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Insulin resistance  -cell dysfunction Type 2 diabetes Adapted from: Beck-Nielson H et al. J Clin Invest 1994;94:1714–1721 and Saltiel AR, Olefsky JM.

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Presentatie over: "Insulin resistance  -cell dysfunction Type 2 diabetes Adapted from: Beck-Nielson H et al. J Clin Invest 1994;94:1714–1721 and Saltiel AR, Olefsky JM."— Transcript van de presentatie:

1 Insulin resistance  -cell dysfunction Type 2 diabetes Adapted from: Beck-Nielson H et al. J Clin Invest 1994;94:1714–1721 and Saltiel AR, Olefsky JM. Diabetes 1996;45:1661–1669 What is Type 2 diabetes? A progressive metabolic disorder characterised by:

2 The Insulin Resistance Syndrome THE INSULIN RESISTANCE SYNDROME Syndrome XReaven’s SyndromeMetabolic Syndrome also known as 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: 1. Reaven GM. Diabetes 1988;37:1595– Haffner SM, Miettinen H. Am J Med 1997;103:152– Campbell IW et al. (eds). Diabetes Mellitus Health Press. UK

3 The Insulin Resistance Syndrome n Type 2 diabetes or impaired glucose tolerance n Obesity n Dyslipidaemia  Blood pressure  Blood pressure n Insulin resistance n Hyperinsulinaemia (initially) n Atherosclerosis DeFronzo, Ferrannini. Diabetes Care 1991; 14 (3):

4 NCEP: Clinical Identification of the Metabolic Syndrome* Risk FactorDefining Level Abdominal obesityWaist circumference Men>102 cm (>40 in) Men>102 cm (>40 in) Women>88 cm (>35 in) Women>88 cm (>35 in) TG  150 mg/dL HDL-C Men<40 mg/dL Men<40 mg/dL Women<50 mg/dL Women<50 mg/dL BP  130/  85 mm Hg Fasting glucose  110 mg/dL Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285: *The metabolic syndrome comprises  3 risk factors.

5 Thiazolidinediones n Produkten –Troglitazone ( Rezulin ) ° Parke Davis (uit de handel genomen omwille van hepatotoxiciteit ) –Pioglitazone ( Actos ) ° Takeda ( Avandia ) ° Smith Kline Beecham –Rosiglitazone ( Avandia ) ° Smith Kline Beecham n 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 hypo’s –effect op het bewaren van de pancreatische insulinesecretie n zowel monotherapie als combinatietherapie n geen vergelijkende studies tussen de drie

6 Thiazolidinediones: Structurally Diverse PPAR  Agonists Sankyo/Parke-Davis Takeda/Lilly Pioglitazone H3CH3C HO Troglitazone O O O S NH CH 3 O O O S NH Et N O SmithKline Beecham ORosiglitazone O O S NH NN CH 3 Saltiel AR. Diabetes 1996; 45:

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

8 1. Werkingsmechanisme n niet volledig begrepen n 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 n verschillende hypotheses –primair effect op vetweefsel n meer differentiatie van subcutaan vetweefsel naar kleine vetcellen n kleine vetcellen verminderen de vrijzetting in de circulatie van FFA en TNFalfa( beide inhibitoren van insuline actie ) n 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) DNA Nuclear receptor ppar  Retinoid X receptor PPre PPAR response elements = gene expression A VANDIA ENHANCES - expression & translocation of GLUT 4 - differentiation of adipocytes

11 Rosiglitazone - PPAR  agonist MuscleAdipocytesLiver GLUT -4 Pre-adipocytes Differentiation Adipocytes TNF alpha Leptine F F A Insulin sensitivity Glucose uptake Lipolysis F F A Macrovascular complications Glucose uptakeGlucogenesis Insulin resistance reduction Euglycemia Microvascular complications

12 Insulin is a Critical Co-Factor in the Activation of PPAR-  by Pioglitazone Response Element Target gene transcription PPAR  Retinoid X Receptor DNA Activation Suppression Co-repressors (SMRT, N-COR, etc.) Co-activators (SRC-1, PGC-1, etc.) Co-FactorINSULIN Adapted from Kersten S, et al. Nature 2000; 405(6785):

13 PPAR  : Primary Downstream Tissue-Specific Effects Fat - Adipocyte differentiation - Glucose uptake by muscle - Expression of TNFα Pancreatic β-Cells - Cell morphology and structure Vascular - VSMC size, type, migration - Endothelial function - Atherogenicity of lipids Muscle - Glucose uptake and utilization Liver - Glucose and VLDL synthesis - Hepatic insulin resistance - Glomerular function and structure Desvergne B, Wahli W. Endocrine Reviews 1999;20(5): Rosen ED, Spiegelman BM. J Biol Chem 2001;276(41): Kelly D. Circ Res 2001;89: Benson S, et al. AJH 2000;13: Guan YF, Breyer MD. Kidney Intl 2001;60: Buchan KW, Hassal DG. PPAR agonists as direct modulators of the vessel wall in cardiovascular disease. Wiley&Sons, 2000, pp Kidneys

14

15 2. Effectiviteit

16 2. Effectiviteit (monotherapie)

17

18 Rosiglitazone compared to glibenclamide after 52 weeks - FPG Treatment Week Mean Fasting Plasma Glucose (mmol/L) RSG 8 mg daily (n=203) SU (Glibenclamide) (n=189) (ROSIGLITAZONE/020 - ITT Population)

19 Effect van Pioglitazone 30 mg in combinatietherapie: HbA1c vermindering Einhorn D, et al. Clin Ther. 2000;22: Kipnes MS, et al. Am J Med. 2001;111: Kaneko T, et al. Jpn J Clin Exper Med. 1997;74: Hanefeld M, et al. Exp Clin Endocrinol Diabetes. 2000;108(suppl 2):S256-S * Weeks 16 Weeks 40 Weeks (open-label) Change in Mean A1C Over Placebo at Endpoint (% points) Sulfonylurea+ Pio 30 mgMetformin + Pio 30 mg * * * * *P  0.05.

20 2. Effectiviteit ( combinatie met sulfonylurea)

21 2. Effectiviteit (combinatie met metformine)

22 2. Effectiviteit ( combinatie met insuline )

23 3. Andere effecten n 1. Microalbuminurie n 2. Bloeddruk

24 Rosiglitazone Reduces Microalbuminuria -53,7 -22, Albumin/Creatinin Ratio (%difference from Baseline) AvandiaDaonil Reduction of pre-existing Microalbuminuria 24,6 19,3 26,6 32, % Patients with Microalbuminuria Base 52 w AvandiaDaonil Patients with Microalbuminuria before and after treatment

25 Avandia Favourably Affects Blood Pressure Bakris G et al. Diabetes 2000;49(Suppl 1):A96,Abs 388 and poster

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

27 ACTOS ® (pioglitazone HCl) Package Insert. 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 )

28 4. Nevenwerkingen : Klasse effect n 2. Hemoglobine –troglitazone : 5 % lager dan normale waarde –Rosiglitazone : - 1 g/dl –pioglitazone : - 1 g/dl n 3. Gewichtstoename –door vocht retentie en meer subcut vet –hoge dosis : gewichtstoename tot 3 kg/jaar n 4. Lipiden

29 Pioglitazone: Body Weight Changes in US Placebo-Controlled Clinical Studies Monotherapy Combination therapy with Metformin with SU with insulin Mean weight gain (kg) Control Pioglitazone 7.5 mg mg mg mg 2.82 Treatment Mathisen A, et al. Diabetes 2000;49:A117.

30 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 months Weight Gain with Thiazolidinediones

31 Starting Pioglitazone Therapy (continued – 2) Dealing with potential weight gain: nWeight gain should be explained as expected with improved glycemic control, regardless of choice of therapy…but some more than others –Diet control will help minimize weight gain –The least weight gain can be expected when used in monotherapy or with metformin…the most with insulin nRapid excessive weight gain may require stopping therapy ACTOS  / Avandia ® EU Prescribing Information 2000.

32 Effect of Pioglitazone on Body Fat Distribution Miyazaki Y, et al. Diabetes 2000;49(suppl):A299. Visceral Fat/ Subcutaneous Fat Ratio *p<0.01 † p< Before Pioglitazone After Pioglitazone 45 mg / 4 months Fat Area (cm²) SubcutaneousVisceral FatRatio Fat Area 300±44 342±44* 144±13 131±16 † 0.59± ±0.06*

33 Dealing with potential edema: nEdema 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 nMost cases of edema are mild nIf edema or fluid retention is rapidly progressive, clinical intervention or stopping the medication may be indicated nEdema and fluid retention can occur early in therapy…even 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 n De triglyceriden n De vrije vetzuren ( nuchter en post-prandiaal ) n De atherogene plasma-index Verhoogt n Maat van de LDL-partikels n HDL-Cholesterol

35 LOCF *p  0.05 vs baseline †p  0.05 vs placebo Pioglitazone + metformine : lipidenprofiel aan het einde van de studie Einhorn D, et al. Clin Ther 2000;22: Hanefeld M, et al. Exp Clin Endocrinol Diabetes 2000;108(suppl 2):S256-S TriglyceridesTotal cholesterol HDL- cholesterol LDL- cholesterol placebo + metformin (n=160) pioglitazone 30 mg + metformin (n=168) * * * * † † Baseline (mmol/L): Change from baseline at 16 weeks (%)

36 Troglitazone (600 mg qd) Rosiglitazone (8 mg bid) Pioglitazone (45 mg qd) LDL-CHDL-CTG King AB. Diabetes Care 2000;23:557. Letter. Effect of Thiazolidinediones on Lipid Values: Report from a Physician’s Clinical Practice Change From Baseline (mg/dL)

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,S JF Blické, Diabetes Metab 2001, 27, T Nikamura et al, J Diabetes & itsz complictions, 2000,14,

39 4. Nevenwerkingen : Unieke effecten n 1. Hepatotoxiciteit –troglitazone : n 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 n 100 X potenter dan Trog en 10 X meer dan pio n kort T1/2 ( 4 h ) ( trog : h) n accumuleert niet in de lever n Advies monitoren ALT na 2 maanden R

40 Starting Pioglitazone Therapy nCheck baseline liver function nAdvise patient re: weight gain and edema nStart with recommended starting dosage nRecheck at 8 weeks for efficacy and liver function nConsider adjusting dosage nRecheck at 16 weeks for efficacy and liver function nRemember: Maximum efficacy seen at 16 weeks and beyond ACTOS  / Avandia ® EU Prescribing Information 2000.

41 Pioglitazone: Pharmacokinetics Patients with Hepatic Impairment n  45% reduction in total pioglitazone mean peak concentrations but no change in mean AUC values N=12 Eckland D, et al. Exp Clin Endocrinol Diabetes 2000;108(suppl 2):

42 n Same convenient once daily dosing Pioglitazone: Pharmacokinetics Age Groups Eckland D, et al. Exp Clin Endocrinol Diabetes 2000;108(suppl 2):

43 4. Nevenwerkingen : Unieke effecten n 2. Myalgie –pioglitazones (33/606) : 5,4 %-2,7 % placebo n 3. Rosiglitazone – minder potentie tot drug interactie

44 Follow-Up: Patients on Pioglitazone Therapy Considerations in long term follow-up… nWith improved control of blood sugar, adjustment in other diabetes medication may be indicated nImprovement in dyslipidaemia can be expected nAfter the first year, periodic recheck of liver function is recommended nDurability of pioglitazone effects have been observed after two years in clinical trials ACTOS  / Avandia ® EU Prescribing Information Hanefeld M, et al. Exp Clin Endocrinol Diabetes 2000;108(suppl 2):S

45 Pioglitazone: Pharmacokinetics Patients with Renal Impairment Healthy controls (n=6) Severe renal impairment (n=9) Moderate renal impairment (n=6) Time (h) Serum pioglitazone concentration (µg/L) Serum concentration-time profile after repeated oral dosing of pioglitazone 45mg once daily n No Dose Reduction Eckland D, et al. Exp Clin Endocrinol Diabetes 2000;108(suppl 2):

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