nature reviews nephrology https://doi.org/10.

1038/s41581-024-00827-z

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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: [email protected]

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Key points 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.
•• Diabetic kidney disease (DKD) is associated with substantial The results of large placebo-controlled trials of novel drug classes
morbidity and cardiovascular mortality, and for nearly two decades, ended this period of failure. Improved kidney outcomes in patients with
the only kidney-protective treatment for DKD was renin–angiotensin CKD with and without diabetes have been demonstrated with sodium
system blockade. glucose cotransporter-2 (SGLT2) inhibitors (CREDENCE (canagliflozin),
DAPA-CKD (dapagliflozin) and EMPA-KIDNEY (empagliflozin) trials)15–17,
•• Positive kidney outcome data have now been reported for SGLT2 the non-steroidal mineralocorticoid antagonist (MRA) finerenone
inhibitors, the mineralocorticoid antagonist finerenone and endothelin (FIDELIO-DKD trial)18 and the selective endothelin receptor antagonist
receptor antagonists. (ERA) atrasentan (SONAR trial)19. Although these findings were met
with great enthusiasm, the number of kidney events observed during
•• GLP1 receptor agonists have been shown to have beneficial effects treatment with these novel drugs remains high. Given the multifactorial
on surrogate kidney end points, and a kidney outcomes trial is causes of DKD, the heterogeneity of the observed histological lesions
underway. and the differing mechanisms of action of the novel pharmacological
agents, combination therapies could offer additional benefits.
•• The advent of novel kidney-protective drugs provides new In this Review, we examine the evidence for the efficacy and safety
therapeutic options for people living with diabetes and kidney disease of combination treatment to reduce DKD progression, based on mecha-
but increases the complexity of treatment decisions for caregivers. nistic and clinical outcome data in people with T2DM, and highlight
ongoing trials that are employing combination therapies. We also
•• Combining drugs may enhance their kidney protective efficacy and extend these data to other causes of CKD and discuss considerations
could potentially reduce the risk of adverse effects that are associated for people with type 1 diabetes mellitus (T1DM). Finally, we discuss
with specific drug classes. current guidelines for the management of CKD and DKD and suggest
that a personalized medicine approach may help to select the right
•• An important goal for the future pharmacological management drugs for the right patient at the right time.
of DKD is to individualize treatment with optimal drug combinations
based on the underlying pathophysiology and guided by tissue or Epidemiology of DKD
serum biomarkers. 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
Introduction to an increased prevalence of T2DM, driven by increasingly sedentary
The prevalence of chronic kidney disease (CKD) that can be attrib- lifestyles and obesity, as well as an increased incidence of T1DM21. CKD,
uted to diabetes mellitus, termed diabetic kidney disease (DKD), has defined as a persistently reduced estimated glomerular filtration rate
increased dramatically in parallel with an increase in the global preva- (eGFR) and/or albuminuria, affects about 30–40% of people with diabe-
lence of type 2 diabetes mellitus (T2DM) in the past 4 decades1–4. In tes over their lifetimes1–4. Globally, approximately 850 million people
addition to hyperglycaemia, comorbid conditions such as obesity, were estimated to have CKD in 2017, including 3.9 million people who
hypertension, atherosclerosis, dyslipidaemia and insulin resistance received dialysis or kidney transplantation owing to kidney failure, for
contribute to kidney damage, making DKD a heterogeneous disorder. which the leading cause is diabetes22.
Yearly screening by measuring serum creatinine concentrations and Increased awareness of the public health impact of diabetes has led
urinary albumin excretion is recommended for all patients with T2DM to improved diabetes case-finding in clinical practice as well as mod-
to facilitate diagnosis of DKD in the early stages and enable initiation est improvements in the control of glycaemia and other intermediate
of appropriate therapies. Strict control of glycaemia reduces the risk of targets related to diabetes complications, such as blood pressure and
developing DKD5, and blood pressure control attenuates progression lipids3. Nonetheless, the prevalence of CKD among people with dia-
of DKD6. For the past 30 years, blockers of the renin–angiotensin sys- betes has remained stable1,3, and temporal trends in the incidence of
tem (RAS) have been the cornerstone of therapy for DKD7–9. However, kidney failure have been variably reported as decreasing, increasing or
residual risk of kidney failure remains high in patients treated with RAS unchanged23–27. As the population prevalence of diabetes has increased
inhibitors, indicating a large unmet medical need. in the past 30 years, the absolute prevalence of CKD and incidence of
In the past 20 years, several approaches that were developed to kidney failure attributable to diabetes have also increased3,28. Moreo-
reduce the DKD burden were unsuccessful. For example, dual RAS block- ver, CKD is associated with markedly increased risks of other diabetes
ade using combination treatment with an angiotensin converter enzyme complications, such as heart failure and atherosclerotic cardiovascular
(ACE) inhibitor and an angiotensin receptor blocker (ARB) (VA-nephron disease (CVD)29,30. Among people with diabetes, CKD is associated with a
trial)10 and direct renin inhibition using aliskiren in combination with ACE loss of life expectancy of approximately 5 years27, and kidney failure with
inhibitor or ARB therapy (ALTITUDE trial)11 did not improve kidney out- a loss of life expectancy of 9–31 years, depending on age at diagnosis31.
comes and were associated with adverse events such as hyperkalaemia Together, these data highlight an urgent need for new approaches to
and acute kidney injury (AKI). Similarly, treatment with the endothelin preventing and treating CKD among people with diabetes.
receptor antagonist avosentan (ASCEND trial)12 or bardoxolone methyl,
which reduces tissue oxidative stress (BEACON trial)13, did not reduce Multifactorial pathophysiology of DKD
the incidence of kidney failure, and both drugs were associated with an The pathophysiology of DKD is complex, particularly in people with
increased incidence of congestive heart failure. Finally, treatment with T2DM (Fig. 1). In T1DM, diabetic glomerulopathy, with the typical

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constellation of thickening of the glomerular basement membrane, tubulointerstitial lesions36. We hypothesize that patients with clas-
mesangial expansion, mesangial nodule formation, and afferent sic glomerular lesions are more likely to benefit from agents that
and efferent glomerular arteriolar hyalinosis, is the predominant affect renal haemodynamic function, whereas those with more
hyperglycaemia-induced kidney lesion. By contrast, the lesions that advanced tubule-interstitial lesions are more likely to benefit from
underlie kidney dysfunction in T2DM are much more diverse32,33. Kid- anti-inflammatory and antifibrotic agents. Reversal of diabetic kid-
ney biopsy studies have demonstrated that only 30–50% of patients ney lesions is possible as demonstrated by a study in patients with
with T2DM and DKD have classic diabetic glomerulopathy and many T1DM that showed regression of glomerular and tubulointerstitial
individuals have ‘atypical patterns of diabetic kidney lesions’, char- lesions and preservation of eGFR following long-term normoglycae-
acterized by severe tubulointerstitial and/or arteriolar and vascular mia obtained with pancreas transplantation37. Thus, given the mixed
abnormalities in the presence of mild or absent glomerular lesions33. lesions in T2DM and novel drugs that target different pathological
IgA nephropathy was a common finding in individuals whose histo- pathways, a precision medicine approach using combination thera-
logical features were not consistent with diabetic nephropathy. These pies may enable more effective targeting of kidney lesions and hence
additional pathological changes, isolated or superimposed on classic improve clinical outcomes.
diabetic glomerulopathy lesions, may be driven by comorbid condi-
tions that are present in many people with T2DM, including ageing, Kidney-protective therapies
obesity, hypertension, dyslipidaemia, atherosclerosis and insulin resist- A number of drugs have shown kidney-protective effects in people with
ance, all of which have been linked to DKD progression34. Changes in DKD in large clinical trials, including RAS blockers, SGLT2 inhibitors,
glomerular haemodynamic function (characterized by whole-kidney the mineralocorticoid receptor antagonist finerenone and ERAs. Stud-
or single nephron hyperfiltration) and activation of pro-inflammatory ies with surrogate kidney end points suggest that GLP1R agonists may
and pro-fibrotic factors also have important roles in inducing kidney also be kidney protective, but the results of large CKD trials of these
damage, and proteinuria may further drive kidney fibrosis in people drugs are not yet available.
with DKD. This heterogeneity in kidney insults underlies the differ-
ing clinical phenotypes of DKD, with approximately 30% of patients Renin–angiotensin–aldosterone blockers
presenting without albuminuria35. RAS inhibition using ACE inhibitors or ARBs remains the cornerstone
The heterogeneity of DKD has potentially important prog- of treatment to reduce the risk of kidney failure in people with DKD.
nostic consequences. In the early stages of DKD, GFR loss was Clinical trial evidence of the kidney-protective properties of RAS
more strongly associated with diabetic glomerulopathy than with 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 Sodium glucose cotransporter-2 inhibitors
T1DM, diabetic retinopathy, proteinuria >0.5 g per day and serum SGLT2 inhibitors lower glycaemia by inducing glucosuria and were ini-
creatinine <2.5 mg/dl (<221 μmol/l), demonstrated a 50% reduction tially developed to reduce HbA1c levels in people with T2DM43. However,
in the risk of death, dialysis, or kidney transplantation with capto- they also exert a variety of physiological effects that underlie kidney
pril therapy independent of blood pressure changes. In addition, the and cardiovascular protection in clinical trials independent of improve-
IDNT trial8, which included 1,715 individuals with T2DM, proteinuria ments in glycaemia44 (Table 1). SGLT2 inhibitors induce transient natriu-
>0.9 g per day and median serum creatinine 1.7 mg/dl (150 μmol/l), resis, reduce effective circulating volume and lower blood pressure.
reported a 20% and 23% reduction in the relative risk of doubling They also activate tubuloglomerular feedback, resulting in lowering
of serum creatinine, kidney failure or serum creatinine >6.0 mg/dl of intraglomerular pressure by efferent vasodilation in people with
(530 μmol/l) in those who were randomly assigned to irbesartan com- normal or reduced kidney function45 and by afferent vasoconstriction
pared with those in the amlodipine and placebo groups, respectively. in those with T1DM and whole-kidney hyperfiltration46. SGLT2 inhibi-
Furthermore, the RENAAL trial in 1,513 participants with T2DM, urine tors also reduce the levels of pro-inflammatory cytokines such as IL-6,
albumin‐to‐creatinine ratio (UACR) ≥300 mg/g or proteinuria ≥0.5 g TNF receptor 2 and high-sensitivity C-reactive protein41 and have sup-
per day and serum creatinine 1.3–3.0 mg/dl (115–265 μmol/l) showed pressive effects on fibrosis, kidney and systemic metabolism, hypoxia
a 16% reduction in the risk of doubling of serum creatinine and kidney and ischaemia-related pathways47. A meta-analysis of 13 randomized,
failure in those randomly assigned to losartan versus placebo9. placebo-controlled, clinical trials involving 90,413 participants, showed
RAS inhibitors have been shown to have blood pressure-independent that in addition to reducing the risk of cardiovascular death or hospi-
kidney-protective effects via inducing dilation of the efferent arteriole, talization for heart failure, SGLT2 inhibitor treatment reduced the risk
which results in lowering of intraglomerular pressure38,39. Intraglo- of a kidney composite end point (sustained decrease in eGFR ≥50%
merular hypertension and hyperfiltration are hallmarks of DKD and from baseline, kidney failure (sustained eGFR <15 ml/min per 1.73 m²)
angiotensin-II is a potent pro-inflammatory cytokine that triggers kidney or death from kidney failure) by 37% (CI 42–31%), with similar effects
inflammation. To what extent this inflammation is prevented by RAS inhi- reported in those with and without diabetes, and across different CKD
bition is uncertain, which could in part explain the residual kidney risk aetiologies and baseline eGFR levels48.
of DKD progression in people with diabetes40,41. The adverse effects that Use of SGLT2 inhibitors is associated with an increased risk of
have been observed with RAS inhibitors are fairly mild, with hypoten- genital mycotic infections, which are usually non-serious and ame-
sion, dizziness and mild hyperkalaemia the most commonly reported, nable to non-prescription topical treatments. They also increase the
whereas ACE inhibitors may induce a dry cough42. 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 Given the detrimental consequences of ETA activation, ET-1 blockade
versus placebo)48. SGLT2 inhibitors may cause volume depletion and by ERAs has been pursued as a potential therapy for CKD and DKD57. In
hypotension, but unlike other pharmacological agents with diuretic animal and human studies, ERAs reduced albuminuria but were associ-
activity, they are not associated with electrolyte abnormalities and have ated with adverse effects of fluid overload and congestive heart failure
been shown to reduce the risk of clinically significant hyperkalaemia owing to ETB receptor blockade. This finding led to the development of
by 15–20%49. selective ERAs that target ETA alone. However, adverse effects remain
an issue as these selective ERAs do still have an effect on ETB58.
Mineralocorticoid receptor antagonists The largest kidney outcome study of a selective ERA to date is
Overactivation of the mineralocorticoid receptor in individuals with the SONAR trial of atrasentan19. This trial had a unique design with an
T2DM leads to increases in reactive oxygen species, inflammation active run-in period that was used to select participants with a UACR
and fibrosis. The MRA spironolactone has been shown to reduce decrease of ≥30% and no substantial fluid retention for inclusion in the
proteinuria and blood pressure in patients with DKD and CKD, but double-blind treatment phase. During a median follow-up of 2.2 years,
increase the risk of hyperkalaemia and hormonal adverse effects such a 35% (CI 12%–51%) reduction in the primary composite kidney end point
as gynecomastia50,51. Finerenone is a novel, selective, non-steroidal MRA (doubling of serum creatinine, kidney failure or death from kidney
that has similar activity in the heart and the kidneys52,53. disease) (Table 1) was observed in the atrasentan group compared
The FIDELIO-DKD trial, which enrolled individuals with CKD with the placebo group. Despite the exclusion of participants who were
and T2DM on maximum tolerated RAS inhibitor therapy, reported prone to developing fluid-related adverse effects during the active
that treatment with finerenone reduced the risk of CKD progression run-in period, fluid retention, anaemia and hospitalization for heart
(a composite of kidney failure, sustained decrease in eGFR of ≥40% failure (3.5% versus 2.6%) were more common in the atrasentan group19.
from baseline or death from kidney disease) compared with placebo Other selective ERAs including darusentan59 and avosentan (ASCEND
during a median follow-up of 2.6 years18. In this study, 17.8% of par- study)12 have also been shown to have beneficial effects on surrogate
ticipants in the finerenone group compared with 21.1% of those in the kidney end points such as albuminuria. However, the development of
placebo group (hazard ratio 0.82; 95% CI 0.73 to 0.93) met the primary these drugs was halted owing to safety issues related to fluid retention.
end point (Table 1). The FIDELITY pooled analysis of data from the
FIDELIO-DKD and FIGARO-DKD trials, which enrolled 13,026 individuals Glucagon-like peptide-1 receptor agonists
with T2DM and CKD, reported that at a median follow-up of 3.0 years, Glucagon-like peptide 1 (GLP1) is a gut-derived incretin hormone that
the c
­ omposite kidney outcome (kidney failure, sustained decrease in is produced following meal ingestion. Native GLP1 and GLP1 receptor
eGFR of ≥57% from baseline over ≥4 weeks or death from kidney disease) (GLP1R) agonists lower blood glucose by stimulating insulin secretion
occurred in 360 patients in the finerenone group (5.5%) compared with and suppressing glucagon release. They also lower blood pressure and
465 of those in the placebo group (7.1%) (HR 0.77; 95% CI 0.67–0.88)54. induce weight loss secondary to the slowing of gastric emptying and the
In addition to the kidney benefits, finerenone treatment also improved triggering of satiety through actions on the central nervous system60,61.
cardiovascular outcomes. The most problematic adverse effect of In large cardiovascular outcome trials, GLP1R agonists reduced
finerenone treatment is hyperkalaemia. The FIDELITY analysis reported CVD and cardiovascular mortality, including in participants with
that hyperkalaemia leading to permanent treatment discontinuation DKD62. Kidney disease outcomes were major secondary outcomes
occurred more frequently in the finerenone group than in the placebo in these trials63,64. Among participants with T2DM and eGFR 30 to
group (1.7% versus 0.6%), even though patients with serum potassium <60 ml/min/1.73 m2, treatment with GLP1R agonists reduced albu-
≥4.8 mM at the screening visit were excluded. In the FIDELIO-DKD trial, minuria and slowed annual eGFR decline to a level that was predic-
hyperkalaemia of any level occurred in nearly 20% of participants in tive of t-e prevention of kidney failure (>0.75 ml/min/1.73 m 2 per
the finerenone group compared with 10% in the placebo group trial55. year compared with placebo)64. In studies that included participants
Importantly, treatment with SGLT2 inhibitors was associated with a with DKD (eGFR <60 ml/min/1.73 m2), the kidney protective effects
lower frequency of hyperkalaemia in this trial. seemed to be more pronounced among those with higher levels of
Another non-steroidal MRA with high MRA specificity, esaxer­ eGFR at baseline65.
enone, is in development. In the ESAX-DN study, which included The results of mediation analyses of clinical trial data suggest that
455 patients with T2DM and UACR 45 to <300 mg/g who were treated changes in glucose levels, blood pressure and body weight only explain
with RAS inhibitors, esaxerenone markedly reduced microalbuminuria 10–25% of the observed kidney benefits of GLP1R agonists, indicating
compared with placebo56. A cardiovascular or kidney outcome trial of that direct actions of GLP-1 receptor agonists on the kidney have a
this drug has not yet been conducted. dominant effect66,67. In experimental studies, GLP1R agonists reduced
immune cell activity and the release of pro-inflammatory cytokines,
Endothelin receptor antagonists suggesting a potential kidney-protective mechanism68,69. GLP-1 recep-
The levels of endothelin-1 (ET-1), a vasoconstrictive factor that is tor agonists have also been shown to stimulate natriuresis and diuresis
­produced in the kidney by glomerular epithelial cells, mesangial in experimental models70, healthy volunteers71 and individuals with
cells and medullary collecting duct cells, are increased in people with overweight72 or diabetes73. As tubules lack a GLP1 receptor, inhibition of
CKD and DKD57. ET-1 binds to endothelin-1 receptor (ETA), which is the sodium hydrogen exchanger-3 has been proposed as a mechanism
localized on the afferent and efferent arterioles of the glomerulus, of GLP1-induced natriuresis73.
podocytes, mesangial cells, vasa recta and arcuate arteries, and Given the emerging body of preclinical and clinical evidence for
endothelin receptor type B (ETB), which is mainly expressed in the beneficial kidney effects of GLP1R agonists, these drugs are now being
collecting system57. Activation of ETA causes arteriolar vasoconstric- prospectively tested in people with DKD. The FLOW study is investigating
tion, podocyte dysfunction, cell proliferation, matrix accumulation and the effects of semaglutide on hard kidney outcomes in 3,534 partici­
inflammation, whereas ETB activation induces natriuresis and diuresis. 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 additional actions, including reducing hyperglycaemia and blood
kidney biopsy samples with the aim of identifying the molecular, struc- pressure. Combinations of these drugs will therefore be encountered
tural and functional actions of GLP1 receptor agonists in participants frequently in clinical practice. Information regarding the effects of
with DKD75. combination therapies can be deduced from animal models and post
hoc analyses of large trials. In addition, small mechanistic studies and
Non-pharmacological approaches to DKD trials that have been specifically designed to assess the kidney effects
Lifestyle interventions are a fundamental component of the care of of combination therapies have begun to emerge.
people with diabetes and CKD. Although high-quality randomized
clinical trials on lifestyle measures in this population are scant, advice Preclinical studies
regarding lifestyle should be reinforced at each clinical opportunity As multiple pathways in various kidney cell types are perturbed in
during intensification of pharmacological treatment. DKD89–93, use of combination therapies with the aim of achieving syner-
In people with CKD, low dietary sodium intake (<2 g or 90 mmol gistic benefit makes sense from a molecular perspective. In addition to
per day) is recommended to control extracellular fluid status and deepening our understanding of the molecular impact of combination
blood pressure, which are often increased in these salt-sensitive therapies, preclinical studies provide information regarding perturbed
individuals76–78. Low sodium intake is also associated with a lower inci- pathways in DKD that are not ameliorated with therapy, highlighting
dence of cardiovascular events in the general population and could opportunities for drug development.
benefit people with diabetes and CKD. Moreover, reduced sodium The effects of combination therapies using ACE inhibitors, thiazo-
intake enhances the blood pressure-lowering effects of RAS inhibitors79. lidinedione (TZD, which activates PPARγ and increases insulin sensitiv-
An ongoing study is assessing the effect of daily sodium intake on blood ity) and SGLT2 inhibitors were investigated using single-nucleus RNA
pressure, kidney function and kidney physiology in patients with T2DM sequencing in a mouse model of advanced DKD (db/db mice with unine-
who are receiving SGLT2 inhibitor therapy (DESIGN trial80). However, phrectomy and kidney renin overexpression)94. Although DKD induced
whether a low-sodium diet reduces DKD progression and the optimal transcriptional changes in all kidney cell types, the most prominently
sodium intake during the different phases of CKD and DKD is uncer- impacted were parietal epithelial cells, principal cells and endothelial
tain. Low protein intake may also prevent kidney function decline81, cells. The monotherapies preferentially rescued perturbed transcripts
potentially by reducing intraglomerular pressure82. in different cell types; TZD rescued about 40% of perturbed transcripts in
The prevalence of overweight and obesity is increased among the thick ascending limb (TAL) and principal cells, whereas SGLT2
individuals with T2DM and kidney disease compared with the general inhibitors rescued approximately 25% of perturbed transcripts in the
population. The LOOK AHEAD trial demonstrated a beneficial effect of TAL. Overall, the percentage of rescued genes was lower in podocytes,
weight loss induced by calorie restriction and physical activity on the juxtaglomerular apparatus and macula densa than in the TAL, which
risk of developing CKD, as demonstrated by reductions in UACR and may reflect lower cell numbers in these populations. Combination
eGFR83. Similarly, metabolic weight loss surgery was shown to protect therapy with ACE inhibitors and TZD rescued about 30% of transcripts
against CKD in individuals with and without T2DM, as reflected by in injured proximal tubule cells and 40% of those in the TAL, whereas
reductions in UACR and eGFR, stressing the importance of weight man- combination therapy with ACE inhibitors and SGLT2 inhibitors rescued
agement as part of lifestyle treatment84. Frequent physical activity is 30% of transcripts in injured proximal tubule cells and 20% of those in
associated with improved quality of life and a reduction in the incidence the TAL. The effects of combination therapies on the proximal tubule
of CVD in people with CKD85–87. However, exercise-based interventions were particularly pronounced, including a reduction in the number
are understudied in this population. The ongoing ACTIDIANE study88 of proximal tubule cells in an injured state, which was not seen with
will provide data on the effects of exercise on kidney function in people monotherapies. Moreover, ligand-receptor analysis, which predicts
with T2DM. The Kidney Disease: Improving Global Outcomes guideline interactions between different cell types, suggested that combina-
recommends a cumulative weekly duration of ≥150 min of physical tion regimens normalized signalling between glomerular endothelial
activity for people with CKD78. Last, smoking cessation is advised for cells and podocytes. As diabetes-induced changes differ between DKD
patients with all stages of diabetes and CKD78. stages and murine models95,96, careful research is needed to character-
ize how transcriptional changes reverse diabetes-induced perturba-
Combination therapies tions throughout all stages of the disease. Caution is also warranted
Despite the availability of several drugs with kidney-protective efficacy, as transcriptional changes in diabetic murine models do not always
the large number of end points reached in the active treatment arms closely align with those that occur in human DKD95. Aligning transcrip-
of the published trials clearly indicate that the number of individuals tome data from human kidney biopsy studies with that from murine
at risk remains high. Thus, a crucial question to address is whether models holds great promise in identifying shared ­transcriptional
combinations of these agents have increased kidney protective effi- changes in human and mouse DKD95.
cacy compared with the respective monotherapies. Given the differ- Other drug combinations have also been tested in preclinical
ing mechanisms of action of the available drugs (Fig. 1 and Table 1), studies. For example, in hypertensive renin-transgenic rats, finerenone
an additional benefit of combination therapies is plausible. Another combined with the SGLT2 inhibitor empagliflozin conferred greater
important consideration, particularly for patients with CKD who are reductions in proteinuria and histopathological kidney lesions than
at risk of polypharmacy, is whether different kidney-protective drugs either agent alone97. Moreover, in db/db mice, combined treatment
can be combined safely without inducing harmful interactions. On with the RAS inhibitor ramipril, empagliflozin and the ERA atrasentan
the other hand, the adverse effects that are associated with particular showed greater efficacy in preserving podocyte number and activat-
drug classes could potentially be mitigated by combination treatment ing the protective intrarenal ACE2–Ang–Mas pathway than any of
with other drug classes. Understanding interactions between the vari- the therapies alone98. Together these data suggest that combination
ous drug classes is also important because some of these classes have therapies may offer additional benefits compared with monotherapies.

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Human studies therapy with SGLT2 inhibitors and RAS inhibitors might protect against
RAS blockers and SGLT2 inhibitors. As outlined above, both RAS AKI by lowering GFR, leading to reduced kidney oxygen consumption
inhibitors and SGLT2 inhibitors reduce glomerular hypertension while maintaining perfusion39,103.
and hyperfiltration. RAS inhibitors induce vasodilation of the effer- The observation that SGLT2 inhibitors, likely in response to
ent arteriole by blocking the endothelial actions of angiotensin II, ongoing osmotic diuresis owing to glucosuria, activate the renin–
whereas SGLT2 inhibitors induce vasodilation of the efferent arteri- angiotensin–aldosterone system (RAAS), resulting in increased con-
ole secondary to activation of tubular glomerular feedback. These centrations of renin, angiotensin and aldosterone45, initially caused
similar glomerular haemodynamic actions could suggest reduced concern because chronic RAAS activation is known to be harmful for
efficacy when the drugs are used in combination38,39. However, post the heart and kidneys. However, the results of clinical trials of SGLT2
hoc analyses of large outcome trials showed that the kidney-protective inhibitors have alleviated these worries. A potential explanation
effects of SGLT2 inhibitors did not differ by RAS inhibitor background for SGLT2 inhibitor-induced cardiovascular and kidney protection
therapy. A meta-analysis of trials of SGLT2 inhibitors in patients with despite increased RAAS activity is that combined SGLT2 inhibitor
T2DM reported hazard ratios for the composite kidney end point and RAS inhibitor treatment activates alternative, non-classic RAAS
versus placebo of 0.52 (95% CI 0.37–0.74) and 0.65 (95% CI 0.30–1.39) pathways such as angiotensin 1–7 and Mas104, which are associated with
for participants who did and did not receive RAS inhibitors, respec- anti-fibrotic and anti-inflammatory effects40.
tively; the P value for interaction was not significant99. However, as
RAS inhibitors are standard of care for T2DM, <20% of the participants SGLT2 inhibitors and GLP1R agonists. Early studies such as DURA-
were not receiving this therapy, limiting the strength of the analysis. TION-8 in patients with T2DM, showed that combination treatment
Furthermore, bias by indication is an issue, as participants who were with SGLT2 inhibitors and GLP1 receptor agonists had greater benefi-
prescribed RAS blockers likely differed from those who did not receive cial effects on blood glucose levels, body weight and blood pressure
RAS blockade and could for example have experienced faster kidney in people with diabetes than either therapy alone105. These additive
disease progression. effects on kidney risk factors can be partially attributed to the distinct
Combination therapy with RAS inhibitors and SGLT2 inhibi- mechanisms of action of these drugs.
tors has also been investigated in mechanistic double-blind trials in A low percentage of participants in the GLP1R agonist trials
participants with T1D1 (ref. 100) and T2DM39. The BETWEEN study used SGLT2 inhibitors. The AMPLITUDE-O trial, which investigated
in young adults with T1DM (age 26 ± 4 years; BMI 26 ± 4 kg/m2; eGFR the cardiovascular and renal effects of efpeglenatide, had the larg-
120 ± 16 ml/min/1.73 m2) reported that empagliflozin–ramipril reduced est percentage of SGLT2 inhibitor users (15%)106. The effects of efpe-
iohexol-measured GFR by 8 ml/min/1.73 m2 compared with placebo– glenatide versus placebo on the kidney composite outcome were not
ramipril, suggesting a reduction in intraglomerular pressure, and modulated by SGLT2 inhibitor treatment (HR 0.70, 95% CI 0.59–0.83,
lowered urinary 8-isoprostane levels, suggesting a decrease in kidney and HR 0.52, 95% CI 0.33–0.83 for non-users and users, respectively;
oxidative stress100. Empagliflozin–ramipril also reduced systolic blood P for interaction > 0.2)107. By contrast, the results of mechanistic
pressure by 4 mmHg, diastolic blood pressure by 3 mmHg and total clinical trials suggest additive kidney protection with SGLT2 inhibi-
peripheral resistance compared with placebo–ramipril, indicating an tors and GLP1R agonists. In the DECADE study, 20 participants with
improvement in systemic haemodynamic function100. DKD and albuminuria completed three 6-week treatment periods,
The RECOLAR crossover trial in participants with T2DM (age during which dapagliflozin 10 mg daily, exenatide long-acting release
66 ± 6 years; BMI 31 ± 3 kg/m2; eGFR 90 ± 12 ml/min/1.73 m2), reported (LAR) 2 mg weekly and both drugs combined were given in a random
that combination therapy with empagliflozin (10 mg) and losartan order108. Combined dapagliflozin–exenatide LAR treatment resulted in
(50 mg once daily) reduced iohexol-measured GFR by 10.9 ml/min, a greater decrease in UACR (26%) than dapagliflozin (22%) or exenatide
3.7 ml/min and 3.4 ml/min and systolic blood pressure by 15 mmHg, LAR (8%) monotherapy. In the DECREASE randomized double-blind
7 mmHg and 3 mmHg compared with placebo, empagliflozin mono- placebo-controlled trial in patients with T2DM and obesity, combina-
therapy and losartan monotherapy, respectively39. These data indicate tion therapy with exenatide twice daily and dapagliflozin 10 mg daily
a clear additive effect of SGLT2 inhibitor and RAS inhibitor combina- resulted in a greater reduction in UACR at 16 weeks (40%), than mono-
tion therapy on markers of systemic and glomerular haemodynamic therapy with dapagliflozin (18%) or exenatide (16%). The dapagliflozin–
function that underlie kidney benefits. exenatide group also showed a greater initial drop in cystatin C eGFR
Combination therapy with drugs that induce reductions in glo- from baseline (−10.4 ml/min/1.73 m2) than the monotherapy groups109.
merular pressure could result in kidney hypoperfusion, particularly A larger initial drop in eGFR and UACR is generally associated with more
under conditions of illness with low fluid intake, potentially increas- favourable kidney outcomes over time.
ing the risk of AKI. Indeed, cases of AKI have been reported in patients Another trial used multiparametric MRI to investigate the kid-
who were receiving SGLT2 inhibitors and RAS blockers101. The risk of ney effects of combination therapy with a SGLT2 inhibitor and a GLP1
AKI in people using RAS inhibitors is poorly investigated. However, receptor agonist in participants with T2DM. This study found that the
a meta-analysis of data from SGLT2 inhibitor trials (in which 80% of SGLT2 inhibitor but not the GLP1 receptor agonist reduced medullary
participants received maximal tolerable doses of RAS inhibitors) sug- kidney oxygenation, whereas the GLP1 receptor agonist but not the
gested that these therapies reduce AKI risk48. This analysis found that SGLT2 inhibitor reduced kidney perfusion110. The combination therapy
allocation to SGLT2 inhibitor versus placebo reduced the risk of AKI reduced both medullary kidney oxygenation and kidney perfusion.
in patients with T2DM (HR 0.79, 95% CI 0.72–0.88; 1,622 events) and in The safety profiles in the combination therapy groups of these stud-
those without diabetes (HR 0.77, 95% CI 0.70–0.88; 2,010 events). As ies were similar to their profiles as individual drugs. Thus, these studies
AKI was not a primary or secondary end point in the SGLT2 inhibitor tri- indicate that SGLT2 inhibitor-GLP1 receptor agonist combination thera-
als, the results of ongoing dedicated trials are needed to confirm these pies may have additive kidney protection. This finding is supported
data102. From a mechanistic perspective, SGLT2 inhibitors or combined by real-world data showing that SGLT2 inhibitor and GLP1 receptor

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agonist combination therapy was associated with a reduction in major for heart failure19. Combination therapy with SGLT2 inhibitors, which
cardiac and cerebrovascular events and heart failure compared with increase red blood cell mass, induce diuresis and lower heart failure
other glucose-lowering drugs111. Whether this benefit extends to kidney hospitalization, could potentially ameliorate these adverse effects.
outcomes remains to be investigated. A post hoc analysis of the SONAR trial showed that among individuals
who were randomly assigned to atrasentan, those who were using
Combination therapies with MRAs. The interaction between finer- SGLT2 inhibitors experienced a greater reduction in UACR at 6 weeks
enone and other kidney-protective drugs has been investigated only (55%) than those who received the ERA alone (38%)117. Participants
a little. Owing to the timing of the FIDELIO-DKD and FIGARO-DKD tri- who received combination therapy also showed greater decreases
als of finerenone, the number of participants who were using SGLT2 in body weight, a marker of fluid retention and B-type natriuretic
inhibitors and/or GLP-1 receptor agonists was fairly low (877 (6.7%) and peptide, a biomarker of fluid congestion, than those who received
944 (7.2%), respectively), limiting the potential for robust subgroup atrasentan alone.
analyses18,112. In the FIDELITY pooled analysis of these trials, finerenone The efficacy and safety of combination therapy with the ERA
treatment versus placebo was associated with similar improvements in zibotentan and the SGLT2 inhibitor dapagliflozin are currently being
kidney outcomes in non-users and users of SGLT2 inhibitors (HR 0.80, investigated in the ZENITH-CKD study118 and the mechanistic ZODIAC
95% CI 0.69–0.92 in non-users and HR 0.42, 95% CI 0.16–1.08 in users trial119, both of which include patients with and without diabetes. Con-
at baseline; P interaction > 0.1)113. Similarly, no interaction was found current SGLT2 inhibitor therapy could reduce ETB blockade-induced
for the effect of finerenone on kidney end points in those who received fluid overload and drive the risk–benefit balance of zibotentan in a
a GLP1R agonist at baseline or at any point during the trial (HR 0.82, more favourable direction.
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 Combination therapies in T1DM. Little evidence is currently available
reduction with finerenone was observed in those using GLP1R agonists to inform the use of combinations of kidney-protective therapies in
versus non-users114. patients with T1DM. Studies of empagliflozin (EASE)120, dapagliflo-
A dedicated crossover study (ROTATE-3) has been conducted with zin (DEPICT)121 and the dual SGLT1 and SGLT2 inhibitor sotagliflozin
the steroidal MRA eplerenone and the SGLT2 inhibitor dapagliflozin. In (InTandem)122–124 in patients with T1DM have focused primarily on
this study, 46 participants with CKD who were receiving the maximum glucose management. However, post hoc analyses of the InTandem-1
tolerable dose of RAS inhibitors were treated with eplerenone 50 mg, and -2 (ref. 125) and the EASE-2 and -3 studies126 reported short-term
dapagliflozin 10 mg or their combination in a random order. The com- changes in eGFR and UACR similar to those seen in patients with T2DM.
bination treatment resulted in a greater reduction in UACR (53%) than The InTandem post hoc analysis reported that in participants with
eplerenone (33%) or dapagliflozin (34%) monotherapy, indicating an baseline UACR ≥30 mg/g, sotagliflozin 200 mg and 400 mg reduced
additive effect115. UACR by 24% and 18%, respectively, versus placebo125. The EASE post
As discussed above, the main limitation for the use of MRAs, includ- hoc analysis reported that in participants with baseline UACR ≥30 mg/g,
ing finerenone, is hyperkalaemia. A meta-analysis of six randomized 26 weeks of treatment with empagliflozin 10 mg (n = 71) and 25 mg
trials of SGLT2 inhibitors reported that these therapies reduced the risk (n = 77), reduced UACR by 16% and 30%, respectively, versus placebo
of clinically significant hyperkalaemia in participants with T2DM and (n = 65)126. A modelling analysis using data from the DEPICT studies and
high cardiovascular risk or CKD49. Moreover, in the ROTATE-3 study, dapa- the Steno Type 1 Risk Engine, found that the addition of SGLT2 inhibitor
gliflozin partly attenuated the eplerenone-induced increase in serum to standard of care for patients with T1DM could lead to a reduction in
potassium levels115. It is interesting to speculate that SGLT2 inhibitors the relative risk of developing kidney failure over 5 years of 5.3% in the
may increase the kidney-protective efficacy of MRAs while also increas- whole cohort and 7.6% in a subgroup with UACR >30 mg/g127. To date,
ing their potential use by mitigating hyperkalaemia. This hypothesis is studies of GLP1R agonists in participants with T1DM have investigated
currently being investigated in the phase II CONFIDENCE trial116. the effects on HbA1c, insulin dose and tolerability, but not on kidney
disease parameters.
Combination therapies with ERAs. Although the SONAR trial showed
kidney benefits of atrasentan, this drug is not currently used in the clinic Combination therapies in non-diabetic CKD. The DAPA-CKD trial17 of
owing to adverse effects of anaemia, fluid overload and hospitalization 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
Glossary 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,
Diabetes case-finding between two variables or conditions by cardiovascular or renal death) of 50%128. The EMPA-KIDNEY trial15 also
A systematic approach to identifying including a mediation variable. included participants with non-diabetic kidney disease (54% of the
patients with a disease. Active screening study population), including 1,669 patients with glomerular disease,
for hyperglycaemia has increased the Steno Type 1 Risk Engine and confirmed the DAPA-CKD results. A subsequent meta-analysis
detection of diabetes in the general A risk calculator that estimates reported that in patients with non-diabetic CKD who were receiving
population. the 10-year risk of fatal or non-fatal standard care, treatment with an SGLT2 inhibitor was associated with
cardiovascular disease in patients with a 31% reduction in the relative risk of progression of kidney disease48.
Mediation analyses type 1 diabetes mellitus. The calculator Participants who received SGLT2 inhibitors had an annual eGFR decline
Statistical models that seek to explain a incorporates clinical and biochemical of 1.6 ml/min/1.73 m2 compared with a mean decline in the placebo
mechanism that underlies a relationship risk parameters. group of 2.4 ml/min/1.73 m2.

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GLP1R agonists could potentially also have protective effects in of glucose, blood pressure and lipids and antiplatelet therapy are rec-
non-diabetic CKD but no conclusive studies in this population are avail- ommended if needed. The potential benefit of combining all agents
able. The ongoing SELECT study in patients with obesity129 will evaluate has not yet been tested in most trials. In addition, studies often do not
the effect of oral semaglutide on kidney outcomes as a secondary end provide evidence on the optimal sequence of drugs, whether all drugs
point. Several smaller studies in participants with obesity-related should be used in combination or if selection should be individualized.
kidney disease are planned or in progress, including the SMART trial, Although most of the available data are from subgroup analyses, most
which is investigating the effects of higher-dose semaglutide (2.4 mg guidelines have reached similar recommendations, which is reassuring
once weekly) on UACR, iohexol-GFR and blood pressure130. Whether and facilitates implementation134–137.
the kidney protective effects of non-steroidal MRA finerenone also
extend to non-diabetic CKD will be studied in the FIND-CKD trial131. Personalized medicine for DKD
Clinical guidelines base their recommendations on robust group-level
Clinical guidelines data from large randomized clinical trials. However, decisions in clini-
Providing guidance on the management of CKD and DKD was fairly cal practice are made on the individual level. A treatment benefit in a
straightforward when RAS inhibitors were the only treatment option, group of individuals does not necessarily mean that all individuals will
but these drugs were not very effective in halting disease progression. benefit equally. DKD is a heterogeneous disease with great variability
Newer guidelines have incorporated the growing evidence of proven in disease progression and treatment responses. Analyses of data from
kidney and cardiovascular protective benefits of multiple agents in randomized controlled trials of RAS inhibitors (RENAAL study) and
people with CKD and made recommendations on their combinations. SGLT2 inhibitors (CANVAS program) showed wide variation in the risk
A 2022 consensus report by the American Diabetes Association and of kidney failure (10–95%), indicating large inter-individual differences
the European Association for the Study of Diabetes recommended in baseline risk. Wide variation in the kidney benefits of RAS inhibitors
use of SGLT2 inhibitors for patients with T2DM and CKD, preferably in and SGLT2 inhibitors have also been observed (0–20%)138,139.
combination with GLP1R agonists if further glucose control is needed, At least two factors may contribute to these variations. First, a
because of the CVD benefit of these agonists in this population132. substantial proportion of people do not tolerate the guideline-advised
The 2022 Kidney Disease: Improving Global Outcomes guide- doses of therapies owing to adverse effects, resulting in suboptimal
line for diabetes management in CKD described a more comprehen- dosing and reduced efficacy. Second, physicians may not adhere to
sive approach for all individuals with T2DM and CKD with first-line optimal blood pressure targets for their patients. For example, guide-
treatment comprising RAS inhibitors and SGLT2 inhibitors for kidney lines recommend the use of optimal blood pressure target doses of ACE
protection with a statin and with metformin if needed for additional inhibitors and ARBs but in the DAPA-CKD trial, only 1,230 participants
glucose lowering133. They suggest the addition of a non-steroidal-MRA (28.6% of the total cohort) received the maximal tolerable dose of RAS
with proven kidney or cardiovascular benefit for those with residual blockers140. A similar proportion of suboptimal dosing of RAS inhibi-
albuminuria (≥30 mg/g) despite use of the maximum tolerated dose of tors was reported in the FIGARO trial19. In the SONAR trial, 10% of par-
RAS inhibitor and of GLP1R agonists for additional glycaemic control ticipants discontinued atrasentan during the open-label active run-in
and CVD benefits. ERAs have not been approved for use in patients with period because of fluid retention, oedema and heart failure19. These
T2DM and CKD and are not recommended for use in this population data indicate that not every patient will derive the same benefit from
owing to their adverse effects. Additional medications for the control the current guideline-recommended therapies, supporting the need

Box 1

Personalization of combination therapy

The advent of novel kidney protective drugs will likely lead to a new Patient B
era of personalized management of diabetic kidney disease (DKD) in A lean (BMI 24 kg/m2) patient with heart failure (NYHA class III; NTproBNP
which combinations of therapies are tailored to individual patients. 850 pg/ml), DKD (eGFR 53 ml/min/1.73 kg/m2; UACR 109 mg/mmol) and
Although patients could potentially be stratified based on histological well-controlled diabetes (HbA1c 7.1%) may benefit from combined
or serum biomarkers, a simpler approach is to initiate treatment based SGLT2 inhibitor and finerenone treatment. Both drugs improve heart
on readily available clinical characteristics. Here, we provide three failure and kidney outcomes.
hypothetical examples of such personalization. Please note that
these examples are based on mechanisms of action and data from Patient C
individual drug trials, not on data from trials of combination therapies. 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
Patient A 35 mg/mmol) might benefit most from SGLT2 inhibitor and ERA
An overweight (BMI 35 kg/m2) patient with DKD (eGFR 46 ml/min/ treatment. This combination does not increase hyperkalaemia and
1.73 kg/m2; UACR 52 mg/mmol) and uncontrolled diabetes (HbA1c likely offers incremental kidney protection. Potassium binders could
9.6%) may benefit from combined SGLT2 inhibitor and GLP1 receptor be given to enable use of maximal RAS blocker therapy in the case
agonist treatment. GLP-1 receptor agonists lower BMI and both of mild hyperkalaemia.
treatments improve hyperglycaemia.

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for approaches that are tailored to the needs and characteristics of indi- to the four drug classes. The best-performing drugs for the individuals
vidual patients. An individualized treatment approach also provides the reduced albuminuria by 40%, whereas albuminuria increased by 2%
opportunity to minimize drug use by selecting the optimal treatment, with the sub-optimal drugs. Moreover, 75% of participants achieved
instead of layering multiple therapies, leading to a large pill burden, the >30% reduction in albuminuria recommended by the American
potential drug–drug interactions, adverse effects and non-adherence. Diabetes Association diabetes guidelines with their best-performing
Unprecedented progress in molecular, genetic, bioinformatic and drug, but only 33% met this target with their first drug141.
imaging technologies has increased understanding of the pathophysi- As DKD is a progressive disease, many people will likely require
ology of DKD and provides the opportunity to phenotype patients in more than one therapy to slow disease progression or to mitigate
more detail than ever before. These approaches could aid the discovery adverse effects. A key question is which combination should be used
of novel molecular markers that predict the responses of individuals to for which patient? In the future, readily available clinical characteristics
treatment. However, despite extensive efforts, these new technologies of individuals may be used to tailor optimal combinations (Box 1). The
have not yet delivered any adequately validated biomarker sets (such ultimate clinical benefit of this approach should ideally be tested in a
as urine, plasma or imaging-based biomarkers) that predict responses randomized controlled trial.
to the current guideline-recommended treatments.
Alternative approaches to predictive biomarkers have been Conclusions and future perspectives
explored. Instead of predicting the response of an individual to a treat- DKD is a prevalent and severe complication of diabetes that amplifies
ment before its initiation, biomarkers could be measured after a few the risk of kidney failure and CVD. Despite efforts to control blood
weeks of treatment to predict if the patient will ultimately benefit from glucose levels, blood pressure and proteinuria through lifestyle modi-
the therapy. This approach was applied in a multicentre crossover study fications and pharmacological interventions, many individuals still
in 63 patients with T1DM or T2DM and CKD that assessed whether experience kidney disease progression. Novel therapeutic approaches,
rotation through four drug classes can optimize albuminuria-lowering such as SGLT2 inhibitors, a non-steroidal MRA and selective ERAs, have
therapy by selecting the best drug for each individual141. As expected, the demonstrated efficacy in slowing deterioration of kidney function.
study showed substantial variation between the participants in response 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,
2
80
high sodium diet multiparametric kidney MRI
ACTIDIANE (NCT03184662) Physical activity twice eGFR >30 ml/min/1.73 m2, eGFR loss Cystatin-C derived eGFR at 2 years 88
weekly >5 ml/min per year (300)
REMODEL (NCT04865770) Semaglutide 1.0 mg T2DM, eGFR 60–90 ml/min/1.73 m2, Multiparametric kidney MRI, biopsy substudy 75
UACR 20–5,000 mg/g (105) (histology, scRNAseq)
FLOW (NCT03819153) Semaglutide 1.0 mg 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
MERCURI-2 (NCT05590143) Dapagliflozin 10 mg Patients undergoing cardiac surgery, AKI according to KDIGO criteria 102
eGFR >30 ml/min/1.73 m2 (784)
CONFIDENCE (NCT05254002) Finerenone 10 mg and eGFR 40–90 ml/min/1.73 m2, Change in UACR 116
empagliflozin 10 mg UACR 300–5,000 mg/g (807)
ZENITH-CKD (NCT04724837) Zibotentan 0.25 mg or eGFR ≥20 ml/min/1.73 m2, Change in UACR 118
1.5 mg, dapagliflozin 10 mg UACR 150–5,000 mg/g (542)
ZODIAC (NCT05570305) Zibotentan 1.5 mg, T2DM, eGFR ≥30 ml/min/1.73 m2, Change in UACR, change in measured GFR 119
dapagliflozin 10 mg UACR 100–3,500 mg/g (38)
SELECT (NCT03574597) Semaglutide 2.4 mg 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)
SMART (NCT04889183) Semaglutide 2.4 mg No diabetes, BMI ≥27 kg/m2, Change in UACR 130
UACR 30–3,500 mg/g,
eGFR ≥25 ml/min/1.73 m2 (98)
FIND-CKD (NCT05047263) Finerenone 10-20 mg 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)
NA (NCT04170543) Tozorakimab (doses 1-4) T2DM, eGFR 25–75 ml/min/1.73 m2, Change in UACR 144
UACR 100–3,000 mg/g (565)
TREASURE (NCT05536804) Tirzepatide 15 mg T2DM or non-diabetic CKD, eGFR Multiparametric kidney MRI, 11C-acetate PET 150
≥30 to ≤ 60 ml/min/1.73 m² (140)
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.

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the heterogeneous nature of kidney lesions and their diverse patho- These ongoing studies will determine the efficacy of novel com-
physiological drivers. These findings underscore the need for inno- pounds to reduce kidney risk; however, other unmet needs remain to be
vative or combined therapeutic strategies that target these distinct addressed. Longer-term outcome studies are needed to better define
­pathophysiological defects (Fig. 1) to further mitigate this risk. the effects of kidney-protective interventions in non-albuminuric
Evidence of the additive effects of specific drug classes on the DKD, which tends to progress more slowly than albuminuric DKD
acute reduction of eGFR, UACR and blood pressure suggests potential but accounts for a large number of cases of kidney failure. This prob-
benefits of combination therapies. However, determining which indi- lem was particularly evident in trials that enrolled participants with
viduals will benefit from specific drugs remains a challenge. The con- non-albuminuric and albuminuric DKD and reached their end point
cept of personalized medicine, which tailors treatments to the unique early, such as several SGLT2 inhibitor trials. A need also exists for better
needs and characteristics of individuals, is becoming increasingly understanding of the distinct pathological and molecular features
plausible as the variety of kidney-protective medications expands. Out- that distinguish DKD in T1DM and T2DM, as well as obesity-related
come trials involving combination therapies and mechanistic studies nephropathy and DKD in T2DM. Further efforts to reduce the kidney
can expedite the development of precision-based medicine (Table 2). burden in people with T1DM are also needed. Finally, whether specific
A deeper understanding of the mechanisms through which treatments drugs are more efficacious at different phases of disease is currently
affect different individuals may enable prediction of which patients are unclear and requires further study.
likely to respond favourably or unfavourably to specific medications The results of ongoing and future mechanistic and outcome stud-
or therapy combinations. The mechanistic REMODEL study75, which ies will provide crucial evidence to potentially improve the manage-
is a sister trial to the large-scale outcome FLOW trial142, exemplifies ment of DKD using combination therapies. Greater understanding of
this approach. REMODEL is incorporating paired biopsy samples and the pathways of beneficial and adverse effects of kidney-protective
comprehensive kidney MRI with the aim of enhancing understanding drugs will enable researchers to develop more targeted and effective
of the mechanisms of action of the GLP1R agonist semaglutide in adults therapies and move towards precision medicine for DKD. In the future,
with T2DM and CKD. advanced techniques for tissue interrogation may be used to inform
In addition to traditional mechanistic studies, advanced tech- the optimal choice of combination therapies for patients with DKD.
niques for tissue interrogation, such as spatial transcriptomics, spa-
tial proteomics and spatial metabolomics, are being developed and Published online: xx xx xxxx
employed. These techniques enable researchers to study biological
processes at single-cell resolution. The effects of therapies can also References
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140. Chertow, G. M. et al. Effects of dapagliflozin in chronic kidney disease, with and without Author contributions
other cardiovascular medications: DAPA-CKD trial. J. Am. Heart Assoc. 12, e028739 (2023). All authors researched data for the article, contributed substantially to discussion of the
141. Curovic, V. R. et al. Optimization of albuminuria-lowering treatment in diabetes by content, wrote the article and reviewed and/or edited the manuscript before submission.
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142. A research study to see how semaglutide works compared to placebo in people with type 2 D.H.V.R. has consulting relationships with Bayer, Boehringer Ingelheim, Eli Lilly, Merck and
diabetes and chronic kidney disease (FLOW). ClinicalTrials.gov https://clinicaltrials.gov/ Sanofi, and receives research operating funding from AstraZeneca, Boehringer Ingelheim-Eli
study/NCT03819153 (2024). Lilly Diabetes Alliance and MSD. Honoraria are transferred to employer Amsterdam UMC.
143. Heerspink, H. J. L. et al. Design of FLAIR: a phase 2b study of the 5-lipoxygenase P.B. reports serving or having served as a consultant for AstraZeneca, Bayer, Bristol-Myers
activating protein inhibitor AZD5718 in patients with proteinuric CKD. Kidney Int. Rep. 6, Squibb, Boehringer Ingelheim, Eli Lilly, LG Chemistry, Sanofi, Novo Nordisk and Horizon
2803–2810 (2021). Pharma. P.B. also serves or has served on the advisory boards and/or steering committees
144. A phase 2b diabetic kidney disease study. ClinicalTrials.gov https://clinicaltrials.gov/ of AstraZeneca, Bayer, Boehringer Ingelheim, Novo Nordisk and XORTX. P.B. receives grant
study/NCT04170543 (2023). support from Eli Lilly, Novo Nordisk, AstraZeneca, Merck, and Horizon Pharma. D.Z.I.C. reports
145. Frimodt-Moller, M., Persson, F. & Rossing, P. Mitigating risk of aldosterone in diabetic serving or having served as a consultant for Boehringer Ingelheim-Lilly, Merck, AstraZeneca,
kidney disease. Curr. Opin. Nephrol. Hypertens. 29, 145–151 (2020). Sanofi, Mitsubishi-Tanabe, AbbVie, Janssen, Bayer, Prometic, BMS, Maze, Gilead, CSL-Behring,
146. Stasch, J. P., Schlossmann, J. & Hocher, B. Renal effects of soluble guanylate cyclase Otsuka, Novartis, Youngene, Lexicon, Inversago, GSK and Novo-Nordisk. He has received
stimulators and activators: a review of the preclinical evidence. Curr. Opin. Pharmacol. operational funding from Boehringer Ingelheim-Lilly, Merck, Janssen, Sanofi, AstraZeneca,
21, 95–104 (2015). CSL-Behring and Novo-Nordisk. I.H.D.B. has received consulting fees from AstraZeneca,
147. Fantus, D., Rogers, N. M., Grahammer, F., Huber, T. B. & Thomson, A. W. Roles of mTOR Bayer, Boehringer-Ingelheim, Cyclerion Therapeutics, George Clinical, Gilead, Goldfinch
complexes in the kidney: implications for renal disease and transplantation. Nat. Rev. Bio, Ironwood, Medscape and Otsuka. P.F. has received fees as consultant and speaker for
Nephrol. 12, 587–609 (2016). AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly company and Novo Nordisk. D.G. has
148. Heerspink, H. J. L. et al. Effects of tirzepatide versus insulin glargine on kidney received lecture or Advisory Board Honoraria from AstraZeneca, Bayer, Boehringer Ingelheim,
outcomes in type 2 diabetes in the SURPASS-4 trial: post-hoc analysis of an open-label, Delta Medical Communications, EASD eLearning, Finnish Association for Vascular Surgery,
randomised, phase 3 trial. Lancet Diabetes Endocrinol. 10, 774–785 (2022). Finnish Nephrology Association, Kidney and Liver Foundation in Finland. F.P. has served as
149. Hammoud, R. & Drucker, D. J. Beyond the pancreas: contrasting cardiometabolic actions a consultant, on advisory boards or as educator for AstraZeneca, Novo Nordisk, Boehringer
of GIP and GLP1. Nat. Rev. Endocrinol. 19, 201–216 (2023). Ingelheim, Sanofi, Mundipharma, MSD, Novartis and Amgen, and has received research grants
150. A study of tirzepatide (LY3298176) in participants with overweight or obesity and chronic to institution from Novo Nordisk, Boehringer Ingelheim, Amgen and AstraZeneca. S.E.R. has
kidney disease with or without type 2 diabetes (TREASURE-CKD). ClinicalTrials.gov participated as a member of scientific advisory boards for AstraZeneca, Bayer, and Travere.
https://clinicaltrials.gov/study/NCT05536804 (2024). P.R. has received research support and personal fees from AstraZeneca, Bayer, and Novo
151. Ruiz-Andres, O. et al. Downregulation of kidney protective factors by inflammation: Nordisk and personal fees from Abbott, Astellas, Bayer, Boehringer Ingelheim, Eli Lilly, Gilead
role of transcription factors and epigenetic mechanisms. Am. J. Physiol. Renal Physiol. and Sanofi. All fees are given to Steno Diabetes Center Copenhagen. K.T. reports consulting
311, F1329–F1340 (2016). relationships with Eli Lilly, Boehringer Ingelheim, AstraZeneca, Pfizer, Bayer and Novo Nordisk,
152. Mora-Fernandez, C. et al. Sodium-glucose co-transporter-2 inhibitors increase Klotho and receives research grants from Travere paid to employer, Providence Inland Northwest
in patients with diabetic kidney disease: a clinical and experimental study. Biomed. Health. S.S.W. is consultant for Wolters Kluwer, Bain, BioMarin, Goldfinch, GSK, Ikena, Strataca,
Pharmacother. 154, 113677 (2022). Google, CANbridge, NovoNordisk, PepGen, Sironax and NovoNordisk, and expert witness
for Davita, Pfizer, Dechert and Aurinia Pharmaceuticals. S.S.W. receives research funding
Acknowledgements from Vertex, Pfizer, JNJ and Natera. H.J.L.H. is consultant for AstraZeneca, Bayer, Boehringer
D.H.V.R. is supported by a senior fellowship of the Dutch Diabetes Foundation and by a Ingelheim, Chinook, CSL Behring, Dimerix, Eli-Lilly, Gilead, Janssen, Merck, Novo Nordisk,
PIONEER + grant of the Dutch Kidney Foundation. P.B. receives salary and research support ProKidney, Travere Therapeutics and Vifor Fresenius. He has received research support from
from the NIDDK (R01 DK129211, R01 DK132399, RO1 HL165433, R21 DK129720 and UC2 AstraZeneca, Boehringer Ingelheim, Janssen and Novo Nordisk.
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 Additional information
Family Center for Women’s Health Research at the University of Colorado, the Department Peer-review information Nature Reviews Nephrology thanks Mark Cooper, Beatriz
of Paediatrics, Section of Endocrinology, and the Barbara Davis Center for Diabetes at Fernandez-Fernandez and Pierre-Jean Saulnier for their contribution to the peer review
University of Colorado School of Medicine. I.H.D.B. is supported by NIH grants R01DK125084, of this work.
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 Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in
Läkaresällskapet), Sigrid Juselius Foundation, Helsinki University Hospital, University of published maps and institutional affiliations.
Helsinki, Minerva Foundation Institute for Medical Research Clinician Scientist, and Academy
of Finland (UAK1021MRI). S.E.R. reports research support from AstraZeneca, Bayer and Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this
NIH/NIDDK [U01DK133092 and U01DK116102] to Joslin Diabetes Center. She also benefited article under a publishing agreement with the author(s) or other rightsholder(s); author
from participation in the Joslin Diabetes research enrichment program funded by P30 self-archiving of the accepted manuscript version of this article is solely governed by the
DK03836. J.A.S. received salary support provided by K08DK124449. K.T. is supported by NIH terms of such publishing agreement and applicable law.
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, © Springer Nature Limited 2024
U01AG076789 and R25DK128858.

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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