moderately elevated triglycerides, e.g. 2 4 mmol/l low protective HDL-cholesterol, e.g mmol/l

Transcription

1 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 Triglycerides HDL-cholesterol cholesterol Well-controlled Type 1 Normal or Normal or Normal or Type 2 Normal Poorly-controlled Type 1 Normal Type 2 or Nephropathy or or 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 mmol/l Other abnormalities in lipoproteins may be important, e.g.: Small dense LDL particles which are highly atherogenic. 131

2 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 Triglycerides HDL-cholesterol Hypothyroidism DRUGS: Alcohol Oestrogens Thiazides (minor effect) Normal or -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: 132

3 HYPERLIPIDAEMIA Premature arcus senilis (in the 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. 133

4 PRACTICAL DIABETES 134 Secondary prevention suggested guidelines (SMAC 1997): Patients with: Treat if total Target total cholesterol: cholesterol Previous myocardial infarction Angina ( LDL-cholesterol ( LDL-cholesterol Ischaemic ECG 3.3) 2.6) Atheromatous carotid or peripheral vascular disease Coronary artery bypass, angioplasty or 4.0 stent ( LDL-cholesterol Diabetic nephropathy, nephrotic syndrome ) 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 ( triglycerides HDL-cholesterol) 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, -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)

5 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 ( total cholesterol 7.0 mmol/l) in patients with 0 or 1 coronary heart disease risk factors. >4.2 mmol/l ( 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). 135

6 PRACTICAL DIABETES 136 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 ), 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:

7 HYPERLIPIDAEMIA Total cholesterol LDL-cholesterol Triglycerides HDL-cholesterol Total:HDL cholesterol ratio (very stringent: 2.6) 2.3 (very stringent: 1.7) 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 LDL- Triglycerides HDLcholesterol cholesterol (%) cholesterol (%) (%) (%) Statin Fibrate Statins (HMG-CoA reductase inhibitors): powerful cholesterol-lowering drugs, with a smaller impact on triglycerides and HDL-cholesterol. Drug Dosage range Comments Atorvastatin 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 g nocte Recently introduced; cerivastatin 300 g simvastatin 20 mg Fluvastatin mg nocte Reputed to be of low potency, but in clinical practice probably as effective as simvastatin Pravastatin mg nocte Used in WOSCOPS primary prevention study and in CARE and LIPID secondary prevention studies Simvastatin mg nocte Used in 4S study 137

8 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 Bezafibrate Bezalip Mono Ciprofibrate Fenofibrate Lipantil Micro 200 Gemfibrozil Dosage range 200 mg tds i (400 mg) daily 100 mg daily i daily (Lipantil Micro 67 I ii daily in renal failure) 600 mg bd; maximum 1500 mg daily 138 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.

9 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. 139

10 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 Yes Yes Yes No Yes No Smoking Yes No Yes Yes No No LVH on ECG* Yes Yes No No No No Age (years) * 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

11 HYPERLIPIDAEMIA Women Hypertension Yes Yes Yes No Yes No Smoking Yes No Yes Yes No No LVH on ECG* Yes Yes No No No No Age (years) * 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):

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