2. 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
3. Magnitude of the Problem of
Cardiovascular Disease
and Diabetes in Egypt
4. 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
5. 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) :
7. 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
8. 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
9. 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)
10. 0
5
10
15
20
25
<28 >28-29 30-31 32-33 34-35 36-37 ≥38
RelativeRiskofDiabetes
Waist Circumference (in)
Abdominal Adiposity Is Associated
With 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.
11. Top 10 countries in
prevalence of diabetes
(20 – 79 age group)
IDF highlights over the world diabetes day 2007
12. Most persons with diabetes
will suffer and die from
cardiovascular consequences
13. 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
14. 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
Eventrate
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
15. 0
20
40
60
80
Adjustedincidence
per1000person-years(%)
Updated mean HbA1c concentration (%)Mean SBP (mmHg)
0
20
40
60
80
Adjustedincidence
per1000person-years(%)
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
17. 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
19. 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.
20. The occurrence of CVD is strongly related to modifiable lifestyles and to pathophysiological risk factors
XDiabetes
Hypertension
High cholesterol
Obesity
Risk Factor Concepts in Prevention
21. 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
22
Adapted from DeFronzo RA. Med Clin N Am 2004;88:787–835.
Prevention Treatment–10 10+ Years
Diagnosis
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 prediabetes
phase and benefits much from primary prevention of
diabetes compared to microvascular disease.
23. 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;33:1665–1673
Selvin E, et al Glycated hemoglobin, diabetes, and cardiovascular risk in nondiabetic adults.
N Engl J Med 2010;362:800–811
24. 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
25. “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)
26. 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;371:1783–1789
Lindström 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;368:1673–1679
Herman 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
27. Diabetes Prevention Program (DPP)
Number 3,234
Age (mean) 51 years
BMI (mean) 34 kg/m2
Clinical condition IGT
Duration (mean) 2.8 years
Lifestyle
58%
Metformin
31%
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 T2DM
Metformin was less
effective than LS
30. 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.
31. Benefit of Intensive Management:
Treatment Goals:
– Intensive TLC
– HgbA1c <6.5%
– Cholesterol <175
– Triglycerides <150
– BP <130/80
0
0
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
32. 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
34. Vinod Patel and John Morrissey,British Journal of Diabetes & Vascular
Disease 2002 2: 58, 2002
35. 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
36. Strategy Complication
Reduction 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.
37. 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.
38. 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
Endpoint(%)
No ASA
ASA
n=533 3711 4502 2368 1031 1276 2539
Endpoint 5 yr MI 7 yr MI 1 yr MCE5 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=.04
p < 0.001
p<0.002
p=NS
p=NS
p=NS
p<0.05
39. 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
41. 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 2.0
Cardiovascular Mortality
-12%
P=0.12
Death
ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-2572
42. 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.
43. 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
44. 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
%peryear
CV mortality, MI, or stroke
1.9
2.1
45. 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
46. 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
47.
48. 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.
50. 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
52. 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)
53. 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
%peryear
Fatal or nonfatal CV event
2.2
2.4
