International Task Force for Prevention of
Coronary Heart Disease

CORONARY HEART DISEASE: REDUCING THE RISK

3.4 Treatment of hyperlipidaemia

3.4.1 Introduction

In the light of recent clinical trials, strong emphasis is now placed on lipid lowering as part of secondary prevention. This is a valuable advance. However, it may have led to the danger of underestimating the case for primary prevention in persons at high risk. Because of the large number of primary events that are rapidly fatal or are followed by cardiac symptoms and disability, the importance of primary prevention cannot be too strongly stated, especially in persons at high global risk.

Past concerns about the safety of lowering plasma cholesterol are no longer tenable. Where an association was detected between low cholesterol and increased mortality, there is evidence that this association was the result of statistical confounding or that the low cholesterol level was the consequence of pre-existing disease such as cancer or other chronic illness. Further, individuals with the genetic disorders of hypobetalipoproteinemia, whose total plasma LDL-cholesterol levels are usually below 75 mg/dL, appear to have normal, or even increased, life expectancy.

The vigour with which lipid-lowering therapy is pursued depends on global cardiovascular risk and on the individual responsiveness of the patient. In primary prevention, hyperlipidaemia is managed primarily by conservative measures, since under controlled conditions, diet may lower LDL-cholesterol by 10-25%.

Every effort should be made to maximize skills in dietary counselling. To enhance motivation, it should be emphasized to the patient that current dietary guidelines enable continued and even enhanced enjoyment of eating. There is a wide variety of enjoyable foods and recipes. The recommended diet is in no way "special" or "unusual". On the contrary, it is similar to the traditional diets which are consumed in regions in of the world in which mortality from CHD and certain cancers is far lower than in most Western countries.

Overweight should be corrected or at least reduced. The patient should be encouraged to take regular aerobic exercise, although patients with coronary heart disease require medical evaluation before embarking on ambitious exercise programmes. Drug treatment should be instituted only after a careful trial of conservative measures have failed, and must be an adjunct to - and not a replacement for - diet and correction of overweight. Actions, indications, side effects and use of the major lipid-lowering drugs are briefly described in the Section 3.4.6 (Drug treatment).

3.4.2 Target levels for lipid-lowering therapy

The goal of lipid-lowering treatment is determined by the patient's global risk. For example, moderate dietary change is all that is needed in a healthy person who has mildly elevated plasma cholesterol level e.g. 270 mg/dL (7.0 mmol/L), and no other risk factor, but a similar cholesterol level in a patient with cardiovascular disease, or with multiple non-lipid risk factors, requires a more exacting diet and full-dosage medication to achieve the appropriate target level of LDL-cholesterol as shown in Table 8. In a person at immutably high risk due, for example, to a strong family history of CHD, high Lp(a) levels, and/or a long history of heavy smoking, it is probably appropriate to reduce modifiable risk factors substantially, also in line with Table 8. It must be said that clinical trial evidence for this concept is lacking, though it is compatible with the epidemiology of multiple risk factors. A definitive choice of target values for LDL-cholesterol lowering will depend on the outcome of trials in which subjects have been randomized to receive treatments of different intensity. LCAS ¹⁹ was the first such study; others are in progress. Until such data become available, the following scheme reflects the balance of exciting knowledge. Not only LCAS, but also recent analysis of the 4S trial and a recent meta-analysis of lipid-lowering trials, all favour the view that CHD risk is reduced by lowering LDL-cholesterol over a wide range. If such target levels are adopted in primary prevention in persons at high risk, every effort should be made to lowering LDL-cholesterol levels by careful, sustained, nutritional and exercise counselling; drug treatment in minimum effective dosage is added if necessary. Although no trial data yet exist, it may be advisable to lower LDL-cholesterol in persons with a raised Lp(a) level (e.g. > 50 mg/dL), especially in those with a positive family history of CHD. The levels shown in Table 8 are supported by the epidemiology of the relationship between LDL-cholesterol and CHD risk. Meta-analyses of existing trials support this concept, and large trials are currently under way to clarify the position further.

Table 8: Target levels for plasma LDL-cholesterol-lowering treatment. Triglyceride target levels have not yet been determined, however a suggested goal is a level of £ 150 mg/dL (1.7 mmol/L).

Global risk	Target Level Reduce LDL-cholesterol to
	mg/dL	mmol/L
Small increase in risk (see section 2.5.1.1)	£ 160	£ 4.0
Moderate increase in risk (see section 2.5.1.2)	£ 135	£ 3.5
High risk (including secondary prevention, see section 2.5.1.3)	< 100	< 2.6

As discussed above, risk decreases with decreasing LDL-cholesterol level: there is no known threshold below which risk ceases to diminish with lower levels. However the absolute decrease in risk is less when LDL-cholesterol is lowered from a relatively low starting point. Most trials with clinical and angiographic end points have to date shown benefit to be greatest when pre-treatment LDL-cholesterol levels are average or elevated e.g. 150 mg/dL (4 mmol/L) or greater. Moreover, a number of angiographic studies showed that significant reduction in clinical cardiac events accompanies the anatomically small favourable effects on coronary atherosclerosis (Table 9).

Table 9: The results of lipid-lowering trials using angiographic primary end-points. In many, a significant reduction inCHD events, or a trend to reduced events, was noted. All but one (HARP) showed a favourable angiographic outcome, with reduced progression and, in many, increased regression of disease. The results of the trials should not be compared in absolute terms because of differences in trial design. A positive sign indicates net improvement (widening) in angiographic appearance, i.e. regression of disease. (BECAIT = Bezafibrate Coronary Atherosclerosis Intervention Trial, CCAIT = Canadian Coronary Atherosclerosis Intervention Trial, CLAS = Cholesterol-Lowering Atherosclerosis Study, FATS = Familial Atherosclerosis Treatment Study, HARP = Harvard Atherosclerosis Reversibility Project, LCAS = Lipid and Coronary Atherosclerosis Study, LOCAT = Lopid (= gemfibrozil) Coronary Angiography Trial, MARS = Monitored Atherosclerosis Regression Study, NHLBI = National Heart, Lung, and Blood Institute, PLAC = Pravastatin Limitation of Atherosclerosis in the Coronary Arteries, POSCH = Program on the Surgical Control of the Hyperlipidaemias, SCRIP = Stanford Coronary Risk Intervention Project, STARS = St. Thomas' Atherosclerosis Regression Study, UCSF-SCOR = University of California at San Francisco Specialized Centers of Research).

Study	Treatment	Years	Cases	Control	% Event Reduction
BECAIT20	Diet + Bezafibrate	5	-0.06 mm	-0.06 mmV	21
CCAIT21	Diet + Lovastatin	2	+0.09 mm	-0.05 mm*V	-
CLAS22	Diet + Resin + Niacin	2	+2.65%	+0.35%	25
CLAS22a	Diet + Resin + Niacin	4	+2.1%	-0.7%*	43
FATS23	Diet + Resin + Niacin	2.5	+3.4%	-2.2%*	80V
FATS23	Diet + Resin + Lovastatin	2.5	+2.15%	-0.9%*	70
HARP24	Diet + stepwise Pravastatin, Nicotinic Acid, Cholestyramine, Gemfibrozilvs vs Lesser Diet	2.5	-0.14 mm	-0.15 mm	-
Lifestyle25	Diet + several other modifications	1	+3.4%	-2.2%	-
LOCAT26	Diet + Gemfibrozil	3	-0.04 mm	-0.09 mmV	-
LCAS27	Diet + Fluvastatin	2.5	-0.02 mm	-0.09 mm	n.s.
MARS28	Diet + Lovastatin	2	+2.2%	+1.6%	24
NHLBI Type II29	Diet + Resin	5	-	-	33
PLAC-I30	Diet + Pravastatin	3	+1.11%	+0.67%	61V
PLAC-II31	Diet + Pravastatin	3	-	-	60
POSCH (5 yr)32	Diet + Surgery ± Resin	9.7	-	-	35V
SCRIP33	Diet + Drugs + Exercise	4	+0.9%	+0.3%*	39V
STARS34	Diet	3	+5.8%	-1.1%	69V
STARS34	Diet + Resin	3	+5.8%	-1.9%*	89V
UCSF-SCOR35	Diet + Resin + Niacin ± Lovastatin	2	+0.8%	-1.5%*	-

^* - Using angiographic criteria for patient entry.
V - statistically significant.

The epidemiology of the relation between LDL-cholesterol and CHD incidence makes it clear that risk is less with lower LDL-cholesterol levels over a very wide range, without a threshold (Figure 5). The results of clinical end-point trials of cholesterol lowering are in conformity with this for levels in the middle and upper part of the range seen in CHD-prone populations. Such trials have, to date, not shown benefit when pre-treatment levels of LDL-cholesterol of less than 125 mg/dL (3.2 mmol/L) are lowered. However, these trials may be less informative than the epidemiology, partly because of the limited numbers of events. To date very few trials have addressed this issue. In a subset analysis of the 4S trial by Pedersen et al and in meta-analyses of lipid-lowering trials by Gould et al and Law et al no evidence was adduced for a threshold level of LDL-cholesterol, below which no additional risk reduction was observed. In the Post Coronary Artery Bypass Graft (CABG) trial, patients were randomized to two levels of treatment; angiographic progress of atherosclerosis in grafts was significantly rarer in the groups in which LDL-cholesterol was reduced to 93 mg/dL (2.4 mmol/L) than when it was 135 mg/dL (3.5 mmol/L).

In patients with CHD or at high risk of CHD, the target levels shown in Table 8 are in conformity with the epidemiology. For subjects at more moderate risk, target levels are higher, and are often attainable by diet and other conservative measures, or less often by a combination of diet and low-dose drug treatment (Table 10).

Table 10: Methods of treating hyperlipidaemia ³⁶. The goal of treatment depends on the estimate of global risk (see Table 8).

3.4.3 The cholesterol-lowering diet

Dietary habits vary greatly throughout the world. For example, in many Asian countries the current national diets contain relatively little saturated fat and cholesterol. The recommendations given below apply to populations consuming a Western or westernized diets. These recommendations may therefore need considerable adaptation to other cultures.

The cholesterol-lowering diet should comprise two distinct principles:

1. reduction and, if possible, correction of even minor degrees of overweight by energy (caloric) restriction;
2. qualitative changes to the habitual diet:

   	Action	Amount allowed40
   1.	Decreased saturated fat resulting in decreased total fat	saturated fat: no more than 7-10% of energy total fat: no more than 30% of energy
   2.	Moderately increased use of mono- and polyunsaturated oils (PUFA) and products, with special emphasis on monounsaturated fatty acids (MUFA)	MUFA: no more than 10-15 % of energy PUFA: no more than 7-8% of energy
   3.	Increased complex carbohydrates and dietary fibre with emphasis on soluble fibre	carbohydrates: > 50% of energy more than 25 g dietary fibre per day
   4.	Decreased dietary cholesterol	less than 300 mg per day

In terms of foods the cholesterol-lowering diet comprises:

• Abundance of plant foods such as whole-grain bread and whole-grain cereals, vegetables (especially root vegetables), salads, fruit, legumes;
• Unhydrogenated vegetable oils as the principle source of fat, especially MUFA-rich oils such as olive oil or rapeseed ("canola") oil;
• Low-fat and fat-free dairy products;
• Fish and low-fat poultry (e.g. with skin removed);
• Small amounts of lean red meat and egg.

Examples of enjoyable balanced diets that have been consumed for many generations are the traditional Mediterranean diet and East Asian diets; the dietary recommendations in this section have many features in common with these eating patterns. These are valuable models for healthy eating in Western countries. Other features of the optimal diet are restriction of sodium intake (see Section 3.5.2 (Non pharmacological treatment of hypertension)) and emphasis on food rich in antioxidants (see Section 2.8.3.2 (Oxidized LDL)).

Cooking methods have a major effect on food composition. To achieve lower fat content, grilling, steaming, boiling and microwave or barbecue cooking are preferable to frying and roasting.

In Table 11, "recommended foods" are generally low in fat and/or high in fibre. These should be used regularly as main components of the daily diet. (Exception: vegetable oils and nuts which are used in moderation because of their favourable fatty acid composition. Due to their high energy content, the amount should be limited.) "Foods for use in moderation" contain unsaturated fats or smaller quantities of saturated fats. Limited amounts of these foods are allowed, including:

• lean red meat up to 180 g/week,
• medium fat cheeses, lean bacon and ham up to once weekly, noting however their high sodium content
• chips or roast potatoes cooked in oils rich in monounsaturated fatty acids and well drained, once or twice weekly, noting that these are energy-dense and unsuitable for overweight persons.

"Foods to be avoided" contain large proportions of saturated or hydrogenated fats and/or cholesterol, and should rarely be used.

Some patients who respond incompletely to the lipid-lowering diet will achieve improved lipid levels when a more stringent diet is introduced. This provides 25-27% of energy from fat, with saturated fat intake of 6-8% of energy and cholesterol content of 200-250 mg per day.

3.4.3.1 Special recommendations for hypertriglyceridaemia

The cholesterol-lowering diet is used, with the following additional features:

1. Normalize or reduce body weight in overweight patients.
2. Moderate alcohol consumption, or, if possible, avoid alcohol completely.
3. Reduce sugar-rich foods in order to lessen intake of calories.
4. Increase consumption of fish rich in omega-3 fatty acids (herring, mackerel, salmon, tuna).
5. If severe chylomicronemia is present, long chain fatty acids should be avoided. Instead, medium chain triglycerides should be used.
6. In the emergency treatment of hypertriglyceridemia, a fat-free diet should be administered for at least three days.

Table 11: Choice of foods in the cholesterol-lowering diet.

3.4.4 Calorie-restricted lipid-lowering diet

Follow the standard lipid-lowering diet, with the following additional guidelines:

1. Fatty foods are strictly limited.
2. Sugar-rich foods, particularly sweets, biscuits, confectionery and pastries, should be avoided.
3. Because of its high energy content, alcohol is best avoided.
4. The diet regimen should be accompanied by a suitable programme of daily exercise.

3.4.4.1 Recommended foods

The following foods may be used in generous helpings in meals or as snacks:
Vegetables (fresh or frozen, not tinned): use cooked or in salad or as crudités. Artichokes, asparagus, cabbage, cauliflower, carrot, celery , chicory, cress, cucumber, endive, French (green) beans, green pepper, leek, lettuce, marrow, mushroom, onion, pumpkin (boiled), radish, spinach, turnip, tomatoes, eggplant (aubergines).
Soup: broth, consommé, other clear soup.
Beverages: coffee or tea with skimmed milk, sugar-free soft drinks, mineral water. Aspartame, saccharine as sweeteners.

3.4.4.2 Foods permitted in controlled quantities.

The following foods are permitted in controlled quantities:
Fruit: Four pieces per day.
Cereal foods: 5 units per day. 1 unit = 1 thin slice of wholemeal bread cut from large loaf, or 1 cup of sugar-free breakfast cereal, or 1/2 cup pasta, or 1/2 cup rice, or 1 small boiled or baked potato.
Legumes (pulses): 1/2 cup, 3 - 4 times a week. Boiled lentils, mung beans, chick peas, butter beans, kidney beans, or pinto beans.
Fish, chicken, turkey, very lean meat: 100 g per day
Dairy foods: 2 units per day. 1 unit = 1 cup skimmed milk or 1/2 cup low-fat milk or 1 cup very-low-fat yoghurt without added sugar or 30 g skimmed, milk-based cottage cheese or 30 g 0% fat fromage frais. Two eggs per week.
Oils and fats: 10 g (2-3 teaspoons) per day. Olive oil, canola oil, corn oil or sunflower oil. Plus 10 g per day of very-low-fat (20%) margarine.
1 cup = 200 ml - 7 fluid ounces. 30 g = 1 ounce

3.4.5 Avoidance of drugs that can cause hyperlipidaemia

Drug-induced secondary hyperlipidaemia (see Table 6) is common. This is most often seen with high doses of thiazide diuretics and with some beta blockers. If drug-induced hyperlipidaemia occurs, the first step is to ensure that the minimum effect dose is being used. If this is unsuccessful, consider substituting an alternative, lipid-neutral drug such as a calcium antagonist or a beta blocker with low intrinsic sympathomimetic activity. If the drug is essential, the minimum effective dose is used.

3.4.6 Drug treatment of hyperlipidaemia

In patients at moderate risk, diet is usually effective in achieving target values. For patients at high risk a short trial of diet (e.g. one-two months) is warranted, however a combination of diet and drug therapy will prove necessary in most cases. At least two sets of lipid measurements should be made during the period. Dietary therapy must be continued after drugs are introduced. In patients with lesser degree of risk, an extended period of diet therapy with repeated conselling is warranted before considering indtroduction of a drug, over a period of at least 6 months.

The clinical decision to prescribe a drug should be based on trial data wherever possible. Six major trials of lipid lowering have been performed in recent years and form the basis of current recommendations. The results of these trials are summarized in Table 12. Four of these trials (the Helsinki Heart Study ⁴², the Scandinavian Simvastatin Survival Study (4S) ⁴³, the West of Scotland Coronary Prevention Study (WOSCOPS) ⁴⁴, and the Cholesterol and Recurrent Events study (CARE, see footnote 4), and the Texas Armed Forces Coronary Artery Prevention Study (TexCAPS)^44a have been published in full. Preliminary information on the Pravastatin in Prevention of Ischemic Disease (LIPID) trial is available and full publication is expected in 1998 or 1999. In addition, several angiographic trials have examined the effects of lipid lowering by drugs or diet on the diameter of the coronary vessels (see Table 9).

Table 12: Results of major recent randomized controlled clinical trials of cholesterol lowering.

These trials have established beyond doubt that lowering of LDL-cholesterol by drugs in addition to diet reduced the incidence of fatal and nonfatal myocardial infarction in both primary and secondary prevention. Total mortality was also reduced by LDL-cholesterol lowering treatment, particularly in individuals with coronary heart disease. Those individuals with the highest pre-treatment LDL-cholesterol levels benefitted most from treatment. Subgroup analyses of these trials have shown that these beneficial effects were seen in all ethnic groups, in both sexes, at all age groups, and in diabetics. A further notable result was the reduction in the treatment group of the incidence of stroke - a pre-defined end point - in the LIPID and CARE studies. Side-effects were not a serious problem in any of these trials and in no trial was cancer more common in the treatment group. No trial showed a significant increase in noncardiovascular mortality rates e.g. death by suicide or by violent or accidental means, in the treatment group. Figure 8 summarizes the relation in the 4S, CARE and WOSCOPS trials between on-treatment cholesterol levels and CHD event rates.

The reduction of risk observed in these trials may not be attributable purely to lowering of LDL-cholesterol; lowering of triglyceride, an increase in HDL-cholesterol, and non-lipid effects may also have contributed to the favourable outcome.

In the CARE study, no benefit was seen in individuals with baseline LDL-cholesterol levels of £ 125 mg/dL (3.2 mmol/L, Table 12). This has raised an issue concerning the benefit of a further reduction in LDL-cholesterol in patients with relatively usual levels. However, in the LIPID and TexCAP studies, the incidence of coronary events was lowered by statin treatment in patients with average baseline LDL-cholesterol levels. In the LIPID and TexCAP studies, the incidence of coronary events was lowered by statin treatment in patients with average baseline LDL-cholesterol levels. Moreover, as mentioned above, the post-CABG study with lovastatin showed further improvement in angiographic findings and revascularization procedures when a baseline LDL-cholesterol of 155 mg/dL (4.0 mmol/L) was intensively reduced to 93 mg/dL [2.4 mmol/L) in comparison to moderate reduction (LDL-cholesterol of 136 mg/dL (3.5 mmol/L)] ⁴⁵.

From this relationship it would be projected that over a wide range of LDL-cholesterol levels, a given absolute reduction in the LDL level will prouduce the same reduction in relative (i.e. proportional) risk. At least in the higher part of this range, clinical trials confirm this prediction. Five years of cholesterol lowering achieves most of the risk reduction that is predicted from epidemiology.

However, the likely effect of lowering LDL-cholesterol on the risk of CHD depends on the global risk of the disease in each individual. Other risk factors than LDL-cholesterol affect the position of the graph; as seen in the figure, a high global risk shifts the graph to the left.

The dose-response curve for lipid-lowering drugs, e.g. statins, is such that the dose determines the percentage reduction, not the absolute reduction in LDL-cholesterol. It follows that a larger dose, of e.g., a statin (or a more potent statin) is needed to lower LDL-cholesterol by a given amount, e.g. 40 mg/dL (1 mmol/L), when the baseline level is low than when it is elevated. Hence a larger dose is required to produce the same percentage reduction in risk seen when the LDL-cholesterol level is average and high risk is largely conferred by other risk factors; this is shown for an LDL-cholesterol reduction of 40 mg/dL (1 mmol/L) in the left-hand slope of the figure.

In summary, current treatment guidelines call for aggressive treatment of cholesterol levels in patients with clinically evident atherosclerotic disease (i.e. in secondary prevention). In most such patients, medications will generally be required. Treatment decisions in primary prevention should be based on the person's global risk of coronary heart disease as outlined in section 1.7. Global risk can be conveniently calculated using the program available on the Task Force internet homepage (http://www.chd-taskforce.com).

3.4.6.1 HMG CoA reductase inhibitors (statins)

HMG CoA reductase inhibitors are a breakthrough in the treatment of high serum cholesterol. Several recent clinical trials as reviewed in Table 12 on page 71 demonstrate that these drugs substantially reduce morbidity and mortality from CHD. They are becoming a mainstay in the management of patients with established CHD (secondary prevention), and they hold great promise for treatment of high-risk patients without evident CHD (primary prevention).

• They are drugs of first choice in familial hypercholesterolaemia. Newer statins have been shown to lower LDL-cholesterol even in receptor-negative homozygous familial hypercholesterolaemia which was hitherto unresponsive to medication.
• They have a moderate effect in lowering triglyceride and in elevating HDL-cholesterol. This effect may be more marked with higher pre-treatment triglyceride values and the use of higher doses of statins or with some of the newer statins.
• Treatment is commenced at minimum dosage. Serum lipids and alanine transferase are measured at 6-8 weeks. The dosage is increased stepwise if necessary to achieve the target lipid level using the lowest effective dose.
• Patients with very high pre-treatment cholesterol levels need combined therapy with a resin. Treatment is initiated using a single drug.
• Statins should not be used in women of child-bearing age unless contraception is fully satisfactory.
• Statins are not generally licensed for use in children (< 14 years of age). The only exception is the use of atorvastatin in homozygous familial hypercholesterolaemia.

3.4.6.1.1 Dosage of HMG CoA reductase inhibitors (statins) ⁴⁶

HMG Co A reductase inhibitors are administered in tablet form:

• atorvastatin 10 - 80 mg/day
• cerivastatin 0.1-0.3 mg/day
• fluvastatin 20-80 mg nightly
• lovastatin 10 - 80 mg once nightly with the evening meal, or in divided doses
• pravastatin 5 - 40 mg nightly
• simvastatin 5 - 40 mg nightly⁴⁷

The use of statins is contraindicated in patients with active hepatic disease or with elevated serum transaminase levels. Important drug interactions should be noted: there is an increased risk of myopathy and of potentially fatal rhabdomyolysis when certain statins are used together with cyclosporine, tacrolimus, nicotinic acid, fibrates, erythromycin, azol antifungal agents and some calcium channel blockers including mibefradil. There are profound differences between the metabolism of statins, and hence major differences in their potential for drug interactions. Grapefruit juice may also interfere with the metabolism of certain statins. Renal failure is a risk factor for muscle side-effects of some statins. Where possible, such incompatibilities should be avoided. If simultaneous administration is essential, dosage should be minimal and titrated gradually with frequent monitoring of plasma creatine kinase activity. The reported side-effects of statins include headache, flatulence, constipation, dyspepsia and elevation of transaminases; rare side-effects are pruritus, rashes, myopathy, rhabdomyolysis and lupus erythematosus. Side-effects are reversible on withdrawal of the drug.

3.4.6.2 Bile acid sequestrants (resins)

Clinical trials have established that lipid lowering by means of bile acid sequestrants reduces the incidence of CHD. In the Lipid Research Clinics Coronary Primary Prevention Trial, a randomised double-blind trial of cholestyramine versus placebo in 3806 men with diet-unresponsive elevation of plasma cholesterol and without heart disease, plasma cholesterol decreased by 19% and coronary events decreased by 39%. Overall there was a 19% reduction in coronary events. Benefit was related to dosage: a lesser reduction was seen in those who complied fully. There was no difference in total cancer rates⁴⁸. Bile acid sequestrants are effective in lowering LDL-cholesterol, both in familial hyper-cholesterolaemia (at full dosage) and in other forms of diet-resistant hypercholesterolaemia (often in lower, easily tolerated dosage):

• HDL-cholesterol increases slightly
• combination with a statin may be useful in severe hypercholesterolaemia
• as triglyceride levels may increase, full doses of resins are not suitable in combined (mixed) hyperlipidaemia unless a triglyceride-lowering drug is also given

3.4.6.2.1 Dosage of bile acid sequestrants (resins)

Administered as powders mixed with fluid. Taken twice daily with meals, or daily at low dosage:

• cholestyramine 4-24 g/day
• colestipol 5-30 g/day

3.4.6.3 Fibric acid derivatives (fibrates)

One of the largest trials performed thus far of fibric acid derivatives was the Helsinki Heart Study, the results of which are summarized in Table 12.

Fibric acid derivatives are frequently prescribed in patients with hypertriglyceridaemia and combined (mixed) hyperlipidaemia. They are heterogeneous in various way, for example their ability to lower LDL-cholesterol and fibrinogen. These differences reflect variation in their molecular mechanism of action. Fibrates reduce serum triglyceride effectively and increase HDL-cholesterol substantially. They can be used in mild to moderate hypercholesterolaemia, in which LDL-cholesterol may be lowered. Treatment is usually commenced with a recommended optimal dosage. Serum alanine transferase levels should be monitored.

3.4.6.3.1 Dosage of fibric acid derivatives (fibrates)

Fibric acid derivatives are administered in tablet (capsule) form:

• bezafibrate 200 mg three times daily or sustained release form, 400 mg daily
• ciprofibrate 100 mg daily
• fenofibrate micronised, 200 mg once daily
• gemfibrozil 600 mg twice daily or sustained release form, 900 mg once daily

3.4.6.4 Nicotinic acid

Nicotinic acid lowers plasma cholesterol and triglyceride levels and raises HDL-cholesterol:

• side effects tend to limit adherence,
• cutaneous flushing and itching, and severe dyspepsia are the most common problems,
• liver disease, gout and diabetes are relative contraindications since hyperuricaemia and decreased glucose tolerance have also been reported.
• Routine monitoring for signs of these diseases is necessary.

3.4.6.4.1 Dosage of nicotinic acid

Nicotinic acid is available as tablets of 25 mg to 500 mg, also in sustained release form:

• starting dose: 100 mg three times daily
• titration of dose up to 2 - 8 g/day.

3.4.6.5 Fish oil

Several population studies have observed lower CHD mortality rates in groups with high fish consumption: in one secondary prevention trial, fatty fish lowered CHD mortality. Recently, however, a large longitudinal study has failed to detect any relationship between the amount of fish consumed and CHD incidence. Though CHD mortality was lower in those consuming fish than in those consuming none, the interpretation of the study results is limited by sources of statistical confounding.

The highly-unsaturated fatty acids of fish oils decrease secretion of triglyceride by the liver, and reduce hypertriglyceridaemia. There is little or no effect on plasma cholesterol level and on HDL-cholesterol, however, LDL-cholesterol level is unchanged or may increase.

In the treatment of hypertriglyceridaemia, if a high intake of fatty fish is ineffective or unacceptable, capsules of fish oil derived from muscle, not liver, may be a suitable alternative. A suitable dose provides 3 g of eicosapentaenoic acid plus docosahexanaenoic acid twice daily.