Sodium Glucose Cotransporter-2 Inhibition and Cardiorenal Protection

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

VOL. 74, NO. 20, 2019

ª 2019 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER

THE PRESENT AND FUTURE JACC REVIEW TOPIC OF THE WEEK

Sodium Glucose Cotransporter-2 Inhibition and Cardiorenal Protection JACC Review Topic of the Week David Z. Cherney, MD, PHD,a,b,c,d,* Ayodele Odutayo, MD, DPHIL,c,e,* Ronnie Aronson, MD,f Justin Ezekowitz, MBBCH, MSC,g John D. Parker, MDh

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Author Disclosures: Dr. Cherney is supported by a Department of Medicine, University of Toronto Merit Award; has received support from the Canadian Institutes of Health Research, Diabetes Canada, the Heart and Stroke/Richard Lewar Centre of Excellence, and the Heart and Stroke Foundation of Canada; has received consulting fees or speaking hono-

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AstraZeneca, Merck, and Sanofi; and has received operating funds from Janssen, Boehringer Ingelheim/Eli Lilly, Lilly, AstraZeneca, and Merck. Dr. Aronson has received advisory fees from Novo Nordisk and Sanofi; and has received research support from Novo Nordisk, Sanofi, AstraZeneca, Eli Lilly, Janssen, and Bausch Health. Dr. Ezekowitz has received support from Sanofi, AstraZeneca, Bayer, and Merck. Dr. Parker has received research funding from Theracos Inc., Novartis Pharmaceuticals, Merck, Ironwood Pharmaceuticals, and Luitpold Pharmaceuticals. Dr. Odutayo has reported that he has no relationships relevant to the con-

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From the aToronto General Hospital Research Institute, UHN, Toronto, Ontario, Canada; bDepartment of Physiology, University of Toronto, Toronto, Ontario, Canada; cDepartment of Medicine, Division of Nephrology, University of Toronto, Toronto, Ontario, Canada; dBanting and Best Diabetes Centre, Toronto, Ontario, Canada; eApplied Health Research Centre, Li Ka Shing Knowledge

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JACC VOL. 74, NO. 20, 2019

Antihyperglycemic Agents, Cardiorenal Protection

NOVEMBER 19, 2019:2511–24

Sodium Glucose Cotransporter-2 Inhibition and Cardiorenal Protection JACC Review Topic of the Week David Z. Cherney, MD, PHD,a,b,c,d,* Ayodele Odutayo, MD, DPHIL,c,e,* Ronnie Aronson, MD,f Justin Ezekowitz, MBBCH, MSC,g John D. Parker, MDh

ABSTRACT Poorly controlled type 2 diabetes mellitus is associated with the development of cardiovascular and renal complications, resulting in significant morbidity and mortality. Intensive glycemic control has been a major focus for clinical trials and novel drug development. However, narrow treatment strategies developed strictly for glycemic control did not confer a large risk reduction in cardiovascular events. There were also only modest effects in reducing the progression of diabetic kidney disease. Recent cardiovascular safety trials and the dedicated renal protection trial CREDENCE (Canagliflozin on Renal and Cardiovascular Outcomes in Participants with Diabetic Nephropathy) have shown that the sodium-glucose cotransporter-2 (SGLT2) inhibitors, a newer generation of antihyperglycemic agents, improve both cardiovascular and renal outcomes when added to guideline-recommended treatment. This review examines the current evidence on the mechanism underlying the cardiorenal effects of SGLT2 inhibitors and summarizes clinical trial evidence and safety data related to the use of SGLT2 inhibitors for cardiovascular and renal protection. (J Am Coll Cardiol 2019;74:2511–24) © 2019 by the American College of Cardiology Foundation.

P

oorly controlled type 2 diabetes mellitus

hypertension, significant hypoglycemic risk, and

(T2DM) is associated with the development

retention of salt and water (1). It is therefore conceiv-

of cardiovascular and renal complications.

able that the benefits of intensive glycemic control

Accordingly, previous clinical trials focused on inten-

are neutralized by significant adverse effects with

sive glycemic control as a strategy to reduce the risk

these older agents. Since 2008, the U.S. Food and

of cardiorenal complications. In contrast with the

Drug Administration has mandated cardiovascular

consistent benefits of glycemic control in patients

outcome trials (CVOTs) to determine the safety of

with type 1 diabetes mellitus (T1DM), intensive

new treatments for T2DM, leading to the develop-

glucose-lowering approaches were associated with

ment of clinical trial programs with newer glucose-

either neutral cardiorenal effects (1), or even harm

lowering therapies. Since that time, clinical trials of

in some trials in adults with T2DM (2). Although the

glucose-lowering therapies have reported safety

physiological mechanisms for this surprising lack of

while documenting either noninferiority to placebo

benefit remain unclear, it is perhaps important that

or improved (“superiority”) clinical outcomes.

the older glucose-lowering therapies used in many

Accordingly, the goal of the present paper was to

of these trials were associated with weight gain,

review recent and emerging cardiovascular and renal

Institute of St. Michael’s Hospital, Toronto, Ontario, Canada; fLMC Diabetes and Endocrinology, Toronto, Ontario, Canada; g

Department of Medicine, Division of Cardiology, University of Alberta, Edmonton, Alberta, Canada; and the hDepartment of

Medicine, Division of Cardiology, Sinai Health System and Lunenfeld-Tanenbaum Research Institute, Toronto, Ontario, Canada. *Drs. Cherney and Odutayo contributed equally to this work and are joint first authors. Dr. Cherney is supported by a Department of Medicine, University of Toronto Merit Award; has received support from the Canadian Institutes of Health Research, Diabetes Canada, the Heart and Stroke/Richard Lewar Centre of Excellence, and the Heart and Stroke Foundation of Canada; has received consulting fees or speaking honorarium or both from Janssen, Boehringer Ingelheim/Eli Lilly, Lilly, AstraZeneca, Merck, and Sanofi; and has received operating funds from Janssen, Boehringer Ingelheim/Eli Lilly, Lilly, AstraZeneca, and Merck. Dr. Aronson has received advisory fees from Novo Nordisk and Sanofi; and has received research support from Novo Nordisk, Sanofi, AstraZeneca, Eli Lilly, Janssen, and Bausch Health. Dr. Ezekowitz has received support from Sanofi, AstraZeneca, Bayer, and Merck. Dr. Parker has received research funding from Theracos Inc., Novartis Pharmaceuticals, Merck, Ironwood Pharmaceuticals, and Luitpold Pharmaceuticals. Dr. Odutayo has reported that he has no relationships relevant to the contents of this paper to disclose. Manuscript received May 9, 2019; revised manuscript received August 30, 2019, accepted September 3, 2019.

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Antihyperglycemic Agents, Cardiorenal Protection

HIGHLIGHTS
Patients with T2DM have high residual risk for the development of cardiovascular complications and diabetic kidney disease progression.
SGLT2 inhibitors have consistently reduced the risk of hospitalization for HF and progression of diabetic kidney disease.
Selection of antihyperglycemic agents in patients with T2DM should take several factors into account, including metabolic requirements, safety, and background presence of CVD, HF, and renal complications.
Ongoing and future trials are required to determine the safety and efficacy of SGLT2 inhibitors in novel settings, including in nondiabetic adults with CVD and/or kidney disease, and in individuals with CVD in the absence of T2DM. outcome trials of sodium-glucose cotransporter-2 (SGLT2) inhibitors, a novel class of medications for the treatment of T2DM. Given the high incidence of diabetic kidney disease (DKD) and cardiovascular disease (CVD) complications in T2DM (3), as well as the rapid evolution of new therapies that target both renal and CVD complications, a review of the impact of SGLT2 inhibitors on clinical outcomes has direct clinical relevance (4–6). In the era of the CREDENCE (Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy) trial (7), which is the first dedicated renal protection study with an SGLT2 inhibitor to report both renal and cardiovascular protection in a DKD cohort, it is particularly important to understand the integrated impact

of

novel

antihyperglycemic

agents

on

cardiovascular-renal-endocrine endpoints.

reductions of 0.6% to 1.0% and weight loss of

ABBREVIATIONS

w2 to 3 kg, primarily a consequence of a

AND ACRONYMS

decrease in adipose tissue (8,9). Beyond effects on traditional cardiovascular risk factors such as HbA 1c and weight, SGLT2 inhibition also reduces plasma uric acid levels by 10% to

AKI = acute kidney injury CKD = chronic kidney disease CVD = cardiovascular disease

15% by increasing uricosuria via exchange of

CVOT = cardiovascular

filtered glucose (10), an effect that has also

outcome trial

been implicated in improving cardiovascular risk in patients with T2DM in CVOTs (11). Overall clinical effects of SGLT2 inhibitors are reviewed in Table 1, according to anticipated changes in patients at different stages of

DKD = diabetic kidney disease eGFR = estimated glomerular filtration rate

ESKD = end-stage kidney disease

HbA1c = glycosylated

chronic kidney disease (CKD).

hemoglobin

SGLT2 INHIBITORS AND NATRIURESIS: SYSTEMIC

HF = heart failure

AND RENAL HEMODYNAMIC EFFECTS. In addi-

HFrEF = heart failure with

tion to the aforementioned glucosuria-based

reduced ejection fraction

beneficial effects on metabolic risk factors,

HR = hazard ratio

SGLT2 inhibition induces an acute natri-

IRR = incidence rate reduction

uretic effect that affects both systemic and

for 1,000 patients over

renal hemodynamic parameters (Figure 1). In the systemic circulation, natriuresis is associated with blood pressure–lowering effects

3 years

MACE = major adverse cardiovascular events

NHE = sodium-hydrogen

of w3 to 5 mm Hg systolic and 1 to

exchanger

2 mm Hg diastolic (8,10). Natriuresis asso-

RAAS = renin-angiotensin-

ciated

with

SGLT2

inhibition

occurs,

as

would be expected, after even a single dose, which also triggers acute changes in estimated through

glomerular

filtration

tubuloglomerular

rate

feedback

(eGFR) path-

aldosterone system

SGLT2 = sodium-glucose cotransporter-2 inhibitor

T1DM = type 1 diabetes mellitus

T2DM = type 2 diabetes

ways (discussed later) (12). On the basis of increased natriuresis and

mellitus

urine output, SGLT2 inhibition is associated with a contraction of plasma volume (as measured by radiolabeled albumin studies) by w7% (13). From a clinical perspective, the contraction of plasma volume may contribute to changes in markers of hemoconcentration with SGLT2 inhibitors such as increases in blood urea nitrogen and hematocrit, although the latter may also be on the basis of increased erythropoiesis (14,15), the mechanisms of which still need to be defined (16,17). Plasma volume contraction may

SGLT2 INHIBITORS: BACKGROUND AND

also underlie modest physiological increases in

METABOLIC EFFECTS

plasma and urine markers of renin-angiotensinaldosterone

system

(RAAS)

activation

(15,18).

SGLT2 INHIBITORS AND METABOLIC EFFECTS IN

Because the increase in urine sodium excretion is

T2DM. By

in

likely transient (ranging from 3 to 5 days) before

the proximal tubule of hyperglycemic individuals,

returning to baseline, the reduction in plasma volume

SGLT2 inhibitors increase glucosuria by as much as

and blood pressure reflects the establishment of a

80 to 100 g/days, resulting in improved glycemic

new steady state. In addition to contraction of plasma

control and weight loss (Figure 1). In patients with

volume, mathematical modeling and skin sodium

preserved

are

content studies using magnetic resonance imaging have

associated with glycosylated hemoglobin (HbA1c)

shown that interstitial sodium content decreases with

blocking

renal

the

function,

SGLT2

SGLT2

transporter

inhibitors

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F I G U R E 1 Selected Physiological Mechanisms Associated With Cardiovascular and Renal Protection With SGLT2 Inhibitors

↓ Solute transport ↓ O2 consumption ↓ Hypoxia/ischemia ↓ Inflammation/fibrosis ↓ Oxidative stress ↓ RAS

↑ Solute transport ↑ O2 consumption ↑ Hypoxia/ischemia ↑ Inflammation/fibrosis ↑ Oxidative stress ↑ RAS Impaired TGF

Normal TGF

Normal GFR

Afferent arteriole vasodilation

Elevated GFR

SGLT-2 Na

Na+/glucose reabsorption

+

+

+

Na

Increased Na+ delivery to macula densa

Decreased Na+ delivery to macula densa

Macula densa

Appropriate afferent arteriole tone

Restored TGF

Na

Increased Na+/glucose reabsorption

Normalization of GFR

Afferent arteriole constriction

+

Na

SGLT-2 inhibition in proximal tubule

+

Na

+

Na

+

Na

+

Na

+

Na

+

NHE3

NHE3

+

Na

NHE3

Na

+ Na + Na

+

Na

+

Distal nephron

Potential Clinical Benefits

Na

+

Na

↑ SGLT-2 bioactivity

↑ Na+ delivery ↑ O2 use ↑ Hypoxia ↑ Epo? ↑ Hct?

↑ Glomerular pressure ↑ Wall tension/shear stress

↓ Glomerular pressure ↓ Wall tension/shear stress

Increased Myocardial Oxygen Delivery?

↓ Cardiovascular events ↓ HHF risk Preserved renal perfusion

Glucosuria

Natriuresis

↓ Preload? ↓ Afterload? ↓ Myocardial ischemia? ↓ Arrhythmia risk?

Feedback

↓ Blood pressure ↓ Plasma volume ↓ Arterial stiffness ↓ Loop diuretics

↓ HbA1c ↓ Body weight ↓ AKI risk

Kidney protection

Physiological changes that occur in the setting of SGLT2 inhibitors, as well as their potential contribution to cardiovascular and renal protection, are depicted. Red boxes represent aberrant changes, whereas yellow boxes represent protective changes. Small red circle with a white line represent inhibition of function. AKI ¼ acute kidney injury; Epo ¼ erythropoietin; GFR ¼ glomerular filtration rate; HbA1c ¼ glycosylated hemoglobin; Hct ¼ hematocrit; HHF ¼ hospitalization for heart failure; GFR ¼ glomerular filtration rate; Naþ ¼ sodium; NHE3 ¼ sodium–hydrogen antiporter 3; O2 ¼ oxygen; SGLT2 ¼ sodium-glucose cotransporter-2; TGF ¼ tubuloglomerular feedback; RAS ¼ renin-angiotensin system.

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Antihyperglycemic Agents, Cardiorenal Protection

T A B L E 1 Anticipated Effects of SGLT2 Inhibitors on Clinical Parameters in Patients With T2DM

CKD Stage

SBP (53,54)

DBP (53,55)

HbA1c (53,54,56)

Weight (53,54,56)

Albuminuria (57)

eGFR (54,56)

Uric Acid (58)

Hematocrit (59)

1-2

Y3–5 mm Hg

Y1–2 mm Hg

Y0.6–0.9%

Y2–3 kg

Y30%–50%

Y3–5 ml/min/1.73 m2

Y10%–15%

[3%–5%

3a

Y3–5 mm Hg

Y1–2 mm Hg

Y0.3–0.5%

Y1–2 kg

Y30%–50%

Y3–5 ml/min/1.73 m2

Y10%–15%

[3%–5%

3b

Y3–5 mm Hg

Y1–2 mm Hg

4

Y1–2 kg

Y30%–50%

Y3–5 ml/min/1.73 m2

4

[3%–5%

4

Y3–5 mm Hg

Y1–2 mm Hg

4

Y1–2 kg

Y30%–50%

Y3–5 ml/min/1.73 m2

NA

NA

5

NA

NA

NA

NA

NA

NA

NA

NA

Double arrow indicates no change. [ ¼ increase; Y ¼ decrease; 4 ¼ no change; CKD ¼ chronic kidney disease; DBP ¼ diastolic blood pressure; eGFR ¼ estimated glomerular filtration rate; HbA1c ¼ glycosylated hemoglobin; NA ¼ not available; SBP ¼ systolic blood pressure; SGLT2 ¼ sodium-glucose cotransporter-2; T2DM ¼ type 2 diabetes mellitus.

SGLT2 inhibition (19), which may contribute to re-

setting of diabetes, however, proximal sodium reab-

ductions in blood pressure and heart failure (HF) risk.

sorption is augmented and leads to decreased distal

Aside from natriuresis-related pathways, blood

delivery of sodium. This action causes afferent vaso-

pressure lowering with SGLT2 inhibition may also be

dilatation and increased glomerular pressure and

related to reduced arterial stiffness (20,21) and im-

hyperfiltration, each a risk for further DKD progres-

provements in endothelial function reported in some,

sion. By blocking SGLT2 pharmacologically, distal

but not all, studies (22–24). In addition, blood pressure

delivery is restored, thereby increasing adenosine

reductions may be related to other factors, including

generation (22), which in turn leads to afferent vaso-

improved glycemic control and weight loss. In contrast

constriction and a decline in glomerular pressure, at

to the HbA 1c-lowering effects that weaken as eGFR

least under conditions of hyperfiltration.

declines because of attenuated levels of glucosuria,

It is perhaps as a result of these changes in

blood pressure–lowering responses to SGLT2 inhibi-

glomerular pressure that SGLT2 inhibitors have been

tion are independent of renal function (25) (Table 1).

shown to reduce albuminuria by 30% to 50%; this

Furthermore, the proximal natriuresis associated

effect occurs over weeks, implicating hemodynamic

with SGLT2 inhibition has important implications for

changes rather than other contributing pathways

renal protection by mitigating hemodynamic and

such as via suppression of inflammation, as the

proinflammatory mechanisms associated with DKD

mechanism of renal protection seen with these

progression that start early in the natural history of the

agents. Furthermore, within 2 to 4 weeks of stopping

disease (8,9). Proximal natriuresis is associated with

these agents, albuminuria partially returns toward

an increase in delivery of sodium to the macula densa,

pre-treatment levels, which would seem to confirm

the sodium-sensing area of the kidney at the level of

that hemodynamic mechanisms are involved (27).

the juxtaglomerular apparatus (Figure 1). It has been

Further research is required to determine if these

hypothesized that SGLT2 inhibition–associated natri-

tubuloglomerular feedback pathways play an impor-

uresis may be indirectly augmented by blocking the

tant role in patients with more advanced DKD.

sodium-hydrogen exchanger (NHE) (16,17), as nonse-

SGLT2 INHIBITION, NONHEMODYNAMIC EFFECTS,

lective SGLT1 and SGLT2 inhibition with phlorizin

AND RENAL PROTECTION. Beyond its renal hemo-

blocks NHE3 in vitro (26). In the absence of studies

dynamic effects, SGLT2 inhibition reduces levels of

with selective agents in in vivo studies, it is not known

inflammatory mediators in experimental models

if this interaction is based on SGLT1 or SGLT2 mecha-

of diabetes, including reductions in the production of

nisms. Nevertheless, NHE3 co-localizes with SGLT2

interleukin-6, activator protein-1, and nuclear factor

only in rodent proximal tubular cells, suggesting a

kB by proximal tubular epithelial cells under hyper-

predominant SGLT2 effect. Under normal physiolog-

glycemic conditions (28). For example, levels of

ical conditions, regardless of ambient glycemia or

interleukin-6 and markers of proximal tubular cell

diabetic status, a decrease in sodium delivery to the

injury were reduced with dapagliflozin treatment in

macula densa due to hypotension or volume depletion

patients with T2DM (29). Furthermore, animal models

leads to reduced adenosine generation at the macula

of DKD in the setting of both T1DM and T2DM have

densa. This action results in afferent arteriolar vaso-

reported reductions in plasma and tissue levels of pro-

dilatation, which preserves renal blood flow and GFR;

inflammatory and pro-fibrotic markers (30). Together,

this physiological effect is called tubuloglomerular

in vivo and in vitro studies support the concept that

feedback (15). Afferent vasodilatation under these

blockade of glucose entry into renal tubular cells at-

conditions is a physiologically desirable effect to pre-

tenuates the production of pro-inflammatory media-

serve renal perfusion and avoid kidney injury. In the

tors, which could protect against DKD progression (29).

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Antihyperglycemic Agents, Cardiorenal Protection

NOVEMBER 19, 2019:2511–24

F I G U R E 2 All-Cause Mortality, Cardiovascular Events, and Renal Outcomes in Cardiovascular Outcome Trials of SGLT-2 Inhibitors

A

Outcome

Total Events

Participants

Placebo

EMPA-REG OUTCOME

HR [95%-CI]

IRR in 1,000 pts. Over 3 yrs [95%-CI]

NNT Over 3 yrs [95%-CI]

events per 1,000 patient years

Primary Outcome MACE

Empagliflozin

772

7,020

37.4

43.9

0.86 [0.74-0.99]

–19.5 [–37.8 to –1.2]

52 [27 to 834]

463

7,020

19.4

28.6

0.68 [0.57-0.82]

–27.6 [–41.5 to –13.7]

37 [25 to 73]

All-Cause Mortality All-Cause Mortality Cardiovascular Outcomes Cardiovascular Mortality

309

7,020

12.4

20.2

0.62 [0.49-0.77]

–23.4 [–35.0 to –11.8]

43 [29 to 85]

Hospitalization for Heart Failure 221

7,020

9.4

14.5

0.65 [0.50-0.85]

–15.3 [–25.3 to –5.3]

66 [40 to 189]

Myocardial Infarction

349

7,020

16.8

19.3

0.87 [0.70-1.09]

–7.5 [–19.6 to 4.6]

134 [52 to ∞]

Stroke

233

7,020

12.3

10.5

1.18 [0.89-1.56]

5.4 [–3.9 to 14.7]

186 [257 to ∞]

152 27 130

6,968 7,020 6,968

6.3 1 5.5

11.5 2.1 9.7

0.54 [0.40-0.75] 0.45 [0.21-0.97] 0.56 [0.39-0.79]

Renal Outcomes Renal Composite ESKD dSCr

0.5

1

Favors SGLT2

B

Outcome

Total Events

Participants

Placebo

2 Favors Placebo

CANVAS PROGRAM

HR [95%-CI]

IRR in 1,000 pts. Over 3 yrs [95%-CI]

NNT Over 3 yrs [95%-CI]

events per 1,000 patient years

Primary Outcome MACE

Canagliflozin

–15.6 [–24.6 to –6.6] 65 [41 to 152] –3.3 [–7.0 to 0.4] 304 [143 to 2,500] –12.6 [–20.9 to –4.3] 80 [48 to 233]

1,011

10,142

26.9

31.5

0.86 [0.75-0.97]

–13.8 [–24.7 to –2.9]

73 [41 to 345]

681

10,142

17.3

19.5

0.87 [0.74-1.01]

–6.6 [–15.0 to 1.8]

152 [67 to ∞]

All-Cause Mortality All-Cause Mortality Cardiovascular Outcomes 453

10,142

11.6

12.8

0.87 [0.72-1.06]

–3.6 [–10.4 to 3.2]

278 [97 to ∞]

Hospitalization for Heart Failure 243

10,142

5.5

8.7

0.67 [0.52-0.87]

–9.6 [–15.0 to –4.2]

105 [67 to 239]

Myocardial Infarction

421

10,142

11.2

12.6

0.89 [0.73-1.09]

–5.7 [–11.9 to 0.5]

176 [85 to ∞]

Stroke

309

10,142

7.9

9.6

0.87 [0.69-1.09]

73 18 60

10,140 10,140 10,140

1.5 0.4 1.2

2.8 0.6 2.4

0.53 [0.33-0.84] 0.77 [0.30-1.97] 0.50 [0.30-0.84]

Cardiovascular Mortality

-5.1 [–11.0 to 0.8]

197 [91 to ∞]

Renal Outcomes Renal Composite ESKD dSCr

0.5

1

Favors SGLT2

C

Outcome

Total Events

Co-Primary Outcomes Cardiovascular Mortality or 913 Hospitalization for Heart Failure MACE

Participants

Dapagliflozin

Placebo

–3.9 [–6.9 to –0.9] 257 [145 to 1,112] –0.6 [–2.0 to 0.8] 1,667 [500 to ∞] –3.6 [–6.4 to –0.8] 278 [157 to 1,250]

2 Favors Placebo

DECLARE-TIMI 58

HR [95%-CI]

IRR in 1,000 pts. Over 3 yrs [95%-CI]

NNT Over 3 yrs [95%-CI]

events per 1,000 patient years

17,160

12.2

14.7

0.83 [0.73-0.95]

–7.5 [–12.7 to –2.3]

134 [79 to 435]

1,559

17,160

22.6

24.2

0.93 [0.84-1.03]

–4.8 [–11.8 to 2.2]

209 [85 to ∞]

1,099

17,160

15.1

16.4

0.93 [0.82-1.04]

–3.9 [–9.5 to 1.7]

257 [106 to ∞]

All-Cause Mortality All-Cause Mortality Cardiovascular Outcomes 494

17,160

7

7.1

0.98 [0.82-1.17]

–0.3 [–4.0 to 3.4]

3,334 [250 to ∞]

Hospitalization for Heart Failure 498

17,160

6.2

8.5

0.73 [0.61-0.88]

–6.9 [–10.8 to –3.0]

145 [93 to 334]

Myocardial Infarction

834

17,160

11.7

13.2

0.89 [0.77-1.01]

–4.5 [–9.6 to 0.6]

223 [105 to ∞]

Stroke

466

17,160

6.9

6.8

1.01 [0.84-1.21]

0.3 [–3.4 to 4]

3,334 [295 to ∞]

365

17,160

3.7

7

0.53 [0.43-0.66]

Cardiovascular Mortality

Renal Outcomes Renal Composite

0.5 Favors SGLT2

1

–9.9 [–13.2 to –6.6]

102 [76 to 152]

2 Favors Placebo

Continued on the next page

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Antihyperglycemic Agents, Cardiorenal Protection

In addition to its potential effects on factors asso-

was reduced by 27%, and the renal composite

ciated with inflammation and fibrosis, SGLT2 inhibi-

(doubling of serum creatinine, renal replacement

tion attenuates pathways linked with hypoxia in the

therapy, or renal death) was also reduced by 47%

kidney. Diabetes is associated with renal paren-

(HR: 0.53; 95% CI: 0.33 to 0.84; IRR: –3.9; 95% CI: –6.9

chymal hypoxia, a phenomenon driven by the

to –0.9). In DECLARE–TIMI 58, the most recent CVOT

increased

metabolic

to be reported, 17,160 patients (40.6% had previous

glucose

reabsorption

requirements that

of

enhanced

results

from

atherosclerotic disease, 10% had a history of HF) were

hyperglycemia-related increased delivery, thereby

randomized to receive dapagliflozin or placebo (38).

accelerating DKD progression (31). SGLT2 inhibition

Dapagliflozin reduced the risk of cardiovascular death

may attenuate renal hypoxia by reducing the energy

or hospitalization for HF (HR: 0.73; 95% CI: 0.61 to

required to reabsorb the filtered load of glucose and

0.88), a treatment effect that was largely driven by

may even improve oxygenation by: 1) contributing to

reductions in HF. The renal endpoint in DECLARE

the increased oxygen-carrying capacity via the rise in

(40% decline in eGFR, end-stage renal disease, or

hematocrit (32); 2) preserving cardiac function and

renal death) was also reduced (HR: 0.53; 95% CI: 0.43

output (33), which would in turn support renal

to 0.66; IRR: –9.9; 95% CI: –13.2 to –6.6). This benefit

perfusion; and 3) stimulating vascular endothelial

was observed even though renal risk was lower at

growth factor levels, which leads to preserved capil-

baseline (baseline eGFR 85 ml/min/1.73 m 2 and 7.4%

lary density and parenchymal oxygenation (34).

with eGFR <60 ml/min/1.73 m 2) compared with the

SGLT2 INHIBITORS AND CLINICAL OUTCOMES IN

EMPA-REG OUTCOME (eGFR 74 ml/min/1.73 m2 ;

CVOTs. Regardless of the responsible mechanism,

26% eGFR <60 ml/min/1.73 m 2) and the CANVAS

pre-specified secondary renal endpoint analyses from

Program

(eGFR

77

ml/min/m 2;

16.4%

eGFR

2

the EMPA-REG OUTCOME (BI 10773 [Empagliflozin]

<60 ml/min/1.73 m ) trials. Importantly, the results

Cardiovascular Outcome Event Trial in Type 2 Dia-

of all CVOTs were consistent in subgroups of adults

betes Mellitus Patients), CANVAS (Canagliflozin Car-

with and without CKD at baseline.

and

In the context of the long-term beneficial renal

DECLARE-TIMI 58 (Dapagliflozin Effect on Cardio-

effects observed in CVOTs, it is important to be aware

vascular

diovascular

Assessment

Study)

Program,

Myocardial

of the potential acute adverse consequences of these

Infarction 58) trial have reported important re-

agents. First, because SGLT2 inhibitors are natri-

ductions in both albuminuria and hard renal end-

uretic, these agents can induce afferent glomerular

points in adults with T2DM and a wide range of

arteriolar

glycemic control at baseline (entry HbA 1c level in

blood

CVOTs, 6.5% to 12%). These effects were consistent

contribute to an increased risk of acute kidney injury

across the range of normoalbuminuria to micro-

(AKI), although this has not been evident in clinical

albuminuria to macroalbuminuria and in patients

trials.

with and without impairment in kidney function

OUTCOME, CANVAS, and DECLARE–TIMI 58) and in

(35–38). In EMPA-REG OUTCOME, the composite of

CREDENCE, the incidence of AKI tended to be lower

doubling of serum creatinine, renal replacement

with SGLT2 inhibition. Nevertheless, in acute illness,

therapy, or renal death was reduced by 36% (hazard

the risk of volume depletion may be augmented, and

ratio [HR]: 0.54; 95% confidence interval [CI]: 0.40 to

a pragmatic strategy would be for clinicians to avoid

0.75; incidence rate reduction for 1,000 patients over

initiating these agents in the acute setting and to

3 years [IRR]: –15.6; 95% CI: –24.6 to –6.6) (Figure 2).

counsel patients to temporarily discontinue their

In the CANVAS Program, albuminuria progression

SGLT2 inhibitor when unwell as part of general “sick

Events-Thrombolysis

In

constriction,

flow.

On

thereby

Theoretically,

the

contrary,

decreasing

these

in

changes

CVOTs

renal may

(EMPA-REG

F I G U R E 2 Continued

Relative and absolute risks are presented, with the corresponding number-needed-to-treat (NNT). Major adverse cardiovascular events (MACE) were defined as the composite of cardiovascular death, nonfatal myocardial infarction, and stroke. The median follow-up was 2.1 years in the EMPA-REG OUTCOME (BI 10773 [Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) trial (A), 2.4 years in the CANVAS (Canagliflozin Cardiovascular Assessment Study) Program (B), and 4.2 years in the DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events–Thrombolysis In Myocardial Infarction 58) trial (C). The renal composite in the EMPA-REG OUTCOME (36) was defined as a doubling of serum creatinine levels (dSCr), initiation of renal replacement therapy, or renal death. The renal composite outcome in the CANVAS (61) trial was defined as a dSCr, end-stage kidney disease (ESKD), or renal death. The renal composite outcome in the DECLARE–TIMI 58 (38) trial was defined as a 40% decrease in estimated glomerular filtration rate to <60 ml/min/1.73 m2, ESKD, or renal death. Where outcomes include the line of no difference, there is also a corresponding number-needed-to-harm, which can be derived as the reciprocal of the upper 95% confidence interval (CI) of the incidence rate reduction (IRR). Positive values for the absolute change should be interpreted as an incidence rate increase. HR ¼ hazard ratio; SGLT2 ¼ sodium-glucose cotransporter-2.

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NOVEMBER 19, 2019:2511–24

T A B L E 2 SGLT2 Inhibitor Trials in Adults With Cardiovascular and Kidney Disease

EMPA-REG OUTCOME

CANVAS Program

DECLARE–TIMI 58

VERTIS CV

Cardiovascular outcome trials No. of patients

7,020

10,142

17,160

8,238

Treatment arms

Empagliflozin 10 mg and empagliflozin 25 mg vs. placebo

Canagliflozin vs. placebo

Dapagliflozin 10 mg vs. placebo

Ertugliflozin 5 mg vs. ertugliflozin 15 mg vs. placebo

Patient population

T2DM and established CVD

T2DM with either established CVD or multiple risk factors

T2DM with either established CVD or multiple risk factors

T2DM and established CVD

Kidney function inclusion criteria

eGFR $30 ml/min/1.73 m2

eGFR $30 ml/min/1.73 m2

eGFR $60 ml/min/1.73 m2

eGFR $30 ml/min/1.73 m2

Primary endpoint

Composite of CV death, nonfatal MI, or nonfatal stroke

Composite of CV death, nonfatal MI, or nonfatal stroke

Composite of CV death, nonfatal MI, or ischemic stroke Cardiovascular mortality or hospitalization for heart failure

Composite of CV death, nonfatal MI, or nonfatal stroke

Secondary endpoints (CV)*

1. CV death, nonfatal MI, nonfatal stroke, hospitalization for unstable angina 2. All-cause death 3. CV death 4. HHF 5. Fatal or nonfatal MI 6. Fatal or nonfatal stroke

1. 2. 3. 4. 5.

1. 2. 3. 4. 5.

1. CV death, nonfatal MI, nonfatal stroke, hospitalization for unstable angina 2. All-cause death 3. CV death 4. HHF 5. Fatal or nonfatal MI 6. Fatal or nonfatal stroke

Secondary endpoints (renal)*

1. Renal composite: Doubling 1. Renal composite: 1. Renal composite: of SCr, ESKD, or death 40% decrease in eGFR to Doubling of SCr with from renal causes <60 ml/min/1.73 m 2 , ESKD, eGFR #45 ml/min/1.73 m2, RRT, or renal death 2. ESKD or renal death 2. ESKD 3. Doubling of SCr 4. New-onset macroalbuminuria 3. Doubling of SCr 4. Incident or worsening nephropathy 5. Progression to macroalbuminuria

Start Completion

All-cause death CV death HHF Fatal or nonfatal MI Fatal or nonfatal stroke

All-cause death CV death HHF Fatal or nonfatal MI Fatal or nonfatal stroke

1. Renal composite: $2 increase in baseline serum creatinine, ESKD, transplantation, or renal death

2010

2009

2013

2013

Completed

Completed

Completed

December 2019

CREDENCE

DAPA-CKD

EMPA-KIDNEY

No. of patients

4,401

4,000

5,000

Treatment arms

Canagliflozin vs. placebo

Dapagliflozin vs. placebo

Empagliflozin vs. placebo

Patient population

CKD þ T2DM

CKD  T2DM

CKD  T2DM

Kidney function inclusion criteria

eGFR $30 to <90 ml/min/1.73 m2) and UACR >300 mg/g

Stage 2-4 CKD (eGFR $25 to <75 ml/min/1.73 m2 and UACR $200 mg/g

eGFR $20 to <45 ml/min/1.73 m2, or $45 to <90 ml/min/1.73 m2 with UACR $200 mg/g

Primary endpoint

Composite of doubling of Composite of $50% sustained serum decline in eGFR or reaching creatinine, ESKD, renal, or ESKD or CV death or renal CV death death

CV death or kidney disease progression (ESKD, sustained decline in eGFR to <10 ml/min/1.73 m2, renal death, or a $40% sustained eGFR decline)

Secondary endpoints (CV)*

1. 2. 3. 4.

1. All-cause death 2. CV death

Secondary endpoints (renal)*

1. Renal composite: doubling of SCr, ESKD, or renal death 2. ESKD 3. Doubling of SCr 4. Renal death

1. Renal composite: $50% sus- 1. CV death or ESKD tained decline in eGFR, ESKD, 2. Renal disease progression or renal death

Start

2014

2017

2018

Completion

Completed

2020

2022

Renal outcome trials

All-cause death CV death MACE HHF

1. All-cause death 2. CV death or HHF

*Selected among endpoints reported in the trial. ClinicalTrials.gov identifier: NCT02065791; ClinicalTrials.gov Identifier: NCT03036150; ClinicalTrials.gov identifier: NCT03594110. CANVAS ¼ Canagliflozin Cardiovascular Assessment Study; CREDENCE ¼ Canagliflozin on Renal and Cardiovascular Outcomes in Participants with Diabetic Nephropathy; CV ¼ cardiovascular; DAPACKD ¼ Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in Patients With Chronic Kidney Disease; DECLARE–TIMI 58 ¼ Dapagliflozin Effect on Cardiovascular Events–Thrombolysis In Myocardial Infarction 58; EMPA-KIDNEY ¼ Study of Heart and Kidney Protection With Empagliflozin; EMPA-REG OUTCOME ¼ BI 10773 [Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients; ESKD ¼ end-stage kidney disease; HHF ¼ hospitalization for heart failure; MI ¼ myocardial infarction; RRT ¼ renal replacement therapy; SCr ¼ serum creatinine; T2DM ¼ type 2 diabetes; UACR ¼ urinary albumin to creatinine ratio; VERTIS CV ¼ Cardiovascular Outcomes Following Ertugliflozin Treatment in Type 2 Diabetes Mellitus Participants With Vascular Disease, The VERTIS CV Study (MK-8835-004); other abbreviations as in Table 1.

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Antihyperglycemic Agents, Cardiorenal Protection

C ENTR AL I LL U STRA T I O N Areas of Overlap for Clinical Trials With Sodium-Glucose Cotransporter-2 Inhibitors in Patients With Chronic Kidney Disease

CREDENCE Trial • Focus on type 2 diabetes (T2D)/ diabetic kidney disease (DKD) • Only completed DKD trial (terminated early due to efficacy) • eGFR ≥30 to <90 ml/min/1.73 m2 and >300 mg/g urine albumin to creatinine ratio (UACR)

DKD, eGFR 30-75 ml/min/1.73 m2 and >300 mg/g UACR

EMPA-KIDNEY Trial • Patients with T1D • DKD + non-DKD etiologies • Lowest eGFR level (20 ml/min/1.73 m2) • Patients with/without albuminuria for eGFR 20-45 ml/min/1.73 m2 • With eGFR >45 ml/min/1.73 m2 must have >200 mg/g UACR

DKD, eGFR 30-75 ml/min/1.73 m2 and >300 mg/g UACR

• T2D • eGFR 45-75 ml/min/1.73 m2 + UACR >300 mg/g • Primary composite includes renal and CV endpoints • Excludes PCKD, immunosuppression

DAPA-CKD Trial DKD + non-DKD etiologies eGFR 25-75 ml/min/1.73 m2 and >200 mg/g UACR

DKD + non-DKD etiologies eGFR 25-75 ml/min/1.73 m2 and >200 mg/g UACR

Cherney, D.Z. et al. J Am Coll Cardiol. 2019;74(20):2511–24.

Characteristics of participants enrolled in currently planned renal outcome trials involving sodium-glucose cotransporter-2 (SGLT2) inhibitors are depicted in the Venn diagram. The red oval corresponds to the CREDENCE (Canagliflozin on Renal and Cardiovascular Outcomes in Participants with Diabetic Nephropathy) trial, the blue oval corresponds to the EMPA-KIDNEY (Study of Heart and Kidney Protection With Empagliflozin) trial, and the gray oval refers to the DAPA-CKD (Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in Patients With Chronic Kidney Disease) trial. CV ¼ cardiovascular; eGFR ¼ estimated glomerular filtration rate; PCKD ¼ polycystic kidney disease; T1D ¼ type 1 diabetes.

day” clinical management (39). Second, the risk of

Mortality in Patients With Chronic Kidney Disease)

diabetic ketoacidosis is increased with SGLT2 in-

and EMPA-KIDNEY (Study of Heart and Kidney Pro-

hibitors, as shown in the DECLARE–TIMI 58 and

tection

CREDENCE trials (7,38). The absolute risk increase is,

Illustration). Third, in a small case series based on

however, small due to how rare this condition is in

the U.S. Food and Drug Administration Adverse Event

the setting of T2DM. It is therefore important to

Reporting System and published case reports, in-

obtain additional data concerning this and other po-

vestigators identified 55 unique cases of Fournier’s

tential serious side effects with these agents in

gangrene in adults receiving SGLT2 inhibitors be-

additional clinical trials involving high-risk patients.

tween March 2013 and January 2019 (40). In contrast,

These trials include ongoing dedicated HF studies

19 cases of Fournier’s gangrene were reported to the

and renal endpoint trials such as DAPA-CKD (Dapa-

U.S. Food and Drug Administration for other glucose-

gliflozin on Renal Outcomes and Cardiovascular

lowering agents between 1984 and 2019. However,

With

Empagliflozin)

(Table

2,

Central

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F I G U R E 3 All-Cause Mortality, Cardiovascular Events, and Renal Outcomes in the CREDENCE Trial

Outcome

Total Events

Participants

Canagliflozin

Placebo

CREDENCE

HR [95%-CI]

IRR in 1,000 pts. Over 3 yrs [95%-CI]

NNT Over 3 yrs [95%-CI]

events per 1,000 patient years

Primary Outcome dSCr, ESKD, Renal or CV Death

585

4,401

43.2

61.2

0.70 [0.59-0.82]

–54.0 [–79.4 to –28.6]

19 [13 to 35]

369

4,401

29.0

35.0

0.83 [0.68-1.02]

–18.0 [–37.6 to 1.6]

56 [27 to ∞]

Renal Composite

377

4,401

27.0

40.4

0.66 [0.53-0.81]

–40.2 [–60.6 to –19.8]

25 [17 to 51]

ESKD

281

4,401

20.4

29.4

0.68 [0.54-0.86]

–27.0 [–44.5 to –9.5]

38 [23 to 106]

dSCr

306

4,401

20.7

33.8

0.60 [0.48-0.76]

–39.3 [–57.6 to –21.0]

26 [18 to 48]

Cardiovascular Mortality

250

4,401

19.0

24.4

0.78 [0.61-1.00]

–16.2 [–32.3 to –0.0]

62 [31 to ∞]

MACE

486

4,401

38.7

48.7

0.80 [0.67-0.95]

–30.0 [–53.3 to –6.7]

34 [19 to 150]

Hospitalization for Heart Failure 230

4,401

15.7

25.3

0.61 [0.47-0.8]

–28.8 [–44.7 to –12.9]

35 [23 to 78]

All-Cause Mortality All-Cause Mortality Renal Outcomes

Cardiovascular Outcomes

0.5 Favors SGLT2

1

2 Favors Placebo

Relative and absolute risks are presented, with the corresponding NNT. Renal composite outcomes are defined in Table 2. The median follow-up was 2.6 years in the CREDENCE (Canagliflozin on Renal and Cardiovascular Outcomes in Participants with Diabetic Nephropathy) trial. The renal composite outcome was defined as dSCr, ESKD, or renal death. Where outcomes include the line of no difference, there is also a corresponding number-needed-to-harm, which can be derived as the reciprocal of the upper 95% CI of the IRR. CV ¼ cardiovascular; other abbreviations as in Figures 1 and 2.

these studies should be interpreted with caution

including contraction of plasma volume and reduc-

given that causality cannot be established with a case

tion in blood pressure, thereby reducing both preload

series, especially because there were fewer cases of

and afterload. The second theory involves SGLT2 in-

this condition in the active treatment group in

hibition causing increased ketone production, which

DECLARE–TIMI 58. Prospective observational studies

can be used for adenosine triphosphate production.

are therefore required to further clarify the risk of

Ketones, used as substrate, can lead to improvements

Fournier’s gangrene with the use of SGLT2 inhibitors.

in myocardial efficiency, although recent experi-

Finally, SGLT2 inhibitors are associated with an

mental evidence (42) has indicated that SGLT2 inhi-

increased risk of mycotic genital infections likely

bition may increase myocardial energy efficiency in a

related to the increase in glucosuria. However, there

manner that is independent of ketone-related path-

is no increase in the incidence of urinary tract in-

ways. Increased renal ketone production may also

fections or pyelonephritis. In addition, the CANVAS

play a role in the observed increase in hematocrit

program initially suggested that canagliflozin may be

levels during SGLT2 inhibition, which can improve

associated with an increased risk of fractures and

oxygen delivery in vulnerable vascular beds such as

amputations, but this finding was not replicated in

the myocardium and renal medulla. The third hy-

subsequent cohort studies (41) or in the CREDENCE

pothesis involves inhibition of sodium-hydrogen ex-

trial (7).

change in myocardial cells, which has been linked to

SGLT2

INHIBITORS

AND

CARDIOVASCULAR

reductions in cardiac hypertrophy, systolic dysfunc-

PROTECTIVE MECHANISMS. In light of the results of

tion, fibrosis, and remodeling (43). The fourth theory

EMPA-REG OUTCOME, the CANVAS Program trials,

involves

and DECLARE–TIMI 58, which reported a reduction in

decreased incidence of sudden cardiac death, possibly

major adverse cardiovascular events (MACE) and/or

due to suppression of the sympathetic nervous system

rates of hospitalization for HF, considerable effort has

(44). Importantly, these salutary mechanisms occur in

been made to explain these somewhat unexpected

the context of neutral risks regarding inducing hypo-

observations. In brief, protection against HF hospi-

glycemia or activating the sympathetic nervous sys-

talization has been attributed to 4 main hypotheses.

tem, side effects that may limit the levels of overall

The first hypothesis involves hemodynamic effects,

end-organ protection from older antihyperglycemic

reduced

arrhythmia

risk,

leading

to

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Antihyperglycemic Agents, Cardiorenal Protection

agents and traditional diuretic agents (45). Many

without HF. Dapagliflozin reduced hospitalization for

of these theories, although credible, remain specula-

HF in those with and without HFrEF, whereas car-

tive in the absence of available published data.

diovascular death and all-cause mortality were only

Nevertheless, animal studies and preliminary human

reduced in patients with HFrEF. Accordingly, SGLT2

data are supportive of a beneficial effect of SGLT2

inhibition may, similar to other established HF ther-

inhibition on cardiac function in the setting of dia-

apies, exert its greatest effects in the setting of

betes, including markers of diastolic (46) and systolic

HFrEF. Further insights into the role of SGLT2 in-

(47) function.

hibitors on HF outcomes and on safety parameters in

Even

though

the

physiological

mechanisms

a specific HF patient cohort will only, however, be

responsible for cardiovascular protection with SGLT2

possible once the results of ongoing dedicated HF

inhibitors are not yet known, their benefits seem to

trials are available.

extend to most subgroups of patients included in

THE CREDENCE TRIAL, RENAL OUTCOMES, AND THE

these trials. For example, in EMPA-REG OUTCOME,

CLINICAL TRIAL LANDSCAPE. The CREDENCE trial

benefits regarding cardiovascular and all-cause mor-

was reported in April 2019 and is the first dedicated

tality, hospitalization for HF, and incident or wors-

renal endpoint trial completed in patients using an

ening

after

SGLT2 inhibitor. This trial included patients with

coronary artery bypass surgery (29); these results

nephropathy

extended

to

patients

eGFR 30 to 90 ml/min/1.73 m 2 and macroalbuminuria

were consistent regardless of sex, ethnicity (48), and

(7). The primary composite endpoint (doubling of

presence or absence of complications such as pe-

serum creatinine, end-stage kidney disease [ESKD],

ripheral vascular disease, HF at baseline, or baseline

and renal or cardiovascular death) was reduced by

CKD (11,29,49). Similarly, in the CANVAS Program and

30% (HR: 0.70; 95% CI: 0.59 to 0.82; p ¼ 0.00001; IRR:

DECLARE–TIMI 58 trial, effects on CVD were consis-

–54.0; 95% CI: –79.4 to –28.6) (Figure 3), an effect

tent across subgroups analyzed to date. In the overall DECLARE–TIMI 58 trial, the risk of

mediated by significant reductions in doubling of creatinine (HR: 0.60; 95% CI: 0.48 to 0.76; IRR: –39.3;

MACE, which was a co-primary endpoint, was not

95% CI: –57.6 to –21.0) and ESKD (HR: 0.68; 95% CI:

significantly reduced, whereas MACE was decreased

0.54 to 0.86; IRR: –27; 95% CI: –44.5 to –9.5). For the

by 14% in both the EMPA-REG OUTCOME and

ESKD endpoint composite, the risk of renal replace-

CANVAS Program trials. It has been suggested that

ment therapy was reduced by 26%. There was no

the lack of MACE benefit in DECLARE–TIMI 58 was

heterogeneity according to CKD stage, baseline albu-

due to the lower baseline CVD risk in this cohort (50).

minuria level, or relevant baseline clinical character-

This hypothesis was supported by the recent obser-

istics. The risk of MACE was reduced significantly by

vation that in patients with previous myocardial

20%, whereas numerical reductions in renal death and

infarction enrolled in DECLARE–TIMI 58, in a group

CV death did not reach statistical significance. The risk

with established risk, MACE was significantly reduced

of hospitalization for HF was consistent with results

by 16%, an effect identical to that observed in EMPA-

from previous CVOTs, with a significant reduction of

REG OUTCOME (50).

39% (HR: 0.61; 95% CI: 0.47 to 0.80; IRR: –28.8; 95% CI:

The results of these CVOTs are also intriguing in

–44.7 to –12.9). From a safety perspective, in accord

that patients with and without a history of HF at

with previous studies, the risks of AKI and hyper-

baseline seemed to benefit, suggesting that SGLT2

kalemia tended to be lower with canagliflozin, and

inhibition may both prevent the development of HF

there was no increased risk of amputation or fracture

and improve patient outcomes when HF is already

as reported in the CANVAS Program (35).

present. Although patients did not undergo detailed

CREDENCE

therefore

revealed

substantial

re-

HF phenotyping in EMPA-REG OUTCOME or CANVAS,

ductions in both renal and CV endpoints that have

the DECLARE–TIMI 58 study provides some data

been reported in previous CVOTs, but in a unique,

regarding the impact of dapagliflozin based on HF

dedicated cohort of DKD patients and with a reas-

type. In this trial, 671 (3.9%) patients had heart failure

suring safety profile. For perspective, the number-

with reduced ejection fraction (HFrEF) at baseline,

needed-to-treat to prevent 1 primary endpoint in

1,316 (7.7%) patients had HF without a known

CREDENCE was 19 over 3 years (Figure 3). For com-

reduction in ejection fraction, and 15,173 (88.4%) had

parison, the number-needed-to-treat in the RENAAL

no history of HF at baseline (51). The co-primary

(Reduction of End Points in NIDDM with the Angio-

endpoint of cardiovascular death/hospitalization for

tensin II Receptor Antagonist Losartan) trial for the

HF was reduced in patients with HFrEF (HR: 0.62;

composite of ESKD, doubling of creatinine, or death

95% CI: 0.45 to 0.86) but not in those without a

with an angiotensin II receptor blocker has been

reduction in their ejection fraction or in patients

estimated to be 34 over 3.4 years. The results of

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CREDENCE therefore suggest a comparable or even

pathways is important to better define patients with

lower number-needed-to-treat effect for canagliflozin

other nondiabetic conditions that may benefit from

on top of standard care (52). Importantly, the current

these treatments (58). Accordingly, there is interest in

standards of care with RAAS inhibition were estab-

the kidney and cardiovascular effects of SGLT2 in-

lished in 2 cohorts that were, together, smaller

hibitors in nondiabetic patients, who may be respon-

compared with CREDENCE (n ¼ 1,513 in RENAAL and

sive to the effects of natriuresis, even in the absence of

n ¼ 1,715 in IDNT [Irbesartan Diabetic Nephropathy

hyperglycemia

Trial]) (53,54). In RENAAL, the risk of the primary

instance, DAPA-CKD is an ongoing trial that will assess

composite (doubling of the baseline serum creatinine

the effect of dapagliflozin on primary renal endpoints

concentration, ESKD, or death) was reduced by 16%,

in a mixed cohort of macroalbuminuric patients with

whereas in IDNT, the risk of doubling of the baseline

DKD and nondiabetic CKD who have eGFR values

serum creatinine concentration, the development of

down to a lower limit of 25 ml/min/1.73 m 2. Likewise,

ESKD, or death from any cause was reduced by 20%.

in EMPA-KIDNEY, patients will be randomized to

The risks of doubling of serum creatinine and ESKD

receive empagliflozin or placebo to determine the

were both reduced in RENAAL, while only the risk of

impact of SGLT2 inhibition on primary renal endpoints

doubling of creatinine was lower in IDNT. The risk of

in a mixed cohort of patients with DKD and nondia-

death was not reduced in either trial.

betic CKD, including patients with T1DM. Importantly,

or

glucose-lowering

results.

For

In this context, the magnitude of the effect in the

in EMPA-KIDNEY, in the group of patients with eGFR

larger CREDENCE cohort (30% reduction in the pri-

values between 20 and 45 ml/min/1.73 m2, patients do

mary endpoint), along with significant reductions in

not have to have any albuminuria, whereas in the

individual renal and cardiovascular endpoints, makes

>45 ml/min/1.73 m 2 group, patients have to be in the

the findings extremely compelling. This is especially

macroalbuminuric range (Table 2, Central Illustration).

the case given the substantial secondary renal

These ongoing trials will ultimately build on the

outcome benefits reported in the 3 completed CVOTs

existing knowledge regarding kidney protection in

with SGLT2 inhibitors. Accordingly, kidney-protective

patients with DKD reported in the CREDENCE trial. For

effects with SGLT2 inhibitors seem to be least compa-

changes in clinical practice, the results of cardiovas-

rable to those achieved with RAAS inhibitors. As a

cular outcome trials have affected cardiovascular and

result, major guidelines such as the American Diabetes

HF recommendations, and they have also lowered the

Association Living Standards–Microvascular Compli-

eGFR threshold for the use of SGLT2 inhibitors in pa-

cations have already started to issue updates regarding

tients for the cardiovascular benefits.

CREDENCE and recommend consideration of SGLT2 inhibition for the treatment of DKD (55). Once EMPAKIDNEY and DAPA-CKD are complete, these trials along with CREDENCE will define the role of SGLT2 inhibitors in patients with and without albuminuria, across a range of eGFR 20 to 90 ml/min/1.73 m 2, and in patients with CKD with and without diabetes. Given that the results of CREDENCE were reported in a cohort on standard background therapy, this trial is pivotal and will have a substantial impact on the clinical care of patients with DKD (56). It is therefore reasonable to anticipate more widespread use of SGLT2 inhibitors for the treatment of DKD by nephrologists, especially for treatment of patients with concomitant kidney disease and CVD.

PRACTICAL CLINICAL CONSIDERATIONS Based on available data from CVOTs and CREDENCE, patients with eGFR $30 ml/min/1.73 m 2 would be eligible for SGLT2 inhibition for cardiorenal protection. Current clinical trial data do not support the use

of

these

agents

in

patients

with

eGFR

<30 ml/min/1.73 m 2, and patients with CKD stage 4 should therefore be considered for enrollment in ongoing

clinical

trials

such

as

EMPA-KIDNEY,

SCORED (Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients With Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk; NCT03315143), and SOLOIST-WHF (Effect of Sotagliflozin on Cardiovascular Events in

UNMET NEEDS AND FUTURE DIRECTIONS

Patients With Type 2 Diabetes Post Worsening Heart Failure; NCT03521934), or in dedicated HF

Based on the modest glycemic effects in CVOTs (by

outcome trials (9). As a further note of caution, cli-

design of the trials) and the large magnitude of renal

nicians should consider being mindful of initiating

benefits, it is likely that renal-protective effects with

SGLT2 inhibitors in certain hemodynamically sensi-

SGLT2 inhibitors are based on glycemic-independent

tive renal conditions, such as significant bilateral renal

physiological

natriuresis

artery stenosis and in patients with a single kidney.

(8,9,57). Further clarification of kidney-protective

Caution should similarly be exercised in patients with

mechanisms,

including

JACC VOL. 74, NO. 20, 2019

Cherney et al.

NOVEMBER 19, 2019:2511–24

Antihyperglycemic Agents, Cardiorenal Protection

rates of renal function decline that are higher than

changing, however, and current guidelines reflect the

anticipated and which may reflect other underlying

shifting use of these therapies toward a greater focus

conditions such as ischemia or glomerulonephritis.

on kidney and cardiovascular endpoints (59). In

After initiation of SGLT2 inhibitors in patients with

addition to cardiovascular benefits in CVOTs (60), the

CKD, monitoring can follow the example set by RAAS

CREDENCE trial has convincingly shown substantial

inhibitor use, including reassessment of eGFR 7 to

protection against hard renal clinical endpoints with

14 days after initiating SGLT2 inhibition in patients

canagliflozin, including the risk of ESKD. Additional

with eGFR <60 ml/min/1.73 m 2 and/or in the setting of

dedicated renal endpoint trials including patients

other renal risk factors such as lower blood pressure or

with nondiabetic kidney disease are underway to test

HF. Changes in eGFR of >w20% should prompt addi-

the hypothesis that renal benefits are independent of

tional follow-up, whereas a >30% decline in eGFR

hyperglycemia. In a similar way, dedicated HF trials

would usually prompt a decrease in dose or temporary

with SGLT2 inhibitors will better define HF benefits in

withholding of therapy. Patients with T2DM generally

patients with and without diabetes, and will also

do not require additional adjustments of glucose-

assess the impact of these therapies in those with

lowering therapies with the exception of patients

preserved and reduced ejection fraction (9). Renal

treated with insulin or sulfonylureas who have main-

protection achieved with SGLT2 inhibitors in both

tained tight glycemic control (HbA1c level <7%) or

CVOTs and in CREDENCE seems to be unique among

those with a history of hypoglycemia. In these cases,

the different classes of antihyperglycemic agents and

the insulin dose may require a 10% to 15% down-

will likely lead to significant changes in clinical

titration, and oral agents that predispose to hypogly-

practice guidelines in the short term.

cemia may have to be decreased or stopped.

CONCLUSIONS

ADDRESS FOR CORRESPONDENCE: Dr. David Z.

Cherney,

Toronto Health

General

Network,

585

Hospital,

Uni-

University

Ave,

SGLT2 inhibitors are currently approved as glucose-

versity

lowering therapies in patients with T2DM. The

8N-845, Toronto, Ontario M5G 2N2, Canada. E-mail:

treatment paradigm for the use of these agents is

[email protected].

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KEY WORDS antihyperglycemic, diabetes, diabetic kidney disease, heart failure

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