SIGN 97: Risk estimation and the prevention of cardiovascular disease

Guideline Index Page | SIGN Methodology

9 Lipid Lowering

9.1 The role of total and low density lipoprotein cholesterol in cardiovascular disease

The link between cardiovascular risk and variation in blood lipid concentration was shown in a study of over 356,000 men aged 35-57 years who were followed up for six years. The study demonstrated a continuous, graded, strong relationship between serum cholesterol and six year age adjusted CHD mortality.181 This relationship persisted in smokers and non-smokers, people with and without hypertension and was evident irrespective of the presence or absence disease.182-184 Evidence level 2++

Low density lipoprotein (LDL) cholesterol usually makes up 60-70% of total serum cholesterol and the strong relationship between total cholesterol level and CHD suggests that LDL cholesterol is a powerful risk factor.185 TheroleofLDLcholesterolinatherosclerosisisconfirmedbystudies carried out in individuals with genetic disorders that result in extreme elevations of cholesterol levels, such as familial hypercholesterolaemia.186 These individuals tend to develop premature CHD with evidence of advanced atherosclerosis even in the absence of any other risk factor for coronary disease.

Epidemiological evidence has shown that populations with higher cholesterol levels experience more atherosclerosis and CHD than populations with lower levels187 and the higher the level of cholesterol, the greater the risk of a coronary event.181 Evidence level 2++

9.2 Measuring lipid levels

LDL cholesterol can be calculated indirectly by measuring total cholesterol, HDL cholesterol and triglycerides from a fasting venous blood sample and applying the Friedewald equation: LDL=TC'HDL'(TG/2.2).188 This method is not suitable for individuals with TG levels >5 mmol/l.

For greatest accuracy 12 hour fasting samples are required as HDL cholesterol and TG levels vary between fasting and non-fasting states. HDL cholesterol is lower by 5% to 10% in the non-fasting state than in the fasting state and TG levels are 20-30% higher.

Given the practical problems of routinely collecting 12 hour fasting samples, non-fasting blood samples are generally collected for estimation of TC and HDL cholesterol.189 Accurate estimation of LDL cholesterol requires a full lipid profile to be carried out on a fasting venous blood sample.

9.3 The benefits of lowering cholesterol for cardiovascular risk

Statins (HMG-CoA reductase inhibitors) are central to lipid lowering therapy in the prevention of first and recurrent vascular events. Statins inhibit cholesterol synthesis in the liver, activating hepatocyte LDL receptors and increasing hepatic uptake of LDL from the circulation.

A meta-analysis of lipid lowering in five randomised, placebo-controlled, double-blind trials included two trials in patients without evidence of cardiovascular disease (n=13,200) and three trials carried out in symptomatic patients (n=17,617). Active treatment with statins was associated with a 34% relative risk reduction (95% CI 23% to 43%; p <0.001) in major coronary events in the primary prevention trials and a 30% relative risk reduction (95% CI 24% to 35%; p<0.001) in the secondary prevention trials. The mean reduction (weighted by sample size) in TC, LDL cholesterol, and triglyceride levels was 20%, 28%, and 13%, respectively, and HDL cholesterol was increased by an average of 5% among the five trials.190 Evidence level 1++

Total cholesterol and CHD mortality reduction was consistent in trials of individuals with and without evidence of cardiovascular disease (see Table 7).

Table 7: CHD mortality and total cholesterol reduction in RCTs of statin therapy

Number of trials (type of population) n Mean total cholesterol reduction Mean relative reduction in CHD mortality 95% CI
5 (pooled results) 30,817 20% 29% 20 to 36%
2 (primary prevention) 13,200 19% 27% -0.5 to 49%
3 (secondary prevention) 17,617 22% 29% 20 to 37%

Two major primary prevention trials included in this meta-analysis were the West of Scotland Coronary Prevention Study (WOSCOPS)191 and the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS).33 In both trials, statin therapy significantly reduced relative risk for major coronary events (WOSCOPS relative risk reduction 29%, 95% CI 15 to 40, ARR 2.5%; AFCAPS/TexCAPS relative risk reduction 37%, 95% CI 21 to 50, ARR 4.1%). WOSCOPS also showed a significant reduction in coronary mortality (relative risk reduction 33%, 95% CI 1 to 55, ARR 0.6%). In AFCAPS/TexCAPS, the numbers of deaths in both placebo and treatment groups were so small that no conclusions could be drawn about effects of lipid lowering therapy on total mortality, however, no significant adverse effects of statin therapy were detected. Evidence level 1++

Regression analyses of RCTs of statin therapy indicate that for every 10% reduction in total cholesterol there will be a 15% reduction in coronary mortality.192 The absolute reduction in total cholesterol in major statin trials averages around 1 mmol/l. This corresponds to a 20% lowering and would be expected to yield an approximate 30% CHD mortality benefit.190,193 Evidence level 1+, 2++, 4

In more recent RCTs of lipid lowering, LDL cholesterol has been identified as a target for therapy. >Large trials of statin therapy in patients with and without CVD have indicated the degree of relative risk reduction for major coronary events which can be achieved from a given lowering of LDL cholesterol. They indicate that for every 1% reduction in LDL cholesterol levels, relative risk for major CHD events is reduced by approximately 1%.194-197 Evidence level 1++, 1+

A meta-analysis of data from 90,056 participants in 14 randomised trials of statin therapy showed that a 1.0 mmol/l reduction in LDL cholesterol lowered the five year relative risk of a major vascular event by 21%, irrespective of sex, age, blood pressure, pre-existing diabetes or history of a previous vascular event (RR 0.79, CI 0.77 to 0.81; p<0.0001; ARR 3.7%).3 Individuals at higher levels of vascular risk gained more in absolute terms from statin intervention. The relative risk reduction of around one fifth per mmol/l LDL translates to 48 (95% CI 39 to 57) fewer individuals having a major vascular event per 1,000 among those with established CHD, compared with 25 (19 to 31) fewer per 1,000 among individuals without established CHD. Evidence level 1++

This meta-analysis indicates an approximately linear relationship between the LDL cholesterol reductions achieved and the reduction in incidence of coronary and vascular events. The proportional reduction in event rate per mmol/l reduction in LDL cholesterol was independent of the presenting level, (ie lowering LDL cholesterol from 4 mmol/l to 3 mmol/l or from 3 mmol/l to 2 mmol/l) both reduce the risk of vascular events by about 21%, thus a reduction of LDL cholesterol from 4 mmol/l to 2 mmol/l might be expected to reduce risk by around 40% (relative risk 0.79 x 0.79 = 0.62).

9.4 How to reduce LDL cholesterol

An extensive systematic review and meta-analysis quantifying the effect of cholesterol lowering on the risk of vascular events in patients with and without CVD emphasised the importance >of cholesterol reduction per se rather than treatment modality.198 Evidence for lipid lowering drugs other than statins is presented in section 9.10. Evidence level 1++

The primary action of statins is to lower LDL cholesterol with only small effects on HDL cholesterol or triglyceride levels (see sections 9.10 and 9.11). Meta-analysis of 164 short term RCTs of lipid lowering by different statins showed the absolute LDL cholesterol reduction associated with different doses of different statins (see Table 8).198 The reductions in LDL cholesterol are dose-dependent and log-linear, so that with each doubling of the dose of statin, LDL levels fall by approximately 6%.

Table 8: Reductions in LDL cholesterol estimated from dose response curves by daily statin dose

statin standard comparator dose absolute LDL reduction (95% CI) % LDL reduction maximum dose absolute LDL reduction (95% CI) % LDL reduction
atorvastatin 10 mg 1.79 mmol/l (1.62 to 1.97) 37% 80 mg 2.64 mmol/l (2.31 to 2.96) 55%
fluvastatin 20 mg 1.02 mmol/l (0.90 to 1.13) 21% 80 mg 1.58 mmol/l (1.40 to 1.76) 33%
lovastatin 20 mg 1.40 mmol/l (1.21 to 1.59) 29% 80 mg 2.15 mmol/l (1.86 to 2.43) 45%
pravastatin 20 mg 1.17 mmol/l (1.10 to 1.23) 24% 40 mg 1.38 mmol/l (1.31 to 1.46) 29%
rosuvastatin 20 mg 2.32 mmol/l (2.20 to 2.44) 48% 40 mg 2.56 mmol/l (2.42 to 2.70) 53%
simvastatin 20 mg 1.54 mmol/l (1.46 to 1.63) 32% 80 mg 2.01 mmol/l (1.83 to 2.19) 42%

Percentage reductions are independent of pretreatment LDL cholesterol concentration and are based on an average baseline LDL level of 4.8 mmol/l.

Note: Iovastatin is not licensed in the UK

This meta-analysis showed that a reduction in LDL cholesterol of 1.6 mmol/l halves the risk of CHD events after two years and that this reduction can be achieved with standard doses of some statins.198

9.5 Statin therapy in high risk individuals without cardiovascular disease

Evidence from WOSCOPS and AFCAPS/TexCAPS indicates that the risk of major coronary events may be significantly reduced by standard doses of statin therapy (see section 9.3).33,191 Evidence level 1++

A systematic review of economic evidence reported that it is cost effective to give statins to individuals without evidence of CVD but with a ten-year 20% risk of CVD with statins compared to providing standard diet and lifestyle measures.199 The model made several simplifying assumptions to conclude that such individuals could be identified with complete accuracy. It used an annual cost for statins of about ?320 per person (a weighted average of the drugs used in the pooled trials). The advent of lower priced generic drugs has reduced the annual cost to under ?50. The cost effectiveness of statin therapy is discussed in Annex 2.

AAll adults over the age of 40 years who are assessed as having a ten year risk of having a first cardiovascular event≥20% should be considered for treatment with simvastatin 40 mg/day following an informed discussion of risks and benefits between the individual and responsible clinician.

[Good practice point]

[Good practice point] In individuals without established cardiovascular disease, lifestyle measures to reduce cholesterol levels should be encouraged, irrespective of the need for pharmacological treatment.

[Good practice point] Secondary causes of dyslipidaemia should be considered and excluded before commencing lipid drug therapy.

Simvastatin undergoes metabolic inactivation by cytochrome P-450 (see section 9.8).

9.6 Statin therapy in individuals with symptomatic cardiovascular disease

Table 8 indicates that treatment with a statin at a standard dose of 10-20 mg is likely to be associated with a 20-50% reduction in LDL level and therefore an approximately similar reduction in the risk of CHD events. Although the reduction in relative risk of CVD events with statin therapy is approximately constant across all baseline levels of total or LDL cholesterol and cardiovascular risk (see Table 7), the absolute risk reduction is affected by global cardiovascular risk, with individuals who are at the highest global risk achieving the greatest absolute risk reduction from statins (see Table 1). Individuals who are at high cardiovascular risk, such as those with established symptomatic CVD or those with familial hypercholesterolaemia, will gain more benefit from more aggressive lipid lowering than individuals at lower absolute levels of risk.

A meta-analysis of trials, including 27,548 patients with established CVD, compared the lipid lowering power of aggressive versus standard doses of statins.200 LDL cholesterol was lowered from an average of 3.33 mmol/l at baseline to 2.59 mmol/l (22% reduction) in the group receiving standard statin doses and to 1.92 mmol/l (42% reduction) in the intensively treated group. The high dose statin therapy was associated with a highly significant 16% relative risk reduction in the composite endpoint of CHD death or any cardiovascular event compared with less intensive statin therapy (event rate 32.3% versus 28.8%, OR 0.84, 95% CI 0.80 to 0.89; p<0.0000001; ARR 3.5%). Cardiovascular death tended to be lower in the high-dose groups in three trials, and neutral in the IDEAL trial.201 Pooling the data yielded a trend to reduction in cardiovascular mortality by 12% (3.8% vs. 3.3%, OR 0.88, 95% CI 0.78 to 1.00, p=0.054). Evidence level 1+

The higher doses of statins were associated with an increase in side effects. It is possible that careful patient selection and removal of those presenting with early indications of statin intolerance or adverse effects within the trials included in the meta-analyses could underestimate the actual risk of harm (see section 9.8).

Trials in this meta-analysis used fixed doses of statins (at low dose vs high dose) and cannot directly justify whether statins should be prescribed at the doses used in trials or titrated to achieveLDLtargets.Thebenefitsshownbythismeta-analysisareinadditiontothoseachievedby standard statin therapy, which has been shown to be highly effective in reducing cardiovascular mortality and events.3

One systematic review reported that it is cost effective to treat with a statin all individuals with cardiovascular disease compared to providing standard diet and lifestyle measures.199 This was confirmedinalargetrialoftreatmentwith40mg/daysimvastatininpeoplewithdifferentlevels of coronary vascular risk.202 The cost effectiveness of statin therapy is discussed in Annex 2. Evidence level 1++, 1+

The statins tested in major trials produced broadly similar beneficial outcomes indicating that their effect is generic rather than statin specific, with different levels of potency among the different drugs. Statin treatment produces substantial total and LDL cholesterol reductions in all individuals at high risk of any type of major vascular event, irrespective of their pre-treatment total or LDL cholesterol values, although the pleiotropic effects of statins are not fully understood and may play an important part in mediating their overall effect.

BAll patients with established symptomatic atherosclerotic cardiovascular disease should be considered for more intensive statin therapy following an informed discussion of risks and benefits between the individual and responsible clinician.

[Good practice point]

9.7 Cholesterol targets for therapy in patients with symptomatic cardiovascular disease

The JBS2 guideline states "there are no clinical trials which have evaluated the relative and absolute benefits of cholesterol lowering to different total and LDL cholesterol targets in relation to clinical events".28 Establishing a cholesterol target for therapy is therefore an extrapolation from< the apparent benefits indicated by major trials of lipid lowering, while maintaining appropriate margins for safety, given that there are still no long term follow up studies of statin therapy. Evidence level 4

Several national guidelines have recommended titration of lipid lowering therapy to achieve LDL cholesterol levels less than 2.5 mmol/l for patients at high cardiovascular risk.28,185 Evidence level 4

Current guidance from the Department of Health in England and Wales recommends that patients with established CHD should receive statins and dietary advice to lower serum cholesterol concentrations either to less than 5 mmol/l (LDL cholesterol to below 3 mmol/l) or by 25% (30% for LDL cholesterol), whichever is greater.203 Evidence level 4

A systematic review of RCTs, cohort studies, and case control studies that examined the independent relationship between LDL cholesterol and major cardiovascular outcomes in patients with LDL cholesterol levels less than 3.36 mmol/l found no clinical trial subgroup analyses, valid cohort or case control analyses suggesting that the degree to which LDL cholesterol responds to a statin independently predicts the degree of cardiovascular risk reduction.204 Evidence level 2++

Although the review indicated that there was compelling evidence for the effectiveness of statin therapy in lowering cholesterol in patients at high cardiovascular risk (regardless of their natural LDL cholesterol values) it concluded that current clinical evidence does not demonstrate that lipid therapy should be titrated to achieve proposed LDL cholesterol targets.

While patients with established symptomatic cardiovascular disease should be considered for intensive statin therapy, the long term safety and cost effectiveness of such therapy has not been established.200 Evidence level 1+

The current NHSScotland target for individuals at high cardiovascular risk is a TC level of <5 mmol/l. This level is consistent with the Quality and Outcomes Framework.205 Evidence level 4

Reducing this target to 4.5 or 4.0 mmol/l would have major resource implications for NHSScotland. Pending further studies on mortality, safety and cost-effectiveness, the guideline development group suggests that current NHSScotland targets are maintained, as the minimum standard of care.

[Good practice point] The existing total cholesterol target of <5 mmol/l in individuals with established symptomatic cardiovascular disease should be regarded as the minimum standard of care.

9.8 Safety of statin therapy

A comprehensive review of all statin trials to date, undertaken by a Task Force of the US National Lipid Association, provides strong support for the safety of statins206 which is endorsed by a second meta-analysis.3 Overall, there was no increased risk of cancer or non-cardiovascular mortality. Raised levels of liver enzymes (aspartate and alanine aminotransferase) to more than three times their upper normal limit occur in fewer than 1% of subjects treated across the dose range of the marketed statins, with the exception of atorvastatin administered at maximal (80 mg) dose and combination statin and ezetimibe therapy (see section 9.10.1). This effect is completely reversible upon withdrawal of treatment. Minor muscle discomfort is common, though its incidence varies.3,207 Myopathy, with raised levels of creatine kinase to more than ten times the upper normal limit, though more serious, is rare, occurring in less than one in 1,000 subjects. Rhabdomyolysis, in which myopathy is associated with end organ (renal) damage is even rarer, with a frequency of less than 1 in 10,000 per year of exposure to statins. Withdrawal of therapy leads to recovery in the majority of cases, although deaths have been reported in some subjects suffering from pathology of several systems and receiving multiple concomitant drug therapies.206 Evidence level 1++, 4

Statins interact with a number of other medications. The risk of myopathy increases when statins are used in combination with fibrates (eg gemfibrozil) or nicotinic acid (niacin) and they should only be used concomitantly under specialist supervision.

Some statins (particularly atorvastatin and simvastatin) are metabolised by cytochrome P450 and concomitant use of other potent inhibitors of this enzyme (eg ?azole? anti-fungal agents >and HIV protease inhibitors) may increase plasma levels of these statins and increase the risk of adverse effects, such as rhabdomyolysis. The risk of serious myopathy is also increased when high doses of simvastatin are combined with less potent cytochrome P450 inhibitors, including amiodarone, verapamil, and diltiazem. The consumption of even modest quantities of grapefruit juice can significantly increase exposure to simvastatin, increasing the risk of serious myopathy. Patients taking atorvastatin should also avoid drinking large quantities of grapefruit juice. These concerns do not apply to fluvastatin, which is metabolised by a different cytochrome P450 enzyme, or to pravastatin and rosuvastatin, which are not substantially metabolised by cytochrome P450.208 Evidence level 4

Statins are contraindicated in patients with active liver disease (or persistently abnormal liver function tests), in pregnancy (adequate contraception is required during treatment and for one month afterwards) and patients who are breast-feeding.131 Evidence level 4

The US National Lipid Association recommends monitoring and testing of patients who are being considered for statin therapy. These are reproduced in annexes 3-6.

Atorvastatin, fluvastatin, pravastatin, rosuvastatin and simvastatin are licensed for use in the UK.

[Good practice point] Patients who are using medications that influence cytochrome P450 metabolism should avoid concomitant use of atorvastatin or simvastatin. In such cases, pravastatin is an acceptable alternative lipid lowering therapy.

9.9 Special considerations

9.9.1 People with diabetes

Statin therapy in people with diabetes appears to be associated with a statistically significant reduction in the relative risk of various clinical endpoints including all-cause mortality and fatal and non-fatal MI.199 Evidence level 1++

Three major trials of statin therapy in individuals with CVD and one trial of individuals with no evidence of CVD involved subgroups of patients with diabetes.33,209-211 There were 483 subjects in the 4S trial with a clinical diagnosis of diabetes. In this subgroup, simvastatin therapy was associated with a 42% reduction in major CHD (fatal and non-fatal CHD) (p=0.001) compared with a 32% reduction in major CHD in subjects without diabetes.210 In the CARE study, 586 subjects with a clinical diagnosis of diabetes were identified. Pravastatin therapy reduced the risk for CHD (fatal plus non-fatal MI, CABG and PTCA) by 25% in the group with diabetes (p=0.05) as compared to 23% in the group without diabetes (p<0.001).210 In the LIPID study, pravastatin reduced the incidence of fatal and non-fatal CHD by 19% in 792 subjects with diabetes (not significant) and 25% in subjects without diabetes (p<0.001). Although the reduction in CHD events in subjects with diabetes was not significant with pravastatin, the test for heterogeneity in response between subjects with and without diabetes was not statistically significant. In AFCAPS/TexCAPS, a primary prevention study, only 155 subjects had a clinical diagnosis of diabetes. Among this small number of subjects, a 42% reduction in CHD was seen (not significant) which was similar to the 37% reduction in CHD seen in the overall study population.33 Evidence level 1++

Individuals over the age of 40 years with diabetes should be considered for statin therapy (see section 3.1).

9.9.2 Familial Hypercholesterolaemia

Subjects with familial hypercholesterolaemia based on clinical or genetic evidence should be considered for aggressive statin therapy, irrespective of their calculated cardiovascular risk. Their total cholesterol will usually exceed 8 mmol/l and may be substantially higher than this. In general, this treatment should only be considered in children of 12 years or older although it may be applied to younger patients at high risk because of severe hypercholesterolaemia if proper monitoring facilities are available.212,213 Under such circumstances, ezetimibe or anion exhange resin therapy may be added to the statin in order to provide adequate cholesterol reduction. Evidence level 1++

9.9.3 Pregnancy

Statins are contraindicated in women who are pregnant or are likely to be pregnant (see section 9.8).131

9.9.4 Elderly people

In the elderly, the decision to start statin therapy should be based on individual ten year cardiovascular risk estimation, life expectancy, and quality of life. Age alone is not a contraindication to drug therapy.195 Evidence level 1+

9.10 Other lipid lowering agents

Meta-analysis of 58 trials of lipid lowering by means other than statins showed a 36% (95% CI 26 to 45%) reduction in risk of CHD death and non-fatal MI associated with a 1.0 mmol/l reduction in LDL cholesterol after six years.198

9. 10. 1 Anion exchange resins

The effect of statins can be accentuated by combining them with agents which interfere with steroid absorption, eg cholestyramine and colestipol. These drugs lower serum total and LDL cholesterol and cause mild and usually transient elevation of triglyceride levels.214,215

Clinical trial evidence from the 1980s demonstrates the benefit of these drugs as monotherapy in primary CHD prevention, but their side effect profile (gastrointestinal irritation, constipation) frequently makes them unacceptable to patients.216 Nevertheless, they may be indicated for the treatment of hypercholesterolaemia where statins are not tolerated or are contraindicated; or they may be added to statin therapy to enhance cholesterol reduction. Whereas doubling the dose of a statin produces only a six percent further reduction in LDL cholesterol, adding a moderate dose of a resin to a statin can further lower LDL cholesterol by 12-16%.217,218 Evidence level 1+

Ezetimibe is a cholesterol absorption inhibitor without significant side effects.219 As monotherapy, its cholesterol lowering capability is modest (a reduction of 15-20% in total cholesterol when prescribed as a single dose of 10 mg) but it has a role in statin-intolerant patients.220,221 Its co- prescription with low dose statin therapy results in a cholesterol reduction equivalent to that seen with maximum dose statin monotherapy. Statin-ezetemibe combination therapy may help in the management of patients in whom there is difficulty in achieving adequate cholesterol reduction despite high dose statin therapy, or who are intolerant of higher doses of statins, or in the treatment of severe genetic hyperlipidaemias.

[Good practice point] Combination therapy of a standard dose statin and anion exchange resin or ezetimibe is indicated in patients who are intolerant of higher-dose statin therapy.

9.10.2 Fibrates

Fibrates are primarily used for lowering triglycerides and raising low HDL levels because their LDL cholesterol lowering effects are generally in the range of 10% or less in persons with primary hypercholesterolemia.

Three major trials, the Helsinki Heart Study (HHS)222,the Bezafibrate Infarction Prevention(BIP) Study223 and the Veterans Affairs HDL Intervention Trial (VA-HIT)224 have shown that fibrates can raise HDL cholesterol by approximately 10-15%. They typically reduce triglyceride by 25-50% with greater reductions occurring in individuals with severe hypertriglyceridaemia.225 Evidence level 1++, 1+

The HHS employed gemfibrozil (600 mg twice daily) to treat asymptomatic middle aged(40-55 years old) men with primary dyslipidaemia (non-HDL cholesterol >5.13 mmol/l). The drug raised HDL cholesterol by 9%, reduced plasma triglyceride by 34%, and lowered the risk of a first coronary event by 34%. This benefit was more strongly associated with both reductions in LDL cholesterol and increases in HDL cholesterol substantiating the proposed protective benefit of the latter.226 Despite its magnitude, the fall in plasma triglyceride appeared to play little role in conferring cardioprotection. Evidence level 1++

The BIP Study employed bezafibrate, 400 mg/day to treat men with existing coronary artery disease, low levels of HDL cholesterol in their circulation and raised triglyceride. Although overall there was no significant reduction in fatal and non-fatal myocardial infarction or sudden death, the drug raised HDL cholesterol by 18% and lowered triglyceride by 21% and, in a subgroup of patients with baseline triglyceride greater than 2.26 mmol/l, the decrease in coronary morbidity and mortality was significant, suggesting that, as in primary CHD prevention,fibrates may help prevent repeat heart attacks, probably through their action on HDL cholesterol and plasma triglyceride. Evidence level 1++

A similar conclusion followed from the outcome of the VA-HIT trial in which 1,200 mg of gemfibrozilwasadministeredtomenwithCHD,lowlevelsofHDLcholesterol(<1.03mmol/l) and LDL cholesterol of 3.62 mmol/l). Treatment lowered fatal and non-fatal MI by 22% (p<0.006) and reduced stroke and transient ischaemic attack risk by 31% and 59% respectively. The main lipid changes were a 6% increase in HDL cholesterol and a 31% fall in triglyceride. Levels of LDL cholesterol remained unchanged throughout the study, although the circulating LDL particles may have become larger, more buoyant, and less atherogenic.227,228 This may help explain why the magnitude of reduction of events with gemfibrozil was greater than appeared likely from HDL cholesterol increases alone. Evidence level 1++

The consistency of these major fibrate-based trials supports the view that HDL cholesterol elevation and triglyceride reduction offer cardiovascular benefit which, at least in part, is independent of LDL cholesterol reduction.

9.10.3 Nicotinic acid

Nicotinic acid, or niacin, is the most effective HDL-raising agent currently available.229 Two forms of niacin are available, crystalline immediate-release which is taken three times daily and modified (extended) release taken once daily. Elevations of 15-35% in HDL cholesterol are reported following dosing with 1-3 g of the drug in its crystalline form, and are usually accompanied by a drop of 20-30% in LDL cholesterol and of 35-50% in triglyceride.230 An RCT that compared the efficacy and safety of treatment with 1.5 g /day immediate release (IR) with modified release (MR) niacin found similar effects on lipids for both preparations.231 Levels of the liver enzyme aspartate aminotransferase (AST) increased 5.0% versus 4.8% (difference not significant) with MR niacin and IR niacin respectively. Fasting plasma glucose increased 4.8% versus 4.5% (not significant). Skin flushing events were more frequent with IR versus MR niacin (1,905 vs 576, p<0.001). Evidence level 1+, 4

In the Coronary Drug Project niacin was administered in a daily dose of 3 g over 6.5 years to men who had already had a myocardial infarction. Treatment reduced the frequency of subsequent events by 14% (p<0.005), though there was no effect on overall mortality.232 After another eight years follow up and despite no attempt being made to maintain those conditions, total mortality showed significant reduction in the niacin treated cohort.233 Evidence level 1+

More recent data were reported in the HATS trial, an angiography based investigation of 160 men and women with low HDL cholesterol (1.0 mmol/l in females and <0.9 mmol/l in males), normal LDL cholesterol, and triglycerides of <4.5 mmol/l.234 When compared to placebo, the combination of simvastatin and niacin lowered LDL cholesterol by 42% and increased HDL cholesterol by 26%. These positive changes in the lipid profile produced 0.4% regression in coronary atherosclerosis over the three year study observation period, while the placebo cohort showed 3.9% stenosis progression, a highly significant difference between the two groups Evidence level 1+

Although this study was not powered to show major coronary endpoint differences as a result of the treatments, of the 38 subjects in the placebo-treated cohort, nine experienced one of these endpoints compared to one in the simvastatin-niacin group (p=0.03).

A meta-analysis of 53 trials (n=16,802) using fibrates and 30 trials (n=4,749) using niacin showed that each drug significantly lowered TC, LDL cholesterol and triglyceride levels and raised HDL cholesterol (see Table 9).235 Fibrates reduced the risk for major coronary events by 25% and current available data for niacin indicate a 27% reduction.233 Evidence level 1+

Table 9: The effect of fibrates and niacin on cholesterol and CHD risk

Fibrates Niacin
53 trials (16,802 subjects) 30 trials (4,749 subjects)
net TC lowering 0.66 mmol/l (95% CI 0.75 to 0.55 mmol/l), p<0.00001), 11% 0.66 mmol/l (95% CI 0.49 to 0.82 mmol/l), p<0.00001), 10%
net HDL raising 0.11 mmol/l (95% CI 0.09 to 0.13 mmol/l p< 0.00001), 10%. 0.17 mmol/l (95% CI 0.13 to0.22 mmol/l, p<0.00001), 16%
net LDL lowering 0.30 mmol/l (95% CI 0.14 to 0.46 mmol/l, p < 0.0002), 8% 0.53 mmol/l (95% CI 0.34 to 0.73 mmol/l, p<0.00001), 12%.
net triglycerides lowering 0.80 mmol/l (95% CI 0.69 to 0.90 mmol/l, p<0.00001), 36% 0.53 mmol/l (95% CI 0.39 to 0.69 mmol/l, p<0.00001), 20%.
CHD risk reduction coronary events: 25% (95% CI 11% to 37%) coronary death: not significant 27% (from Coronary Drug Project)

AIndividuals with hypertriglyceridaemia (>1.7 mmol/l) and/or low high density lipoprotein cholesterol level (<1 mmol/l in men, or <1.2 mmol/l in women) should be considered for treatment with a fibrate or nicotinic acid.

9. 11 Management of combined dyslipidaemia

Combined dyslipidaemia, characterised by abnormalities in all of the major lipoprotein species, is associated with increased risk of vascular disease which goes beyond that produced by raised LDL cholesterol alone. Plasma triglyceride is elevated, HDL cholesterol is low and LDL particles are smaller, denser and more atherogenic than normal.236,237 This profile clusters in particular disease states and is particularly characteristic of the metabolic syndrome and diabetes mellitus (diabetic dyslipidaemia). Evidence level 2+, 4

A number of clinical trials have shown that LDL cholesterol lowering with statins reduces the risk of vascular events (myocardial infarction, stroke and coronary revascularisation) in diabetic subjects with raised LDL cholesterol (see also section 9.9.1).238,239 The greater the LDL cholesterol reduction, the greater the benefit.240 Evidence level 1++, 1+

The largest vascular endpoint trial undertaken with fibrates (FIELD) provided limited evidence for their benefit in a similar diabetic cohort.241 Although treatment with fenofibrate did not significantly reduce the risk of a coronary event, it produced a 24% reduction (p=0.01) in risk of non-fatal MI. There was a non-significant rise in coronary deaths, but overall cardiovascular disease events (fatal and non-fatal myocardial infarction, stroke and coronary and carotid revascularisation) fell by 11% (p=0.35). Fenofibrate treatment resulted in less albuminuria progression (p=0.002) and less retinopathy requiring laser treatment (p=0.0003). Pancreatitis and pulmonary embolism risk rose in the actively treated group (p=0.031 and 0.022 respectively). Evidence level 1+

In FIELD there was a significantly greater increase in statin use in subjects allocated to the placebo cohort, but a prespecified statistical adjustment made to take account of statin use suggested that attribution of failure to achieve primary endpoint benefit to post-randomisation statin drop-in therapy might not explain the outcomes of this trial.

Combined statin/fibrate therapy improves the entire dyslipidaemic profile over that seen with statin therapy alone. Trials have reported a significant increase in HDL cholesterol levels and significant reductions in triglyceride and LDL cholesterol levels in patients on combined statin/fibrate therapy compared to patients on statins or fibrate monotherapy.242,243 The effect of combined statin/fibrate therapy has not been tested on cardiovascular endpoints, and it is not possible to recommend this combination as an effective method of reducing CVD risk. Evidence level 1+

It has been suggested that the potential for impaired metabolism of statins with gemfibrozil244 may be greater than with other fibrates, such as fenofibrate.245 This is supported by evidence from healthy volunteers that the combination of fenofibrate with statins is associated with minimal differences in the concentrations of either fenofibrate or statin.246 In contrast, the concurrent use of certain statins with gemfibrozil has shown a two- to three-fold increase in statin levels.247 Analyses of the US Food and Drug Administration Adverse Event Reporting System have suggested that the use of fenofibrate with statins results in fewer reports of rhabdomyolysis per million prescriptions than does the use of gemfibrozil with statins.248 Evidence level 3, 4

AStatins are the drugs of choice in the management of diabetic subjects with mixed dyslipidaemia and elevated low density lipoprotein cholesterol.

[Good practice point] Combination therapy with a statin and a fibrate may be required for combined dyslipidaemia.

[Good practice point] Particular care should be taken when coadministering statins with gemfibrozil.

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