JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 82, NO.

2, 2023

ª 2023 THE AUTHORS. PUBLISHED BY ELSEVIER ON BEHALF OF THE AMERICAN

COLLEGE OF CARDIOLOGY FOUNDATION. THIS IS AN OPEN ACCESS ARTICLE UNDER

THE CC BY-NC-ND LICENSE (http://creativecommons.org/licenses/by-nc-nd/4.0/).

THE PRESENT AND FUTURE

JACC REVIEW TOPIC OF THE WEEK

Cardiovascular Outcomes in Patients

With Diabetes and Kidney Disease
JACC Review Topic of the Week

Javier Morales, MD,a Yehuda Handelsman, MDb

ABSTRACT

Chronic kidney disease (CKD) and cardiovascular disease (CVD) have a significant inter-relationship in patients with
diabetes. Controlling blood pressure, dyslipidemia, and glucose levels is a common treatment approach to managing CVD
risk in patients with CKD and diabetes; despite strict control, however, a high residual risk remains. This review focuses on
patients who require pharmacotherapy, in whom new and existing cardiorenal therapies (renin-angiotensin-aldosterone
system inhibitors, sodium-glucose cotransporter-2 inhibitors, glucagon-like peptide-1 receptor agonists, and nonste-
roidal mineralocorticoid receptor antagonists) with differing mechanisms of action and safety profiles can reduce car-
diovascular risk beyond the outcomes achieved with blood pressure, dyslipidemia, or glycemic control alone. Several
treatment guidelines have been updated recently to reflect new evidence. Studies of these cardiorenal agents used in
combination are ongoing, and results are awaited with interest, with the hope that potential synergistic effects may lead
to further improvements in cardiovascular outcomes. (J Am Coll Cardiol 2023;82:161–170)
© 2023 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open
access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

D iabetes and chronic kidney disease (CKD)

are known risk factors for cardiovascular
(CV) disease, and the presence of both diag-
noses has an additive effect on risk.1-3 In 2017, the
events, HF, and CV mortality compared with out-
comes in patients without diabetes.1
Owing to the large number of patients at risk of CV
complications associated with CKD and diabetes,
global prevalence of CKD was estimated at 9.1%, lead- early detection of CKD and prompt initiation of novel
ing to around 1.2 million deaths and >2.6 million kid- forms of therapy to manage CKD and CV risk are
ney replacement therapies per year.4 Nearly one-half crucial for this patient group. Lifestyle interventions,
of all patients with CKD stages 4 and 5 will develop including a healthy diet, exercise, weight manage-
CV disease (CVD), and approximately 40% to 50% of ment, and smoking cessation, are recommended as
all deaths in this population are associated with CV the foundation of efforts to reduce CV risk in patients
mortality due to fatal atherosclerosis-related compli- with CKD and diabetes.6 For patients who require
cations as well as heart failure (HF) and fatal arrhyth- pharmacotherapy, focus has traditionally been on
mias. 2 Diabetes is considered one of the most controlling hyperglycemia, hypertension, and dysli-
common causes of CKD (approximately 30%-40% of pidemia to reduce CV risk, but the residual risk in
patients with diabetes will develop CKD) 5 and is also patients with CKD and diabetes remains high despite
Listen to this manuscript’s independently linked to increased incidence of CV strict control.7,8 The current review discusses the role
audio summary by
Editor-in-Chief
Dr Valentin Fuster on
www.jacc.org/journal/jacc. From aDepartment of Medicine, Donald and Barbara Zucker School of Medicine, Hofstra University, Hempstead, New York, USA;
and the bMetabolic Institute of America, Tarzana, California, USA.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’
institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information,
visit the Author Center.

Manuscript received January 30, 2023; revised manuscript received April 14, 2023, accepted April 20, 2023.

ISSN 0735-1097 https://doi.org/10.1016/j.jacc.2023.04.052

162 Morales and Handelsman JACC VOL. 82, NO. 2, 2023

Diabetes, CKD, and Cardiovascular Outcomes JULY 11, 2023:161–170

ABBREVIATIONS of cardiorenal therapies in CV risk manage-

AND ACRONYMS HIGHLIGHTS
ment in this patient population beyond what
can be achieved with blood pressure, lipid,  In patients with diabetes, advanced
ACE = angiotensin-converting
enzyme
and glucose control. chronic kidney disease increases cardio-
vascular risk and heart failure.
ADA = American Diabetes PATHOPHYSIOLOGY OF CKD IN
Association
DIABETES AND CV COMPLICATIONS  Control of hypertension, dyslipidemia,
ARB = angiotensin receptor
blocker
and hyperglycemia does not eliminate
The Kidney Disease: Improving Global Out- residual cardiovascular risk.
ASCVD = atherosclerotic
comes (KDIGO) Diabetes Work Group defines
cardiovascular disease
 Combination therapy is recommended to
CKD as abnormalities of kidney structure or
CKD = chronic kidney disease
function, present for >3 months, with impli-
reduce risk, and novel therapies for
CV = cardiovascular chronic kidney disease and diabetes may
cations for health. CKD is classified based on
CVD = cardiovascular disease
cause, glomerular filtration rate category (G1-
improve cardiovascular outcomes.
eGFR = estimated glomerular
G5), and albuminuria category (A1-A3).6 The
filtration rate
THERAPIES FOR PATIENTS WITH CKD
use of the urine albumin:creatine ratio
EMA = European Medicines IN DIABETES
Agency (UACR) together with the presence and
FDA = U.S. Food and Drug
duration of diabetes can establish the diag-
There are several treatment approaches that can
Administration nosis of kidney disease related to diabetes
provide cardiorenal protection in patients with T2D
GLP-1 RA = glucagon-like without the need for a biopsy. CKD may
and CKD. In addition to established drugs such as
peptide-1 receptor agonist result from prerenal (reduced renal perfusion
angiotensin-converting enzyme (ACE) inhibitors and
HF = heart failure pressure) or postrenal (obstruction) causes,
angiotensin II receptor blockers (ARBs), a number of
HFpEF = heart failure with although it is often caused by intrinsic pa-
preserved ejection fraction relatively new treatment classes present notable data
thologies of the vessels, glomeruli, or tubular
HFrEF = heart failure with showing cardiorenal protection in these patients.
interstitium in the kidney.
reduced ejection fraction These include sodium-glucose cotransporter-2
Hypertension and diabetes are the most
HFSA = Heart Failure Society (SGLT2) inhibitors, glucagon-like peptide-1 receptor
common causes of CKD among all other po-
of America agonists (GLP-1 RAs), and, recently, the novel
tential causes, such as kidney infections,
hHF = hospitalization for heart nonsteroidal mineralocorticoid receptor antagonists
failure
polycystic kidney disease, glomerulone-
(MRAs).
phritis, interstitial nephritis, autoimmune
KDIGO = Kidney Disease:
Improving Global Outcomes diseases, and drug-induced kidney injury. RAAS INHIBITORS. Hypotension, reduced blood vol-

MACE = major adverse Hypertension is an important cause of ne- ume, and reduced cardiac output activate the renin–
cardiovascular events phropathy whereby increased blood pressure angiotensin–aldosterone compensatory homeostasis
MRA = mineralocorticoid causes renal microvascular damage and response. 13 RAAS activation leads to vasoconstriction,
receptor antagonist glomerular injury. However, globally, type 2 sodium reabsorption, and increased release of
RAAS = renin-angiotensin- diabetes (T2D) is the most prevalent cause, noradrenaline, aldosterone, and antidiuretic hor-
aldosterone system
accounting for 2.5 million CKD diagnoses in mone. Inappropriate, prolonged activation can lead
SGLT2 = sodium-glucose
2019.2,3,9 Hyperglycemia in diabetes in- to hypertension and other detrimental effects on the
cotransporter-2
creases the likelihood of advanced glycation CV and renal systems. RAAS inhibitors such as ACE
T2D = type 2 diabetes
end-product formation, hypoxia, oxidative inhibitors and ARBs are established antihypertensive
UACR = urine
injury, renin-angiotensin-aldosterone sys- agents in patients with CKD because of their blood
albumin:creatinine ratio
tem (RAAS) activation (driven by the over- pressure–lowering and antiproteinuric effects.14 ACE
activation of the mineralocorticoid receptor), and inhibitors and ARBs are believed to reduce protein-
increased production of inflammatory and fibrotic uria and protect the kidney by reducing glomerular
factors. 10 These events, beyond dyslipidemia and hypertension via efferent arteriolar vasodilation, and
hypertension, lead to direct and secondary pathway- by blocking angiotensin II–mediated and aldosterone-
activated CVD and CKD through inflammation, mediated inflammation, tubular apoptosis, and
vascular dysfunction, fibrosis, and endothelial fibrosis.15 ACE inhibitors also improve metabolic
injury.11 The complex pathophysiology of CKD in control and attenuate any structural changes to
diabetes, together with its CV complications, pro- the glomerulus.15
vides many potential mechanistic targets in A meta-analysis of 76 trials of patients with CKD of
therapy.12 any cause (N ¼ 37,538) reported that ACE inhibitors
JACC VOL. 82, NO. 2, 2023 Morales and Handelsman 163
JULY 11, 2023:161–170 Diabetes, CKD, and Cardiovascular Outcomes

and ARBs, compared with placebo, reduced the risk of demand among other mechanisms. 19 Currently, 4
major adverse CV events (major adverse cardiovas- SGLT2 inhibitors are approved by the U.S. Food and
cular events [MACE], a composite of myocardial Drug Administration (FDA) and the European Medi-
infarction, stroke, hospitalization for HF [hHF], and cines Agency (EMA): canagliflozin, dapagliflozin,
CV death) (ACE inhibitor OR: 0.82; 95% CI: 0.71-0.92; empagliflozin, and ertugliflozin.
ARB OR: 0.76; 95% CI: 0.62-0.89), although there was Several randomized controlled trials have reported
no significant reduction in CV death specifically. 16 In improvements in cardiorenal outcomes after SGLT2
patients with nondialysis CKD stages 3 to 5 of any inhibitor treatment by ameliorating CKD and reducing
cause (estimated glomerular filtration rate rates of hHF, progression of CVD, and mortality. The
[eGFR] <60 mL/min/1.73 m 2 and elevated serum CREDENCE (Canagliflozin and Renal Events in Dia-
creatinine levels), a meta-analysis reported a betes with Established Nephropathy Clinical Evalua-
decrease in the OR for MACE to 0.73 (95% CI: 0.64- tion) study reported that canagliflozin improved renal
0.84; 30 studies, 34,538 patients) and a decrease in outcomes in patients with T2D and CKD, with a 30%
the OR for CV death to 0.73 (95% CI: 0.63-0.86; 19 lower relative risk of the primary cardiorenal com-
studies, 21,862 patients) after treatment with ACE posite outcome compared with placebo (HR: 0.70;
inhibitors.17 95% CI: 0.59-0.82; P ¼ 0.00001) and lowered the risk
Studies involving patients with diabetes do not of CV death, myocardial infarction, or stroke (HR:
show such strong beneficial CV effects. The Micro- 0.80; 95% CI: 0.67-0.95; P ¼ 0.01), and risk of hHF (HR:
HOPE (Microalbuminuria, Cardiovascular and Renal 0.61; 95% CI: 0.47-0.80; P < 0.001). 20 The DAPA-CKD
Outcomes–Heart Outcomes Prevention Evaluation) (Dapagliflozin and Prevention of Adverse Outcomes
study (N ¼ 3,577) involving patients with diabetes and in Chronic Kidney Disease) study also showed
CKD found that ramipril lowered the risk of MACE by improved cardiorenal composite outcomes after
25% (95% CI: 12%-36%).18 However, a subgroup meta- treatment with dapagliflozin in patients with T2D (HR:
analysis showed that, in patients with CKD and dia- 0.64; 95% CI: 0.52-0.79) and without T2D (HR: 0.50;
betes, neither ACE inhibitors nor ARBs significantly 95% CI: 0.35-0.72).21 Furthermore, EMPA-KIDNEY
17
lowered the odds of CV events and all-cause death. (Study of Heart and Kidney Protection with Empagli-
It is hypothesized that the benefit of adequate gly- flozin), the largest and broadest trial to date focusing
cemic control on disease progression is more impor- on SGLT2 inhibitor treatment in CKD, reported
tant than the direct effect of RAAS inhibition, reduced progression of kidney disease or death from
especially in the early stages of diabetic nephropathy, CV causes in the SGLT2 inhibitor group compared with
and it acts as a confounding factor.17 Evidence sup- placebo (HR: 0.72; 95% CI: 0.64-0.82; P < 0.001).22
porting CV benefit from RAAS inhibition specifically A kidney-protective effect of SGLT2 inhibitors was
in patients with CKD in diabetes is limited owing to reported in a meta-analysis of 4 studies (N ¼ 38,723)
the lack of studies directly analyzing this patient in patients with T2D. 23 SGLT2 inhibitors significantly
group, and further research is required. reduced the risk of kidney replacement (dialysis or
The main adverse effect of RAAS inhibitor therapy transplantation) or death due to kidney disease
is hyperkalemia, especially as reduced kidney func- (relative risk: 0.67; 95% CI: 0.52-0.86). SGLT2 in-
tion in advanced stages of CKD can lead to further hibitors have also been shown to improve CV out-
potassium retention. However, the clinical benefit comes in patients with CKD and diabetes in a recent
outweighs this risk in most patients. In addition, meta-analysis of 8 trials (N ¼ 26,106).24 This drug
hyperkalemia management strategies such as class was associated with a reduced progression of
reducing potassium intake or prescribing loop di- CKD, risk of MACE (HR: 0.83; 95% CI: 0.75-0.93), and
uretics and potassium binders can be used to mark- HF. Another meta-analysis of 15 trials in 20,241 pa-
edly reduce the risk of hyperkalemia. With tients with HF reported a reduced incidence of hHF
appropriate hyperkalemia avoidance and manage- (OR: 0.69; 95% CI: 0.62-0.76) after SGLT2 inhibitor
ment strategies, most patients with CKD (including therapy. 25 Therefore, regardless of diabetes status,
those with advanced CKD) would benefit from RAAS SGLT2 inhibition is important in the treatment of both
inhibition. HF and CKD.26-28
SGLT2 INHIBITORS. SGLT2 inhibitors have been The mechanism of action of SGLT2 inhibitors is not
developed to treat hyperglycemia in patients with entirely clear; it may partly involve diuresis, changes
T2D by inhibiting glucose reabsorption in the prox- in cardiac preload, and/or neurohormonal impact on
imal tubule of the kidney. They have also been found metabolism and the heart. Although SGLT2 inhibitors
to reduce cardiorenal risk, possibly through reduction are generally safe, volume depletion can occur and
of oxidative stress, inflammation, and metabolic hypoglycemia may arise when treatment is combined
164 Morales and Handelsman JACC VOL. 82, NO. 2, 2023

Diabetes, CKD, and Cardiovascular Outcomes JULY 11, 2023:161–170

with insulin or insulin secretagogues. 29 A safety It is speculated that GLP-1 RAs could improve
analysis of 8 trials (N ¼ 26,568) revealed that SGLT2 kidney outcomes through their effects on weight loss,
inhibitors were associated with an increased risk of decreased glomerular filtration pressure, anti-
genital mycotic infection (risk ratio: 3.75; 95% CI: inflammation, and inhibition of the sodium–
3.00-4.67) and, rarely, euglycemic ketoacidosis (risk hydrogen exchanger 3. The ongoing phase 3, ran-
ratio: 2.57; 95% CI: 1.53-4.31). 30 No ketoacidosis was domized, placebo-controlled FLOW (A Research
reported in the DAPA-CKD study of 4,303 participants Study to See How Semaglutide Works Compared to
with eGFR 25 to 75 mL/min/1.73 m 2. 28 Placebo in People With Type 2 Diabetes and Chronic
GLUCAGON-LIKE PEPTIDE-1 RECEPTOR AGONISTS. Kidney Disease; NCT03819153) study, evaluating
GLP-1 acts on the GLP-1 receptor, leading to improved semaglutide in patients with T2D and CKD, is the first
blood glucose homeostasis. GLP-1 RAs stimulate the study dedicated to investigating kidney outcomes
receptor and replicate the beneficial effects of GLP-1, resulting from treatment with a GLP-1 analogue.36
namely blood glucose regulation (through an increase Although GLP-1 RAs have a well-characterized safety
in insulin secretion and suppression of glucagon), profile, the drug class has been associated with mild
weight reduction (by reducing appetite and gastric gastrointestinal adverse reactions, but these are
motility), reduction of inflammation, improved CV likely to be subjective.37
function, neuroprotection, and renoprotection. 31 MINERALOCORTICOID RECEPTOR ANTAGONISTS.
Currently, 5 GLP-1 RAs are approved by the FDA and Steroidal MRAs such as spironolactone and epler-
the EMA: exenatide, lixisenatide, liraglutide, dula- enone are recommended in guidelines for managing
glutide, and semaglutide. Only semaglutide is avail- hypertension38 and HF. 39 Their CV benefits are pri-
able in oral form; the rest are injectable. marily related to blocking the profibrotic and
In the major CV outcomes trials of GLP-1 RAs pro-inflammatory effects of aldosterone.40 RALES
(LEADER [Liraglutide Effect and Action in Diabetes: (Randomized Aldactone Evaluation Study) was the
Evaluation of Cardiovascular Outcome Results],32 first seminal study to confirm the clinical benefits of
SUSTAIN 6 [Trial to Evaluate Cardiovascular and MRAs. It included patients with severe HF and a left
Other Long-term Outcomes with Semaglutide in ventricular ejection fraction #35% who were being
Subjects with Type 2 Diabetes], 33 and REWIND treated with an ACE inhibitor, a loop diuretic, and, in
[Researching Cardiovascular Events With a Weekly most cases, digoxin (N ¼ 1,663). In this population,
Incretin in Diabetes]34 ), there was a significant spironolactone reduced the risk of death by 30%
reduction in risk of adverse CV outcomes compared compared with placebo and risk of hHF by 35%. 41
with placebo. In the LEADER trial (N ¼ 9,340), lir- Similar results were shown for eplerenone compared
aglutide was associated with a lower incidence of the with placebo in EMPHASIS-HF (Eplerenone in Mild
composite outcome (death from CV causes, nonfatal Patients Hospitalization and Survival Study in
myocardial infarction, or nonfatal stroke) compared Heart Failure) (N ¼ 2,737) in patients with HF and left
with placebo (HR: 0.87; 95% CI: 0.78-0.97), driven ventricular ejection fraction #30% who were being
primarily by a lower rate of CV mortality, whereas treated with an ACE inhibitor and/or ARB. 42 A recent
rates of stroke, nonfatal myocardial infarction, and meta-analysis has confirmed the benefits of steroidal
hHF were numerically lower. 32 The REWIND MRAs in HF.43
(N ¼ 9,901) and SUSTAIN 6 (N ¼ 3,297) trials also re- However, steroidal MRAs are associated with an
ported reduced rates of the same composite endpoint increased risk for hyperkalemia and are contra-
compared with placebo for dulaglutide (HR: 0.88; indicated in advanced stages of CKD, and their use is
95% CI: 0.79-0.99) and semaglutide (HR: 0.74; limited by adverse effects such as gynecomastia and
95% CI: 0.58-0.95). 33,34 An improvement in CKD, a vaginal bleeding. 39 In patients with diabetes and
secondary endpoint, was also noted in these trials. CKD, steroidal MRAs have not shown CV benefits,
A recent meta-analysis of 8 trials (N ¼ 60,080) possibly because they are often used for only short
showed that GLP-1 RAs reduced the composite kidney durations.44 To provide mineralocorticoid receptor
outcome comprising macroalbuminuria, doubling of inhibition with a reduced risk of hyperkalemia and
serum creatinine, >40% decline in eGFR, kidney side effects associated with traditional steroidal
replacement therapy, or death from kidney failure, MRAs, a distinct class of MRAs was discovered more
and worsening of kidney function (HR: 0.79; 95% CI: than a decade ago. Nonsteroidal MRAs have a distinct
0.73-0.87) in patients with T2D.35 The same analysis structure and affinity and selectivity to the mineral-
reported a reduction in MACE after treatment with ocorticoid receptor, and thus a different clinical and
GLP-1 RAs (HR: 0.86; 95% CI: 0.80-0.93).35 side-effect profile compared with steroidal MRAs.
JACC VOL. 82, NO. 2, 2023 Morales and Handelsman 165
JULY 11, 2023:161–170 Diabetes, CKD, and Cardiovascular Outcomes

Currently, only 1 nonsteroidal MRA, finerenone, is Several other nonsteroidal MRAs are in develop-
approved by the FDA and the EMA for patients with ment, including apararenone, KBP-5074, and
CKD in diabetes. AZD9977. One, esaxerenone, is currently approved
In the ARTS-HF (Mineralocorticoid Receptor only in Japan, for hypertension; it reduced UACR in
Antagonist Tolerability Study–Heart Failure) study, patients with diabetes and albuminuria, 49,50 and
finerenone treatment reportedly correlated with early reports indicate potential benefit in HFrEF and
possible improvement of HF with reduced ejection HFpEF.51,52
fraction (HFrEF) in patients with HFrEF and CKD Hyperkalemia remains a risk with nonsteroidal
and/or diabetes.45 A similar percentage of patients MRAs, especially in patients with reduced eGFR,
experienced a decrease of >30% in N-terminal pro–B- although the risk is less compared with that of ste-
type natriuretic peptide levels in the finerenone roidal MRAs. In the ARTS study (N ¼ 392) in patients
groups vs eplerenone (30.9% vs 37.2%; P > 0.42). In with HFrEF and/or CKD, fewer cases of hyperkalemia
an exploratory analysis, fewer patients in the “10 mg (5.3% vs 12.7%) were reported in the finerenone group
uptitrated to 20 mg” finerenone group experienced than in the spironolactone group. 53 This outcome was
death from any cause (HR: 0.13; 95% CI: 0.02-1.07), confirmed in a meta-analysis of 3 trials comparing
CV hospitalization (HR: 0.56; 95% CI: 0.34-0.93), and finerenone vs spironolactone or eplerenone in pa-
emergency presentation to hospital for worsening tients with chronic HF (N ¼ 1,520). Serious adverse
chronic HF (HR: 0.58; 95% CI: 0.33-1.02). 45 However, events, including hyperkalemia, and discontinua-
the short follow-up of 90 days limits the conclusions tions of treatment because of adverse events were
that can be drawn from the data. Similar trends to- significantly lower in the finerenone groups than in
ward a greater reduction in N-terminal pro–B-type the steroidal MRAs groups. 54
natriuretic peptide with nonsteroidal vs steroidal The risk of hyperkalemia can be managed by po-
MRAs have been reported in the only other studies tassium monitoring and avoidance, and by using
that compared finerenone vs a steroidal MRA (spi- potassium-lowering therapies (diuretics and potas-
ronolactone in ARTS, and eplerenone in ARTS-HF sium binders). 55 In addition, steroidal MRA effects
46
Japan). such as high hormonal and metabolic side effects,
Two trials examined the effect of finerenone on CV long half-lives, significant antiandrogenic effect, and
and renal outcomes in patients with diabetes and off-target activity have not been observed with the
CKD, the FIDELIO-DKD (Finerenone in Reducing nonsteroidal MRA finerenone.40
Kidney Failure and Disease Progression in Diabetic
Kidney Disease) (N ¼ 5,734) and the FIGARO-DKD GUIDELINE RECOMMENDATIONS
(Finerenone in Reducing Cardiovascular Mortality
and Morbidity in Diabetic Kidney Disease) (N ¼ 7,437) The KDIGO 2021 guideline for the management of
trials. The data of these phase 3, multicenter, double- blood pressure in CKD14 and the 2022 clinical practice
blind placebo-controlled trials were pooled and guideline update for diabetes management in CKD
analyzed in the FIDELITY (FInerenone in chronic recommend the use of ACE inhibitors or ARBs at the
kiDney diseasE and type 2 diabetes: Combined maximum tolerable dose in patients with diabetes,
FIDELIO-DKD and FIGARO-DKD Trial programme hypertension, and albuminuria because of the anti-
analYsis) study.47 Compared with placebo, finerenone albuminuric and antihypertensive properties of these
reduced the risk of the CV composite outcome of CV drugs, while acknowledging that these drugs can be
death, nonfatal myocardial infarction, nonfatal used in the absence of hypertension. 6 The KDIGO
stroke, or hHF by 14% (HR: 0.86; 95% CI: 0.78-0.95). guidelines recommend a systolic blood pressure
This effect was driven primarily by a reduction in the target of <120 mm Hg provided that measurements
risk of hHF of 22% (HR: 0.78; 95% CI: 0.66-0.92). are obtained in a standardized manner; however,
Finerenone also reduced the risk of the kidney com- other guidelines recommend a less intensive target
posite endpoint of $57% decline in eGFR, kidney (<130 mm Hg).56 The KDIGO guidelines also recom-
failure, or death from kidney failure by 23% (HR: 0.77; mend SGLT2 inhibitor therapy for all patients with
95% CI: 0.67-0.88). The reduction in hHF observed in T2D, CKD, and eGFR $20 mL/min/1.73 m 2. The same
these trials additionally supports finerenone as a guidelines recommend the use of GLP-1 RAs in pa-
therapy for HF with preserved ejection fraction tients with T2D and CKD who have not achieved
(HFpEF); the exclusion of patients with symptomatic individualized glycemic targets despite treatment
HFrEF may have resulted in the inclusion of patients with metformin and SGLT2 inhibitors, or who are
with HFpEF, an underdiagnosed group accounting for unable to tolerate those medications. Furthermore,
most HF cases. 48 these guidelines advocate a nonsteroidal MRA with
166 Morales and Handelsman JACC VOL. 82, NO. 2, 2023

Diabetes, CKD, and Cardiovascular Outcomes JULY 11, 2023:161–170

T A B L E 1 Comparative Efficacy of Cardiovascular Therapies in Patients With CKD of Diabetes vs Placebo

Drug Class First Author, Study Type No. of Trials N Population Efficacy on MACE (95% CI)

ACE inhibitors Zhang et al,17 meta-analysis 30 34,538a CKD  T2D OR: 0.73 (0.64-0.84)
CKD and T2D OR: 0.89 (0.74-1.07)
ARBs Zhang et al,17 meta-analysis 30 34,538a CKD  T2D OR: 0.83 (0.70-0.98)
CKD and T2D OR: 0.87 (0.75-1.01)
SGLT2 inhibitors Kaze et al,24 meta-analysis 8 26,106 CKD and T2D HR: 0.83 (0.75-0.93)
GLP-1 RAs Sattar et al,35 meta-analysis 8 60,080 T2D  CKD HR: 0.86 (0.80-0.93)
12,060 T2D and CKD HR: 0.88 (0.77-1.01)
Nonsteroidal MRAs Agarwal et al,47 2 13,026 CKD and T2D HR: 0.86 (0.78-0.95)
FIDELITY pooled analysis

a
Patients with chronic kidney disease (CKD) in studies that evaluated the effect of angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) on
cardiovascular outcomes. The number of patients with diabetes who were analyzed as part of the subgroup analysis was not provided.
GLP-1 RA ¼ glucagon-like peptide-1 receptor agonist; MACE ¼ major adverse cardiovascular events; MRA ¼ mineralocorticoid receptor antagonist; SGLT2 ¼ sodium–glucose
cotransporter 2; T2D ¼ type 2 diabetes.

proven cardiorenal benefit, such as finerenone, in pa- The benefits of combination therapy of different
tients with T2D and CKD (eGFR $25 mL/min/1.73 m 2, classes of drugs in the treatment of HF are recognized
and albuminuria $30 mg/g [3 mg/mmol], normal by the American College of Cardiology, the American
serum potassium concentration) despite the Heart Association, and the Heart Failure Society of
maximum tolerated dose of RAAS inhibitor.6 America (HFSA). In the 2022 American Heart Associ-
The American Diabetes Association (ADA) Stan- ation/American College of Cardiology/HFSA guideline
dards of Medical Care in Diabetes recommend ACE for the management of heart failure, 4 drug classes
inhibitors or ARBs as first-line therapy for hyperten- are highlighted as important in the management of
sion in people with diabetes and coronary artery HF: RAAS inhibitors, MRAs, beta-blockers, and SGLT2
disease.57 To control blood pressure in patients with inhibitors.39 These recommendations are particularly
diabetes, the ADA suggests using the maximum important for patients with diabetes and CKD, as
tolerated dose of an ACE inhibitor or ARB. If one class many also have HF.
is not tolerated, the guideline recommends There is increasing acknowledgment that combi-
substituting with the other. In patients with T2D and nation therapy is beneficial in reducing CV risk in pa-
established atherosclerotic CVD (ASCVD), multiple tients with CKD and diabetes. The 2018 consensus
ASCVD risk factors, or diabetic kidney disease, use of report by the ADA and the European Association for
an SGLT2 inhibitor with proven CV benefit is advised the Study of Diabetes suggests using a combination of
by the ADA to reduce the risk of MACE and/or hHF.57 GLP-1 RAs and SGLT2 inhibitors in patients with T2D
Moreover, for patients with T2D and established and ASCVD and/or CKD who are not meeting their
HFpEF or HFrEF, the guidelines recommend treat- glycated hemoglobin targets with either medication
ment with an SGLT2 inhibitor with proven benefit to alone. 58 The consensus statement by the American
reduce the risk of worsening HF, hHF, and CV death. Association of Clinical Endocrinologists and the
To reduce the risk of MACE, the same guidelines American College of Endocrinology proposes the
recommend GLP-1 RAs with proven CV benefit in combined use of an SGLT2 inhibitor and a GLP-1 RA in
patients with T2D and established ASCVD or in- patients with or at high risk of ASCVD and/or CKD
dicators of high CV risk, established CKD, or HF.57 independently of glycemic control. 59 The Diabetes,
MRA therapy is advised for patients with hyperten- CardioRenal Metabolic Diseases Task Force practice
sion who are not meeting blood pressure targets recommendations suggest, in a multispecialty
while taking 3 classes of antihypertensive medica- consensus, adding finerenone in combination with an
tions. 57 The ADA issued a joint consensus report with SGLT2 inhibitor to ARB or ACE inhibitor therapy for
KDIGO on the management of diabetes in CKD, in preventing HF and CKD progression in patients with
which they recommend a nonsteroidal MRA with diabetes and CKD. 12 Finally, the potential benefit of
proven cardiorenal benefit for patients with T2D, combination therapy with finerenone and glucose-
eGFR $25 mL/min/1.73 m 2, normal serum potassium, lowering and antihypertensive medications in pa-
and albuminuria (UACR $30 mg/g) to reduce CKD tients with T2D and persistent albuminuria is consid-
progression and CV events.9 ered in the latest ADA/KDIGO statement, highlighting
JACC VOL. 82, NO. 2, 2023 Morales and Handelsman 167
JULY 11, 2023:161–170 Diabetes, CKD, and Cardiovascular Outcomes

C ENTR AL I LL U STRA T I O N Therapies to Reduce Cardiovascular Risk in Chronic Kidney Disease and Diabetes

Morales J, et al. J Am Coll Cardiol. 2023;82(2):161–170.

There are several treatment strategies available for patients with diabetes and chronic kidney disease (CKD) that can reduce the risk of cardiovascular (CV) and kidney disease.
Each class of drugs has a distinct mechanism of action, opening up the possibility for combination therapy. Some combinations, such as renin–angiotensin–aldosterone system
(RAAS) inhibitors and mineralocorticoid receptor antagonists (MRAs), warrant more caution owing to common adverse effects. *Adverse reactions of special interest. Other
side effects may also occur. Please refer to the corresponding prescribing information for more information.
ACE ¼ angiotensin-converting enzyme; ARB ¼ angiotensin receptor blocker; GI ¼ gastrointestinal; GLP-1 RA ¼ glucagon-like peptide-1 receptor agonist; SGLT2 ¼ sodium–
glucose cotransporter-2.
168 Morales and Handelsman JACC VOL. 82, NO. 2, 2023

Diabetes, CKD, and Cardiovascular Outcomes JULY 11, 2023:161–170

T A B L E 2 General Prescribing Information for Patients With CKD in Relation to Estimated GFR

GFR Category (mL/min/1.73 m 2)

G5 G4 G3b G3a G1 and G2

Class Drug <15 15-29 30-44 45-59 $60

ACE inhibitors Ramiprila Dose adjustment required Dose adjustment required Dose adjustment required No dose adjustment No dose adjustment
required required
Lisinoprilb Dose adjustment required Use with caution No dose adjustment No dose adjustment No dose adjustment
required required required
ARBs Candesartanc No dose adjustment No dose adjustment No dose adjustment No dose adjustment No dose adjustment
required required required required required
Losartanc No dose adjustment No dose adjustment No dose adjustment No dose adjustment No dose adjustment
required required required required required
SGLT2 Canagliflozin Contraindicated Contraindicated Not recommended Dose adjustment required No dose adjustment
inhibitors required
Dapagliflozind Contraindicated Use with caution Use with caution No dose adjustment No dose adjustment
required required
GLP-1 RAs Liraglutide No dose adjustment No dose adjustment No dose adjustment No dose adjustment No dose adjustment
required required required required required
Dulaglutide No dose adjustment No dose adjustment No dose adjustment No dose adjustment No dose adjustment
required required required required required
sMRAs Spironolactone Not recommended Not recommended Dose adjustment required No dose adjustment No dose adjustment
required required
Eplerenonee Contraindicated Contraindicated Use with caution Use with caution No dose adjustment
required
nsMRAs Finerenonef Not recommended Not recommended Dose adjustment required Dose adjustment required No dose adjustment
required

Recommendations in relation to glomerular filtration rate (GFR) are approximations based on the U.S. Food and Drug Administration drug labels. Always refer to the most up-to-date prescribing information
before prescribing. Other patient factors may necessitate dose adjustment, and close monitoring is required. aNo dose adjustment required for GFR >40 mL/min/1.73 m2. bNo dose adjustment required for
GFR >30 mL/min/1.73 m2. cExercise caution in renal impairment. dInsufficient data to support dosing recommendations for GFR <45 mL/min/1.73 m2. eWhen treating hypertension, contraindicated if
GFR <50 mL/min/1.73 m2. fAppropriate to prescribe for GFR $25 mL/min/1.73 m2.
nsMRA ¼ nonsteroidal mineralocorticoid receptor antagonist; sMRA ¼ steroidal mineralocorticoid receptor antagonist; other abbreviations as in Table 1.

the results of preclinical studies and that further individually tailored to each patient’s needs. The ongoing
clinical research on these combinations is needed. 9 CONFIDENCE (Combination Effect of Finerenone and
Empagliflozin in Participants With Chronic Kidney Disease
SUGGESTED APPROACH and Type 2 Diabetes Using a UACR Endpoint) study in
patients with CKD in diabetes is evaluating finerenone in
The current review has outlined the role of CV risk– combination with the SGLT2 inhibitor empagliflozin; it will
reducing therapies in the management of patients with provide more information on how this approach could be
CKD in diabetes (Table 1). GLP-1 RAs, SGLT2 inhibitors, incorporated into CKD or T2D treatment guidelines.61
and nonsteroidal MRAs offer CV risk reduction benefit Because finerenone is recommended in the guidelines for
beyond what is achievable with blood pressure and the treatment of patients with diabetes, its use in combi-
glycemic control. Based on the limited research to date, nation with other therapeutic agents is inevitable in a real-
we believe that combination treatment involving ACE world setting. Two ongoing observational real-world evi-
inhibitors or ARBs, SGLT2 inhibitors, and nonsteroidal dence studies, FIRST-2 (Finerenone FIRST [Finerenone
MRAs would further improve kidney and CV outcomes Research of Early Safety and Effectiveness, Part 2.0;
in patients with CKD in diabetes (Central Illustration). NCT05703880; estimated study completion date
Under certain conditions, GLP-1 RAs may also be used, September 2023]) and FINE-REAL (A Non-interventional
but evidence to support their benefit in improving renal Study Providing Insights Into the Use of Finerenone in a
outcomes is currently lacking. Although the mechanism Routine Clinical Setting; NCT05348733; estimated study
of action of each drug class remains largely speculative, completion date January 2028), are investigating the use of
the potential variability in these mechanisms, together finerenone in patients with CKD and T2D, and they should
with post hoc data from related trials of CV outcomes provide further information on its use in combination with
showing the benefit of combination therapies, offers the other medication.
possibility of an additive treatment effect with combi- Hyperkalemia is a known side effect of RAAS inhibitors
nation therapy.60 and, more so, of MRAs. For patients in later stages of CKD,
Owing to the lack of comparative efficacy trials, thera- the benefits and disadvantages of this combination
pies should be tested in different combinations and approach should be carefully weighed. Nevertheless,
JACC VOL. 82, NO. 2, 2023 Morales and Handelsman 169
JULY 11, 2023:161–170 Diabetes, CKD, and Cardiovascular Outcomes

combinations of SGLT2 inhibitors and loop diuretics (if MRAs, and possibly GLP-1 RAs provide a potentially
needed) lead to a reduction in blood potassium levels. The additive benefit in patients with CKD and diabetes
addition of potassium binders is becoming an accepted and are being increasingly recommended. A call to
strategy to manage hyperkalemia, allowing the use of action is to advance efforts to introduce clinicians to
potassium-raising drugs in populations with CKD.55 Blood the contemporary data and medical-directed guide-
potassium levels should still be monitored with this line therapy, and have the clinicians incorporate
combination approach. Table 2 summarizes consider- these in the management of patients with diabetes
ations when prescribing some of the aforementioned and CKD to improve patient quality of life and reduce
drugs in relation to eGFR levels. morbidity and mortality.
ACKNOWLEDGMENTS The authors thank Norbert
CONCLUSIONS
Chmurzynski and Constantinos Bezos, 3 Stories High,

Lowering of blood pressure, lipid, and blood glucose UK, for their medical writing support, which was

levels, together with the use of RAAS inhibitors, is funded by Bayer, in accordance with the 2022 Good

widely implemented to reduce CV risk and deterio- Publication Practice guidelines.

ration of kidney function in patients with CKD in

diabetes. Recent outcomes trials have shown signifi- FUNDING SUPPORT AND AUTHOR DISCLOSURES
cant impact on CKD and CV risk reduction in these
Medical writing support was funded by Bayer, in accordance with the
patients after treatment with SGLT2 inhibitors,
2022 Good Publication Practice guidelines. Dr Morales has received
nonsteroidal MRAs, and, to some extent, with GLP-1 consultant and speaker honoraria from Novo Nordisk, Lilly, Boeh-
RAs. Such trials have led to the development of ringer Ingelheim, Abbott, Amgen, Bayer, Zealand Pharma, and Sanofi.

evidence-based guideline recommendations by Dr Handelsman has received research grants and consultant and
speaker honoraria from Amarin, Amgen, Applied Therapeutics,
several medical societies, including KDIGO, the ADA,
AstraZeneca, Bayer, Boehringer Ingelheim, Corcept, Esperion, Ionis,
and the HFSA among others, incorporating these Mankind Pharma, Merck, Merck-Pfizer, Novartis, Novo Nordisk,
classes of medications to manage patients with CKD Regor Therapeutics, Sanofi, and Vertis.

and diabetes. However, despite a notable develop-

ment in the management of this population, a high ADDRESS FOR CORRESPONDENCE: Dr Javier
residual risk of end-stage kidney disease, HF, CVD, Morales, Advanced Internal Medicine Group, P.C., 2200
and mortality remains. Combinations of ACE in- Northern Boulevard, East Hills, New York 11548, USA.
hibitors or ARBs, SGLT2 inhibitors, nonsteroidal E-mail: saxodoc@gmail.com. Twitter: @saxodoc.

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