diabetes en dialyse - de baar

Diabetes en Dialyse

SYMPOSIUM DIABETES en NIERZIEKTEN Radboud University Medical Center Nijmegen

The Netherlands

January 22nd 2009

Renal replacement therapy in patients

with diabetes as primary diagnosis

0

5

10

15

20

25

30

35

40

45

50

Netherlands Australia Sweden Germany Italy USANetherlands Australia Sweden Germany Italy USA

Locatelli et al.; J Am Soc Nephrol 2004

diabetes

hypertension

GMN

cystic kidney

other/unknown

USRDS 2003; Am J Kidney Dis 2003

Primary diagnosis of new patients at initiation

0 1 2 3 4 5

Duration of dialysis, years

100

60

80

40

20

0

Pa

tië

nt

su

rviv

al, %

Patient survival on dialysis for patients with chronic GN or DNP

CGN

DNP

USRDS 2000; Am J Kidney Dis 2000

0

10

20

30

40

50

60

DiabPts Non-diab Pts

LVH

IHD

Cardiac failure

6 18 30 42 54 66 78

1.0

0.6

0.2

0.4

0.8

0

Months

Cu

mu

lati

ve

pro

po

rtio

n e

ven

t-fr

ee

Cardiac findings in diabetic patients on dialysisP

erce

nta

ge

(%)

First episode of new-onset ischaemic heart disease in

diabetic and non-diabetic subjects on RRT

DiabPts

Non-diabPts

Foley et al.; Diabetologia 1997

Diabetic patients appear to be more sensitive than nondiabetics to inadequate dialysis prescriptions. It has been estimated, for example, that there is a seven percent increase in mortality in diabetics for every 0.1 unit decline in Kt/V.

Collins, AJ. How can the mortality rate of chronic dialysis patients be

reduced? Semin Dial 1993

The potential importance of malnutrition is suggested by the observation that the increase in mortality (when compared to nondiabetics) largely disappears if reductions in the plasma albumin and creatinine concentrations (that primarily reflect inadequate intake) are taken into account

Lowrie EG; Lew NL; Huang WH. Race and diabetes as death risk predictors in hemodialysis patients. Kidney Int Suppl 1992

50

60

70

80

90

100

0 6 12 18 24 30

Diabetes

Non-diabetes

Month of treatment

% t

ech

niq

ue s

urv

iva

l

Percentage technique survival for diabeticand non-diabetic patients on CAPD

Serkes KD et al.; Perit Dial Int 1990

Dialysis in patients with diabetes

• decreased survival rate due to cardiovascular disease

• cave: inadquate dialysis prescriptions

• cave nutritional status

• decreased (PD-) technique survival rate

• (progression of microvascular diabetic complications)

Would optimal treatment of diabetes improve these outcomes?

Aggregate Clinical EndpointsAggregate Clinical Endpoints

0.5 1 2

0.88

0.90

0.94

0.84

1.11

0.75

0.029

0.34

0.44

0.052

0.52

0.0099

Any diabetes related endpoint

Diabetes related deaths

All cause mortality

Myocardial infarction

Stroke

Microvascular

RR p

Favours: conventionalintensive

Relative Risk& 95% CI

UKPDS; Lancet 1998

DIGAMI study; BMJ 1997

Intensive insulin treatment in acute myocardial

infarction patients with diabetes mellitus

0 1 2 3 4 5Years in study

Dea

th r

ate

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Control

Infusion

0 1 2 3 4 5Years in study

Dea

th r

ate

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Control

Infusion

Intensive insulin therapy in

critically ill patients

Van den Berghe et al.; NEJM 2001

0 20 40 60 80 100 120140160

Su

rviv

al

in U

CI

(%)

100

96

92

88

84

80

00 20 40 60 80 100 120140160

Su

rviv

al

in U

CI

(%)

100

96

92

88

84

80

0

Intensive

Control

0 20 40 60 80 100 120140160

Su

rviv

al

in U

CI

(%)

100

96

92

88

84

80

00 20 40 60 80 100 120140160

Su

rviv

al

in U

CI

(%)

100

96

92

88

84

80

0

Intensive

Control

Days after admission

0 2 4 6 8 10Years from hemodialysis initiation

Cu

mu

lati

ve

surv

iva

l ra

te1.0

0.8

0.6

0.4

0.2

0

HbA1c < 7.5

HbA1c > 7.5

Cumulative survival curves for diabetic ESRD subjects on hemodialysis

with good and poor glycemic control

Morioka et al.; Diab Care 2001

UKPDS; Lancet 1998

Any diabetesAny diabetes--related endpointsrelated endpoints

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0 3 6 9 12 15

Pro

po

rtio

n o

f pa

tien

ts w

ith

eve

nts

Years from randomisation

Conventional

Chlorpropamide

Glibenclamide

Insulin

C v G v Ip = 0.36

Any diabetesAny diabetes--related endpointsrelated endpoints

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0 3 6 9 12 15

Pro

po

rtio

n o

f pa

tien

ts w

ith

eve

nts

Years from randomisation

Conventional

Chlorpropamide

Glibenclamide

Insulin

C v G v Ip = 0.36

Current treatment modalities for (type 2) diabetes mellitus

• Sulfonylurea (meglitinides)

• Biguanides

• Thiazolidinediones (PPAR gamma agonists)

• Insulin

• GLP-1 (analogen)

• DPP-IV inhibitors

• (alpha-glucosidase inhibitors)

SURSUR

pyruvate

pyruvate

citrate

isocitrate

αααα-ketoglutarate

suc-CoA

succinate

fumarate

malate

oxaloacetate

FADH2

FAD

NADNADH

pyruvate

pyruvate

citrate

isocitrate

αααα-ketoglutarate

suc-CoA

succinate

fumarate

malate

oxaloacetate

FADH2

FAD

NADNADH

TZD

Oral hypoglycemic agents

• sulfonylureas

SURSUR

Sulfonylureas

• Tolbutamide 1-2 g/day

• Gliclazide 80-360 mg/day

• Glipizide 2.5-10 mg/day

SURSUR

• Chlorpropamide

• Glibenclamide

• Acetohexamide/tolazamide

• Glyburide, glimepiride etc.

Oral hypoglycemic agents

• biguanides (metformin)

pyruvate

pyruvate

citrate

isocitrate

αααα-ketoglutarate

suc-CoA

succinate

fumarate

malate

oxaloacetate

FADH2

FAD

NADNADH

pyruvate

pyruvate

citrate

isocitrate

αααα-ketoglutarate

suc-CoA

succinate

fumarate

malate

oxaloacetate

FADH2

FAD

NADNADH

lactate

carbohydrates

Amino acids

acetylCoAFatty Acids

Ketones

Oral hypoglycemic agents

• Thiazolidinediones (pioglitazone, rosiglitazone)

TZD

Glucose regulation

Insulin sensitivity

Lipid metabolism

Vascular tone

Cell proliferation

and differentiation

Thiazolidinediones

Pharmacokinetics of rosiglitazone

Chapelsky MC et al.; J Clin Pharmacol. 2003

Renal impairement normal

mild

moderate

severe

Lin SH et al.;Am J Kidney Dis. 2003

Thiazolidinediones

Rosiglitazone improves glucose metabolism in PD patients

Mortality All-Cause CV

Treatment Measure AHR 95%CI AHR 95%CI

Pt-level: RGZ, yes vs. no 1.341.01-1.77

1.501.06-2.12

Facility-level: 75th vs. 25th %ile of facility RGZ prescription

1.231.12-1.35

1.181.01-1.38

J. M. Albert et al. ASN San Fransisco 2007

Thiazolidinediones

Rosiglitazone Is Associated with Increased Mortality among

Diabetic HD Patients in the US DOPPS.

Insulin therapy

• Renal clearance• Insulin degradation• Hepatic insulin metabolism

• Insulin sensitivity• Insulin secretion

Insulin therapy

• subcutaneous insulin in PD patients

• twice-daily intermediate/regular insulin

• basal-bolus regime

• CSII (insulin pump therapy)

Insulin therapy

Subcutaneous insulin in PD patients (basal-bolus regime)

• conventional long-acting insulin (NPH, lente)

once- or twice daily with conventional regular insulin

• long-acting insulin-analogue (glargine, detemir)

with short-acting insulin analogues (lispro, aspart)

• long-acting insulin-analogue (glargine, detemir)

with conventional regular insulin

Insulin therapy

Insulin therapy

Insulin therapy

Insulin therapy

Intraperitoneal insulin in PD patients

• use regular insulin four times daily in CAPD

• use regular insulin (in all dialysis containers) in CCPD

and either i.p. regular insulin for the daytime exchange

or supplemental s.c. infusion for meals

Intraperitoneal insulin in PD patients

Quellhorst E., JASN 2002

Quellhorst E., JASN 2002

Intraperitoneal insulin in PD patients

Insulin therapy

• subcutaneous insulin in HD patients

• twice-daily intermediate/regular insulin

• basal-bolus regime

• CSII (insulin pump therapy)

HOE DIT AF TE STEMMEN MET DE DIALYSE?

Current / future aspects:

• GLP-1 (glucagon like peptide) and -/ GIP

(gastric inhibitory polypeptide)

• GLP-1/GIP derivatives (exendin-4, liraglutide)

• DDP-IV inhibitors (sitagliptine/vildagliptine)

GLP-1 (glucagon like peptide)

Renal insufficiency

Control subjects

Meier JJ et al., Diabetes 2004

Therapy

• Special problems

• hyperglycemia

• severe hyperglycemia and ketoacidosis

• hypoglycemia

• alternating hypoglycemia and hyperglycemia

(gastroparesis, education)

• diabetic foot problems

Dr. Gerald Vervoort

Radboud University Medical Centre Nijmegen

The Netherlands