Cardiovascular Disease and Diabetes WADE 2010wadepage.org/files/file/2010annualMtg/ashley WADE blue... · 2012. 3. 14. · Diabetes Care Jan 2010 44 Mr. H. 65 year old male Cardiac

Cardiovascular Disease and Diabetes WADE 2010

Phoebe Ashley, MD - WADE 4/1/5/10 1

Diabetes and the Cardiovascular Connection

Phoebe A. Ashley, MD, FACC

Oregon Cardiology, PC

Medical Director, OHVI Cardiovascular Wellness and Rehabilitation Program

Phoebe A. Ashley, M.D., FACCOregon Cardiology, P.C.

Medical Director, OHVI Cardiovascular Wellness & Rehabilitation Program

2

Today’s Agenda

1. What is Cardiovascular Disease?

Coronary Artery Disease and Heart Attack

2. What is the BIG DEAL?

3. Risk Factors for Cardiovascular Disease

4. The Guidelines/Risk Factor Management

Glucose Control-How Low Should We Go?

Risk Factor Treatment Strategies

5. Additional Risk Factors to Consider

3

Ms. J56 year old woman• Diabetes

• High Blood Pressure

• High Cholesterol

• Depression

Presents with throat tightness at 1:30 pm

“You have a cold, wait here”

In Radiology at 8:00 pm . . .

The Resuscitation Room . . .

4

The Rest of the Story . . .

• Status-post a successful intervention of the right coronary artery.

• Moderately reduced ventricular function with chronic congestive heart failure What is

Cardiovascular Disease?

1.

6

Congestive Heart Failure 6%

High Blood Pressure 5%

Diseases of the Arteries

4%Rheumatic Fever/

Rheumatic Heart Disease 4%

Congenital Cardiovascular

Defects

0.4%

Other

13%

Stroke

18%

Coronary Heart Disease

54%

Percentage Breakdown of Deaths from Cardiovascular Diseases



7

Fatty Streaks

85% of people ages 21-39 years have fatty streaks

8

Arteriosclerosis

Image courtesy of Andrew Bourne, M.D.

Women are less likely to

have calcified, mixed

composition lesions

9

Ischemic Heart Disease

What is the BIG DEAL?

2.

11

Coronary Artery Disease 2006:A Disease of the Arteries of the Heart

• >6.9 million Americans are affected each year

− 785,000 new heart attacks

− 470,000 recurrent attacks

− 631,636+ deaths

12

Percentage of All Deaths Caused by Heart Disease in 2004

27.2All

27.5White

22.7Hispanic

24.6Asians/Pacific Islander

19.8American Indian/Alaskan Native

25.8African American

% of DeathsRace/Ethnic Group



13

The Risk

• Coronary Artery Disease:#1 cause of death in women and men

in America and in most industrialized nations

• Stroke:#3 cause of death of Americans

14

Leading Causes of Death for All Males and Females

United States: 2002

434

289

69 6134

494

269

64 42 39

0

100

200

300

400

500

A B C D E A B D F E

Males

Females

A Total CVD B CancerC AccidentsD Chronic Lower Respiratory Diseases

E Diabetes MellitusF Alzheimer’s Disease

Source: CDC/NCHS

15

(United States: 1979United States: 1979--2006). 2006). Source: NCHS and NHLBI.Source: NCHS and NHLBI.

350

400

450

500

550

79 80 85 90 95 00 06

Years

De

ath

s in

Th

ou

sa

nd

s

Males Females

CVD Disease Mortality Trends for Males and CVD Disease Mortality Trends for Males and

FemalesFemales

Risk Factors

4.

17

Risk Factors

Non-modifiable versus Modifiable

18

#1 Risk Factor:Family History of Premature Heart Disease

Father with Heart Disease < age 55

Mother with Heart Disease < age 65

Need comparable photo of a man



19

Non-modifiable Risk Factors

SEX

20

Non-modifiable Risk Factors

AGE

21

What About Menopause?

Estrogen

Weight &

Blood

Pressure

HDL

LDL &

Triglycerides

22

Modifiable Risk Factors

• Diabetes/Glucose Intolerance*

• Tobacco

• High Blood Pressure*

• Hyperlipidemia*

• Obesity*

• Obstructive Sleep Apnea*

• Lack of Exercise

• Drug Use

• Dental Disease

• Newer Modifiable Risks

− Hostility/Anger

− Stress*

− Anxiety/Depression

23

0

2

4

6

8

10

1958 '61 '64 '67 '70 '73 '76 '79 '82 '85 '88 '91 1994

FORECAST

0

5

10

15

20

25

2000 20250

2

4

6

8

10

1958 '61 '64 '67 '70 '73 '76 '79 '82 '85 '88 '91 1994

Millions

The Diabetes ExplosionNumber of Actual Cases

The New York Times - September 7,1999

24

Diabetes is a Coronary Heart

Disease Equivalent



25

Mr. B.24 year old Hispanic male

Cardiac Risk Factors:

• None

Symptoms:

• Intermittent exertional throat tightness

Presentation #3 . . .

26

The Evaluation

• ECG: Normal

• CXR: Normal

• Laboratories:

− Glucose 240

− Sodium 132

− Potassium 5.2

− Creatinine 1.6

− Troponin 8.3

27

Angiography

28


• Cardiac Surgery Consultation

• Cardiac Rehabilitation

• Aggressive management of risk factors

• Diet and Exercise

29

Physiologic Effects of Hyperglycemia

30

Cardiovascular Effects of Hyperglycemia



31

Insulin’s Effects

32

Characteristics of Metabolic Risk

• Central Obesity

• Insulin Resistance

• Dysproteinemia

• Hypertension

• American Diabetic Association and the American College of Cardiology Foundation

established lipid guidelines for patients with metabolic syndrome, Spring 2008

33

Acanthosis Nigricans

34

Acanthosis Nigricans and Skin Tags

• Clinical marker of hyperinsulinism and metabolic syndrome

• Skin tags are not often seen before the age of 40 years

• The severity of skin darkening and number of skin tags parallel the degree of insulin resistance

• Weight reduction and improvement in IR can result in partial resolution of acanthosis nigricans

35

Assessment of IR

• Accurate assessment is difficult

• Testing FBG and insulin levels is not standardized to reflect diagnostic cutoff points for IR Diamanti-Kandrarakis, et al, 2004

• TG/HDL ratio is a simple way to assess the likelihood of a patient being IR

− TG/HDL > 3.5/1 is suggestive of IR Laws, et al, 1992

36

A Typical Patient

• 36 year old obese woman with PCOS presents for further evaluation of difficult to control hypertension

• Medications: HCTZ 25 mg, Micardis 80 mg, Amlodipine 5 mg, Spironolactone 50 mg bid, Metformin 1000 mg bid

• Blood pressure 165/92 mmHg



37

The Classic Definition Of PCOS-NIH Consensus

• Anovulation

• Irregular menses

− 25% of women with PCOS have regular menses

• Hyperandrogenism

− Hirsutism/acne/diffuse alopecia

− Elevated testosterone or DHEA-S

38

Criteria for Metabolic Syndrome in Women with PCOS

149-199 mg/dL2 hour BG following glucose challenge (75g) *

110-126 mg/dLFBG

SBP >130;DBP >85 mmHgBlood Pressure

150 mg/dLTriglycerides

>35 inchesWaist Circumference

CUTOFF VALUERISK FACTOR

39

Insulin Resistance (IR) and PCOS

• All patients diagnosed with PCOS should be considered as having IR and are at increased risk of developing type II diabetes and cardiovascular disease American Association of Clinical Endocrinologists position statement, 2005

• Excess adipose tissue appears to be the primary source of IR

• IR in lean women with PCOS appears to be secondary

to abnormalities in postreceptor insulin signaling Dunaif, et al 1989

40

Metabolic Syndrome and CV Risk

Even in the absence of CVD and diabetes, individuals

with metabolic syndrome have a significantly higher risk

of CAD and all cause mortality Hu, et al 2004

41

Prevalence of Metabolic Syndrome

42

What’s the Risk of Heart Disease for People with Diabetes?

For Men:

2-3 times greater

For Women:

4-6 times greater



43

Who Should Be Screened?

• Those > 45 years of age (particularly if BMI > 25)− Repeat in 3 years if normal

• Screen earlier and more often if BMI > 25 plus:

− Physically inactive− First degree relative with Type 2 DM− High risk ethnic group

− Hypertensive > 140/90 mmHg− HDL < 35 and/or Triglycerides > 250

− History of gestational DM or baby > 9 lbs− History of PCOS− Previous IGT or IFG

− History of vascular disease

Diabetes Care Jan 2010

44

Mr. H.65 year old male

Cardiac Risk Factors:

• Dyslipidemia

• Hypertension

Symptoms:

• Marked diaphoresis following an evening meal

45

Mr. H., cont.

• ECG consistent with anterior myocardial infarction

• Troponin 3.2

• Creatinine 1.3

• Non-fasting Glucose 176

• Hematocrit 39

46

The Widow Maker

47

• Multi-vessel coronary artery disease

• Status-post staged percutaneous interventions

• Lipid management

• Blood pressure issues

• Persistently elevated blood sugars


48

Patients presenting with chest pain and an acute coronary syndrome have a 70% chance of having

diabetes or pre-diabetes



49

Prediabetes

• Impaired glucose tolerance (IGT)

− Plasma glucose > 140 mg/dl but < 200 mg/dl after 75 gram glucose load

− Better predictor of individuals who will go on to DM

• Impaired fasting glucose (IFG)

− Fasting plasma glucose concentration > 100 mg/dl but < 126 mg/dl

• Hemoglobin A1c > 5.7%

Rate of progression to DM is ~25% over 3-5 years for either IGT or IFG

Progression 8-10% per year in recent prevention trials

50

Diagnosing Diabetes Mellitus

• Screening for Glucose Abnormality: Prediabetes

− Fasting glucose > 100 mg/dl

− Random glucose > 130 mg/dl

− HbA1c > 6.0%

• Diagnosis of Diabetes:

− HbA1c 6.5-6.9% confirmed by plasma glucose test

− HbA1c > 7.0% confirmed by plasma glucose test or another HbA1c

Consensus Statement. J Clin Endocrinol Metab 2008;93:2447-2453

51

Diagnosing Diabetes in 2010

• HbA1c > 6.5%

• Fasting blood glucose of 126 mg/dl or higher

• A 75 gram glucose tolerance test with a two hour

glucose value > 200 mg/dl

• Should have two positive tests to make the diagnosis

Diabetes Care 2010;33(suppl1)

52

Developing Type 2 Diabetes

Prediabetes

Diabetes

~57 million people in the US have prediabetes

We can delay or prevent diabetes with diet and exercise

Normal Blood Glucose

53

Contribution of Diabetes to CHDStrong Heart Study

Hazard Ratio 6.3 3.1

Prevalence 60% 50%

Attributable risk 76% 51%

Women Men

Diabetes is the engine driving the increase in CVD

54

UKPDS Myocardial Infarction (cumulative)UKPDS Myocardial Infarction (cumulative)fatal or non fatal myocardial infarction, sudden death573 of 3867 patients (15%)

0%

10%

20%

30%

0 3 6 9 12 15

% o

f pa

tien

ts w

ith a

n e

ven

t

Years from randomization

Intensive

Conventional

p=0.052

Risk reduction 16%(95% CI: 0% to 29%)

UKPDS 35: Lancet. 1998, 352:837-53.



55

UKPDS HbA1c trend

cross-sectional, median values

06

7

8

9

0 3 6 9 12 15

Hb

A1

c (

%)

Years from randomisation

Conventional

Intensive

6.2% upper limit of normal range

UKPDS 35: Lancet. 1998, 352:837-53. 56

Selvin, Ann Intern Med. 2004:141:421-431

Estimated Cardiovascular Disease Risk Reduction from a 0.9% reduction in HbA1c:

UKPDS and Meta-Analysis of Prospective Cohort Studies

↓↓↓↓ 20%*↓↓↓↓ 35%Peripheral Vascular Disease

↓↓↓↓ 13%*↓↓↓↓ 6%Fatal CHD and MI

↓↓↓↓11%*↓↓↓↓16%CHD and MI (fatal and nonfatal)

↓↓↓↓ 16%*↑↑↑↑11%Stroke (fatal and nonfatal)

Meta-AnalysisUKPDSOutcome

* P 40yrs

60.5

>55 yrs

66

40-79

62.2

Age group

mean age

USEurope /AsiaNorth AmericaPopulation

1,79111,14010,251# Participants

97%58%62%Male

ADVANCE VADTACCORD

ACCORD Study Group, NEJM 2008, 358:2545-2559.ADVANCE Collaborative Group, NEJM 2008, 358:2560-2572.

VADT Study Results ADA Scientific Session San Francisco, 2008In Press, Diabetes Obesity and Metabolism, 2008

60

ACCORD, ADVANCE and VADT Baseline Clinical Characteristics

40%32%35%Prior CVD

9.47.58.3Baseline A1c

312832.2BMI

97.278 93.5Weight kg

11.5810Duration DM

ADVANCE VADTACCORD

ACCORD Study Group, NEJM 2008, 358:2545-2559.

ADVANCE Collaborative Group, NEJM 2008, 358:2560-2572.VADT Study Results ADA Scientific Session San Francisco, 2008

In Press, Diabetes Obesity and Metabolism, 2008



61

Therapeutic Approach: ACCORD, ADVANCE and VADT

75 v 71%

85 v 78%

55 v 45%

90 v 74%

- - -

74 v 67 %

17 v 11%

94 v 84 %

41 v 24 %

- - -

95 v 87 %

91 v 58 %

87 v 74 %

73 v 58 %

12 v 4 %

Meds (Inten v Std)

Metformin

TZD (Rosi)

Oral Hypoglycemic

Insulin

Exenatide

Stepped Approach:

Met BMI ≥27;

SU BMI 10Kg

No

ADVANCE

NoNoIncreased Mortality

Rosigliatzone?

VADTACCORD*Intensive vs Std

ACCORD Study Group, NEJM 2008, 358:2545-2559.ADVANCE Collaborative Group, NEJM 2008, 358:2560-2572.

VADT Study Results ADA Scientific Session San Francisco, 2008In Press, Diabetes Obesity and Metabolism, 2008

64

Hazard Ratios for the Primary Outcome and Death from Any Cause in Pre-specified Subgroups: ACCORD Study

N Engl J Med 358;24, 2008

Prior

CVD

A1c

>8.1

Age



67

ADA Consensus Statement on Medical Management of Hyperglycemia in Type 2 Diabetes

• Achieve and maintain near normoglycemia, A1c 9%) to good control (e.g. A1c < 7%)”

• “For selected individual patients, providers might reasonably suggest even lower A1c goals than the general goal of 7%, if this can be achieved without significant hypoglycemia or other adverse effects of treatment. Such patients might include those with short duration of diabetes, long life expectancy, and no significant CVD”

Diabetes Care 2010;33(suppl 1)

69

ADA SOC 2010 Glycemic Goals

• Lowering A1c to below or around 7% has been shown to reduce microvascular and neuropathic complications of type 1 and 2 diabetes. Therefore the goal for microvascular disease prevention is < 7% in nonpregnant adults (A)

• RCT of intensive vs standard glycemic control have not shown a significant reduction in CVD outcomes. Until more evidence becomes available, the general goal of < 7% appears reasonable for many adults for macrovascular risk reduction (B)

70


• Clinical trials have shown a small but incremental benefit in microvascular outcomes with A1c values closer to normal.

• For select patients providers might reasonably suggest

even lower A1c goals than 7 % if this can be achieved without significant hypoglycemia or other adverse effects. Such patients might include those with short

duration of diabetes, long life expectancy and no significant CVD (B)

71


• Less stringent A1c goals than < 7% may be appropriate for patients with the following (C):

− History of severe hypoglycemia

− Limited life expectancy

− Advanced microvascular or macrovascularcomplications

− Extensive co-morbid conditions

− Those with long-standing diabetes in whom the general goal is difficult to attain despite DSME, glucose monitoring and effective doses of multiple agents including insulin

72

Pathogenesis of T2DM and Drug Class Targets

Inzucchi, 2009



73

Type 2 Diabetes Treatment Strategies: 2008

74

GLP-1 Agonist, Exenatide:Effect on Cardiovascular Risk Factors

Klonoff DC, et al. Curr Med Res Opin 2008;24:275-286.

75

Algorithm for the Metabolic Management ofType 2 Diabetes

The ADA and EASD released a

new consensus statement in November 2008 for the treatment

of patients with type 2 diabetes.

Nathan DM, et al. Diabetes Care

2009; 32:193-203.

76

Thiazolidinediones (TZDs) and Risk of Heart Failure

• TZDs have been under intense scrutiny in recent years after

rosiglitazone was linked to increased CV morbidity and mortality

• ACC/AHA insufficient evidence to support the use of pioglitazone

over rosiglitazone, as both drugs increase the risk of heart failure

− Neither drug should be initiated in patients with class III/IV heart failure

• These drugs should not be used with the expectation of benefit in

ischemic heart disease events Circulation, published online 2/23/2010

• ACCORD, ADVANCE, VADT demonstrated no increased mortality

with the use of rosiglitazone

• FDA planning public meeting in July 2010 to present all heart-

related safety data with updated assessment of risks and benefits

of rosiglitazone and treatment of T2DM

Pharmacology Watch April 2010

77

What About Blood Pressure?

78

Blood Pressure Classification

>160 or >100Stage 2 Hypertension

140-159 or 90-99Stage 1 Hypertension

120-139 or 80-89Prehypertension



79

Hypertension and CVD Risk

• HTN prevalence ~ 50 million people in the United States

• Persons who are normotensive at age 55 have a 90% lifetime risk for developing HTN.

• For persons over age 50, SBP is a more important than

DBP as CVD risk factor.

80


• The BP relationship to risk of CVD is continuous, consistent, and independent of other risk factors

• Each increment of 20/10 mmHg doubles the risk of CVD across the entire BP range starting from 115/75 mmHg

• Those with SBP 120–139 mmHg or DBP 80–89 mmHg

should be considered prehypertensive and require health-promoting lifestyle modifications to prevent CVD.

81


Risk of Heart Attack or Stroke Based Upon BP

115/75 mmHg Ideal for non-diabetics

>120/80 mmHg Pre-Hypertension

135/85 mmHg 2x greater risk



82

Benefits of Lowering Blood Pressure

50%Heart Failure

20-25%Myocardial Infarction

35-40%Stroke Incidence

Average Percent Reduction

83

Lifestyle Modification

2-4 mmHgModeration of alcohol consumption

4-9 mmHgPhysical Activity

2-8 mmHgDietary sodium reduction

8-14 mmHgAdopt DASH eating plan

5-20 mmHg/10Kg weight

loss

Weight reduction

Approximate SBP Reduction (range)

Modification

84

Compelling Indications for Drug Classes

NKF Guideline,

Captropril Trial,

RENAAL, IDNT,

REIN, AASK

ACEI

ARB

Chronic Kidney

Disease

NKF-ADA

Guideline,

UKPDS, ALLHAT

Thiazides, BB,

ACEI, ARB, CCB

Diabetes

ALLHAT, HOPE,

ANBP2, LIFE,

CONVINCE

Thiazides, BB,

ACEI, CCB

High CAD Risk

Clinical Trial Basis

Initial Therapy Options

Compelling Indication



85

Hypertension Management in Diabetics in

2010

86

Blood Pressure and Type II DiabetesACCORD BP study March 2010

• 4733 patients, randomized, nonblinded, to intensive therapy (SBP < 120mmHg) or standard therapy (SBP < 140mmHg)

• Primary endpoint: nonfatal myocardial infarction, nonfatal stroke, or CV death

• Secondary end point: primary outcome plus revascularization or nonfatal CHF; major coronary disease events; and fatal or nonfatal CHF

• Mean follow-up of 4.7 years

• No significant difference in the primary end point or prespecified secondary end points except in the cases of stroke

NEJM 2010;DOI:10.1056/NEJMoa1001286

87

Blood Pressure and Type II DiabetesACCORD BP study March 2010

• 40% reduction in stroke for 5-10 mmHg reduction in blood pressure

• Patients in the intensive-therapy group were more likely

to suffer adverse events due to antihypertensive therapy 3.3% vs 1.3% (p



91

• Status post single vessel coronary artery bypass grafting

• Subsequently diagnosed with high cholesterol and insulin resistance


92

Hyperlipidemia

The “GOOD” (HDL)

The “BAD” (LDL)

The “UGLY” (Triglycerides)

93

High Density Lipoprotein:HDL = Good Cholesterol

Low HDL is BAD

94

HDL is an Antioxidant

• HDL is a carrier of antioxidant enzymes that can breakdown pro-inflammatory lipids

• Paraoxonase

• PAF acetylhydrolase

95

CholChol pickpick--upup

LiverLiverHLHL Small Small

VLDLVLDL

IDLIDL SmallSmallLDLsLDLs

LargeLargeLDLsLDLsHDL3HDL3

HDL2bHDL2b HDL3HDL3CholChol PickPick--UpUp

Muscle/Fat tissueMuscle/Fat tissue

LPLLPL

endothelial cellsendothelial cells

RemovalRemovalByBy

LiverLiverCETPCETP

CholChol return from HDL2 to LDLreturn from HDL2 to LDL

* Apo B ** Apo B *

* Antioxidant *

* Paraoxonase *

* LDL pattern B* LDL pattern B

LDL more susceptible LDL more susceptible to oxidative damage *to oxidative damage *

LargeLarge

VLDLVLDLRemnantRemnant

Small Small LDLsLDLs

Rapid entryRapid entry

OxidationOxidation

PlaquePlaque

HLHL

* Variable TG and PL content* Variable TG and PL content--

Oxidative susceptibilityOxidative susceptibility

III

aII

b

IIIa

IIIbIVa

IVb

96

HDL vs LDL as a Predictor of Coronary Heart Disease

• The Framingham Heart Study showed that the lower the level of HDL-C, the greater the risk of a coronary event, regardless of LDL-C level

•

• In fact, a person with a “desirable” LDL-C of 100 mg/dLbut a low HDL-C of 25 mg/dL has the same risk for an event as a patient with an LDL-C of 220 mg/dL who has an HDL-C of 45 mg/dL1,2

• As many as two-thirds of patients with CHD have low levels of HDL-C (≤40 mg/dL)3

1Gordon T, et al. Am J Med 1977;62:707; 2Castelli WP. Can J Cardiol 1988; (4 suppl

A):5A; 3 Rubins, HB, et al. Am J Cardiol 1995;75:1196



97

Is HDL The Protector Of The CV System?

• Low HDL is a powerful predictor of risk for coronary heart disease; raising HDL reduces coronary heart disease risk

• 1% decrease in risk with 1% increase in HDL

• Both statins and fibrates reduce risk across all HDL

levels

Eur Heart J Suppl (2204)6 (Suppl A):A19-A22

98

Management of HDL

• Lifestyle intervention

− Diet

− Exercise

− Tobacco cessation

• Drug options

− Niacin (+10-30%)

− Fibrates (+5-25%

− Statins (+3-12%)

99

Low Density Lipoprotein:LDL = Bad Cholesterol

• Better predictor of coronary artery disease in men than in women

• Plateaus in men after age 50, continues to rise in

women until at least age 65

100

Triglycerides=Ugly

• Underestimation of the association between TG and disease in a multivariate analysis

• Individual genetic susceptibility may play an important

role in the relationship between plasma TG levels and CVD

• 76% increase in CVD risk in women

• 31% increased CVD risk in men

(Associated with 1 mmol/L increase in TG levels)

101

Lipids And Lipoproteins in Patients with Insulin Resistance and T2DM

• Clustering of interrelated plasma lipid and lipoprotein abnormalities

− Reduced HDL2b

− Predominance of small dense LDL particles

− Elevated triglyceride levels

• Increased hepatic secretion of TG-rich VLDL and impaired clearance of VLDL is central in the

pathophysiology of “metabolic” dyslipidemia

102

Components Of The VAP Profile

• Non-HDL

− Difference between total cholesterol and HDL-C

− Includes all cholesterol present in lipoprotein particles considered atherogenic

• LDL

• Lipoprotein(a)

• IDL

• VLDL

• May be a better tool for risk assessment than LDL-C

• Secondary target in patients with high TG: Goal non-HDL is 30 mg/dl higher that that for LDL-C



103

Components of The VAP Profile

• LDL Particle Size

− A (desirable)

− A/B

− B

• HDL subunits

− HDL-2 is cardioprotective

• Apo B-100

104

Lipoprotein Guidelines in Patients with Metabolic Risk (MR)

• Patients with known cardiovascular disease or diabetes plus one or more additional major CV risk factor

− LDL < 70 mg/dl

− Non-HDL < 100 mg/dl

− apo-B < 80 mg/dl

− TG 55 in a woman; >45 in a man

105

Lipoprotein Guidelines in Patients with Metabolic Risk (MR)

• Patients without diabetes, but with two or more additional major CV risk factors

• Diabetics without other major CV risk factors

− LDL < 100 mg/dl

− Non-HDL < 130 mg/dl

− apo-B < 90 mg/dl

− TG 55 for a woman;> 45 for a man

106

The VAP Profile

107

Although behavioral interventions such as diet and exercise can improve diabetic dyslipidemia,

most diabetic patients will need pharmacological

therapy to reach treatment goals

Archives of Internal Medicine, 164(7):April 12, 2004

108

Statin Therapy in Diabetics?

• 18,686 patients with diabetes

• Meta-analysis of 14 randomized trials of statins

• Statins should be considered for all diabetic individuals who are at sufficiently high risk of vascular events



109

Niacin Therapy

• Niacin improves all lipoprotein abnormalities− Ideal for treating a wide variety of lipid disorders

− Metabolic syndrome

− Diabetes

− Isolated low HDL

− Hypertriglyceridemia

• Converts small LDL particles into more buoyant, less atherogenic cholesterol

• 3 formulations− Immediate release

− Long-acting

− Extended release

110

Niacin Therapy in Diabetes

• Major drug for treatment of diabetic dyslipidemias

• Is effective for separately treating diabetic dyslipidemiaassociated with abnromal LDL size, HDL2, and Lp(a) independent of hemoglobin levels

• Must be used with modern and aggressive oral

hypoglycemic agents or insulin,

Metabolism 51;9:September 2002, 1120-1127

111

Niacin + Simvastatin Therapy in Diabetes

• Effective, safe and well tolerated

• Slowed the progression of atherosclerosis among individuals with know CAD and moderately low HDL

112

Case: 1734 (7/95) Courtesy of Dr. M. Guarneri

Rx = Niacin 1,500 mgRx = Niacin 1,500 mg

TGTG = 109 = 109 --> 119 mg/dl> 119 mg/dl

LDLCLDLC = 121 = 121 --> 109> 109

LDL LDL IIIa+bIIIa+b = 36% = 36% --> 15%> 15%

HDLCHDLC = 42 = 42 --> 45> 45

HDL2b = 19% HDL2b = 19% --> 34%> 34%

Lp(aLp(a) = 2 ) = 2 --> 4> 4

Conclusion:Conclusion:

MinorMinor change in lipidschange in lipids

Big Change Big Change in LDL & HDL in LDL & HDL subclass distributionsubclass distribution

34%Increased HDL2b

Reduced Small LDL

15%

113

ACCORD Lipid Study

• 5518 patients (2765 fenofibrate plus simavastatin/2753 placebo plus simvastatin)

• Men seemed to benefit from fenofibrate therapy, with

trend toward harm in woman

• The combination of fenofibrate and simvastatin did not

reduce the rate of fatal CV events, nonfatal myocardial infarction, or nonfatal stroke, as compared with simvastatin alone

• Patients with higher triglycerides and lower HDL cholesterol levels benefitted from fenofibrate therapy in

addition to simvastatin

NEJM 2010;DOI:10.1056/NEJMoa1001282

114

Mr. M

• 53 y/o bank executive with T2DM, and dyslipidemiapresents at 2:30 pm following a fainting spell during a post lunch meeting

• ECG reveals a lateral myocardial infarction

• Laboratories: Troponin 6.2

Cr 1.1

Platelets 357

Hct 42

• Outpatient Labs: HgA1c 6.1%, LDL 86, HDL48, TG 158



115

Blood Cholesterol is NOT the Best

Indicator of Heart Disease Risk

• However...

80% of people who develop CAD havethe same blood cholesterol valuesas those who do notdevelop CAD

High blood cholesterol is an important CAD risk factor

Coronary Heart Disease Risk and Total

Serum Cholesterol in Framingham

150 200 250 300 350 4000

10

20

30

40

Total Serum Chol (mg/dl)

% P

op

ula

tio

n MINo MI

80%

116

35% of CHD Occurs in People With Total Cholesterol < 200 mg/dL

Framingham Heart Study: 26-Year Follow-up

No CHD

CHD

150 200 250 300

Total Cholesterol (mg/dL)

Adapted from Atherosclerosis. 1996:124(suppl);S1–S9.

117

Beyond High Cholesterol and Hypertension: Factors Responsible for Atherosclerosis and the Induction of

Acute MI in Diabetes

118

Atherosclerosis Is an Inflammatory Disease

Libby et al. Libby et al. CirculationCirculation 2002;105:11352002;105:1135--1143.1143.

EE--SelectinSelectin, ,

PP--SelectinSelectinLDLLDL

OxLDLOxLDL

LL--SelectinSelectin, ,

IntegrinsIntegrinsVCAMVCAM--1, 1,

ICAMICAM--11

MM--CSFCSF

MCPMCP--11

MacrophageMacrophage

Activation & DivisionActivation & Division

MonocyteMonocyte

Intima

Media

Smooth Muscle CellMigration

Other Other

inflammatory inflammatory

triggerstriggers

119

Inflammation is a Risk Factor for MI

P-Trend < 0.001

P



121

Aspirin Therapy in Diabetes ?

YES

122

Aspirin Therapy in Diabetes

• Platelets in patients with diabetes are often hypersensitive in vitro to platelet aggregating agents

• The major mechanism is increased production of thromboxane

• Excess thromboxane release is seen in T2 diabetics with CVD

• Aspirin blocks thromboxane synthesis by acetylating platelet cycloxygenase

123

Serine Kinase IKKB

• Recent studies have implicated fatty acid-dependent activation of serine kinase IKKB, which plays a role in tissue inflammation in pathogenesis of insulin

resistance.

• High dose salicylates have been shown to inhibit IKKB

activity

• 25% reduction in fasting plasma glucose

• 15% reduction in TC and CRP

• 50% reduction in TG

• 30% reduction in insulin clearance

• 20% reduction in basal rates of hepatic glucose production

• 20% improvement in insulin stimulated peripheral glucose uptake

J Clin Invest 109(10); 2002:1321-1326

124

Recommendations for Aspirin Therapy in Diabetic Patients

• Secondary prevention in diabetic patients with h/o myocardial infarction, vascular bypass procedure, stroke or tia, peripheral vascular disease, claudication and/or angina (A)

• Primary prevention in T1 and T2 diabetics at increased CV risk (>40 years, Fhx of CVD, HTN, smoking, dyslipidemia, albuminuria (A) (C)

• Contraindications: aspirin allergy, bleeding tendency, anticoagulant therapy*, recent gastrointestinal bleeding, and clinically active hepatic disease Other antiplatelet agents may be a reasonable alternative for patients with high risk. (E)

• Aspirin therapy should not be recommended for patients under the age of 21 years because of the increased risk of Reye’s syndrome associated with aspirin use in this population. People under the age of 30 have generally not been studied. (E)

Diabetes Care January 2004 vol. 27 no. suppl 1 s72-s73; NEJM 321; 1989:129-135: Jama 268;1992:1292-1300

125

Aspirin and ACE Inhibitor Therapy

• In patients with CVD, the benefits of ACEI therapy are reduced when used in conjunction with aspirin therapy

126

In Cases of Aspirin Allergy . . .

• Clopidogrel is a reasonable alternative

− In the CAPRIE trial, clopidogrel (75 mg) was slightly more effective than aspirin (325 mg) in reducing the

combined risk of stroke, myocardial infarction, or

vascular death in diabetic and nondiabetic subjects

Lancet 348:1329–1339, 1996



127

Mrs. S73 year old grumpy obese

woman• High Blood Pressure

• Diabetes

• Atrial Fibrillation

Presents for further evaluation of palpitations that often

awaken her from sleep

At night . . .

128


• Diagnosis and treatment of sleep apnea has led to improvement in the patient’s energy level, crabbiness, blood pressure, blood sugar control, and a reduction in

her episodes of arrhythmia

129

Obstructive Sleep Apnea

• Cardiovascular Conditions Associated with Obstructive Sleep Apnea

HypertensionCardiac Arrhythmias

BradycardiaSinus Bradycardia

Atrioventricular Block

Tachydysrhythmia

Supraventricular Tachycardia

Atrial FibrillationVentricular Tachycardia

Left Ventricular Systolic DysfunctionLeft Ventricular Diastolic DysfunctionCongestive Heart FailureStroke

Coronary Artery DiseasePulmonary Hypertension

130

Vascular Inflammation in Obesity and Sleep Apnea Circulation 2010;121:1014-1021

• Untreated OSA rather than obesity is a major determinant of vascular endothelial dysfunction, inflammation, and elevated oxidative stress in obese

patients

• Cardiometabolic effects of OSA include:

Increased growth hormoneIncreased cortisol, leptin

Insulin resistanceDysglycemia

Reactive plateletsHeightened sympathetic tone

Increased hs-CRPHypertension

131

Restorative Sleep Is A Must !

132

Obesity is a U.S. Epidemic

• Obesity is strongly associated with increased risk of heart attack and death from heart disease

• Nearly 33% of

children are

overweight

• 66% of adults are overweight



133

Obesity Truths

• 54 percent of all Americans clean their plates even when they're full

• 39 percent eat when they see food

• 20 percent eat when depressed

• 19 percent keep eating until stuffedSource: Prevention poll, Spring 1998

134 135

Childhood Obesity

• It is easier to prevent obesity in childhood than to cure it in adulthood.

• A 6 year old obese child has a 25% chance of being an obese adult

• A 12 year old obese child has a 75% chance of being an obese adult.

136

Ms. D.Young Ms. JA happy sedentary young girl who likes to eat

• By age 8:

− Weight 195 lbs.

− Diagnosed with Type II, “adult onset” diabetes

• By age 18:

− Weight 412 lbs.

− Sought treatment for her obesity

137

How to Calculate Body Mass Index (BMI)

BMI = Weight ÷÷÷÷ Height 2 x 703

Example:

Weight: 185 lbs.

Height: 64 in. (5’4”)

185 ÷÷÷÷ (64 x 64 = 4096) = .045 x 703 = 31.6 BMI

Normal BMI: 18.5-24.9

Overweight: 25.0-29.9

Obese: > 30.0

Morbidly Obese: > 50

138

Obesity Prevalence

in 1993

15-19% in 12 states

20+% in 0 states

Centers for Disease Control and Prevention, 2003

Obesity is Increasing Rapidly Throughout the United States



139

Obesity Prevalence

by 2003

15-19% in 15 states

20-24% in 31 states

25+% in 4 states

Obesity is Increasing Rapidly Throughout the United States

Obesity Prevalence

in 1993

15-19% in 12 states

20+% in 0 states

Centers for Disease Control and Prevention, 2003

140

Obesity Trends* Among U.S. AdultsBRFSS, 2006

(*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person)

No Data



145

Obesity Treatment

• Diet and exercise critical

• Counseling/behavioral modification

• Medications

• Bariatric surgery

146

How Much Exercise?

• General recommendations have been increasing over time

• 40 minutes of aerobic exercise daily to one hour daily

• This should be combined with muscle building activity at least three times per week

Paul D. Thompson et al, Exercise and Physical Activity in the Prevention and Treatment of Atherosclerotic Cardiovascular Disease: A Statement From the Council on Clinical Cardiology Circulation, Jun 2003; 107: 3109 –3116

147

YIKES!

148

Stress

75-90% of all visits to healthcare providers result from

stress-related disorders American Institute of Stress

149

How Does Stress Contribute to Heart Disease ?

Blood Pressure Increases

Cholesterol Increases

Tendency to Overeat

Exercise Less

Smoke, Drink, Take Drugs

Stress Makes

Other Factors Worse

Can cause persistently

elevated levels of

stress hormones

• Adrenaline

• Cortisol

Effects of

Chronic Stress

Changes the way

blood clots, increasing

risk of heart attack

150

Stress Management and Exercise

• A study examining the effects of exercise or stress management training on “mental stress tests”

• 107 patients with CAD and ischemia on baseline mental stress testing compared to control

• 4 month training in exercise or SM, 5 year follow up

• Stress management training: risk of cardiac events 74% lower than controls and decreased ischemia on repeat testing

• Exercise training decreased risk but not statistically significant

Blumenthal et al, Arch of Int Med, 1997, Oct 27;157(19):2213-2223



What Should YOU Do?

6.

152

Be Sure to Stop and Smell the Roses

153

Promotion of Health

Nutrition Movement

Restorative

Sleep

Stress

Reduction

Health is not simply the absence of disease, but the presence of a state of

well being

154

Prevention Is the Key

• Be Proactive

• Identify and Treat Patient’s Risk Factors

• Educate

• Encourage Patients To Talk With Family and

Friends

• Get Moving

155

Thank You

Documents

Cardiovascular Disease and Diabetes WADE 2010wadepage.org/files/file/2010annualMtg/ashley WADE blue... · 2012. 3. 14. · Diabetes Care Jan 2010 44 Mr. H. 65 year old male Cardiac