Agrylin PacRim Marketing Plan 2004

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Macrovascular clinical need in early T2DM
Prof. Dang Van Phuoc
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The Glucose Paradox
Macrovascular disease is the biggest killer in
T2DM, yet is only moderately improved by good
glycaemic control
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CVD is the biggest killer in T2DM

• CV deaths accounts for 75 of all all deaths in
  DM1
• 80 of people with diabetes develop CVD1
• The prevalence of T2DM is growing fast, not least
  in developing countries.
• In the US, men have a lifetime 33 chance of
  getting diabetes, and women 39.3
• In the UK from 1981 to 20004
• Smoking, cholesterol and BP control averted
  30,000 coronary deaths
• Secondary prevention averted 35,000 coronary
  deaths
• BUT obesity caused 2100 more deaths
• Physical inactivity caused 2700 more deaths
• AND diabetes caused 2900 more deaths
• National Diabetes Data Group, Diabetes in
  America. 1995
• TBD
• Narayan KM, et al. JAMA 2003290(14)1884-1890
• Unal B, et al. Circulation 2004 10911011107

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CV risk and hyperglycaemia

• ADA
• The role of hyperglycaemia in cardiovascular
  complications is still unclear
• Genuth S et al Diab Care 200326(Suppl 1)S28-32
• Clinical guidelines for glycosylated haemaglobin
  levels are based on cut-off points relevant for
  the prevention of microvascular complications
• ADA Guidelines Diab Care 200427(Suppl 1)S15-35
• The risk for macrovascular complications seems to
  set in much earlier than those for microvascular
  complications

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Chronic hyperglycaemia in mature T2DM only weakly
drives CV risk UKPDS 35

• Prospective observational study

80
Myocardial infarction plt0.001 Microvascular end
points plt0.0001
Microvascular disease 37 risk reduction per 1
reduction HbA1c Plt0.001
60
MI 14 risk reduction Per 1 reduction
HbA1c Plt0.001
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Adjusted incidence per 1000 person years
20
0
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10
8
9
5
6
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Updated mean HbA1c ()
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Was the UKPDS just underpowered?
Relative risk in CVD per 1 increase in A1c from
a meta-analysis of various cohort studies
1.8
1.55 (0.92-1.43)
1.6
1.32
(1.19-1.45)
1.18
1.17
1.16
1.4
1.13
(1.1-1.26)
(1.09-1.25)
(1.07-1.26)
(1.06-1.2)
1.2
RR per 1 increase in HbA1c
1
Type 1
0.8
Diabetes
0.6
Type 2
diabetes
0.4
0.2
0
CV Disease
CHD
Fatal CHD
Stroke
PAD
(CHDstroke)
Macrovascular endpoint
Stettler MD et al, Am Heart J 2006152(1)27-37
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CV risk is probably weakly linked to chronic
hyperglycaemia

• Chronic hyperglycaemia in mature T2DM seems to
  have a small CV risk-elevation effect.
• This is much smaller than for microvascular
  endpoints, which are entirely determined by
  hyperglycaemia.
• The CV protective effect of A1c reduction in T2DM
  is much smaller than for BP, LDL, TG, HDL and BMI
  control.
• The UKPDS identified no lower or upper limit risk
  threshold for either.

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Chronic hyperglycaemia probably directly induces
macrovascular inflammation through AGE formation
?CoEQ reduction (saturated mitochondrial voltage
gradient)
?Glucose(c)
Polyol pathway
Capillary damage (microvascular)
O2
O2-
Mitochondrion
?F6P(c)
Hexosamine pathway

Nucleus
NF-?B (autocrine)
PKC pathway

?PPAR(n) active
?G3P(c)
?ADPR(n)
AGE pathway
?GAPDH(n) Complex
?GAPDH(c) Complex
Cytokine release (IL-1, TNF)
NF-?B (endocrine)
?1.3DPG(c)
Macrophage/ mesangial cell
Endocrine and paracrine signaling through RAGE
Brownlee M. Diab 2005541615-1625 Libby P, et
al. Circulation 20021062760-2763
Arterial damage (macrovascular)
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How can we account for the glucose paradox?

• Trial underpowering - Just a weak link?
• CV risk is driven by concurrent but incidental
  metabolic pathologies?
• However hypertension, obesity and dyslipidaemia
  are estimated to account for only about 20 of
  the CV risk seen in T2DM.
• Early damage, accentuated by pharmacological
  strategies?

CV risk from hyperglycaemia
Lipid, BP and obesity ameliorate risk in later
dyslipidaemia through additive effects on
atheroma and plaque stability.
Dysglycaemic continuum
Insulin resistance through driving the clustering
of metabolic defects? Insulin resistance
directly? Early pre-diabetic prandial
hyperglycaemia? Early hyperinsulinaemia?
Chronic hyperglycaemia Chronic prandial
hyperglycaemic spikes? Chronic hyperinsulinaemia?
Adapted from Libby P et al, Circulation
20021062760-2763
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The point-of-no-return for CV risk occurs very
early in dysglycaemic continuum
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CV risk sets in long before T2DM

• Metaregression analysis from 20 prospective
  observational studies of non-diabetic individuals
  followed for 12.4 years

Regression coefficients
Relative risk versus non-
between FPG/2hPPG and CV
diabetic range for non-diabetic
event rate
individuals
plt0.00064
p0.056
1.58 (1.19- 2.1)
1.2
1.6
1.029 (0.438- 1.62)
1.55
1
1.5
0.817 (-0.02-1.655)
0.8
1.45
1.4
Relative Risk
Regression coefficients
0.6
1.33 (1.06-1.67)
1.35
0.4
1.3
0.2
1.25
1.2
0
IFG (FPG6.1mmol/L)
IGT (2hPPG7.8 mmol/L)
IFG (FPG6.1
IGT (2hPPG7.8
mmol/L)
mmol/L)
Regression coefficient for relationship where
data from top quartile removed to account for
possible bias of undiagnosed T2DM
Risk relative to FPG of 4.2 mmol/L (modeled).
Significant correlations seen glucose quatile and
CV risk for pre-diabetic range
Beverley B, et al. Diab Care 199821(3)360-366
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Insulin resistance is implicated in the metabolic
syndrome and CV risk
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CVD and metabolic risk factors in MS

• The risk of CVD is driven by the number of risk
  factors present, although less so than the risk
  for T2DM

Wilson PWF et al. Circulation 20051123066-3072
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IR correlates with the magnitude of other
metabolic risk factors

• San Antonio study CV risk factors across IR
  quintiles as measured by HOMA at baseline

All p(trend) lt 0.0001 quintile thresholds 1.0,
1.6, 2.5, 4.8. Adjusted for age, sex and
ethnicity.
Hanley AJG, et al. Diab Care 200225(7)1177-1184
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IR associates with visceral obesity and
endothelial function

• IR associates with visceral obesity and
  endothelial dysfunction, but not adipose obesity.

Cleland SJ, et al. Hypertens 2000 35507511.
Banerji MA, et al. Am J Physiol 1997
273E425E432.
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Insulin resistance is implicated in driving a
number of inflammatory and pro-thrombotic factors
that induce plaque formation and instability
Nesto RW. Am J Med 2004116(Suppl 5A)11S-22S
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Is insulin resistance a core aetiology in
diabetic CVD?
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IR is an independent CV risk factor in MS

• The San Antonio Heart Study showed a 2x RR over 8
  years for CV events in non-diabetic men with IR,
  when adjusted for LDL, HDL, TG, smoking, sBP.

Quintile 5
Quintile 4
HOMA-IR at baseline
Quintile 3
Quintile 2
0
1
2
3
4
5
Odds ratio for risk of CVD (95 CI)
Quintile of HOMA-IR adjusted for age, sex,
ethnicity, LDL, triglyceride, HDL, systolic blood
pressure, smoking, alcohol consumption, leisure
time exercise and waist circumference (median
split) P for trend 0.0185
Hanley AJG, et al. Diab Care 200225(7)1177-1184
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Obesity not IR may drive fibrinolytic and
inflammatory activity in T2DM
A1c showed no significance for trend (p0.650)
(Versus) geometric means adjusted for age, sex,
ethnicity. Kahn SE et al. Diabetes
2006552357-2363.
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Prandial Hyperglycaemia and CV Risk in Early
Diabetes
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Early intervention in PPG has a CV protective
effect

• STOP-NIDDM Acarbose significantly reduces the
  risk of CV events relative to placebo over 3.8
  years

Chiasson JL, et al. JAMA 2003290(4)486-494
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PPG in pre-diabetes is linked to oxidative stress
and atheromic progression

• Oxidative stress is more strongly linked to acute
  fluctuations but not sustained hyperglycaemia in
  T2DM (n21, 21 matched non-diabetic controls)

• Acarbose showed a significant reduction in IMT
  progression versus placebo in a STOP-NIDDM
  sub-analysis (acarbose significant independent
  variable by linear regression analysis for BP,
  lipids, smoking, sex and age).

P0.027
Hanley AJG, et al. Diab Care 200225(7)1177-1184
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Just how is IR implicated in CV risk?

• IR, obesity, dyslipidaemia, hypertension seem to
  shape a unique inflammatory and pro-thrombotic
  environment in the macro-vasculature very early
  in T2DM.
• But just what is cause and effect with respect to
  these pathologies?

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Obesity
Insulin resistance
Liver
Adipose tissue (visceral)
Skeletal muscle
FFA? (? IR?, endothelial dysfunction?)
Early prandial hyperglycaemia
Oxidation
?VLDL (?TG) dyslipidaemia
Hyperinsulinaemia
?sdLDL
?Oxidative stress?
?HDL
IR induced ?FFA flux into endothelial cells
Arterial stenosis Smooth muscle
proliferation Plaque instability Thrombotic
priming
Chronic fasting hyperglycaemia
?Prandial lipaemia
Hyperinsulinaemia
?AGE
Endothelial FFA oxidation
?AGE
?NO, PC ?Endothelin, AII
?CRP, ?PAI-1 ?Fibrinogen
Cytokine signaling
Vasoconstriction Endothelial dysfunction
Liver
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Addressing macrovascular clinical need in T2DM

• Just where is the point-of-no-return for CVD risk
  elevation in T2DM?
• Are glycaemic definitions of disease useful in
  approaching CV clinical need in T2DM? Is T2DM an
  inflammatory pathology?
• What is the relationship between metabolic
  pathologies in the early disease that creates the
  unique atheromic environment?
• How should we start incorporating IR into our
  intervention strategies for CV risk management in
  T2DM, and when should they begin?
• Is hyperinsulinaemia a risk factor, and how
  across the natural history of the disease?
• How can we bring convergence to the disciplines
  of cardiology and endocrinology to benefit DM
  patients?

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Discussion
The next meetings agenda Meeting
cardiovascular clinical need in T2DM