse effects. Additional medications for the control
Box 1
Personalization of combination therapy
The advent of novel kidney protective drugs will likely lead to a new
era of personalized management of diabetic kidney disease (DKD) in
which combinations of therapies are tailored to individual patients.
Although patients could potentially be stratified based on histological
or serum biomarkers, a simpler approach is to initiate treatment based
on readily available clinical characteristics. Here, we provide three
hypothetical examples of such personalization. Please note that
these examples are based on mechanisms of action and data from
individual drug trials, not on data from trials of combination therapies.
Patient A
An overweight (BMI 35 kg/m2) patient with DKD (eGFR 46 ml/min/
1.73 kg/m2; UACR 52 mg/mmol) and uncontrolled diabetes (HbA1c
9.6%) may benefit from combined SGLT2 inhibitor and GLP1 receptor
agonist treatment. GLP-1 receptor agonists lower BMI and both
treatments improve hyperglycaemia.
Nature Reviews Nephrology
of glucose, blood pressure and lipids and antiplatelet therapy are rec-
ommended if needed. The potential benefit of combining all agents
has not yet been tested in most trials. In addition, studies often do not
provide evidence on the optimal sequence of drugs, whether all drugs
should be used in combination or if selection should be individualized.
Although most of the available data are from subgroup analyses, most
guidelines have reached similar recommendations, which is reassuring
and facilitates implementation134–137.
Personalized medicine for DKD
Clinical guidelines base their recommendations on robust group-level
data from large randomized clinical trials. However, decisions in clini-
cal practice are made on the individual level. A treatment benefit in a
group of individuals does not necessarily mean that all individuals will
benefit equally. DKD is a heterogeneous disease with great variability
in disease progression and treatment responses. Analyses of data from
randomized controlled trials of RAS inhibitors (RENAAL study) and
SGLT2 inhibitors (CANVAS program) showed wide variation in the risk
of kidney failure (10–95%), indicating large inter-individual differences
in baseline risk. Wide variation in the kidney benefits of RAS inhibitors
and SGLT2 inhibitors have also been observed (0–20%)138,139.
At least two factors may contribute to these variations. First, a
substantial proportion of people do not tolerate the guideline-advised
doses of therapies owing to adverse effects, resulting in suboptimal
dosing and reduced efficacy. Second, physicians may not adhere to
optimal blood pressure targets for their patients. For example, guide-
lines recommend the use of optimal blood pressure target doses of ACE
inhibitors and ARBs but in the DAPA-CKD trial, only 1,230 participants
(28.6% of the total cohort) received the maximal tolerable dose of RAS
blockers140. A similar proportion of suboptimal dosing of RAS inhibi-
tors was reported in the FIGARO trial19. In the SONAR trial, 10% of par-
ticipants discontinued atrasentan during the open-label active run-in
period because of fluid retention, oedema and heart failure19. These
data indicate that not every patient will derive the same benefit from
the current guideline-recommended therapies, supporting the need
Patient B
A lean (BMI 24 kg/m2) patient with heart failure (NYHA class III; NTproBNP
850 pg/ml), DKD (eGFR 53 ml/min/1.73 kg/m2; UACR 109 mg/mmol) and
well-controlled diabetes (HbA1c 7.1%) may benefit from combined
SGLT2 inhibitor and finerenone treatment. Both drugs improve heart
failure and kidney outcomes.
Patient C
A patient with hyperkalaemia (potassium 5.8 mmol/l), near-normal
glycaemia (HbA1c 6.8%) and DKD (eGFR 44 ml/min/1.73 kg/m2; UACR
35 mg/mmol) might benefit most from SGLT2 inhibitor and ERA
treatment. This combination does not increase hyperkalaemia and
likely offers incremental kidney protection. Potassium binders could
be given to enable use of maximal RAS blocker therapy in the case
of mild hyperkalaemia.
Review article

for approaches that are tailored to the needs and characteristics of indi-
vidual patients. An individualized treatment approach also provides the
opportunity to minimize drug use by selecting the optimal treatment,
instead of layering multiple therapies, leading to a large pill burden,
potential drug–drug interactions, adverse effects and non-adherence.
Unprecedented progress in molecular, genetic, bioinformatic and
imaging technologies has increased understanding of the pathophysi-
ology of DKD and provides the opportunity to phenotype patients in
more detail than ever before. These approaches could aid the discovery
of novel molecular markers that predict the responses of individuals to
treatment. However, despite extensive efforts, these new technologies
have not yet delivered any adequately validated biomarker sets (such
as urine, plasma or imaging-based biomarkers) that predict responses
to the current guideline-recommended treatments.
Alternative approaches to predictive biomarkers have been
explored. Instead of predicting the response of an individual to a treat-
ment before its initiation, biomarkers could be measured after a few
weeks of treatment to predict if the patient will ultimately benefit from
the therapy. This approach was applied in a multicentre crossover study
in 63 patients with T1DM or T2DM and CKD that assessed whether
rotation through four drug classes can optimize albuminuria-lowering
therapy by selecting the best drug for each individual141. As expected, the
study showed substantial variation between the participants in response
to the four drug classes. The best-performing drugs for the individuals
reduced albuminuria by 40%, whereas albuminuria increased by 2%
with the sub-optimal drugs. Moreover, 75% of participants achieved
the >30% reduction in albuminuria recommended by the American
Diabetes Association diabetes guidelines with their best-performing
drug, but only 33% met this target with their first drug141.
As DKD is a progressive disease, many people will likely require
more than one therapy to slow disease progression or to mitigate
adverse effects. A key question is which combination should be used
for which patient? In the future, readily available clinical characteristics
of individuals may be used to tailor optimal combinations (Box 1). The
ultimate clinical benefit of this approach should ideally be tested in a
randomized controlled trial.
Conclusions and future perspectives
DKD is a prevalent and severe complication of diabetes that amplifies
the risk of kidney failure and CVD. Despite efforts to control blood
glucose levels, blood pressure and proteinuria through lifestyle modi-
fications and pharmacological interventions, many individuals still
experience kidney disease progression. Novel therapeutic approaches,
such as SGLT2 inhibitors, a non-steroidal MRA and selective ERAs, have
demonstrated efficacy in slowing deterioration of kidney function.
However, a considerable residual risk persists, potentially owing to

Table 2 | Ongoing mechanistic and outcome studies of kidney-protective therapies

Study (trial number) Intervention Population (n) Outcome(s) Ref.

DESIGN (NCT05727579) Ertugliflozin 15 mg, low and T2DM, eGFR 60–90 ml/min/1.73 m (35) Measured GFR, blood pressure,
high sodium diet
ACTIDIANE (NCT03184662) Physical activity twice
weekly
REMODEL (NCT04865770) Semaglutide 1.0 mg
FLOW (NCT03819153) Semaglutide 1.0 mg
MERCURI-2 (NCT05590143) Dapagliflozin 10 mg
CONFIDENCE (NCT05254002) Finerenone 10 mg and
empagliflozin 10 mg
ZENITH-CKD (NCT04724837) Zibotentan 0.25 mg or
1.5 mg, dapagliflozin 10 mg
ZODIAC (NCT05570305) Zibotentan 1.5 mg,
dapagliflozin 10 mg
SELECT (NCT03574597) Semaglutide 2.4 mg
SMART (NCT04889183) Semaglutide 2.4 mg
FIND-CKD (NCT05047263) Finerenone 10-20 mg
NA (NCT04170543) Tozorakimab (doses 1-4)
TREASURE (NCT05536804) Tirzepatide 15 mg
AKI, acute kidney disease; CKD, chronic kidney disease; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate; GFR, glomerular filtration rate; KDIGO, Kidney Disease:
Improving Global Outcomes; NA, not available; scRNAseq, single-cell RNA sequencing; T2DM, type 2 diabetes mellitus; UACR, urine albumin-to-creatine ratio.
2
80
multiparametric kidney MRI
eGFR >30 ml/min/1.73 m2, eGFR loss Cystatin-C derived eGFR at 2 years 88
>5 ml/min per year (300)
T2DM, eGFR 60–90 ml/min/1.73 m2, Multiparametric kidney MRI, biopsy substudy 75
UACR 20–5,000 mg/g (105) (histology, scRNAseq)
eGFR 25–75 ml/min/1.73 m2, eGFR decline >50%, kidney failure, death from 74
UACR 300–5,000 mg/g (3,534) kidney disease, death from CVD
Patients undergoing cardiac surgery, AKI according to KDIGO criteria 102
eGFR >30 ml/min/1.73 m2 (784)
eGFR 40–90 ml/min/1.73 m2, Change in UACR 116
UACR 300–5,000 mg/g (807)
eGFR ≥20 ml/min/1.73 m2, Change in UACR 118
UACR 150–5,000 mg/g (542)
T2DM, eGFR ≥30 ml/min/1.73 m2, Change in UACR, change in measured GFR 119
UACR 100–3,500 mg/g (38)
BMI ≥27 kg/m2, history of CVD (17,609) Time to first occurrence of a composite 129
end point (cardiovascular death, non-fatal
myocardial infarction or non-fatal stroke)
No diabetes, BMI ≥27 kg/m2, Change in UACR 130
UACR 30–3,500 mg/g,
eGFR ≥25 ml/min/1.73 m2 (98)
No diabetes, eGFR 25–90 ml/min/ eGFR slope 131
1.73 m2, UACR 200–3,500 mg/g,
BMI ≥27 kg/m2 (1,580)
T2DM, eGFR 25–75 ml/min/1.73 m2, Change in UACR 144
UACR 100–3,000 mg/g (565)
T2DM or non-diabetic CKD, eGFR Multiparametric kidney MRI, 11C-acetate PET 150
≥30 to ≤ 60 ml/min/1.73 m² (140)

Nature Reviews Nephrology

Review article
the heterogeneous nature of kidney lesions and their diverse patho-
physiological drivers. These findings underscore the need for inno-
vative or combined therapeutic strategies that target these distinct
­pathophysiological defects (Fig. 1) to further mitigate this risk.
Evidence of the additive effects of specific drug classes on the
acute reduction of eGFR, UACR and blood pressure suggests potential
benefits of combination therapies. However, determining which indi-
viduals will benefit from specific drugs remains a challenge. The con-
cept of personalized medicine, which tailors treatments to the unique
needs and characteristics of individuals, is becoming increasingly
plausible as the variety of kidney-protective medications expands. Out-
come trials involving combination therapies and mechanistic studies
can expedite the development of precision-based medicine (Table 2).
A deeper understanding of the mechanisms through which treatments
affect different individuals may enable prediction of which patients are
likely to respond favourably or unfavourably to specific medications
or therapy combinations. The mechanistic REMODEL study75, which
is a sister trial to the large-scale outcome FLOW trial142, exemplifies
this approach. REMODEL is incorporating paired biopsy samples and
comprehensive kidney MRI with the aim of enhancing understanding
of the mechanisms of action of the GLP1R agonist semaglutide in adults
with T2DM and CKD.
In addition to traditional mechanistic studies, advanced tech-
niques for tissue interrogation, such as spatial transcriptomics, spa-
tial proteomics and spatial metabolomics, are being developed and
employed. These techniques enable researchers to study biological
processes at single-cell resolution. The effects of therapies can also
be studied at the tissue level as shown in rodent studies94. By provid-
ing a more detailed understanding of the mechanisms of action and
injury, these techniques may help to define more precise and effective
treatments for DKD. For example, given the haemodynamic effects of
SGLT2 inhibitors, one may hypothesize that the best responders will be
those with classic glomerulopathy. By contrast, as non-steroidal MRAs
predominantly target inflammation and fibrosis, people with advanced
tubulointerstitial lesions may be most likely to benefit. GLP1R agonists
could reduce obesity-associated hyperfiltration and have important
anti-inflammatory and antioxidant effects that may reduce glomerular,
tubulointerstitial and vascular lesions.
Several novel drugs with kidney-protective potential are also
in development. These include a 5-lipoxygenase activating protein
(FLAP) inhibitor143, IL-33 inhibitors144, specific aldosterone synthase
inhibitors145 and soluble guanylate cyclase activators146. Compounds
that improve renal substrate metabolism, such as mitochondrial pep-
tides, bioavailable small molecule activators of AMPK and mechanistic
target of rapamycin complex 1 (mTORC1) inhibitors147, may also hold
promise in the treatment of DKD, as even small improvements in fuel
utilization may result in substantial improvements in kidney function
and clinical outcomes. The combined GLP1 and glucose-dependent
insulinotropic polypeptide (GIP) agonist tirzepatide has been shown
to reduce UACR in people with diabetes and CKD148. Similar to GLP1,
GIP stimulates insulin secretion. However, GIP also induces pancreatic
secretion of glucagon149, increases the sensitivity of adipose tissue
to insulin and suppresses appetite and food intake while increasing
energy expenditure through central nervous system mechanisms149.
Tirzepatide may improve kidney function by improving kidney energy
metabolism and reducing kidney lipotoxicity related to intra-kidney fat
accumulation. This hypothesis is being investigated in the TREASURE
study150, which is employing multiparametric MRI and PET in people
with obesity and CKD in the presence or absence of diabetes.
Nature Reviews Nephrology
These ongoing studies will determine the efficacy of novel com-
pounds to reduce kidney risk; however, other unmet needs remain to be
addressed. Longer-term outcome studies are needed to better define
the effects of kidney-protective interventions in non-albuminuric
DKD, which tends to progress more slowly than albuminuric DKD
but accounts for a large number of cases of kidney failure. This prob-
lem was particularly evident in trials that enrolled participants with
non-albuminuric and albuminuric DKD and reached their end point
early, such as several SGLT2 inhibitor trials. A need also exists for better
understanding of the distinct pathological and molecular features
that distinguish DKD in T1DM and T2DM, as well as obesity-related
nephropathy and DKD in T2DM. Further efforts to reduce the kidney
burden in people with T1DM are also needed. Finally, whether specific
drugs are more efficacious at different phases of disease is currently
unclear and requires further study.
The results of ongoing and future mechanistic and outcome stud-
ies will provide crucial evidence to potentially improve the manage-
ment of DKD using combination therapies. Greater understanding of
the pathways of beneficial and adverse effects of kidney-protective
drugs will enable researchers to develop more targeted and effective
therapies and move towards precision medicine for DKD. In the future,
advanced techniques for tissue interrogation may be used to inform
the optimal choice of combination therapies for patients with DKD.
Published online: xx xx xxxx
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Acknowledgements
D.H.V.R. is supported by a senior fellowship of the Dutch Diabetes Foundation and by a
PIONEER + grant of the Dutch Kidney Foundation. P.B. receives salary and research support
from the NIDDK (R01 DK129211, R01 DK132399, RO1 HL165433, R21 DK129720 and UC2
DK114886), JDRF (3-SRA-2022-1097-M-B, 3-SRA-2022-1243-M-B, and 3-SRA-2022-1230-M-B),
the Boettcher Foundation, the American Heart Association (20IPA35260142), the Ludeman
Family Center for Women’s Health Research at the University of Colorado, the Department
of Paediatrics, Section of Endocrinology, and the Barbara Davis Center for Diabetes at
University of Colorado School of Medicine. I.H.D.B. is supported by NIH grants R01DK125084,
R01DK132399, R01DK126373, and grant funding from JDRF. D.G. is supported by Wilhelm
and Else Stockmann Foundation, Liv och Hälsa Society, Medical Society of Finland (Finska
Läkaresällskapet), Sigrid Juselius Foundation, Helsinki University Hospital, University of
Helsinki, Minerva Foundation Institute for Medical Research Clinician Scientist, and Academy
of Finland (UAK1021MRI). S.E.R. reports research support from AstraZeneca, Bayer and
NIH/NIDDK [U01DK133092 and U01DK116102] to Joslin Diabetes Center. She also benefited
from participation in the Joslin Diabetes research enrichment program funded by P30
DK03836. J.A.S. received salary support provided by K08DK124449. K.T. is supported by NIH
research grants R01MD014712, U2CDK114886, UL1TR002319, U54DK083912, U01DK100846,
OT2HL161847, UM1AI109568, OT2OD032581 and CDC project number 75D301-21-P-12254.
S.S.W. is supported by research grants R01DK108803, U01DK130060, U01DK133092,
U01AG076789 and R25DK128858.
Author contributions
All authors researched data for the article, contributed substantially to discussion of the
content, wrote the article and reviewed and/or edited the manuscript before submission.
Competing interests
D.H.V.R. has consulting relationships with Bayer, Boehringer Ingelheim, Eli Lilly, Merck and
Sanofi, and receives research operating funding from AstraZeneca, Boehringer Ingelheim-Eli
Lilly Diabetes Alliance and MSD. Honoraria are transferred to employer Amsterdam UMC.
P.B. reports serving or having served as a consultant for AstraZeneca, Bayer, Bristol-Myers
Squibb, Boehringer Ingelheim, Eli Lilly, LG Chemistry, Sanofi, Novo Nordisk and Horizon
Pharma. P.B. also serves or has served on the advisory boards and/or steering committees
of AstraZeneca, Bayer, Boehringer Ingelheim, Novo Nordisk and XORTX. P.B. receives grant
support from Eli Lilly, Novo Nordisk, AstraZeneca, Merck, and Horizon Pharma. D.Z.I.C. reports
serving or having served as a consultant for Boehringer Ingelheim-Lilly, Merck, AstraZeneca,
Sanofi, Mitsubishi-Tanabe, AbbVie, Janssen, Bayer, Prometic, BMS, Maze, Gilead, CSL-Behring,
Otsuka, Novartis, Youngene, Lexicon, Inversago, GSK and Novo-Nordisk. He has received
operational funding from Boehringer Ingelheim-Lilly, Merck, Janssen, Sanofi, AstraZeneca,
CSL-Behring and Novo-Nordisk. I.H.D.B. has received consulting fees from AstraZeneca,
Bayer, Boehringer-Ingelheim, Cyclerion Therapeutics, George Clinical, Gilead, Goldfinch
Bio, Ironwood, Medscape and Otsuka. P.F. has received fees as consultant and speaker for
AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly company and Novo Nordisk. D.G. has
received lecture or Advisory Board Honoraria from AstraZeneca, Bayer, Boehringer Ingelheim,
Delta Medical Communications, EASD eLearning, Finnish Association for Vascular Surgery,
Finnish Nephrology Association, Kidney and Liver Foundation in Finland. F.P. has served as
a consultant, on advisory boards or as educator for AstraZeneca, Novo Nordisk, Boehringer
Ingelheim, Sanofi, Mundipharma, MSD, Novartis and Amgen, and has received research grants
to institution from Novo Nordisk, Boehringer Ingelheim, Amgen and AstraZeneca. S.E.R. has
participated as a member of scientific advisory boards for AstraZeneca, Bayer, and Travere.
P.R. has received research support and personal fees from AstraZeneca, Bayer, and Novo
Nordisk and personal fees from Abbott, Astellas, Bayer, Boehringer Ingelheim, Eli Lilly, Gilead
and Sanofi. All fees are given to Steno Diabetes Center Copenhagen. K.T. reports consulting
relationships with Eli Lilly, Boehringer Ingelheim, AstraZeneca, Pfizer, Bayer and Novo Nordisk,
and receives research grants from Travere paid to employer, Providence Inland Northwest
Health. S.S.W. is consultant for Wolters Kluwer, Bain, BioMarin, Goldfinch, GSK, Ikena, Strataca,
Google, CANbridge, NovoNordisk, PepGen, Sironax and NovoNordisk, and expert witness
for Davita, Pfizer, Dechert and Aurinia Pharmaceuticals. S.S.W. receives research funding
from Vertex, Pfizer, JNJ and Natera. H.J.L.H. is consultant for AstraZeneca, Bayer, Boehringer
Ingelheim, Chinook, CSL Behring, Dimerix, Eli-Lilly, Gilead, Janssen, Merck, Novo Nordisk,
ProKidney, Travere Therapeutics and Vifor Fresenius. He has received research support from
AstraZeneca, Boehringer Ingelheim, Janssen and Novo Nordisk.
Additional information
Peer-review information Nature Reviews Nephrology thanks Mark Cooper, Beatriz
Fernandez-Fernandez and Pierre-Jean Saulnier for their contribution to the peer review
of this work.
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1
Department of Endocrinology and Metabolism, Amsterdam University Medical Centers, VUMC, Amsterdam, The Netherlands. 2Diabetes Center,
Amsterdam University Medical Centers, VUMC, Amsterdam, The Netherlands. 3Research Institute for Cardiovascular Sciences, VU University, Amsterdam,
The Netherlands. 4University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA. 5Department of Medicine, Division of Nephrology, Toronto
General Hospital, University of Toronto, Toronto, Ontario, Canada. 6Division of Nephrology and Kidney Research Institute, University of Washington,
Seattle, Washington, USA. 7Department of Medicine, University of Padua, Unit of Medical Clinic 3, Padua, Italy. 8Minerva Foundation Institute for Medical
Research, Helsinki, Finland. 9Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. 10Joslin Diabetes Center,
Harvard Medical School, Boston, Massachusetts, USA. 11Steno Diabetes Center, Copenhagen, Denmark. 12Nephrology Division, Department of Medicine,
University of Michigan, Ann Arbor, Michigan, USA. 13Providence Medical Research Center, Providence Inland Northwest Health, Spokane, Washington,
USA. 14Department of Medicine, University of Washington School of Medicine, Spokane and Seattle, Washington, USA. 15Nephrology Division, Kidney
Research Institute and Institute of Translational Health Sciences, University of Washington, Spokane and Seattle, Washington, USA. 16Section of
Nephrology, Boston University Chobanian & Avedisian School of Medicine and Boston Medical Center, Boston, Massachusetts, USA. 17Department of
Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. 18The George Institute
for Global Health, Sydney, New South Wales, Australia.

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