PROFESSOR OF CARDIOLOGY ; ASSIUT UNIVERSITY

13 May 2015

Magnitude of the problem of CVD and Type 2

diabetes.

Primary prevention of diabetes.

Secondary prevention of CVD and the

rationale for intensive glycemic, BP, and lipid

control.

Agenda

Magnitude of the Problem of

Cardiovascular Disease

and Diabetes in Egypt

28

19

12

9

6

5.1

0 5 10 15 20 25 30

Vascular Disease

Infectious Disease

Cancer

Injuries

Pulmonary Disease

AIDS

Mortality (%)

Prevalence of Cardiovascular Disease

Ischemic Heart Disease Cerebrovascular Disease

World Mortality from Ischemic Heart Disease

and Cerebrovascular Disease

6-54 55-83 84-111 112-224IHD Mortality (per 100 000) :

Top 10 Leading Risk Factors of Cause of Death

IDF/IAS/NHLBI/AHA/WHF Joint Scientific Statement on

Diagnosis of Metabolic Syndrome (>=3 criteria required for diagnosis)

(Alberti et al. Circulation 2009)

MetS is considered as a Major risk factor for T2DM and atherothrombotic complications

MetS confers a 5–10 years risk of:

5-fold increase in the risk of T2DM .

2-fold increase inthe risk of developing CVD.

2- to 4-fold increased risk of stroke.

3- to 4-fold increased risk of MI.

2-fold the risk of dying from MI.

Risk of Metabolic Syndrome

Global Prevalence of Obesity, WHO 2011

Egypt 30.2% of men and 50.8% - 70.9% of women

( based on IDF European cutpoints (94 cm men and 80 cm women)

(based on new Egyptian WC cutpoints (97.5 cm men and 92.3 cm

women, Sliem HA et al. Indian J Endocrinol Metab 2012; 16: 67-71)

0

5

10

15

20

25

<28 >28-29 30-31 32-33 34-35 36-37 ≥38

Rela

tive R

isk o

f D

iab

ete

s

Waist Circumference (in)

Abdominal Adiposity Is AssociatedWith Increased Risk of Diabetes

P value for trend <0.001

Carey VJ, et al. Am J Epidemiol. 1997;145:614-619Carey VJ, et al. Body fat distribution and risk of non-insulin-dependent diabetes mellitus in women: the Nurses’ Health Study. Am J Epidemiol. 1997;145:614-619.

Top 10 countries in

prevalence of diabetes(20 – 79 age group)

IDF highlights over the world diabetes day 2007

Most persons with diabetes

will suffer and die from

cardiovascular consequences

Alexander CM, Antonello S Pract Diabet 2002;21:21-28.

67%CHD, stroke & peripheral

vascular disease.

Other.

Causes of mortality in diabetics

Among people with diabetes, macro-vascular complications

are the leading causes of morbidity and mortality.

2/3 of People With Diabetes Die of CVD

Months

K Malmberg, et al. Circulation 102:1014–1019, 2000

3 6912 15 18 21 24

0.25

0.20

0.15

0.10

0.05

0.0

Eve

nt r

ate

RR = 2.88 (2.37-3.49)

RR=1.99 (1.52-2.60)

RR=1.71 (1.44-2.04)

RR=1.00

Diabetes/+CVD (N=1148)

No Diabetes/+CVD (N=3503)

Diabetes/-CVD (N=569)

No Diabetes/-CVD (N=2796)

OASIS Study: Total Mortality

0

20

40

60

80

Ad

juste

d in

cid

en

ce

per 1

00

0 p

erso

n-y

ears (

%)

Updated mean HbA1c concentration (%)Mean SBP (mmHg)

0

20

40

60

80

Ad

juste

d in

cid

en

ce

per 1

00

0 p

erso

n-y

ears (

%)

5 6 7 8 9 10 11110 120 130 140 150 160 170

Myocardial infarction

Microvascular endpoints

Microvascular endpoints

Myocardial infarction

Adler AI, et al. BMJ. 2000;321:412-419.; Stratton IM, et al. BMJ. 2000;321:405-412.Reprinted with permission from the BMJ Publishing Group.

Elevated SBP and HbA1c in Type 2 Diabetes Increases

the Incidence of MI and Microvascular Endpoints in UKPDS

Stamler J et al. Diabetes Care. 1993;16:434-444.

Ca

rdio

va

sc

ula

r M

ort

ality

Ra

te p

er

10

,00

0 P

ati

en

t-Y

ea

rs

SBP (mm Hg)

Nondiabetic patients

Diabetic patients

250

200

150

100

50

0<120 120–139 140–159 160–179 180–199 200

Elevated SBP in Type 2 Diabetes Increases

Cardiovascular Mortality

16

Most Cardiovascular Patients Have

Abnormal Glucose Metabolism

35% 31%

34%

37%18%

45%

37% 27%

36%

Glucose Tolerance in

Patients with AMI study

n = 164

Euro Heart Survey

n = 1920

China Heart Survey

n = 2263

PrediabetesNormoglycemia Type 2 Diabetes

Anselmino M, et al. Rev Cardiovasc Med. 2008;9:29-38.

1/3 of patients presenting with myocardial infarction

have undiagnosed diabetes mellitus

Approaches Prevention of CVD

Approaches to Prevention of CVD

Risk factors, such as cholesterol or blood pressure, obesity have

a wide bell-shaped distribution, often with a “tail” of high values.

The occurrence of CVD is strongly related to modifiable lifestyles and to pathophysiological risk factors

XDiabetes HypertensionHigh cholesterolObesity

Risk Factor Concepts in Prevention

Requires a multifaceted approach:

A) Primary prevention of diabetes.

B) Targeting all risk factors:- Hyperglycemia

- Hypertension

- Dsylipidemia

- Obesity

- Microalbuminuria

- Smoking

- Sedentary lifestyle

- Diet

CVD Risk Prevention and Diabetes

CDA CPG Expert Committee. Can J Diabetes. 2006;30:230-240.

Fourth Joint Task Force Recommendation,ESC, 2007 American Diabetes Association. Diabetes Care. 2006.

22

22

Adapted from DeFronzo RA. Med Clin N Am 2004;88:787–835.

Prevention Treatment–10 10+ YearsDiagnosis

Macrovascular complications

Microvascular complications

0

IFG/IGT Type 2 diabetes (Overt diabetic phase)

Blood

glucose

b-cell function

Insulin

resistance

IFG: impaired fasting glucose

IGT: impaired glucose tolerance

(Prediabetic phase)

Why Primary Prevention of Diabetes?

Macrovascular complications starts during the prediabetesphase and benefits much from primary prevention of diabetes compared to microvascular disease.

Prediabetes : Why Primary Prevention of Diabetes?

The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 2001;24:S5-S20

American Diabetes Association. Diabetes Care 2010;33:S11-61

FPG

126 mg/dL

100 mg/dL

7.0 mmol/L

5.6 mmol/L

Prediabetes

Normal

Diabetes Mellitus

2-Hour PG on OGTT

200 mg/dL

140 mg/dL

11.1

mmol/L

7.8 mmol/L

Impaired Glucose

Tolerance

Normal

Diabetes Mellitus

Hemoglobin A1C

6.5%

6.0%

Prediabetes

Normal

Diabetes Mellitus

In people with with IFG or IGT, approximately 50% will

develop type 2 diabetes during a 10-year follow-up.

Early intervention is needed to delay or prevent the

development of diabetes. This will lead to prevention of

morbidity and mortality from diabetes-related CVD.

Zhang Xet al. A1C level and future risk of diabetes: a systematic review. Diabetes Care 2010;33:1665–1673Selvin E, et al Glycated hemoglobin, diabetes, and cardiovascular risk in nondiabetic adults.N Engl J Med 2010;362:800–811

The “Population Approach” for

Diabetes and CVD Risk Reduction

Populations with western lifestyles of high-fat diets,

physical inactivity, and tobacco use are at high risk of

T2DM and CVD.

Public health services such as education, organizational

partnerships, and legislation/policy (Anti-Tobacco

policies).

Activities in community settings: schools, worksites,

mosques, churches, healthcare facilities,

Public education campaign to reduce smoking, fat

consumption, blood pressure, and cholesterol

“High Risk Approach” for Prevention/Delay

of Type 2 Diabetes

High risk patients with IGT (A), IFG (E) undergo support

program targeting weight loss of 7% of body weight and

increasing physical activity to at least 150 min/week of

moderate activity such as walking.

Metformin therapy for prevention of type 2 diabetes may

be considered in those with IGT (A), IFG (E), especially for

those with BMI >35 kg/m2, aged <60 years, and women

with prior GDM (A)

At least annual monitoring for the development of

diabetes in those with prediabetes is suggested. (E)

Screening for and treatment of modifiable risk factors for

CVD is suggested. (B)

Trial Treatment R R

• Finnish Diabetes Intensive D+E vs control ↓ 58%

Prevention Study

• Da Qing Study D, E or D+E vs control ↓ 42%

• DPP Intensive D+E vs placebo ↓ 58%

Metformin vs placebo ↓ 31%

• STOP-NIDDM Acarbose vs placebo ↓ 21%

• TRIPOD Troglitazone in GDM ↓ 56%

large studies of lifestyle intervention showed sustained

reduction in the rate of conversion to type 2 diabetes

Diabetes Prevention Program

Li G, et al The long-term effect of lifestyle interventions to prevent diabetes in the China Da Qing Diabetes Prevention

Study: a 20-year follow-up study. Lancet 2008;371:1783–1789Lindström J, et al., Finnish Diabetes Prevention Study Group. Sustained reduction in the incidence of type 2 diabetes by lifestyle intervention: follow-up of the Finnish Diabetes Prevention Study (7 yrs). Lancet2006;368:1673–1679Herman WH, et al., Diabetes Prevention Program Research Group. The cost-effectiveness of lifestyle modification or metformin in preventing type 2 diabetes in adults with impaired glucose tolerance. Ann Intern Med2005;142:323–332

Diabetes Prevention Program (DPP)

Number 3,234Age (mean) 51 yearsBMI (mean) 34 kg/m2

Clinical condition IGTDuration (mean) 2.8 years

Lifestyle58%

Metformin31%

Randomize

d patients

Metformin group

+ standard lifestyle counseling

Placebo

+ standard lifestyle counseling

Intensive nutrition

and exercise group

DPP. N Engl J Med 2002; 346: 393-403

58% reduction

in T2DMMetformin was less

effective than LS

Approaches to Secondary

Prevention of CVD

Secondary Prevention Strategies

Proven strategies include:

– Diabetes management (reduction of

hyperglycemia)

– Cholesterol-lowering

– Blood pressure reduction

– Antiplatelet therapy

– Smoking cessation

– Dietary therapy and exercise

Risk factor modification is the cornerstone of

secondary prevention of CVD.

Benefit of Intensive Management:

Treatment Goals:

– Intensive TLC

– HgbA1c <6.5%

– Cholesterol <175

– Triglycerides <150

– BP <130/80

00

10

20

40

50

60

Conventional Therapy

Intensive Therapy

30

Months of Follow Up

Primary End Point=CV events (%)

12 24 36 48 60 72 84 96

n =80

n =80

Gaede, P. et al, NEJM 2003;348:390-393

Gæde P et al. N Engl J Med 2003;348:383-393.

The Relative Risk of the Development or Progression of Microvascular

Disease during Follow-up of 7.8 Years in the Intensive-Therapy Group,

as Compared with the Conventional-Therapy Group

Stratton IM, et al., BMJ. 2000; 321(7258): 405-412.

Vinod Patel and John Morrissey,British Journal of Diabetes & Vascular Disease 2002 2: 58, 2002

The Alphabet Strategy: ABC of Reducing Diabetes Complications

A A1c Target

Aspirin Daily

B Blood Pressure Control

C Cholesterol Management

Cigarette Smoking Cessation

D Diabetes and Pre-Diabetes

Management

E Exercise

F Food Choices

Strategy ComplicationReduction of Complication

Blood glucose control Heart attack 37%1

Blood pressure control

Cardiovascular disease

Heart failure

Stroke

Diabetes-related deaths

51%2

56%3

44%3

32%3

Lipid control

Coronary heart disease mortality

Major coronary heart disease event

Any atherosclerotic event

Cerebrovascular disease event

35%4

55%5

37%5

53%4

Treating the ABCs Reduces Diabetic Complications

1 UKPDS Study Group (UKPDS 33). Lancet. 1998;352:837-853.2 Hansson L, et al. Lancet. 1998;351:1755-1762.3 UKPDS Study Group (UKPDS 38). BMJ. 1998;317:703-713.4 Grover SA, et al. Circulation. 2000;102:722-727.5 Pyŏrälä K, et al. Diabetes Care. 1997;20:614-620.

As a primary prevention strategy in those with type 1

or type 2 diabetes at increased cardiovascular risk

(10-year risk >10%).

ADA. VI. Prevention, Management of Complications. Diabetes Care 2013;36(suppl 1):S33.

Antiplatelet Agents

Secondary prevention strategy in those with diabetes

with a history of CVD

For patients with CVD and documented aspirin allergy

clopidogrel (75 mg/day) should be used

Combination therapy with aspirin and clopidogrel for

up to a year after an acute coronary syndrome.

1. Steering Committee of the Physicians' Health Study Research

Group. NEJM 1989;321:129-35

2. ETDRS Investigators. JAMA 1992;268:1292

3. Antiplatelet Trialists' Collaboration. BMJ 1994; 308:81

0

5

10

15

20

25

PHS ETDRS APT BIP PPP POPADAD JPAD

Endpoin

t (%

)

No ASA

ASA

n=533 3711 4502 2368 1031 1276 2539

Endpoint 5 yr MI 7 yr MI 1 yr MCE 5 yr CV Death 4 yr MCE 7yr MCE 4 yr MCE #

Events 26 vs 11 283 vs 241 502 vs 415 183 vs 133 20 vs 22 117 vs 116 86 vs 68

Diabetes Mellitus: Effect of Aspirin on

(MACE and CV Death)

4. Harpaz D et al. Am J Med 1998;105:494

3. Sacco M et al. Diabetes Care 2003;26:3264

4. Belch J et al. BMJ 2008; 337:a1840

5. Ogawa H et al. JAMA 2008; 300: 2134

p=.04p < 0.001

p<0.002

p=NS

p=NS

p=NS

p<0.05

United Kingdom Prospective Diabetes Study (UKPDS): 10-Year Follow-Up

Effect of Intensive Glycemic Control in T2 DM

Sulphonylurea vs. Conventional

Therapy

Insulin vs. Conventional

Therapy

Holman RR et al. NEJM 2008;359:1577-89

Intensive glycemic control in DM reduces the long-term risk of

myocardial infarction

ACCORD Intensive Glycemic Control in T2 DM

+35%

P=0.02

Discontinued intensive glycemia treatment

Cardiovascular Mortality

Cardiovascular death 253 289 12% (-4 to 26)

All deaths 498 533 7% (-6 to 17)

Non-cardiovascular death 245 244 0% (-20 to 16)

Number of patients with event

Intensive Standard

(n=5,571) (n=5,569)

Relative risk

reduction (95%CI)

Favors

Intensive

Favors

Standard

Hazard ratio

0.5 1.0 2.0Cardiovascular Mortality

-12%P=0.12

Death

ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-2572

ACCORD vs. ADVANCE

• One possible explanation of the difference in findings

between the two studies was that the rate of HbA1c

reduction was much greater in ACCORD (1.4%

reduction within 4 months than in ADVANCE 0.5% at 6

months and 0.6% at 12 months).

• Experts speculate that more aggressive treatment can

more likely lead to hypoglycemia requiring attention, as

was clearly the case in ACCORD.

HOT: Cardiovascular Events by Target

DBP in Diabetes Subgroup

18,000 patients with DBP 100 to 115 mm Hg into 3 groups by target DBP levels treated with ACEi, BB, diur

0

2

4

mace

ACCORD SBP

• Systolic BP at 1 year: 119 mm Hg in intensive

group vs. 134 mm Hg in standard group

• CV mortality, MI, or stroke: 1.9%/yr vs.

2.1%/yr, respectively

• CV mortality: 1.3%/yr vs. 1.2%/yr (p = 0.55),

respectively

• Serious adverse events: 3.3% vs. 1.3% (p <

0.001), respectively, due to increase in

hypokalemia and serum creatinine

Trial design: Type 2 diabetics were randomized to systolic BP <120 mm Hg (n = 2,362) vs.

systolic BP <140 mm Hg (n = 2,371). Mean follow-up was 4.7 years.

Results

Conclusions

• Goal systolic BP <120 mm Hg was not

superior to a goal systolic BP <140 mm Hg

• Similar incidence of CV outcomes in both

groups; however, more adverse events in the

intensive group

Presented by Dr. William Cushman at ACC.10/i2 Summit

(p = 0.20)

Systolic BP

<120 mm Hg

Systolic BP

<140 mm Hg

% p

er

ye

ar

CV mortality, MI, or stroke

1.92.1

In patients aged ≥18 years with diabetes, initiate

pharmacologic treatment at systolic BP ≥140mmHg or

diastolic BP ≥90mmHg and treat to a goal systolic BP

<140mmHg and goal diastolic BP <90mmHg. (Expert

Opinion–Grade E)

For Adults with diabetes aim for the same BP goals as in the general population

Treat if BP >140/90; Aim for <140/90

Blood Pressure Control in Diabetics

Diabetes Mellitus: Effect of Statins

Cholesterol Treatment Trialists’ (CTT) Collaborators. Lancet 2008;37:117-25

Meta-analysis

of 18,686

patients with

DM

randomized to

treatment with

a HMG-CoA

Reductase

Inhibitor

Summary

• Most persons with diabetes will suffer and die from

cardiovascular consequences.

• “Prediabetes” (IFG and/or IGT), indicates a relatively

high risk for the future development of diabetes.

• Early intervention is needed to delay or prevent the

development of diabetes. This will lead to prevention of

morbidity and mortality from diabetes-related CVD.

• Combined control of risk factors can result in up to

50% reductions in risk for cardiovascular disease.

49

What explains sharp decline in CVD Mortality Rates

in Western countries? USA, 1980-2000

Ford et al. NEJM 2007; 356: 2388.Lessons and warnings. Heart 2008;94 1105-8.

Risk factors modifications and improved treatments made

a sharp decline in CVD mortality over the last 3 decades

2013 Prevention Guidelines ASCVD Risk Estimator

Available at www.cardiosource.com

Moderate weight loss improves cardiovascular and metabolic risk factors

At 4 weeks

(11.1 mm Hg)

(6.5%) (17 mg/dL)

(94 mg/dL)

(37 mg/dL)

0

2

4

mace

ACCORD Lipid

• CV mortality, MI, or stroke: 2.2%/year with

fenofibrate vs. 2.4%/year with placebo

• Primary outcome plus revascularization or

hospitalization for CHF: 5.4%/year vs.

5.6%/year (p = 0.30), respectively

• All-cause mortality: 1.5%/year vs. 1.6%/year

(p = 0.33), respectively

• Exploratory analysis: possible benefit in men

vs. women (p for interaction = 0.01)

Trial design: Type 2 diabetics treated with a statin were randomized to fenofibrate (n =

2,765) vs. placebo (n = 2,753). Mean follow-up was 4.7 years.

Results

Conclusions

• Among type 2 diabetics treated with a statin,

there was no long-term benefit from

fenofibrate compared with placebo

• Composite CV outcomes were similar

between the two groups

Presented by Dr. Henry Ginsberg at ACC.10/i2 Summit

(p = 0.32)

Fenofibrate Placebo

% p

er

ye

ar

Fatal or nonfatal CV event

2.22.4

Subclinical Atherosclerosis

Atherosclerotic Clinical Events

Hyperglycemia

AGE

Oxidative

stress

Inflammation

IL-6

CRP

SAA

Infection

Defense

mechanisms

Pathogen burden

Insulin Resistance

HTN

Endothelial

dysfunction

Dyslipidemia

LDL

TG

HDL

Thrombosis

PAI-1

TF

tPA

Disease Progression

Biondi-Zoccai GGL et al. JACC 2003;41:1071-1077.

Mechanisms by which Diabetes Mellitus

Leads to CVD

Stratton IM, et al., BMJ. 2000; 321(7258): 405-412.