Cardiovascular disease, hypertension, lipids, and myocardial infarction

The glycaemic disturbance (of Type 2 diabetes) may be mild, but the rest of the disease is not

George Alberti, 1988

Diabetic patients, particularly those with Type 2 diabetes and those with proteinuria, are at very considerable risk of excessive morbidity and mortality from cardiovascular, cerebrovascular and peripheral vascular disease leading to myocardial infarction (MI), strokes and amputations. Much effort must be given to reducing as far as possible the risk factors which are known to predispose to major atheromatous arterial disease. Many effective measures can now be taken, adding considerably to the complexity of treating diabetic patients, especially those with Type 2 diabetes. The difficulties and dangers of polypharmacy are discussed on site.

Coronary artery disease

Cardiovascular disease is substantially increased in diabetes, hyperglycaemia representing an independent risk factor. It is the chief cause of death and this observation strongly influences the management of diabetes by the important focus on reducing the risk factors responsible.

Diabetes more than doubles the risk of cardiovascular disease. In the United Kingdom, 35% of deaths are attributable to cardiovascular causes, compared with about 60% in those with Type 2 diabetes, and 67% of Type 1 diabetic patients alive after 40 years of age. The relative risk is greater for women than for men, so that the sex ratio is equal in those with diabetes, with a loss of the usual male predominance. The development of myocardial infarction over a period of seven years in middle-aged diabetic patients without known pre-existing coronary heart disease (CHD) is the same as that in non-diabetics with existing CHD. The presence of proteinuria and even microalbuminuria is associated with a particularly large risk of CHD and a high mortality from MI.

Those at especially high risk of developing CHD include

• Smokers
• Hypertensives
• Those with insulin resistance associated with obesity
• Patients of Asian origin
• Those with microalbuminuria
• Those with diabetic nephropathy (macroalbuminuria)
• Those with poor glycaemic control (16% increased risk of MI for every 1% increase in HbA1C)
• Those with hyperlipidaemic states

Prevention of cardiovascular disease: effects of lowering blood pressure

Those with a high risk of cardiovascular disease stand to gain proportionately greater benefit by reduction of risk factors. Two recently published major trials demonstrated exactly what can be achieved.

The United Kingdom Prospective Diabetes Study (UKPDS): tight v less tight blood pressure control (mean 144/82 mm Hg v 154/87 mm Hg). Benefits:

• heart failure reduced by 56%
• strokes reduced by 44%
• combined myocardial infarction, sudden death, stroke, peripheral vascular disease reduced by 34% (MI alone was reduced non-significantly by 16%).

There were also considerable benefits on the development of retinopathy and proteinuria.

Heart Outcomes Prevention Evaluation (HOPE) and MicroHOPE study: this study over 4.5 years comprised 9297 patients overall and included 3577 diabetic patients (98% with Type 2 diabetes). Patients with diabetes and one other risk factor for cardiovascular disease were randomly treated with the angiotensin converting enzyme (ACE) inhibitor ramipril 10 mg daily or placebo. Systolic blood pressure decreased by approximately 2 to 3 mm Hg and yielded a reduction of combined MI, strokes, and deaths from cardiovascular diseases of 25%.

The demonstrated benefits included:

• myocardial infarction relative risk reduced by 22%
• stroke relative risk reduced by 33%
• cardiovascular death relative risk reduced by 37%.

It was concluded that ACE inhibitors were the first line treatment for blood pressure control in diabetes. Despite some caveats relating to the handling of the study, this treatment should probably be extended to normotensive patients with high cardiovascular risks.

There have been several other published multicentre trials: the results of the HOPE and other studies are well summarised by Bilous R, HOPE and other recent trials of antihypertensive therapy in Type 2 diabetes; in Amiel S ed. Horizons in Medicine, Royal College of Physicians of London, 2002.

Blood pressure management

Blood pressure should be checked annually or more frequently as indicated. Borderline readings should be re-checked several times before the decision to use medication is taken. Before using pharmacological agents, the measures shown in the box all have some effect on reducing blood pressure:

Blood pressure > 160/100 mm Hg should always be treated in those with and without diabetes aiming for a level of < 140/80mm Hg (audit standard < 140/90mm Hg).

Blood pressure 140-159/90-99 mm Hg should be treated in diabetic patients, most aggressively in those with cardiovascular risk factors, especially if there is evidence of end organ damage; aim for < 140/80 mm Hg.

Blood pressure > 140/80 mm Hg should be treated if there is evidence of target organ damage or if the 10-year CHD risk exceeds 15%, aiming for a level < 140/80mm Hg. Blood pressure > 130/80 mm Hg should be treated in those with microalbuminuria or macroalbuminuria.

Factors that affect blood pressure

• Salt restriction
• Weight reduction or exercise programmes
• Reduction of excessive alcohol intake rimes

Choice of antihypertensive drugs

The key objective is to lower blood pressure by any means because most of the benefits relate to the blood pressure achieved rather than the drug used. There are however additional advantages using ACE inhibitors or angiotensin 2 receptor antagonists. Indeed, results of the recent losartan intervention for end point reduction (LIFE) study showed additional benefits resulting from the use of the angiotensin 2 receptor antagonist losartan when compared with β blocker atenolol, despite comparable blood pressure reduction. Many, probably most, patients will need more or than one drug to achieve the intended goal. A pragmatic approach to treatment it is often needed.

First and foremost, the key objective when choosing antihypertensive drugs is to lower blood pressure by any means because most of the benefits relate to the blood pressure achieved rather than the drug used

ACE inhibitors or angiotensin 2 receptor blockers are the first choice in those with microalbuminuria. ACE inhibitors, angiotensin 2 receptor blockers, cardioselective β blockers or thiazide diuretics are reasonable first line treatment in those without microalbuminuria. Long acting dihydropyridine calcium channel antagonists (for example, amlodipine) have an important role in treating hypertension and are second line agents.

Guidelines for choice of antihypertensive drugs

• Those with heart failure should have an ACE inhibitor whenever possible, which can be combined with a diuretic
• Conversion to an angiotensin 2 receptor blocker is helpful if a patient develops cough on an ACE inhibitor
• Addition of an angiotensin 2 receptor blocker to an ACE inhibitor will have an additive benefits on blood pressure but not on microalbuminuria
• Blood pressure in some African and Caribbean patients may respond better to calcium channel antagonists and diuretics than to other agents

Lipids and diabetes

Hyperlipidaemias also commonly exist in those with diabetes and increase still further the risk of ischaemic heart disease, especially in Type 2 diabetes. Detection and control of hyperlipidaemia can effectively reduce MI, coronary deaths and overall mortality. Indeed, even when low density lipoprotein (LDL) cholesterol is normal or even slightly raised in Type 2 diabetes (the major abnormalities being low HDL cholesterol and high triglyceride) the LDL particles may be qualitatively different and more atherogenic.

Screening for dyslipidaemia

This is an essential aspect of the annual review. If the lipid profile is entirely normal, further screening could be postponed for three to five years unless circumstances change. An elevated triglyceride needs confirmation when fasting.

Diabetic control

Optimising diabetic control often improves an abnormal lipid profile in Type 1 diabetes and sometimes in Type 2 diabetes.

Other medications and alcohol

Some drugs and also a high alcohol intake disturb plasma lipids (see table) and this aspect of treatment must be examined and if necessary modified.

Lifestyle measures

The importance of stopping smoking, weight reduction and exercise are described in site. Advice on low fat diets is also needed. Hypertension must be treated.

Lipid modifying drugs

Statins are the first line of drugs for treating hypercholesterolaemia; and fibrates for treating hypertriglyceridaemia. Statins and fibrates can be used alone or together for treating mixed hyperlipidaemia. Specialist advice should be taken on resistant or complex hyperlipidaemic states.

Some causes of secondary hyperlipidaemia

	Main lipid abnormalities
Alcohol abuse	↑ Triglyceride, ↑ HDL
Therapeutic drugs (diuretics, oral contraceptives retinoids, corticosteroids, anabolic steroids, progestogens related to testosterone)	↑ Triglyceride or cholesterol or both, ↓HDL
Hypothyroidism	↑ Cholesterol
Chronic renal failure	↑ Triglyceride
Nephrotic syndrome	↑ Cholesterol, ± ↑ triglyceride
Cholestasis	↑ Cholesterol
Bulimia	↑ Triglyceride
Anorexia nervosa	↑ Cholesterol
Pregnancy	↑ Triglyceride

Targets for treatment

The current targets for cholesterol and other lipid fractions are now the same for primary prevention in diabetes as for secondary prevention in people without diabetes. They are as follows:

• total cholesterol <5.0 mmol/l
• fasting triglyceride <2.0 mmol/1
• LDL cholesterol <3.0 mmol/1
• high density lipoprotein (HDL) cholesterol >1.1 mmol/1.

It is desirable that the ratio (HDL cholesterol)/(total cholesterol — HDL cholesterol) should be >0.25. Alternatively, the total cholesterol/HDL cholesterol should be <3.0.

There is much debate as to whether lipid lowering agents are of any value if started over the age of 75 years.

Targets for blood lipids control suggested by the European Diabetes Policy Group

	Low risk	At risk	High risk
Serum total cholesterol
mmol/1	< 4.8	4.8-6.0	> 6.0
mg/dl	< 185	184-230	> 230
Serum LDL cholesterol
mmol/1	< 3.0	3.0-4.0	> 4.0
mg/dl	< 115	115-155	> 155
Serum HDL cholesterol
mmol/1	> l.2	1.0-1.2	< l.0
mg/dl	> 46	39-46	< 39
Serum triglycerides
mmol/1	< l.7	1.7-2.2	> 2.2
mg/dl	< 150	150-200	> 200

Heart Protection Study

This huge double blind trial of 20 000 people at increased risk of vascular disease examined the benefits of treatment with simvastatin 40 mg daily, and reported its results in March 2002. The vascular event rate curves began to separate by the end of the first year, and the absolute benefits of treatment were seen to increase over time, becoming very obvious after five to six years. The major results are shown overleaf.

Cardiovascular disease, hypertension, lipids, and myocardial infarction

• reduction in vascular deaths 17%
• reduction in major vascular events 24%
• reduction in strokes 2*7%.

Treatment benefits were not only obvious among patients who had previously had an MI but also in those with prior cerebrovascular or peripheral vascular disease. Benefits were also demonstrated for diabetic patients without previous CHD. Both sexes benefited equally, and elderly patients over 75 years of age were seen to benefit to the same extent as younger patients.

The implications of the results of this study for diabetic patients are obvious, and serious consideration with regard to offering treatment with a statin drug must be given.

Severe hyperlipidaemic states

Extreme mixed hyperlipidaemias are, on rare occasions, associated with uncontrolled diabetes. The plasma has a milky appearance, and xanthomata appear in the skin as bright yellow papules particularly at the elbows, knees and buttocks. Even the retina assumes the pallor of lipaemia retinalis described as the “peaches and cream” appearance. The condition normally resolves when glycaemic control is achieved, lipid levels often return to normal, and the xanthomata disappear. Most but not all patients have Type 2 diabetes. The condition needs to be carefully monitored, and it is often wise to administer lipid lowering drugs until resolution. Sometimes they need to be continued indefinitely.

Myocardial infarction (MI)

The greater risk of CHD in diabetic patients is accompanied by a greater risk of MI: approximately 10% of all Mis occur in diabetic patients. Unfortunately, mortality rates are also about twofold higher. The increased mortality is attributable to left ventricular dysfunction leading to left ventricular failure and cardiogenic shock.

Presentation of myocardial infarction in those with diabetes is the same as in those without, although a greater proportion lack chest pain. Absence of cardiac pain has been attributed to the cardiac denervation although this concept lacks conviction.

Treatment

Thrombolysis

This should be used in diabetic patients for the same indications as for non-diabetics. The risk of vitreous haemorrhage in those with proliferative retinopathy is negligible. The benefits to diabetic patients with MI appears even greater than to those without diabetes.

Aspirin 300 mg

Given at the onset of a myocardial infarction, enteric coated aspirin 75-150 mg daily should be continued indefinitely thereafter.

Insulin treatment

Commenced at the onset of an MI, insulin treatment leading to optimal glycaemic control confers benefits on reducing mortality after discharge from hospital. The DIGAMI (Diabetes, Insulin, Glucose infusion in Acute Myocardial Infarction) study examined 620 patients with established or newly diagnosed diabetes (plasma glucose exceeding 11.1 mmol/l): an insulin and glucose infusion was started at presentation, followed by a multiple insulin injection regimen for at least three months. Twelve-month mortality was reduced by 30%. Confirmation of these results is required, but at present this study presents the best evidence available for the management of diabetes after myocardial infarction.

All diabetic patients, newly diagnosed and with established disease should be treated with insulin, and in many, this should be continued indefinitely. Some discretion needs to be used among elderly patients, or others who cannot easily or comfortably use insulin, in whom other simple measures can also achieve very good diabetic control.

Coronary artery bypass grafts and angioplasty

Decisions advising on the need for invasive coronary artery treatments are made in the same way as for non-diabetics. Coronary artery bypass grafts may offer an improved prognosis to those with diabetes after spontaneous Q wave infarction compared with angioplasty, and further investigations of this apparent benefit are in progress.

After myocardial infarction

Half the patients after their first MI die during the following twelve months, and half of those die before they reach hospital. Continuing optimal management of all risk factors is strongly recommended.

Management of risk factors after myocardial infarction

• Cessation of smoking
• Optimal blood pressure management
• Optimal diabetic control normally with insulin
• Optimal lipid control
• Use of aspirin, β Mockers, ACE inhibitors as indicated