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CLINICAL RESEARCH STUDY

EMPA-REG OUTCOME: The Nephrologist’s Point of


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Christoph Wanner, MD
Department of Medicine, Division of Nephrology, Würzburg University Clinic, Germany.

ABSTRACT

There is increasing evidence that sodium glucose cotransporter 2 (SGLT2) inhibitors have renoprotective
effects, as demonstrated by the renal analyses from clinical trials including Empagliflozin Cardiovascular
Outcome Event Trial in Type 2 Diabetes Mellitus PatientseRemoving Excess Glucose (EMPA-REG
OUTCOME), CANagliflozin Treatment And Trial Analysis versus SUlphonylurea (CANTATA-SU), and the
dapagliflozin renal study. The potential mechanisms responsible are likely multifactorial, and direct reno-
vascular and hemodynamic effects are postulated to play a central role. This report reviews the renal outcomes
data from key SGLT2 inhibitor clinical trials, discusses the hypotheses for SGLT2 inhibitor-associated
renoprotection, and considers the main renal safety issues associated with SGLT2 inhibitor treatment.
Ó 2017 The Author. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).  The American Journal of Medicine (2017)
130, S63-S72

KEYWORDS: Canagliflozin; Dapagliflozin; Empagliflozin; Renal outcomes; Renoprotection; Sodium glucose


cotransporter 2 inhibitors

Since the publication 15 years ago of the Irbesartan Diabetic the renoprotective effects of angiotensin-converting enzyme
Nephropathy Trial (IDNT)1 and the Reduction of Endpoints in inhibitors and angiotensin II receptor blockers in patients with
Non-insulin dependent diabetes mellitus with the Angiotensin type 2 diabetes (T2DM) and nephropathy, there have been no
II Antagonist Losartan (RENAAL) study,2 which investigated new interventions or approved medications for the treatment of
diabetic kidney disease (diabetic nephropathy).3-8 Although
Funding: This work was supported by Boehringer Ingelheim Phar-
the progression of kidney disease has decreased with advances
maceuticals, Inc. Writing support was provided by Debra Brocksmith, MB, in blood pressure (BP) control and renin-angiotensin-
ChB, PhD, of Envision Scientific Solutions, which was contracted and aldosterone system (RAAS) blockade, many patients with
funded by Boehringer Ingelheim Pharmaceuticals, Inc. The author received T2DM still suffer from chronic kidney disease (CKD) and will
no direct compensation related to the development of the manuscript. progress to end-stage renal disease and require dialysis. The
Conflict of Interest: CW received grants from the European Founda-
tion for the Study of Diabetes (EFSD), personal fees from Boehringer
prevalence of T2DM is increasing,9 and improved life ex-
Ingelheim (steering committee membership, lecturing), and personal fees pectancy is leading to a higher proportion of elderly patients
from Janssen (data safety monitoring board membership). with T2DM; an escalating demand for clinical nephrology
Authorship: The author meets criteria for authorship as recommended services, including an increase in the requirement for renal
by the International Committee of Medical Journal Editors (ICMJE). The dialysis, can be expected.10 Consequently, there is a profound
author was fully responsible for all content and editorial decisions, was
involved at all stages of manuscript development, and approved the final
and urgent need for new drug therapies that prevent, treat, or
version that reflects the author’s interpretation and conclusions. Boehringer slow the progression of diabetic kidney disease given that
Ingelheim was given the opportunity to review the manuscript for medical current treatments are only moderately effective.11
and scientific accuracy as well as intellectual property considerations.
This article is co-published in The American Journal of Medicine
(Vol. 130, Issue 6S, June 2017) and The American Journal of Cardiology PATHOPHYSIOLOGY OF DIABETIC KIDNEY
(Vol. 120, Issue 1S, July 1, 2017). DISEASE
Requests for reprints should be addressed to Christoph Wanner, MD,
Department of Medicine, Division of Nephrology, University Hospital,
In diabetes, chronic hyperglycemia causes substantial
Oberduerrbacherstr. 6, Wuerzburg D-97080, Germany. morbidity and mortality due to the resulting macrovascular
E-mail address: Wanner_C@ukw.de disease (ie, atherosclerotic cardiovascular disease) and

0002-9343/Ó 2017 The Author. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/
licenses/by-nc-nd/4.0/).
http://dx.doi.org/10.1016/j.amjmed.2017.04.007
S64 The American Journal of Medicine, Vol 130, No 6S, June 2017

microvascular disease (ie, kidney disease, retinopathy, and as well. The mechanism of action of SGLT2 inhibitors has
neuropathy).12 Diabetic kidney disease develops gradually been described in detail in previous reviews.15,16 Briefly,
over many years and has several separate but interrelated effectively all of the glucose filtered by the kidney in a healthy
stages, including reversible glomerular hyperfiltration, individual is reabsorbed and returned to the blood circulation,
normal glomerular filtration and normoalbuminuria, normal and a negligible amount is excreted in the urine.15 Renal
or decreasing glomerular filtration and microalbuminuria, glucose reabsorption is predominantly mediated by SGLT2,
declining glomerular filtration and macroalbuminuria, and with lesser involvement by its family member SGLT1. Evi-
end-stage renal disease.13 Several well-defined pathophysi- dence suggests that in patients with T2DM, the expression
ologic mechanisms of diabetic kidney disease have been and activity of SGLT2 is increased in the presence of hy-
described, including hemodynamic, metabolic, and inflam- perglycemia, resulting in additional glucose reabsorption and
matory pathways, as reviewed in detail by Toth- preservation of elevated blood glucose levels.15,17 Pharma-
Manikowski and Atta.14 In the hemodynamic pathways of cologic inhibition of SGLT2 in the kidney reduces the
diabetic kidney disease, RAAS activation leads to increased capacity for renal glucose reabsorption by up to 50%.18 As
levels of angiotensin II, causing efferent arteriolar vaso- SGLT2 reabsorbs sodium and glucose in a cotransport
constriction and hyperfiltration; there is also increased manner, SGLT2 inhibitors also cause natriuresis and are
expression of another efferent arteriolar vasoconstrictor, associated with an antihypertensive effect.19 The mechanism
endothelin-1.14 In terms of metabolic pathways, hypergly- of SGLT2 inhibition occurs independently of insulin secre-
cemia leads to generation of free oxygen radicals, causing tion, and is not affected by pancreatic b-cell function or the
inhibition of glyceraldehyde-3-phosphate dehydrogenase, degree of insulin resistance.15 (A review of the efficacy and
which prevents normal glycolysis and results in a backlog of safety of SGLT2 inhibitors is presented by Thrasher in this
glycolysis precursors, leading to upregulation of the polyol issue.20) In addition to their glucose-lowering effect,
and hexosamine pathways and the production of advanced increasing evidence suggests that SGLT2 inhibitors have
glycation end-product precursors and cofactors for protein renoprotective effects, as discussed below.
kinase C activation.14 These metabolic effects are associated
with various pathophysiologic processes affecting the kid-
ney, including increased transcription of inflammatory cy-
SUMMARY OF RENAL FUNCTION RESULTS FROM
tokines, renal cell hypertrophy, increased mesangial matrix EMPA-REG OUTCOME AND OTHER PHASE III
components, and damage to the glomerular basement EMPAGLIFLOZIN STUDIES
membrane, which contribute to glomerular hyperfiltration.14 The cardiovascular and renal outcomes data from
With regard to the inflammatory pathways, hyperglycemia EMPA-REG OUTCOME have been described.21,22 Briefly,
results in 1) increased expression of nuclear factor-kB, a the study population included patients with T2DM, estab-
transcription factor that regulates gene expression relating to lished cardiovascular disease, and an estimated glomerular
processes including inflammation, immunity, and apoptosis; filtration rate (eGFR) 30 mL/min/1.73 m2.21,22 Patients
2) activation of the Janus kinase/signal transducers and ac- were randomized (N ¼ 7020) to receive either empagliflozin
tivators of transcription (JAK/STAT) signaling pathway, (10 mg or 25 mg) or placebo once daily, in addition to
which relays extracellular chemical signals to gene pro- standard care.21 Prespecified renal outcomes included inci-
moters; and 3) increased expression of inflammatory cyto- dent or worsening nephropathy (defined as progression to
kines, such as interleukins and tumor necrosis factor-a.14 macroalbuminuria, doubling of the serum creatinine level,
Other pathways that may also contribute to diabetic kid- initiation of renal-replacement therapy, or death from renal
ney disease include decreased podocyte autophagic activity disease) and incident albuminuria (defined as urinary albu-
and upregulation of sodium glucose cotransporter 2 min:creatinine ratio [UACR] 30 mg/g).22 Several additional
(SGLT2) expression, both of which are associated with prespecified renal microvascular outcomes and a post hoc
hyperglycemia.14 renal composite outcome were also analyzed.22 Patients in
EMPA-REG OUTCOME had the following baseline char-
acteristics: mean age, w63 years; mean BP, w135/77
MECHANISM OF ACTION OF SGLT2 INHIBITORS mm Hg; mean duration of T2DM >10 years, w57%;
SGLT2 inhibitors are glucose-lowering agents that target the baseline eGFR 60 and <90 mL/min/1.73 m2, w52%;
kidney to reduce the reabsorption of glucose and promote received RAAS inhibition with angiotensin-converting
glucose excretion in the urine, thereby reducing hyperglyce- enzyme inhibitors or angiotensin II receptor blockers,
mia in patients with T2DM. Three SGLT2 inhibitors e w80%; and UACR<30 mg/g, w59%.21 The median obser-
canagliflozin, dapagliflozin, and empagliflozin e have been vation period was 3.1 years.21 Empagliflozin treatment (10-
approved for the treatment of T2DM by regulatory agencies in mg and 25-mg pooled dose group) was associated with a
the United States (US), European Union (EU), and other parts statistically significant 39% reduction in relative risk of
of the world. Three more SGLT2 inhibitors e ipragliflozin, incident or worsening nephropathy vs placebo
luseogliflozin, and tofogliflozin e have regulatory approval in (Figure 1A).22 Statistically significant relative risk re-
Japan, but are not currently available in either the US or EU ductions for empagliflozin vs placebo were also observed
markets; other SGLT2 inhibitors are in clinical development for progression to macroalbuminuria, doubling of serum
Wanner EMPA-REG OUTCOME: Nephrology S65

creatinine levels, and the initiation of renal-replacement 4 weeks and then stabilized in the empagliflozin group,22
therapy (Figure 1B).22 No statistically significant difference which is suggestive of decreased intraglomerular pressure.
in the rate of incident albuminuria between the treatment At the post-treatment follow-up, after cessation of study
groups was observed. Events consistent with acute renal drug, patients in the empagliflozin group (10-mg and 25-mg
failure (including acute kidney injury) and hyperkalemia doses) had an adjusted mean difference from placebo in the
occurred less frequently in the empagliflozin group than in change from baseline eGFR of 4.7 mL/min/1.73 m2
the placebo group.22 Mean eGFR decreased over the first (P <.001 for both comparisons).22 Assuming a rate of

A 100 Hazard ratio: 0.61 (95% CI: 0.53-0.70)


90 p <0.001

80
Cumulative Probability

70
of Event (%)

60

50

40

30
Placebo
20

10 Empagliflozin
0
0 6 12 18 24 30 36 42 48
Month

No. at risk
Empagliflozin 4,124 3,994 3,848 3,669 3,171 2,279 1,887 1,219 290
Placebo 2,061 1,946 1,836 1,703 1,433 1,016 833 521 106

B Empagliflozin Placebo
No. with event/ Rate/1,000 No. with event/ Rate/1,000
Renal Outcome Measure No. analyzed (%) patient-yr No. analyzed (%) patient-yr Hazard Ratio (95% CI) p Value
Incident or worsening nephropathy or cardiovascular death 675/4,170 (16.2) 60.7 497/2,102 (23.6) 95.9 0.61 (0.55-0.69) <0.001

Incident or worsening nephropathy 525/4,124 (12.7) 47.8 388/2,061 (18.8) 76.0 0.61 (0.53-0.70) <0.001

Progression to macroalbuminuria 459/4,091 (11.2) 41.8 330/2,033 (16.2) 64.9 0.62 (0.54-0.72) <0.001

Doubling of serum creatinine level accompanied by eGFR 70/4,645 (1.5) 5.5 60/2,323 (2.6) 9.7 0.56 (0.39-0.79) <0.001
of ≤45 mL/min/1.73 m2

Initiation of renal replacement therapy 13/4,687 (0.3) 1.0 14/2,333 (0.6) 2.1 0.45 (0.21-0.97) 0.04

Doubling of serum creatinine level accompanied by eGFR 81/4,645 (1.7) 6.3 71/2,323 (3.1) 11.5 0.54 (0.40-0.75) <0.001
of ≤45 mL/min/1.73 m2, initiation of renal replacement
therapy, or death from renal disease

Incident albuminuria in patients with a normal albumin level 1,430/2,779 (51.5) 252.5 703/1,374 (51.2) 266.0 0.95 (0.87-1.04) 0.25
at baseline

0.125 0.25 0.5 1.0 2.0 4.0

Empagliflozin better Placebo better

Figure 1 (A) Kaplan-Meier analysis of incident or worsening nephropathy in EMPA-REG OUTCOME.22 Estimates of the probability
of a first occurrence of a prespecified renal composite outcome of incident or worsening nephropathy among patients who received at
least one dose of either empagliflozin or placebo are shown. Because of the declining numbers of patients at risk, Kaplan-Meier curves
have been truncated at 48 months. (B) Risk comparison for renal outcomes in EMPA-REG OUTCOME.22 All the analyses shown were
performed with the use of Cox regression in patients who received at least one dose of either empagliflozin or placebo. All analyses were
prespecified except for the composite outcome of a doubling of the serum creatinine level, initiation of renal-replacement therapy, or
death from renal disease. eGFR ¼ estimated glomerular filtration rate. Reprinted from22: Wanner C, Inzucchi SE, Lachin JM, et al.
Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375:323-334. Copyright Ó2016 Massachusetts
Medical Society. Reprinted with permission from Massachusetts Medical Society.
S66 The American Journal of Medicine, Vol 130, No 6S, June 2017

decline in eGFR of approximately 4 mL/min/1.73 m2 per <30 mg/g, w84%. The main efficacy endpoint for this
year in T2DM patients,23 an eGFR gain of 4.7 mL/min/1.73 m2 analysis was the yearly rate of decline in eGFR over 104
could be translated into delaying the need for dialysis by weeks of follow-up, and exploratory efficacy endpoints
approximately 1.0 year. The study concluded that empa- were the least squares mean change from baseline in eGFR
gliflozin is associated with a slower progression of diabetic and UACR. Results demonstrated that the annual rate of
kidney disease and lower rates of clinically relevant renal decline in eGFR was statistically significantly lower in both
events vs placebo when added to standard care in patients canagliflozin groups vs glimepiride (canagliflozin 100 mg:
with T2DM at high cardiovascular risk.22 This renal analysis 0.5 mL/min/1.73 m2 per year; 95% CI, 0.0-1.0; canagliflozin
was not without limitations, as it was not a dedicated renal 300 mg: 0.9 mL/min/1.73 m2 per year; 95% CI, 0.4-1.4;
trial, and renal events were either reported by the in- glimepiride: 3.3 mL/min/1.73 m2 per year; 95% CI, 2.8-3.8;
vestigators or derived from laboratory data and not pro- P <.01 for each canagliflozin group vs glimepiride).27 The
spectively adjudicated. same trend occurred in a subgroup analysis of patients with
Evidence of renoprotection was also observed in earlier UACR 30 mg/g (n ¼ 230; 15.9% of total population). An
Phase III studies of empagliflozin. When empagliflozin was acute reduction in eGFR was observed for canagliflozin
added to existing glucose-lowering therapy in patients with groups after 4 weeks of treatment, which was followed by
T2DM and CKD (N ¼ 741), UACR improved with empa- stabilization in the rate of long-term decline in eGFR, and is
gliflozin, compared with placebo at week 52.24 Fewer pa- similar to observations reported with empagliflozin. This is
tients receiving empagliflozin vs those receiving placebo suggestive of altered renal hemodynamics and reduced
progressed from no albuminuria to microalbuminuria, and intraglomerular pressure. UACR increased over time with
from microalbuminuria to macroalbuminuria (eg, stage 3 glimepiride, remained stable with canagliflozin 100 mg, and
CKD, eGFR 30 and <60 mL/min/1.73 m2: 12.2% vs decreased with canagliflozin 300 mg over year 1 to return to
22.2% and 2.0% vs 11.4% for empagliflozin 25 mg and baseline levels at year 2. In the subgroup of patients with
placebo, respectively). More patients with stage 3 CKD UACR 30 mg/g, canagliflozin (100 mg and 300 mg)
receiving empagliflozin 25 mg improved from macro- significantly decreased UACR over time (31.7% and 49.3%
albuminuria at baseline to microalbuminuria, or micro- reductions, respectively) relative to glimepiride. A modest
albuminuria to no albuminuria, at end of treatment (32.6% vs and comparable improvement in blood glucose concentra-
8.6% and 27.5% vs 21.4% for empagliflozin 25 mg and tions was observed across all treatment groups (glycated
placebo, respectively).24 Small decreases in eGFR were hemoglobin [HbA1c] reduction 0.8%-0.9% at year 1, and
observed in the empagliflozin groups, and these returned to 0.6%-0.7% at year 2), suggesting these beneficial effects on
baseline levels by the end of the 3-week follow-up period.24 kidney function are not mediated by blood glucose over this
In a randomized controlled trial of empagliflozin (25 mg once relatively short period. Similar proportions of patients across
daily, n ¼ 769) vs glimepiride (1-4 mg once daily, n ¼ 780) each treatment group (w3% for each) experienced adverse
as add-on to metformin in T2DM, assessment of mean eGFR events potentially related to kidney function (not further
indicated that renal function was preserved from baseline to defined).27 In terms of study limitations, CANTATA-SU
week 104 with empagliflozin.25 The adjusted mean differ- was not a dedicated renal study and the renal events were
ence in eGFR from baseline to week 104 for empagliflozin vs not adjudicated. The follow-up period was 2 years,27 which
glimepiride was 3.3 mL/min/1.73 m2 (95% confidence in- was shorter than that for EMPA-REG OUTCOME.22 In
terval [CI], 2.0-4.7; P <.0001).25 Furthermore, UACR addition, eGFR was not measured after drug discontinua-
improved with empagliflozin compared with glimepiride.25 tion, so it was not possible to verify whether the initial
decrease in eGFR observed in the canagliflozin group was
reversible.27 It was further noted that the lack of a placebo
SUMMARY OF RENAL FUNCTION RESULTS FROM arm meant that no conclusion could be made about whether
OTHER SGLT2 INHIBITOR STUDIES canagliflozin was renoprotective or glimepiride worsened
A secondary analysis of renal data from a 2-year random- the progression of kidney disease.
ized controlled trial comparing canagliflozin and glimepiride A post hoc analysis of data from a 104-week randomized
in patients with T2DM, CANagliflozin Treatment And Trial controlled trial of dapagliflozin (NCT00663260)28 included
Analysis versus SUlphonylurea (CANTATA-SU; 166 patients with T2DM and stage 3 CKD with increased
NCT00968812),26 was recently published.27 Patients were albuminuria (UACR 30 mg/g).29 Patients were randomized
randomized (N ¼ 1450) to receive either canagliflozin to receive once-daily doses of dapagliflozin 10 mg, dapa-
(100 mg or 300 mg) or glimepiride (up-titrated to 6-8 mg) gliflozin 5 mg, or placebo. More patients in the dapagli-
once daily on a background of metformin therapy. Patients flozin groups moved to a lower UACR category compared
with eGFR 55 mL/min/1.73 m2 (or 60 mL/min/1.73 m2 with the placebo group (33.9% and 39.6% for dapagliflozin
if based on restriction of metformin use in the local label) 10 mg and 5 mg, respectively, vs 15.8% for placebo);
were included in the study. Other patient characteristics at similarly, fewer patients receiving dapagliflozin compared
baseline were as follows: mean age, w56 years; mean BP, with placebo progressed to a higher UACR category.29 In
w130/79 mm Hg; mean duration of T2DM, w6.6 years; addition, more patients in the dapagliflozin groups achieved
received background RAAS inhibition, w61%; and UACR normoalbuminuria status than in the placebo group (17.8%
Wanner EMPA-REG OUTCOME: Nephrology S67

and 18.9% vs 7.0% for dapagliflozin 10 mg, dapagliflozin dapagliflozin 10-mg group, 1.9% of subjects in the dapa-
5 mg, and placebo, respectively).29 There was an initial gliflozin 5-mg group, and 3.5% of subjects in the placebo
decrease in eGFR within the first 4 weeks of dapagliflozin group.29 There were no between-group differences in the
therapy and no further decline through the 104-week frequency of serious renal adverse events (w1.8%-1.9% for
period.29 Renal adverse events, mostly associated with each).29 This analysis is limited by being post hoc and by its
increased creatinine, occurred in 10.7% of subjects in the small sample size.29

5
Kidney protection
Transport work Kidney growth
Renal O2 consumption Albuminuria 2
Blood
Albuminuria Inflammation glucose
1 2
PBow SGLT2
? NHE3
GFR

4
[Na+/CI–/K+]MD
HIF Glucosuria Natriuresis
Osmotic diuresis Uricosuria
Insulin need/levels 3
Glucagon
? 6 3
5
3
Lipolysis and hepatic
gluconeogenesis ECV/blood pressure
Kidney/heart Uric acid levels
Mild ketosis
? 5 protection Body fat and weight

Figure 2 A summary of possible mechanisms of renal protection associated with SGLT2 in-
hibitors.19 The pleiotropic effects of SGLT2 inhibition may provide cardioprotective and renal pro-
tective effects via several mechanisms: (1) SGLT2 inhibition attenuates primary proximal tubular
hyper-reabsorption in the kidney in diabetes, increasing/restoring the tubuloglomerular feedback
signal at the macula densa ([Naþ/Cl/Kþ]MD) and hydrostatic pressure in Bowman’s space (PBow).
This reduces glomerular hyperfiltration, beneficially affecting albumin filtration and tubular transport
work, and thus, renal oxygen consumption; (2) by lowering blood glucose levels, SGLT2 inhibitors
can reduce kidney growth, albuminuria, and inflammation; (3) SGLT2 inhibitors have a modest os-
motic diuretic, natriuretic, and uricosuric effect, which can reduce ECV, blood pressure, serum uric
acid levels, and body weight. These changes may have beneficial effects on both the renal and car-
diovascular systems; (4) SGLT2 may be functionally linked to NHE3, such that SGLT2 inhibition may
also inhibit NHE3 in the proximal tubule, with implications on the natriuretic, GFR, and blood
pressure effect; (5) SGLT2 inhibition reduces insulin levels and the need for therapeutic or endogenous
insulin and increases glucagon levels. As a consequence, lipolysis and hepatic gluconeogenesis are
elevated. These metabolic adaptations reduce fat tissue/body weight and hypoglycemia risk, and result
in mild ketosis, potentially having beneficial effects on both the renal and cardiovascular systems; (6)
SGLT2 inhibition may also enhance renal HIF content, which may have renal protective effects. White
text boxes indicate affected variables; gray text boxes indicate processes that link SGLT2 inhibition to
the reduction in GFR. Green arrows demonstrate consequences; red arrows indicate changes in
associated variables (increase/decrease). ECV ¼ extracellular volume; GFR ¼ glomerular filtration
rate; HIF ¼ hypoxia-inducible factor; NHE3 ¼ sodium-hydrogen antiporter 3; SGLT2 ¼ sodium
glucose cotransporter 2. Reprinted from19: Vallon V, Thomson SC. Targeting renal glucose reab-
sorption to treat hyperglycaemia: the pleiotropic effects of SGLT2 inhibition. Diabetologia.
2017;60:215-225. Reprinted with permission of Springer.
S68 The American Journal of Medicine, Vol 130, No 6S, June 2017

A recent commentary comparing the renal analyses from similar to that observed in T1DM patients with normal renal
EMPA-REG OUTCOME and CANTATA-SU suggested filtration.33 Reduced secretion of atrial natriuretic peptide
that these data provide replication of renal effects and that may have a role in lowering intraglomerular pressure, but
renoprotection may be a class effect of SGLT2 inhibitors any relationship with SGLT2 inhibition is currently specu-
that is additive to RAAS blockade.30 lative.27 In addition, treatment with an SGLT2 inhibitor in a
mouse model of T1DM prevented diabetes-induced in-
creases in GFR, attenuated albuminuria, and reduced
POSSIBLE MECHANISMS FOR IMPROVEMENT IN markers of kidney hypertrophy and inflammation.32 Renal
RENAL FUNCTION WITH SGLT2 INHIBITORS hemodynamic changes that reduce glomerular hyper-
The potential mechanisms responsible for the improved filtration and intraglomerular pressure are manifested clini-
renal outcomes observed with SGLT2 inhibition are likely cally as acute reductions in albuminuria and eGFR, followed
to be multifactorial (Figure 2)19; direct renovascular and by longer-term eGFR stabilization, and should equate to
hemodynamic effects are postulated to have a key role.22 improved long-term kidney outcomes.27 Meta-analyses of
SGLT2 inhibition reduces proximal tubular sodium reab- clinical trial data suggest that a 30% reduction in albumin-
sorption, and thus, increases sodium delivery to the macula uria was associated with a 24% reduction in the risk of end-
densa, which activates tubuloglomerular feedback and stage renal disease,34 assuming other markers of kidney
afferent arteriolar vasomodulation (Figure 3; see also renal disease were stable.27 Reductions in vascular stiffness35,36
protection video in supplemental materials),31 resulting in and vascular resistance35 associated with SGLT2 inhibitor
decreased renal blood flow and decreased glomerular therapy may also contribute to the observed improvements
hyperfiltration.31,32 SGLT2 inhibition also was found to in renal disease progression.22
significantly improve intraglomerular hypertension in pa- The effect of systemic or renal neurohormonal factors on
tients with type 1 diabetes mellitus (T1DM) and renal renal outcomes associated with SGLT2 inhibitor therapy
hyperfiltration, achieving a mean intraglomerular pressure should also be considered.36,37 Data from SGLT2 inhibitor

A normal TGF B impaired TGF C restored TGF

elevated
appropriate macula afferent GFR decreased increased
densa normalization Na+ delivery
afferent arteriole Na+ delivery afferent
normal of GFR
arteriole vasodilation to macula arteriole to macula
GFR
tone densa constriction densa

increased
Na+/glucose
Na+/glucose
reabsorption
reabsorption

SGLT2 SGLT2
SGLT2
inhibition
in proximal
tubule

glucosuria

Normal physiology Hyperfiltration in early stages SGLT2 inhibition reduces


of diabetic nephropathy hyperfiltration via TGF

Figure 3 Possible renal hemodynamic effects associated with SGLT2 inhibition.31 Under physiological conditions, TGF signaling
maintains stable GFR by modulation of preglomerular arteriole tone. In cases of conditional increases in GFR, the macula densa within
the juxtaglomerular apparatus senses an increase in distal tubular sodium delivery and adjusts GFR via TGF accordingly (A); under
chronic hyperglycemic conditions (diabetes mellitus), increased proximal SGLT2-mediated reabsorption of sodium (Naþ) and glucose
impairs this feedback mechanism. Thus, despite increased GFR, the macula densa is exposed to lowered sodium concentrations. This
impairment of TGF signaling likely leads to inadequate arteriole tone and increased renal perfusion (B); and SGLT2 inhibition with
empagliflozin treatment blocks proximal tubule glucose and sodium reabsorption, which leads to increased sodium delivery to the
macula densa. This condition restores TGF via appropriate modulation of arteriolar tone (eg, afferent vasoconstriction), which, in turn,
reduces renal plasma flow and hyperfiltration (C). GFR ¼ glomerular filtration rate; SGLT2 ¼ sodium glucose cotransporter 2; TGF ¼
tubuloglomerular feedback. Reprinted from31: Cherney DZ, Perkins BA, Soleymanlou N, et al. Renal hemodynamic effect of sodium-
glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation. 2014;129:587-597. Available at: http://circ.
ahajournals.org/content/129/5/587. Reprinted with permission.
Wanner
Table Use of Canagliflozin, Dapagliflozin, and Empagliflozin in Patients with Renal Impairment49-51,56-58
US Label e Prescribing Information

Canagliflozin50 Dapagliflozin49 Empagliflozin51

EMPA-REG OUTCOME: Nephrology


Assess renal function prior to initiating SGLT2 inhibitor treatment and periodically thereafter
Dose adjustment and more frequent renal function
monitoring are recommended in patients with
eGFR <60 mL/min/1.73 m2
Limit dose of canagliflozin to 100 mg once daily in patients No dose adjustment is needed in patients with mild renal No dose adjustment is needed if eGFR 45 mL/min/1.73 m2
with moderate renal impairment with an eGFR 45 to impairment (eGFR 60 mL/min/1.73 m ) 2

<60 mL/min/1.73 m2
Canagliflozin should not be initiated in patients with an Dapagliflozin should not be initiated in patients with an Empagliflozin should not be initiated in patients with an
eGFR <45 mL/min/1.73 m2 eGFR <60 mL/min/1.73 m2 eGFR <45 mL/min/1.73 m2
Canagliflozin is not recommended when eGFR is persistently Dapagliflozin is not recommended in patients with an Discontinue empagliflozin if eGFR is persistently
<45 mL/min/1.73 m2 eGFR persistently between 30 and <60 mL/min/1.73 m2 <45 mL/min/1.73 m2
SGLT2 inhibitors are contraindicated in patients with severe renal impairment (eGFR <30 mL/min/1.73 m2), ESRD, or on dialysis
EU Label e Summary of Product Characteristics

Canagliflozin56 Dapagliflozin57 Empagliflozin58


Assess renal function prior to initiating SGLT2 inhibitor treatment and at least annually thereafter; prior to initiating concomitant medication that may reduce renal
function and periodically thereafter; at least 2-4 times/year for renal function approaching moderate renal impairment
Efficacy of SGLT2 inhibitor treatment is dependent on renal function: efficacy is reduced in patients who have moderate renal impairment and likely absent in patients
with severe renal impairment
No dose adjustment is needed in patients with an No dose adjustment is indicated in patients with mild renal No dose adjustment is needed in patients with an
eGFR 60 to <90 mL/min/1.73 m2 or CrCl 60 mL/min to impairment (eGFR 60 mL/min/1.73 m2 or CrCl 60 mL/ eGFR 60 mL/min/1.73 m2 or CrCl 60 mL/min
<90 mL/min min)
Canagliflozin should not be initiated in patients with an Dapagliflozin is not recommended for use in patients with Empagliflozin should not be initiated in patients with an
eGFR <60 mL/min/1.73 m2 or CrCl <60 mL/min moderate to severe renal impairment (eGFR <60 mL/min/ eGFR <60 mL/min/1.73 m2 or CrCl <60 mL/min
1.73 m or CrCl <60 mL/min)
2

In patients tolerating canagliflozin with an eGFR In patients tolerating empagliflozin with an eGFR
persistently <60 mL/min/1.73 m2 or CrCl <60 mL/min, persistently <60 mL/min/1.73 m2 or CrCl <60 mL/min,
dose should be adjusted to or maintained at 100 mg dose should be adjusted to or maintained at 10 mg once
once daily daily
Canagliflozin should not be used in patients with an
eGFR <45 mL/min/1.73 m2 or CrCl <45 mL/min
Canagliflozin should be discontinued when eGFR is Dapagliflozin should be discontinued if eGFR <60 mL/min/ Empagliflozin should be discontinued when eGFR is
persistently <45 mL/min/1.73 m2 or CrCl is persistently 1.73 m2 or CrCl <60 mL/min persistently <45 mL/min/1.73 m2 or CrCl is persistently
<45 mL/min <45 mL/min
SGLT2 inhibitors should not be used in patients with ESRD or on dialysis, as these agents are not expected to be effective in these patients
CrCl ¼ creatinine clearance; eGFR ¼ estimated glomerular filtration rate; ESRD ¼ end-stage renal disease; SGLT2 ¼ sodium glucose cotransporter 2.

S69
S70 The American Journal of Medicine, Vol 130, No 6S, June 2017

studies in T1DM and T2DM demonstrated an increase in with SGLT2 inhibitor treatment, the US Food and Drug
circulating RAAS mediators (angiotensin II, aldosterone).31,38 Administration reinforced the existing warning in the
Empagliflozin had no significant effects on vagal tone and respective drug labels to include information on this po-
sympathetic nervous system activity during clamped eugly- tential risk and recommendations for its minimization.48-51
cemia and hyperglycemia in patients with T1DM.36 There was no association between empagliflozin and
Small reductions in serum uric acid levels were observed increased risk of acute kidney injury in the EMPA-REG
with empagliflozin treatment during EMPA-REG OUTCOME OUTCOME study.21 Overall safety signals seen in obser-
and may be involved in the cardiovascular and renal benefits vational studies (real-world observations) are potentially
reported.21,22 The exact role is currently unclear39,40; however, confounded by concomitant treatment or other conditions
there is evidence from observational studies that elevated uric that may bias the findings. Nonetheless, clinicians should
acid levels can cause hypertension, vascular damage, and consider factors that may predispose patients to acute kidney
impaired renal function.41 Adequately powered randomized injury prior to therapy initiation (eg, hypovolemia, chronic
clinical trials are required to fully evaluate the effects of uric renal insufficiency, concomitant medications, such as di-
acid reduction on renal outcomes.40 uretics), consider temporary discontinuation of SGLT2 in-
Modest reductions in BP and body weight are associated hibitor treatment during periods of reduced oral intake or
with SGLT2 inhibitor therapy and are believed to be fluid loss, and discontinue therapy promptly and institute
attributable, at least in part, to SGLT2 inhibitor-associated treatment if acute kidney injury should occur.
natriuresis.30 It is also possible that decreased sodium SGLT2 inhibition has been evaluated in clinical trials of
reabsorption could affect proximal tubular cell energetics patients with T2DM and various stages of CKD.24,52-54 In a
and, by extension, influence other functions of these meta- review of clinical trial data by Scheen,55 clinical efficacy of
bolically active cells.30 SGLT2 inhibitors in terms of HbA1c reduction was main-
Glucagon may have an important role in maintaining tained in patients with mild CKD (stage 2; eGFR 60-89 mL/
heart and kidney function.42 At relatively high doses, min/1.73 m2), decreased in patients with moderate CKD
glucagon induces vasodilation with concomitant increases in (stage 3a and 3b; eGFR 45-59 mL/min/1.73 m2, and 30-44
renal plasma flow, eGFR, and electrolyte excretion; these mL/min/1.73 m2, respectively), particularly stage 3b, and
changes are more evident in patients with diabetes, which was virtually eliminated in those with severe CKD (stage 4;
may be due to the modified insulin-to-glucagon ratio.42 eGFR 15-30 mL/min/1.73 m2). The short-term reductions in
Glucagon is responsible for the increase in natriuresis in eGFR that were observed in clinical trials with canagliflozin,
the fasting state,43 and has direct action (with vasopressin) dapagliflozin, and empagliflozin are suggestive of an early
in protein-induced hyperfiltration and the excretion of ni- hemodynamic effect of treatment that becomes attenuated
trogen end products.44 Empagliflozin has been shown to over time, and do not imply the development of progressive
increase blood glucagon levels (and endogenous glucose renal injury.24,52-54 Subgroup analysis of cardiovascular
production) in patients with T2DM.45 outcomes from EMPA-REG OUTCOME showed consistent
The activation of hypoxia-inducible factor 1 (HIF-1) and benefit in patients with low eGFR vs those with higher or
subsequent erythropoiesis may also confer renal protective normal eGFR levels.21 It should be noted that SGLT2 in-
effects. HIF-1, consisting of an oxygen-sensitive a subunit and hibitor agents are contraindicated in patients with severe
a constitutively expressed b subunit, is a key protein that reg- renal impairment; details from US and EU labels on the use
ulates protective cellular responses in the kidney (and other of canagliflozin, dapagliflozin, and empagliflozin in patients
organs) to hypoxia; erythropoiesis is one of several biological with varying degrees of renal impairment are summarized in
processes related to kidney function that is regulated by the Table.49-51,56-58 This labeling reflects that urinary
HIF-1.46 A recent in vitro study reported that dapagliflozin glucose excretion, and thus, the glucose-lowering efficacy of
induces HIF-1 in murine ischemic renal tissue and human SGLT2 inhibitors, decreases with increasing renal impair-
ischemic cultured renal tubular cells.47 It is plausible that a ment (ie, as eGFR declines).55 In addition, the risk of renal-
HIF-1-induced increase in erythropoietin e related to SGLT2 related adverse events increases with declining eGFR.
inhibition e could lead to a subsequent improvement in oxygen
delivery and other associated renal protective effects.
Lastly, SGLT2 inhibitor-associated changes in blood CONCLUSION
volume or renal perfusion may alter serum creatinine turn- The renal benefits of SGLT2 inhibitors, as well as the car-
over and renal function assessments; however, further diovascular benefits of empagliflozin, should be considered
research is required.22 by physicians when selecting glucose-lowering medication
for the management of patients with T2DM and high car-
diovascular risk. The renal findings from clinical trials of
RENAL SAFETY WITH SGLT2 INHIBITORS AND empagliflozin, canagliflozin, and dapagliflozin can be
USE IN PATIENTS WITH RENAL IMPAIRMENT assessed definitively when data from 2 ongoing renal out-
General safety issues associated with SGLT2 inhibitors are comes trials are published; namely, Canagliflozin and Renal
discussed in the review by Thrasher in this issue.20 Events in Diabetes with Established Nephropathy Clinical
Following postmarketing reports of acute kidney injury Evaluation (CREDENCE; NCT02065791),59 and
Wanner EMPA-REG OUTCOME: Nephrology S71

CANagliflozin cardioVascular Assessment Study-Renal 14. Toth-Manikowski S, Atta MG. Diabetic kidney disease: pathophysi-
endpoints (CANVAS-R; NCT01989754).60 Another renal ology and therapeutic targets. J Diabetes Res. 2015;2015:697010.
15. Abdul-Ghani MA, DeFronzo RA. Inhibition of renal glucose reab-
study to investigate the effect of dapagliflozin on albumin- sorption: a novel strategy for achieving glucose control in type 2 dia-
uria in stage 3 CKD is recruiting participants betes mellitus. Endocr Pract. 2008;14:782-790.
(NCT02547935).61 Given the renal results from EMPA- 16. DeFronzo RA, Davidson JA, Del Prato S. The role of the kidneys in
REG OUTCOME, questions about treatment risk and glucose homeostasis: a new path towards normalizing glycaemia.
benefit may extend to patients with diabetic kidney disease Diabetes Obes Metab. 2012;14:5-14.
17. Rahmoune H, Thompson PW, Ward JM, Smith CD, Hong G, Brown J.
who are not at high cardiovascular risk. Specifically, phy- Glucose transporters in human renal proximal tubular cells isolated
sicians may wish to consider the use of empagliflozin for the from the urine of patients with non-insulin-dependent diabetes. Dia-
treatment of diabetic kidney disease and albuminuria in a betes. 2005;54:3427-3434.
patient without a prior cardiovascular event but with 18. Abdul-Ghani MA, Defronzo RA, Norton L. Novel hypothesis to
declining renal function, and not postpone such treatment explain why SGLT2 inhibitors inhibit only 30-50% of filtered glucose
load in humans. Diabetes. 2013;62:3324-3328.
until the patient has survived a myocardial infarction. 19. Vallon V, Thomson SC. Targeting renal glucose reabsorption to treat
However, this approach will require additional studies hyperglycaemia: the pleiotropic effects of SGLT2 inhibition. Dia-
before a firm recommendation can be determined for this betologia. 2017;60:215-225.
patient population. In conclusion, the results from EMPA- 20. Thrasher J. Management of type 2 diabetes: available therapies. Am J
REG OUTCOME, CANTATA-SU, and the dapagliflozin Med. 2017;130(suppl 6):S4-S17.
21. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular
renal study about renal protective outcomes are encour- outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:
aging, and indicate that SGLT2 inhibitor agents offer a 2117-2128.
promising therapeutic option in the future management of 22. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and pro-
patients with T2DM. gression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375:
323-334.
23. Altemtam N, Russell J, El Nahas M. A study of the natural history of
diabetic kidney disease (DKD). Nephrol Dial Transplant. 2012;27:
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