Pioglitazone And The Heart. Prof. Hilla Knobler Diabetes and Metabolic Disease Unit Kaplan Medical Center, Rehovot

Transcription

1 Pioglitazone And The Heart Prof. Hilla Knobler Diabetes and Metabolic Disease Unit Kaplan Medical Center, Rehovot

2 Background

3 Type 2 diabetes management- un-met needs At diagnosis of type 2 diabetes: More than 20% of patients already have complications Up to 50% of -cell function has already been lost and continue to deteriorate with time ~ 80% of patients are insulin resistant Current management: Majority of patients do not achieve target HbA 1c goals over time despite polypharmacy There are only few RCT published until now that prove the efficacy of diabetic treatment in reducing CVD complications

4 Hyperglycemic treatment what is needed from a diabetic medication? 1. Reduce hyperglycemia and accompanying metabolic abnormalities 2. Durability of hypoglycemic effect (reduce progression of beta cell failure) 3. Reduce complications especially CVD 4. Good safety profile Does pioglitazone fulfill these needs?

5 Agenda 1. Mechanisms of TZDs action & the differences between specific TZDs 2. Pioglitazone and the metabolic profile 3. Piogltazone and beta cells 4. Pioglitazone and diabetic complications- CVD 5. The safety profile of pioglitazone 6. Where is the role of pioglitazone in T2DM treatment?

6 Mechanisms of TZDs action & the differences between specific TZDs

7 Peroxisome proliferator-activated receptors (PPARs) Subtype PPARα PPARδ PPARγ Distribution liver, kidney heart, gut skeletal muscle adipose tissue most tissues adipose tissue skeletal muscle liver, heart kidney Physiological involvements lipid oxidation gluconeogenesis adipocyte differentiation glucose uptake gluconeogenesis glycogenesis glycolysis fatty acid uptake lipogenesis adipocyte differentiation Diabetes 1996; 45:1661 J Clin Invest 1997; 99: 2416

8 Thiazolidinediones mode of action PPARγ forms a heterodimer with the retinoid X receptor in the nucleus (PPARγ-RXR) Binding of TZD to PPARγ allows the PPARγ-RXR complex to activate regulatory DNA sequences (response elements) Activation of response elements initiates transcription of specific genes (e.g. those involved in lipid and carbohydrate metabolism)

9 Activation of PPAR Alters Expression of Specific Genes Co-repressors (SMRT, N-COR, etc.) Co-activators (SRC-1, PGC-1, etc.) TZD PPAR RXR Retinoic Acid AGGTCA X AGGTCA PRE (DR-1) Lipoprotein Lipase, PEPCK,αP 2 Coding Sequences

10 Development of Thiazolidindiones O CH 3 CH 3 O CH 3 CH AL-294, Takeda Cl AL-321, Takeda Precursors S O O O NH OC 2 H 5 CH 3 O 1978 Ciglitazone, Takeda Prototype S O O NH HO O NH N S O O N Rosiglitazone, SKB 1982 O NH S N O O Pioglitazone, Takeda O NH O S O O Troglitazone, Sankyo Takeda Chemical Industries Ltd.; Data on file

11 Molecular Targets of PPAR Action Yki-Jarvinen H. N Engl J Med 2004;351:

12 TZDs Regulate Different Genes Total number of activated genes=147 Total pioglitazone=52 Total rosiglitazone=65 Total troglitazone=122 Total number of repressed genes=179 Total pioglitazone=70 Total rosiglitazone=140 Total troglitazone=126 Pioglitazone Rosiglitazone Pioglitazone Rosiglitazone Troglitazone Troglitazone

13 Fold induction (PPAR ) Fold induction (PPAR ) Activation of PPAR- and PPAR- by Pioglitazone or Rosiglitazone Pioglitazone Rosiglitazone 4 PPAR 8 4 PPAR PPAR Fold induction (PPAR ) PPAR Fold induction (PPAR ) log[conc.(m)] log[conc.(m)] 0 Sakamoto J et al. BBRC 2000;278:

14 The effect of TZDs on hyperglycemia and the metabolic profile

15 TZDs and glucose control

16 Metabolic Control in Type 2 Diabetes by pioglitazone Muscle Adipose Glucose uptake & utilisation pioglitazone Adipose tissue diffrentatiation Fat storage Free fatty acids Reduced glucose and TG levels Liver Glucose uptake VLDL synthesis

17 Mean change in HbA 1c (%) Pioglitazone vs Placebo as Add-on to Metformin & an SU: HbA 1c Results from PROactive * -0.4% * * * -0.9% Placebo (n=660) Pioglitazone (n=654) Baseline Final visit Months *p< vs placebo Scheen A et al. Diabet Med 2009;26:

18 Mean change in HbA 1c (%) Pioglitazone vs Glibenclamide as Add-on to Metformin: HbA 1c Results Glibenclamide plus metformin (n=250) Pioglitazone plus metformin (n=250) 8.0 * * *p<0.05, p<0.005 Time (months) 42 Hanefeld M et al. Curr Med Res Opin 2006:22:

19 Progression to Permanent Insulin Use: Pioglitazone vs Glibenclamide Proportion of patients progressing to permanent insulin use Proportion Annual progression rate Pioglitazone 55/ % Glibenclamide 138/ % Log-rank test: p<0.001 for pioglitazone vs glibenclamide Hanefeld M et al. Curr Med Res Opin 2006:22:

20 New-onset diabetes (%) TRIPOD: Treating Insulin Resistance Reduces Incidence of Type 2 Diabetes TRoglitazone In Prevention Of Diabetes (n=236 Hispanic women with gestational diabetes) 60 Annual incidence 12.1% 40 55% RRR HR=0.45 ( )* Placebo % 0 Troglitazone 400 mg * Unadjusted Follow-up (months) Buchanan TA et al. Diabetes 2002;51:

21 TRIPOD & PIPOD: TZDs prevent -Cell Failure PPAR activation: 55% RRR for new-onset diabetes (HR=0.45; 95%CI= ) Effect was most prominent in women, with initial increase in insulin sensitivity & accompanying large reduction in insulin output Protection persisted 8 months after cessation of active treatment PPAR activation associated with preserved -cell function TRIPOD & PIPOD studies demonstrate that prevention of Type 2 diabetes is possible through ß-cell rest TRIPOD=Troglitazone in Prevention of Diabetes PIPOD=Pioglitazone in Prevention of Diabetes Buchanan TA et al. Diabetes 2002;51:

22 TZDs and lipid profile

23 % change from baseline to 24 weeks Pioglitazone vs Rosiglitazone Monotherapy: Effects on Lipids * Pioglitazone Rosiglitazone 10 5 * * LDL-C HDL-C Triglycerides Total cholesterol *p<0.001 vs rosiglitazone; p=0.002 vs rosiglitazone Goldberg RB et al. Diabetes Care 2005;28:

24 LDL particle size (nm) Pioglitazone vs Rosiglitazone Monotherapy: Effects on LDL Particle Size Baseline Endpoint Baseline Endpoint Mean Δ in LDL particle size (nm) Rosiglitazone Pioglitazone 20.5* 20.4* *p<0.001 between baseline & endpoint p=0.005 between treatment groups Goldberg RB et al. Diabetes Care 2005;28:

25 TZDs and the adipose tissue

26 Effect of Thiazolidinediones on Fat Topography Intramuscular Fat Intrahepatic Fat High TG High FFA TZD Subcutaneous Fat TG FFA Subcutaneous Fat Intra-arterial Fat Intraabdominal Fat Artery Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:

27 TZDs REVERSE ADIPOSOPATHY IL-6 FFA TNF Leptin ADIPOCYTE Resistin PAI-1 Adiponectin Angiotensinogen

28 TZDs and CVD

29 Pioglitazone: effects on CVD risk factors LIPIDS Triglycerides HDL LDL Small dense LDL COAGULATION PAI-1 Fibrinogen Platelet aggregation Endothelin 1 VASCULAR EFFECTS Blood volume Blood pressure Intima-media thickness Endothelial function Vascular permeability INFLAMMATION CRP, Interleukin-6 ICAM, VCAM, MCP-1 MMP-9 TNFa Adiponectin No hypoglycemic effect! Patel CB et al. Diabetes Vasc Dis Res 2006;3:65 71

30 PROACTIVE

31 PROACTIVE (n=5238): TIME TO DEATH, MI, OR STROKE CARDIOVASCULAR OUTCOMES FROM PIOGLITAZONE META-ANALYSIS OF CLINICAL TRIALS Kaplan-Meier Event Rate0.15 LANCET 366: ,2005 HR = 0.84 Placebo P=0.027 Pioglitazone TIME (months) FDA and Center for Drug Evaluation & Research; July 30,2007 (n = 5,203) HR = 0.75 Comparator Pioglitazone (n = 5,944) CI = TIME (weeks)

32 Kaplan-Meier Event Rate Effect of Pioglitazone on recurrent stroke in patients with previous stroke Wilcox R et al. STROKE 2007; 38: Placebo (51 / 498) 0.08 HR-0.53 P= Pioglitazone (27 / 486) 0 N at Risk: Time (months)

33 Kaplan-Meier Event Rate EFFECT OF PIOGLITAZONE ON RECURRENT MI IN PATIENTS WITH PREVIOUS MI Erdmann E. et al. JACC 2007; 49: Placebo (88 / 1215) HR-0.72 P= Pioglitazone (65 / 1230) # at 2455 risk: Time (months) 36

34 Kaplan-Meier Event Rate Despite significant increase in rate of admission for CHF in the pioglitazone group vs. placebo (6% vs. 4%) there was no increase in mortality from serious CHF HR 0.71 p=0.13 Placebo (37/108) 34.3% % 0.2 Pioglitazone (40/149) Erdmann et al, Diabetes Care; 2007; 30:

35 Risk of MI, IHD or composite of MACE Events from Meta-analyses with Rosiglitazone or Pioglitazone versus Comparators Rosiglitazone meta-analyses Friedrich et al. (MI) a 25 Selvin et al. (CV morbidity) 22 GSK-ICT (MI) 7,8,20,21 Friedrich et al. (IHD) a 25 Schuster et al. (MI) 17 FDA (Serious IHD) 9,21 Nissen & Wolski (MI) 6 Sing et al. (MI) 10 FDA (IHD) 9,21 Psaty & Furberg (MI) 16 Diamond et al. (MI, highest estimate) 15 Dahbreh & Econom opoulos (MI, lowest estimate) 19 GSK-ICT (IHD) 7,8,20,21 Bracken (MI, excl.record) 18 Diamond et al. (MI, lowest estimate) 15 Bracken (MI, incl.record) 18 Dahbreh & Econom opoulos (MI, lowest estimate) 19 Monami et al. (MI) 23 FDA (CV death/mi/stroke) 7,8,20,21 GSK-ICT (CV death/mi/stroke) 7,8,20,21 Manucci et al (Non-fatal coronary events) 24 Manucci et al (Non-fatal MI) 24 Pioglitazone metaanalyses Hazard Ratio Selvin et al (CV morbidity, incl.proactive) 22 Selvin et al (CV morbidity, incl.proactive) 22 Nagajothi et al (MI) 34 Lincoff et al (Death/MI) 28 Perez et al (Death/MI/stroke, incl.proactive) 29 Lincoff et al (Death/MI/stroke, incl. PROacitve) 28 Manucci et al (Non-fatal coronary events) 33 Lincoff et al (MI) 28 Lincoff et al (Death/MI/stroke, excl.proactive) 28 Perez et al (Death/MI/stroke, excl.proactive) 29 Schernthaner G & Chilton R. Diab.Metab.Obes 2010; 12:

36 TZDs impact on carotid IMT Study (year) Treatment Patients Duration (weeks) Change in IMT (mm) p Minamikawa et al (1998) Troglitazone 400 mg Usual care T2DM 26 Troglitazone 0.08 Usual care 0.03 <0.001 Koshiyama et al (2001) Pioglitazone 30 mg Usual care T2DM 26 Pioglitazone , Usual care <0.001 Sidhu et al (2004) Rosiglitazone 8 mg Placebo Stable CAD 48 Rosiglitazone 0.01 Placebo Langenfeld et al (2005) Pioglitazone 45 mg Glimepiride 2.7 mg (mean) T2DM 26 Pioglitazone 0.05 Glimepiride 0.01 <0.005 Minamikawa J et al. J Clin Endocrinol Metab 1998;83: ; Koshiyama H et al. J Clin Endocrinol Metab 2001;86: ; Sidhu JS et al. Arterioscler Thromb Vasc Biol 2004;24: ; Langenfeld MR et al. Circulation 2005;11:

37 Change in PAV (%) PERISCOPE study: change in percent atheroma volume (%) p< Glimepiride (n=181) Pioglitazone (n=179) p= p=0.44 Nissen S et al. JAMA 2008;299:

38 The effect of pioglitazone vs. glimeperide on carotid IMT

39 The safety profile of pioglitazone Weight gain CHF Osteoporosis and fractures Bladder carcinoma?

40 Weight gain with TZDs In clinical trials of pioglitazone, there is evidence of doserelated weight gain 1 In four, 1-year, double-blind studies comparing treatment of over 3,700 patients with Type 2 diabetes with pioglitazone, metformin or gliclazide 2 : Mean weight increased with both pioglitazone & gliclazide, but decreased with metformin Mean weight increase with pioglitazone was 2.8 kg 1. Actos (pioglitazone) SmPC, Takeda Global Research Development Centre (Europe) Ltd. 2. Belcher G et al. Diabetes Res Clin Pract 2005;70:53 62

41 Effect of Thiazolidinediones on Fat Topography High TG High FFA TZD TG FFA Intramuscular Fat Intrahepatic Fat Subcutaneous Fat Subcutaneous Fat Intra-arterial Fat Intraabdominal Fat Artery Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:

42 TZDs activate ENaC via PPARγ & promote extra cellular fluid (ECF) expansion cortex TZDs medulla PPAR amiloride Vasa rectae ENaC Na+ ECF, Edema Guan et al. Nature Medicine 2005;11:

43 Pioglitazone and CHF Fluid Retention *5-10% of TZD-treated patients develop edema; < 1% of these individuals develop CHF *Pioglitazone has to be avoided in patients with CHF *Start with low dose and increase gradually especially in the elderly *Fluid retention can be treated with distally collecting duct acting diuretics (aldactone) and TZD dose reduction * If edema does not resolve, TZD should be discontinued

44 ADOPT: fracture event rate Rosiglitazone (n=1456) Metformin (n=1454) Glyburide (n=1441) Men (%) Women (%) * 3.5* Upper limb Lower limb * Hip Spine *p<0.01 vs rosiglitazone; p<0.05 vs rosiglitazone Kahn SE et al. Diabetes Care 2008;31:

45 BLADDER CANCER AND PIOGLITAZONE: FRENCH (CNAMTS) STUDY Unadjusted HR = 0.82 Adjusted HR = 1.20* KAISER PERMANENTE NORTHERN CALIFORNIA 7 cases/10,000 pt-years in control group 8 cases/10,000 pt-years in all PIO-treated T2DM 10 cases/10,000 pt-years in all PIO-treated T2DM > 24 months *not adjusted for smoking

46 Where is the role of pioglitazone in the treatment of type 2 DM?

47 U.K.-based General Practice Research Database (22,457 patients) what is next after metformin? JCEM 2012

48 what is needed from a diabetic medication? Does pioglitazone fulfill these needs? 1. Reduce hyperglycemia and accompanying metabolic abnormalities 2. Durability of hypoglycemic effect (reduce progression of beta cell failure) 3. Reduce complications especially CVD 4. Good safety profile Pioglitazone YES YES -especially in early DM YES The drug has to be tailored according to the recent individualized approach

49 Clinical characteristics to be considered before starting pioglitazone treatment For 1. Significant insulin resistance 2. Early DM 3. CVD-high risk 4. Hypoglycemia Against 1.Lean insulin deficient patient 2. Middle age female 3. History of CHF 4. History of bladder ca or hematuria

50 תודה על ההקשבה!