Transcript Scioto County Medical Society

Diabetes and Cardiovascular
Diseases in Type 2 Diabetes:
From UKPDS to Steno 2
Dara P. Schuster, MD
Cardiovascular Disease
• Early, aggressive interventions for
risk reduction
• New, more effective therapies for
treatment of HTN and hyperlipidemia
• Dramatic improvement in
cardiovascular interventions
• Marked reduction in smoking
Yet the increase in prevalence of obesity and diabetes
is epidemic, with CVD the leading complication of DM
Diabetes Doubles Risk for MI
Mortality Despite Advances in
Cardiac Care
The Metabolic Syndrome:
A Network of Atherogenic Factors
Glycemic disorders
Dyslipidemia
Visceral
Obesity
Insulin
Resistance
- Small, dense LDL
- Hypertriglyceridemia
-Postprandial lipemia
 Free Fatty
Acids
Hypertension
Impaired thrombolysis
-  PAI-1, fibrinogen
Endothelial dysfunction/
inflammation
Brunzell J, Hokanson J. Diabetes Care. 1999;22(Suppl 3):C10-C13.
McFarlane S, et al. J Clin Endocrinol Metab. 2001;86(2):713-718.
Frohlich M, et al. Diabetes Care. 2000;23(12):1835-1839.
Kuusisto J, et al. Circulation. 1995;91:831-837.
Parulkar AA, et al. Ann Intern Med. 2001;134:61-71.
Hseuh WA, et al. Diabetes Care. 2001;24(2):392-397.
Lebovitz H. Clin Chem. 1999;45(8B):1339-1345.
-  CRP, MMP-9,
adiponectin
Microalbuminuria
Atherosclerosis
- Low HDL
Cardiovascular Mortality Associated
With Metabolic Syndrome
14
Incidence of CV Mortality
12
12
10
8
6
p < 0.001
4
2.2
2
0
No MS
MS
Diabetes Care 2001;24:683
Association of MI* With the
Metabolic Syndrome and
Individual Components
Obesity, Insulin Resistance and Endothelial Dysfunction
Obesity
Hyperinsulinemia
FFA
TNF-
leptin
resistin
adiponectin
Insulin
Resistance
Caballero AE. Obes Res. 2003; 11: 1278-1289
FFA
IL-1
IL-6
PAI-1
TNF-
leptin
adiponectin
CRP
Endothelial
Dysfunction
Hyperglycemia
Hypertension
Dyslipidemia
Altered coag/fib
Diabetes and Heart Failure:
Current Knowledge
Relation of Glucose
Tolerance Status to LVM
Treatment Standards for
Cardiovascular Disease in
Diabetes
Stenting in Diabetes: Clinical
and Angiographic Outcomes
BARI – Mortality after CABG vs. PTCA, 2000
BARI I: Poorer Outcome with
Revascularization in Diabetics
100
Non DM PTCA 86.8%
Non DM CABG 86.4%
Percent Survival
80
DM CABG
76.4%
DM PTCA
55.7%
60
40
Treatment Comparisons
Non-diabetics: p=0.72
Diabetics:
p=0.0011
20
0
0
1
2
3
4
5
6
7
Years
Revascularization in Diabetes:
• Co-morbidity (PVD , CRF )
• Peri-procedural complications 
• Worse long-term clinical outcomes
• death , MI , stroke 
• Excessive restenosis
• intimal hyperplasia 
• negative remodeling 
• Accelerated atherosclerosis
• progression of disease 
• small vessel/diffuse disease 
BARI 2-D
All-cause mortality
CVD mortality & MI
Angina, employment
Retinopathy
Neuropathy
Nephropathy
PVD
HbA1c, BP, cholesterol
Cost-effectiveness
Blood Glucose Relates to
Mortality
and Risk for Heart Failure in MI
Glycemic Control and Risk of
Development of HF in
Diabetes
Improved Glycemic Control Has Been
Shown to Reduce the
Risk of Complications
According to the United Kingdom Prospective Diabetes
Study (UKPDS) 35, Every 1% Decrease in A1C Resulted in:
14%
21%
12%
37%
Decrease
in risk of any
diabetes-related
end point
(P<.0001)
Decrease
in risk of MI
(P<.0001)
Stratton IM et al. BMJ. 2000;321:405-412.
Decrease
in risk of
stroke
(P=.04)
Decrease
in risk of
microvascular
complications
(P<.0001)
ADA Standards of Care
• ADA recommends a general A1C target of <7%
• The goal of therapy for the individual patient is to
achieve an A1C as close to normal (<6%) as
possible without hypoglycemia
• More stringent glycemic goals may reduce the risk
of serious diabetes-related complications
• Less stringent treatment goals may be appropriate
for certain patient populations and patients with
severe or more frequent hypoglycemia
American Diabetes Association. Diabetes Care. 2006;29:S4-S42.
The Role of Combination Therapy in
Improving Glycemic Control: AACE
Recommendations
• To reduce the risk of serious disease-related
complications,1,2 AACE recommends:
– Target A1C goal of ≤6.5%2,3
– Intensive treatment of type 2 diabetes (i.e., earlier
intervention with
appropriate therapies and persistent titration to achieve
goal)2,3
• AACE recommends combining medications
with different mechanisms of action to target
multiple defects2,3
1. Stratton IM, et al. BMJ. 2000;321:405-412.
2. Davidson J, et al. Implementation Conference for ACE Outpatient Diabetes Mellitus Consensus Conference
Recommendations: Position Statement. July 8, 2005. Available at:
http://www.aace.com/meetings/consensus/odimplementation/index.php. Accessed May 25, 2006.
3. Davidson J, et al. Road Map for the Prevention and Treatment of Type 2 Diabetes. 2005. Available at:
http://www.aace.com/meetings/consensus/odimplementation/index.php. Accessed May 25, 2006.
The Rationale for Combination Therapy:
Multiple Mechanisms of Action Targeting
Multiple Sites
Glucose
Increase Insulin Secretion in
Functioning Pancreatic b-Cells2
Sulfonylureas/Secretagogues
Primarily
Decreases Hepatic
Glucose Production*1
Liver
Insulin
Pancreas
Metformin
Skeletal
Muscle
Decrease Insulin Resistance
and Increase Peripheral
Glucose Uptake3
Thiazolidinediones
* Also decreases intestinal absorption of glucose and increases peripheral glucose uptake and utilization.
1. Glucophage [prescribing information]. Bristol-Myers Squibb.
2. Amaryl [prescribing information]. Aventis Pharmaceuticals.
3. AVANDIA® (rosiglitazone maleate) [prescribing information]. GlaxoSmithKline.
Adipose
Tissue
Effect of Aspirin Use on
Survival in Patients With CAD
Syst-Eur: Reduction in Event
Rate in Adults (60 Years) With
Diabetes
HOT: Cardiovascular Events by
Target DBP in Diabetes
Subgroup
MRFIT: Impact of Diabetes on
Cardiovascular Disease
Mortality
Steno-2: Study Design
Steno-2: Treatment Goals
Steno-2: Multifactorial
Intervention and CV Events in
Type 2 Diabetes
ACE Inhibitor Therapy for
Patients With Diabetes
HOPE: Outcomes
in Patients With Diabetes
BIP: b-Blocker Treatment
Improves Survival of Patients
With Diabetes
ACCORD
First occurrence of a major
cardiovascular disease event:
• Nonfatal MI
• Nonfatal Stroke
• Cardiovascular Death
MI’s, Strokes, and Deaths adjudicated by a
committee masked to treatment assignment
Other ACCORD Outcomes
• Other cardiovascular outcomes
• Total mortality
• Microvascular outcomes
• Health-related Quality of Life (subset)
• Cost-effectiveness (subset)
ACCORD Timeline
1/03
Training
2/03 - 6/05
Recruit >8800 pts (30 months)
7/05 - 2/09
Follow-up (44 months)
3/09 - 6/09
Participant close-out (4 months)
7/09 - 3/10
Analysis & reporting (9 months)
Summary
Age
Pts
F/U
DM
Micro?
UKPDS
53
5102
10
50% mild +/-
Steno-2
55.1
160
7.8
T2DM
new Dx
Type 2
Microalbum
+/-
StopNIDDM
54.3
1368
3
IGT
No
None
in 6mo
Plan: 4-8
10,000
Type 2
>3mo
+/-
Yes or
+RF
Plan:
2800
Type 2
+/-
YES!
ACCORD >40
or
>55
BARI-2D >25
5
CAD?
Summary, cont
End pt micro
End pt macro
Looking at
spec Rx?
Unique ?
UKPDS
Primary
p=0.052
Yes
Largest study of type 2
yet
Steno-2
Secondary Primary
No
Decr in CAD w/
multiintervention
approach
Stop-NIDDM
No
Yes –
acarbose
CAD prevented in IGT by
decr in PPG
ACCORD
Secondary Primary
No
Large, ++center multiinterventional
BARI-2D
Secondary Primary mortality
Yes
CAD tmt trial
Secondary
DREAM:
Diabetes Reduction Approaches with
ramipril and rosiglitazone Medications
• Funded by King Pharmaceuticals, Aventis,
SmithKline Beecham in conjunction with CIHR
• F/U to the HOPE trial (heart outcomes prevention
evaluation)
• 5.5 year study
• Rosiglitazone reduced the risk of Diabetes by
60%
• Rosiglitazone had no effect on CVD outcome
UKPDS Follow-up
•
UKPDS 66 Patients with fatal MI had higher
HbA(1c) than those with nonfatal MI (odds
ratio 1.17 per 1% HbA(1c), P = 0.014).
Patients with fatal stroke had higher
HbA(1c) than those with nonfatal stroke
(odds ratio 1.37 per 1% HbA(1c), P = 0.007).
Stevens et. al. Diabetes care vol. 27, no. 1 (2004 Jan): 201-7.
•
High BP is detrimental to each aspect of
diabetic retinopathy; a tight BP control
policy reduces the risk of clinical
complications from diabetic eye disease.
Matthews DR, et. al. Archives of ophthalmology. vol. 122, no.
11 (2004 Nov): 1631-40
The Need for Early Intervention
• Norfolk Cohort (EPIC) – HbA1c predicted
CVD
• Nurses Health Study – CVD RR 3.17 before
dx and 3.97 after dx.
• Meta-analysis – progressive relationship
between glu and CVD at levels below DM
Dx
• DECODE – glucose and CVD did not show
a threshold effect (hazard ratios, IGT 1.1,
1.6 DM)
Khaw,et.al. BMJ 2001, 25. Hu et.al. Diabetes Care 2002:25. Coutinho et.al. Diabetes Care 1999:22. Decode study
group Diabetes Care 2003:26.
Earlier Addition of Rosiglitazone vs Uptitration of SU
Rosiglitazone Added to SU Confers Durable
Control Over 2 Years
Intent-to-Treat*
7.8
7.6
7.6
7.4
7.4
Mean A1C (%)
Mean A1C (%)
7.8
7.2
Completers†
7.2
7
7
Glipizide Uptitration Arm (n = 106)
6.8
6.8
Rosiglitazone + Glipizide (n = 113)
Glipizide Uptitration Arm (n = 50)
Rosiglitazone + Glipizide (n = 90)
6.60
6.60
0
6
12
18
24
12
18
24
Months
Months
* This is a repeated measures analysis accounting for baseline A1C, visit and treatment-visit interaction, and the correlation
among visits within a patient. Baseline values reflect the average baseline A1C across all treatments as estimated using this
model. All available values are utilized, including early visits from patients who subsequently withdrew from treatment. The A1C
values at these early visits are reflected in estimated means for subsequent visits based on trends within each treatment.
† Data shown are for those subjects who completed the study without experiencing glycemic failure.
Data on file, GlaxoSmithKline.
0
6
Effect of Pioglitazone
Monotherapy on the Atherogenic
Index of Plasma (AIP)*
Rosiglitazone Treatment Improves
LDL Particle Density Phenotype
Relative floatation (Rf)
Rf <0.2632 (small dense)
Rf 0.2632 (large, more buoyant)
100
Patients (%)
80
60
70
55
45
40
30
20
0
Pre-RSG
Week 8
Study 108. Data on file. GlaxoSmithKline.
Effect of Pioglitazone on
Abdominal Fat Distribution
Brachial Artery Flow in IGT and PVD Before
and 4 Months After Troglitazone Therapy
700
600
Before occlusion
700
*
After occlusion
600
500
500
Flow 400
(mL/min)
300
400
*
200
100
100
0
0
*P<0.05 Before vs after occlusion (N=10).
©1999
PPS
*
*
300
200
Fasting 30 min 1 h
Before therapy
*
2h
Fasting 30 min 1 h
After therapy
2h
Avena R et al. J Vasc Surg. 1998;28:1024-1031.
Impact of Treating Insulin
Resistance: Effects of TZDs on
Carotid Artery IMT
Effects of Thiazolidinediones on Potential
Determinants of Vasculopathy
Parameter
Troglitazone
Pioglitazone
 in vivo
 in vitro
 in vivo
 in vitro
No effect in vitro
 in vivo*
 in vitro
 in vivo
 in vitro
 in vitro*
PAI-1
Platelet aggregation
Intimal hyperplasia
Smooth muscle cell
proliferation/migration
Endothelial function
*Experimental animal study
Avena R et al. J Vasc Surg. 1998;28:1024-1031.
Ehrmann DA et al. J Clin Endocrinol Metab.
1997;82:2108-2116.
Igarashi M et al. Horm Metab Res. 1997;29:444-449.
©1999
Ishizuka
T et PPS
al. Diabetes. 1998;47:1494-1500.
Kotchen TA et al. Am J Physiol. 1996;270:R660-R666.
Marx N et al. Circ Res. 1998;83:1097-1103.
Minamikawa J et al. J Clin Endocrinol Metab.
1998;83:1818-1820.
Morikang E et al. Am J Hypertens. 1997;10:440-446.
Notoya Y et al. Diabetes. 1998;47:A365-366. Abstract.
Yamakawa K et al. Diabetes. 1998;47:A366. Abstract.
Effect of Rosiglitazone on
Microalbuminuria
Earlier Addition of Rosiglitazone vs Uptitration of SU
Safety Profile Over a 2-Year Period
Glipizide Uptitration Arm (n = 111)
60
Rosiglitazone + Glipizide (n = 116)
Adverse Events (%)
50
40
32%
27%
23%
30
9%
20
9% 10.3%
2.7% 3.4%
10
0
Symptomatic
Hypoglycemia
Edema
Rosenstock J, et al. Diabetes Obes Metab. 2006;8:49-57.
Data on file, GlaxoSmithKline.
Cardiac
Ischemia
CHF