MANAGEMENT OF DIABETIC PATIENTS WITH CKD
Roberto Pecoits-Filho, MD, PhD, FASN, FACP
PUCPR, Curitiba, BRAZIL
KDIGO Diabetes Conference | February 5-8, 2015 | Vancouver, Canada
Disclosure of Interests
Honoraria
Astra Zeneca, Novartis
Trial participation and research grants
Amgen, Genzyme, Jansen, Astra Zeneca
Consultoria
Jansen, Astra Zeneca, Abbvie
1. International Diabetes Federation. IDF Diabetes Atlas. 6th ed.
http://www.idf.org/diabetesatlas. Published 2013. Accessed January 2, 2014.
2. Gilmer TP, O’Connor PJ. Strategies to reduce the cost of renal complications
in patients with type 2 diabetes. Diabetes Care. 2011;34:2486-2487.
Cerebrovascular Disease Retinopathy (18.9%)
Myocardial infarction (9.8%)
Angina (9.5%)
Coronary heart disease (9.1%)
Nephropathy (27.8%)
Neuropathy
Peripheral Vascular Disease
Ulceration/amputation
(22.9%)
I
Hyperfiltration
GFR
UAE
0 5 10 20
Duration of diabetes (years)
15 25
150
120
90
60
30
0
GF
R (
mL
/min
/1.7
3 m
2)
30
10
1
0.1
0.01
0
Lo
g U
AE
(g/2
4h
)
II
Silent DN
III
Incipient DN
IV
Overt DN
V
ESRD
Natural history of diabetic nephropathy
• DN, diabetic nephropathy; ESRD, end-stage renal disease; GFR, glomerular filtration rate; UAE, urinary
albumin excretion
• Pugliese G. Acta Diabetol 2014;51:905–915
Non-albuminuric renal impairment in Type 2 diabetes The Third National Health and Nutrition Examination Survey (NHANES III)
• A total of 1197 patients with Type 2 diabetes
Kramer HJ, et al. JAMA 2003;289:3273–3277
36%
Albuminuria
45%
19%
0
20
40
60
80
Pre
va
len
ce
(%
)
13%
Renal
impairment*
Normo Micro Macro
Risk of progression to proteinuria in the STENO-2 trial
CI, confidence interval; RR, relative risk
Fioretto P, et al. Nat Rev Endocrinol 2010;6:19–25
Conventional
treatment
Intensive
treatment
60
40
20
0
P=0.01
24
10
39
20
46
25
Residual
risk
3.8 7.8 13.3
Duration of follow-up (years)
RR: 0.44
(95% CI: 0.25, 0.77)
P=0.004
Pa
tie
nts
(%
)
Multifactorial intervention failed to eliminate
the risk of new-onset diabetic nephropathy in
patients with Type 2 diabetes
Trends in diabetes-related complications among
US adults with diagnosed diabetes 1990–2010
ESRD, end-stage renal disease
Gregg EW, et al. N Eng J Med 2014;370:1514–1523
150
125
100
75
50
25
4 2 0
Eve
nts
pe
r 1
0,0
00
ad
ult
po
pu
lati
on
wit
h d
iag
no
se
d d
iab
ete
s
1990 1995 2000 2005 2010
Acute myocardial infarction
Stroke
Amputation
ESRD
Death from hyperglycaemic crisis
Year
Incident counts and adjusted rates of ESRD, by
primary diagnosis
ESRD, end-stage renal disease; GN, glomerulonephritis; USRDS, United States Renal Data System
USRDS annual data report 2014
Diabetes
Hypertension
GN
Cystic
kidney
Rate
per
mil
lio
n p
op
ula
tio
n
0
50
100
15
0
200 Rates
81 84 87 90 93 96 99 02 05 08 11
Year
Diabetes
Hypertension
GN
Cystic
kidney
Nu
mb
er
of
pati
en
ts (
in t
ho
usa
nd
s)
0
1
0
2
0
3
0
4
0
5
0
Counts
8
1
8
4
8
7
9
0
9
3
9
6
9
9
0
2
0
5
0
8
11
Year
Brazil
France
Germany
United States
Study design Target ≈ 12,000 CKD patients
Census • CKD stage 3b to 5 (non dialysis, non-renal
transplant) patients
• ≥18 yrs old
• All causes of CKD
Inclusion • 60–90 per clinic with eGFR <60
mL/min/1.73 m2
Follow-up • 3 years (up to 5 years in France)
• Before and after starting RRT
Data
collection
(longitudinal)
• Abstraction from medical records
• Nephrologist survey
• Patient questionnaire
32 clinics
(target=30)
40 clinics
(target=40) 29 clinics
(target=40)
20 clinics
(target=20)
Japan 30 clinics
(target=30)
CKDopps protocol and countries (2016)
CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; RRT, renal replacement therapy.
Prevalence of hypertension and diabetes
• PRELIMINARY: From CKDopps census (all clinic patients); N=14,769 (France), 925
(Germany), 1897 (Brazil), 3221 (USA); eGFR <60 mL/min/1.73m2
100
0
80
60
40
20
93
87 86
93
50
41 38
43
Hypertension * Diabetes
Brazil France Germany USA
* Among sampled patients
% o
f p
ati
en
ts
Age distribution
eGFR, estimated glomerular filtration rate
• PRELIMINARY: From CKDopps census (all clinic patients); N=14,769 (France), 26,093
(Germany), 1328 (Brazil), 2851 (US); eGFR <60 mL/min/1.73m2
Median
age
Brazil 68 yrs
Germany 74 yrs
France 73 yrs
USA 71 yrs
50
0
40
30
20
10
4
18–44 45–64 65–74 75–84 ≥85
8
13 15
10
28
44
32
25
31
24
28 29
27
15
22
31
2
5 7
Brazil France Germany USA
Age (years)
% o
f p
ati
en
ts
Reported causes of chronic kidney disease
100
75
50
25
0
Brazil France Germany USA
563 3043 1028 859 Number of patients:
% o
f p
ati
en
ts
Other Hypertension Glomerulonephritis Diabetes
22
33
8
46
19
16
30
39
9
20
35
6
37
19 22
39
J Am Coll Cardiol 2008; 52:1527-39
Anorexia induced decrease in cfood intake
Dietary restriction-induced food intake
Decrease in insulin metabolization
Interferance in pharmacokinetics of hypoglicemic drugs
Decreased renal gluconeogenesis
Increase in insulin half life
Diabetes mellitus
Decrease in renal glucose excretion
Uremic toxicity –induced insulin resistance
Accumulation ofvcounterbalance hormones
Insulin resistance
Hypoglicemia Hyperglicemia
Inflammation-induced insulin resistance
Pecoits-Filho et al. Diabetology & Metabolic Syndrome, 2016
Risk of severe hypoglycaemia is increased in CKD
1
1.21
1.66
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
2
Creatinine (µmol/L)
Hazard
Rati
o
<88 88-115 >115
*P<0.001 Miller ME, et al. BMJ 2010;340:b5444
*
*
ACCORD study
eGFR (ml/min) >60 30-59 15-29 <15 dialysis)
Metformin
Glimepiride
Gliblenclamide
Pioglitazone
Vildagliptin
Sitagliptin
Saxagliptin
Linagliptin
Exenatide
Liraglutide
Insulin
Dapagliflozin
Canagliflozin
Empagliflozin
Figure 2 HbA1c levels and mortality in patients on dialysis
Abe, M. & Kalantar-Zadeh, K. (2015) Haemodialysis-induced hypoglycaemia and glycaemic disarrays
Nat. Rev. Nephrol. doi:10.1038/nrneph.2015.38
Permission obtained from Wiley © Rhee, C. M. et al. Semin. Dial. 27, 135–145 (2014)
Questions and Answers
Which of the following clinical presentation in diabetes were not significantly improved over the last 3 decades?
a. Myocardial infarction
b. Stroke
c. End stage kidney disease
d. Amputation
Questions and Answers
Which of the following clinical presentation in diabetes were not significantly improved over the last 3 decades?
a. Myocardial infarction
b. Stroke
c. End stage kidney disease
d. Amputation
Clinical case
70 years old man, type 2 DM for 12 years
• PA 150/90mmHg (Amlodipine 10mg/day)
• LDL 120mg/dL (Simvastatin 20mg/day)
• TG 245mg/dL
BMI 29
Metformin 1.5g/day and gliblencamide 5mg/day
HbA1C 7.9
1.4
52
70
| Presentation Title | Presenter Name | Date | Subject | Business Use Only 24
Questions and Answers
How would you best stratify the risk(s) of this patient?
a. Patient at low risk of progression to end stage kidney disease
b. Patient at high risk for a cardiovascular event
c. Patient at high risk of progression to end stage kidney disease
d. Patient at very high risk of progression to end stage kidney disease and cardiovascular disease
Questions and Answers
How would you best stratify the risk(s) of this patient?
a. Patient at low risk of progression to end stage kidney disease
b. Patient at high risk for a cardiovascular event
c. Patient at high risk of progression to end stage kidney disease
d. Patient at very high risk of progression to end stage kidney disease and cardiovascular disease
KDIGO Diabetes Conference | February 5-8, 2015 | Vancouver, Canada
Lifestyle & Dietary Potential
Dietary – Restrict dietary salt
– Fruit and vegetables
– Mediterranean diet
– Dietary fibre
– Calorie control
– Limited cola
beverages
Physical exercise
Weight reduction
Smoking cessation
Alcohol reduction
Increase fitness
Improve blood pressure
Improve glycemic
control
Reduce albuminuria
Improve survival,
vascular health,
etc.
What can we do?
What should we do?
KDIGO Diabetes Conference | February 5-8, 2015 | Vancouver, Canada
Modulators of the lipid pattern
• Proteinuria & Nephrotic syndrome
• Peritoneal dialysis & uremic toxins & NS
• Hemodialysis & Heparin administration
• Immunosuppression & polypharmacy
• Insulin resistance
KDIGO Diabetes Conference | February 5-8, 2015 | Vancouver, Canada
4D 216 125 34 224
AURORA 175 100 45 156
SHARP 189 107 43 203
ALERT 249 158 52 192
Pattern of dyslipidemia
TC LCL-C HDL-C TG
mg/dl
32.6
Lp(a)
KDIGO Diabetes Conference | February 5-8, 2015 | Vancouver, Canada
PLANET I
Prospective EvaLuation of ProteinuriA and KidNey
Function in diabetic (PLANET I) and non-diabETic
(PLANET II) Patients with progressive Kidney Disease
Renal effects of atorvastatin and rosuvastatin in patients with diabetes
who have progressive renal disease (PLANET I): a randomised clinical
trial
•The Lancet Diabetes & Endocrinology, Available online 4 February 2015,
KDIGO Diabetes Conference | February 5-8, 2015 | Vancouver, Canada
Rosuvastatin 10 mg
Rosuvastatin 40 mg
Atorvastatin 80 mg
0.6
0.8
1.0
1.2
1.4
Pro
tein
/cre
ati
nin
e (
mg
/g)
on
-tre
atm
en
t/b
aseli
ne r
ati
o
0 26 52 Weeks
LOCF
325 patients with T1- or T2-Diabetes
Primary Endpoint: Proteinuria
No. of patients
R10 107 98 91 107
R40 116 108 103 116
A80 102 92 81 102
KDIGO Diabetes Conference | February 5-8, 2015 | Vancouver, Canada
Ch
an
ge f
rom
baselin
e e
GF
R
mL
/min
/1,7
3m
2
0 26 52 Weeks
LOCF
-12
0
4
8
12
-8
-4
* *
Rosuvastatin 10 mg
Rosuvastatin 40 mg
Atorvastatin 80 mg
Secondary Endpoint: Change in eGFR
No. of patients
R10 107 100 93 107
R40 116 111 103 115
A80 102 92 84 101
Kidney Disease: Improving Global Outcomes
Fibrates in CKD
J Am Coll Cardiol. 2012;60:2061-71
Cardiovascular eventseGFR 30-59.9 ml/min/1.73m2
Cardiovascular death
Stroke
Events
32
Total
199
Events
49
Total
200 0.66 (0.44-0.98), p=0.04
Fibrate Placebo
Risk Ratio; 95% CIFavours Fibrate
Favours Placebo
(I² = 0.0%, p for hetero=0.72)eGFR ≥60 ml/min/1.73m2
VA-HIT
FIELD 57 295 60 224 0.72 (0.53-0.99), p=0.04
Overall 89 494 109 424 0.70 (0.54-0.89), p=0.004
265 1065 329 1067 0.81 (0.70-0.93), p=0.002
(I² = 40.4%, p for hetero=0.195)
VA-HIT
FIELD 555 4600 623 4676 0.91 (0.81-1.01), p=0.07
Overall 820 5665 952 5743 0.86 (0.77-0.96), p=0.009
0.5 0.7 1 1.5 2
eGFR 30-59.9 ml/min/1.73m2
10 199 13 200 0.77 (0.35-1.72), p=0.529
(I² = 0.0%, p for hetero=0.443)eGFR ≥60 ml/min/1.73m2
VA-HIT
FIELD 18 295 26 224 0.53 (0.30-0.94), p=0.028
Overall 28 494 39 424 0.60 (0.38-0.96), p=0.032
37 309 50 329 0.79 (0.53-1.17), p=0.002
(I² = 70.3%, p for hetero=0.066)
VA-HIT
FIELD 122 4600 101 4676 1.23 (0.95-1.59), p=0.07
Overall 159 4909 151 5005 1.01 (0.66-1.56), p=0.966
eGFR 30-59.9 ml/min/1.73m2
6 199 15 200 0.40 (0.16-1.02), p=0.054
(I² = 48.7%, p for hetero=0.163)eGFR ≥60 ml/min/1.73m2
VA-HIT
FIELD 23 295 20 224 0.87 (0.49-1.55), p=0.643
Overall 29 494 35 424 0.65 (0.31-1.36), p=0.250
52 1065 61 1067 0.85 (0.60-1.22), p=0.002
(I² = 0.0%, p for hetero=0.868)
VA-HIT
FIELD 135 4600 155 4676 0.89 (0.71-1.11), p=0.07
Overall 187 5665 216 5743 0.88 (0.72-1.06), p=0.178
All-cause mortality
eGFR 30-59.9 ml/min/1.73m2
22 199 22 200 1.01 (0.58-1.76), p=0.986
(I² = 0.0%, p for hetero=0.503)eGFR ≥60 ml/min/1.73m2
VA-HIT
FIELD 43 295 41 224 0.80 (0.54-1.18), p=0.254
Overall 65 494 63 424 0.86 (0.62-1.18), p=0.355
176 1065 198 1067 0.89 (0.74-1.07), p=0.218
(I² = 72.9%, p for hetero=0.055)
VA-HIT
FIELD 313 4600 282 4676 1.13 (0.97-1.32), p=0.129
Overall 489 5665 480 5743 1.01 (0.80-1.27), p=0.948
P for hetero b/teGFR subgroups
p=0.12
p=0.11
p=0.44
p=0.43
Cardiovascular eventseGFR 30-59.9 ml/min/1.73m2
Cardiovascular death
Stroke
Events
32
Total
199
Events
49
Total
200 0.66 (0.44-0.98), p=0.04
Fibrate Placebo
Risk Ratio; 95% CIFavours Fibrate
Favours Placebo
(I² = 0.0%, p for hetero=0.72)eGFR ≥60 ml/min/1.73m2
VA-HIT
FIELD 57 295 60 224 0.72 (0.53-0.99), p=0.04
Overall 89 494 109 424 0.70 (0.54-0.89), p=0.004
265 1065 329 1067 0.81 (0.70-0.93), p=0.002
(I² = 40.4%, p for hetero=0.195)
VA-HIT
FIELD 555 4600 623 4676 0.91 (0.81-1.01), p=0.07
Overall 820 5665 952 5743 0.86 (0.77-0.96), p=0.009
0.5 0.7 1 1.5 2
eGFR 30-59.9 ml/min/1.73m2
10 199 13 200 0.77 (0.35-1.72), p=0.529
(I² = 0.0%, p for hetero=0.443)eGFR ≥60 ml/min/1.73m2
VA-HIT
FIELD 18 295 26 224 0.53 (0.30-0.94), p=0.028
Overall 28 494 39 424 0.60 (0.38-0.96), p=0.032
37 309 50 329 0.79 (0.53-1.17), p=0.002
(I² = 70.3%, p for hetero=0.066)
VA-HIT
FIELD 122 4600 101 4676 1.23 (0.95-1.59), p=0.07
Overall 159 4909 151 5005 1.01 (0.66-1.56), p=0.966
eGFR 30-59.9 ml/min/1.73m2
6 199 15 200 0.40 (0.16-1.02), p=0.054
(I² = 48.7%, p for hetero=0.163)eGFR ≥60 ml/min/1.73m2
VA-HIT
FIELD 23 295 20 224 0.87 (0.49-1.55), p=0.643
Overall 29 494 35 424 0.65 (0.31-1.36), p=0.250
52 1065 61 1067 0.85 (0.60-1.22), p=0.002
(I² = 0.0%, p for hetero=0.868)
VA-HIT
FIELD 135 4600 155 4676 0.89 (0.71-1.11), p=0.07
Overall 187 5665 216 5743 0.88 (0.72-1.06), p=0.178
All-cause mortality
eGFR 30-59.9 ml/min/1.73m2
22 199 22 200 1.01 (0.58-1.76), p=0.986
(I² = 0.0%, p for hetero=0.503)eGFR ≥60 ml/min/1.73m2
VA-HIT
FIELD 43 295 41 224 0.80 (0.54-1.18), p=0.254
Overall 65 494 63 424 0.86 (0.62-1.18), p=0.355
176 1065 198 1067 0.89 (0.74-1.07), p=0.218
(I² = 72.9%, p for hetero=0.055)
VA-HIT
FIELD 313 4600 282 4676 1.13 (0.97-1.32), p=0.129
Overall 489 5665 480 5743 1.01 (0.80-1.27), p=0.948
P for hetero b/teGFR subgroups
p=0.12
p=0.11
p=0.44
p=0.43
Questions and Answers
What would be your preferred approach to the dyslipidemia in the case presented?
a. Keep the treatment with simvastatin
b. Add a fibrate
c. Associate ezetimibe to simvastatin
d. Change to rosuvastatin
Questions and Answers
What would be your preferred approach to the dyslipidemia in the case presented?
a. Keep the treatment with simvastatin
b. Add a fibrate
c. Associate ezetimibe to simvastatin
d. Change to rosuvastatin
Lipid control
LDLc <70 mg/dl or a 50% reduction
• Statins are safe and efficient for CV protection
- SHARP
• Atorvastatin e fluvastatin don’t require adjustment
• Sinvastatin, pravastatin, rosuvastatin, pitavastatin require
• Fibrates may be important in a subgroup of patients
Crude rates of thromboembolism OFF warfarin therapy by category of eGFR
among adults with nonvalvular AF.
Go A S et al. Circulation 2009;119:1363-1369 Copyright © American Heart Association
AFIB/CKD/ATRIA Study
HOT- bleeding by Kidney function
Hazard
ratio (
95%
CI)
20 30 45 60 90 120
0.6
1.0
2.0
4.0
8.0
Any bleeding
6.0
p for trend =0.0005
HR 1.77 (1.09-2.86) per halving of GFR
*
* Reference
eGFR (ml/min/1.73 m2)
Bleeding with warfarin in AF
Jun et al, BMJ 2015
Major Regulatory Agency
Recommendations for Novel Oral
Anticoagulants in Patients with CKD
Hart RG et al. Nat Rev Nephrol. 2012; 8(10):569-78
Anticoagulation and platelet antiaggregation therapy
Progressive increased risk of bleeding
• individualize treatment
KDIGO Diabetes Conference | February 5-8, 2015 | Vancouver, Canada
Relationship Between Achieved BP and Decline in
Kidney Function from Primary Renal Endpoint Trials
Update from Kalaitzidis R and Bakris GL In: Handbook of Chronic Kidney Disease Daugirdas J (Ed.) 2011
Normal decline in GFR
Nondiabetes
MDRD. N Engl J Med. 1993
AIPRI. N Engl J Med. 1996
REIN. Lancet. 1997
AASK. JAMA. 2002
Hou FF, et al. N Engl J Med. 2006
Parsa A et.al. NEJM 2013
Diabetes
Captopril Trial. N Engl J Med.
1993
Hannadouche T, et al. BMJ. 1994
Bakris G, et al. Kidney Int. 1996
Bakris G, et al. Hypertension.
1997
IDNT. NEJM. 2001
RENAAL. NEJM. 2001
ABCD. Diabetes Care (Suppl).
2000
KDIGO Diabetes Conference | February 5-8, 2015 | Vancouver, Canada
Data from the ADVANCE trial Zoungas S, et.al. Diabetes Care 2009;32 (11):2068-2074
KDIGO Diabetes Conference | February 5-8, 2015 | Vancouver, Canada
Summary of Guideline Goal BP and Initial Therapy in
Kidney Disease to Reduce CKD Progression?
Group Goal BP
(mmHg) Initial Therapy
2014 Expert Panel (2014)
ADA (2015)
<140/90
<140/90
ACE Inhibitor/ARB
ACE Inhibitor/ARB*
KDIGO/KDOQI (NKF) (2012)
<140/90
(130/80 if
proteinuric)
ACE Inhibitor/ARB
ESH (2007+ 2009) <130/80 ACE Inhibitor/ARB*
KDOQI (NKF) (2004) <130/80 ACE Inhibitor/ARB*
JNC 7 (2003) <130/80 ACE Inhibitor/ARB*
Am. Diabetes Assoc (2003) <130/80 ACE Inhibitor/ARB*
Canadian HTN Soc. (2002) <130/80 ACE Inhibitor/ARB*
Natl. Kidney Foundation (2000) <130/80 ACE Inhibitor*
JNC VI (1997) <130/85 ACE Inhibitor
Hipertension
Risk factor for the progression of diabetic kidney diasease
• KDIGO recomendation: <130/90mmHg if albuminuria
Unique features in diabetes:
• Volume related (diuretics and sodium restriction often needed)
• Frequent nocturnal and mask hypertension
• Consider ABPM
SPRINT / ACCORDEON
ACEs or ARBs mandatory
Glycemic control
No important comorbidities, GFR higher than - 6.5-7%.
Longer diabetes duration, eGFR lower than 60ml/min – 7-8%.
Questions and Answers
What is the degree of kidney dysfunction currently recommended for metformin discontinuation?
a. Serum creatinine higher that 1.5mg/dL
b. Creatinine clearance lower then 30ml/min
c. eGFR lower than 45ml/min
d. eGFR lower than 30ml/min
Questions and Answers
What is the degree of kidney dysfunction currently recommended for metformin discontinuation?
a. Serum creatinine higher that 1.5mg/dL
b. Creatinine clearance lower then 30ml/min
c. eGFR lower than 45ml/min
d. eGFR lower than 30ml/min
eGFR (ml/min) >60 30-59 15-29 <15 dialysis)
Metformin
Glimepiride
Gliblenclamide
Pioglitazone
Vildagliptin
Sitagliptin
Saxagliptin
Linagliptin
Exenatide
Liraglutide
Insulin
Dapagliflozin
Canagliflozin
Empagliflozin
Questions and Answers
Which of the following hypoglycemic drugs have shown a reduction in the risk of progression to ESRD
a. Insulin
b. Metformin
c. Pioglitazones
d. SGLT2 inhibitors
Questions and Answers
Which of the following hypoglycemic drugs have shown a reduction in the risk of progression to ESRD
a. Insulin
b. Metformin
c. Pioglitazones
d. SGLT2 inhibitors
10
8
6
4
2
0
6 0 12 18 24 30 36 42 48 54
HR: 0.78
95% CI (0.67, 0.92)
P=0.003
Liraglutide
Placebo
4668
4672
4635
4643
4561
4540
4492
4428
4400
4316
4304
4196
Liraglutide
Placebo
Patients at risk
4210
4094
4114
3990
1632
1613
454
433
Pa
tie
nts
wit
h a
n e
ve
nt
(%)
Time since randomisation (months)
LEADER: Time to first renal event Macroalbuminuria, doubling of serum creatinine, ESRD, renal death
The cumulative incidences were estimated with the use of the Kaplan–Meier method, and the hazard ratios with the use of the Cox proportional-hazard
regression model; the data analyses are truncated at 54 months because less than 10% of the patients had an observation time beyond 54 months
CI, confidence interval; ESRD, end-stage renal disease; HR, hazard ratio
Marso SP, et al. N Eng J Med 2016; June 13 [Epub ahead of print]
Vlado Perkovic et al (2015): Renal effects of canagliflozin in type 2 diabetes mellitus, Current Medical Research and Opinion
66
Ad
juste
d m
ea
n (
SE
) e
GF
R
(mL
/min
/1.7
3m
2)
70
72
74
76
78
68
0 4 12 28 52 66 80 94 108 122 136 150 164 178 192 206
Empagliflozin 10 mg
Empagliflozin 25 mg
Placebo
Weeks
Placebo
Empagliflozin 10 mg
2323
2322
2322
2295
2290
2288
2267
2264
2269
2205
2235
2216
2121
2161
2156
2064
2114
2111
1927
2012
2006
1981
2064
2067
1763
1839
1871
1479
1540
1563
1262
1314
1340
1123
1180
1207
977
1024
1063
731
785
838
448
513
524
171
193
216 Empagliflozin 25 mg
After initial decrease, long term weekly
changes of:
EMPA (10 mg): +0.48±0.04 mL/min
EMPA (25 mg): +0.55 ±0.04 mL/min
PBO: –0.04 ±0.04
P<0.001 for both
EMPA groups vs
placebo
EMPA-REG: Change in eGFR over time
eGFR, estimated glomerular filtration rate; SE, standard error
Wanner C. N Engl J Med 2016; June 14 [Epub ahead of print]
0.13 0.25 0.50 1.00 2.00
Favours placebo Favours empagliflozin
P value
<0.0001
<0.0001
0.0009
0.0409
N with event/n analysed
Empagliflozin Placebo HR (95% CI)
525/4124
459/4091
388/2061 0.61 (0.53, 0.70)
330/2033 0.62 (0.54, 0.72)
70/4645 60/2323 0.56 (0.39, 0.79)
13/4687 14/2333 0.45 (0.21, 0.97)
New onset or
worsening of
nephropathy
New-onset
macroalbuminuria
Doubling of
serum creatinine
Initiation of
renal
replacement
therapy
EMPA-REG: New onset or worsening of
nephropathy
CI, confidence interval; HR, hazard ratio
Wanner C. N Engl J Med 2016; June 14 [Epub ahead of print]
Pa
tien
ts w
ith
eve
nt
(%)
7
6
5
3
2
0
1
6 12 18 24 30 36 42 48 0
4
HR: 0.54
(95% CI: 0.40, 0.75)
P=0.0002
Placebo
Empagliflozin
Months
4645
2323
4500
2229
4377
2146
4241
2047
3729
1771
2715
1289
Empagliflozin
Placebo
No. of patients
2280
1079
1496
680
360
144
EMPA-REG: Doubling of serum creatinine,
initiation of renal replacement therapy or death
due to renal disease
Wanner C. N Engl J Med 2016; June 14 [Epub ahead of print]
Sodium–glucose cotransporter 2 inhibition and cardiovascular risk reduction in patients with type 2 diabetes: the
emerging role of natriuresis
Kidney International, Volume 89, Issue 3, 2016, 524–526
http://dx.doi.org/10.1016/j.kint.2015.12.038
Back to our patient: what changes in the management when kidney
disease is present?
• Start an ACEi or ARB – target <130/90mmHg
• Aspirin
• Warfarin
• Simvastatin/Ezetimibe – target LDLc 70mg/dL
• Reduce the metformin dose to half
• Add a SGT2i target HbA1C 7%
– Weight, BP, albuminuria, eGFR
GLP-1 agonist
DPP inhibitors
PPARγ agonist
SGL2i
Glucose lowering
AGE inhibitors
RAGE antagonists
PKC inhibitors
e.g. ruboxistaurin
TGF-β or CTGF
Antibodies
Pirfenidone
Glucose
AGEs and RAGE
PKCα and PKC β
Other
Blood pressure
All
ET-1
Other
Growth factors
CTGF
TGF-β
VEGF
Fibrosis Inflammation Albuminuria
Diabetic nephropathy
Antihypertensives
ACE inhibitors
Or ARBs
Endothelin
Receptor blockers
e.g. atrasentan
VEGF antibodies
Fineberg D, et al. Nat Rev Endocrinol 2013;9:713–723