TZDs and Atherosclerosis: Evolution from Translational to Clinical Science

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TZDs and AtherosclerosisEvolution from
Translational to Clinical Science

• Darren K. McGuire, MD, MHSc
• University of Texas Southwestern Medical Center
  at Dallas
• 5th Annual Diabetes Summit Linking Science to
  Medicine
• November 12, 2005

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Thiazolidinedione DrugsThe Glitazones

• Ciglitazone (1982)
• Fibrate derivative to lower cholesterol
• Unexpected glucose-lowering in animal models
• Mechanism completely unknown
• Subsequently identified as an agonist to the
  PPAR? receptor
• Orphan of nuclear-receptor superfamily of
  ligand-activated transcription factors
• Coordinate regulator of glucose and lipid
  metabolism
• Presently represent 21 of US oral anti-diabetic
  drug market

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Beyond Fat and Glucose Cardiovascular Effects of
the TZDs

• PPAR? expressed in a broad array of cells
  associated with CVD
• Vascular ECs
• Vascular SMCs
• T-lymphocytes
• Monocyte/macrophages
• Cardiac Myocytes
• Renal tubules
• Potential for myriad cardiovascular effects

ATVB 1999 19546-551. Circ Research, 1998
831097-1103 Am J Path, 1998153 17-23.
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TZDs Summary Effects on Preclinical CVD
Intermediates

• Cell preparations
• ? smooth muscle cell migration/proliferation
• ? inflammatory cascade
• monocytes/macrophages
• ? adipocyte PAI-1 expression
• ? myocyte hypertrophy

• Animal models
• ? atherosclerosis
• ? response to balloon-mediated arterial injury
• ? infarct size
• improve post-infarction remodeling
• ? cardiac steatosis

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Troglitazone Inhibits Fatty Streak Formation in
LDLR-/- Mouse
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Effects of TZDs on Conventional CVD Risk Factors
Chiquette E, et al. Arch Int Med 2004 164
2097 Goldberg R, et al. Diabetes Care 2005 28
1547.
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Influence of Rosiglitazone on Coronary Blood Flow
14 Men T2DM w/o CAD PET Coronary Flow
Evaluation Baseline vs. 6-months of Rosiglitazone
Plummer EV et al. Diabetes 2002 51(Suppl 2)
A151 (abstract)
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Effect of TZDs on Carotid Intimal Media Thickness
(IMT)
135 w/ T2DM Tro vs Usual 6 months
Patients Treatments Duration
106 w/ T2DM Pio vs Usual 6 months
92 w/ CAD Rosi vs Placebo 12 months
173 w/ T2DM Pio vs Glimepiride 6 months
Minamikawa J et al. J Clin Endocrinol Metab.
1998831818 Koshiyama H et al. J Clin
Endocrinol Metab. 2001863452Sidhu JS et al.
Arterioscler Thromb Vasc Biol. 200424930
Langenfeld MR et al. Circulation. 20051112525
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Effect of TZDs on Restenosis after Coronary
Stenting
52 w/ T2DM Tro vs Usual 6 months Neointimal Area
Patients Treatments Duration Endpoint
157 w/ T2DM Tro vs Usual 6 months Neointimal Area
44 w/ T2DM Pio vs Usual 6 months Neointimal Area
95 w/ T2DM Rosi vs Usual 6 months Restenosis
42 non-DM Pio vs Placebo 6 months Neointimal
Volume
Takagi et al. J Am Coll Cardiol 2000 36 1529
Takagi et al. Am J Cardiol 2002 89 318 Takagi
et al. Am Heart J 2003 146 e5 Choi et al.
Diabetes Care 2004 27 2654 Marx et al. Circ
2005 In Press
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Association Between Glucose Therapy and Outcomes
after MI
N8872 w/ AMI and DM, mean age 76.4 years
Inzucchi SE et al. Diabetes Care. 2005281680-9.
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Controlled CV Studies of TZDs
Study Rx N Duration 1o Endpoint PROactive Pio
vs Plac 5238 ?2.5 yrs MACE IRIS Pio vs
Plac 3136 3 yrs CVA/MI Met Rosi RECORD Rosi
SU 4000 6 yrs MACE Met SU BARI 2D IP vs
IS 3000 5 yrs All-cause Death DREAM Rosi vs
Plac 4000 3 yrs New DM/Death (Ram vs Plac)
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PROactive Study Design
PROspective Actos Clinical Trial In
macro-Vascular Events
5238 patients 19 European Countries
Mean2.9 years Treatment (Event Driven gt760
events)
1o composite endpoint MI/ACS/CVA/Amputation/Revas
c/Death Principal 2o Endpoint Death/MI/CVA
Dormandy JA, et al. Lancet 2005 366 1279
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PROactive Eligibility Criteria

• Inclusion
• Type 2 diabetes
• Age 35-75
• HgbA1cgt6.5
• CVD
• MI (gt6 months)
• CVA (gt6 months)
• PCI/CABG (gt6 months)
• ACS (gt3 months)
• Cath/Stress test
• Sx PAD

• Exclusion
• Type 1 diabetes
• Insulin monotherapy
• CHF (Class II-IV)
• Planned revascularization
• Gangrene/Rest pain
• Significant liver disease
• Dialysis
• Use of TZD

Dormandy JA, et al. Lancet 2005 366 1279
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PROactive Selected Baseline Characteristics
Pioglitazone Placebo Characteristic
(n2605) (n2633) Men () 67 66 White
() 98 99 Mean age (yrs) 62 62 Median DM duration
(yrs) 8 8 Prior MI () 47 46 gt2 CVD Inclusion
criteria () 47 47 HbA1c () 7.8 7.8 HDL
(mg/dl) 42.5 42.5
Dormandy JA, et al. Lancet 2005 366 1279
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PROactive Baseline Use of Selected Medications
Pioglitazone Placebo Characteristic
(n2605) (n2633) Metformin () 57 57 Sulfonylure
a () 57 56 Insulin () 30 31 Anti-platelet agent
() 85 83 Statin () 43 43 ACEI/ARB
() 70 70 ?-Blocker () 55 54
Dormandy JA, et al. Lancet 2005 366 1279
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PROactive Study Drug Compliance Among
Completers
Drug Discontinuation Pioglitazone 16 Placebo
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PROactive-Results.com
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PROactive Time to 1o Composite Endpoint
Death, MI, CVA, ACS, Leg Revascularization or
Amputation, PCI, or CABG
Dormandy JA, et al. Lancet 2005 366 1279
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PROactive Time to Principal 2o Composite Endpoint
Death, MI, CVA
Dormandy JA, et al. Lancet 2005 366 1279
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PROactive Effects on CHF
Pioglitazone (n2605)
Placebo (n2633) Adverse Event Events
Patients Events Patients p-value Any
CHF 417 281 (11) 302 198 (8) lt0.0001 CHF not
requiring hospitalization 160 132 (5) 117 90
(3) 0.003 CHF requiring hospitalization 209 14
9 (6) 153 108 (4) 0.007 Fatal CHF 25 25
(1) 22 22 (0.8) 0.634
Dormandy JA, et al. Lancet 2005 366 1279
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PROactive Net Effects on Efficacy Safety

• Apples vs. Oranges
• Compare All Events
• 97 vs. 115
• OR
• Compare 1st Events
• 58 vs. 83
• Hierarchy of events

Yki-Järvinen H. Lancet 2005 366 1241
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TZDs Increase Peripheral Edema Risk

• Peripheral edema is common with TZDs
• All TZDs to date
• 3-16 of treated patients
• Dose-dependent
• Worse with insulin
• Worse with elderly
• FDA labeling modification 4/2002 for CHF
• Clinical importance unknown
• Vascular leak vs. Volume expansion vs. Cardiac
  toxicity?
• VEGF
• Ca-Channel blocking properties
• Renal sodium handling

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Effect of Troglitazone on Myocardial Steatosis
ZDF Rat Model
7 week old ZDF (fa/fa)rats Fed Standard Chow
Troglitazone
No Troglitazone
6-13 weeks
Zhou et al. Proc Natl Acad Sci USA. 2000971784
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Collecting Duct PPAR? Potential Mechanism for
Volume Expansion

• PPAR? discovered in inner medullary collecting
  duct (CD) of the mouse
• CD-specific PPAR? knockout mouse model
• Treatment with Vehicle vs Rosiglitazone

Zhang H et al. PNAS 2005 102 9406
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Collecting Duct PPAR? Potential Mechanism for
Fluid Retention
?15.5
?34.9
Zhang H et al. PNAS 2005 102 9406
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Managing TZD-Related Fluid Retention by Various
Treatment Options
N381 w/ T2DM Rxd w/ 4mg BID of Rosiglitazone X
12 Weeks 260 (63) w/ Hct ? ?0.5 (mean
2.9) Randomized to 1 of 5 treatment groups X
7days more
Karalliedde J et al. Diabetes. 200554(suppl
1)A20
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TZDs and CVD Conclusions

• TZD effects on a spectrum of CVD intermediates
  suggest may be especially beneficial
• PROactive results demonstrate reduced CVD risk
  with pioglitazone versus placebo
• Statistical challenges and CHF signal warrant
  additional investigation
• trials are underway to further address these
  issues
• Concern remains with regard to CHF
• Mechanism and relevance remains unclear
• Most likely due to volume overload from
  perturbation of sodium handling, and not cardiac
  toxicity
• Continued caution with Class I-II CHF
  contra-indicated in Class III IV