Received: 20 December 2022 Revised: 30 May 2023 Accepted: 30 May 2023

DOI: 10.1111/dom.15181

REVIEW ARTICLE

Management of the ‘wicked’ combination of heart failure and

chronic kidney disease in the patient with diabetes

David S. H. Bell MB 1 | Janet B. McGill MD 2 | Terri Jerkins MD 3

1
Southside Endocrinology, Irondale,
Alabama, USA Abstract
2
Division of Endocrinology, Metabolism and Patients with type 2 diabetes are at an increased risk of developing heart failure and
Lipid Research, Washington University School
of Medicine, St. Louis, Missouri, USA chronic kidney disease. The presence of these co-morbidities substantially increases
3
Midstate Endocrine Associates, Nashville, the risk of morbidity as well as mortality in patients with diabetes. The clinical focus
Tennessee, USA
has historically centred around reducing the risk of cardiovascular disease by targeting
Correspondence hyperglycaemia, hyperlipidaemia and hypertension. Nonetheless, patients with type
David S. H. Bell, MB, Southside Endocrinology,
2 diabetes who have well-controlled blood glucose, blood pressure and lipid levels may
1900 Crestwood Boulevard, Suite 201,
Irondale, AL 35210, USA. still go on to develop heart failure, kidney disease or both. Major diabetes and car-
Email: dshbell@yahoo.com diovascular societies are now recommending the use of treatments such as sodium-
Funding information glucose co-transporter-2 inhibitors and non-steroidal mineralocorticoid receptor
Bayer antagonists, in addition to currently recommended therapies, to promote cardiorenal pro-
tection through alternative pathways as early as possible in individuals with diabetes and
cardiorenal manifestations. This review examines the most recent recommendations for
managing the risk of cardiorenal progression in patients with type 2 diabetes.

KEYWORDS
cardiovascular disease, chronic kidney disease, diabetic nephropathy, heart failure, type
2 diabetes

1 | I N T RO DU CT I O N leading cause of end-stage kidney disease (ESKD).7,8 In 2021, the

The increasing prevalence of type 2 diabetes (T2D) is a growing clini-
1
cal burden worldwide. Heart failure (HF) and chronic kidney disease
(CKD) are common complications that often occur in individuals with
T2D, and the presence of both HF and CKD significantly increases
morbidity and mortality in this group.2
HF often presents as the first cardiovascular (CV) event in
patients with T2D3 and affects more than 30% of such patients, mak-
ing it a major cause of mortality in this population.4 Patients with
established T2D have a 33% higher risk of hospitalization for heart
5
failure (hHF) than individuals without diabetes. Patients with HF and
prediabetes are also at a greater risk of all-cause mortality and cardiac
events compared with those with normoglycaemia.6 Diabetic kidney
disease (DKD) is observed in 40% of patients with T2D, and is the
global prevalence of diabetes was more than 500 million individuals
worldwide, and this number is expected to rise to more than 750 million
in 2045.9 It is therefore essential to optimize treatment strategies
for managing both HF and CKD to decrease global morbidity and
mortality.10
Management of T2D has notably improved over the last two
decades, largely by focusing on the optimization of blood glucose,
blood pressure and lipid levels. Despite reaching treatment goals with
current strategies, a residual risk for developing HF and CKD
remains.11 Cardiac and renal complications associated with T2D can
arise together and co-exist as cardiorenal syndrome (CRS).12 CRS
describes the interplay between the heart and kidney and classifica-
tions of such syndromes arose based on initial organ damage or insult
(heart or kidney), and whether the disorders were acute or chronic.12

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© 2023 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Diabetes Obes Metab. 2023;1–10. wileyonlinelibrary.com/journal/dom 1


2 BELL ET AL.
The CRS categories acknowledge that HF, whether acute or chronic, can
lead to kidney damage with a reduced estimated glomerular filtration
rate (eGFR). The opposite is also true, in that progressive kidney damage
can lead to HF with congestion.13 The bidirectional interaction of HF
and kidney disease can be seen from placebo groups of major CV out-
comes trials such as DAPA-HF,14 EMPEROR-Reduced15 and
EMPEROR-Preserved. 16
These show the presence of CKD in partici-
pants with HF. In addition, patients with CKD typically also present with
HF, such as in DAPA-CKD17-19 and CREDENCE.20 There was presence
of HF in all participants, both with or without T2D.21 Notably, the major
recent clinical trials did not use CRS categories as entry criteria, but did
capture onset or progression of CKD. As such, future meta-analyses may
add insights into this combined disorder.
The emergence of effective treatments such as sodium-glucose
co-transporter-2 (SGLT2) inhibitors and non-steroidal mineralocorti-
coid receptor antagonists (MRAs) highlights the importance of tar-
geting alternative pathways to improve cardiorenal outcomes in
patients with T2D. Major diabetes and cardiology societies22–25 are
updating their guidelines by recommending these targeted
26
approaches. Here, we review the clinical rationale for initiating
cardiorenal-protective therapy beyond the traditional risk factor-
reduction strategies of hyperglycaemia, hypertension and dyslipi-
daemia in individuals with T2D and summarize the evidence for its
benefit.
F I G U R E 1 Pathophysiology underlying HF and CKD in patients with type 2 diabetes. CKD, chronic kidney disease; HF, heart failure; LV, left
ventricle; RAAS, renin–angiotensin–aldosterone system; SNS, sympathetic nervous system
14631326, 0, Downloaded from https://dom-pubs.onlinelibrary.wiley.com/doi/10.1111/dom.15181 by Cochrane Germany, Wiley Online Library on [22/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
2 | LI T E RA T U R E S E A R CH S T RA T E GY
In preparation for this review, we searched the PubMed database for
articles published until July 2022. We identified articles on the man-
agement of CKD and HF using the terms ‘chronic kidney disease’ and
‘HF’. Articles on clinical studies related to the management of CKD
associated with T2D were identified using the terms ‘diabetes’,
‘kidney’, ‘management’, ‘treatment options’, ‘SGLT2 inhibitors’ and
‘MRAs’. We also reviewed the reference lists of articles identified in
these searches for other relevant papers illustrating pathophysiology
underlying HF and CKD in T2D.
3 | THE P ATHOPHYSIO LO GY
U N DE R L Y I N G H F A N D C K D I N T 2 D
The pathogenesis of HF and CKD in patients with T2D can be attrib-
uted to the disrupted metabolic pathways associated with hypergly-
caemia, hypertension, inflammation and fibrosis.27 As previously
mentioned, a bidirectional interaction between the heart and the
kidneys exists (Figure 1). In addition, the sympathetic nervous sys-
tem (SNS) and the renin–angiotensin–aldosterone system (RAAS)
contribute to the stimulation of pathways associated with HF and
CKD.28

BELL ET AL.
The aetiology of HF in patients with T2D can be explained
through the cardiotoxic triad of diabetic cardiomyopathy, hyperten-
1
sion and coronary artery disease (CAD). The term diabetic cardiomy-
opathy describes ventricular dysfunction in individuals without
29
hypertension and CAD. The term can also be used to describe myo-
cardium dysfunction that is prevalent in patients with diabetes.30 The
presence of myocardial ischaemia is thought to induce changes in car-
diac biochemistry. Impaired cardiac cells and tissues contribute to
reduced cardiac function and are linked to abnormalities in
electrophysiology.1,31
Cardiac ischaemia, whether attributable to large or small vessel
disease, is responsible for pathophysiological changes in the myocar-
dium.1,32 This myocardial dysfunction, combined with hypertension,
leads to fibrosis and dysregulated systolic function; the process is fur-
ther aggravated by activation of the renin–angiotensin system (RAS)
and the SNS. The result is a loss of cardiac myocytes and development
of HF.1,32 RAS and SNS activation causes disorganized compensatory
cellular hypertrophy that is also known as ‘cardiac remodel-
1,32
ling’. A state of dysregulated gene expression lowers both dia-
stolic and systolic ventricular function, and is thought to influence
HF progression.1,33 Reduced ventricular function may arise as a
means to lessen the energy expenditure of the dysfunctional/
1,33
weakened myocardium.
Macrovascular cardiac impairments, such as myocardial infarction,
34
are common in patients with T2D. Vascular dysfunction may result
from oxidative stress, which occurs when there is an imbalance of
endogenous oxidants and antioxidants.35 The presence of oxidative
stress may accumulate from varying factors. This loss in redox homeo-
stasis in reactive oxygen species (ROS) and reactive nitrogen species
amounts to activation of the immune system and a proinflammatory
and profibrotic environment. Although physiological levels of ROS are
essential for proper cell function, overproduction of these molecules
is known to stimulate both cardiac and renal dysfunction.35–37 It is
important to note that, in the kidney and vascular tissues, oxidative
stress leads to hypertension, while hypertension also promotes oxida-
tive stress.37 Together, oxidative stress and inflammation are critical
36
in CKD-related pathologies. Furthermore, inflammation and oxida-
tive stress contribute to the structural and functional diastolic dys-
38
function observed in HF with preserved ejection fraction (HFpEF).
Inflammation promotes fibrotic tissue production, impairing opti-
mal myocyte contraction and resulting in suboptimal cardiac func-
tion.28,39 Fibrosis is a crucial aspect of tissue repair and is regarded as
a pathological phenomenon that is prevalent in chronic inflammatory
diseases.40 Overactive fibrosis can lead to the development of HF and
41
CKD (Figure 1).
In endothelial cells, mineralocorticoid receptor (MR) activation
leads to higher levels of ROS, resulting in oxidative stress, which is
associated with vascular inflammation.42 Based on evidence from ani-
mal models and from studies on primary hyperaldosteronism, aldoste-
rone has been reported to cause left ventricular (LV) remodelling by
inducing cardiomyocyte hypertrophy, chronic inflammation and extra-
cellular matrix dysregulation.43,44 The underlying mechanism involves:
activation of extracellular signal-regulated kinases, c-Jun N-terminal
14631326, 0, Downloaded from https://dom-pubs.onlinelibrary.wiley.com/doi/10.1111/dom.15181 by Cochrane Germany, Wiley Online Library on [22/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
3
protein kinases and protein kinase c-alpha44; phosphorylation of both
light- and heavy-chain myosin; and production of cardiotrophin-1,
which can cause cardiomyocyte hypertrophy and increase the expres-
sion of myosin light chains.45 Aldosterone also promotes inflammatory
cytokine formation,46 macrophage activation and macrophage proin-
flammatory factor production, while also increasing the expression of
intercellular adhesion molecules on endothelial cells, which facilitate
macrophage attachment to the endothelium. The ensuing fibrosis of
the myocardium occurs when degradation of the extracellular matrix
by metalloproteinases is exceeded by matrix production.43 This leads
to decreased contractility, non-compliant ventricles, as well as
increased myocardial ischaemia. Fibrosis, in addition to LV hypertro-
phy, results in both systolic and diastolic dysfunction. The damage to
the myocardium may also be exacerbated by a high-salt diet.47
Hyperglycaemia disrupts intraglomerular pressure control and
leads to intraglomerular hypertension in the kidneys, which has been
shown to activate metabolic pathways that contribute to the accumu-
lation of ROS48; this, in turn, leads to mitochondrial dysfunction, as
well as upregulation of pro-oxidant enzymes.48 Abnormal glucose
metabolism and dysregulated intracellular signalling also contribute to
inflammation, fibrosis, and endothelial and epithelial injury, resulting
in CKD.27 Evidence suggests that MR overactivation promotes inflam-
mation and fibrosis, as well as influencing the progression of CKD and
cardiovascular disease (CVD).49
4 | THE I MPORTA NC E OF M ONITO R ING
C A R D I O R E N A L R I S K I N P A T I E N T S W I T H T2 D ,
HF AN D CK D
The co-existence of cardiorenal complications in patients with T2D is
common; thus, it is important to conduct routine monitoring of T2D
patients to assess their risk of developing HF and CKD.
For CKD screening, the American Diabetes Association (ADA)
guidelines recommend an annual assessment of urinary albumin levels
and eGFR in all patients with T2D, regardless of treatment.22,50 Guid-
ance from the 2023 ADA Standards of Care for CKD and risk manage-
ment also advise that patients with established DKD should be
monitored multiple times a year to guide therapy.50 Monitoring serum
potassium in patients taking diuretics is important to prevent cardiac
arrythmias caused by hypokalaemia. Individuals receiving angiotensin-
converting enzyme (ACE) inhibitors, angiotensin receptor blockers
(ARBs) or MRAs should also have their medication dosages adjusted
to diminish additional CKD-related risks.22
The presence of LV hypertrophy is common in patients with T2D
and is also a major CVD risk.51 Somaratne et al.51 reported that even
echocardiograms are insufficient to detect LV hypertrophy, but are
superior to N-terminal pro-B-type natriuretic peptide levels and elec-
trocardiograms, and thus highlights the need for alternative tools to
detect LV hypertrophy in patients with T2D. Meanwhile, the preva-
lence of LV hypertrophy, as measured by echocardiography, in asymp-
tomatic patients with T2D is high,51 and routine screening for
patients with T2D who are asymptomatic for CVD is not

4 BELL ET AL.
recommended at this time, provided atherosclerotic CVD risk factors
are treated as per the 2023 ADA guidelines.52
53
Hadjkacem et al. reviewed the value of assessing masked arte-
rial hypertension (HTN). Masked HTN (MHTN) is associated with
CVD risk, a risk that is similar to that of permanent HTN and is com-
mon in patients with T2D. The results revealed that systematic
screening for MHTN through 24-hour blood pressure monitoring in
patients with T2D provided an insightful indication of CVD risk. This
investigation emphasizes the need for screening tools to ensure opti-
mal monitoring of cardiorenal risk to facilitate timely clinical interven-
tion for patients with T2D.
The TOPCAT trial noted that more than one-third of participants
with T2D and HFpEF had microvascular complications and a greater
number of adverse outcomes than those without microvascular dis-
38,54
ease. The report from the trial recommends that during routine
screening of patients with T2D, physicians should also take note of
structural and functional changes of the heart, eyes, kidneys and
peripheral nerves to prevent further adverse outcomes. Therefore,
routine monitoring of patients with T2D for early renal damage is not
only a key component for delaying CKD progression through testing
for eGFR and albuminuria, but also contributes to improved CVD risk
stratification.55
5 | T R E A T M E NT S S H O W N T O I M P R O V E
H F A N D C K D I N P A T I E N T S W I T H T 2D
5.1 | The role of SGLT2 inhibitors in the
management of HF and for improving renal outcomes
SGLT2 inhibitors are able to improve cardiorenal outcomes through
various mechanisms of action, including via reductions in blood pres-
sure, arterial stiffness and endothelial dysfunction.14 A shift in bioen-
ergetics may also explain the beneficial CVD outcomes from SGLT2
56
inhibitors. Substituting ketone metabolism for fat consumption and
glucose oxidation improves energy efficiency and reduces the work-
56
load placed on the myocardium. Preclinical research has shown that
the cardioprotective characteristics of dapagliflozin observed in dia-
betic cardiomyopathy may involve modulation of ion homeostasis as a
way to reduce fibrosis and inflammation, and improve systolic func-
tion.57 It is thought that SGLT2 inhibitors decrease inflammation and
oxidative stress through activation of the nitric oxide–soluble
guanylyl–protein kinase G pathway, contributing to attenuated dia-
58
stolic stiffness of the left ventricle in HFpEF.
There are numerous renal benefits of SGLT2 inhibition including
the positive effect on glomerular haemodynamics, which leads to
long-term preservation of kidney function. SGLT2 inhibitors target
mechanistic pathways that reduce intraglomerular pressure and the
glomerular filtration rate.59 Other modes of action that have been
proposed are hypoxia reduction and activating transcription factors.59
However, to better understand the mechanisms underlying the
cardiorenal-protective properties of SGLT2 inhibitors, further investi-
gation in humans is required.
14631326, 0, Downloaded from https://dom-pubs.onlinelibrary.wiley.com/doi/10.1111/dom.15181 by Cochrane Germany, Wiley Online Library on [22/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
CV outcomes trials such as DAPA-HF,14 CANVAS,60,61
EMPEROR-REDUCED,15 EMPA-REG62 and EMPEROR-PRESERVED63
show the cardioprotective and renoprotective benefits of SGLT2 inhibi-
tor treatment in patients with T2D. Compared with placebo, SGLT2
inhibitors reduced the risk of hHF, as seen with dapagliflozin (DAPA-
HF14; hazard ratio [HR]: 0.75; 95% confidence interval [CI]: 0.65, 0.85;
P < .001) and with canagliflozin (CANVAS Program61; HR: 0.67; 95% CI:
0.52, 0.87). Additionally, compared with placebo, empagliflozin treat-
ment reduced the total numbers of hHF in patients in EMPEROR-
Reduced (HR: 0.70; 95% CI: 0.58, 0.85; P < .001),15 in EMPA-REG (HR:
0.65; 95% CI: 0.50, 0.85; P = .002),62 in EMPEROR-PRESERVED (HR:
0.73; 95% CI: 0.61, 0.88; P < .001)63 and in EMPA-KIDNEY (HR: 0.86;
95% CI: 0.78, 0.95; P = .003).64
SGLT2 inhibitor trials with empagliflozin, dapagliflozin and cana-
gliflozin also revealed significant relative reductions of primary renal
outcomes.65 In DAPA-CKD,17 dapagliflozin was shown to exhibit
renoprotective benefits regardless of diabetes status, age, cause of
CKD, baseline albuminuria (< 1000 vs. > 1000 mg/g) and eGFR (< 45
vs. > 45 mL/min/1.73m2).18 The HR for the composite outcome of a
sustained decline in the eGFR of at least 50%, ESKD or death from
renal causes, was 0.56 (95% CI: 0.45, 0.68; P < .001). Canagliflozin
treatment was able to reduce the relative risk of composite of ESKD,
doubling of creatinine levels or renal death by 34% (HR: 0.66; 95% CI:
0.53, 0.81; P < .001), as well as lowering the risk of ESKD by 32%
(HR, 0.68; 95% CI, 0.54 to 0.86; P = .002).20
The EMPA-KIDNEY trial now also provides evidence of renal pro-
tection in patients without T2D. Patients with CKD at risk of further
disease progression in this trial experienced a lower risk of the com-
posite outcome of worsening kidney disease (defined as ESKD, a sus-
tained decrease in eGFR to < 10 mL/min/1.73m2, a sustained
decrease in eGFR of ≥ 40% from baseline, or death from renal causes)
or CV-related death following empagliflozin treatment compared with
placebo.64
For patients with T2D, HF and CKD, treatment selection will
need to be patient-specific and may depend on the CKD stage of the
patient, as well as the presence of co-morbidities.28 Adverse effects
should be considered when administering treatment options. The use
of SGLT2 inhibition has been associated with volume contraction
because of osmotic diuresis. Although these effects may be mild and
infrequent, they need to be monitored, particularly in elderly patients
and patients utilizing diuretics.58 Other clinical risks of SGLT2 inhibi-
tors, such as euglycaemic diabetic ketoacidosis, have been noted,
but were not observed in the CREDENCE20,66 and DAPA-CKD
trials.17,18,58 The 2022 ADA and Kidney Disease: Improving Global
Outcomes (KDIGO) consensus statement recommends monitoring
blood or urine ketones for managing diabetic ketoacidosis, as well as
maintaining low-dose insulin in insulin-requiring patients.67
SGLT2 inhibitor administration is also associated with an
increased risk of hypoglycaemia.58 This risk increases with higher
doses in patients with T2D, CKD and HF who are also taking insulin
or sulphonylureas, suggesting that careful dosage adjustments of anti-
diabetes therapy should be implemented when managing these
patients,58,67,68 to avoid hypoglycaemia.37
 14631326, 0, Downloaded from https://dom-pubs.onlinelibrary.wiley.com/doi/10.1111/dom.15181 by Cochrane Germany, Wiley Online Library on [22/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
BELL ET AL. 5

5.2 | The role of MRAs in the reduction of CV and
kidney outcomes
Fibrosis and inflammation are caused by overactivation of the MR.69
Selectivity of MR antagonism varies between MRAs. Although it
shows lower selectivity, the first-generation steroidal MRA spirono-
lactone is more potent than the second-generation MRA eplere-
none.69 The non-steroidal MRA finerenone has been shown to inhibit
detrimental gene activation independent of aldosterone
inhibition,70–72 whereas steroidal MRAs such as spironolactone and
71
eplerenone show partial agonism on co-factor recruitment.
Patients with T2D and HF exhibited clinical improvements follow-
ing MRA treatment compared with non-MRA therapy, with lower all-
cause mortality, CV mortality and hHF.73 Treatment with steroidal or
non-steroidal MRAs is also thought to positively impact individuals with
HF with reduced ejection fraction (HFrEF) and those with HFpEF, as
seen in the Randomised Aldactone Evaluation Study74 and TOPCAT
trial, respectively.38,54
75,76 77
The FIDELIO-DKD and FIGARO-DKD trials examined the effi-
cacy and safety of the non-steroidal MRA finerenone on kidney and CV
outcomes from early to advanced CKD in patients with T2D. Finerenone
treatment resulted in a lower risk of CKD progression and CV events in
75,76
patients with CKD and T2D compared with placebo. It is worth not-
ing that the patient populations in these trials had co-morbidities and
were at a high risk of both kidney and CV events; nonetheless, HbA1c
and blood pressure levels were sufficiently controlled. Filippatos et al.76
reported that, in patients with CKD and T2D, finerenone lowered the risk
of new-onset atrial fibrillation or flutter, as well as the risk of cardiorenal
events. In FIDELITY,78 the prespecified analysis of FIDELIO-DKD75,76 and
FIGARO-DKD,77 finerenone treatment taken in addition to standard of
care reduced the risk of clinically meaningful CV and kidney outcomes in
patients with T2D over a broad spectrum of kidney function.78
Finerenone was shown to be well tolerated by patients in the
FIDELIO-DKD75,76 and FIGARO-DKD77 trials. However, the risk of
adverse events should still be carefully considered when administering
this drug. The FIDELIO-DKD trial, which evaluated the non-steroidal
MRA finerenone in patients with CKD and T2D, found that hyperka-
laemia resulted in a 2.3% discontinuation rate in the finerenone group
compared with 0.9% in the placebo group.22,76 Hyperkalaemia was
reported in 18.3% of finerenone-treated patients compared with 9.0%
of those receiving placebo.22,76 No mortalities related to hyperkalae-
mia were observed. Similarly, in the FIGARO-DKD77 trial and FIDEL-
ITY analysis,78 the frequency of hyperkalaemia-related adverse events
was higher in the finerenone-treated group compared with the pla-
cebo group, yet no hyperkalaemia-related adverse events were
fatal.77,78 To manage the risk of hyperkalaemia, it is recommended
that serum potassium and eGFR are measured in all patients prior to
initiation of finerenone treatment. Frequent monitoring of patients on
concomitant medications is also encouraged. Prescribing information
for finerenone advises against starting finerenone treatment if serum
potassium is more than 5.0 mEq/L.79
Historically, MRAs have been linked with an increased risk of hyper-
kalaemia.22,80 Currently there is no therapeutic option for patients with
T2D at risk of CVD and CKD that is not associated with a risk of hyperka-
laemia. However, MRAs could offer benefit for this patient group when
appropriate monitoring for hyperkalaemia is taken into consideration.

TABLE 1 Management recommendations for patients with T2D and HF

Patients with T2D and HFrEF

Medication Guidance Source

β blocker Treatment of individuals with HF with reduced 10.46 ADA Standards of Care 202352
ejection fraction should include a β blocker with
proven cardiovascular outcomes benefit, unless
otherwise contraindicated
Patients with T2D and HFrEF or HFpEF
SGLT2 inhibitor In patients with T2D and established HFpEF or HFrEF, an 10.42a and 10.42b from ADA Standards of Care 202352,81
SGLT2 inhibitor with proven benefit in this patient The discussion of evidence to support this new
population is recommended to reduce the risk of recommendation was included in the last paragraph of
worsening HF and cardiovascular death the section ‘Glucose-Lowering Therapies and Heart
Recommendation 10.42b was added to recommend Failure’ (Erratum, summary of revisions)81
treatment with an SGLT2 inhibitor in individuals with
T2D and established HF with either preserved or
reduced ejection fraction to improve symptoms,
physical limitations and quality of life
Metformin In patients with T2D with stable HF, metformin may be ADA Standards of Care 202352
continued for glucose lowering if the estimated
glomerular filtration rate remains > 30 mL/min/1.73m2,
but should be avoided in unstable or hospitalized
individuals with HF

Abbreviations: ADA, American Diabetes Association; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with
reduced ejection fraction; SGLT2, sodium-glucose co-transporter-2; T2D, type 2 diabetes.
 14631326, 0, Downloaded from https://dom-pubs.onlinelibrary.wiley.com/doi/10.1111/dom.15181 by Cochrane Germany, Wiley Online Library on [22/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
6 BELL ET AL.

6 | UPDATED GUIDELINE
RECOMMENDATIONS FOR THE
MANAGEMENT OF PATIENTS WITH T2D
Optimal management of T2D involves collaboration between multidis-
ciplinary teams of clinicians, including primary care providers, endocri-
25
nologists, cardiologists and nephrologists. The management of
patients with T2D has historically focused on controlling risk factors
such as elevated blood pressure and optimizing blood glucose and
lipid levels to prevent CV disease and reduce the risk of DKD.7 Man-
agement recommendations for patients with T2D with HF and CKD
are summarized in Tables 1 and 2.
Guidelines from the American Heart Association82 and ADA83
recommend treating patients with diabetes using ACE inhibitors or
ARBs,84 MRAs and SGLT2 inhibitors.83 The KDIGO guidelines advise
reducing the risk of CV complications and CKD progression in patients
with T2D by implementing a multifactorial approach.25 However,
despite guideline-recommended treatments such as metformin, many
patients with well-controlled blood pressure and blood glucose pro-
gress to kidney disease and/or develop CV co-morbidities,85,86
highlighting the complex nature of cardiorenal protection. The US
Food and Drug Administration (FDA) has not only approved SGLT2
inhibitors for their antihyperglycaemic properties in the treatment of
T2D, but also for the reduction of CV events.87 The 2019

TABLE 2 Management recommendations for patients with T2D and CKD

Drug ADA Standards of Care 202350
Main therapies
Metformin • Metformin is contraindicated in patients with an eGFR
< 30 mL/min/1.73m2
• While taking metformin, eGFR should be monitored
• The benefits and risks of continuing treatment should
be reassessed when eGFR decreases to < 45 mL/
min/1.73m2
• Metformin should not be initiated for patients with an
eGFR < 45 mL/min/1.73m2
• Metformin should be temporarily discontinued at the
time of or before iodinated contrast imaging
procedures in patients with eGFR 30-60 mL/
min/1.73m2
RAS inhibitor at maximal An ACE inhibitor or an ARB is not recommended for the
tolerated dose primary prevention of CKD in people with diabetes who
have normal blood pressure and a normal urine albumin:
creatinine ratio
SGLT2 inhibitor Summary of revisions: 2023 ADA Standards of Care81:
recommended for patients with eGFR ≥ 20 mL/
min/1.73m2 and urinary albumin ≥ 200 mg/g creatinine
to reduce CKD progression and CV events81
Additional risk-based therapya
GLP-1 RA For additional CV risk reduction, a GLP-1 RA can be
considered if eGFR ≥ 25 mL/min/1.73m2
Non-steroidal MRA 10.43: For people with T2D and CKD with albuminuria
treated with maximum tolerated doses of ACE inhibitor
or ARB, addition of finerenone is recommended to
improve CV outcomes and reduce the risk of CKD
progression52,81
Steroidal MRA Summary of revisions in the 2023 ADA Standards of
Care81: MRAs are now recommended along with other
medications for CV and kidney protection rather than as
alternatives when other treatments have not been
effective
ADA and KDIGO consensus statement67
Metformin is recommended for patients with T2D, CKD
and eGFR ≥ 30 mL/min/1.73m2
The dose should be reduced to 1000 mg daily for
patients with eGFR 30-44 mL/min/1.73m2 and for
some patients with eGFR 45-59 mL/min/1.73m2 who
are at high risk of lactic acidosis
An ACE inhibitor or ARB is recommended for patients
with T2D who have hypertension and albuminuria,
titrated to the maximum antihypertensive or highest
tolerated dose
An SGLT2 inhibitor with proven kidney or CV benefit is
recommended for patients with T2D, CKD and eGFR
≥ 20 mL/min/1.73m2
Once initiated, the SGLT2 inhibitor can be continued at
lower levels of eGFR
GLP-1 RA with proven CV benefit is recommended for
patients with T2D and CKD who do not meet their
individualized glycaemic target with metformin and/or
an SGLT2 inhibitor, or who are unable to use these
drugs
A non-steroidal MRA with proven kidney and CV benefit
is recommended for patients with T2D, eGFR
≥ 25 mL/min/1.73m2, normal serum potassium
concentration and albuminuria (ACR ≥ 30 mg/g)
despite maximum tolerated dose of RAS inhibitor
Steroidal MRA is recommended if needed for resistant
hypertension and if eGFR ≥ 45 mL/min/1.73m2

Abbreviations: ACE, angiotensin-converting enzyme; ACR, albumin:creatinine ratio; ADA, American Diabetes Association; ARB, angiotensin receptor
blocker; CKD, chronic kidney disease; CV, cardiovascular; eGFR, estimated glomerular filtration rate; GLP-1 RA, glucagon-like peptide-1 receptor agonist;
KDIGO, Kidney Disease: Improving Global Outcomes; MRA, mineralocorticoid receptor antagonist; RAS, renin–angiotensin system; SGLT2, sodium-
glucose co-transporter-2; T2D, type 2 diabetes.
a
Regular reassessment of glycaemia, albuminuria, blood pressure, CV disease risk and lipids is recommended.

BELL ET AL.
ADA/European Association for the Study of Diabetes consensus rec-
ommends using SGLT2 inhibitors in addition to metformin in people
with diabetes and HF (especially HFrEF) to reduce hHF, major adverse
CV events and CV death.68,88 New guidance from the 2023 ADA
Standards of Care recommends treatment with an SGLT2 inhibitor in
individuals with T2D and established HF with either preserved or
reduced ejection fraction to improve symptoms, physical limitations
and quality of life. ADA recommendations specifically for people with
HF are summarized and outlined in Table 1.81 The KDIGO guidelines
suggest the use of ACE inhibitors or ARBs to reduce blood pressure in
25
patients with T2D and CKD. The ADA guidance recommends these
agents as the preferred first-line therapy for blood pressure control in
patients with diabetes, hypertension, an eGFR of less than 60 mL/
min/1.73m2 and a urine albumin: creatinine ratio of 300 mg/g or
22,50,89–92
higher, because of their ability to prevent CKD progression.
However, the recommendations do not support combining these
treatments because of the risk of acute kidney injury or hyperkalae-
mia.25,50,93,94 The 2022 ADA and KDIGO consensus statement rec-
ommends an ACE inhibitor or ARB for patients with T2D with
hypertension and albuminuria, titrated to the maximum tolerated
dose,67 and this is supported by the 2023 ADA Standards of Care
(Table 1).50 To slow the progression of CKD in patients with T2D and
CKD, the ADA recommends reducing urinary albumin of 300 mg/g or
higher by 30% or more for patients with macroalbuminuria.22,50 How-
ever, clinicians should be aware that some patients with T2D may
experience ESKD in the absence of albuminuria.95
Management recommendations for patients with T2D and CKD
(Table 2) include the ADA Standards of Care guidance for SGLT2
inhibitor treatment for patients at high risk of CKD progression.22,50
Empagliflozin87 and dapagliflozin have been approved by the FDA for
use in patients with T2D for their effects on kidney/HF outcomes.
The 2022 KDIGO guidelines recommend treating patients with T2D
and CKD, and an eGFR of less than 20 mL/min per 1.73m2, with an
SGLT2 inhibitor.67 The consensus statement is also in favour of
administering an SGLT2 inhibitor or glucagon-like peptide-1 receptor
agonist to patients with T2D with either established atherosclerotic
CVD or kidney disease, as part of a CV risk reduction protocol and
glucose-lowering management.67
Guidance from the 2022 American Association of Clinical Endo-
crinologists96 recommends finerenone to reduce CKD progression
and CV events in patients with CKD who are at an increased risk of
CV events or CKD progression, and who are treated with maximum
96
tolerated doses of ACE inhibitor or ARB. The 2022 ADA and KDIGO
consensus statement affirmed that a non-steroidal MRA with proven
kidney and CV benefit is recommended for patients with T2D, an
eGFR of 25 mL/min/1.73m2 or higher, normal serum potassium con-
centration and albuminuria (ACR ≥ 30 mg/g) despite receiving the
maximum tolerated dose of RAS inhibitor. The statement highlights
that finerenone is currently the only non-steroidal MRA with evidence
supporting its cardiorenal benefits.67 New additions to the 2023 ADA
standards of care for CVD and risk management include finerenone as
treatment in individuals with T2D and CKD with albuminuria receiving
the maximum tolerated doses of ACE inhibitor or ARB (Table 2).81
14631326, 0, Downloaded from https://dom-pubs.onlinelibrary.wiley.com/doi/10.1111/dom.15181 by Cochrane Germany, Wiley Online Library on [22/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
7
7 | CONC LU SIONS
The increasing prevalence of T2D is an ongoing clinical burden world-
wide, and the pathophysiology of T2D and its cardiorenal complica-
tions remain complex. Patients with T2D are at an increased risk of
developing HF and CKD; therefore, identifying therapeutic solutions
is a priority. There is now strong evidence favouring the use of SGLT2
inhibitors to improve CV and kidney outcomes, such as hHF and
ESKD, in patients with T2D, with guidelines also recommending them
as first-line treatment for patients with diabetes and a high risk of CV
or kidney disease. Furthermore, finerenone is recommended for
reducing the incidence of kidney outcomes in individuals with T2D
and a wide range of kidney function. The mechanism of action of
finerenone is distinct from other traditional MRAs, and it reduces
CKD progression and the severity of CV events with a lower inci-
dence of hypokalaemia in patients with T2D. Advances in treatment
options have indeed shown promising results in improving clinical out-
comes for patients with T2D, HF and CKD.
AUTHOR CONTRIBU TIONS
All the authors have made substantial contributions to the conception
and design, or acquisition of data, or analysis and interpretation of
data. All the authors were involved in drafting the manuscript or revis-
ing it critically for important intellectual content, giving final approval
of the version to be published. Each author has participated suffi-
ciently in the work to take public responsibility for appropriate por-
tions of the content. Each author has agreed to be accountable for all
aspects of the work in ensuring that questions related to the accuracy
or integrity of any part of the work are appropriately investigated and
resolved.
AC KNOW LEDG EME NT S
Medical writing support, under the guidance of the authors, was pro-
vided by Ananya Das, PhD, 3 Stories High, London, UK, and medical
writing support and article processing charges were funded by Bayer,
in accordance with Good Publication Practice 2022 guidelines (Ann
Intern Med 2022 [Epub 30 August 2022]; https://doi.org/10.7326/
M22-1460).
FUNDING INF ORMATI ON
Medical writing support and article processing charges were funded
by Bayer, in accordance with Good Publication Practice 2022 guide-
lines (Ann Intern Med 2022 [Epub 30 August 2022]).
CONFLIC T OF INTER E ST STATEMENT
DSHB states no conflicts of interest. TJ has received speaker fees for
Novo Nordisk, Bayer HealthCare Pharmaceuticals and Corcept Thera-
peutics, all unrelated to this work. JBM has received institutional
grants from Medtronic, Novo Nordisk, Beta Bionics, JDRF and
National Institutes of Health (NIH). She has received consulting fees
from Bayer HealthCare Pharmaceuticals, Boehringer Ingelheim, Gilead
Sciences, Inc., Mannkind Corporation, Novo Nordisk, Salix, Proven-
tionBio and Thermo Fisher. She has received honoraria from Bayer

8 BELL ET AL.
HealthCare Pharmaceuticals and Thermo Fisher. She has received
support for attending meetings from Bayer HealthCare Pharmaceuti-
cals and Thermo Fisher Endocrine Society, ADA, and participation on
a Data Safety Monitoring Board or Advisory Board from NIH and Jaeb
Center for Health Research, all unrelated to this work.
P EE R R EV I E W
The peer review history for this article is available at https://
www.webofscience.com/api/gateway/wos/peer-review/10.1111/dom.
15181.
DATA AVAI LAB ILITY S TATEMENT
Data sharing is not applicable to this article as no new data were
created or analyzed in this study.
ORCID
David S. H. Bell https://orcid.org/0000-0002-3035-6126
Janet B. McGill https://orcid.org/0000-0002-6228-6521
RE FE R ENC E S
1. Bell DS. Heart failure: the frequent, forgotten, and often fatal compli-
cation of diabetes. Diabetes Care. 2003;26(8):2433-2441. doi:10.
2337/diacare.26.8.2433
2. Forman DE, Butler J, Wang Y, et al. Incidence, predictors at admission,
and impact of worsening renal function among patients hospitalized
with heart failure. J Am Coll Cardiol. 2004;43(1):61-67. doi:10.1016/j.
jacc.2003.07.031
3. Birkeland KI, Bodegard J, Eriksson JW, et al. Heart failure and chronic
kidney disease manifestation and mortality risk associations in type
2 diabetes: a large multinational cohort study. Diabetes Obes Metab.
2020;22(9):1607-1618. doi:10.1111/dom.14074
4. McGurnaghan S, Blackbourn LAK, Mocevic E, et al. Cardiovascular
disease prevalence and risk factor prevalence in type 2 diabetes: a
contemporary analysis. Diabet Med. 2019;36(6):718-725. doi:10.
1111/dme.13825
5. Cavender MA, Steg PG, Smith SC Jr, et al. Impact of Diabetes mellitus
on hospitalization for heart failure, cardiovascular events, and death:
outcomes at 4 years from the reduction of atherothrombosis for con-
tinued health (REACH) registry. Circulation. 2015;132(10):923-931.
doi:10.1161/CIRCULATIONAHA.114.014796
6. Mai L, Wen W, Qiu M, et al. Association between prediabetes and
adverse outcomes in heart failure. Diabetes Obes Metab. 2021;23(11):
2476-2483. doi:10.1111/dom.14490
7. Alicic RZ, Rooney MT, Tuttle KR. Diabetic kidney Disease: challenges,
Progress, and possibilities. Clin J Am Soc Nephrol. 2017;12(12):2032-
2045. doi:10.2215/CJN.11491116
8. Vallianou NG, Mitesh S, Gkogkou A, Geladari E. Chronic kidney Disease
and cardiovascular Disease: is there any relationship? Curr Cardiol Rev.
2019;15(1):55-63. doi:10.2174/1573403X14666180711124825
9. Sun H, Saeedi P, Karuranga S, et al. IDF Diabetes atlas: global, regional
and country-level diabetes prevalence estimates for 2021 and projec-
tions for 2045. Diabetes Res Clin Pract. 2022;183:109119. doi:10.
1016/j.diabres.2021.109119
10. Kovesdy CP. Epidemiology of chronic kidney disease: an update 2022.
Kidney Int Suppl. 2022;12(1):7-11. doi:10.1016/j.kisu.2021.11.003
11. Rangaswami J, Bhalla V, de Boer IH, et al. Cardiorenal protection with
the newer antidiabetic agents in patients with Diabetes and chronic
kidney Disease: a scientific statement from the American Heart Asso-
ciation. Circulation. 2020;142(17):e265-e286. doi:10.1161/CIR.
0000000000000920
14631326, 0, Downloaded from https://dom-pubs.onlinelibrary.wiley.com/doi/10.1111/dom.15181 by Cochrane Germany, Wiley Online Library on [22/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
12. Ronco C, McCullough P, Anker SD, et al. Cardio-renal syndromes:
report from the consensus conference of the acute dialysis quality ini-
tiative. Eur Heart J. 2010;31(6):703-711. doi:10.1093/eurheartj/
ehp507
13. Pliquett RU. Cardiorenal syndrome: An updated classification based
on clinical hallmarks. J Clin Med. 2022;11(10):2896. doi:10.3390/
jcm11102896
14. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin
in patients with heart failure and reduced ejection fraction. N
Engl J Med. 2019;381(21):1995-2008. doi:10.1056/NEJMo
a1911303
15. Packer M, Anker SD, Butler J, et al. Cardiovascular and renal out-
comes with empagliflozin in heart failure. N Engl J Med. 2020;383(15):
1413-1424. doi:10.1056/NEJMoa2022190
16. Wagdy K, Nagy S. EMPEROR-Preserved: SGLT2 inhibitors break-
through in the management of heart failure with preserved ejection
fraction. Glob Cardiol Sci Pract. 2021;2021(3):e202117. doi:10.
21542/gcsp.2021.17
17. Heerspink HJL, Stefansson BV, Correa-Rotter R, et al. Dapagliflozin in
patients with chronic kidney Disease. N Engl J Med. 2020;383(15):
1436-1446. doi:10.1056/NEJMoa2024816
18. Wheeler DC, Stefansson BV, Jongs N, et al. Effects of dapagliflozin
on major adverse kidney and cardiovascular events in patients with
diabetic and non-diabetic chronic kidney disease: a prespecified anal-
ysis from the DAPA-CKD trial. Lancet Diabetes Endocrinol. 2021;9(1):
22-31. doi:10.1016/S2213-8587(20)30369-7
19. Heerspink HJL, Cherney D, Postmus D, et al. A pre-specified analysis
of the dapagliflozin and prevention of adverse outcomes in chronic
kidney Disease (DAPA-CKD) randomized controlled trial on the inci-
dence of abrupt declines in kidney function. Kidney Int. 2022;101(1):
174-184. doi:10.1016/j.kint.2021.09.005
20. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal out-
comes in type 2 Diabetes and nephropathy. N Engl J Med. 2019;
380(24):2295-2306. doi:10.1056/NEJMoa1811744
21. McCullough PA, Amin A, Pantalone KM, Ronco C. Cardiorenal nexus:
a review with focus on combined chronic heart and kidney failure,
and insights from recent clinical trials. J Am Heart Assoc. 2022;11(11):
e024139. doi:10.1161/JAHA.121.024139
22. American Diabetes Association Professional Practice Committee,
Draznin B, Aroda VR, et al. 11. Chronic kidney Disease and risk man-
agement: standards of medical Care in Diabetes-2022. Diabetes Care.
2022;45(Suppl 1):S175-S184. doi:10.2337/dc22-S011
23. American Diabetes Association Professional Practice Committee. 10.
Cardiovascular Disease and risk management: standards of medical
Care in Diabetes-2022. Diabetes Care. 2022;45(Suppl 1):S144-S174.
doi:10.2337/dc22-S010
24. American Diabetes Association. Standards of medical Care in
Diabetes-2022 abridged for primary care providers. Clin Diabetes.
2022;40(1):10-38. doi:10.2337/cd22-as01
25. Disease K. Improving global outcomes Diabetes work G. KDIGO
2020 clinical practice guideline for Diabetes Management in Chronic
Kidney Disease. Kidney Int. 2020;98(4S):S1-S115. doi:10.1016/j.kint.
2020.06.019
26. Jacob S, Krentz AJ, Deanfield J, Ryden L. Evolution of type 2 Diabetes
management from a Glucocentric approach to cardio-renal risk reduc-
tion: The new paradigm of care. Drugs. 2021;81(12):1373-1379. doi:
10.1007/s40265-021-01554-6
27. Sugahara M, Pak WLW, Tanaka T, Tang SCW, Nangaku M. Update on
diagnosis, pathophysiology, and management of diabetic kidney dis-
ease. Nephrology (Carlton). 2021;26(6):491-500. doi:10.1111/nep.
13860
28. Ceriello A, Catrinoiu D, Chandramouli C, et al. Heart failure in type
2 diabetes: current perspectives on screening, diagnosis and manage-
ment. Cardiovasc Diabetol. 2021;20(1):218:218. doi:10.1186/s12933-
021-01408-1

BELL ET AL.
29. Rubler S, Dlugash J, Yuceoglu YZ, Kumral T, Branwood AW,
Grishman A. New type of cardiomyopathy associated with diabetic
glomerulosclerosis. Am J Cardiol. 1972;30(6):595-602. doi:10.1016/
0002-9149(72)90595-4
30. Kenny HC, Abel ED. Heart failure in type 2 Diabetes mellitus.
Circ Res. 2019;124(1):121-141. doi:10.1161/CIRCRESAHA.118.
311371
31. Bell DS. Diabetic cardiomyopathy. A unique entity or a complication
of coronary artery disease? Diabetes Care. 1995;18(5):708-714. doi:
10.2337/diacare.18.5.708
32. Eichhorn EJ, Bristow MR. Medical therapy can improve the biological
properties of the chronically failing heart. A new era in the treatment
of heart failure. Circulation. 1996;94(9):2285-2296. doi:10.1161/01.
cir.94.9.2285
33. Bristow M. Etomoxir: a new approach to treatment of chronic heart
failure. Lancet. 2000;356(9242):1621-1622. doi:10.1016/S0140-
6736(00)03149-4
34. An J, Nichols GA, Qian L, et al. Prevalence and incidence of microvas-
cular and macrovascular complications over 15 years among patients
with incident type 2 diabetes. BMJ Open Diabetes Res Care. 2021;9(1):
e001847. doi:10.1136/bmjdrc-2020-001847
35. Podkowinska A, Formanowicz D. Chronic kidney Disease as oxidative
stress- and inflammatory-mediated cardiovascular Disease. Antioxi-
dants (Basel). 2020;9(8):752. doi:10.3390/antiox9080752
36. Daenen K, Andries A, Mekahli D, Van Schepdael A, Jouret F,
Bammens B. Oxidative stress in chronic kidney disease. Pediatr
Nephrol. 2019;34(6):975-991. doi:10.1007/s00467-018-4005-4
37. Ponikowski P, Voors AA, Anker SD, et al. ESC guidelines for the
diagnosis and treatment of acute and chronic heart failure: The task
force for the diagnosis and treatment of acute and chronic heart fail-
ure of the European Society of Cardiology (ESC)developed with the
special contribution of the heart failure Association (HFA) of the
ESC. Eur Heart J. 2016;37(27):2129-2200. doi:10.1093/eurheartj/
ehw128
38. Tromp J, Lim SL, Tay WT, et al. Microvascular Disease in patients
with Diabetes with heart failure and reduced ejection versus pre-
served ejection fraction. Diabetes Care. 2019;42(9):1792-1799. doi:
10.2337/dc18-2515
39. Simmonds SJ, Cuijpers I, Heymans S, Jones EAV. Cellular and molecu-
lar differences between HFpEF and HFrEF: a step ahead in an
improved pathological understanding. Cell. 2020;9(1):242. doi:10.
3390/cells9010242
40. Wynn TA, Ramalingam TR. Mechanisms of fibrosis: therapeutic trans-
lation for fibrotic disease. Nat Med. 2012;18(7):1028-1040. doi:10.
1038/nm.2807
41. Prabhu SD, Frangogiannis NG. The biological basis for cardiac repair
after myocardial infarction: from inflammation to fibrosis. Circ Res.
2016;119(1):91-112. doi:10.1161/CIRCRESAHA.116.303577
42. Gorini S, Kim SK, Infante M, et al. Role of aldosterone and mineralo-
corticoid receptor in cardiovascular aging. Front Endocrinol (Lausanne).
2019;10:584. doi:10.3389/fendo.2019.00584
43. Tsai CH, Pan CT, Chang YY, et al. Left ventricular remodeling and dys-
function in primary aldosteronism. J Hum Hypertens. 2021;35(2):131-
147. doi:10.1038/s41371-020-00426-y
44. Okoshi MP, Yan X, Okoshi K, et al. Aldosterone directly stimulates
cardiac myocyte hypertrophy. J Card Fail. 2004;10(6):511-518. doi:
10.1016/j.cardfail.2004.03.002
45. Fiebeler A, Schmidt F, Müller DN, et al. Mineralocorticoid receptor
affects AP-1 and nuclear factor-kappab activation in angiotensin II-
induced cardiac injury. Hypertension. 2001;37(2 Pt 2):787-793. doi:
10.1161/01.hyp.37.2.787
46. Liao C-W, Liao C-W, Lin Y-T, et al. The relation among aldosterone,
galectin-3, and myocardial fibrosis: a prospective clinical pilot follow-
up study. J Invest Med. 2016;64(6):1109-1113. doi:10.1136/jim-
2015-000014
14631326, 0, Downloaded from https://dom-pubs.onlinelibrary.wiley.com/doi/10.1111/dom.15181 by Cochrane Germany, Wiley Online Library on [22/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
9
47. Catena C, Colussi G, Novello M, et al. Dietary salt intake is a determi-
nant of cardiac changes after treatment of primary aldosteronism: a
prospective study. Hypertension. 2016;68(1):204-212. doi:10.1161/
hypertensionaha.116.07615
48. Matoba K, Takeda Y, Nagai Y, Yokota T, Utsunomiya K, Nishimura R.
Targeting redox imbalance as an approach for Diabetic kidney
Disease. Biomedicines. 2020;8(2):40. doi:10.3390/biomedicines8020040
49. Epstein M. Aldosterone and mineralocorticoid receptor signaling as
determinants of cardiovascular and renal injury: from Hans Selye to the
present. Am J Nephrol. 2021;52(3):209-216. doi:10.1159/000515622
50. ElSayed NA, Aleppo G, Aroda VR, et al. 11. Chronic kidney Disease
and risk management: standards of Care in Diabetes-2023. Diabetes
Care. 2023;46(Suppl 1):S191-S202. doi:10.2337/dc23-S011
51. Somaratne JB, Whalley GA, Poppe KK, et al. Screening for left ventricu-
lar hypertrophy in patients with type 2 diabetes mellitus in the commu-
nity. Cardiovasc Diabetol. 2011;10:29. doi:10.1186/1475-2840-10-29
52. ElSayed NA, Aleppo G, Aroda VR, et al. Cardiovascular Disease and
risk management: standards of Care in Diabetes-2023. Diabetes Care.
2023;46(Suppl 1):S158-S190. doi:10.2337/dc23-S010
53. Hadjkacem F, Triki F, Frikha H, et al. Masked arterial hypertension in
patients with type2 diabetes mellitus: prevalence, associated factors
and cardiovascular impact. Ann Cardiol Angeiol (Paris). 2022;71(3):
136-140. doi:10.1016/j.ancard.2021.10.018
54. Solomon SD, Claggett B, Lewis EF, et al. Influence of ejection fraction
on outcomes and efficacy of spironolactone in patients with heart
failure with preserved ejection fraction. Eur Heart J. 2016;37(5):455-
462. doi:10.1093/eurheartj/ehv464
55. Lamprea-Montealegre JA, Shlipak MG, Estrella MM. Chronic kidney
disease detection, staging and treatment in cardiovascular disease
prevention. Heart. 2021;107(16):1282-1288. doi:10.1136/heartjnl-
2020-318004
56. Mudaliar S, Alloju S, Henry RR. Can a shift in fuel energetics explain
the beneficial cardiorenal outcomes in the EMPA-REG OUTCOME
study? A unifying hypothesis. Diabetes Care. 2016;39(7):1115-1122.
doi:10.2337/dc16-0542
57. Arow M, Waldman M, Yadin D, et al. Sodium-glucose cotransporter
2 inhibitor dapagliflozin attenuates diabetic cardiomyopathy. Cardio-
vasc Diabetol. 2020;19(1):7. doi:10.1186/s12933-019-0980-4
58. Fonseca-Correa JI, Correa-Rotter R. Sodium-glucose cotransporter
2 inhibitors mechanisms of action: a review. Front Med (Lausanne).
2021;8:777861. doi:10.3389/fmed.2021.777861
59. Sen T, Heerspink HJL. A kidney perspective on the mechanism of
action of sodium glucose co-transporter 2 inhibitors. Cell Metab.
2021;33(4):732-739. doi:10.1016/j.cmet.2021.02.016
60. Radholm K, Figtree G, Perkovic V, et al. Canagliflozin and heart failure in
type 2 Diabetes mellitus: results from the CANVAS program. Circulation.
2018;138(5):458-468. doi:10.1161/CIRCULATIONAHA.118.034222
61. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovas-
cular and renal events in type 2 Diabetes. N Engl J Med. 2017;377(7):
644-657. doi:10.1056/NEJMoa1611925
62. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular
outcomes, and mortality in type 2 Diabetes. N Engl J Med. 2015;
373(22):2117-2128. doi:10.1056/NEJMoa1504720
63. Anker SD, Butler J, Filippatos G, et al. Empagliflozin in heart failure
with a preserved ejection fraction. N Engl J Med. 2021;385(16):1451-
1461. doi:10.1056/NEJMoa2107038
64. The E-KCG, Herrington WG, Staplin N, et al. Empagliflozin in patients
with chronic kidney Disease. N Engl J Med. 2023;388(2):117-127. doi:
10.1056/NEJMoa2204233
65. McGuire DK, Shih WJ, Cosentino F, et al. Association of SGLT2 inhib-
itors with cardiovascular and kidney outcomes in patients with type
2 Diabetes: a meta-analysis. JAMA Cardiol. 2021;6(2):148-158. doi:
10.1001/jamacardio.2020.4511
66. Jardine M, Zhou Z, Lambers Heerspink HJ, et al. Kidney, cardiovascu-
lar, and safety outcomes of canagliflozin according to baseline

10
albuminuria: a CREDENCE secondary analysis. Clin J Am Soc Nephrol.
2021;16(3):384-395. doi:10.2215/CJN.15260920
67. de Boer IH, Khunti K, Sadusky T, et al. Diabetes Management in
Chronic Kidney Disease: a consensus report by the American Diabe-
tes Association (ADA) and kidney Disease: improving global outcomes
(KDIGO). Diabetes Care. 2022;45:3075-3090. doi:10.2337/dci22-
0027
68. Joseph JJ, Deedwania P, Acharya T, et al. Comprehensive Manage-
ment of Cardiovascular Risk Factors for adults with type 2 Diabetes:
a scientific statement from the American Heart Association. Circula-
tion. 2022;145(9):e722-e759. doi:10.1161/CIR.0000000000001040
69. Agarwal R, Kolkhof P, Bakris G, et al. Steroidal and non-steroidal min-
eralocorticoid receptor antagonists in cardiorenal medicine. Eur Heart
J. 2021;42(2):152-161. doi:10.1093/eurheartj/ehaa736
70. Kolkhof P, Nowack C, Eitner F. Nonsteroidal antagonists of the min-
eralocorticoid receptor. Curr Opin Nephrol Hypertens. 2015;24(5):417-
424. doi:10.1097/MNH.0000000000000147
71. Grune J, Beyhoff N, Smeir E, et al. Selective mineralocorticoid recep-
tor cofactor modulation as molecular basis for Finerenone's antifibro-
tic activity. Hypertension. 2018;71(4):599-608. doi:10.1161/
HYPERTENSIONAHA.117.10360
72. Amazit L, Le Billan F, Kolkhof P, et al. Finerenone impedes
aldosterone-dependent nuclear import of the mineralocorticoid
receptor and prevents genomic recruitment of steroid receptor
Coactivator-1. J Biol Chem. 2015;290(36):21876-21889. doi:10.
1074/jbc.M115.657957
73. Chen MD, Dong SS, Cai NY, et al. Efficacy and safety of mineralocor-
ticoid receptor antagonists for patients with heart failure and diabe-
tes mellitus: a systematic review and meta-analysis. BMC Cardiovasc
Disord. 2016;16:28. doi:10.1186/s12872-016-0198-2
74. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on
morbidity and mortality in patients with severe heart failure. Random-
ized Aldactone evaluation study investigators. N Engl J Med. 1999;
341(10):709-717. doi:10.1056/NEJM199909023411001
75. Bakris GL, Agarwal R, Anker SD, et al. Effect of Finerenone on chronic
kidney Disease outcomes in type 2 Diabetes. N Engl J Med. 2020;
383(23):2219-2229. doi:10.1056/NEJMoa2025845
76. Filippatos G, Bakris GL, Pitt B, et al. Finerenone reduces new-onset
atrial fibrillation in patients with chronic kidney Disease and type
2 Diabetes. J Am Coll Cardiol. 2021;78(2):142-152. doi:10.1016/j.jacc.
2021.04.079
77. Pitt B, Filippatos G, Agarwal R, et al. Cardiovascular events with
Finerenone in kidney Disease and type 2 Diabetes. N Engl J Med. Eur
Heart J. 2021;385(24):2252-2263. doi:10.1056/NEJMoa2110956
78. Agarwal R, Filippatos G, Pitt B, et al. Cardiovascular and kidney out-
comes with finerenone in patients with type 2 diabetes and chronic
kidney disease: the FIDELITY pooled analysis. Eur Heart J. 2022;43(6):
474-484. doi:10.1093/eurheartj/ehab777
79. Bayer HealthCare Pharmaceuticals Inc. Highlights of Prescribing Infor-
mation: KERENDIA (finerenone) tablets, for oral use. U.S. Food and Drug
Administration website; 2021. https://www.accessdata.fda.gov/
drugsatfda_docs/label/2021/215341s000lbl.pdf Accessed: 10
November, 2022.
80. Sarafidis PA, Memmos E, Alexandrou ME, Papagianni A. Mineralocor-
ticoid receptor antagonists for nephroprotection: current evidence
and future perspectives. Curr Pharm des. 2018;24(46):5528-5536.
doi:10.2174/1381612825666190306162658
81. ElSayed NA, Aleppo G, Aroda VR, et al. Summary of revisions: stan-
dards of Care in Diabetes-2023. Diabetes Care. 2023;46(Suppl 1):S5-
S9. doi:10.2337/dc23-Srev
82. Heidenreich PA, Bozkurt B, Aguilar D, et al. AHA/ACC/HFSA guide-
line for the Management of Heart Failure: a report of the American
College of Cardiology/American Heart Association joint committee
14631326, 0, Downloaded from https://dom-pubs.onlinelibrary.wiley.com/doi/10.1111/dom.15181 by Cochrane Germany, Wiley Online Library on [22/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
BELL ET AL.
on clinical practice guidelines. Circulation. 2022;145(18):e895-e1032.
doi:10.1161/CIR.0000000000001063
83. McDonagh TA, Metra M, Adamo M, et al. ESC guidelines for the diag-
nosis and treatment of acute and chronic heart failure. Eur Heart J.
2021;42(36):3599-3726. doi:10.1093/eurheartj/ehab368
84. Cosentino F, Grant PJ, Aboyans V, et al. ESC guidelines on diabetes,
pre-diabetes, and cardiovascular diseases developed in collaboration
with the EASD. Eur Heart J. 2019;41(2):255-323. doi:10.1093/
eurheartj/ehz486
85. Barrera-Chimal J, Jaisser F. Pathophysiologic mechanisms in diabetic
kidney disease: a focus on current and future therapeutic targets. Dia-
betes Obes Metab. 2020;22(Suppl 1):16-31. doi:10.1111/dom.13969
86. Giugliano D, Maiorino MI, Bellastella G, Esposito K. The residual car-
diorenal risk in type 2 diabetes. Cardiovasc Diabetol. 2021;20(1):36.
doi:10.1186/s12933-021-01229-2
87. Boehringer Ingelheim International GmbH. Highlights of prescribing
information: JARDIANCE® (Empagliflozin Tablets), for Oral Use. U.S.
Food and Drug Administration website; 2021. https://www.
accessdata.fda.gov/drugsatfda_docs/label/2021/204629s026lbl.pdf
Accessed: 10 November, 2022.
88. Buse JB, Wexler DJ, Tsapas A, et al. 2019 update to: Management of
Hyperglycemia in type 2 Diabetes, 2018. A consensus report by the
American Diabetes Association (ADA) and the European Association
for the Study of Diabetes (EASD). Diabetes Care. 2020;43(2):487-493.
doi:10.2337/dci19-0066
89. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on
renal and cardiovascular outcomes in patients with type 2 diabetes
and nephropathy. N Engl J Med. 2001;345(12):861-869. doi:10.1056/
NEJMoa011161
90. Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of
the angiotensin-receptor antagonist irbesartan in patients with
nephropathy due to type 2 diabetes. N Engl J Med. 2001;345(12):
851-860. doi:10.1056/NEJMoa011303
91. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of
angiotensin-converting-enzyme inhibition on diabetic nephropathy.
The collaborative study group. N Engl J Med. 1993;329(20):1456-
1462. doi:10.1056/NEJM199311113292004
92. Effects of ramipril on cardiovascular and microvascular outcomes in
people with diabetes mellitus: Results of the HOPE study and
MICRO-HOPE substudy. Heart outcomes prevention evaluation
study investigators. Lancet. 2000;355(9200):253-259.
93. Breyer MD, Susztak K. The next generation of therapeutics for
chronic kidney disease. Nat Rev Drug Discov. 2016;15(8):568-588.
doi:10.1038/nrd.2016.67
94. Rawshani A, Rawshani A, Franzen S, et al. Risk factors, mortality, and
cardiovascular outcomes in patients with type 2 Diabetes. N Engl J
Med. 2018;379(7):633-644. doi:10.1056/NEJMoa1800256
95. Yamanouchi M, Furuichi K, Hoshino J, Ubara Y, Wada T. Nonprotei-
nuric diabetic kidney disease. Clin Exp Nephrol. 2020;24(7):573-581.
doi:10.1007/s10157-020-01881-0
96. Blonde L, Umpierrez GE, Reddy SS, et al. American Association of
Clinical Endocrinology Clinical Practice Guideline: developing a Dia-
betes mellitus comprehensive care Plan-2022 update. Endocr Pract.
2022;28(10):923-1049. doi:10.1016/j.eprac.2022.08.002
How to cite this article: Bell DSH, McGill JB, Jerkins T.
Management of the ‘wicked’ combination of heart failure and
chronic kidney disease in the patient with diabetes. Diabetes
Obes Metab. 2023;1‐10. doi:10.1111/dom.15181