Cardiovascular Risk Factors and Type 2 Diabetes

1
Cardiovascular Risk Factors and Type 2 Diabetes
2
What is type 2 Diabetes?

• Type 2 diabetes is a condition of premature
  cardiovascular complications in the setting of
  chronic hyperglycaemia.

3
Background-Facts

• Worldwide explosion of type 2 diabetes
• Prevalence is 3 in Caucasian population.
• Prevalence is 6 in ethnic minorities.
• 114 all adults
• 18 40-75 yrs
• 15 gt75yrs
• By 2025 more people will have diabetes worldwide
  than now live in North America.

4
Economic/Social facts

• 114 adults
• 18 40-75
• 15 gt75
• 13 Unaware of Dx

• By 2025 more people worldwide will have diabetes
  than now live in N.America
• 2-4 fold greater risk of stroke and heart disease
• 65 of deaths from CVS disease

5
Background-Facts

• By 2010, 3m people in UK will have type 2
  disease.
• 5 of health resources overall and 10 of
  in-patient resources spent on diabetes.
• Twice as likely to be admitted to hospital.
• Length of stay is likely to be twice as long.

6
Vascular problem.

• Life expectancy is reduced by 10 years.
• 75 of patients with type 2 diabetes die of
  cardiovascular complications.
• 75 of hospital admissions are for CVS disease.
• 2-4 fold increased risk of heart disease and
  stroke.
• After trauma, diabetes is the main cause of lower
  limb amputation.
• Main cause of ESRD requiring dialysis and
  blindness.

7
Financial Cost

• In 2000, 4.88 billion (8.9 of health budget)
  spent on diabetes.
• Uncomplicated 1500
• Macrovascular 3000
• Macro Micro 5000

8
Impact of Diabetes on Cardiovascular Mortality
50 40 30 20 10
Diabetic patients Non-Diabetic patients

Mortality per 1,000 Persons



0 1 2 3
Number of Risk Factors
Risk factors analyzed were smoking,
dyslipidemia, and hypertension
Diabetes Care 12 573-579, 1989
9
Coronary Heart Disease - Mortality
Male
60 50 40 30 20 10 0
With Diabetes
Female
Without Diabetes
CHD Mortality/1,000
Male
Female
0-3 4-7 8-11 12-15
16-19 20-23
Duration of Follow-up (yrs)
Diagnosed between 35 and 65 years of age
Am J Med 90(2A) 56S-61S,1991
10
Interrelationship BetweenAtherosclerosis and
Insulin Resistance

• Insulin Resistance

Hyper-insulinemia
Hypertri-glyceridemia
Small,dense LDL
Hypercoag-ulability
Hypertension
Obesity
Diabetes
Low HDL
Atherosclerosis
11
Modifiable CVD Risk Factors

• Glucose
• Hypertension
• Obesity
• Dyslipidemia
• Cigarette smoking
• Proteinuria
• Sedentary lifestyle
• Procoagulant state

12
1 Blood glucose

• UKPDS Study in type 2 disease. If HbA1C was
  reduced from 7.9 to 7 the incidence of MI was
  reduced by 16.

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CHD Mortality Rates by Degree of Glucose
Tolerance Paris Prospective Study
Incidence rate/1,000
Normal IGT Type 2 glucose
tolerance
Horm Metab Res 15 (Suppl) 41-46, 1985
15
Post prandial hyperglycaemia.-IGT

• B cell dysfunction results in loss of first phase
  insulin release resulting in PP hyperglycaemia.
• DECODE study. 25,000 subjects. Raised 2h glucose
  is an independent indicator for cardiovascular
  and all-cause mortality

16
Relationship Between CHD and HbA1c
25
CHD mortality
All CHD events
20
15
Incidence ()
10
5
0
lt6.0
6.0-7.9
gt7.9
HbA
1C
3.5-year incidence of CHD deaths and
events. Diabetes 43 960-967, 1994
17
Targets

• Fasting BS lt7mmol/l
• Glycated HB lt7

18
Treatments

• Metformin
• Sulfonylureas
• PP glucose sensors
• Thiazolidinediones
• Insulin

19
2 Blood Pressure

• MRFIT study Curvilinear relationship between SBP
  and CVD mortality. Similar to non diabetics but 3
  fold greater.
• UKPDS Tight BP control 144/82.
  All deaths reduced by 32 Stroke reduced by
  44 Heart failure reduced by 56.
• HOT study A reduction of 10mmHg in DBP (90 to 80)
  led to a reduction in all major CVS events by
  51.

20
Blood Pressure and CVD
113
Women
174
Men
119
74
90
56
77
48
Age-adjusted CV Event Rate/1,000
Age-adjusted CV Event Rate/1,000
59
36
31
50
38
23
15
24
105 135 165 195
105 135 165 195
Systolic BP (mmHg)
Systolic BP (mmHg)
No Glucose Intolerance
Glucose Intolerance
Am Heart J 121 1268-1273, 1991
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Major Outcomes of the HOT TrialDiabetes Subgroup
Diastolic Target
Plt0.005
Events/ 1000 Pt-Yrs
P0.016
Plt0.045
Lancet 351 1755-1762, 1998
23
Effect on Major Cardiovascular Events - 4 years
51 Risk Reduction vs. lt 90 group
Events/ 1000 pt-years
Diabetic Patients n1501, P0.005
Non-Diabetic Patients n18790, PNS
Lancet 351 1755-1762, 1998
24
Guidelines for the Treatment of HBP

• Initial Tx
• Lifestyle modification
• Smoking cessation
• Weight reduction
• Increase physical activity

• Pharmacologic Tx
• Alb- several choices
• Alb ACE inhibitor
• Multiple drugs often required

• Goals of Therapy
• BP 140/80
• BP lt 130/75

Diabetes Care 23 (Suppl 1) S32-S42, 2000
25
Pharmacologic Treatment for Hypertension

• ACE (HOPE)
• AR-11 blockers (LIFE PRIME)
• Diuretics
• Beta- blockers
• Alpha-blockers
• Calcium channel blockers
• Centrally acting anti-hypertensives

Diabetes Care 23 (Suppl 1) S32-S42, 2000
26
4 OBESITY

• Obesity (BMI gt30) increases the risk of CAD.
• The most powerful risk factor for type 2
  diabetes.
• Obesity magnifies the risks for each individual
  CVS risk factor.
• 10 reduction is associated with substantial
  reduction in CVS risk.

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Effect of Waist Circumference on Insulin
Sensitivity
90
90
Women (R0.71)
Men (R0.65)
75
75
60
60
Glycemic Disposal Rate (mmol/kg/min)
Glycemic Disposal Rate (mmol/kg/min)
45
45
30
30
15
15
0
0
27
31
35
39
43
47
23
27
31
35
39
43
47
Waist Circumference (inches)
Waist Circumference (inches)
Diabetes 42 273-281, 1993
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Goals for Weight Loss

• Negotiate realistic attainable goals
• Seek gradual weight loss (? 2 lbs/wk)
• Prescribe a regular exercise program
• Modest weight loss (5-10 of initial body weight)
  is beneficial

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Medical Nutrition Therapy (MNT)for Weight Loss

• Consult with a registered dietitian
• Diet
• calories (by 250-500 kcal/day)
• total fat (especially saturated fat)
• Increase dietary fiber
• Physical activity/exercise
• Behavior change
• Maintenance is key

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Effect of Orlistat in Diabetic Patients on Weight
Loss
-2-4-6-8
Placebo
Orlistat
Mean (SEM) ChangeBody Weight
Plt0.001
-5
0
4
12
20
28
36
44
52
Week
Diabetes Care 21 1288-1294, 1998
0
32
Dose Ranging Clinical Trial of Sibutramine in Non
Diabetic Patients
End of Treatment
0
-2
-4
Mean Change in Weight
Placebo 10 mg 15 mg
-6
-8
-10
24
27
30
0
4
8
12
16
20
24
Treatment Week
Obes Res 6 285-291, 1998
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5 LIPIDS

• Elevated VLDL
• Elevated small dense LDL particles
• Elevated triglycerides
• Reduced HDL
• All are independently atherogenic.

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Rate of CVD Death, by Total Cholesterol,in Men
With and Without Diabetes
Diabetes (n5136)
CHD Mortality/10,000 p-y
No Diabetes (n342,815)
Serum Cholesterol (mg/dl)
N Engl J Med 1999341650-8 Diabetes Care 16
434-444, 1993
35
Major Coronary Events in 4SDiabetics and
Non-Diabetics
Diabetes n 202 No Diabetes n 4220
55risk reduction
Diabetes by Hx, SimvaDiabetes by Hx, Placebo
P 0.002
No Diabetes by Hx, SimvaNo Diabetes by Hx,
Placebo
P 0.0001
Years Since Randomization
Diabetes Care 20 614-620, 1997
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Factors that Affect Lipoprotein Levels in
Diabetes

• Hyperglycemia
• Insulin deficiency
• Underlying genetic disorder
• Obesity
• Renal disease, hypothyroidism, liver disease
• Drugs (e.g., diuretics and beta-blockers)
• Diet (e.g., high fat)
• Alcohol

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Treatment Of Dyslipidemia

• Improve glucose control
• Weight loss if overweight
• Daily exercise
• Smoking cessation
• Low saturated fat, low cholesterol diet
• Pharmacologic treatment frequently necessary

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Impact of Baseline Smoking on MI inType 2
DiabetesUKPDS

• Hazards Ratio (95 CI)
• Never Smoked 1
• Ex-Smoker 1.08 (0.75 - 1.54)
• Current Smoker 1.58 (1.11 - 2.25)

CAD Fatal or non-fatal MI, or angina with
abnormal ECG
BMJ 316 823-828, 1998
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Smoking Cessation

• Physician must encourage
• Associated with weight gain
• Management intensify diet and exercise
• Pharmacologic treatment
• Use nicotine replacement with caution

40
6-Year Incidence of Diabetes Related to Fitness
Levels and BMI
Ann Int Med 130 89-96, 1999
41
Physical Fitness Predicts Cardiovascular Mortality
Pulse Rate
1569
1394
1273
1127
Follow-up Time (years)
Adjusted death rate. Quartiles reflect heart
rates during stage 2 exercise.
NEJM 319 1379-1384, 1988
42
Walking Small Changes Big Results
n1,564 University of Pennsylvania Alumnae
RiskofCVD
16
33
lt 3 Milesper Week
gt 6 Milesper Week
3-6 Milesper Week
Am J Epidemiol 150 408-416, 1999
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Exercise Guidelines

• Medical evaluation for CAD, PVD, and neuropathy
• Choose activity patient enjoys (walking -
  minimum 20 min 3x/wk)
• Educate on hypoglycemia
• Proper foot care and footwear
• Blood glucose monitoring - pre and post
• Insulin or carbohydrate adjustments when
  necessary
• Medical ID

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6 Insulin resistance

• Strong association between high fasting insulin
  and CHD mortality.
• High insulin levels are
  mitogenic in smooth muscle cells
  lipogenic
  stimulate PAI-1 production.
• Associated with obesity, hypertension and
  abnormal lipids.
• Carotid I/M thickness increased.
• Lifestyle changes, metformin, thiazolidinediones.

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7 Procoagulant state.

• Increased platelet stickiness.
• Increase in fibrinogen levels
• Increase in factor VII
• Increase in PAI-1
• These are related to hyperglycaemia

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Use of Aspirin in Diabetes
25
22
20
PatientsExperiencingCardiovascularEvents()
18
15
12
10
10
9
5
4
0
Placebo
Placebo
Placebo
ASA
ASA
ASA
US MDs
APT
ETDRS
Physicians Health Study (US MDs) relative
risk (RR) 0.39 (NS), NEJM 1989 Antiplatelet
Trialists Collaboration (APT) 2 P lt 0.002, BMJ
1994 Early Treatment Diabetes Retinopathy Study
(ETDRS) relative risk (RR) 0.83 (P 0.04),
JAMA 1992
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8 Oxidative stress

• ROS implicated in the development of insulin
  resistance.
• High ROS associated with oxidative stress.
• ROS induce endothelial dysfunction by consuming
  antioxidants and causing LDL oxidation.
• Correct with anti-oxidants such as vitamin C E
  folic acid.

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9 Microalbuminuria

• Microalbuminuria increases the risk for CVD
  twofold. It occurs in 10-20 of subjects with
  type 2 diabetes. Early identification targets
  patients for aggressive management against
  progression to overt renal disease, but also
  provides a marker for CVD.

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Targets

• Fasting blood glucose lt7mmol/l
• Glycated haemoglobin lt 7
• SBP lt140mmHg (130)
• DBP lt 80mmHg (70).
• Total Cholesterol lt 5mmol/l
• HDL-C gt 1 mmol/l
• LDL-C lt 2mmol/l
• Triglycerideslt1.5mmol/l
• BMI, smoking, exercise

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Evaluation

• ECG
• Autonomic dysfunction (Postural hypotension and
  resting pulse)
• 24 h ABP
• ETT
• Echocardiography
• Thallium scans
• Angiography

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Treatments

• 1 OHA/PP glucose regulators/insulin resistance
• 2 Insulin analogues.
• 3 ACE/ARB/B-blockers
• 4 Orlistat/Sibutramine
• 5 Statins/fibrates
• 6 Aspirin
• 7 Vitamins C/E, Folic acid.

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Summary

• Care of the patient with type 2 diabetes requires
  meticulous attention to glucose, blood pressure,
  lipids, obesity and platelet stickiness if we are
  to address the huge burden of CVS morbidity and
  mortality that accompanies this disease.