Stella S. Daskalopoulou and Dimitri P. Mikhailidis

A 62-year-old man with intermittent claudication was referred for vascular risk factor modification. He had no history of myocardial infarction (MI) or stroke. He was smoking 20 cigarettes/day. His family history was negative for premature vascular events. He was not taking any medication. He was advised to start aspirin 75 mg/day, but he stopped taking these tablets because of “stomach discomfort”. The patient’s total cholesterol was 228 mg/dL (5.9 mmol/L). His blood pressure required treatment with amlodipine and a thiazide diuretic. The patient eventually stopped smoking after referral to the smoking cessation clinic in our hospital.

Question 1

Which of the following investigations would you order?

A.  Fasting serum glucose.

B.  Urine glucose to make a diagnosis of diabetes mellitus. C.  Fasting serum triglycerides.

D.  Fasting serum high-density lipoprotein cholesterol (HDL-C). E.  Thyroid function tests.

A.  Requesting a fasting serum glucose level is an essential test in all patients with vascular disease. In this case the fasting glucose was 87 mg/dL (4.8 mmol/L); this is satisfactory.

Interpretation of fasting glucose values:

There are three categories in which a patient can be placed relative to fasting serum glucose levels:

•Normal: fasting glucose <110 mg/dL (<6.0 mmol/L).

•Impaired fasting glucose (IFG): fasting glucose 110–125 mg/dL (6.0–6.9 mmol/L).

•Diabetesmellitus:fastingglucose ³ 126mg/dL(³7.0mmol/L).IFGisassociatedwith anincreasedriskofvasculareventsandconversiontodiabetesmellitus.Furthermore, a glucose level in the IFG range can be one of the features of the metabolic syndrome (also known as insulin resistance or Reaven’s syndrome)1 (Table 16.1).

S.S.Daskalopoulou ( )

Department of Medicine, McGill University, Montreal, QC, Canada

Table 16.1  Features of metabolic syndrome*

1.Abdominal obesity (waist circumference): Men ³ 102 cm (³40 in.)

Women ³ 88 cm (³36 in.)

2.Triglycerides

³150 mg/dL (³1.7 mmol/L)

3.High-density lipoprotein cholesterol (HDL-C): Men <40 mg/dL (<1.0 mmol/L)

Women <50 mg/dL (<1.3 mmol/L)

4.Blood pressure: ³130/³85 mmHg

5.Fasting glucose: ³110 mg/dL (³6.1 mmol/L)

*According to the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III guidelines,1 any three or more of these five features are diagnostic of the metabolic syndrome. Other factors that may coexist in these patients include a family history of type 2 diabetes, South Asian ethnicity, decreased physical activity, smoking, elevated serum urate levels and evidence of fatty liver (abnormal levels of aminotransferases, ALT/AST). A new consensus definition of metabolic syndrome has been proposed in 2009.2 The new definition interpret waist circumference by ethnicity and the glucose value is 100 mg/dL (5.6 mmol/L).

B.  This patient’s urine was tested when he was first seen in outpatients. The renal threshold for glucose is a serum level of about 180–200 mg/dL (10–11 mmol/L). Therefore, testing urine for glucose will not detect IFG or early/mild diabetes. Clinicians must not rely on a urine glucose test to exclude IFG or early diabetes. In view of the serum ­glucose value (see A, above), it is not surprising that the urine glucose test was negative. However, testing the urine was an opportunity to exclude proteinuria, another indicator of vascular risk.

C.  The fasting triglyceride level in this patient was 141 mg/dL (1.6 mmol/L) – this is satisfactory.

Interpretation of fasting triglyceride values:

There has been considerable confusion regarding the importance of triglycerides. There are several reasons for this, including:

•Interactions with other lipid variables: serum triglyceride and HDL-C levels are inversely related. HDL-C is a “protective” lipoprotein.

•Interactions with potential risk factors: elevated serum triglyceride levels are associated with impaired fibrinolysis and possibly elevated plasma levels of fibrinogen. Both type 2 diabetes and metabolic syndrome are associated with raised serum triglyceride levels.

•There is evidence (post-hoc analysis) from the Scandinavian Simvastatin Survival Study (4S) that IFG and diabetic patients benefit from treatment with simvastatin.3 More recently, a trial in type 2 diabetic patients without established vascular disease showed a beneficial effect of atorvastatin 10 mg/day (vs. placebo) in reducing the risk of first cardiovascular events, including stroke.4 Both diabetes and metabolic syndrome are common in patients with peripheral arterial disease (PAD).5 Furthermore, both diabetes and PAD are considered as coronary heart disease (CHD) equivalent and need to be treated aggressively.1

•Triglyceridelevelsvaryconsiderablywithinanyindividual:thisvariabilityincludes the fact that fasting triglycerides may be considerably lower than non-fasting levels in some patients. There is evidence that postprandial triglyceride levels also predict vascular risk, but this measurement is not easily standardised. Therefore, assessment of triglyceride status is best represented by a fasting sample (12to 14-h overnightfast;wateronlyallowed).Fastingserumtriglyceridelevelsmaybeindependent vascular risk factors.6 Hypertriglyceridaemia is often associated with secondary causes that aggravate the patient’s tendency to this type of dyslipidaemia (Table 16.2). These causes need to be addressed.

Fasting triglyceride levels are defined in the NCEP ATP III guidelines1:

•Borderline high: 150–199 mg/dL (1.7–2.2 mmol/L).

•Moderately elevated: 200–499 mg/dL (2.3–5.6 mmol/L).

•Severe hypertriglyceridaemia: ³500 mg/dL (³5.6 mmol/L).

According to these guidelines,1 the treatment priority for cases with severe hypertriglyceridaemia shifts from LDL-C to the triglyceride levels. This is because of the increasedriskofacutepancreatitisassociatedwithseverehypertriglyceridaemia.1 For milder hypertriglyceridaemia, the priority for treatment remains the LDL-C level.1

D.  The fasting HDL-C level in this patient was 46 mg/dL (1.2 mmol/L) – this is satisfactory.

Interpretation of fasting HDL-C values:

A raised HDL-C level is a protective factor, whatever the levels of other lipid variables.1,7, 8 The recent NCEP ATP III guidelines1 recommend that HDL-C levels should ideally be ³ 40 mg/dL (³1.0 mmol/L).1,7,8 A low HDL-C level is also predictive of the risk of stroke.9,10 The importance of HDL-C in reducing the risk of vascular events is supported by the findings of a secondary prevention trial (VA-HIT).10

E.  The thyroid function tests were normal.

It is useful to routinely assess thyroid function in dyslipidaemic patients. This is because hypothyroidism is not uncommon and it is associated with dyslipidaemia (see Table 16.2). There is also some evidence showing that hypothyroid patients are more likely to have “muscle-related” side effects if they are given a statin. Hypothyroidism can also be difficult to spot unless the clinical features are obvious. Replacement with thyroxine is usually associated with a beneficial change in the lipid profile and body weight.

Table 16 2  Secondary causes of hypertriglyceridaemia/hypercholesterolaemia Excessive alcohol intake

Diabetes mellitus Hypothyroidism

Some types of liver disease Some types of renal disease Obesity/diet

Drugs: beta-blockers, thiazides, oestrogens, anabolic steroids, corticosteroids, tamoxifen, protease inhibitors, retinoids, ciclosporin

Table 16.3  CHD equivalents according to the NCEP ATP III guidelines1 Peripheral arterial disease

Abdominal aortic aneurysm Symptomatic carotid artery disease Diabetes mellitus

Multiple risk factors conferring a calculated risk for a vascular event ³ 20% over the next 10 years

Question 2

What drug would you use to treat this patient’s dyslipidaemia? What are your target levels? The main target for lipid-lowering treatment is the LDL-C level. Since PAD is considered a coronary heart disease (CHD) equivalent1 (Table 16.3), the LDL-C target is 100 mg/ dL (2.6 mmol/L) in the USA1 and 96 mg/dL (2.5 mmol/L) in Europe.11 The NCEP ATP III guidelines were revised in 2004 to include an optional LDL-C target of 70 mg/dL (1.8 mmol/L) for very high-risk patients.12 As explained above, the HDL-C and triglyceride levels are secondary targets. A full fasting lipid profile should be obtained before making any decision regarding treatment. In the case presented above, the fasting values were: total cholesterol = 228 mg/dL (5.9 mmol/L), HDL-C = 46 mg/dL (1.2 mmol/L), LDL-C = 155 mg/dL (4.0 mmol/L) and triglycerides = 141 mg/dL (1.6 mmol/L). The drug of choice is a statin to achieve the LDL-C target. Statins also improve HDL-C and triglyc-

eride levels, although these latter effects may be relatively small.

There is also evidence that treatment with statins decreases morbidity and mortality and improves symptoms in patients with PAD.5,13 Furthermore, there is convincing evidence that statins reduce the risk of stroke.13–15 Several studies have also shown that aggressive lipid lowering is associated with a reduced progression of atherosclerotic carotid artery disease.14,15 Patients with PAD are likely to have some degree of carotid artery disease. PAD is also a strong predictor of the risk of stroke.

Question 3

What modifiable risk factors would you like to address in a high-risk patient, as in this case?

Smoking

Smoking cessation is of paramount importance. The vast majority of PAD patients are, or have been, smokers. Furthermore, smoking is associated with adverse effects on several variables that predict vascular events. For example, smoking can lower serum HDL-C levels, raise serum triglyceride levels, increase insulin resistance and elevate plasma fibrinogen concentrations.16 Smoking may even predict the progression of PAD and graft occlusion after infrainguinal bypass surgery.17 There is evidence that the vascular risk is greater in smokers than in non-smokers, despite the use of statins.18 In PAD, quitting may