macrovascular disease

Slides current until 2008

Macrovascular disease

Cardiovascular disease

Macrovascular diseaseCurriculum Module III-7d

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• Coronary heart disease

• Cerebrovascular disease

• Peripheral vascular disease

• What is an “event”?


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• Major cause of increased morbidity and mortality in diabetes

• Underlying abnormality: atherosclerosis

Williams 1999


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What is atherosclerosis?

• Process in which deposits of fatty substances, cholesterol, cellular waste products and calcium build up in the wall of an artery. This build up is called plaque

• Plaques can grow large enough to significantly reduce the blood flow through an artery. An acute event occurs when they become fragile and rupture

• Plaques that rupture cause blood clots that can block blood flow or break off and travel to another part of the body causing a heart attack and stroke


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Coronary heart disease

Known risk factors

• Age

• Gender

• Family history

• Lipid abnormalities

• Hypertension

• Smoking

• Diabetes


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Coronary heart disease in diabetes

• It is more common and occurs earlier than in people without diabetes

• Ethnic differences– Caucasians: more myocardial infarctions– Chinese/Japanese: more strokes

• Women lose gender protection

• Myocardial infarction is often painless (silent)

• Albuminuria increases risk of vascular event

Laing 1999


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Coronary heart disease in diabetes

Compared to people without diabetes, people with type 2 diabetes have:

• The same risk of heart attack as those who have already had a heart attack

• Two- to three-fold higher risk of heart failure

Sudden death occurs:- 50% more often in men - 300% more often in womenthan in peers without diabetes but of the same age

Haffner 1998


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Myocardial infarction and diabetes

People with diabetes havepoor prognosis evenafter adjustments for infarct size and risk factors.


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Controlling risk factors

Research shows the benefits of reducing the controllable risk factors for atherosclerosisControllable risk factors are:• Dyslipidaemia (especially LDL or "bad"

cholesterol)• Smoking and exposure to tobacco

smoke • High blood pressure • Diabetes • Obesity • Physical inactivity


Slide 10 of 49ACTIVITY


Case discussion

TJ is newly diagnosed with diabetes. He smokes one pack of cigarettes a day and does not do any exercise. His blood pressure is 150/95 and his BMI is 30.

• What are his risk factors?• What else should you assess? • How will you approach him regarding his risk factors?


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Controlling risk factors

• Lifestyle intervention: modify diet, lose weight, exercise, stop smoking, drink a glass of red wine

• Lipid-lowering agents

• ACE inhibitors

• Aspirin

• Benefits of glycaemic control?

NCEP 2005




• What dose should be taken?

• For whom is aspirin recommended?

• What are the side effects of aspirin?

• What are the contraindications to aspirin?

• Is there any other medicine that can be used if aspirin is contraindicated?

Use of aspirin


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Diabetes Intervention and Complication Study (EDIC)

Metabolic memory

• Follow-up of people who participated in the DCCT. The difference in glycaemic control had all but disappeared

• A total follow-up of 18 years


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57% reduction during EDIC follow-up period

Metabolic memory

Microvascular disease Macrovascular disease

Diabetes Intervention and Complication Study (EDIC)


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United Kingdom Prospective Diabetes Study (UKPDS)

Conventional

Intensive

0 3 6 9 12 150

10

20

30

0

10

20

30Myocardial infarctionp=0.052

Strokep=0.52

Time from randomisation (years)

0

10

20

30

Microvascular endpointsp=0.0099

0 3 6 9 12 15

Time from randomisation (years)

Pati

ents

wit

h e

vents

(%

)

Pati

ents

wit

h e

vents

(%

)P

atie

nts

with

eve

nts

(%

)

UKPDS 1998


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Post-study monitoring of UKPDS

Metabolic memory: micro- and macrovascular complications

• Myocardial infarction p=0.042, RR 0.86 (0.74-0.99)

• Microvascular disease P=0.0002, RR 0.72 (0.6- 0.86)


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Dyslipidaemia

• Main predictors of CVD mortality

– LDL and HDL cholesterol

• Lipid profile in type 2 diabetes

– raised triglycerides

– low HDL

– raised small dense LDL particles


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Lipids

IDF – type 2 diabetes

LDL <2.5 mmol/L (<95 mg/dl)

Triglyceride <2.3 mmol/L (<200 mg/dl)

HDL cholesterol >1.0 mmol/L (>39 mg/dl)

Canada

Primary targetSecondary target

LDL-C </= 2.0 mmol/LTC:HDL-C <4.0 mmol/L

United States LDL <100 mg/dl

Triglycerides <150 mg/dl

HDL >40 mg/dl

IDF 2005, CDA 2006, ADA 2004


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Lipids: clinical trials

Lipid-lowering agents called statins have an established role in both primary and secondary prevention.

Scandinavian Simvastatin 1994


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Lipids: side effects of statins

• Muscle pain (with or without an increase in muscle enzymes)

• Increase of liver enzymes

• Rhabdomyolysis:

– more common when statins and fibrates are used in combination

• Cluster nightmares and sleep disturbance

Durrington 2000




• What lipid-lowering agents are available in your country?

• What is common practice in relation to the use of lipid-lowering agents in your country?

Use of lipid-lowering agents


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Hypertension in diabetes

Prevalence

• Approximately twice that of people without diabetes

• More common in men than women before age of fifty


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Hypertension in diabetes

• Loss of day/night variation in blood pressure

– may be a sign of autonomic neuropathy

• Type 1: normotensive until renal disease develops

• Type 2: hypertensive before sign of renal disease


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Hypertension

JNC 7 and ADA recommendations

• Hypertension blood pressure: ≥140/90mmHg

• Target blood pressure goal in diabetes: 130/80mmHg

• Many people require three or more drugs to achieve the recommended target

ADA 2004, JNC7


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Reducing hypertension

• Decrease salt

– ACE inhibitors and ARBs work more effectively

• Avoid non-steroidal anti-inflammatory medicines

• Reduce alcohol to recommended levels

• Stop smoking

• Recommendations from the DASH study:

Doing one of the above is equivalent to a 10 mmHg drop or one antihypertensive tablet


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Anti-hypertensive medications

• ACE-inhibitors (-prils)

• A2 Receptor blockers (Atacand, Avapro, Karvea, Micardis, Teveten)

• Calcium antagonists (Dihydropyridine: Norvasc, Zanidip, Adalat ; and non-dihydropyridine: Verapamil, Diltiazem)

• Diuretics

• B-blockers


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Side effects of anti-hypertensive medications

• ACE-inhibitors (hyperkalaemia, cough, angioedema, rise in creatinine)

• A2 Receptor blockers (angioedema, rise in creatinine)


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• Calcium antagonists

– Dihydropyridine: fluid retention, flushing, tachycardia

– Non-dihydropyridine: fluid retention, constipation, bradycardia


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• Calcium antagonists

– Dihydropyridine: fluid retention, flushing, tachycardia

– Non-dihydropyridine: fluid retention, constipation, bradycardia

• Diuretics: dehydration, hypokalaemia, impotence


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• Calcium antagonists – Dihydropyridine: fluid retention, flushing,

tachycardia– Non-dihydropyridine: fluid retention,

constipation, bradycardia• Diuretics: dehydration, hypokalaemia, impotence• B-blockers: asthma, claudication, tiredness,

impotence


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Meta-analysis of BP treatment

• Seven sets of overview covering 29 randomized trials (n=162341)

• Mean duration of follow-up ranged from 2.0 to 8.4 years, providing data on 700,000 patient years

• Overall, for most comparisons between a half and three-quarters of participants remained on their randomly assigned study treatment

• A little over half achieved target BP


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Meta-analysis of BP treatment

• ACE inhibitors are better than calcium channel blockers in most endpoints, especially in mortality and heart failure

• Overall, ACE inhibitors are comparable to beta-blockers and diuretics used in combination. However, calcium channel blockers are again slightly inferior, especially in terms of heart failure

• A2 Receptor blockers are especially

useful in preventing stroke, heart failure and major cardiovascular events

Lancet 2005;366:907-913


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Meta-analysis of various anti-hypertensive regimens

• Magnitude of blood pressure reduction is the greatest determinant of efficacy in reducing cardiovascular disease

• The only exception may be in severe cardiac failure in which calcium antagonist may be inferior

Lancet 362 : 1527, 2003




• What is the recommended blood pressure target in your country?

• What is the most common approach to treating hypertension in your country?

Hypertension


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Isolated systolic hypertension

• Systolic blood pressure increases with age due to stiffening of arterial wall

• Several studies (SHEP and Syst-EUR) have shown that treatment of systolic hypertension reduces risk of stroke and cardiovascular events

Shep 1991, Birkenhager 2000


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Sometimes risk factors need to be treated even if they seem normal

• Micro Hope Study

• Heart Protection Study

• CARDS Study

A newer concept

Gerstein 2002, Heart Protection 2002, CARDS


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Heart Protection Study

• Large study, over 20 000 adults (~5000 with diabetes)

• Randomized to 40 mg simvastatin or placebo

Findings

• 25% reduction in first-time ischaemic stroke

• Transient ischaemic attacks and carotid endarterectomy or angioplasty also significantly reduced

• Reductions by end of second year of treatment


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Heart failure in diabetes

• Two to three times more common in diabetes

• Under-recognized and under-treated

• Progressive syndrome

• Systolic heart failure (not pumping)

• Diastolic heart failure (not relaxing, more common in diabetes)

– determined by echocardiography


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Treatment of heart failure

• ACE inhibitor

• Beta blocker

• Diuretic

• Daily weight

• Fluid management


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Cerebrovascular disease in diabetes

• Strokes occur twice as often in diabetes and hypertension than those with hypertension alone

• Transient Ischaemic Attacks (TIAs) occur two to six times more often

IDF 2001


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Cerebrovascular disease

Prevention

• Anti-hypertensive therapy

• Aspirin therapy

• Statin therapy (CARD Study)

• ACE inhibitor therapy (Progress Study)


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Summary


• Major cause of early morbidity and mortality

• Aggressive treatment of dyslipidaemia and hypertension

• Intensive treatment of modifiable risk factors

– lifestyle: increase physical activity

– improved diet: reduce total and saturated fat, increase monounsaturated fat, antioxidants and flavonoids

CDA 2003, ADA 2005


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Review question

1. Which of the following findings on a lipid profile of a person with diabetes is NOT considered a risk factor?

a. High levels of triglycerides

b. High levels of HDL cholesterol

c. High levels of LDL cholesterol

d. High total cholesterol-HDL ratio


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Review question

2. A 40-year old woman with obesity and type 2 diabetes is concerned about heart attacks because of “heart trouble runs in the family”. Which of the following responses would provide accurate information?

a. Only men with diabetes need to be concerned about coronary heart disease

b. Women with diabetes are at a higher risk for heart attacks before menopause than pre-menopausal women who do not have diabetes

c. If your weight decreases to your target level, your risk of heart attacks will be no greater than a woman who does not have diabetes

d. When you have diabetes, a family history of heart disease is not an additional risk factor


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Review question

3. A man with type 2 diabetes and hypertension has a blood pressure of 162/94 after several months of taking an antihypertensive medication. What is the next step in his treatment?

a. To further decrease his fat intake

b. To perform a stress electrocardiogram

c. To add an additional antihypertensive drug

d. To discontinue the present anti-hypertensive medication and try a different one


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Review question

4. In which of the following persons with diabetes would aspirin be contraindicated as preventive therapy?

a. An elderly man with type 2 diabetes who has had a thrombotic stroke

b. A 19-year old woman who has had type 1 diabetes since she was 5 years old

c. A 50-year old overweight woman with type 2 diabetes who smokes but has no evidence of coronary artery disease

d. A 38-year old man with type 1 diabetes and evidence of coronary artery disease


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Answers

1. b

2. b

3. c

4. b


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References

1. Williams G, Pickup JC. Handbook of Diabetes 2nd ed. London: Blackwell Science, 1999.

2. Laing SP, Swerdlow AJ, Slater SD, Botha JL, Burden AC, et al. The British Diabetic Association Cohort Study, II: cause-specific mortality in patients with insulin-treated diabetes mellitus. Diabet Med 1999; 16: 466-71.

3. Larsen J, Brekke M, Sandvik L, Arnesen H, Hanssen KF, et al. Silent Coronary Atheromatosis in Type 1 Diabetic Patients and Its Relation to Long-Term Glycaemic Control. Diabetes 2002; 51: 2637-41.

4. Diabetes Control and Complications Trial, Epidemiology of Diabetes Interventions and Complications Research Group. Intensive Diabetes Therapy and Carotid Intima-Media Thickness in Type 1 Diabetes Mellitus. N Engl J Med 2003; 348: 2294-303.

5. UK Prospective Diabetes Study Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes. Lancet 1998; 352: 837-53.

6. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease; the Scandinavian Survival Study. Lancet 1994; 344: 1383-9.

7. Durrington P, Sniderman A. Hyperlipidemia 2000. Oxford: Health Press.

8. US Department of Health and Human Services. The 7th Report of the Joint National Committee on prevention, detection, evaluation and treatment of high blood pressure.(JNC 7) National Institutes of Health, 2003.

9. American Diabetes Association. Treatment of hypertension in adults with diabetes, Diabetes Care 2004; 27(suppl 1): S80-S82.


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References

10. Williams B, Poulter NR, Brown MJ, et al. Guidelines for management of hypertension: report of the fourth working party of the British Hypertension Society, 2004. BHS IV. J Hum Hypertens 2004; 18: 139-85.

11. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug and treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA 1991; 265: 3255-64.

12. Birkenhager WH, Staessen JA, Gasowski J, de Leeuw PW. Effects of antihypertensive treatment on endpoints in the diabetic patients randomised in the Systolic Hypertension in Europe (Syst-Eur) trial. Nephrol 2000; 13(3): 232-7.

13. Gerstein HC. Reduction of cardiovascular events and microvascular complications in diabetes with ACE inhibitor treatment: HOPE and MICRO-HOPE. Diabetes Metab Res Rev 2002; 18(suppl 3): S82-5.

14. Heart Protection Study Collaborative Group. MRC/BHF Heart protection Study of cholesterol lowering with simvastatin in 2536 high-risk individuals: a randomised placebo controlled trial. Lancet 2002; 360(9326): 7-22.

15. Haffner SM, Lehto S, Ronnemaa T, et al. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Eng j Med 1998; 339: 229-234.

16. Canadian Diabetes Association. Dyslipidemia in Adults with Diabetes. Canadian Journal of Diabetes 2006; 30(3): 230-240.

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