Behandling af gamle med diabetes

herunder

Nye diagnostiske kriterier, prævalens, prognose, behandlingsmål ogbehandlingsguidelines

Jan Erik HenriksenLedende overlæge, klinisk lektor, PhD

Endokrinologisk afd. M

Odense Universitet Hospital

Diagnosen Diabetes

1997 diagnosenFPG = 7.8 mM2 timers PG

= 11.1 mM

FPG = 7.0 mM

2 timers OGTT11.1 mM

2009 diagnosen !Vurdering af HbA1c som diagnostisk værktøj

Hvilken værdi ?

Ca 28.000 personer fra ni forskellige lande

HbA1c < 6.5 % stort ser ingen med retinopati

Begrænsninger!• Omkostninger

• Hæmoglobinopatier

• Hæmolytisk anæmi

• Kronisk malaria

• Efter større blødninger – blodtransfusion

• Hurtigt indsættende diabetes (fx DM1)

• Alder – race ?

Prævalens og prognose

Anders Green

Model for udvikling af diabetes i DK

Ultimo år

Antal patienter

700,000

270.98537.12461.15077.13547.65527.68812.0664.7362.830601I alt

138.83413.90731.10844.13726.99013.7835.0942.1171.401297Mænd

132.15123.21730.04232.99820.66513.9056.9722.6191.429304Kvinder

I alt80+70-7960-6950-5940-4930-39

20-

29

10-

190-9

Antal diabetikere 2009

1,591,701,482009

1,571,631,512008

1,621,691,542007

1,651,711,602006

1,691,771,622005

1,701,801,602004

1,751,831,682003

1,751,881,642002

1,761,821,702001

1,841,921,762000

1,861,981,751999

1,851,901,791998

1,901,961,831997

AlleMændKvinder

Diabetikeres dødelighed set i forhold til den øvrige

befolkning

Relativ dødelighed

Hvor langt skal Hba1c ned?

UKPDS – HbA1c – EndpointsEpidemiology

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

UKPDS10-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 allocatedeither to conventional therapy at their GP or intensive treatment at Steno Diabetes Center

Conventional

Intensive

Endpoint examinations

Microvascular Macrovascular

4 years 8 years

n=80

n=80

n=160

Microvascular Macrovascular

4 years 8 years

Hba1c

Syst BT

Dia BT

Total Kol

LDL

Triglycerid

Kardiovaskulær

sygdom

Død

Steno-2: Number Needed to Treatfor 13 Years to Prevent One ---

Death 5 patients

Cardiovascular death 8 patients

Major cardiovascular event 3 patients

Progression of nephropathy 5 patients

Dialysis 16 patients

Laser treatment 7 patients

ACCORD ADVANCEVADT

de korte ”akutte” studier

Standard vs. intensive BG treatment

ACCORD

Standard: Goal: HbA1c 7 -7.9%

Intensive: Goal: HbA1c <6%

ADVANCE

Standard: SU other than gliclazide MR + anyother anti-diabetic drugs.

Intensive: Gliclazide MR + any other anti-diabetic

drugs Goal: HbA1c <6.5%

VADT

Standard: Goal: HbA1c 8%-9%

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

ACCORD Study Group. N Engl J Med. 2008;358:2545-59.

A1C (%)

Time (years)

Standard therapy

Intensive therapy

6

9.0

8.5

8.0

7.5

7.0

6.5

6.0

00 1 2 3 4 5

Which patients will benefit of strict glycaemic control?

Hazard Ratios for the Primary outcomePost-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 occuredwhen intensive participants failed to reduce HbA1c in yr 1

Riddle MC et al. Diabetes Care 2010; 33: 983-90.

Number of participants withsevere hypoglycemia

Intensive Standard P

N (%) N (%)

Requiring any assistance 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 Therapythe 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, ”treatmentresistance”

ADVANCE

ADVANCE: Treatment effect on glucose control

ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-72.

Follow-up (months)

Mean A1C (%)

Standard control

Intensive control

10.0

9.0

8.0

7.0

6.0

5.0

0.00 6 12 18 24 30 36 42 48 54 60 66

P < 0.001

VADT

HbA1c-VADT

Intensive Glucose-Lowering Therapy Reduces CardiovascularDisease 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 ReducesCardiovascular Disease Events in Veterans AffairsDiabetes 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 3.1 p=0.0001

• Age/10 yr 2.1 p<0.0001

• HDL/10 mg 0.7 p<0.008

• Baseline HbA1c 1.2 p<0.02

• Severe hypoglycaemia 4.0 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 peoplegiven oral combination and insulin-based therapies.

Mean follow-up was 4.5 years and 5.2 years.

Currie CJ et al. Lancet 2010;

Age: 59.7-67.9 yr.

Duration: 5.2-5.6 yr.

Age: 60.3-66.3 yr.

Duration: 6.8-8.2 yr.

N = 27965. N = 20005.

OHA Insulin

Interpretation

• Low and high mean HbA1c values were associated with increased all cause mortality and cardiac events

Final HbA1c conclusionGlycaemic 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

Glucose (G)

Carbohydrate

Glucose

DIGESTIVE ENZYMES

Insulin(I)

I

AcarboseReduces absorption --

SulphonylureaRepaglinide

Stimulates insulin secretion

++

MetforminReduces hepaticglucose output +

Limited effect on insulin resistance

--Thiazolidinediones

Reduce Insulin Resistance

-- ++--

I

I

II

I

I

I

G

G

G

G

G

G

G

G

IG

GG

GLP1, Exenatide, Liraglutide

DPP-4 hæmmere,

Sitagliptin, Vildagliptin, Saxagliptin, Linagliptin

The Incretin Effect, GLP-1 and Exenatide

The Incretin Effect Demonstrates the Response to Oral vs IV Glucose

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.

Ve

no

us

Pla

sm

a G

luc

os

e (

mm

ol/

L)

Time (min)

C-p

ep

tid

e (

nm

ol/

L)

11

5.5

0

01 60 120 180 01 60 120 180

0.0

0.5

1.0

1.5

2.0

Time (min)02

02

Incretin Effect

Oral Glucose

IV Glucose

**

*

*

**

*

The Incretin Effect Is Reduced in Patients With Type 2 Diabetes

0

20

40

60

80

Ins

uli

n (

mU

/L)

0 30 60 90 120 150 180

Time (min)

** *

** **

0

20

40

60

80

0 30 60 90 120 150 180

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.

Patients With Type 2 DiabetesControl Subjects

Intravenous GlucoseOral Glucose

GLP-1 effekter i mennesket

Promotes satiety and reduces appetite

Beta cells:Enhances glucose-dependent insulin

secretion

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.

Liver:↓ Glucagon reduces

hepatic glucose output

Alpha cells:↓ Postprandial

glucagon secretion

Stomach:Helps regulate

gastric emptying

GLP-1 secreted upon

the ingestion of food

Mechanism of Action of DPP-4 inhibition

Release ofactive incretinsGLP-1 and GIP ���� Blood glucose

in fasting and postprandial

states

Ingestion of food

���� Glucagon(GLP-1)

���� Hepatic glucose

production

GI tract

DPP-4 enzyme

InactiveGLP-1

XDPP-4

inhibitor

• Incretin hormones GLP-1 and GIP are released by the intestine throughout the

day, and their levels increase in response to a meal.

���� Insulin(GLP-1 and

GIP)

Glucose-dependent

Glucose dependent

Pancreas

InactiveGIP

Concentrations of the active intact hormones are increased by DPP-4 inhibition, thereby increasing and prolonging the actions of these hormones.

Beta cells

Alpha cells

���� Glucose uptake by peripheral

tissue

Byetta (Exenatide)Victoza (Liraglutide)

Synthetic version of salivary protein found in the Gila monster

JanuviaJanumetGalvusEucreasOnglyzaTrajenta

Nye behandlinger til Type 2 diabetes

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↑

Beta-cellen?

TZD

Hypo

Sikkerhed!

Vægt↑

Pris

αααα-Gluc. Inhibitor

CVD↓?Hypo

Lille effektGI-biv

Glinid

Hurtig virkning

Pris

Hypo

Vægt↑

GLP-1 analoger

Hypo

Vægttab

CVD/beta-celle effekt?

Kvalme osv.

Pris

DPP-4 inhibitor

Hypo

Vægt↑

Ingen biv.

Beta-celleeffekt?

Pris

Insulin

Virker altid

Hypo

Vægt↑

Pris

Behandling af type 2 diabetes mellitus – anno 2010

Ole Snorgaard 2010

Algoritme for behandling af hyperglykæmi ved T2DM

Metformin1 Undtagelser:

1. Metformin tåles ikke2 : gå til 2. valg, hvis behandlingsmål ikke kan opnås ved

livsstilsændring.

2. Svær hyperglykæmi med symptomer3 og /eller akutte tilstande4: start insulin –

behandling. Skift til eller suppler med metformin når tilstanden er stabiliseret.

3. Nedsat nyrefunktion5:

- Vælg Insulin, evt. DPP4-hæmmer, Sulfonylurinstof med kort halveringstid, eller

pioglitazon under kontrol af nyrefunktion.

Debut - 1. valg

2. Valg6,7

Intensiveret behandling6

Sulfonylurinstof (SU)8

/repaglinid10

Undgå ved/hos:

øget risiko for hypoglykæmi,

alkoholmisbrug, ældre eneboende,erhvervschauffører, stilladsarbejdere

, svært nedsat nyrefunktion.

InsulinAltid 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.

DPP4-

hæmmer9

Undgå ved svært

nedsat

nyrefunktion.

Erfaringsgrund-

laget ved

langtidsbehandling

er begrænset.

Pioglitazon12

Svær insulinresistens

og/eller fedtlever.

Undgå ved:

Hjerteinsufficiens,

Osteoporose,

Svært nedsat

nyrefunktion,

Leverinsufficiens.

GLP-111

Til udvalgte patienter,

hvor et vægttab er

central i behandlingen.

Erfaringsgrundlaget er

begrænset.

Behandlingen skal

gives subcutant.

InsulinInsulin 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.

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.

Tabletbehandling Injektionsbehandling I særlige tilfælde

Metformin gives uanset HbA1c.Gastrointestinale bivirkninger ved Metformin kan skyldes for hurtig dosis-øgningTilføj metformin, når diagnosen er verificeret og behandlingen stabiliseretAkutte tilstande med manglende fødeindtagelse og/eller potentielt ustabil hæmodynamik og/eller nyrefunktion: Hyperglykæmien behandles med hurtigt virkende insulin indtil tilstanden er stabil.Absolut kontraindíkation hvis eGFR < 30 ml/min,

forsigtighed (dosishalvering og regelmæssig kontrol af nyrefunktion) ved eGFR 30-60 ml/min.

Metformin kan kombineres med alle de øvrige lægemidler.

SU kan kombineres med de øvrige, men pågrund af risikoen for hypoglyæmi kun med insulin i særlige tilfælde og aldrig med meglitinid. Hvis GLP-1 tillægges SU-behandling, 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

Basal (langsomvirkende) insulin 1-2 gange dagligt

Blandingsinsulin (langsom- og hurtigvirkende) morgen og/eller aften

Start på insulinbehandling:

Basal/bolus:Tillæg af hurtigtvirkende 1-3 gange dagligt

Intensivering:

Blandingsinsulin(langsom- og hurtigvirkende) Morgen, middag og aften

Basal/bolus:Basal 1-2 gange og hurtigtvirkende 3 gange dagligt

Final conclusion

• Glycaemic target should be individualized based on – diabetes duration– co-morbidities (CVD)– risk of hypoglycemia – risk of weight gain – “risk of” polypharmacia– Age

• New diagnostic criteria• Rapid growing population

• New promising drugs on the market