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1SEPTEMBER 2020
This report was made possible by an unrestricted educational grant from AstraZeneca. The content of the report is independent of the sponsor. The expert participated voluntarily.
An educational programme for general practice developed by international experts.
What you will gain…Participation in this fully accredited CPD programme gives you the opportunity to learn how:• Evaluate the evidence for renal protection with SGLT-2 inhibitors from cardiovascular outcomes trials in type 2
diabetes mellitus • Explore the cardiorenal linkage in heart failure protection with SGLT-2 inhibitors
Module 5
Evidence for the renal benefits of SGLT-2 inhibitors in diabetes
© 2020 deNovo Medica
xxxx
Dr Subodh VermaDivision of Cardiac SurgerySt Michael’s Hospital
Professor of Surgery and Pharmacology & ToxicologyUniversity of Toronto, Toronto, ON, Canada
Canada Research Chair in Cardiovascular Surgery
Expert‘Acting on
the Evidence’ offers you the opportunity
to obtain free CPD points
Renal benefits of SGLT-2 inhibitors in diabetes
2 SEPTEMBER 2020
3 CEUs
Module 5: Renal benefits of SGLT-2 inhibitors in diabetes
IntroductionChronic kidney disease remains an important complication of type 2 diabetes mellitus (T2DM); control of risk factors and the use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are foundational therapy, paramount to reducing diabetic kidney disease. Three large cardiovascular outcomes trials (CVOTs) with sodium-glucose co-transporter-2 (SGLT-2) inhibitors
have now provided data that these agents similarly reduce renal events, quite profoundly, across a broad spectrum of patients with or without established cardiovascular disease. Many other ongoing trials will evaluate the efficacy of SGLT-2 inhibitors as a renal protective strategy in people with or without diabetes, with established renal disease, and renal disease in heart failure.
Mechanism of action of SGLT-2 inhibitors – proposed renal protective pathwaysSGLT-2 inhibitors limit the reabsorption of both glucose and sodium in the proximal tubule of the kidney, resulting in glycosuria and natriuresis.1 There is overlap between the SGLT-2 mechanisms suggested to be involved
in renal protection with those mechanisms that have been proposed to explain their cardiovascular benefit (Figure 1);2 both direct and indirect mechanisms may mediate the renal protection of these agents.
Click here to watch the video
Other modulesModule 1Cardiovascular prevention and heart failure in diabetes
Module 2Cardiovascular outcome trials in diabetes
Module 3Renal protection in type 2 diabetes
Module 4Review of renal therapies prior to SGLT-2 inhibitors
Module 6Safety of SGLT-2 inhibitors and side-effects
Figure 1. Proposed renal protective pathways of SGLT-2 inhibitors
Potential direct
cardiovascular effects improved
cardiac function with maintenance of renal perfusion
↑ Oxygenation of tubular cells
based on ↓ demand for solute transport and ↑ haematocrit leading to
↑ oxygen delivery
“Loop diuretic sparing” effect
– preservation of intravascular volume and reduced volume
overload
Improved metabolic parameters
(↓ HbA1c, weight)
↓ Blood pressure, even
in the presence of CKD ↓ endothelial
dysfunction, ↓ arterial stiffness
↓ Intraglomerular pressure due to
tubuloglomerular feedback effects
↓ Albuminuria, reducing possible
direct toxic effects on renal tubules
↓ Ambient proinflammatory/
profibrotic pathways (experimental evidence only)
Protection against diabetic kidney
disease
Renal benefits of SGLT-2 inhibitors in diabetes
3SEPTEMBER 2020
3 CEUs
SGLT-2 inhibitors promote relative afferent arteriole vasoconstriction, thereby reducing intraglomerular hypertension;3 renin-angiotensin-aldosterone system (RAAS) blockers act on efferent arteriole vasodilatation to reduce intraglomerular
hypertension. The combination of SGLT-2 inhibitors and RAAS blockers is complementary, with the potential for additive reductions in intraglomerular pressure that benefit the kidney (Figure 2).
What is the evidence of SGLT-2 inhibitor benefit for renal function preservation? A starting point from which to understand the significance of the SGLT-2 inhibitors, canagliflozin, dapagliflozin and empagliflozin, arises from evidence-based data.
A comparative study of canagliflozin versus glimepiride has shown that canagliflozin preserved renal function in relatively low-risk individuals with normal renal function, compared to the ongoing decline seen in patients on sulphonylurea treatment (Figure 3).4 The estimated glomerular filtration rate (eGFR) slope reductions are
greater with the sulphonylurea compared to the SGLT-2 inhibitor and that relationship remains consistent even in people with urine albumin-to-creatinine ratios (UACRs) >3.4mg/mmol. In fact, eGFR slopes are steeper with sulphonylurea therapy than those seen in the overall population (Figure 4).5 The DERIVE study of dapagliflozin demonstrated an initial dip in eGFR, explained as a recalibration secondary to afferent arteriole vasoconstriction and due to changing intraglomerular haemodynamics and intraglomerular pressures.
Figure 2. Clinical implications of the pharmacological actions and haemodynamic effects of SGLT-2 inhibition and RAAS blockade
Haemodynamic effects and clinical implications
Pharmacological actions
A
B
C
• Decreased intraglomerular pressure due to increased afferent resistance in T1D-H patientsa
• Decreased hyperfiltration
• Decreased intraglomerular pressure due to decreased efferent resistance
• Decreased hyperfiltration
• Proven renal protection in clinical trials
• Normalisation of intraglomerular pressure due to increased afferent and decreased efferent resistance?
• Potential for additive intraglomerular pressure reduction?
• Potential for long-term renal protection?
RAAS: renin–angiotensin–aldosterone system; T1D-H: type 1 diabetes hyperfiltrationa SGLT-2 inhibitors are not indicated for use in type 1 diabetes in South Africa
Afferent AfferentEfferent Efferent
SGLT-2 inhibition
Afferent constriction
RAAS blockade
Efferent dilation
SGLT-2 inhibition and RAAS blockade
Afferent constriction and Efferent dilation
Renal benefits of SGLT-2 inhibitors in diabetes
4 SEPTEMBER 2020
3 CEUs
It is important to understand that the renal protective benefits of an SGLT-2 inhibitor are distinct and independent of changes in HbA1c, weight and blood pressure. Pooled analyses with empagliflozin from five phase III randomised controlled trials of patients with either microalbuminuria or macroalbuminuria assessed the proportion of the benefit dependent on or independent of HbA1c, weight or blood pressure. The percentage change in geometric mean UACR from baseline to week 24 was independent of HbA1c, weight and blood pressure changes (Figure 5).6
The impact of empagliflozin on HbA1c and systolic blood pressure as stratified by GFR is important. With declining GFR, the HbA1c lowering efficacy is reduced substantially. In addition, with declining GFR there is no reduction in the blood pressure lowering efficacy of empagliflozin (Figure 6); if anything, the effect on blood pressure tends to be greater when the GFR is lower. The haemodynamic benefits persist despite a lack of HbA1c reduction, particularly at the lower GFRs.
Figure 3. Canagliflozin preserves renal function in low-risk individuals with normal renal function
Figure 4. Canagliflozin slows eGFR decline
The haemodynamic benefits persist despite a lack of HbA1c reduction, particularly at the lower GFRs
2
0
–2
–4
–6
–8
2
0
–2
–4
–6
–8Glimep-
irideCanagli-
flozin 100mg
Canagli-flozin
300mg
Glimep-iride
Canagli-flozin
100mg
Canagli-flozin
300mg
eGFR
slo
pe
(ml/m
in/1
.73m
2 per
yea
r)
eGFR
slo
pe
(ml/m
in/1
.73m
2 per
yea
r)
Overall population UACR ≥3.4mg/mmol group
Secondary analysis of n=1 450 individuals with T2DM and taking metformin 2 years of follow-up
eGFR: estimated glomerular filtration rate; UACR: urinary albumin-to-creatinine ratio
0
–2
–4
–6
–8
–10
0 12 24 36 48 60 72 84 96 108
LS m
ean
chan
ge (S
E) in
eG
FR
from
bas
elin
e (m
l/min
/1.7
3m2 )
Follow-up (weeks)
Glimepiride88.6
Baseline eGFR (ml/min/1.73m2)
Canagliflozin 100mg90.1
Canagliflozin 300mg93.5
Glimepiride
Canagliflozin 100mg
Canagliflozin 300mg
Renal benefits of SGLT-2 inhibitors in diabetes
5SEPTEMBER 2020
3 CEUs
EMPA-REG OUTCOME: What have we learned about renal outcomes with empagliflozin treatment?EMPA-REG OUTCOME evaluated 7 000 patients randomised to one of three arms: placebo, empagliflozin 10mg and empagliflozin 25mg. These T2DM patients all had established cardiovascular disease or atherosclerotic cardiovascular disease
(ASCVD). For the outcome of major adverse cardiovascular events (MACE), empagliflozin treatment achieved super-iority. There was a 35% reduction of the heart failure outcome in actively treated patients.
Figure 6. Impact of empagliflozin on HbA1c and systolic blood pressure as stratified by eGFR
Figure 5. Empagliflozin-mediated UACR changes are largely independent of HbA1c, systolic blood pressure and weight
Pooled analysis of 5 Phase III RCTs with T2DM cohortsn=636 with microalbuminuria (UACR 3.4–34mg/mol) | n=215 with macroalbuminuria (UACR >34mg/mol)
A1c Weight SBP
Adj
uste
d m
ean
(95%
CI)
diff
eren
ce
vs p
lace
bo in
gm
ean
chan
ge
from
bas
elin
e in
UAC
R (%
)
Adj
uste
d m
ean
(95%
CI)
diff
eren
ce
vs p
lace
bo in
gm
ean
chan
ge
from
bas
elin
e in
UAC
R (%
)
Adj
uste
d m
ean
(95%
CI)
diff
eren
ce
vs p
lace
bo in
gm
ean
chan
ge
from
bas
elin
e in
UAC
R (%
)
20
0
–20
–40
–60
–80
20
0
–20
–40
–60
–80
20
0
–20
–40
–60
–80Total A1c-
indepen-dent
A1c- asso-ciated
Total Weight loss
indepen-dent
Weight loss-asso-ciated
Total SBP-indepen-
dent
SBP- asso-ciated
CKD: chronic kidney disease; gmean: geometric mean; RCT: randomised trail; SBP: systolic blood pressure; T2DM: type 2 diabetes; UACR: urinary albumin-to-creatinine ratio.*P<0.05 (treated set; last observation carried forward).
Primary assessment was the % change in gmean UACR from baseline to week 24
changechange
change
* * ** **
eGFRTreatment difference
Empagliflozin vs Placebo(95% CI), %
≥90ml/min/1.73m2
≥60 to <90ml/min/1.73m2
≥30 to <60ml/min/1.73m2
<30ml/min/1.73m2
eGFRTreatment difference
Empagliflozin vs Placebo(95% CI), %
≥90ml/min/1.73m2
≥60 to <90ml/min/1.73m2
≥30 to <60ml/min/1.73m2
<30ml/min/1.73m2
–1.5 –1 –0.5 0 0.5 –12–10 –8 –6 –4 –2 0 2
Systolic blood pressureA1c
Renal benefits of SGLT-2 inhibitors in diabetes
6 SEPTEMBER 2020
3 CEUs
Renal composite in EMPA-REG OUTCOMEThe renal outcome was a composite of progression to macroalbuminuria, a doubling of serum creatinine with an eGFR <45ml/min/1.73m2, initiation of renal replacement therapy (RRT) or death from renal disease. A profound 39% relative risk reduction (RRR) for the renal endpoint was demonstrated with empagliflozin versus placebo (Figure 7).7
There are various markers by which the renal outcomes can be measured: incident or worsening nephropathy by
itself; progression to macroalbuminuria; reduction of serum creatinine levels that were accompanied by an eGFR <45ml/min/1.73m2; initiation of RRT; or the composite of doubling of serum creatinine accompanied by an eGFR <45ml/min/1.73m2, initiation of RRT or death from renal disease. The individual outcomes from EMPA-REG are shown in Figure 8. The point estimates of the renal outcomes all favour empagliflozin and the hazard ratios are profound, indicative of an approximate 50% RRR.
Figure 7. EMPA-REG OUTCOME: renal composite
Figure 8. EMPA-REG OUTCOME: individual renal outcome measures
The point estimates of the renal outcomes all favour empagliflozin and the hazard ratios are profound, indicative of an approximate 50% RRR
OutcomePlacebo Empagliflozin
HR (95% CI) P-valueNo. with event/No. analysed (%)
Rate/1 000 patient years
No. with event/No. analysed (%)
Rate/1 000 patient years
Incident or worsening nephropathy or CV death
497/2102(23.6)
95.9675/4170
(16.2)60.7
0.61(0.55–0.69)
<0.001
Incident or worsening nephropathy388/2061
(18.8)76.0
525/4124(12.7)
47.80.61
(0.53–0.70)<0.001
Progression to macroalbuminuria330/2033
(16.2)64.9
459/4091(11.2)
41.80.62
(0.54–0.72)<0.001
Doubling of serum creatinine level accompanied by an eGFR ≤45ml/min/1.73m2
60/2323(2.6)
9.770/4645
(1.5)5.5
0.56(0.39–0.79)
<0.001
Initiation of renal replacement therapy14/2333
(0.6)2.1
13/4687(0.3)
1.00.45
(0.21–0.97)0.04
Doubling or serum creatinine level accompanied by an eGFR ≤45ml/min/1.73m2, initiation of renal replacement therapy or death from renal disease
71/2323(3.1)
11.581/4646
(1.7)6.3
0.54(0.40–0.75)
<0.001
Incident albuminuria in patients with a normal albumin level at baseline
703/1374(51.2)
266.01430/2779
(51.5)252.5
0.95(0.87–1.04)
0.25
Favours empagliflozin Favours placebo
0.125 0.25 0.5 1 2
• Progression to macroalbuminuria
• Doubling of serum creatinine with an eGFR of ≤45ml/minute/1.73m2
• Initiation of renal-replacement therapy
• Death from renal disease
100
80
60
40
20
00 6 12 18 24 30 32 42 48
Part
icip
ants
wit
h ev
ent
(%)
Placebo
Empagliflozin
HR (95% CI) 0.61 (0.53, 0.70)P<0.001
Month
Significant reduction in the renal composite
No signal of increased acute kidney injury risk
Renal benefits of SGLT-2 inhibitors in diabetes
7SEPTEMBER 2020
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What are the effects of empagliflozin on eGFR by albuminuria status?In examining the impact of empagliflozin on GFR in people with normoalbuminuria, microalbuminuria and macroalbuminuria, a noticeable stabilisation of the GFR is observed with empagliflozin compared to a decline in GFR observed in the
placebo group across patients with normo-, micro- or macroalbuminuria. Empagliflozin demonstrated a profound reduction in UACR in patients with micro- and macroalbuminuria (Figure 9).6
What is the relationship between glycaemia and renal protection?In respect of the interaction between glycaemia and renal protection after week 12, the evidence of reduced incident or worsening nephropathy clearly favours empagliflozin treatment.
Clearly, the benefit of an SGLT-2 inhibitor on incident or worsening nephropathy is totally independent of changes in HbA1c and also independent of baseline HbA1c level.8
Figure 9. EMPA-REG OUTCOME: effects of empagliflozin on UACR by albuminuria status
Normoalbuminuria Microalbuminuria Macroalbuminuria
Adj
uste
d gm
ean
(95%
CI)
UACR
(mg/
g)
Adj
uste
d gm
ean
(95%
CI)
UACR
(mg/
g)
Adj
uste
d gm
ean
(95%
CI)
UACR
(mg/
g)16
12
8
4
0
120
80
40
0
1000
800
600
400
200
0Baseline Last
value on treatment
Follow-up Baseline Last value on
treatment
Follow-up Baseline Last value on
treatment
Follow-up
gmean: geometric mean; UACR: urinary albumin-to-creatinine ratio.
Median 3.1 years
Median 34 days
Median 3.1 years
Median 34 days
Median 2.9 years
Median 35 days
Placebo (n=959) Placebo (n=422) Placebo (n=140)Empagliflozin (n=1985) Empagliflozin (n=933) Empagliflozin (n=307)
EMPA vs PBO1 (–8,10)P=0.89
EMPA vs PBO–22 (–32,–11)
P=0.0003 EMPA vs PBO–29 (–44,–10)
P=0.005
EMPA vs PBO–15 (–22,–7)
P=0.0004
EMPA vs PBO–42 (–49,–34)
P<0.0001EMPA vs PBO–49 (–60,–36)
P<0.0001
Renal benefits of SGLT-2 inhibitors in diabetes
8 SEPTEMBER 2020
3 CEUs
What have we learned about renal protection from the CANVAS Program? CANVAS studied a mixed population of 10 000 T2DM patients with and without established ASCVD, randomised to placebo, canagliflozin 100mg and canagliflozin 300mg. Recruited patients had an eGFR >30ml/min/1.73m2, as was also the case in the EMPA-REG
OUTCOME trial. With regard to the primary cardiovascular outcomes from the CANVAS Program, MACE was reduced by 14% and hospitalisation for heart failure by 33%. These differences appeared quite early in the trial.
Renal composite of the CANVAS ProgramThe renal outcome was a composite of a 40% reduction in eGFR, requirement for RRT or death from renal causes. There was a 40% RRR, highly statistically significant, in favour of canagliflozin versus placebo (Figure 11).9 The composite renal outcome and all of the individual renal outcome components were reduced, including the cardiorenal outcome with canagliflozin.
There was no increased signal of acute kidney injury (AKI) and there were indications that the use of an SGLT-2 inhibitor is beneficial with regard to AKI. Progression of albuminuria was also reduced, with a 27% RRR. The effects of canagliflozin to prevent GFR decline occurred across the various strata of eGFR, relative to placebo.
Figure 10. EMPA-REG OUTCOME: the effects of empagliflozin on incident or worsening nephropathy stratified by HbA1c
OutcomeNo. with event/No. analysed (%)
HR (95% CI)P-interaction
valuePlacebo Empagliflozin
Incident or worsening nephropathy
All patients 388/2061 (18.8) 524/4124 (12.7) 0.61 (0.53–0.70)
All patients, adjusted for baseline and time-dependent control of A1c (<7.5%)
388/2061 (18.8) 525/4123 (12.7) 0.65 (0.57–0.74)
Baseline A1c
<7.0% 27/111 (24.3) 37/264 (14.0) 0.55 (0.34–0.91)
7.0 to <8.0% 170/933 (18.2) 214/1814 (11.8) 0.60 (0.49–0.73) 0.6907
8.0 to <9.0% 126/704 (17.9) 161/1348 (11.9) 0.58 (0.46–073)
≥9.0% 65/313 (20.8) 113/697 (16.2) 0.72 (0.53–0.98)
Incident or worsening nephropathy after week 12
All patients 368/2027 (18.2) 513/4089 (12.5) 0.63 (0.55–0.72)
Change in A1c from baseline to week 12
Reduction ≥median 104/611 (17.0) 301/2595 (11.6) 0.63 (0.50–0.78)
Reduction <median 264/1416 (18.6) 212/1493 (14.2) 0.70 (0.58–0.84) 0.4628
Reduction ≥0.5% 89/504 (17.7) 268/2376 (11.3) 0.58 (0.46–0.74)
Reduction <0.5% or increase 279/1532 (18.3) 245/1712 (14.3) 0.72 (0.61–0.86) 0.1593
Reduction ≥0.3% 127/731 (17.4) 343/2860 (12.0) 0.64 (0.52–0.78)
Reduction <0.3% or increase 241/1296 (18.6) 170/1228 (13.8) 0.68 (0.56–0.83) 0.6575
Favours empagliflozin Favours placebo
0.25 0.5 1
Renal benefits of SGLT-2 inhibitors in diabetes
9SEPTEMBER 2020
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Renal composite of DECLARE-TIMI 58The composite renal outcome included a 40% reduction in eGFR, end-stage renal disease (ESRD), and renal or cardiovascular death. This outcome was substantially reduced in the dapagliflozin treatment arm, with a 24% RRR, in a very broad population of patients primarily at much lower risk than the EMPA-REG and CANVAS cohorts and, most importantly,
excluding people with eGFR <60ml/min/1.73m2. The DECLARE-TIMI 58 results relate to quite healthy patients from a renal standpoint and despite this, dapagliflozin treatment demonstrated a significant renal benefit. There was no significant increase in AKI and numerically fewer cases of AKI were seen in people treated with dapagliflozin (Figure 13).
DECLARE-TIMI 58: dapagliflozin and renal functionOf the 17 000 T2DM patients enrolled in DECLARE-TIMI 58, dapagliflozin use in primary prevention was evaluated in 60% of patients, with the remaining 40% being assessed in respect of dapagliflozin used as secondary prevention. This is the largest and the longest of all of the three SGLT-2 inhibitor studies, and also the broadest in terms of the populations that it enrolled.
Patients were randomised to placebo or dapagliflozin and the trial was event-driven, with a median follow-up of 4.2 years. Dual primary outcomes were MACE, with a 7% RRR that is not statistically superior but clearly non-inferior, and the outcome of cardiovascular mortality and heart failure, reduced by 17% with a p-value of 0.0054 for superiority (Figure 12).9
Figure 12. DECLARE-TIMI 58: MACE and cardiovascular mortality/hospitalisation for heart failure
The DECLARE-TIMI 58 study included about 60% of patients in primary prevention, 40% in secondary prevention; it is the largest and the longest of all of the three SGLT-2 inhibitor studies and also the broadest in terms of the populations that it enrolled
10
7.5
5
2.5
0
10
7.5
5
2.5
00 6 12 18 24 30 36 42 48 0 6 12 18 24 30 36 42 48
Months since randomisation Months since randomisation
Pati
ents
wit
h ev
ents
(%)
Pati
ents
wit
h ev
ents
(%)
MACE CV mortality/HHF
CV: cardiovascular; HHF: hospitalisation for heart failure; MACE: major adverse cardiovascular events
HR (95% CI) 0.93 (0.84, 1.03)P<0.001 for non-inferiorityP=0.017 for superiority
HR (95% CI) 0.83 (0.73, 0.95)P=0.005 for superiority
Placebo Placebo
Dapagliflozin Dapagliflozin
Figure 11. CANVAS Program: renal composite
• 40% ↓ eGFR
• Requirement for renal replacement therapy
• Death from renal causes
10
8
6
4
2
00 26 52 78 104 130 156 182 208 260 286 312 338
Cum
ulat
ive
prob
abili
ty
of e
vent
(%)
Placebo
Canagliflozin
HR (95% CI) 0.60 (0.47, 0.77)
Weeks No signal of increased acute kidney injury risk
Renal benefits of SGLT-2 inhibitors in diabetes
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Key outcomes by baseline renal functionKey trial outcomes by baseline renal function include a 40% reduction in eGFR, and a very significant 24% RRR for ESRD,
or renal or cardiovascular death, with no statistical heterogeneity in patients across the three categories of eGFR (Figure 14).
Secondary prevention of renal events in established cardiovascular diseaseMeta-analyses of data from those with established cardiovascular disease in the EMPA-REG, CANVAS and DECLARE cohorts indicate almost identical individual benefits of each of the SGLT-2 inhibitors, as well as the class benefit, in secondary prevention. Hazard ratios of 0.54 in EMPA-REG, 0.59 in CANVAS and 0.55 in DECLARE were observed, with a cumulative overall RRR of 44% for renal events (Figure 15). In patients with T2DM and multiple risk factors, DECLARE
demonstrated a significant reduction in renal events, even in people without established cardiovascular disease, of the order of 50%.10 “I think this is a profound moment to recognise the unbelievable and unprecedented renal protective benefits that are being observed with these agents in both primary and secondary prevention populations and in many cases on top of ACE inhibitor treatment and adequate blood pressure control,” Dr Verma stated.
Figure 14. DECLARE-TIMI 58: key outcomes by baseline renal function
I think this is a profound moment to recognise the unbelievable and unprecedented renal protective benefits that are being observed with these agents in both primary and secondary prevention populations and in many cases on top of ACE inhibitors and adequate blood pressure control
eGFR stratumn/N
HR (95% CI)P-inter- action valuePlacebo Canagliflozin
CV death/Hospitalisation for heart failure 496/8578 417/8582 0.83 (0.75–0.95) 0.37
<60 86/659 55/606 0.78 (0.55–1.09)
60 to <90 252/3894 199/3838 0.79 (0.66–0.95)
>90 163/4025 163/4137 0.96 (0.77–1.19)
MACE 803/8759 756/8582 0.93 (0.84–1.03) 0.99
<60 104/659 85/606 0.92 (0.69–1.23)
60 to <90 390/3894 367/3838 0.95 (0.82–1.09)
>90 309/4025 304/4137 0.94 (0.80–1.10)
40% ↓ eGFR, ESRD, or renal or CV death 480/8578 370/8582 0.76 (0.67–0.87) 0.97
<60 76/659 53/606 0.77 (0.64–1.09)
60 to <90 240/3894 182/3838 0.76 (0.63–0.93)
>90 164/4025 135/4137 0.79 (0.63–0.99)
Favours dapagliflozin Favours placebo
0.125 0.25 0.5 1 2
Figure 13. DECLARE-TIMI 58: renal composite
• 40% ↓ eGFR
• ESRD
• Renal or CV death
6
4
2
00 180 360 540 720 900 1080 1260 1440
Prob
abili
ty o
f eve
nt (%
)
Placebo
Dapagliflozin
Dapagliflozin 4.3% vs Placebo 5.6%HR (95% CI) 0.76 (0.67, 0.87)P<0.001
Days No signal of increased acute kidney injury risk
Renal benefits of SGLT-2 inhibitors in diabetes
11SEPTEMBER 2020
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Placebo SGLT-2i HR (95% CI)
With ECVD
EMPA-REG OUTCOME 11.5 6.3 0.54 (0.40–0.75)
CANVAS Program 10.5 5.4 0.59 (0.44–0.79)
DECLARE-TIMI 58 8.7 4.8 0.55 (0.41–0.75)
Fixed effects model for ECVD (P<0.0001) 0.56 (0.47–0.67)
With multiple risk factors
CANVAS Program 6.6 4.1 0.63 (0.39–1.02)
DECLARE-TIMI 58 6.0 3.1 0.51 (0.37–0.69)
Fixed effects model for multiple risk factors (P<0.0001) 0.54 (0.42–0.71)
The cardiorenal hypothesis for heart failure protectionA nephrocentric perspective of the cardiorenal hypothesis for heart failure protection with SGLT-2 inhibitors suggests that these agents facilitate proximal tubular natriuresis that triggers tubuloglomerular feedback; a reduction in intraglomerular hypertension is then responsible for reductions in albuminuria and preservation of renal function. The reduced blood pressure and arterial stiffness, along with the reduced
cardiac afterload, improve ‘spilling’ conditions and facilitate left ventricular remodelling. Preservation of systemic sodium and water homeostasis facilitates maintenance of euvolaemia, reducing cardiac preload, myocardial wall stress and further optimising filling conditions (Figure 16).1 Overall reductions in renal systemic inflammation also have an effect on left ventricular remodelling.
Figure 15. Secondary prevention: progression of renal disease with SGLT-2 inhibitors in the presence of established cardiovascular disease
Meta-analyses of data from those with established cardiovascular disease in the EMPA-REG, CANVAS and DECLARE cohorts indicate almost identical individual benefits of each of the SGLT-2 inhibitors, as well as the class benefit, in secondary prevention
Figure 16. A nephrocentric perspective of the cardiorenal hypothesis for heart failure protection with SLGT-2 inhibitors1
Events per 1 000 patient years
Favours SGLT-2i Favours placebo
0.25 0.5 1 2
↑ promixal tubular natriuresis
↑ tubuloglomerular feedback
↓ intraglomerular hypertension
Preservation of systemic NA+/water
homeostais
↓ albuminuria preservation of renal function
↓ blood pressure↓ areterial stiffness
↓ renal, systemic inflammation ↓ cardiac afterload
↓ LV remodelling
↓ arrhythmogenesis
↓ Myocardial wall tension
↓ cardiac preload
SGLT-2 inhibition
Maintenance of euvolaemia
↓ Risk for hospitalisation for heart failure and CV events
Renal benefits of SGLT-2 inhibitors in diabetes
12 SEPTEMBER 2020
3 CEUs
SGLT-2 inhibitor CVOTs and renal outcome trials – currently announcing resultsDAPA-CKD and DELIGHT have announced their results recently while EMPA-KIDNEY’s results are expected mid-2022. CREDENCE is a dedicated diabetic kidney disease trial of diabetes patients with HbA1c 6.5-10.5, GFRs between 30 and 90ml/min/1.73m2 with UACRs >34 and <565 on maximally tolerated ACE inhibitors or ARBs and randomised to canagliflozin 100mg versus placebo. This trial was stopped early on the achievement
of prespecified efficacy criteria that included the primary composite of ESRD, doubling of serum creatinine, renal or cardiovascular death on top of standard of care (results announced, available online).11 Other upcoming trials with renal data using dapagliflozin have recently been stopped early because of the overwhelming efficacy of the drug, according to the independent data monitoring committees.
References Click on reference to access the scientific article1. Heerspink HJL, Perkins BA, Fitchett DH, et al. Sodium
glucose cotransporter 2 inhibitors in the treatment of
diabetes mellitus: Cardiovascular and kidney effects,
potential mechanisms, and clinical applications.
Circulation 2016; 134(10): 752-772.
2. Heerspink HJL, Kosiborod M, Inzucchi SE, et
al. Renoprotective effects of sodium-glucose
cotransporter-2 inhibitors. Kidney Int 2018; 94(1):
26-39.
3. Skrtić M, Yang GK, Perkins BA, et al. Characterisation
of glomerular haemodynamic responses to SGLT-2
inhibition in patients with type 1 diabetes and renal
hyperfiltration. Diabetologia 2014; 57(12): 2599-2602.
4. Leiter LA, Yoon KH, Arias P, et al. Canagliflozin
demonstrates durable glycaemic improvements over 104
weeks versus glimepiride in subjects with type 2 diabetes
mellitus on metformin: A randomised, double-blind,
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5. Heerspink HJL, Desai M, Perkovic V, et al. Canagliflozin
slows progression of renal function decline
independently of glycaemic effects. J Am Soc Nephrol
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7. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin
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8. Cooper ME, Inzucchi SE, Zinman B, et al. Glucose control
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9. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and
cardiovascular outcomes in type 2 diabetes. N Engl J
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10. Zelniker TA, Wiviott SD, Raz I, et al. SGLT-2 inhibitors for
primary and secondary prevention of cardiovascular and
renal outcomes in type 2 diabetes: a systematic review
and meta-analysis of cardiovascular outcome trials.
Lancet 2019; 393(10166): 31-39.
11. Mahaffey KW, Jardine MJ, Bompoint S, et al.
Canagliflozin and cardiovascular and renal outcomes in
type 2 diabetes mellitus and chronic kidney disease in
primary and secondary cardiovascular prevention groups.
Results from the randomized CREDENCE trial. Circulation
2019; 140(9): 739-750.
DisclaimerThe views and opinions expressed in the article are those of the presenters and do not necessarily reflect those of the publisher or its sponsor. In all clinical instances, medical practitioners are referred to the product insert documentation as approved by relevant control authorities.
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