Nierziekten en diabetes

Nierziekten en diabetes
Dr. Gerald Vervoort
Dept. of General Internal Medicine and Nephrology
Radboud University Nijmegen Medical Centre
Never underestimate the power of a great story
di
wo
do
vr
• Diabetische nefropathie (bij type 1 en type 2 diabetes)
• Epidemiologie
• Pathofysiologie
• Risicofactoren
• Behandeling
• SGLT-2 remmers
Epidemiologie
Diabetische nefropathie (DNP) (in type 1)
wat bepaalt de incidentie en prevalentie van DNP
1. Voorkomen van diabetes mellitus
2. Patient’s risk
3. Mortaliteit (alvorens DNP te ontwikkelen)
Epidemiologie
Time trends in type 1 diabetes incidence in boys and girls
Epidemiologie
% Diab. Nefropathie
100
“Classical view”
80
60
40
20
0
-10 -5
0
5
10
Type 2 diabetes
15 20 25 30 Jaren DM
Type 1 diabetes
Epidemiologie
8%
Cumulative Incidence of End-stage Renal Disease Among Male and Female
Patients With Type 1 Diabetes According to Age at Diagnosis of Diabetes.
Epidemiologie
Epidemiologie
Cumulative incidence of Microalbuminuria
Cumulative incidence
20
<1970
1970-1974
1975-1979
1980-1984
1985-1989
1990-1994
1995-1999
>=2000
15
10
5
0
0
10
20
30
Years since diagnosis DM
type 1 DM
B. Veldman en G. Vervoort, 2008
(unpublished data)
Pathofysiologie
Pathofysiologie
Glucose
Polyol pathway
Glucose
Sorbitol
Glucose-6-P
Fructose-6-P
Hexosamine pathway
GFAT
Glyceraldehyde-3-P
NAD+
GAPDH
NADH
Fructose
-
1,3-diP-glycerate
Glucosamine-6-P
DHAP
UDP-GlcNAc
alpha-Glycerol-P
DAG
PKC pathway
Methylglyoxal
AGEs
AGE pathway
O2-
ROS
PARP
PKC
Pathofysiologie
Diabetes mellitus
Hyperglycemia
ROS
glycolytic intermediates
AGEs
Oxidative stress
Intracellulaire
signaling
PKC, MAPK
NF-
Growth Factors
Cytokines
TGF- , VEGF,
IGF-1, CTGF, bFGF
ECM accumulation
celproliferation
permeability
Transcription factors
AP-1 Sp-1
Pro-coagulant
factors
PAI-1
inflammation
thrombosis
Diabetic Nephropathy
Hemodynamic
factors
NO, AT-II, endothelin
intracapillary pressure
vasoconstriction
ischemia
Pathofysiologie
Diabetes
Hyperglycemie
Other factors
Complicaties
Pathofysiologie
Pathofysiologie
Glucose
Glucose
Sorbitol
Fructose
Glucose-6-P
Fructose-6-P
GFAT
Glyceraldehyde-3-P
NAD+
GAPDH
NADH
Glucosamine-6-P
DHAP
UDP-GlcNAc
alpha-Glycerol-P
DAG
-
1,3-diP-glycerate
Methylglyoxal
AGEs
Glyoxalase I
ROS
PKC
Pathofysiologie
Glyoxalase-I overexpression
O. Brouwers et al, Maastricht
Potential new treatment modalities in preventing diabetic
angiopathy
• Aldose reductase inhibitors
• GFAT inhibitors
• PKC inhibitors
(LY333531)
• AGE breakers / AGE inhibitors
(pimagedine)
• anti-oxidants
• TGF-beta inhibitors
(ACE-inhibitors)
• PARP inhibitors
• vitamin B1
• glyoxalase stimulation
Risk factors
Cumulative incidence of persistent microalbuminuria in the DCCT
Risk factors
Unmet need
Cumulative incidence of persistent microalbuminuria in the DCCT
Risk factors
Risk factors
ESRD
± 10% x 25% = 3%
Risk factors
Risk factors for long-term renal outcome in microalbuminuric pts
Treatment
Spironolactone diminishes UAE in type 1 diabetic patients with microalb.
* 60% reduction in UAE
* 10% hyperkalemia (>5.7 mmol/l)
* no change in RR
S. Nielsen et al, STENO Denmark
Eplerenone study in microalbuminuric Pts with
RR < 130/80 or maximum antiHt therapy
G.Vervoort, K. Kramers, J. Deinum
Preliminary results
Mortality
type 1 diabetic Pts. from the FinnDiane study,
stratified for the presence and severity of
albuminuria (A), estimated GFR (B)
Mortality
Mortality risk of type 1 diabetic Pts.
Mortality
Chronic kidney disease is the dominant contributor to excess
mortality in type 1 diabetes.
Consequently, if you have type 1 diabetes, prevention of
chronic kidney disease is currently the best way to reduce your
risk of a premature death.
Type 1 diabetes pts lose 3 years of their life mainly due to renal
disease.
Epidemiologie
Diabetische nefropathie (DNP) in type 2 diabetes
wat bepaalt de incidentie en prevalentie van DNP
1. Voorkomen van diabetes mellitus
2. Patient’s risk
3. Mortaliteit (alvorens DNP te ontwikkelen)
Epidemiologie
350.000.000
Epidemiologie
Epidemiologie
Kaplan-Meier plots of proportion of patients with microalbuminuria, macroalbuminuria,
reduced creatinine clearance (CrCl), doubling of plasma creatinine, or any one of these,
after diagnosis of type 2 diabetes.
Retnakaran R et al.
Epidemiologie
EASD 2011
Finnish study in type 2 diabetes
20 yrs follow-up
332000 pts
105000 died
= 30%
Factor 100!!!
941 developed ESRD
= 0,3%!!
Let op: incidentie ESRD > for younger people 2-3%
Epidemiologie
Natuurlijk beloop van diabetische nefropathie
Diabetes mellitus
Functionele veranderingen
Structurele veranderingen
Bloeddruk stijging
Microalbuminurie
Proteinurie
kreatinine stijgt
Nierfunctieverlies
10-15 jr
Epidemiologie
50% of Pts with GFR< 60 ml/min are normoalbuminuric
Are albuminuric and GFR decreased people different??
P. Fioretto
Epidemiologie
Albuminuria or renal
impairment
Albuminuria
Renal impairment
Prognostic importance??
(systolic) RR
UAE
Creatinine
Ethnicity
Male
Increased waist circumference
LDL cholesterol
Smoking
Female
Decreased waist circumference
Age
Albuminuria increases CV death more than GFR-decrease
Epidemiology/Treatment
New data from the ADVANCE trial
after 5 yr follow up intensive glucose lowering treatment
(HbA1c <6,5%)
• risk ESRD
HR 0.35 (0.15-0.83)
• risk renal death
HR 0.85 (0.45-1.63)
• ESRD and/or renal death
HR 0.64 (0.38-1.08)
• doubling of creatinine
NS
Epidemiology/Treatment
New data from the ADVANCE trial
Significant predictors for renal events
• eGFR
• UAE
• (systolic) RR
• HbA1c
• Diabetic retinopathy
• Male sex
• Level of formal education
ROC curve, 0.83 (95% CI, 0.80-0.87)
Epidemiology/Treatment
Initial ARB-induced decrease in albuminuria predicts
long term renal outcome in DMT2 with microalbuminuria
• post-hoc analysis of IRMA-2
• 2 yr follow up
• 531 microalb. subjects
Initial change in UAE was independently associated with eGFR slope;
The more UAE reduction the less eGFR decline, irrespective of blood pressure
Hellemons, Groningen
Decline in eGFR from 6 to 24 months for groups of UAE and SBP change in 531 type 2
diabetic patients with microalbuminuria.
Hellemons M E
Treatment
What about blood pressure
New guidelines???
<140/90 (130/80)?
Niet diastolisch <70-75 mmHg
Niet systolisch <110 mmHg
SGLT-2 inh.
SGLT-2 remmers (“gliflozines”)
• dapagliflozin
• canagliflozin
• BI 10773
• TS-071
• ipragliflozin
• sergliflozin
• LX4211 (combined SGLT-2 and SGLT-1 inhibitor)
SGLT-2 inh.
SGLT-2 inh.
GFR 100 ml/min ~ glucose 10 mmol/l ~ 1440 mmol glucose
~ 250 gram glucose
SGLT-2 inh.
Dapagliflozin and/or metformin in treatment-naïve T2DM patients;
24 week trial; n=638
MET
DAPA 10mg
DAPA 10mg +
MET
HbA1c (%)
-1.44
-1.45
-1.98*
FPG (mmol/l)
-1.93
-2.58#
-3.35*
Weight (kg)
-1.36
-2.73#
-3.33*
Urinary tract
infection
4.3%
11%
7.6%
Genital
infection
2.4%
12.8%
8.5%
Langste follow-up DAPA: 2 yr
SGLT-2 inh.
Ipragliflozin in Japanese type 2 patients: BRIGHTEN Study
Phase 3 study; 16 weeks follow-up
HbA1c
FPG
Body
weight
Baseline
8.32
9.7
67.18
IPRA
-0.76
-2.2
-2.36
Placebo
+0.47
+0.3
-0.89
Difference
-1.23
-2.5
-1.47
RR
-3.2 mmHg
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