Glycemic control in advanced CKD

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Transcript Glycemic control in advanced CKD

Renal Highlights 2016
Disclosure belangen Prof.dr. W. van Biesen
(potentiële)
Belangenverstrengeling
Geen
Voor bijeenkomst mogelijk relevante
relaties met bedrijven
Geen
•
•
•
•
Sponsoring of onderzoeksgeld
Honorarium of andere (financiële)
vergoeding
Aandeelhouder
Andere relatie, namelijk
• Geen
• De transportkosten en een
honorarium voor deze
voordracht wordt voorzien
door Baxter; er is geen direct
verband tussen Baxter en de
huidige voordracht
ERBP Guideline on management of
diabetics with advanced CKD
ERBP Mission
improve the outcome of patients with
kidney disease in a sustainable way,
through enhancing the accessibility of
knowledge on patient care, in a format
that stimulates its use in clinical
practice.
Outline
• Is intensive glycemic control as measured by
HbA1C advantageous in diabetic patients with
CKD 3b-5d?
• What oral agent should be preferred as first
line agent in patients with CKD 3b-5d with
impaired glucose tolerance/diabetes
HbA1c is significantly correlated to eGFR
K. Shima; Ann Clin Biochem; 2012, vol. 49, 68-74
With thanks to Rikke Borg
Hb, EPO & Hb A1C
Inaba JASN 18:896 2007
Adjusted mortality rate in ESRD and DM: HbA1c
Adjusted mortality rate in ESRD and DM: HbA1c
CKD and Glycaemic Control
Kovesdy AJKD 52:766 2008
CKD and Glycaemic Control
Kovesdy AJKD 52:766 2008
CKD and Glycaemic Control
Kovesdy AJKD 52:766 2008
1,25-Vitamin D improves
Insulin Sensitivity
16 Insulin resistant
HD patients
PTH 798 pg/ml
did not change during study
RCT
1.8 µg 1,25-vitamin D
X3/week for 4 weeks
vs. Control (group 2)
Triglycerides 198148 mg/dL
E
Oral glucose tolerance test
Before:  and after: 
Euglycaemic clamp study
A: Insulin stimulated
glucose metabolism
B: Insulin concentration
Mak KI 53,1353 1998
Incretins
Incretins
Idorn KI 2013;
83:915
Considerations in advanced CKD patients
Increased risk of hypoglycemia
• Decreasing renal mass leads to impaired gluconeogenesis and glycenolysis
• Decreased renal clearance of insulin
• Decreased clearance of hypoglycemic drugs
• comorbidity and co-medication
Increasing impaired glucose tolerance
• Peripheral insulin resistance in CKD from counter-regulatory hormones,
electrolyte abnormalities, uremic acidosis, and accumulation of uremic
toxins
Shortened life expectancy
Increased cardiovascular risk +++
Cochrane review Hemmingsen et al, BMJ, 2011
Cochrane review Hemmingsen et al, BMJ, 2011
Cochrane review Hemmingsen et al, BMJ, 2011
Cochrane review Hemmingsen et al, BMJ, 2011
Non fatal myocardial infarction
Cochrane review Hemmingsen et al, BMJ, 2011
Cochrane review Hemmingsen et al, BMJ, 2011
Conclusions
Hard evidence for LACK of impact on all cause mortality by actively lowering
HbA1C
Insufficient evidence for a 10% relative risk reduction in cardiovascular mortality
and non-fatal myocardial infarction
Insufficient evidence for reduction in microvascular disease (combination of
retinopathy, nephropathy
STRONG evidence for increased risk of severe hypoglycaemia
Conclusions
Hard evidence for LACK of impact on all cause mortality by actively lowering
HbA1C
Insufficient evidence for a 10% relative risk reduction in cardiovascular mortality
and non-fatal myocardial infarction
Insufficient evidence for reduction in microvascular disease (combination of
retinopathy, nephropathy
At least in studies with an overwhelming majority of non advanced CKD patients!!!!!!
Conclusions
• First concern: avoid hypoglycemia
• If no hypoglycemia’s and HbA1C>7%: try to
intensify hypoglycemic treatment
• Take into consideration comorbidity and
age of patients
Comprehensive risk analysis:
yes
FRAILTY or ONE of the following:
• Risk for hypoglycaemia (see figure)
• Poor motivation and attitude of patient
• Decreased general life expectancy
• Cardiovascular disease
• Micro-vascular complications
≤ 69 mmol/mol
no
Patient on therapy wth
Lifestyle only
or
therapy with low or absent hypoglycaemia risk *
yes
≤ 53 mmol/mol
no
Diabetes duration < 10
years
no
yes
≤ 64 mmol/mol
≤ 58 mmol/mol
* drug-drug interactions
* hepatic failure
* CKD stage 5
* gastroparesis
* Metformin
* Alpha glucosidase inhibitors
* DPP-IV inhibitors
* Incretin mimetics
* TZD’s
* SGLT-2 inhibitors
* Short acting SU
derivates or SU
derivates with inactive
metabolites
* meglitinides
Hypoglycaemia risk
* Insulin
* Long acting SU
derivates with active
metabolites
Why do you always have to be different?
Oral antidiabetics in CKD
Arnouts NDT 2014
Metformin Method of Action
•
•
•
•
•
•
Increases insulin sensitivity
Reduces glucose absorption from intestine
Increases peripheral glucose uptake in cells
Reduces gluconeogenesis in the liver
Reduces weight
Hypoglycaemia rare
UKPDS Study
• 4209 patients with Type 2 DM
• Creatinine <175 mmol/l
• Randomised to
• Diet or
• Insulin-sulphonylurea
(normal weight)
• Metformin
(Body weight >120% IBW)
Holman NEJM 359:1577 200
METFORMIN
in advanced CKD:
Scheen AJ. Metformin and lactate acidosis. Acta Clin Belg 2011, 66 (5): 329-331
METFORMIN
•
•
•
•
•
•
•
First drug of choice in all current guidelines
Cheap
No hypoglycemic risk
Weight-neutral or reducing effect
Lipid- lowering effect
Well characterized efficacy and safety profile
Impressive preventive effects with prevention of:
– Diabetes
– Micro- and macrovascular complications
– Major events in patients with heart failure
– Apoptotic neuron death
– Cancer
– Osteopenie
– Mortality in lactic acidosis not related to to metformin
METFORMIN: LACTIC ACIDOSIS
Scheen AJ. Metformin and lactate acidosis. Acta Clin Belg 2011, 66 (5): 329-331
A coctail of risk aversion and WYSIATI effects
Herrington WG, Levy JB. Metformin: effective and safe in renal disease. Int Urol Nephrol
2008; 40: 411-417
A coctail of risk aversion and WYSIATI effects
Herrington WG, Levy JB. Metformin: effective and safe in renal disease. Int Urol Nephrol
2008; 40: 411-417
METFORMIN: LACTIC ACIDOSIS
– No firm data that lactic acidosis is more frequent
in patients on metformin (Salpeter, Cochrane
review)
– Evidence that outcome of lactic acidosis is BETTER
in patients on vs not on metformin
– We have to distinguish
• Lactic acidosis type A: caused by tissue hypoxia/liver damage
• Lactic acidosis type B: caused by intoxication, eg metformin
– We have to to distinguish:
• Metformin as CAUSE of the lactic acidosis
• Metformin as a drug in a patient who develops lactic acidosis
because of other reasons
• Mixed forms
Recommendations
• We recommend metformin in a dose adapted to renal
function as a first line agent when lifestyle measures alone
are insufficient to get HbA1C in the desired range (1B)
• We recommend to add on to meformin a drug with a low
risk for hypoglycaemia as a second agent when
improvement of glycaemic control is deemed appropriate
according to guideline (1D)
• There is insufficient evidence to support insulin over an
additional oral agent as add on second line treatment
• We recommend instructing patients to withhold
metformin in conditions of pending dehydration, when
undergoing contrast media investigations, or when there is
a risk for AKI
advice for clinical practice
•
•
Consider to provide patients with credit-card type flyers with instructions on when to
temporarily withdraw methformin
drugs with low risk for hypoglycaemia: (figure)
–
–
–
–
–
•
drugs with moderate risk for hypoglycaemia:
–
–
•
Short acting SU derivates or SU derivates with inactive metabolites
meglitinides
drugs with high risk for hypoglycaemia:
–
–
•
Metformin
Alpha glucosidase inhibitors
DPP-IV inhibitors
Incretin mimetics
SGLT-2 inhibitors
Insulin
Long acting SU derivates or derivates with active metabolites
in patients with diabetes and eGFR <45 who are on metformin, the decision to withhold the
drug 48 hours before and after administration of contrast media should be taken by the
treating physician, balancing the probability for emergence of contrast induced nephropathy
(type and amount of contrast, intravenous vs intra-arterial), and presence of other coexisting factors that might cause sudden deterioration of kidney function (dehydration, use
of NSAID, use of inhibitors of the RAAS system) against the potential harms by stopping the
drug (which should be considered low in view of the short period that it should be
withheld).
When to start dialysis?
When to start dialysis?
Study
Cooper et
al.(7)
Publicatio
n Year
Time
Frame
Location
Characteristi
cs
Study design
N
% DM
Modality (%
HD)
Methods
Outcomes
2010
RCT (IDEAL
2000study)
2008
N = 828
Australia/ 34% DM
New
44% HD
Zealand
Cox
regression
Mortality
Inclusion criteria
Exclusion criteria
Patients’
Intervention (n=) Outcom
characteristic Comparator(n=) e(s)
s
Duration
Patients were
eligible for
inclusion in the
study if they had
progressive chronic
kidney disease
(patients with a
failing kidney
transplant were
eligible) and an
estimated GFR
between 10.0 and
15.0 ml per minute
per 1.73 m2
Exclusion: < 18
years of age, eGFR<
10.0 ml/min,
planned living
donation within 12
months, cancer
that was likely to
affect mortality
Age: 60.3 yrs
Gender: 65%
male
DM (as PRD):
34%
eGFR at
start: 9.9
ml/min/1.73
m2
Results
Late start of
Mortalit HR 1.04 (0.83dialysis group
y
1.30) p=0.75. P
(eGFRCG between
for interaction
5-7 ml) (n=424)
for early or late
Early start of
start of dialysis
dialysis group
with diabetes =
(eGFRCG between
0.63.
10-14 ml)(n=404)
FU until
November 2009
Quality
of
evidenc
e
NewcastleOttawa
Score
(Cochrane risk
of bias for the
RCT's)
Notes
High
selection bias:
low
performance
bias: unclear
detection
bias: low
attrition bias:
low reporting
bias: low
other bias:
unclear
Randomized
controlled trial with
proper subgroup
analysis for
interaction in
diabetics.
When to start dialysis?
Lipid lowering strategies?
Lipid lowering strategies?
Sharp trial
Sharp trial
Lipid lowering strategies?
Lipid lowering strategies?