Behandling af gamle med diabetes
herunder
Nye diagnostiske kriterier, prævalens,
prognose, behandlingsmål og
behandlingsguidelines
Jan Erik Henriksen
Ledende overlæge, klinisk lektor, PhD
Endokrinologisk afd. M
Odense Universitet Hospital
Diagnosen Diabetes
1997 diagnosen
2 timers PG
= 11.1 mM
FPG = 7.0 mM
2 timers OGTT
11.1 mM
FPG = 7.8 mM
2009 diagnosen !
Vurdering af HbA1c som diagnostisk værktøj
Hvilken værdi ?
HbA1c < 6.5 % stort ser
ingen med retinopati
Ca 28.000 personer fra ni
forskellige lande
Begrænsninger!
• Omkostninger
• Hæmoglobinopatier
• Hæmolytisk anæmi
• Kronisk malaria
• Efter større blødninger – blodtransfusion
• Hurtigt indsættende diabetes (fx DM1)
• Alder – race ?
Prævalens og prognose
Model for udvikling af diabetes i DK
Antal patienter
700,000
Ultimo år
Anders Green
Antal diabetikere 2009
0-9
1019
2029
30-39
40-49
50-59 60-69 70-79
Kvinder
304
1.429
2.619
6.972
13.905
20.665 32.998
30.042
23.217 132.151
Mænd
297
1.401
2.117
5.094
13.783
26.990 44.137
31.108
13.907 138.834
I alt
601
2.830
4.736
12.066
27.688
47.655 77.135
61.150
37.124 270.985
80+
I alt
Relativ dødelighed
Diabetikeres dødelighed set i forhold til den øvrige
befolkning
Kvinder
Mænd
Alle
1997
1,83
1,96
1,90
1998
1,79
1,90
1,85
1999
1,75
1,98
1,86
2000
1,76
1,92
1,84
2001
1,70
1,82
1,76
2002
1,64
1,88
1,75
2003
1,68
1,83
1,75
2004
1,60
1,80
1,70
2005
1,62
1,77
1,69
2006
1,60
1,71
1,65
2007
1,54
1,69
1,62
2008
1,51
1,63
1,57
2009
1,48
1,70
1,59
Hvor langt skal Hba1c ned?
UKPDS – HbA1c – Endpoints
Epidemiology
20
08
0.9 % point in difference
between the two groups
Difference in HbA1c was only 0.6 % point between the
metformin group and the conventional group
UKPDS
10-year post-trial monitoring
from 1997-2007
”Metabolic memory” or ”glucose memory”
underscoring the importance of optimal glycaemic control
from time of diagnosis
Multifactorial intervention
Steno Type 2 Study-Design
• An open, parallel trial comprising 160 Caucasian type 2
diabetic patients with microalbuminuria
• With consealed randomisation patients were allocated
either to conventional therapy at their GP or intensive
treatment at Steno Diabetes Center
Conventional
n=80
4 years
8 years
Microvascular
Macrovascular
n=160
Endpoint examinations
n=80
Intensive
Microvascular
Macrovascular
4 years
8 years
Hba1c
Total Kol
Syst BT
LDL
Dia BT
Triglycerid
Død
Kardiovaskulær
sygdom
Steno-2: Number Needed to Treat
for 13 Years to Prevent One --Death
Cardiovascular death
Major cardiovascular event
Progression of nephropathy
Dialysis
Laser treatment
5 patients
8 patients
3 patients
5 patients
16 patients
7 patients
ACCORD
ADVANCE
VADT
de korte ”akutte” studier
Standard vs. intensive BG treatment
Standard: Goal: HbA1c 7 -7.9%
ACCORD
Intensive: Goal: HbA1c <6%
Standard: SU other than gliclazide MR + any
other anti-diabetic drugs.
ADVANCE
Intensive: Gliclazide MR + any other anti-diabetic
drugs Goal: HbA1c <6.5%
Standard: Goal: HbA1c 8%-9%
VADT
Intensive: Goal: HbA1c <6%
Tight glycaemic control reduces
primary endpoint but not mortality
Accord
Advance
VADT
Primary CVD endpoint
10 %
6%
13 %
CVD mortality
39 %*
12 %
32 %
Total mortality
22 %*
7%
6%
What if the trials had been longer than 5 years ?
ACCORD
ACCORD: Treatment effects
on glucose control
9.0
8.5
Standard therapy
8.0
A1C (%)
7.5
7.0
6.5
6.0
0
Intensive therapy
0
1
2
3
4
5
6
Time (years)
ACCORD Study Group. N Engl J Med. 2008;358:2545-59.
Which patients will benefit
of strict glycaemic control?
Hazard Ratios for the Primary outcome
Post-hoc analyses ACCORD
Mortality in relation to
treatment and HbA1c
Risk of death over a range of HbA1c
Steady increase of risk from 6 to 9% HbA1c with intensive strategy
Excess risk with intensive strategy vs standard occured above HbA1c 7%
Riddle MC et al. Diabetes Care 2010; 33: 983-90.
Excess risk with intensive strategy vs standard occured
when intensive participants failed to reduce HbA1c in yr 1
Riddle MC et al. Diabetes Care 2010; 33: 983-90.
Number of participants with
severe hypoglycemia
Requiring any assistance
Intensive
Standard
N (%)
N (%)
P
830 (16.2)
261 (5.1) <0.001
Requiring medical assistance 538 (10.5)
179 (3.5) <0.001
Severe hypoglycaemia in
ACCORD study
• 5 death of the excess of 57 death in the
intensive arm could be explain by
hypoglycaemia
• Thus the increase risk of death in the
intensive arm can not be explained by
hypoglycaemia
Miller ME et al. BMJ 2010
Compared with Standard Therapy
the Intensive Strategy had:
• Lower HbA1c
• Greater use of medications:
- more multiple OAD: 70 % vs 45 % on 3-5 oral classes
- more insulin: 77 % vs. 55 % on insulin
- more combination OAD and insulin: 62 % vs. 18 % on 3-5
OAD + insulin
• More severe hypoglycemia 10.5 % vs. 3.5 %
• More weight gain 28 % vs. 14 % > 10 kg
Possible Reasons for increased Mortality
with Intensive Treatment in ACCORD
•
•
•
•
Hypoglycemia
Rapid glucose lowering
Weight gain
Medication interactions, ”treatment
resistance”
ADVANCE
ADVANCE: Treatment
effect on glucose control
10.0
9.0
8.0
Mean
A1C (%)
Standard control
7.0
P < 0.001
6.0
Intensive control
5.0
0.0
0
6
12 18 24 30 36 42 48 54 60 66
Follow-up (months)
ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-72.
VADT
HbA1c-VADT
Intensive Glucose-Lowering Therapy Reduces Cardiovascular
Disease Events in Veterans Affairs Diabetes Trial Participants
With Lower Calcified Coronary Atherosclerosis
Reaven PD et al. Diabetes 2009; 58: 2642-48
Intensive Glucose-Lowering Therapy Reduces
Cardiovascular Disease Events in Veterans Affairs
Diabetes Trial Participants With Lower Calcified
Coronary Atherosclerosis
Reaven PD et al. Diabetes 2009; 58: 2642-48
VADT-Predictors of CV death
HR
•
•
•
•
•
Prior CV events
Age/10 yr
HDL/10 mg
Baseline HbA1c
Severe hypoglycaemia
3.1
2.1
0.7
1.2
4.0
p=0.0001
p<0.0001
p<0.008
p<0.02
p<0.008
VADT conclusions
• Intensive
- CV events slightly reduced (231 vs. 263, ns)
- CV mortality slightly increased (19 vs 15, ns)
• Main predictor of MI was recent severe
hypoglycemic episode
• Early glycaemic control is beneficial
• Late intensive control (eg. > 12-15 years after
diagnosis) produces little extra benefit
• No CV risk attributed to any particular therapy
What is the optimal level of
HbA1c in relation to outcomes
and deaths in type 2 diabetes?
An epidemiological study from UK
Currie CJ et al. Lancet 2010
Hazard ratios for all-cause mortality by HbA1c in people
given oral combination and insulin-based therapies.
Mean follow-up was 4.5 years and 5.2 years.
Insulin
OHA
Age: 59.7-67.9 yr.
Duration: 5.2-5.6 yr.
N = 27965.
Currie CJ et al. Lancet 2010;
Age: 60.3-66.3 yr.
Duration: 6.8-8.2 yr.
N = 20005.
Interpretation
• Low and high mean HbA1c values were
associated with increased all cause
mortality and cardiac events
Final HbA1c conclusion
Glycaemic control and CVD outcomes
• Early intervention and intensive control is
worthwhile if it can be obtained without
high risk of severe hypoglycaemia and
major increase in weight
• After long diabetes duration the effect of
intensive glycaemic control seems to be
minimal and in some groups of patients may
even increase mortality
• However there are still many unanswered
questions, including questions about the
choice of agents
Behandling af hyperglykæmi
Treatments for Type 2 Diabetes
GLP1, Exenatide, Liraglutide
Acarbose
Carbohydrate
-
Sitagliptin, Vildagliptin, Saxagliptin,
Linagliptin
DIGESTIVE ENZYMES
+
Stimulates insulin
secretion
G
G
(I)
G
Metformin
-
I
G
Limited effect on insulin
resistance
I
G
-
G
Insulin
I
Reduces hepatic
glucose output +
I
I
I
G
G
G
Sulphonylurea
Repaglinide
(G)
e
s
luco
I
Glucose
G
Reduces
absorption
DPP-4 hæmmere,
I
G
I
G
-
+
Thiazolidinediones
Reduce Insulin Resistance
The Incretin Effect, GLP-1 and Exenatide
The Incretin Effect Demonstrates
the Response to Oral vs IV Glucose
2.0
11
*
C-peptide (nmol/L)
Venous Plasma Glucose (mmol/L)
Oral Glucose
IV Glucose
5.5
1.5
*
*
*
Incretin Effect
*
1.0
*
*
0.5
0.0
0
01 02
60
120
Time (min)
180
01 02
60
120
Time (min)
Mean ± SE; N = 6; *P ≤.05; 01-02 = glucose infusion time.
Nauck MA, et al. Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses. J Clin
Endocrinol Metab. 1986;63:492-498. Copyright 1986, The Endocrine Society.
180
The Incretin Effect
Is Reduced in Patients With Type 2 Diabetes
Intravenous Glucose
Oral Glucose
Insulin (mU/L)
Control Subjects
Patients With Type 2 Diabetes
80
80
60
60
40
40
*
* * *
*
*
*
*
20
* *
20
0
0
0
30
60
90 120 150 180
0
30
Time (min)
*P ≤.05 compared with respective value after oral load.
Nauck MA, et al. Diabetologia. 1986;29:46-52. Reprinted with permission from Springer-Verlag © 1986.
60
90
120 150 180
Time (min)
GLP-1 effekter i
mennesket
GLP-1 secreted upon
the ingestion of food
Promotes satiety and
reduces appetite
Alpha cells:
↓ Postprandial
glucagon secretion
Beta cells:
Enhances glucosedependent insulin
secretion
Liver:
↓ Glucagon reduces
hepatic glucose output
Stomach:
Helps regulate
gastric emptying
Adapted from Flint A, et al. J Clin Invest. 1998;101:515-520.; Adapted from Larsson H, et al. Acta Physiol Scand. 1997;160:413-422.;
Adapted from Nauck MA, et al. Diabetologia. 1996;39:1546-1553.; Adapted from Drucker DJ. Diabetes. 1998;47:159-169.
Mechanism of Action of DPP-4
inhibition
Ingestion
of food
GI tract
Pancreas
Release of
active incretins
GLP-1 and GIP
DPP-4
inhibitor
X
Inactive
GLP-1
DPP-4
enzyme
Glucose
dependent
Insulin
(GLP-1 and
GIP)
Beta cells
Alpha cells
Blood glucose
in fasting and
postprandial
states
Glucosedependent
Glucagon
(GLP-1)
Inactive
GIP
Glucose
uptake by
peripheral
tissue
Hepatic
glucose
production
• Incretin hormones GLP-1 and GIP are released by the intestine throughout the
day, and their levels increase in response to a meal.
Concentrations of the active intact hormones are increased by DPP-4 inhibition,
thereby increasing and prolonging the actions of these hormones.
Nye behandlinger til Type 2 diabetes
Byetta (Exenatide)
Victoza (Liraglutide)
Synthetic version of salivary protein
found in the Gila monster
Januvia
Janumet
Galvus
Eucreas
Onglyza
Trajenta
Behandling af type 2 diabetes mellitus – anno 2010
Livsstilsintervention (diæt, vægtkontrol og øget fysisk aktivitet)
Metformin (glykæmisk kontrol, reduktion i kardiovaskulær sygdom)
Ingen hypoglylkæmi, ingen vægtstigning
Tillæg af anden (oral) agent (glykæmisk kontrol)
SU
Billig
Hypo
Vægt↑
Betacellen?
Glinid
Hurtig
virkning
Pris
Hypo
Vægt↑
TZD
DPP-4
GLP-1
α-Gluc.
Inhibitor inhibitor analoger
Hypo
CVD↓?
Hypo
Sikkerhed!
Lille effekt
Vægt↑
GI-biv
Pris
Hypo
Vægt↑
Ingen biv.
Beta-celle
effekt?
Pris
Insulin
Hypo
Virker altid
Vægttab
Hypo
CVD/betaVægt↑
celle effekt?
Pris
Kvalme osv.
Pris
Algoritme for behandling af hyperglykæmi ved T2DM
Debut - 1. valg
1
Metformin
Gastrointestinale
gives uanset
bivirkninger
HbA1c.ved Undtagelser:
Metformin kan skyldes for hurtig dosis-øgning
Metformin
1. Metformin tåles ikke2 : gå til 2. valg, hvis behandlingsmål ikke kan opnås ved
Tilføj metformin, når diagnosen
er verificeret og behandlingen stabiliseret
livsstilsændring.
Akutte tilstande med manglende
fødeindtagelse og/eller potentielt
2. Svær hyperglykæmi med symptomer3 og /eller akutte tilstande4: start insulin –
behandling.
Skift til eller suppler med
metformin når tilstanden erbehandles
stabiliseret.
ustabil hæmodynamik og/eller
nyrefunktion:
Hyperglykæmien
3. Nedsat nyrefunktion5:
Absolut kontraindíkation
hvis
eGFR
<
30
ml/min,
med hurtigt virkende insulin
indtil
erSulfonylurinstof
stabil. med kort halveringstid, eller
- Vælg
Insulin, tilstanden
evt. DPP4-hæmmer,
forsigtighed (dosishalvering og regelmæssigpioglitazon
kontrol
afkontrol
nyrefunktion)
ved eGFR 30-60 ml/min.
under
af nyrefunktion.
2. Valg6,7
Tabletbehandling
DPP4Sulfonylurinstof (SU)8
hæmmer9
/repaglinid10
Undgå ved svært
nedsat
nyrefunktion.
Erfaringsgrundlaget ved
langtidsbehandling
er begrænset.
Undgå ved/hos:
øget risiko for hypoglykæmi,
alkoholmisbrug, ældre eneboende,
erhvervschauffører, stilladsarbejdere
, svært nedsat nyrefunktion.
Injektionsbehandling
GLP-111
Insulin
Til udvalgte patienter,
hvor et vægttab er
central i behandlingen.
Erfaringsgrundlaget er
begrænset.
Behandlingen skal
gives subcutant.
Altid behandlingen ved svær
hyperglykæmi og kan bruges som 2. valg
til alle. Behandlingsmålet bør dog
primært søges opnået med anden
behandling ved svær overvægt, øget
risiko for hypoglykæmi, alkoholmisbrug,
ældre eneboende, erhverschauffører,
stilladsarbejdere og lignende.
I særlige tilfælde
Pioglitazon12
Svær insulinresistens
og/eller fedtlever.
Undgå ved:
Hjerteinsufficiens,
Osteoporose,
Svært nedsat
nyrefunktion,
Leverinsufficiens.
Intensiveret behandling6
Insulin
Insulin er det naturlige valg ved behov for intensivering:
1. Fortsæt metformin og tillæg insulin.
2. Intensiver igangværende insulinbehandling.
3. Hos udvalgte patienter kan kombination af insulin + DPP-4
eller GLP-1 + evt. metformin forsøges (specialistopgave) 13.
Ole Snorgaard 2010
Andre kombinationsmuligheder (max. 3 lægemidler,
specialistopgave):
1. Metformin + DPP-4/GLP-1 + Sulfonylurinstof.
2. Metformin + Sulfonylurinstof + pioglitazon.
3. DPP-4/GLP-1 + Sulfonylurinstof + pioglitazon.
4. Acarbose kan indgå i stedet for én af de øvrige i kombinationerne.
Metformin kan kombineres med alle de
øvrige lægemidler.
SU kan kombineres med de øvrige, men på
grund af risikoen for hypoglyæmi kun med
insulin i særlige tilfælde og aldrig med
meglitinid. Hvis GLP-1 tillægges SUbehandling, bør SU dosis halveres indtil
man har overblik over effekten og hvis
HbA1c er < 70 mmol/mol (8,5%).
GLP-1 og DPP4-hæmmer i kombination er
ikke undersøgt.
GLP-1 kan kombineres med glitazon,
mens GLP-1 - insulin kombinationen
undersøges i øjeblikket.
DPP4-hæmmer kan kombineres med
glitazon, mens DPP4 - insulin
kombinationen undersøges i øjeblikket.
Acarbose kan kombineres med alle de
øvrige.
Glitazoner og insulin i kombination
bruges flere steder i udlandet, i
Danmark er det ikke rekommanderet.
Algoritmer for insulinbehandling af
type 2 diabetes
Start på insulinbehandling:
Basal
(langsomvirkende)
insulin 1-2 gange
dagligt
Blandingsinsulin
(langsom- og
hurtigvirkende)
morgen og/eller aften
Intensivering:
Basal/bolus:
Tillæg af
hurtigtvirkende
1-3 gange dagligt
Blandingsinsulin
(langsom- og
hurtigvirkende)
Morgen, middag og aften
Basal/bolus:
Basal 1-2 gange og
hurtigtvirkende
3 gange dagligt
Final conclusion
• New diagnostic criteria
• Rapid growing population
• Glycaemic target should be
individualized based on
–
–
–
–
–
–
diabetes duration
co-morbidities (CVD)
risk of hypoglycemia
risk of weight gain
“risk of” polypharmacia
Age
• New promising drugs on the market