Agrylin PacRim Marketing Plan 2004

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MANAGEMENT OF CARDIOVASCULAR DISEASES IN DIABETIC
PATIENTS ROLE OF THIAZOLINEDIONE

• Prof. Pham Nguyen Vinh
• Heart Institute of Ho Chi Minh City
• Tam Duc Heart Hospital

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Cardiovascular problems in diabetic patient

• Systemic hypertension
• Coronary artery disease
• Heart failure
• Arrythmias atrial fibrillation and sudden
  cardiac death
• Peripheral and cerebrovascular disease

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IR associated with multiple factors involved in
CVD
Hyperglycaemia
Hypertension
Dyslipidaemia
IR
Microalbuminuria
Hypofibrinolysis
Endothelial dysfunction
Inflammation
Atherosclerosis, CVD
IR Insuline Resistance Festa A et al.
Circulation 2000 102 427 Reaven GM. Annu Rev
Med 1993 44 12131.
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High rate of restenosis in patients with diabetes

• Stents are commonly used to reduce blockages in
  blood vessels of the heart
• In some patients, blockages return because of
  cell growth inside the stent (restenosis)
• Diabetes patients have a high rate of restenosis
• Up to 3266

Artery
Plaque
Stent
Balloon
Stent
Restenosis
Choi D et al. Diabetes Care 2004 27 265460.
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Blood pressure and diabetes

• Hypertension 3 times more common in type 2 DM
  patients
• Obesity, increasing age, onset of renal disease
  increase the prevalence of HTN/diabetic
  patients
• Salomaa VV et al. BMJ 1991 302 493-496
• Baba T et al. Drugs 1997 54 197-234

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Management of hypertension in diabetic patients

• Ryden Lars et al. Guidelines on diabets,
  pre-diabetes and cardiovascular dieases
  executive summary. Eur. H. Journal 2007 28
  88-130

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Management of hypertension in diabetic patients

• Ryden Lars et al. Guidelines on diabets,
  pre-diabetes and cardiovascular dieases
  executive summary. Eur. H. Journal 2007 28
  88-130

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Renal artery stenosis may be responsible for both
renal insufficiency and hypertension in diabetic
patient
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Coronary artery disease in diabetic patient

• Diabetes 19-23 in Acute Coronary Syndrome
  (ACS)
• Bartnik M Diabetes among ACS patients to be
  about 45
• Sources Malmberg K et al. Circulation 2000
  102 1014-1019
• Bartnik M. Glucose regulation and coronary
  artery disease. Karolinska Institutet,
• Stockholm 2005 (ISBN 91-7140-401-5)

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Management of ACS in diabetic patient

• ACS Acute Coronary Syndrome
• Ryden Lars et al. Guidelines on diabetes,
  pre-diabetes and cardiovascular
• diseases executive summary. Eur. H. Journal
  2007 28 88-130

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Management of ACS in diabetic patient

• Ryden Lars et al. Guidelines on diabetes,
  pre-diabetes and cardiovascular
• diseases executive summary. Eur. H. Journal
  2007 28 88-130

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Management of ACS in diabetic patient

• Ryden Lars et al. Guidelines on diabetes,
  pre-diabetes and cardiovascular
• diseases executive summary. Eur. H. Journal
  2007 28 88-130

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Treatment targets for patients with diabetes and
coronary artery disease (CAD)

• Ryden Lars et al. Guidelines on diabetes,
  pre-diabetes and cardiovascular
• diseases executive summary. Eur. H. Journal
  2007 28 88-130

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Treatment targets for patients with diabetes and
coronary artery disease (CAD)

• Ryden Lars et al. Guidelines on diabetes,
  pre-diabetes and cardiovascular
• diseases executive summary. Eur. H. Journal
  2007 28 88-130

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Treatment targets for patients with diabetes and
coronary artery disease (CAD)

• Ryden Lars et al. Guidelines on diabetes,
  pre-diabetes and cardiovascular
• diseases executive summary. Eur. H. Journal
  2007 28 88-130

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Treatment targets for patients with diabetes and
coronary artery disease (CAD)

• Ryden Lars et al. Guidelines on diabetes,
  pre-diabetes and cardiovascular
• diseases executive summary. Eur. H. Journal
  2007 28 88-130

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Beta-blockade/diabetic CAD patient

• Oral BBs are recommended for all diabetic
  patients with ACS
• BBs beta-blockers
• Lopez-Sendon J et al. Eur Heart J 2004 25
  1341-1362

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Diabetes and Coronary revascularization

• PCI Percutaneous Coronary Intervention
• Ryden Lars et al. Guidelines on diabetes,
  pre-diabetes and cardiovascular
• diseases executive summary. Eur. H. Journal
  2007 28 88-130

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Diabetes and Coronary revascularization

• PCI Percutaneous Coronary Intervention
• Ryden Lars et al. Guidelines on diabetes,
  pre-diabetes and cardiovascular
• diseases executive summary. Eur. H. Journal
  2007 28 88-130

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Rosiglitazone in diabetic coronary patient
RSG ? hyperglycaemia
RSG ? BP
RSG ? HDL and ? sdLDL
RSG ? microalbuminuria
RSG ? PAI-1
RSG ? IR
RSG ? vascular reactivity
RSG ? CRP
Atherosclerosis, CVD
? Atherosclerosis, CVD?
Festa A et al. Circulation 2000 102
427Reaven GM. Annu Rev Med 1993 44 12131.
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Rosiglitazone effect on coronary artery minimal
lumen diameter in patients post-coronary stenting
Controln 45
3.5
RSG 4 mg/dayn 38
3.0
2.5
2.0
1.5
Minimal lumen diameter (mm)
1.0
0.5
0
Pre-stent
Post-stent
Follow-up 6 months
p 0.009 versus control Patients treated for 6
months
Choi D et al. Diabetes Care 2004 27 265460.
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Heart failure and diabetes
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Prevalence of heart failure and glucose
abnormalities

• Strong association between diabetes and heart
  failure
• Heart failure 12 in diabetes compared with 3
  in individuals without diabetes
• Thrainsdottir IS et al. Diabets Care 2005 28
  612-616

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Management of heart failure in diabetic patient

• Ryden Lars et al. Guidelines on diabetes,
  pre-diabetes and cardiovascular
• diseases executive summary. Eur. H. Journal
  2007 28 88-130

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Management of heart failure in diabetic patient

• Ryden Lars et al. Guidelines on diabetes,
  pre-diabetes and cardiovascular
• diseases executive summary. Eur. H. Journal
  2007 28 88-130

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Rosiglitazone useful in heart failure diabetic
patient ?
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Low potential for drug-drug interactions
Rosiglitazone is neither subject to, nor
associated with, any clinically relevant
pharmacokinetic or pharmacodynamic drug
interactions with
CYP3 A4 substrates (e.g. statins, calcium channel
blockers, OCPs)

• Oral hypoglycaemic agents

Ranitidine
Digoxin
OCPs oral contraceptive pills Harris RZ et al.
J Clin Pharmacol 1999 39 1189-94 Di Cicco RA
et al. J Clin Pharmacol 2000 401280-5 Jiller
AK et al. Eur J Clin Pharmacol 2001 57 105-9
Freed MI et al. Diabetes Med 1999 16 (Suppl 1)
47. Abstract P59 Inglis AM et al. J Clin
Pharmacol 2001 41 683-90 Di Cicco RA et al. J
Clin Pharmacol 2000 40 1516-21 Miller AK et
al. Clin Ther 2002 24 1062-71
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Rosiglitazone is the only available TZD not
metabolised by CYP450 3A4

• Rosiglitazone is primarily metalolised by CYP 450
  2C8, an uncommon pathway, and 2C9 as a monor
  athway

Majority of drugs with known pathways are
metalolised via the CYP 450 3A 4 pathway
including calcium channel blockers, statins and
macrolide antibiotics
3A4 52
All other pathways
Rogiglitazone has no clinically significant drug
interactions with a range of medications
including acarbose, digoxin, ethanol, glyburide,
metformin, nifedipine, oral contraceptives,
ranitidine and warfarin
AVANDIA package insert. Reseasrch Triangle
Park, NC GlaxoSmithKline May 2004
AnzenbacherP, anzenbacherova E. Cell Mol Life
Sci 2001 58 737-47
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TZDs and CHF evidence from clinical trials

• Very low incidence of CHF in TZD-treated
  patients, as monotherapy or in combination (with
  agents other than insulin)

Pathogenesis not fully elucidated Probably
involves increase in plasma volume
Noclinically significant changes in left
ventriclular mass, left ventricular ejection
fraction or end-diastolic volume
OAD oral anti-diabetic drugs Nesto RW et al.
Circulation 2003 108 2941-8 Nesto RW et al.
Diabetes Care 2004 27256-63
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Recommendations for TZD use in diabetes patiens
with and without symptomatic heart disease

• EF ejection fracion. NYHA New York Heart
  Association
• Recommendations are from the AHA/ADA Consensus
  Statement
• In patients with NYHA class I or II CHF
  categories, TZDs may be used cautionusly, with
  initiation of treatment at the lower doses.
  Observation with gradual dose escalation is
  warranted to identify weight gain, oedema or an
  exacerbation of CHF

Nesto RW et al. Circulation 2003 108 2941-8
Nesto RW et al. Diabetes Care 2004 27256-63
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Diabetes and aterial fibrillation

• ALFA study 13.1 diabetes in patients with
  chronic atrial fibrillation
• Levy S et al. Circulation 1999 99 3028-3035

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Diabetes and sudden cardiac death

• Framingham study SCD in all ages X4 in
  diabetes
• Kannel WB et al. Am Heart J 1998 136 205-212

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Management or prevention of atrial fibrillation
and sudden cardiac death in diabetes (1)

• Ryden Lars et al. Guidelines on diabetes,
  pre-diabetes and cardiovascular
• diseases executive summary. Eur. H. Journal
  2007 28 88-130

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Management or prevention of atrial fibrillation
and sudden cardiac death in diabetes (2)

• Ryden Lars et al. Guidelines on diabetes,
  pre-diabetes and cardiovascular
• diseases executive summary. Eur. H. Journal
  2007 28 88-130

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Diabetes and peripheral or cerebrovascular disease
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Diabetes increases peripheral and cerebrovascular
disease

• Diabetes X2 to X4 incidence of peripheral
  vascular disease
• Diabetes X2 incidence of stroke
• Sources Beckman JA et al. JAMA 2002 287
  2570-2581
• Folsom AR et al. Diabetes Care 1999 22
  1077-1083

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Management of peripheral arterial disease in
diabetes

• Ryden Lars et al. Guidelines on diabetes,
  pre-diabetes and cardiovascular
• diseases executive summary. Eur. H. Journal
  2007 28 88-130

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Management of peripheral arterial disease in
diabetes

• Ryden Lars et al. Guidelines on diabetes,
  pre-diabetes and cardiovascular
• diseases executive summary. Eur. H. Journal
  2007 28 88-130

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Management of stroke in diabetes

• Ryden Lars et al. Guidelines on diabetes,
  pre-diabetes and cardiovascular
• diseases executive summary. Eur. H. Journal
  2007 28 88-130

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Conclusion

• Cardiovascular disease big problem in diabetic
  patient
• Rosiglitazone helpful in tight control of
  coronary artery disease
• Rosiglitazone not for use in HF patient with
  NYHA gt 3
• Rosiglitazone can be combined with Insulin and
  other OAD

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Discussion
ADOPT, TZDs and CHF
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Discussion
How should the key messages and recommendations
from ADOPT and DREAM be communicated?