David Levy, MD, FRCP
Plant sterols, hydrogenated to stanols, reduce cholesterol absorption. At the recommended intake of 2 g/day they can lower total cholesterol by 12–14% and LDL by 13–16% (e.g. 0.3 mmol/L, 12 mg/dL) in both type 1 and 2 patients. Like ezetimibe, they have no effect on HDL or triglycerides (see Table 12.3) or on inflammatory markers such as high-sensitivity CRP.
The indication for these agents is as a nutraceutical at a fixed dose of 2 g/day in mild hypercholesterolemia.
Though there is the expected variability in clinical response, at its maximum it is a clinically useful effect, though only about one-third as potent as a statin, and is additive to that of other LDL-lowering agents (including ezetimibe). The difficulty and paradox is that at present they are mostly incorporated into dairy products, as they are fat-soluble (though a soy-based drink is available in the UK). They therefore have to be taken daily as a food (nutraceutical), for example 1.5 tablespoons of margarine, or more conveniently as a small yoghurt drink. The products are expensive and compliance is a problem. In the UK, Benecol and Flora pro.activ brands are available; the former is lower in carbohydrate calories.
The w-3 polyunsaturated fatty acids
The w-3 (also known as n-3) polyunsaturated fatty acids are ‘essential’ in that they cannot be endogenously synthesized and must be obtained from food. The major long-chain fatty acids EPA and DHA are found in greatest concentrations in the flesh of oily fish, and the livers of both oily and non-oily fish.
The indications for the w-3 polyunsaturated fatty acids are:
- post-myocardial infarction prophylaxis starting within 3 months of an event;
- in combination with a statin in mild–moderate mixed hyperlipidemia;
- in patients with macrovascular disease (stroke and heart failure);
- in vitamin D insufficiency.
Low dose (EPA + DHA 1 g daily)
There is no effect on the conventional lipid profile, but there is significant reduction in:
- sudden death in postmyocardial infarction patients (GISSI- Prevenzione, 1999);
- secondary stroke events in Japanese (JELIS, 2008; EPA 600 mg t.d.s.);
- hospitalization for heart failure (GISSI-HF, 2008).
High dose (EPA + DHA 2–8 g daily)
Hepatic VLDL synthesis is lowered, and hepatic [)-oxidation and peripheral VLDL clearance is increased, resulting in dose-dependent triglyceride lowering (~10% at 2 g, ~40% at 8 g) (see Table 12.3). LDL and HDL levels both increase by about 6%, depending on the baseline triglyceride level. Although effective and well tolerated, very large doses of fish oils are needed to achieve the same degree of triglyceride lowering as more convenient doses of fibrates or niacin (see below). Prescription preparations (e.g. Omacor, UK; Lovaza, USA) contain 1 g EPA + DHA per capsule, compared with standard high-strength fish oil capsules, which contain about 300 mg each, while 10 mL of high-strength liquid fish oil contains about 1.9 g, usually in an EPA/DHA ratio of 3:2. Though fish consumption is important, oily fish provides only 1 g per serving of 56–84 g (2–3 ounces), and it is therefore difficult to achieve adequate intakes for triglyceride lowering through fish intake alone. Dietary intake in Americans with diabetes is very low indeed, with a mean of 160 mg/day in the Look AHEAD study (though intake still correlated well with triglyceride level and more weakly with HDL-cholesterol) . Flax (linseed) and other plant seeds contain long-chain fatty acids, for example linolenic acid, and these can be substituted for fish oils in vegetarians. However, it is generally thought that conversion to the w-3 series is low.
Up to 4 g daily of w-3 fatty acids (Omacor) are safe in combination with statins in combined hyperlipidemias; other combinations, for example with niacin or fibrates, would be logical in patients with severe hypertriglyceridemia, but there are no formal studies and the combinations are unlicensed. There have been concerns about worsening glycemic control with w-3 fatty acid treatment, but the effect is small and not clinically relevant. Proprietary preparations of fish oils may contain small amounts of vitamin D, for example 5 µg (200 units) per 10 mL.
Niacin (nicotinic acid)
Niacin (nicotinic acid, vitamin B3) has a long history of use in lipid disorders. While it only modestly reduces total cholesterol by about 10%, the effect on LDL-cholesterol may be as much as 30% because of its powerful effects on metabolic syndrome-related lipid abnormalities of elevated triglycerides and depressed HDL-cholesterol, improving each by 20–30%. It can therefore be considered a broad-spectrum antidyslipidemic agent.
The indications for niacin are:
- secondary myocardial infarction prevention combined with a statin, especially in insulin-resistant dyslipidemia (elevated triglycerides, depressed HDL);
- after CABG.
Secondary prevention studies combining niacin with either a statin or bile-acid resin in patients with established coronary artery disease have shown decreased progression of atherosclerosis (quantitative coronary angiography and CIMT) and, allowing for the small numbers of patients recruited into trials of this vintage (1970s to 1990s), reduced recurrent clinical events. Patients with the metabolic syndrome appear to benefit even more .
Niacin has been less used of late because the high doses required to produce these benefits (1–2 g daily) frequently cause flushing and itching, which can be severe, although the intensity and frequency of the attacks decreases with use. Nevertheless, in clinical practice persistence with niacin treatment is poor. There have also been concerns about increased insulin resistance and blood glucose levels in both diabetic and non-diabetic patients. In diabetic patients, mean fasting glucose levels rise by a median of only 0.2 mmol/L (4 mg/dL) and HbA1c by 0.2% (2 mmol/mol), undetectable on routine testing, and clinically not relevant compared with the benefit of niacin treatment.
An extended-release preparation (Niaspan) has been joined by a fixed-dose combination (Tredaptive), containing laropiprant, a selective blocker of the receptor for the prostaglandin PGD2 responsible for the cutaneous flushing. Still, 60% of patients will experience mild flushing or worse in the first week of treatment, compared with 80% taking other forms of nicotinic acid; in maintenance treatment, 55% will have some flushing, though 40% are classified as mild. This important treatment still requires detailed explanation and support in the early phases of treatment if adherence is to be maximized. Medication is taken at night, increasing from 1 g nicotinic acid/20 mg laropiprant to 2 g/40 mg after a month (there is likely to be increased flushing for about 3 weeks when the dose is increased). The triple combination of niacin, ezetimibe and simvastatin is effective and safe in patients with mixed hyperlipidemias treated for over a year .
The first agents to be effective in LDL lowering, but usually difficult to use in practice because of limiting gastrointestinal side-effects and the inconvenience of taking unpalatable and insoluble powders several times a day. They rapidly fell out of use after the introduction of statins.
The indications for the bile-acid sequestrants are as follows:
- LDL lowering in patients intolerant of statins;
- in combination with statins where further LDL lowering is required to reach target.
Colesevelam, more potent than the earlier agents, better tolerated and presented as tablets rather than resin, was introduced in 2000. LDL can fall a further 10–16% when added to a statin and although the mechanisms are not known, HbA1c may fall by up to 0.8% (this is a consistent effect in RCTs, and in the USA it is licensed for its blood glucose-lowering effect). Gastrointestinal side-effects are still quite frequent, for example constipation in 20%, and high doses are required for the full LDL-lowering effect (six 625-mg tablets daily). It is effective, safe and well tolerated in patients with familial hypercholesterolemia already taking a statin and ezetimibe. While potentially valuable in some patients, it is currently very expensive in the UK.
Severe hypertriglyceridemia (Box 12.3)
Syndromes with very high triglycerides (> 20 mmol/L, 2000 mg/dL) are uncommon (e.g. 1 in 1000 in the population), but are over-represented in diabetes and alcoholism (presumably especially so where the two are combined). The underlying genetic conditions are uncommon but there are several of them, contributing to a common phenotype in clinical practice, including:
- lipoprotein lipase gene mutations;
- associated apoC2 abnormalities (Fredrickson hyperlipoproteinemia type I), exacerbated by insulin deficiency;
- Fredrickson hyperlipoproteinemia types IIb, III (dysbetalipoproteinemia) and V;
- chylomicronemia syndrome.
Poorly controlled type 2 diabetes, at diagnosis or beyond, is a common cause of severe mixed hyperlipidemia, often remitting completely when the diabetes comes under control. Lipid-lowering treatment is not needed under these circumstances, unless there is residual hypertriglyceridemia once the diabetes is treated. Fatty liver, a common accompaniment, exacerbates the problem. Triglycerides above 10 mmol/L predispose to acute pancreatitis, and the National Cholesterol Education Program guidelines in the USA recommend triglycerides should be the primary therapeutic target when above 5 mmol/L.
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David Levy, MD, FRCP, Consultant Physician, Gillian Hanson Centre, Whipps Cross University Hospital; Honorary Senior Lecturer
Queen Mary University of London London, UK
This edition first published 2011, © 2011 by David Levy. 1st edition 1998 (Greenwich Medical Media/Cambridge University Press) 2nd edition 2006 (Altman Publications)