Insulin

1
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
2
The Insulin Resistance Syndrome
Insulin resistance is strongly associated with
certain cardiovascular risk factors, including
hyperinsulinaemia, impaired glucose tolerance,
hypertension, increased serum triglycerides,
decreased HDL-cholesterol and obesity Together,
these metabolic disturbances are referred to as
THE INSULIN RESISTANCE SYNDROME
also known as
Syndrome X
Reavens Syndrome
Metabolic Syndrome
1. Reaven GM. Diabetes 19883715951607 2.
Haffner SM, Miettinen H. Am J Med
1997103152162 3. Campbell IW et al. (eds).
Diabetes Mellitus 1996. Health Press. UK
3
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
4
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.
5
Thiazolidinediones

• Produkten
• Troglitazone ( Rezulin ) Parke Davis (uit de
  handel genomen omwille van hepatotoxiciteit )
• Pioglitazone ( Actos ) Takeda
• Rosiglitazone ( Avandia ) Smith Kline Beecham
• werken in op de insulineresistentie
• insuline sensitizer thv lever, vetcel en spier
• op die manier minder circulerend insuline
• verbetering van enkele andere aspecten van het
  syndroom X
• geen hypos
• effect op het bewaren van de pancreatische
  insulinesecretie
• zowel monotherapie als combinatietherapie
• geen vergelijkende studies tussen de drie

6
Thiazolidinediones Structurally Diverse PPARg
Agonists
Sankyo/Parke-Davis
O
Et
NH
Takeda/Lilly
S
O
N
O
Pioglitazone
Saltiel AR. Diabetes 1996 45 1661-1669.
7
Thiazolidinediones

• 1. Werkingsmechanisme
• 2. Effectiviteit
• 3. Andere effecten
• 4. Nevenwerkingen ( Klasse en unieke effecten )
• 5. Avandia, praktische aspecten

8
1. Werkingsmechanisme

• niet volledig begrepen
• ligand voor PPARgamma subtype of PPAR familie van
  nucleaire receptoren
• transcriptie factor ter regulatie van gen
  expressie
• heeft bindingsplaatsen voor retinoid en tzd
• tzd activeert gen expressie
• proteine producten zorgen voor lipide transport
  en metabolisme en insuline actie
• deze receptoren komen voor in hoge concentratie
  in vetweefsel, in minder concentratie in
  macrofagen en in kleine hoeveelheden in
  spiercellen

9
1. Werkingsmechanisme

• verschillende hypotheses
• primair effect op vetweefsel
• meer differentiatie van subcutaan vetweefsel naar
  kleine vetcellen
• kleine vetcellen verminderen de vrijzetting in de
  circulatie van FFA en TNFalfa( beide inhibitoren
  van insuline actie )
• geen of lichtjes meer apoptose van visceraal vet
• vooral effect op de spier receptoren

10
Thiazolidinediones PPAR ? agonists
(PPAR) Peroxisome Proliferator Activator
Receptors are Nuclear Receptors (protein)
ENHANCES - expression translocation of
GLUT 4 - differentiation of adipocytes
Retinoid X receptor
AVANDIA
DNA
PPre
Nuclear receptor ppar ?
PPAR response elements gene expression
11
Rosiglitazone - PPAR g agonist
12
Insulin is a Critical Co-Factor in the Activation
of PPAR-g by Pioglitazone
Co-Factor INSULIN
Co-activators (SRC-1, PGC-1, etc.)
Co-repressors (SMRT, N-COR, etc.)
Retinoid X Receptor
PPARg
Activation
Suppression
DNA
Target gene transcription
Response Element
Adapted from Kersten S, et al. Nature 2000
405(6785)421-424.
13
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.
14
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15
2. Effectiviteit
16
2. Effectiviteit (monotherapie)
17
2. Effectiviteit (monotherapie)
18
Rosiglitazone compared toglibenclamide after 52
weeks - FPG
RSG 8 mg daily (n203) SU (Glibenclamide) (n189)
Mean Fasting Plasma Glucose (mmol/L)
8.0
7.0
0
0
2
4
6
8
12
16
26
38
52
Treatment Week
(ROSIGLITAZONE/020 - ITT Population)
19
Effect van Pioglitazone 30 mg in
combinatietherapie HbA1c vermindering
0
-0.5
12 Weeks
Change in Mean A1C Over Placebo at Endpoint (
points)

-0.83
16 Weeks
-1
40 Weeks (open-label)

-1.24

-1.30
-1.5

-1.45
-1.70
-2
Sulfonylurea Pio 30 mg
Metformin Pio 30 mg
P?0.05.
Einhorn D, et al. Clin Ther. 2000221395-1409.
Kipnes MS, et al. Am J Med. 200111110-17.
Kaneko T, et al. Jpn J Clin Exper Med.
1997741515-1539. Hanefeld M, et al. Exp Clin
Endocrinol Diabetes. 2000108(suppl 2)S256-S266.
20
2. Effectiviteit ( combinatie met sulfonylurea)
21
2. Effectiviteit (combinatie met metformine)
22
2. Effectiviteit ( combinatie met insuline )
23
3. Andere effecten

• 1. Microalbuminurie
• 2. Bloeddruk

24
Rosiglitazone Reduces Microalbuminuria
25
Avandia Favourably Affects Blood Pressure
Bakris G et al. Diabetes 200049(Suppl 1)A96,Abs
388 and poster
26
4. 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

27
Safety Cardiac Considerations

• Pioglitazone, like other TZDs, can cause fluid
  retention when used alone or in combination with
  other antidiabetic agents
• Fluid retention may lead to or exacerbate heart
  failure
• Patients should be observed for signs and
  symptoms of heart failure, and pioglitazone
  should be discontinued if any deterioration in
  cardiac status occurs
• Pioglitazone has not been tested in patients with
  NYHA class III and IV cardiac status
• In Europe,pioglitazone is contraindicated in
  patients with heart failure or a history of heart
  failure( NYHA class I-IV )

ACTOS (pioglitazone HCl) Package Insert.
28
4. 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

29
Pioglitazone Body Weight Changes in US
Placebo-Controlled Clinical Studies
Mathisen A, et al. Diabetes 200049A117.
30
Weight Gain with Thiazolidinediones

• Weight gain is variable with TZD use. More weight
  gain can be expected when used in combination
  with insulin.
• The least weight gain is seen when TZDs are used
  either as monotherapy or in combination with
  Metformin.
• When used in combination with Sulphonylureas
  weight gain is intermediate
• Weight gain may be ameliorated with caloric
  restriction
• Weight gain usually plateaus in a few months
  after starting therapy or may, in some patients,
  not plateau for as long as 10-12 months

31
Starting Pioglitazone Therapy(continued 2)

• Dealing with potential weight gain
• Weight gain should be explained as expected with
  improved glycemic control, regardless of choice
  of therapybut some more than others
• Diet control will help minimize weight gain
• The least weight gain can be expected when used
  in monotherapy or with metforminthe most with
  insulin
• Rapid excessive weight gain may require stopping
  therapy

ACTOS ? / Avandia EU Prescribing Information
2000.
32
Effect of Pioglitazone onBody Fat Distribution
Before Pioglitazone
0.75
After Pioglitazone 45 mg / 4 months
34244
350
0.70
30044
0.65
300
0.590.08
0.60
0.55
250
Visceral Fat/ Subcutaneous Fat Ratio
Fat Area (cm²)
0.50
0.440.06
200
0.45
0.40
14413
150
13116
0.35
0.30
100
Subcutaneous Visceral Fat Ratio Fat Area
plt0.01 plt0.05
Miyazaki Y, et al. Diabetes 200049(suppl)A299.
33

• Dealing with potential edema
• Edema may occur in a minority of patients
• The lowest incidence of edema was seen with
  pioglitazone as monotherapy
• The highest incidence was seen when pioglitazone
  used in combination with insulin
• Most cases of edema are mild
• If edema or fluid retention is rapidly
  progressive, clinical intervention or stopping
  the medication may be indicated
• Edema and fluid retention can occur early in
  therapyeven before the normal 8 week return
  therefore patients should be advised to call if
  edema becomes a problem

ACTOS ? / Avandia EU Prescribing Information
2000.
34
Effect van Pioglitazone op diabetische
dyslipidemie

• Vermindert
• De triglyceriden
• De vrije vetzuren ( nuchter en post-prandiaal )
• De atherogene plasma-index
• Verhoogt
• Maat van de LDL-partikels
• HDL-Cholesterol

35
Pioglitazone metformine lipidenprofiel aan
het einde van de studie
15


11.9
10.2

8.5
10
7.7

4.1
5
Changefrombaselineat 16 weeks()
1.5
1.1
0
-5
placebo metformin (n160)
-10
pioglitazone 30 mg metformin (n168)
-9.7


-15
Triglycerides
Total
HDL-
LDL-
cholesterol
cholesterol
cholesterol
Baseline (mmol/L)
3.09
3.06
3.39
1.11
1.09
5.51
5.49
3.37
LOCFp ? 0.05 vs baseline p ? 0.05 vs placebo
Einhorn D, et al. Clin Ther
2000221395-1405. Hanefeld M, et al. Exp Clin
Endocrinol Diabetes 2000108(suppl 2)S256-S267.
36
Effect of Thiazolidinediones on Lipid Values
Report from a Physicians Clinical Practice
Troglitazone (600 mg qd)
Rosiglitazone (8 mg bid)
Pioglitazone (45 mg qd)
60
47
50
40
30
ChangeFromBaseline (mg/dL)
20
11.5
7.2
6.5
10
1.5
0.5
0
-1.1
-10
-5
-20
-21
-30
LDL-C
HDL-C
TG
King AB. Diabetes Care 200023557. Letter.
37
Avandia provides an effect on lipids
38
Vergelijking tussen pioglitazone en roziglitazone
effecten op de lipiden
B Goke, Exp Clin Endocrinol Diabetes, 2000,
108,S243-249 JF Blické, Diabetes Metab 2001,
27,279-285 T Nikamura et al, J Diabetes itsz
complictions, 2000,14,250-254
39
4. 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

40
Starting Pioglitazone Therapy

• Check baseline liver function
• Advise patient re weight gain and edema
• Start with recommended starting dosage
• Recheck at 8 weeks for efficacy and liver
  function
• Consider adjusting dosage
• Recheck at 16 weeks for efficacy and liver
  function
• Remember Maximum efficacy seen at 16 weeks and
  beyond

ACTOS ? / Avandia EU Prescribing Information
2000.
41
Pioglitazone PharmacokineticsPatients with
Hepatic Impairment

• ? 45 reduction in total pioglitazone mean peak
  concentrations but no change in mean AUC values

N12
Eckland D, et al. Exp Clin Endocrinol Diabetes
2000108(suppl 2)234-242.
42
Pioglitazone PharmacokineticsAge Groups

• Same convenient once daily dosing

Eckland D, et al. Exp Clin Endocrinol Diabetes
2000108(suppl 2)234-242.
43
4. Nevenwerkingen Unieke effecten

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

44
Follow-Up Patients on Pioglitazone Therapy

• Considerations in long term follow-up
• With improved control of blood sugar, adjustment
  in other diabetes medication may be indicated
• Improvement in dyslipidaemia can be expected
• After the first year, periodic recheck of liver
  function is recommended
• Durability of pioglitazone effects have been
  observed after two years in clinical trials

ACTOS ? / Avandia EU Prescribing Information
2000. Hanefeld M, et al. Exp Clin Endocrinol
Diabetes 2000108(suppl 2)S256-266.
45
Pioglitazone PharmacokineticsPatients with
Renal Impairment

• No Dose Reduction

Healthy controls (n6)
Moderate renal impairment (n6)
Severe renal impairment (n9)
Serum pioglitazone
concentration (µg/L)
Serum concentration-time profile after repeated
oral dosing of pioglitazone 45mg once daily
Time (h)
Eckland D, et al. Exp Clin Endocrinol Diabetes
2000108(suppl 2)234-242.
46
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