Download Hyperlipidaemia

Chapter
14
Hyperlipidaemia
Hyperlipidaemia in diabetes is common. Hypercholesterolaemia confers a 2–3-fold increased coronary heart disease
risk in the diabetic compared with the non-diabetic patient
at any given cholesterol level, but few prospective studies
have been carried out specifically in diabetes. Guidelines for
management of diabetic hyperlipidaemia are therefore
poorly defined.
Lipid levels in diabetes:
Total/LDL
cholesterol
Triglycerides
HDL-cholesterol
Well-controlled
Type 1
Type 2
Normal or↓
Normal
Normal or↓
↑
Normal or ↑
↓
Poorly-controlled
Type 1
Type 2
Nephropathy
↑
↑
↑ or ↑↑
↑
↑ or ↑↑
↑ or ↑↑
Normal
↓
↓
• Uncomplicated type 1 diabetes is not associated with any
specific lipid abnormalities.
• Typical ‘type 2’ dyslipidaemia (also found in patients
with metabolic syndrome X, see Chapter 1):
• normal or moderately elevated total and LDLcholesterol
• moderately elevated triglycerides, e.g. 2–4 mmol/l
• low protective HDL-cholesterol, e.g. 0.6–0.8 mmol/l
• Other abnormalities in lipoproteins may be important, e.g.:
• Small dense LDL particles which are highly atherogenic.
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PRACTICAL DIABETES
•
Postprandial lipaemia.
Elevated lipoprotein (a).
• Uncontrolled type 1 or 2 diabetes, especially when
newly-diagnosed, is often associated with severely
deranged lipid levels, particularly elevated triglycerides,
and treatment decisions should be deferred until stable
control has been achieved with diet, oral hypoglycaemics
or insulin (no less than 3 months).
• The converse is also true: always consider undiagnosed
type 2 diabetes in patients presenting with elevated lipids,
particularly disproportionately elevated triglycerides.
•
Secondary causes of hyperlipidaemia in diabetes:
Condition
Cholesterol
Hypothyroidism
↑
Triglycerides
HDL-cholesterol
Alcohol
↑
↑
Oestrogens
↑
↑
↑
Normal or ↓
↑
↓
DRUGS:
Thiazides (minor effect)
b-Blockers
↑
• Always check thyroid function in the hyperlipidaemic
diabetic patient:
• Overt hypothyroidism (TSH >10 mU/l with
decreased thyroid hormone levels) – treatment with
thyroxine may reduce total cholesterol, but only by
~10% in the presence of a cholesterol >6.2 mmol/l.
• Subclinical (biochemical) hypothyroidism (TSH
6–9 mU/l with normal thyroid hormone levels) is not
consistently associated with elevated cholesterol.
Check lipids again after TSH has been normalized
(remember TSH takes 6 weeks to stabilize after a
change in thyroxine dosage).
Coexisting primary causes of hyperlipidaemia:
Familial hypercholesterolaemia:
• Common, particularly the heterozygous form. Consider
it in the presence of:
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HYPERLIPIDAEMIA
•
•
•
•
Premature arcus senilis (in the 30–40-year age group).
Tendon xanthomata and xanthelasmata.
Family history of premature coronary artery disease
(<50 years of age) in non-diabetic first-degree relatives.
Predominant hypercholesterolaemia (>8.0) with
normal triglycerides.
Familial combined hyperlipidaemia
The commonest familial form of hyperlipidaemia in young
survivors of myocardial infarction (up to 1% prevalence in
the general population). Shares many features in common
with the dyslipidaemia of the insulin resistance syndrome
(syndrome X).
Management
Secondary prevention
The 4S (simvastatin) and CARE and LIPID (pravastatin)
studies confirmed that lowering cholesterol in the non-diabetic angina or post-myocardial infarction (MI) patient with
average cholesterol levels (4–7 mmol/l) reduced fatal and
non-fatal coronary events by ~30%; stroke risk in the
CARE study was also reduced by ~30%. Diabetic patients
in the 4S study had an even greater reduction of MI risk
(~55%) after treatment with simvastatin.
All patients with documented coronary artery disease
should have lipid lowering therapy with a statin if total cholesterol >4.8. A significant difference in mortality emerges
after about 2 years of treatment – so all appropriate patients
should be offered treatment if life expectancy is likely to be
>2 years, regardless of age.
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PRACTICAL DIABETES
Secondary prevention – suggested guidelines (SMAC 1997):
Patients with:
Treat if total
cholesterol:
Target total
cholesterol
Previous myocardial infarction
.4.8
,4.5
Angina
Ischaemic ECG
(; LDL-cholesterol
.3.3)
(; LDL-cholesterol
,2.6)
Atheromatous carotid or peripheral
vascular disease
Coronary artery bypass, angioplasty or
stent
,4.0
(; LDL-cholesterol
Diabetic nephropathy, nephrotic syndrome
2.3–2.4)
• Many guidelines use LDL-cholesterol levels rather than
total cholesterol, which adds to the confusion in situations when HDL is not or cannot be measured. LDL
cannot routinely be measured directly, but can be calculated using the Friedewald equation if triglycerides <4.5:
LDL-cholesterol = total cholesterol –
+ HDL-cholesterol)
(triglycerides
2.19
• Note that the LDL-cholesterol will be underestimated if
a non-fasting value is used in the equation.
• Aggressive lipid lowering therapy is justified in patients
with:
• saphenous vein grafts (accelerated atheroma in
grafted vessels), stents and angioplasty; and
• clinical proteinuria or nephrotic syndrome – coronary risk is massively increased compared with the
non-proteinuric patient; see Chapter 10).
Remember the importance of long term treatment with
aspirin, b-blockers and ACE inhibitors in post-MI patients
(see Chapter 7).
Primary prevention
Highly contentious field, where evidence is emerging all the
time. WOSCOPS (1996) showed that coronary events
could be reduced by the use of pravastatin in ‘average’
Scotsmen (mean total cholesterol 7.0 mmol/l, annual coronary event risk 1.5%). The AFCAPS/TexCAPS study (1998)
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HYPERLIPIDAEMIA
found a similar degree of benefit with even lower mean
total cholesterol levels (5.7 mmol/l).
• Screening. Strategy depends on established practice and
local guidelines. Most diabetes clinics screen all adult
patients, but this is appropriate only if treatment guidelines
are not age-specific (see below). Most clinics will contain
some low-risk people who have been inappropriately
treated with a statin or a fibrate for many years, with the
aim of ‘normalising’ cholesterol levels, without regard for
their risk-factor status. It is very difficult in practice to stop
such treatment, unless patients wish to do so. Most middle-aged and elderly people attending hospital diabetes
clinics will by virtue of coexisting complications merit
screening on the basis, for example, of the Sheffield table.
• Measurements. Full fasting lipid profile (total cholesterol, triglycerides, HDL-cholesterol), though there is a
case for measuring just total and HDL-cholesterol levels
– which can be done on a non-fasting sample (see
Sheffield table, below).
• Thresholds for treatment. Cholesterol level alone is a
poor predictor of coronary events, and a risk factor
approach must be used. Any of the following have current validity:
1. Use a simple rule, for example, the USA NCEP
approach.
LDL-cholesterol levels at which drug treatment can be considered after an adequate trial of dietary therapy:
>4.9 mmol/l (ù total cholesterol 7.0 mmol/l) in patients
with 0 or 1 coronary heart disease risk factors.
>4.2 mmol/l (ù total cholesterol 6.2 mmol/l) in patients
with $ 2 risk factors.
Risk factors
• Current smoking.
• Hypertension (blood pressure >140/90 or antihypertensive medication).
• Obesity (BMI >27, especially if central obesity).
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PRACTICAL DIABETES
• HDL-cholesterol <0.9 mmol/l.
• Family history of premature coronary heart disease (clinical coronary disease or sudden death in 1st degree male
relatives <55 y or 1st degree female relatives <65 y).
• Age >45 (men), postmenopausal women.
• Diabetes.
2. Treat diabetic patients as if they all have subclinical coronary artery disease ie. use secondary prevention thresholds (above) and treat all patients with total
cholesterol >4.8 mmol/l. The epidemiological evidence
to support this approach is that diabetic patients without
previous MI have a similar MI risk as nondiabetic
patients with previous MI.
3. Use the Sheffield risk table (see pages 140–141), which
takes into account the following risk factors:
• diabetes
• smoking
• hypertension
• ECG evidence of left ventricular hypertrophy in
hypertensive patients (S wave in V1 + R wave in V6
>35 mm and flat or inverted T waves in the left precordial leads)
• The value of the Sheffield table is controversial, but
the risk equations it uses have an impeccable epidemiological pedigree (the USA Framingham Study), confirmed by more recent European data (PROCAM
Study).
• Use the risk table conferring an annual coronary event
rate of 3.0% (other tables for event rates of 1.5 and 4.5%
have been published and a 2% annual risk rate is advocated by some). The table for total:HDL-cholesterol
ratio, rather than just total cholesterol improves sensitivity, leaves specificity unchanged and is probably more
appropriate for women and people with diabetes.
• Treatment targets: not clarified, but appropriate targets
in high-risk diabetic populations (e.g. South Asians)
would be:
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HYPERLIPIDAEMIA
Total cholesterol
,4.5
LDL-cholesterol
,3.2 (very stringent: ,2.6)
Triglycerides
,2.3 (very stringent: ,1.7)
HDL-cholesterol
.1.0
Total:HDL cholesterol ratio
,5
Treatment
Traditionally, a low saturated fat diet is tried for 3–6 months
followed by drug treatment if necessary. However, diet
reduces total cholesterol only by 2–5% in many cases, and a
better approach in secondary prevention is to implement
diet, weight reduction, increased activity, smoking cessation
programme and medication together. Diet alone should be
given more emphasis in primary prevention.
Medication
Drug class
Total
cholesterol
(%)
LDLcholesterol
(%)
Triglycerides
(%)
HDLcholesterol
(%)
Statin
↓20–30
↓25–35
↓10-15
↑6–10
Fibrate
↓10
↓20
↓30–40
↑30
Statins (HMG-CoA reductase inhibitors): powerful cholesterol-lowering drugs, with a smaller impact on triglycerides
and HDL-cholesterol.
Drug
Dosage range Comments
Atorvastatin
10–80 mg daily
Recently introduced; no end-point studies
Long-acting; does not have to be given at night
More potent, mg for mg, in reducing triglycerides
and LDL-cholesterol than other agents
Licensed for use in heterozygous and
homozygous familial hypercholesterolaemia, and
in familial combined hyperlipidaemia
Cerivastatin
100–300 mg nocte Recently introduced; cerivastatin 300 mg ù
simvastatin 20 mg
Fluvastatin
20–80 mg nocte
Reputed to be of low potency, but in clinical
practice probably as effective as simvastatin
Pravastatin
10–40 mg nocte
Used in WOSCOPS primary prevention study and
in CARE and LIPID secondary prevention studies
Simvastatin
10–40 mg nocte
Used in 4S study
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PRACTICAL DIABETES
• Rapidly acting: maximum effect at 4 weeks, so
dose–titration can be rapid. All statins have clear
dose–response relationships.
• Stroke: retrospective analysis of 45, prospective analysis
of the CARE study, and meta-analyses suggest considerable benefit. Use in patients with established cerebrovascular disease (previous stroke, carotid stenosis) and total
cholesterol >4.8 (see above).
• Should be taken at night (except atorvastatin, which can
be taken at any time).
• Check liver functions before treatment: do not use if
transaminases >3x upper limit of reference range. There
is no need to monitor liver functions routinely if normal
pretreatment.
• Creatine kinase (CK). Measure only if myalgia develops;
discontinue if CK >10x upper limit of reference range.
Remember CK levels are normally higher in black
patients. Mild myalgia is common – most patients will
discontinue medication of their own accord. It is worthwhile trying another statin in the event of side-effects
(other than rhabdomyolysis).
Fibrates
Helsinki Heart Study (primary prevention, 1987) showed
benefit in reducing CHD incidence, but not mortality. No
secondary prevention studies.
Drug and examples of preparations
Dosage range
Bezafibrate
200 mg tds
Bezalip Mono
i (400 mg) daily
Ciprofibrate
100 mg daily
Fenofibrate
Lipantil Micro 200
i daily (Lipantil Micro 67 I – ii daily in
renal failure)
Gemfibrozil
600 mg bd; maximum 1500 mg daily
• Consider use of fibrates in secondary prevention when
statins have had to be withdrawn (any reduction in cholesterol level will be of benefit), and in primary prevention
when there is moderately raised cholesterol, but markedly
elevated triglycerides and low HDL-cholesterol.
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HYPERLIPIDAEMIA
• Use fibrates in patients at high risk of pancreatitis
(triglycerides >6 mmol/l).
• Combination therapy with statin and fibrate in mixed
hyperlipidaemias. Previously thought to carry a high risk
of rhabdomyolysis, but in practice very rare, and probably
should be used more frequently in diabetes, especially in
very high risk patients with severe hypertriglyceridaemia
(eg. nephrotic syndrome, coronary bypass and stents).
Various combinations have been described (eg. fluvastatin
40 mg daily + gemfibrozil 600 mg bd; fluvastatin or simvastatin 40 mg daily + fenofibrate 200 mg daily); the
potentially most potent combination (high-dose atorvastatin + micronised fenofibrate) has not yet been reported.
Other drugs
• Resins: less effective than statins (lower total cholesterol
~15%), more troublesome to take, and can aggravate
hypertriglyceridaemia. Consider using them in the
hypercholesterolaemic patient intolerant of both statins
and fibrates:
• cholestyramine, e.g. Questran Light – 4g (one
sachet) daily, increasing to 3–6 sachets daily, in
divided doses; or
• colestipol, e.g. Colestid – 5–30 g (1–6 sachets)
daily, in divided doses.
• Fish oils, nicotinic acid, etc.: should be prescribed only
by lipid specialists. Although fish oils reduce triglycerides and raise HDL-cholesterol, they may increase
atherogenicity of LDL-cholesterol.
• Aspirin: all patients taking lipid-lowering medication
should also take low dose aspirin, 75 mg daily.
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PRACTICAL DIABETES
Sheffield table for primary prevention of coronary heart disease
Showing serum total:HDL cholesterol ratio conferring an estimated risk of
coronary events of 3.0% per year in people with diabetes
Men
Hypertension
Smoking
LVH on ECG*
Age (years)
70
68
66
64
62
60
58
56
54
52
50
48
46
44
42
40
38
36
34
32
30
28
26
#25
Yes
Yes
Yes
Yes
No
Yes
Yes
Yes
No
No
Yes
No
Yes
No
No
No
No
No
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.1
2.3
2.4
2.6
2.9
3.1
3.4
3.8
4.2
4.7
5.2
5.8
6.6
7.6
8.7
10.2
2.0
2.1
2.2
2.3
2.5
2.7
2.9
3.1
3.3
3.6
3.9
4.2
4.6
5.1
5.6
6.1
6.8
7.6
8.6
9.7
3.0
3.2
3.4
3.6
3.8
4.1
4.4
4.7
5.1
5.5
6.0
6.5
7.1
7.8
8.6
9.5
10.5
3.6
3.8
4.0
4.3
4.6
4.9
5.3
5.7
6.1
6.6
7.1
7.8
8.5
9.3
10.2
4.4
4.7
5.0
5.3
5.6
6.0
6.5
7.0
7.5
8.1
8.8
9.6
10.4
5.3
5.6
5.9
6.3
6.7
7.2
7.7
8.3
9.0
9.7
10.5
* Hypertensive subjects only
INSTRUCTIONS
• Choose the table for men or women.
• Identify the correct column for smoking, hypertension and diabetes.
• In normotensive subjects assume LVH absent. If no ECG is available in hypertensive
subjects, assume LVH is absent.
• Identify the row showing the age of the subject.
• Read off the cholesterol:HDL ratio at the intersection of the appropriate column and row:
• If there is no entry, lipids need not be measured
• If there is an entry, measure serum total cholesterol and HDL
• If the average cholesterol:HDL ratio on two or more measurements is at or above
the level shown, and the serum total cholesterol is $5.5 mmol/l – consider
treatment with a statin.
• If HDL not available, assume 1.2.
• The table can be used to look forward to need for measurement or treatment at an
older age.
140
HYPERLIPIDAEMIA
Women
Hypertension
Smoking
LVH on ECG*
Age (years)
70
68
66
64
62
60
58
56
54
52
50
48
46
44
42
40
38
36
34
#33
Yes
Yes
Yes
Yes
No
Yes
Yes
Yes
No
No
Yes
No
Yes
No
No
No
No
No
2.0
2.0
2.0
2.0
2.0
2.0
2.1
2.1
2.2
2.3
2.7
2.9
3.2
3.6
4.1
4.8
5.7
6.9
8.6
2.7
2.7
2.8
2.8
2.9
3.0
3.1
3.1
3.4
3.7
4.0
4.3
4.8
5.3
6.1
7.1
8.4
10.1
4.1
4.2
4.2
4.3
4.4
4.6
4.8
5.0
5.3
5.6
6.1
6.6
7.3
8.2
9.4
4.9
5.0
5.1
5.2
5.3
5.5
5.7
6.0
6.3
6.8
7.3
7.9
8.8
9.8
6.1
6.1
6.2
6.4
6.5
6.7
7.0
7.4
7.8
8.3
9.0
9.8
7.2
7.3
7.4
7.6
7.8
8.1
8.4
8.8
9.3
9.9
* Hypertensive subjects only
NOTES
• Do not use for decisions on secondary prevention.
• Use the table after appropriate advice on smoking, diet and control of systolic blood
pressure to <160 mm Hg.
• Those with total cholesterol: HDL ratio $8.0 may have familial hypercholesterolaemia
and should be considered individually.
• The table may underestimate CHD risk in some individuals:
• British Asians
• those with very strong family history of premature CHD
• those with familial hyperlipidaemia
Reference: Haq IU, Jackson PR, Yeo WW, Ramsay LE. A comparison of methods for
targeting CHD risk for primary prevention. Heart 1997; 77 (Suppl 1): 36.
141