Narrative reviews
Anatomy and physiology Pharmacology Cardiovascular diseases
Volume 211 - Issue 2

An updated review of lipid‐modifying therapy

Author:  Leon A Simons

Med J Aust 2019; 211 (2): 87-92. || doi: 10.5694/mja2.50142
Published online: 22 April 2019

A review of the legislation may be warranted to assess the balance between professional and public interests

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Summary

  • Statin drugs reduce low‐density lipoprotein (LDL)‐cholesterol (LDL‐C) and cardiovascular risk. Ezetimibe may be used to supplement statin therapy, or used alone in cases of statin intolerance. Statin‐associated side effects do occur, especially muscle symptoms and new onset diabetes, but they do not detract from the benefits of statin therapy.
  • Inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) reduce LDL‐C and cardiovascular risk. Evolocumab is subsidised in Australia for patients with familial hypercholesterolaemia when LDL‐C is not adequately controlled with maximum doses of statin or ezetimibe or when statin therapy is contraindicated.
  • Fenofibrate reduces triglycerides and cardiovascular risk in patients with type 2 diabetes when triglycerides are elevated and high‐density lipoprotein (HDL) is low.
  • A role for dietary omega‐3 fatty acids and esters in reducing cardiovascular risk remains controversial.
  • All cases of secondary cardiovascular disease prevention merit intensive lipid therapy, unless a contraindication exists. Lipid therapy is justified in cases of primary prevention when absolute risk is high, especially when lipids are highly elevated or when multiple risk factors are present.
  • Clinical management requires a focus on the predominant lipid disorder present, namely hypercholesterolaemia, hypertriglyceridaemia or combined hyperlipidaemia.
  • There is an ongoing problem of poor long term persistence on lipid therapy, as well as reduced awareness by practitioners of poor risk factor control.

Lipid abnormalities, especially raised serum levels of low‐density lipoprotein (LDL)‐cholesterol (LDL‐C), are causally related to atherosclerotic cardiovascular disease (CVD). However, selected lipid interventions have been shown to improve CVD risk.1

This narrative review used PubMed sources of original studies and review articles from 2005 to 2018 as well as specialist society publications, guidelines and conference proceedings to formulate a broadly evidence‐based overview of the field as applied to clinical practice.

Lipid interventions: an overview of clinical trials

Statin drugs

Numerous placebo‐controlled trials with statin drugs (ie, HMG‐CoA reductase inhibitors) testify to the efficacy and general safety of statins in reducing CVD risk.2,3,4,5 The evaluated statins in major trials include simvastatin, pravastatin, lovastatin, fluvastatin, pitavastatin, atorvastatin and rosuvastatin.

The trials show that statin treatment to reduce LDL‐C in 10 000 patients over 5 years would prevent about 1000 major CVD events in patients with pre‐existing CVD (ie, in secondary prevention). This therapy would prevent about 500 CVD events in patients at increased risk but with no pre‐existing CVD (ie, in primary prevention).1 Lower risk patients will achieve lesser benefits.5

The Cholesterol Treatment Trialists’ Collaboration has published a series of reports that underpin these benefits. A 2005 report, based on 14 statin trials, confirmed a significant 21% relative risk reduction in major CVD events for every mmol/L reduction in LDL‐C over 5 years.2 A 2010 report, based on 26 statin trials, explored whether more intensive statin therapy (40–80 mg atorvastatin or 10–20 mg rosuvastatin daily) might be more effective than less intensive therapy (simvastatin 20–40 mg daily). More intensive therapy produced an additional 15% reduction in major CVD events.3 The findings suggest that reducing LDL‐C by 2–3 mmol/L, a change that can be achieved in routine clinical practice, might reduce relative risk by around 40–50%.

A 2015 report, based on 27 trials, showed that men and women who have equivalent CVD risk similarly benefited from statin therapy.4 Overall, statins were of significant benefit independent of baseline LDL‐C, secondary or primary prevention status, type 2 diabetes or non‐diabetes, treated hypertension or smoking status.2,3,4,5

A meta‐regression analysis looked at trials employing statin or non‐statin therapies that upregulated LDL receptor activity. Similar reductions with either treatment were noted in the relative risk for major CVD events per unit reduction in LDL‐C.6 Lower achieved LDL‐C levels were associated with lower rates of major coronary events.

The combination of statin with ezetimibe produced a further average reduction in LDL‐C of about 25% and reduced the relative risk of major CVD events by a further 6% compared with statin alone.7 In this trial, patients with a prior history of coronary artery bypass surgery treated with this combination achieved a 20% additional reduction in major CVD events,8 while benefits were enhanced in patients with diabetes.9

The lowest CVD event rates are achieved in those groups achieving the lowest LDL‐C levels and a mantra has arisen: “in regard to LDL‐C, the lower the better”. Patients receiving statin therapy should also follow standard diet and lifestyle advice, with appropriate attention to other major risk factors such as hypertension, diabetes and cigarette smoking.10

Relatively little clinical trial data with statin therapy are available for older patients, especially those aged over 85 years.11 This lack of data remains a major issue with the ageing, healthy population. On a purely empirical basis, statins should not be suspended in the context of secondary prevention if an older patient has a reasonable life expectancy and a good quality of life.12 Introduction of statin therapy for primary prevention in older people is problematic and will depend on the balance of risk, benefit and possible side effects.12 There is a potential role here for coronary artery calcium (CAC) scoring, which will be discussed later in this review.

In the matter of adverse events in clinical trials with statins, treatment of 10 000 patients for 5 years would be associated with just one case of rhabdomyolysis and five cases of myopathy (ie, severe muscle problems), 75 new cases of diabetes and seven haemorrhagic strokes.1 Adverse event rates reported in controlled trials seem to underestimate what is observed in routine clinical practice, possibly because of narrow inclusion and exclusion criteria. Nevertheless, the benefits of statin therapy will still heavily outweigh any negative aspects.

PCSK9 inhibitors

The enzyme proprotein convertase subtilisin/kexin type 9 (PCSK9) has been shown to regulate LDL‐C levels through its binding to LDL receptors, ultimately limiting their recycling to the cell surface, and hence reducing tissue uptake of LDL‐C from the extracellular fluid. Loss of function mutations in the gene coding for PCSK9 are associated with low LDL‐C and reduced coronary risk.13 Alirocumab and evolocumab are fully humanised monoclonal antibodies to PCSK9. These products are self‐injected subcutaneously using a pre‐filled, fixed‐dose “pen”, usually every 2 weeks.

PCSK9 inhibitors produce large reductions in LDL‐C whatever the background lipid therapy, if any.14 Based on serial coronary intravascular ultrasound studies, evolocumab added to statin therapy induced atheroma regression in some patients with symptomatic coronary disease.15 This finding has found support in secondary prevention trials. Both evolocumab and alirocumab significantly reduced the relative risk of CVD outcomes by 15% in patients already using statins.16,17 Alirocumab reduced total mortality by a significant 15%, but a significant difference in mortality was not found with evolocumab. This differential is difficult to explain. Adverse event rates on either drug were similar to placebo rates, except for a slight excess of local injection‐site reactions.16,17

Evolocumab therapy was not associated with cognitive impairment.18 Both evolocumab and alirocumab reduced CVD events in the presence of diabetes, but with no increase in new‐onset diabetes or worsening in glycaemia.19,20 Evolocumab reduced CVD events across all strata of the inflammatory marker high‐sensitivity C‐reactive protein.21

Triglyceride‐lowering drugs

Compared with LDL, a relationship between elevated triglycerides and CVD risk has been more difficult to define, but it is present.22,23 This relationship appears much stronger in the presence of diabetes and low levels of high‐density lipoprotein (HDL).24,25 Highly elevated triglycerides (> 10 mmol/L) are associated with increased risk of acute pancreatitis and will always require intervention.

Clinical trial evidence suggests that a fibrate drug such as fenofibrate may reduce the relative risk of a major CVD event in patients with type 2 diabetes by around 30% when baseline triglycerides are elevated (> 2.0 mmol/L) and HDL‐cholesterol (HDL‐C) is low (< 0.9 mmol/L).26,27 This effect is additional to any benefits of concurrent statin therapy. These same studies showed that fenofibrate therapy reduces the risk of microvascular disease, in particular reducing the progression of established diabetic retinopathy, an effect independent of lipid levels.28,29

CVD risk reduction requires simultaneous attention to all risk factors, but this is difficult to test experimentally. One small study in type 2 diabetes — the Steno‐2 study in Denmark — targeted intensive intervention versus usual care for lipids, blood pressure, glycaemia and cigarette smoking.30 At long term follow‐up, total mortality was 46% lower in the intensive intervention group, with reduction in CVD, heart failure and renal disease.31 This type of study has not been replicated on a larger scale or in other patient groups.

Omega‐3 fatty acids or esters, generally from marine sources, also reduce elevated triglycerides in selected patients.32 Reviews and meta‐analyses have not confirmed any CVD benefit of omega‐3 supplementation in primary or secondary prevention.33,34 A large study in primary prevention using 1 g per day of omega‐3 fatty acid also failed to show CVD protection.35 A recent study using very high dose omega‐3 supplements of concentrated ester at 4 g per day in mixed primary–secondary prevention (71% secondary), with all patients taking statin therapy, showed significant CVD benefit.36 However, this benefit was much smaller in patients without prior CVD and did not reach statistical significance. The role of omega‐3 supplementation remains controversial, but the latter study suggests that very high dose omega‐3 in secondary prevention may have a clinical role, especially if these new findings can be confirmed.

A meta‐analysis of CVD outcome trials that employed fibrates, niacin or omega‐3 fatty acids to reduce triglycerides showed a relative risk reduction in CVD events of 12% in all patients (ten studies), a reduction of 18% in those with elevated triglycerides (nine studies), and a reduction of 29% in those with elevated triglycerides and low HDL (eight studies).24

HDL‐raising drugs

HDL has a proven negative association with CVD risk. High dose niacin, which also reduces LDL and triglycerides, or inhibitors of cholesterol ester transfer protein have been used to increase HDL‐C.37,38,39 Unfortunately, controlled trials with niacin against a background of statin therapy have failed to reduce CVD events in secondary prevention.37,38 while similar trials with inhibitors of cholesterol ester transfer protein have been disappointing.39 Similar outcome trials have not been conducted in primary prevention or specifically in patients with low HDL. The use of high dose niacin remains minimal because of serious side effects, while cholesterol ester transfer protein inhibitors may never reach routine clinical practice.

Dietary advice and nutriceuticals

Guidelines generally recommend a reduction in saturated fat intake to reduce coronary heart disease risk as a preamble to any drug therapy.10 However, recent reports challenge the merit of such dietary advice.40,41 The association of dairy intake with CVD and mortality was examined prospectively in 21 countries in 136 000 subjects over 9 years.41 Dairy consumption was actually associated with lower total mortality and reduced major cardiovascular events.

There is evidence that the Mediterranean diet, principally consisting of a high consumption of olive oil, legumes, unrefined cereals, fruits and vegetables; moderate to high consumption of fish; moderate consumption of dairy products (mostly as cheese and yoghurt); and low consumption of non‐fish meat products, is associated with reduced CVD and with other health benefits.42

Nutriceuticals have recently been reviewed, but effects on CVD outcomes have not been appropriately studied.43

Lipoprotein(a)

Lipoprotein(a), a genetically determined component of the LDL particle, is increasingly recognised as a risk factor for CVD.44,45 It is known that elevated plasma levels of lipoprotein(a) are reduced by niacin or PCSK9 inhibitors, but we await specific trials to evaluate whether reduction in lipoprotein(a) reduces CVD risk.

Practical usage of lipid‐modifying drugs

Statins

Statins very effectively reduce LDL‐C, especially if patients persist with medication intake. Unfortunately, there is an ongoing problem of poor long term persistence with statins.46

Statins have additional and potentially beneficial effects on the cardiovascular system which may be independent of LDL‐C reduction, so‐called pleiotropic effects.47 These effects include increased expression of nitric oxide synthase, reduced production of pro‐inflammatory cytokines and reduced platelet reactivity. Such effects are not currently evaluated in routine clinical management and their contribution to the benefits of statin therapy remains uncertain.

There are some well documented statin‐associated side effects: muscle symptoms, new onset diabetes, drug–drug interactions (P450 3A4 pathway), liver dysfunction and central nervous system symptoms.48 Many prescribers and patients seek to avoid statin therapy because of concern for these side effects. Fear‐mongering on television, the internet or other lay media generally portray side effects without true perspective, while minimising the benefits of the therapy.

Muscle symptoms may occur in perhaps 10% of patients treated with statins.48 Patients previously reporting myalgia were challenged with statin and placebo in a large double‐blind, crossover study.49 Forty‐four per cent of patients experienced symptoms while using atorvastatin but not with placebo, 28% did so with placebo but not with atorvastatin, 10% did so on both, and 18% had no symptoms at all.49 While some myalgia may not be causally related to statin therapy, sensitive and careful ongoing management is required to reduce CVD risk. This might be through a switch to another statin at low dose (especially pravastatin), less frequent administration of low dose statin, or the use of non‐statin therapy such as ezetimibe. Other precipitating factors should be excluded, including hypothyroidism, vitamin D deficiency or drug–drug interaction.48 There is no convincing evidence that a supplement of coenzyme Q10 will assist here, beyond a placebo effect.

Up to 20% of patients may manifest new onset diabetes when using a statin, supposedly with more potent statins.50 A large study with rosuvastatin found that much of this excess risk occurred in patients with background risk factors for type 2 diabetes, in particular patients with evidence of impaired fasting glucose (ie, fasting glucose > 5.5 mmol/L). While glucose levels during treatment will require monitoring, it is reassuring that CVD and mortality benefits with rosuvastatin were similar in patients with or without new onset diabetes.51

Simvastatin and atorvastatin are excreted via the liver P450 3A4 pathway and extra care is required with the concomitant administration of drugs that interact with this pathway. Commonly used examples are macrolide antibiotics, antifungals and protease inhibitors.48 Rosuvastatin is excreted via the 2C9 pathway to a large extent, while pravastatin is exclusively excreted in the urine, being a water‐soluble molecule. This may underlie a slightly reduced potential for muscle problems with pravastatin at lower doses.

Significant liver dysfunction (ie, elevated transaminases, not an isolated elevation in γ‐glutamyl transpeptidase) is uncommon with statins, as are central nervous system side effects.

Anion exchange resins such as cholestyramine are no longer in common use. LDL apheresis is an option for severe cases of familial hypercholesterolaemia (FH), but this is demanding and of limited availability.

Fibrates

Gemfibrozil is no longer widely used because of a well known drug–drug interaction with statins leading to muscle symptoms.48 Fenofibrate is less likely to cause such issues, but caution is required when combination therapy is indicated.

Justification for use of fibrates in a non‐diabetes setting is derived from older intervention studies.24,25 They reduce triglycerides, achieve some HDL raising if triglycerides are elevated, and have a modest but variable beneficial effect on LDL‐C. Fenofibrate has a low risk of muscle problems when used without statins.

Ezetimibe

This drug partially inhibits intestinal cholesterol absorption and is a useful supplement to statin therapy or can be used as a non‐statin alternative.52 Ezetimibe reduces LDL‐C by around 25% independently of statin therapy. Additional CVD protection has been demonstrated against a background of statin therapy.7,53 Ezetimibe is generally well tolerated and has been used empirically in combination with fenofibrate.

PCSK9 inhibitors

Because of very high cost, this therapy will generally be used as a supplement to conventional treatment in patients needing further help to reach LDL‐C targets. PCSK9 inhibitors will usually reduce LDL‐C by a further 50%.14 They may also be used as solo therapy (or sometimes combined with ezetimibe) in patients intolerant to statins.

Evolocumab (but not alirocumab as at 1 November 2018) is subsidised in Australia for patients with FH when LDL‐C is not adequately controlled with the maximum recommended doses of atorvastatin, rosuvastatin or ezetimibe or when statin therapy is contraindicated.54 The Pharmaceutical Benefits Scheme subsidy guidelines are complex and have additional requirements, such as documentation of the presence of FH, an LDL‐C level greater than 3.3 mmol/L in the presence of symptomatic atherosclerotic CVD, or an LDL‐C level greater than 5.0 mmol/L in other instances.54

Who and how to treat with lipid‐modifying drugs

Intensive lipid‐modifying therapy is essential in all instances of secondary CVD prevention, provided it can be tolerated.10 Less intensive therapy is indicated in primary prevention in patients at high CVD risk.55 Patients with heterozygous FH are a group at high CVD risk, whether in secondary or primary prevention.

LDL‐C target in secondary prevention remains at 1.8 mmol/L or lower, an arbitrary level;10 the target in primary prevention remains at 2.0 mmol/L or lower.55 Arbitrary targets exist for triglycerides and HDL‐C (< 2.0 and ≥ 1.0 mmol/L, respectively), but these are not based on evidence from intervention studies.55 A target non‐HDL‐C greater than 2.5 mmol/L is also suggested, as this does not require fasting and takes into account the cholesterol content of triglyceride‐rich lipoproteins and remnants.

Patients hospitalised with an acute coronary syndrome are prescribed, or should be prescribed, intensive statin therapy, generally atorvastatin 80 mg daily, in addition to other standard therapy. In chronic care situations, patients are usually started on a lower dose of statin (eg, 10 mg), but with a plan to up‐titrate in doubling doses every 6–8 weeks if LDL‐C target is not approximated. For patients who are not reaching the target LDL‐C despite maximum‐tolerated dose of statin, supplementary ezetimibe can be added. The addition of a PCSK9 inhibitor should also be considered in relevant cases.54

The general approach to predominant patterns of hyperlipidaemia or dyslipidaemia is based on the following arbitrary definitions: hypercholesterolaemia (cholesterol ≥ 6.0 mmol/L and triglyceride < 4.0 mmol/L), hypertriglyceridaemia (triglyceride ≥ 4.0 mmol/L and cholesterol < 6.0 mmol/L), and combined hyperlipidaemia (cholesterol ≥ 6.0 mmol/L and triglyceride ≥ 4.0 mmol/L). This approach has changed little since this subject was last reviewed in 2005.56 What has changed is the stronger justification for treatment and availability of more treatment resources. A guide to management with lipid‐modifying drugs is presented in the Box.

The current Australian guidelines for lipid management were published in 2012.10,55 While science has advanced over the intervening years, these guidelines still remain appropriate and relevant. New guidelines on cholesterol management were recently published in the United States.57 In secondary prevention, high intensity or maximally tolerated statin therapy is recommended with the aim of reducing LDL‐C by at least 50%. Target LDL‐C is still 1.8 mmol/L, but more aggressive therapy with multiple drugs is recommended in patients at very high CVD risk (eg, history of multiple CVD events or multiple risk factors). In primary prevention, a target for LDL‐C is not explicitly stated, but careful assessment of overall CVD risk is recommended.57

In the context of primary prevention, it is essential to assess absolute CVD risk, either with one of the standard risk calculators55 or manually by looking at the overall risk profile. Patients with a 5‐year CVD risk greater than 15% are certainly at high risk, but those at lower risk should still be considered for drug therapy when lipids are highly elevated or when multiple risk factors are present.

Selection of patients in primary prevention for lipid therapy is sometimes challenging and guidelines suggest a potential role here for coronary artery calcium (CAC) scoring.57,58 The CAC score has been shown to be predictive of CVD events.59 The American guidelines, in brief, suggest that with a CAC score of 0, statins may be withheld if other major risk factors are absent; a CAC score from 1 to 99 favours statin therapy, especially in patients aged 55 years or over; a CAC score of 100 or over strongly favours statin therapy in any adult, if no contraindication exists.57 The pattern of recommendation in Australian guidelines is somewhat similar, but CAC assessment in not covered by Medicare reimbursement.58

To summarise the general principles of lipid therapy, it is essential to exclude any contribution from subclinical hypothyroidism, nephrosis, diabetes or alcohol‐sensitivity, the latter in cases of marked hypertriglyceridaemia. The full effect of diet and, ultimately, drug therapy is generally apparent within 6 weeks. Side effects, lipid responses, glucose, creatinine, liver and muscle enzymes should all be reviewed at that stage. Follow‐up at later intervals of time is not evidence‐based, but may assist with better compliance and with reassurance about drug safety. All relevant risk factors should be monitored.

In children and adolescents with severe FH, therapy with statins or LDL apheresis is now offered, but can be quite challenging. In such cases, specialist support is recommended.60,61,62

A report card on lipid management in Australia

Based on statistics from the Pharmaceutical Benefits Scheme, at least 80% of Australian patients at high coronary risk (ie, with prior coronary disease, diabetes and/or hypertension) are prescribed a lipid drug, mostly a statin.63 On the other hand, long term persistence is generally unsatisfactory, with more than 50% of patients newly initiated to statins having discontinued therapy within one year.46

An examination of patients with chronic angina in general practice found that risk factor control overall was frequently suboptimal, despite being perceived as satisfactory by general practitioners.64 Only 17% of lipid profiles were at target according to national guidelines. Only 55% of patients with an acute coronary syndrome are receiving high intensity lipid‐lowering therapy 6–12 months after hospital discharge.65

Future directions

Antisense oligonucleotide therapies to lower the circulating levels of apolipoprotein B of LDL (mipomersen),62 PCSK9 (inclisiran),66 apolipoprotein(a)67 and apolipoprotein C368 (to reduce triglycerides) have already been developed or remain in development. These treatments will be of future interest in selected patients.

Inflammatory processes also contribute to plaque instability, leading to an acute coronary syndrome. While conventional anti‐inflammatory drugs have not been successful at CVD event reduction, the use of a new anti‐inflammatory agent known as canakinumab — a monoclonal antibody targeting interleukin‐1‐β — has produced a significant reduction in CVD events in a secondary prevention context and independently of lipid changes.69 This treatment is the subject of ongoing study.

ATP citrate lyase, an enzyme upstream from HMG‐CoA, is a new emerging target for pharmacotherapy. Recent studies with bempedoic acid, an orally active inhibitor of this enzyme, have demonstrated safe and effective LDL‐C reduction in the presence or absence of statin therapy. Long term CVD outcome studies are now in progress.70

Conclusion

Lipid interventions with statins lower cardiovascular risk. Ezetimibe may be used as a supplement to statin therapy, or used alone in cases of statin intolerance. There exist statin‐associated side effects, in particular muscle symptoms and new onset diabetes, which require careful management. Inhibitors of PCSK9 reduce LDL‐C and cardiovascular risk. Evolocumab is subsidised in Australia for patients with FH where LDL‐C is not adequately controlled with maximum doses of statin or ezetimibe, or when statin therapy is contraindicated. Lipid interventions to reduce triglycerides with fenofibrate lower cardiovascular risk in patients with type 2 diabetes when triglycerides are elevated and HDL is low. All cases of secondary prevention need intensive lipid therapy, unless a contraindication exists. Lipid therapy is justified in cases of primary prevention at high absolute risk, when lipids are highly elevated or when multiple risk factors are present.

Box – A general guide to the use of lipid‐modifying drugs

T2DM = type 2 diabetes mellitus. HDL = high‐density lipoprotein. PCSK9 = proprotein convertase subtilisin/kexin type 9. * Interrupt if creatine kinase is more than five times the upper reference, if severe myalgia develops, or if alanine aminotransferase and aspartate aminotransferase are more than three times the upper reference.◆

Author

  • Leon A Simons1,2
  • 1. UNSW Sydney, Sydney, NSW
  • 2. St Vincent's Hospital, Sydney, NSW

Correspondence: L.Simons@unsw.edu.au

Competing interests

Leon Simons has received consultancy fees and research support for clinical trials from manufacturers of statin drugs and PCSK9 inhibitors.

References

Provenance: Commissioned; externally peer reviewed.

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