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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

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diabetes and cardiovascular diseases in type 2 diabetes from ukpds to steno 2
Diabetes and Cardiovascular Diseases in Type 2 Diabetes: From UKPDS to Steno 2 

Dara P. Schuster, MD

cardiovascular disease
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

slide5

The Metabolic Syndrome: A Network of Atherogenic Factors

  • Glycemic disorders
  • Dyslipidemia
  • - Low HDL
  • - Small, dense LDL
  • Hypertriglyceridemia
  • Postprandial lipemia
  • Hypertension
  • Impaired thrombolysis
  • - PAI-1, fibrinogen
  • Endothelial dysfunction/
  • inflammation
  • - CRP, MMP-9, adiponectin
  • Microalbuminuria

Insulin

Resistance

 Free Fatty

Acids

VisceralObesity

Atherosclerosis

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.

slide8

Obesity, Insulin Resistance and Endothelial Dysfunction

FFA

IL-1

IL-6

PAI-1

TNF-

leptin

adiponectin

Obesity

CRP

FFA

TNF-

leptin

resistin

adiponectin

Endothelial

Dysfunction

Hyper-

insulinemia

Hyperglycemia

Hypertension

Dyslipidemia

Altered coag/fib

Insulin

Resistance

Caballero AE. Obes Res. 2003; 11: 1278-1289

stenting in diabetes clinical and angiographic outcomes
Stenting in Diabetes: Clinical and Angiographic Outcomes

BARI – Mortality after CABG vs. PTCA, 2000

slide13

BARI I: Poorer Outcome with Revascularization in Diabetics

100

Non DM PTCA 86.8%

Non DM CABG 86.4%

DM CABG 76.4%

DM PTCA 55.7%

80

60

Percent Survival

40

Treatment Comparisons

Non-diabetics: p=0.72

Diabetics: p=0.0011

20

0

Years

0

1

2

3

4

5

6

7

slide14

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

improved glycemic control has been shown to reduce the risk of complications
Improved Glycemic Control Has Been Shown to Reduce the Risk of Complications

According to the United Kingdom Prospective DiabetesStudy (UKPDS) 35, Every 1% Decrease in A1C Resulted in:

14%

12%

21%

37%

Decrease

in risk of microvascular

complications

(P<.0001)

Decrease in risk of any diabetes-related end point

(P<.0001)

Decrease in risk of stroke

(P=.04)

Decreasein risk of MI

(P<.0001)

Stratton IM et al. BMJ. 2000;321:405-412.

ada standards of care
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
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

Skeletal Muscle

The Rationale for Combination Therapy:Multiple Mechanisms of Action Targeting Multiple Sites

Glucose

Increase Insulin Secretion in Functioning Pancreatic b-Cells2

Sulfonylureas/Secretagogues

PrimarilyDecreases Hepatic

Glucose Production*1

Liver

Insulin

Pancreas

Metformin

Adipose Tissue

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.

slide33

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

slide34

Other ACCORD Outcomes

  • Other cardiovascular outcomes
  • Total mortality
  • Microvascular outcomes
  • Health-related Quality of Life (subset)
  • Cost-effectiveness (subset)
slide35

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)

dream diabetes reduction approaches with ramipril and rosiglitazone medications
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 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
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.

slide41
Earlier Addition of Rosiglitazone vs Uptitration of SU Rosiglitazone Added to SU Confers Durable Control Over 2 Years

Intent-to-Treat*

Completers†

Mean A1C(%)

Mean A1C(%)

0

0

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.

rosiglitazone treatment improves ldl particle density phenotype

Relative floatation (Rf)

Rf <0.2632 (small dense)

Rf 0.2632 (large, more buoyant)

Rosiglitazone Treatment Improves LDL Particle Density Phenotype

100

80

70

55

60

45

Patients (%)

40

30

20

0

Pre-RSG

Week 8

Study 108. Data on file. GlaxoSmithKline.

brachial artery flow in igt and pvd before and 4 months after troglitazone therapy

Before occlusion

700

700

*

After occlusion

*

600

600

500

500

*

*

400

400

*

300

300

200

200

100

100

0

0

Fasting

30 min

1 h

2 h

Fasting

30 min

1 h

2 h

Brachial Artery Flow in IGT and PVD Before and 4 Months After Troglitazone Therapy

Flow(mL/min)

Before therapy

After therapy

Avena R et al. J Vasc Surg. 1998;28:1024-1031.

*P<0.05 Before vs after occlusion (N=10).

©1999 PPS

effects of thiazolidinediones on potential determinants of vasculopathy
Effects of Thiazolidinediones on Potential Determinants of Vasculopathy

Parameter Troglitazone Pioglitazone

PAI-1  in vivo  in vitro

Platelet aggregation  in vitro No effect in vitro

Intimal hyperplasia  in vivo  in vivo*

Smooth muscle cell proliferation/migration  in vitro  in vitro

Endothelial function  in vivo  in vitro*

*Experimental animal study

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.

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.

Ishizuka T et al. Diabetes. 1998;47:1494-1500.

Kotchen TA et al. Am J Physiol. 1996;270:R660-R666.

©1999 PPS

slide49

Earlier Addition of Rosiglitazone vs Uptitration of SU Safety Profile Over a 2-Year Period

32%

27%

23%

10.3%

9%

9%

2.7%

3.4%

CardiacIschemia

Symptomatic Hypoglycemia

CHF

Edema

Rosenstock J, et al. Diabetes Obes Metab. 2006;8:49-57.

Data on file, GlaxoSmithKline.

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