A progressive metabolic disorder 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 1994;94:1714–1721 and Saltiel AR, Olefsky JM. Diabetes 1996;45:1661–1669

The Insulin Resistance Syndrome 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 Reaven’s Syndrome Syndrome X Metabolic Syndrome 1. Reaven GM. Diabetes 1988;37:1595–1607 2. Haffner SM, Miettinen H. Am J Med 1997;103:152–162 3. Campbell IW et al. (eds). Diabetes Mellitus 1996. Health Press. UK

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

NCEP: Clinical Identification of the Metabolic Syndrome* Risk Factor Defining Level Abdominal obesity Waist circumference Men >102 cm (>40 in) Women >88 cm (>35 in) TG 150 mg/dL HDL-C Men <40 mg/dL Women <50 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. 2001;285:2486-2497.

Thiazolidinediones werken in op de insulineresistentie : 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 hypo’s effect op het bewaren van de pancreatische insulinesecretie zowel monotherapie als combinatietherapie geen vergelijkende studies tussen de drie

Thiazolidinediones: Structurally Diverse PPARg Agonists H3C HO Troglitazone O S NH CH3 Sankyo/Parke-Davis SmithKline Beecham O Rosiglitazone S NH N CH3 O Et NH Takeda/Lilly S N O O Pioglitazone Saltiel AR. Diabetes 1996; 45: 1661-1669.

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

niet volledig begrepen 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

verschillende hypotheses 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

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

Rosiglitazone - PPAR g agonist Muscle Adipocytes Liver GLUT -4 Pre-adipocytes Differentiation TNF alpha Leptine F F A Insulin sensitivity Glucose uptake Lipolysis Macrovascular complications Glucogenesis Insulin resistance reduction Euglycemia Microvascular

Insulin is a Critical Co-Factor in the Activation of PPAR-g by Pioglitazone Co-activators (SRC-1, PGC-1, etc.) Co-repressors (SMRT, N-COR, etc.) PPARg Retinoid X Receptor Activation Suppression DNA Target gene transcription Response Element Adapted from Kersten S, et al. Nature 2000; 405(6785):421-424.

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 Kidneys Desvergne B, Wahli W. Endocrine Reviews 1999;20(5):649-688. Rosen ED, Spiegelman BM. J Biol Chem 2001;276(41):37731-37734. Kelly D. Circ Res 2001;89:935-937. Benson S, et al. AJH 2000;13:74-82. Guan YF, Breyer MD. Kidney Intl 2001;60:14-30. Buchan KW, Hassal DG. PPAR agonists as direct modulators of the vessel wall in cardiovascular disease. Wiley&Sons, 2000, pp. 350-366.

2. Effectiviteit

2. Effectiviteit (monotherapie)

2. Effectiviteit (monotherapie)

Mean Fasting Plasma Glucose (mmol/L) Rosiglitazone compared to glibenclamide after 52 weeks - FPG 11.0 10.0 9.0 RSG 8 mg daily (n=203) SU (Glibenclamide) (n=189) Mean Fasting Plasma Glucose (mmol/L) 8.0 7.0 2 4 6 8 12 16 26 38 52 Treatment Week (ROSIGLITAZONE/020 - ITT Population)

Effect van Pioglitazone 30 mg in combinatietherapie: HbA1c vermindering -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. 2000;22:1395-1409. Kipnes MS, et al. Am J Med. 2001;111:10-17. Kaneko T, et al. Jpn J Clin Exper Med. 1997;74:1515-1539. Hanefeld M, et al. Exp Clin Endocrinol Diabetes. 2000;108(suppl 2):S256-S266.

2. Effectiviteit ( combinatie met sulfonylurea)

2. Effectiviteit (combinatie met metformine)

2. Effectiviteit ( combinatie met insuline )

3. Andere effecten 1. Microalbuminurie 2. Bloeddruk

Rosiglitazone Reduces Microalbuminuria -53,7 -22,6 -60 -50 -40 -30 -20 -10 Albumin/Creatinin Ratio (%difference from Baseline) Avandia Daonil Reduction of pre-existing Microalbuminuria 24,6 19,3 26,6 32,8 5 10 15 20 25 30 35 % Patients with Microalbuminuria Base 52 w Patients with Microalbuminuria before and after treatment

Avandia Favourably Affects Blood Pressure Ambulatory Systolic Blood pressure -3 -2 -1 1 2 3 4 5 6 7 Baseline Week 28 Week 52 Week 76 Week 100 mm Hg Avandia 4mg bd Daonil Ambulatory Diastolic Blood Pressure -5 -4 Bakris G et al. Diabetes 2000;49(Suppl 1):A96,Abs 388 and poster

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

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.

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

Pioglitazone: Body Weight Changes in US Placebo-Controlled Clinical Studies Monotherapy Combination therapy with Metformin with SU with insulin Mean weight gain (kg) Control -1.28 -1.36 -0.77 -0.04 Pioglitazone 7.5 mg -0.59 15 mg 1.30 1.91 2.30 30 mg 1.29 0.95 2.92 3.73 45 mg 2.82 Treatment Mathisen A, et al. Diabetes 2000;49:A117.

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

ACTOS  / Avandia ® EU Prescribing Information 2000. 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 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 Rapid excessive weight gain may require stopping therapy ACTOS  / Avandia ® EU Prescribing Information 2000.

Visceral Fat/ Subcutaneous Fat Ratio Effect of Pioglitazone on Body Fat Distribution Before Pioglitazone 0.75 After Pioglitazone 45 mg / 4 months 342±44* 350 0.70 300±44 0.65 300 0.59±0.08 0.60 250 0.55 Fat Area (cm²) Visceral Fat/ Subcutaneous Fat Ratio 0.50 200 0.44±0.06* 0.45 144±13 0.40 150 131±16† 0.35 100 0.30 Subcutaneous Visceral Fat Ratio Fat Area *p<0.01 †p<0.05 Miyazaki Y, et al. Diabetes 2000;49(suppl):A299.

ACTOS  / Avandia ® EU Prescribing Information 2000. 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 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.

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

Pioglitazone + metformine : lipidenprofiel aan het einde van de studie 15 * † 11.9 10.2 * 10 8.5 7.7 * 4.1 Change from baseline at 16 weeks (%) 5 1.1 1.5 -5 placebo + metformin (n=160) -10 pioglitazone 30 mg + metformin (n=168) -9.7 * † -15 Triglycerides Total HDL- LDL- cholesterol cholesterol cholesterol Baseline (mmol/L): 3.39 3.37 5.49 5.51 1.09 1.11 3.06 3.09 LOCF *p  0.05 vs baseline †p  0.05 vs placebo Einhorn D, et al. Clin Ther 2000;22:1395-1405. Hanefeld M, et al. Exp Clin Endocrinol Diabetes 2000;108(suppl 2):S256-S267.

Effect of Thiazolidinediones on Lipid Values: Report from a Physician’s Clinical Practice Troglitazone (600 mg qd) Rosiglitazone (8 mg bid) Pioglitazone (45 mg qd) 60 50 47 40 30 Change From Baseline (mg/dL) 20 11.5 10 7.2 6.5 1.5 0.5 -1.1 -10 -5 -20 -21 -30 LDL-C HDL-C TG King AB. Diabetes Care 2000;23:557. Letter.

Avandia provides an effect on lipids

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

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

ACTOS  / Avandia ® EU Prescribing Information 2000. 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.

Pioglitazone concentration (ng/mL) Pioglitazone: Pharmacokinetics Patients with Hepatic Impairment  45% reduction in total pioglitazone mean peak concentrations but no change in mean AUC values Pioglitazone concentration (ng/mL) Pioglitazone AUC (ng•hr/mL) 1000 250 500 750 12 24 36 48 60 72 Time (hours) 30 42 16 8 10 100 10000 Normal Hepatic impairment N=12 Eckland D, et al. Exp Clin Endocrinol Diabetes 2000;108(suppl 2):234-242.

Pioglitazone: Pharmacokinetics Age Groups Same convenient once daily dosing 200 400 600 800 1000 1200 1400 12 24 36 48 60 72 84 96 108 120 132 144 156 Hours after Dosing Mean Concen- tration (ng/mL) Non-Elderly Elderly Mean Concentrations (ng/mL) of Total (Pioglitazone and its Metabolites) in Serum, Comparing Elderly and Non-Elderly Subjects Eckland D, et al. Exp Clin Endocrinol Diabetes 2000;108(suppl 2):234-242.

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

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 2000;108(suppl 2):S256-266.

Pioglitazone: Pharmacokinetics Patients with Renal Impairment No Dose Reduction 400 800 1200 1600 Healthy controls (n=6) Moderate renal impairment (n=6) Severe renal impairment (n=9) Serum pioglitazone concentration (µg/L) 20 40 60 80 100 120 Serum concentration-time profile after repeated oral dosing of pioglitazone 45mg once daily Time (h) Eckland D, et al. Exp Clin Endocrinol Diabetes 2000;108(suppl 2):234-242.