Diabetes type 2

1
Diabetes type 2

• Kortrijk, 6 september 2004

2
Diabetes A Growing Global Crisis
189 million people in 2003 324 million projected
for 2025 72 increase
38.2 44.2 16
81.8 156.1 91
25.0 39.7 59
18.2 35.9 97
13.6 26.9 98
10.4 19.7 88
1.1 1.7 59
Adapted from Zimmet P et al. Diabet Med.
200320693-702.
3
Diabetes pandemie
Wereldwijd 150 000 000 patienten meer dan 50
in India, China en VS Europa 10 000 000
patienten Belgie type 1 35000 type 2 230
000 gediagnosticeerd 450 000 geschat. Men
verwacht tegen 2025 300 miljoen type 2
patienten In Belgie tegen 2010 bijna 600 000 type
2 patienten
4
Estimated Lifetime Risk of Developing Diabetes
in the United States for Those Born in 2000

• Men 33
• Women 39
• Hispanics are at greatest lifetime risk
• Men 45
• Women 53
• When diagnosed at age 40 years
• Men lose 12 life-years and 19 quality-adjusted
  life-years
• Women lose 14 life-years and 22 quality-adjusted
  life-years

Narayan KMV et al. JAMA. 20032901884-1890.
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Diabetes Mellitus in the US Health Impact of
the Disease

6th leading cause of death
Renal failure
Life expectancy 5 to 10 yr

Blindness
Cardiovasculardisease 2X to 4X
Diabetes
Nerve damage in 60 to 70 of patients
Amputation
Diabetes is the no. 1 cause of renal failure,
new cases of blindness, and nontraumatic
amputations
Diabetes Statistics. October 1995 (updated 1997).
NIDDK publication NIH 96-3926. Harris MI. In
Diabetes in America. 2nd ed. 19951-13.
7
Impact of Type 2 Diabetes

• Lifestyle implications
• heart disease, kidney failure, blindness and foot
  ulceration
• Increased risk of mortality
• risk of death more than doubled
• Heavy burden on healthcare resources
• approximately 8 of total healthcare budgets in
  the developed world

Balkau, 1999 WHO, 1998
8
What about Belgium ?

• Bron IMS Health CODE 2 in BIGE N28 maart 2000
• 3000 Euro per patiënt / jaar
• totaal 1 miljard Euro per jaar
• 6,7 van het totale gezondheidsbudget

9
Most of the costs of diabetes are related to
hospitalization
Oral anti-diabetic drugs 27
Ambulatory 18
Hospitalizations 55
Other drugs 2025
10
Socio-economische impact
Kostprijs ( The Economic Impact of the Diabetic
Foot, Van Acker K )
11
Increased HbA1c and SBP Are Associated With
Increased Morbidity and Mortality
Microvascular end points1,2
Myocardial infarction1,2
50
70
60
HbA1c
HbA1c
40
50
SBP
30
40
Incidence (per 1000 PY)
30
20
SBP
20
10
10
0
0
HbA1c () SBP (mm Hg)
HbA1c () SBP (mm Hg)

• SBPsystolic blood pressure PYperson-year.
• Stratton IM et al. BMJ. 2000321405-412.
• Adler AI et al. BMJ. 2000321412-419.

12
Lessons from UKPDSBetter control means fewer
complications
EVERY 1 reduction in HBA1C
REDUCED RISK
-21
1
Deaths from diabetes
-14
Heart attacks
-37
Microvascular complications
-43
Peripheral vascular disorders
plt0.0001
UKPDS 35. BMJ 2000 321 405-12
13
ADA criteria voor diagnose diabetes mellitus
(1997)
14
Casus 1

• Man, 45 jaar, roker
• VG appendectomie, AHT R/Amlor 5 mg
• Familiale voorgeschiedenis
• moeder DM2
• vader overleden na AMI
• Klinisch onderzoek
• BMI 32
• Bloeddruk 145/85
• Abd omtrek 105 cm
• Nu jaarlijks routine labo

• Wat doen ????
• Therapeutische richtlijnen

15
Casus 1

• Labo
• Glucose N 120 mg/dl
• HbA1c 6.2
• chol 220 mg/dl
• TG 250 mg/dl
• LDL chol 145 mg/dl
• HDL chol 42 mg/dl
• Insuline 24 mU/L

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Casus 1

• Labo
• Glucose N 120 mg/dl
• HbA1c 6.2
• chol 220 mg/dl
• TG 250 mg/dl
• LDL chol 145 mg/dl
• HDL chol 42 mg/dl
• Insuline 24 mU/L

• Diagnose
• IFG
• Metabool syndroom
• abd. Omtrek
• Ins. Resistentie
• Dyslipidemia
• AHT
• M.O. familiaal

17
Casus 1

• Therapie
• 1. Risicofactoren
• roken
• gewicht
• beweging 3 X30
• BD
• familie ?

18
Casus 1

• Therapie
• 1. Risicofactoren
• roken
• gewicht
• beweging 3 X30
• BD
• familie ?

• Andere vragen ?
• Diabetes dieet ?
• Statine ?
• Aspirine ?
• Metformine ?
• Glucometer ?
• CONTINUUM RISICOFACTOREN

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What is Type 2 diabetes?
A progressive metabolic disorder characterised by
Type 2 diabetes
Insulin resistance
?-cell dysfunction
Adapted from Beck-Nielson H et al. J Clin Invest
19949417141721 and Saltiel AR, Olefsky JM.
Diabetes 19964516611669
21
Insulin Resistance and the development of Type 2
diabetes
Insulin resistance
Glucose
Evolution
Insulin production
Time
IGT
Overt diabetes
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The Insulin Resistance Syndrome

• Type 2 diabetes or impaired glucose tolerance
• Obesity
• Dyslipidaemia
• Blood pressure
• Insulin resistance
• Hyperinsulinaemia (initially)
• Atherosclerosis

DeFronzo, Ferrannini. Diabetes Care 1991 14 (3)
173-94
23
Conditions Associated With Insulin Resistance
Adapted from DeFronzo. Diabetes Care 1991 14(3)
173-94.
24
NCEP Clinical Identification of the Metabolic
Syndrome
Risk Factor Defining Level Abdominal
obesity Waist circumference Men gt102 cm (gt40
in) Women gt88 cm (gt35 in) TG ?150 mg/dL HDL-C
Men lt40 mg/dL Women lt50 mg/dL BP ?130/?85 mm
Hg Fasting glucose ?110 mg/dL
The metabolic syndrome comprises ?3 risk factors.
Expert Panel on Detection, Evaluation, and
Treatment of High Blood Cholesterol in Adults.
JAMA. 20012852486-2497.
25
Dr. DeFronzo (Berlin 2004)
Other definition 1. Fasting plasma insulin gt
of 21 or BMI gt of 28.9 kg/m² 2.
Fasting plasma insulin gt of 16 and BMI gt 27.5
26
Prevalence of Complications at Time of Diagnosis
United Kingdom Prospective Diabetes Study (UKPDS)
Complication Any complication Retinopathy Abnorma
l ECG Absent foot pulses (? 2) and/or ischemic
feet Impaired reflexes and/or decreased vibration
sense Myocardial infarction/angina/claudication St
roke/transient ischemic attack
Prevalence () 50 21 18 14 7 2-3 1
Some patients had more than 1 complication at
diagnosis
Adapted from UKPDS VIII. Diabetologia 1991 34
877-890.
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Strategie

1. Preventie van diabetes type 2
2. Vroege argwaan en vroege behandeling (ICEBERG
   theorie)
3. Belang van totale behandeling van de patient dwz.
   Alle risicofactoren 11 2
4. Rationele behandeling
5. Op die manier verbetering van cardiovasculaire
   prognose en microvasculaire complicaties

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Double jeopardy type 2 diabetes and
hypertension and cardiovascular risk
250
No diabetes
Diabetes
200
150
CVD death rate (per 10,000 person-year)
100
50
0
lt 120
120139
140159
160179
180199
? 200
Systolic blood pressure (mmHg)
29
Goals
HbA1c lager dan 6.5 Bloeddruk lager dan 130/80
mm Hg Lipiden LDL cholesterol onder de 100
mg/dl HDL cholesterol hoger dan 40/50 (vrouwen)
mg/dl triglyceriden lager dan 150 mg/dl Aspirine
(bij alle patienten ouder dan 40 jaar) BMI lt 25
kg/m² ROOKSTOP !!!! LICHAAMSBEWEGING!!!!DIEET!!!!
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Basic Steps in the Management of Type 2 Diabetes
insulin
oral plus insulin
oral combination
oral monotherapy
diet exercise
32
Treatments for Type 2 Diabetes
33
Reducing insulin resistance may be the key to
controlling type 2 diabetes and its
cardiovascular complications
DeFronzo, Ferrannini. Diabetes Care 1991 14 (3)
173-94
34
Oral Anti-diabetic Drugs Differ by Mode of
Action and Results
Class Main Actions Typical HbA1c Reduction,
Insulin secretagogues (sulphonylureas, glitinides) Potentiate insulin secretion 1.0-2.0
Biguanides (metformin) Inhibit hepatic glucose production 1.0-2.0
Thiazolidinediones Enhance insulin action at liver, fat, and muscle 0.5-1.0
?-Glucosidase inhibitors Delay GI absorption of carbohydrates 0.5-1.0
GIgastrointestinal. Adapted from Nathan DM. N
Engl J Med. 20023471342-1349.
35
Orale antidiabetica
Insulin-augmenting agents Insulin-assisting
agents Sulfonylurea Biguanides
(Metformin) Glinides
Alpha-glucosidase inhibitoren
Thiazolidinediones
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Biguaniden
Docmetformi (Docpharma) 500-850 mg Glucophage
(Merck) 500-850 mg Merck-metformine (Merck)
500-850 mg Metformax (Menarini) 850 mg
deelbaar !! Metformiphar (Unicophar) Actiemechan
isme verhogen gevoeligheid lever en perifere
weefsels verhogen van GLUT 4
transporters inhibitie gluconeogenese verhogin
g glycogeen synthese
38
Biguaniden
Andere effecten verlagen LDL, TG en
FFA Gewichtsverlies Dosis zo maximaal
mogelijk tot max. 3 maal 850 mg Nevenwerking
1. GI 2. Lactaaintolerantie 3. CI lever
en nierfalen (creat gt1.4 bij vr en bij man gt
1.5), 4. 5.5 is intolerant M.O.- Bij
nevenwerkingen terug naar vorige dosis en na 2
weken opnieuw pogen op te drijven - Bij
contraststof onderzoek of operatie pas opnieuw
starten als 2 dagen normale nierfunctie
39
Thiazolidinediones wie en wat?

• Produkten
• Troglitazone ( Rezulin ) Parke Davis (uit de
  handel genomen omwille van hepatotoxiciteit )
• Pioglitazone ( Actos ) Eli Lilly 15-30 mg
• Rosiglitazone ( Avandia ) GSK 4-8 mg
• werken in op de insulineresistentie PLEIOTROOP
  effect
• insuline sensitizer thv lever, vetcel en spier
• minder circulerend insuline
• geen hypos
• bewaren van de pancreatische insulinesecretie

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Thiazolidinediones PPAR ? agonisten
(PPAR) Peroxisome Proliferator Activator
Receptoren zijn Nucleaire Receptoren
(proteine)
Verbetert expressie translocatie
GLUT4 differentiatie van adipocyten
opname FFAs en lipogenese Vermindert
productie TNF? aanmaak leptine productie
resistine
Retinoid X receptor
AVANDIA
DNA
PPre
Nucleair receptor ppar ?
PPAR response elements gene expression
41
PPAR? Primary DownstreamTissue-Specific
Effects
Kidneys
Desvergne B, Wahli W. Endocrine Reviews
199920(5)649-688. Rosen ED, Spiegelman BM. J
Biol Chem 2001276(41)37731-37734. Kelly D.
Circ Res 200189935-937. Benson S, et al. AJH
20001374-82. Guan YF, Breyer MD. Kidney Intl
20016014-30. Buchan KW, Hassal DG. PPAR
agonists as direct modulators of the vessel wall
in cardiovascular disease. WileySons, 2000, pp.
350-366.
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Nevenwerkingen Klasse effect

• 1. Oedeem
• dubbel blind tr(mono, comb metf.) bij patienten
  onder Avandia
• 4 tot 5 oedeem
• metformine 2,2 , placebo 1,3
• dubbel blind bij patienten onder Actos
• 4,8 ( mono) vs 1,2 placebo
• comb met Insuline (15,3 vs 7 )
• mild oedeem, goed beantwoordend aan diuretica
• bij ernstig oedeem stop TZD

43
Nevenwerkingen Klasse effect

• 2. Hemoglobine
• troglitazone 5 lager dan normale waarde
• Rosiglitazone - 1 g/dl
• pioglitazone - 1 g/dl
• 3. Gewichtstoename
• door vocht retentie en meer subcut vet
• hoge dosis gewichtstoename tot 3 kg/jaar
• 4. Lipiden

44
Nevenwerkingen Unieke effecten

• 1. Hepatotoxiciteit
• troglitazone
• 48 leverfalen 28 doden en 15
  levertransplantatie
• achteraf gezien bleek dat ook in vitro
  troglitazone hepatotoxisch was voor levercellen
• conc troglit 15 tot 20 X hoger in lever dan in
  plasma
• rosiglitazone
• 100 X potenter dan Trog en 10 X meer dan pio
• kort T1/2 ( 4 h ) ( trog 16-34 h)
• accumuleert niet in de lever
• Advies monitoren ALT na 2 maanden R

45
Nevenwerkingen Unieke effecten

• 2. Myalgie
• pioglitazones (33/606) 5,4 -2,7 placebo
• 3. Rosiglitazone
• minder potentie tot drug interactie

46
Insulin augmenting agents SU

• Short acting (administration before meals)
• 
  Diamicron-Glurenorm
• Long acting (once daily) Amarylle,
  Uni-Diamicron
• Reason for choice short/long compliance of
  patient
• When failing of insulin secretion- high glucose
  , adding to metformin, intolerance of
  metformin

47
Characteristics of commonly used sulfonylurea
Generic name Brand name Posology
Duration of action Excretion (h)
(Tolbutamide) Rastinon (Tolazamide) Tolinase
(Chlorpropamide)Diabinese 125-250mg/d 60 Renal G
libenclamide Daonil 5 2.5-15mg/d 60 Renal Eugl
ucon 5/Bevoren 5 Glipizide Glibenese
5 2.5-20mg/d lt 24 Renal 80 Minidiab
5 Gliquidone Glurenorm 30 30-90mg/d 7 Hepatic
95 Gliclazide Diamicron 80 Merck
Gliclazide 40-160mg/d lt 24 Renal
70 Glimepiride Amarylle 2/3/4 1-8mg/d 24 Renal
60
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Long acting SUs
Amarylle (Aventis) glimepiride 1-8
mg/dag werkt 24 uur 60 renale excretie Uni
Diamicron (Servier) 30 mg dagelijks 1 tot 4
co in 1 orale inname duur 12 uur switch 1
tablet 80 mg DM 1 co UniDiamicron
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Casus 2

• Zelfde man
• Nu klacht van droge mond

• Labo
• glycemie N 240 mg/dl
• hbA1c 8
• chol 220 mg/dl
• LDL 140 mg/dl
• HDL chol 42 mg/dl
• Trig 480 mg/dl
• Insuline 34 mU/L
• Wat ?

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Casus 2

• Diagnose
• diabetes
• Type ? D/C peptide, GAD as
• Therapie
• Diabetes dieet
• Beweging
• Gewicht
• Rookstop
• Aspirine
• TG ?

• SUR/Met/TZD/ins ?
• Hoeveel ?
• Glucometer ?
• Dagprofielen !!!!
• Wanneer controle ?
• Verder
• AS ?
• urine
• oftalmologie

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Casus 3

• Man 54 jaar
• Familiale VG
• CABG vader
• DM 2 moeder
• Med Vg
• DM 2
• R/ 2 co Diamicron
• HP
• AMI
• HbA1c 7.8

• Insuline ?

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Insulinetherapie ?????
--.- is the mean HbA1c of patients with type 2
being started on insulin -- of patients with
type 2 diabetes treated with SU need insulin by 6
years of follow up -- of patients with type 2
diabetes treated with SU need insulin by 9 years
of follow up
53
Insulinetherapie ????
10.4 is the mean HbA1c of patients with type 2
being started on insulin -- of patients with
type 2 diabetes treated with SU need insulin by 6
years of follow up -- of patients with type 2
diabetes treated with SU need insulin by 9 years
of follow up
54
Insulinetherapie ?????
10.4 is the mean HbA1c of patients with type 2
being started on insulin 53 of patients with
type 2 diabetes treated with SU need insulin by 6
years of follow up -- of patients with type 2
diabetes treated with SU need insulin by 9 years
of follow up
55
Insulinetherapie ????
10.4 is the mean HbA1c of patients with type 2
being started on insulin 53 of patients with
type 2 diabetes treated with SU need insulin by 6
years of follow up 80 of patients with type 2
diabetes treated with SU need insulin by 9 years
of follow up
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BARRIERS TO INSULIN THERAPYReassurance About
Theoretical Concerns
Insulin therapy in Type 2 DM Improves Insulin
Sensitivity by Reducing Glucotoxicity Probably
Reduces Cardiovascular Risk Causes Modest Weight
Gain Rarely Causes Severe Hypoglycemia
57
Hoe insuline starten ?

• Verder orale aan dezelfde dosis
• Start 1 injectie insuline 10 U (bedtime)
• NPH (bedtime)
• Glargine (bedtime or with evening meal) in case
  of hypo
• Titreer de dosis wekelijks op basis van de
  nuchtere glycemie Increase 8 U if FPG gt 180
  mg/dL
• Increase 6 U if FPG 140-180
• Increase 4 U if FPG 120-140
• Treat to target (use FPG lt120mg/dl)
• Verminder de dosis van de orale als hypos overdag

Easiest way to start insulin
58
Initiating Basal Insulin TherapyTreat-to-Target
Trial Tactics

• Continue oral agent(s) at same dosage
• Add single daily insulin dose (10 IU)
• Glargine (morning, with evening meal, or at
  bedtime)
• NPH (bedtime)
• Titrate dose weekly according to fasting SMPG
• Increase by 8 IU if FPG gt180 mg/dL (gt10 mmol/L)
• Increase by 6 IU if FPG 140-180 mg/dL (7.8-10
  mmol/L)
• Increase by 4 IU if FPG 120-140 mg/dL (6.7-7.8
  mmol/L)
• Increase by 2 IU if FPG ?120 mg/dL (?6.7 mmol/L)
• Treat-to-target usually FPG ?100 mg/dL (?5.6
  mmol/L), unless hypoglycaemia prevents further
  titration
• Reduce insulin dosage (2-4 IU/d per adjustment)
  if serious hypoglycaemia occurs

Please see full prescribing information for
insulin glargine (rDNA origin) injection. Please
see full prescribing information for NPH human
insulin (rDNA origin) isophane suspension. NPHneu
tral protamine Hagedorn SMPGself-monitored
plasma glucose FPGfasting plasma
glucose. Riddle MC et al. Diabetes Care.
2003263080-3086.
59
En verder ???

• Op basis van de streefwaarden naar 2 of 4
  injecties ..
• als HbA1c 7 (6.5 ) niet wordt behaald.
• Op moment van 2 injecties best stop SUR

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Insulinetherapie onmiddellijk superieur in
volgende gevallen

• Heel hoge HbA1c met onmiddellijk complicaties
  (micro en macrovasculair bij diagnose) best
  onmiddellijk insuline
• (potentieel) Zwangere vrouwen
• Operaties gepland
• Patient wil zelf insuline
• Heel ernstig risicoprofiel

61
Treatment Milestones in Diabetes
1950s
2000
1960
1922
Late1970s
1946
1952
1975
1993
1996
1998
Insulin glargine
NPH insulin
HbA1ctesting
DCCT
Biguanides
Insulin pump
Insulintherapy
Sulphonylureatherapy
UKPDS
Blood glucose self-monitoring
Lente insulin therapy
Rapid-acting insulin analogues
NPHneutral protamine Hagedorn DCCTDiabetes
Control and Complications Trial UKPDSUnited
Kingdom Prospective Diabetes Study. Data from
Tattersall RB. In Pickup JC, Williams G, eds.
Textbook of Diabetes. 3rd ed. Boston, Mass
Blackwell Science 2003. US FDA Center for Drug
Evaluation and Research. Available at
http//www.fda.gov/cder/da/ddpa696.htm. Accessed
18 March 2003. Lantus Consumer Information.
Available at http//www.fda.gov/cder/consumerinfo
/druginfo/lantus.htm. Accessed 18 March 2003.
62
Insulin excursions in a non-diabetic
70
Normal free insulin levels (Mean) Meals
60
50
40
Insulin (mU/l)
30
20
10
0
Time of day
Dinner
Breakfast
Lunch
Adapted from Polonsky et al. 1988
63
Insuline excursies bij vier injecties
70
Normal free insulin levels (Mean) Meals
60
50
40
Insulin (mU/l)
30
20
10
0
Time of day
Dinner
Breakfast
Lunch
Adapted from Polonsky et al. 1988
64
Limitations of todays soluble human insulin

• Inability of s.c. injected soluble insulin to
  mimic the physiological pattern of endogenous
  insulin secretion observed in non-diabetic
  subjects after meals
• Delayed onset of action (30-60 min after
  injection) i.e. should be injected 30-60 min
  prior to a meal
• Prolonged duration of action (6-8 hrs after
  injection)
• The higher the dose - the longer the duration of
  action
• Absorption and duration of action dependent on
  injection site

65
Insulin Analogues
Human Insulin Dimers and hexamers in solution
A-chain
B-chain
Aspart1 Limited self-aggregation Monomers in
solution
Asp
Lispro2 Limited self-aggregation Monomers in
solution
Lys Pro
Glargine3 Soluble at low pH Forms
microprecipitates at neutral (subcutaneous) pH,
slow glargine release
Gly
Arg Arg

1. Novolog package insert. Bagsvaerd, Denmark
   Novo Nordisk Pharmaceuticals, Inc 2004.
2. Humalog package insert. Indianapolis, Ind Eli
   Lilly and Company 2002.
3. Lantus package insert. Frankfurt, Germany
   Aventis Pharma Deutschland GmbH 2003.

66
Action Profiles of Insulin Analogues
Aspart, lispro, glulisine, 2-5 h
Regular, 6-8 h
NPH, 13-16 h
Ultralente, 18-24 h
Glargine, 24 h
Plasma insulin level
2
4
6
8
10
12
14
16
18
20
22
24
0
Time (h)
NPHneutral protamine Hagedorn.
67
NPH insulin shows high within-subject variability
(GIR profiles in 3 patients with type 1 diabetes)
Dose at each injection NPH insulin 0.4U/kg, tigh
Data from study1450 (T. Heise et al. Diabetes
2003 52 ( Suppl.1) A121)
68
Current insulin preparations and
theirpharmacokinetics following s.c. injection
Glargine
1-2 hours
peakless
gt24 hours
Adapted from Burge and Schade. 1997
69
Structure of insulin detemir
70
Terugbetalingscriteria Lantus

• TERUGBETALING VOOR 1 JAAR
• Patient behoort tot groep 1 of 2 van diabetes
  conventie
• Patient met type 2 onder combinatie met orale OAD
  en 1 injectie Insuline EN 1 van de 2 volgende
  voorwaarden
• . HbA1c gt 7.5 onder combinatie van OAD en 1
  injectie NPH, ULtratard, Humuline Long of
  Menginsulines
• . Ernstig hypoglycemie (nood aan hulp van derden)
  onder combinatie van OAD met 1 maal per dag NPH,
  Ultratard HM, Humuline long, Menginsulines
• VERLENGING VOOR 12 MAANDEN
• 1. conventiepatient groep 1 of 2
• 2. 1 injectie Lantus en OAD en HbA1c lt 7 op
  een test die de laatste 3 maanden is uitgevoerd
  (Bewijzen)

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