Atherosclerosis starts in childhood: a practical guide to improve its outcomes through lipid management in primary care

Atherosclerotic cardiovascular disease (ASCVD) is the most common cause of death and disability worldwide, and dyslipidaemia is a primary and treatable risk factor for the disease. Despite widespread availability and use of lipid-lowering medications, poor health outcomes and reduced quality of life due to ASCVD remain major unmet needs within the UK. Guidelines from the National Institute for Health and Care Excellence (NICE) aim to support identification of high-risk individuals and to optimise management so that fewer people experience acute cardiovascular (CV) events, such as myocardial infarction or stroke, or develop peripheral vascular disease. ASCVD development may begin in childhood and many people experience onset of vascular disease or events despite having cholesterol levels beneath the thresholds defined by NICE for initiation of lipid-lowering therapy. Clinical guidelines tend to favour sequential introduction of medications (usually beginning with statin monotherapy) although combination therapy (from the start of treatment) may provide improvements in long-term CV protection, as demonstrated in other disease areas (e.g., hypertension, type 2 diabetes mellitus). European and international recommendations provide more stringent thresholds that are based upon low-density lipoprotein cholesterol (LDL-C) concentration, rather than the non-high-density lipoprotein cholesterol measures stipulated by NICE; lower LDL-C levels are aimed for as CV risk rises. This article reviews current understanding concerning the mechanisms believed to underpin development of ASCVD, guideline recommendations for management of disease and the evidence supporting more robust therapeutic approaches to lipid lowering. Finally, recommendations are made to support healthcare professionals in improving lipid management, with a treatment algorithm more closely aligned to European guidelines and a range of quick reference resources provided to help guide empowering conversations with patients regarding the importance of lipid lowering for lifetime risk management.

The enduring burden of atherosclerotic cardiovascular disease

Atherosclerotic cardiovascular disease (ASCVD) represents the leading global cause of morbidity and mortality.^1,2 ASCVD is the greatest driver of severe disability in the UK, where it is also the most frequent cause of death in men and the second most common reason for mortality in women.^3–6 The prescribing of lipid-lowering medications has helped to lower ASCVD-associated mortality rates across the UK, although the rate of decline has slowed in the past decade.^3–6 Prevalence of ASCVD varies substantially across localities and the burden of disease is typically higher among older adults, deprived populations, South Asian or Black ethnicities and people with multiple chronic comorbidities (e.g., type 2 diabetes mellitus [T2DM], chronic kidney disease [CKD]).^5–8 Data from the Office for National Statistics have shown stark inequalities in both life expectancy and the number of healthy years lived, revealing differences of approximately 20 years for the expected number of years spent in ‘good’ health among people living in the most deprived areas compared with those in the least deprived locations across England.⁹ Similar patterns of reduced lifespan and healthspan across the income spectrum have been shown in Wales and Scotland.¹⁰ Cardiovascular diseases (CVDs) and events, such as heart attack and stroke, are among the key health conditions believed to be responsible for driving differences between healthy life expectancy and overall lifespan.^10,11 Prevention and effective management of ASCVD therefore represents a significant and ongoing area of unmet need that must be tackled in order to reduce associated long-term disability and disparities in health outcomes.⁶

ASCVD is multifactorial and polygenic.^2,6,12–22 Atherosclerosis results from the entry and build-up of cholesterol-containing particles (lipoproteins) in the wall of the artery, accelerated by injury to the arterial wall and genetic vulnerability to lipoprotein retention here.^2,18,23–25 Modifiable risk factors that increase injury to the vascular wall and the formation of atherosclerotic plaques include obesity and overweight, hypertension, diabetes, insulin resistance and dyslipidaemia.^2,6,12–14 Lifestyle choices, such as smoking, diet and alcohol intake play a key role in influencing the likelihood of developing ASCVD, and family history and genetic factors (e.g., familial hypercholesterolaemia [FH]) are also predictive of disease.^2,6,12–14 A growing body of evidence has linked non-traditional factors with increased incidence and worsening of ASCVD.^15–22 These include non-modifiable risk factors, such as autoimmune disease and inflammatory conditions (e.g., rheumatoid arthritis, inflammatory bowel disease, gout), CKD, erectile dysfunction and human immunodeficiency virus (HIV), as well as metabolic disorders such as insulin resistance and metabolic dysfunction-associated steatotic liver disease (MASLD)/metabolic dysfunction-associated steatohepatitis (MASH).^15–22 In females, risk may be elevated among post-menopausal women and those with polyendocrine metabolic ovarian syndrome (PMOS), premature menopause and adverse pregnancy outcomes.^18,19 Some studies have suggested that polygenic risk scores might help in identifying people with certain genetic factors, beyond the traditional indicators of risk.¹⁸ Psychological, environmental and social factors can increase the chances of developing ASCVD.^18,21 These include chronic psychological stress, depression, anxiety, poor sleep, low socioeconomic status and air pollution.^18,21

An overview of atherosclerosis mechanisms

The biological mechanisms underlying ASCVD development are complex and believed to be initially driven by dysfunction within the endothelial cells lining the internal walls of the arteries (the arterial intima; figure 1).^2,23–25 Over time, endothelial dysfunction causes the vascular wall to become damaged, allowing lipoproteins carrying lipids (in the form of cholesterol and triglycerides) into the bloodstream to cross the endothelial barrier and become trapped in the compromised arterial wall.^2,23–25 The build-up of cholesterol- and triglyceride-carrying lipoproteins eventually leads to the formation of atherosclerotic plaques (atherogenesis).^2,23–25 A hallmark of early plaque development is the presence of lipid-containing ‘foam cells’, comprising immune cells (known as macrophages) that are recruited to the artery wall to ‘mop up’ and remove excess lipids, as well as endothelial cells and smooth muscle cells that have taken up lipoproteins carrying cholesterol and triglycerides.^23,26 Foam cells stimulate inflammatory signals that cause further disruption within the walls of the artery.^23,26

The main types of lipoproteins that accumulate in the artery wall contain a protein called apolipoprotein B (ApoB), which (among other functions) allows the transport of cholesterol to the tissues.^23,27 ApoB-containing lipoproteins are also associated with the triggering of oxidative stress and inflammatory pathways.^2,23–25 Early visible signs of plaque development are observed as ‘fatty streaks’ that form along the artery wall.^2,28 Plaque growth and increasing inflammation cause the blood vessels to become narrowed and smooth muscle cells within the vascular walls begin to multiply and migrate to try to compensate for reduced blood flow capacity, causing arterial changes (or remodelling).^2,23,29 Rupture of the plaques can cause blood clot formation (thrombosis) and onset of acute CV events, such as ischaemic stroke, critical limb ischaemia or myocardial infarction (MI).^{2,13,23,29,30} Endothelial dysfunction may begin in childhood (within the first decade of life), with atherosclerosis developing over a lifetime of exposure to ApoB-containing lipoproteins (figure 2), making early identification of risk critical in lowering the chances of vascular event occurrence or development of established disease.^2,23,31–33

ApoB-containing lipoproteins include low-density lipoprotein (LDL), lipoprotein (a) [Lp(a)], intermediate-density lipoprotein (IDL), very low-density lipoprotein (VLDL) and chylomicron (CM) remnants (figure 3).²⁹ LDL is the primary carrier of cholesterol in the bloodstream and the concentration of LDL-cholesterol (LDL-C; sometimes referred to as ‘bad cholesterol’ in the literature) is typically used as an indicator for risk of ASCVD onset or worsening disease.^12,13,27,29 In contrast, high-density lipoprotein cholesterol (HDL-C) is widely believed to be cardioprotective and may be described as ‘good cholesterol’ in educational materials.^23,29 HDL is the smallest of the lipoproteins and does not contain the ApoB protein.^23,34 HDL facilitates ‘reverse cholesterol transport’, involving the removal and transport of excess cholesterol from the tissues to the liver for recycling and excretion.^23,34 It is thought to have anti-inflammatory and anti-oxidant effects that help to protect the endothelial cells, while its anti-thrombotic properties reduce platelet aggregation and risk of blood clots.^23,29,34 Triglycerides, the body’s primary energy store, are transported in the bloodstream by lipoproteins such as CM and VLDL.^23,29 After hydrolysis by lipoprotein lipase (LPL), triglycerides are released as free fatty acids, providing an energy source for muscle or they may be stored in adipose tissue.^23,29 Elevated triglycerides contribute to atherogenic remnant particles and, at very high levels, increase the risk of acute pancreatitis.^23,29 High triglyceride levels (hypertriglyceridaemia) are a risk factor for ASCVD (independent of LDL-C levels).^12,30 The term, dyslipidaemia, usually refers to high concentrations of LDL-C and/or triglycerides and low HDL-C in the blood.²

Cholesterol/lipid testing

The UK National Institute for Health and Care Excellence (NICE) supports cholesterol/lipid testing for people with ASCVD risk and the latest Quality and Outcomes Framework (QoF) indicators from NHS England provide additional incentives for testing and monitoring in primary and secondary CVD prevention.^3,35 Ideally, clinical decisions regarding CV risk would be made using information pertaining to all lipid parameters. In UK clinical practice, a standard lipid profile will comprise laboratory measurement of total cholesterol, HDL-C and triglyceride levels, with the non-HDL-C and LDL-C levels calculated from these measures (table 1).^{3,12,13,29,30,35} High total cholesterol, triglycerides and non-HDL-C indicate greater risk of ASCVD and acute CV events.^{3,12,13,29,30} The NICE guideline for CVD, NG238, recommends specialist referral for those individuals with total cholesterol levels >9.0 mmol/L or non-HDL-C >7.5 mmol/L, and urgent specialist review when triglyceride levels are >20 mmol/L (when no association with excess alcohol intake or poor glycaemic control is evident) due to considerably increased risk of acute pancreatitis.³ Current NICE guidance does not require that a fasting sample should be obtained and non-fasting samples are easier to obtain in daily practice.^3,29 Lipid profiles, particularly triglyceride levels, may vary according to when the person last ate a meal and fasted samples are appropriate in instances where hypertriglyceridaemia is a concern or the person is starting a medication that could cause severe hypertriglyceridaemia (e.g., corticosteroids).²⁹ Individuals recovering from triglyceride-related pancreatitis should also have a fasted lipid test, which can be taken at the same time as other tests requiring fasting (e.g., glucose).²⁹ Fasting status must be stated in request documentation and laboratory reports.²⁹

While most of the lipid-lowering studies published to date used LDL-C levels as their main endpoint marker for CV risk reduction, guidelines from the European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) and the American College of Cardiology (ACC)/American Heart Association (AHA) as well as recommendations from HEART UK/the Association for Laboratory Medicine also support the use of ApoB as a reliable marker for atherogenic risk as this parameter reflects the particle number present.^{12,13,29,30,36,37} Elevated Lp(a) is also an independent risk factor for ASCVD and measurement of this parameter provides a strong indication of genetic risk.²⁹ Lp(a) concentration ≥250 nmol/L denotes a doubling of risk for ASCVD.^29,37 Lifetime levels tend to stay consistent, unless secondary causes of elevation are present (e.g., CKD, untreated overt hyperthyroidism), and a single measurement is usually sufficient.²⁹ HEART UK/the Association for Laboratory Medicine support ApoB and Lp(a) measurement as part of an enhanced lipid profile, alongside standard parameters, to aid further risk stratification during diagnosis and treatment selection.^{12,13,29,30,36} In general, ApoB measurement is only currently available at specialist lipid services, which may not be accessible to most NHS primary care providers, although greater demand for these tests may result in them becoming more widely available.²⁹ Circumstances in which an enhanced lipid profile using ApoB testing might be appropriate include investigations relating to familial dysbetalipoproteinaemia, hypo- and abetalipoproteinaemia, hypertriglyceridaemia and presence of lipoprotein X (in ratio with total cholesterol).²⁹ Lp(a) measurement would be indicated for certain targeted populations comprising those with personal/family history of premature ASCVD (aged <60 years) or first-degree relatives with elevated serum Lp(a), FH or other genetic dyslipidaemias, people with calcific aortic valve stenosis or individuals who have a borderline increased 10-year CV event risk calculated to be >10% but <15%.²⁹

Currently available lipid-lowering therapies and their mechanisms of action

Randomised controlled trials (RCTs), real-world data and meta-analyses have demonstrated that lowering of LDL-C is associated with reduction in risk for major CV events, including fatal and non-fatal MI and ischaemic strokes.^{13,14,23,38–65} Achievement of LDL-C levels <1.8 mmol/L (or 70 mg/dL according to US parameters) can result in stabilisation and potential regression of atherosclerotic plaques, slowing of disease progression and lowering of heart attack and stroke risk.^66–68

Lipid-lowering therapies are therefore recommended in the UK, Europe and the US for primary and secondary ASCVD prevention.^{3,12,13,30,37,69} As highlighted in the latest ACC/AHA recommendations, early treatment is critical in reducing lifelong ASCVD risk associated with ongoing exposure to atherogenic lipoproteins.³⁷ Approved pharmacotherapies that aim to lower LDL-C levels typically leverage mechanisms that block cholesterol production or absorption within the body or promote excretion of cholesterol (table 2; figure 4).^56,58 Due to their complementary mechanisms of action, some treatments (e.g., statins and ezetimibe, ezetimibe and bempedoic acid – with/without statin therapy) have been shown to provide additive efficacy in reducing LDL-C levels and improving CV risk when used in combination.^{13,23,53,55–58,70–77} Current NICE NG238 and European guidelines therefore recommend combination therapy when first-line monotherapy has not provided sufficient reduction in lipids.^3,12,13,30

Targeting LDL-C synthesis

Statins, the recommended first-line treatment option in lipid management, inhibit a critical enzyme in the LDL-C synthesis pathway called 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase.^{3,12,13,30,56} When the body detects lower levels of cholesterol in the blood following inhibition of the HMG-CoA reductase pathway, expression of LDL receptors at the surface of liver cells will be upregulated to compensate, causing greater uptake of LDL-C from the bloodstream and further lowering of circulating levels.^56,58 Data also support a role for statins in reducing inflammation and oxidative stress responses in the blood vessels, improving endothelial cell function and lowering the risk of plaque rupture.²³ An extensive body of evidence has demonstrated that statin treatment is associated with dose-dependent reductions in LDL-C and triglycerides as well as increases in HDL-C.^{3,12,13,30,36,51,56,78} Current NICE guidelines, as well as ESC/EAS and American guidance, recommend first-line statin therapy for the primary prevention of CVD in adults, based upon a plethora of RCT data, observational studies, meta-analyses and cost-effectiveness analysis.^{3,12,13,30,36,37,78–81} Among the many large-scale studies examining the effects of statins, data from the Cholesterol Treatment Trialists’ (CTT) Collaboration revealed a drop in the risk of major vascular events of approximately one-third with intensive statin therapy.^38,48 The reduction in major events was proportional to the absolute LDL-C reduction, even in people with lower starting LDL-C levels (<2.0 mmol/L).³⁸

Bempedoic acid inhibits another key enzyme in cholesterol production, hepatic adenosine triphosphate (ATP) citrate lyase, which acts at an earlier stage in the pathway (upstream) to the HMG-CoA reductase targeted by statins.^{23,52,54,56,58} The large-scale RCT, CLEAR Harmony, demonstrated statistically significant additional reductions in LDL-C (up to 18.1% versus placebo) and no further treatment-related adverse events (AEs) when bempedoic acid was given in combination with the maximum tolerated dose of statin in people with ASCVD or heterozygous FH, or both (P<0.001).^63,82 Treatment outcomes were sustained over a period of 2.5 years with continued combination therapy.⁸³ The CLEAR Outcomes trial showed that LDL-C lowering with bempedoic acid monotherapy was associated with a lower risk of major adverse CV events in people with or at high risk of CVD who were unable/unwilling to take statins due to AEs.^62,64 In line with the outcomes demonstrated by the CTT Collaboration, analysis from the CLEAR Outcomes trial demonstrated that risk reduction was proportional to the magnitude of absolute LDL-C lowering achieved.⁸⁴ Bempedoic acid/ezetimibe combination therapy (with/without statins) has also demonstrated benefits in LDL-C lowering compared to monotherapy with either of these agents.⁵² Bempedoic acid may be added to statin therapy or ezetimibe when further LDL-C reduction is required.^3,85

Reducing LDL-C absorption and enhancing its clearance from the body

Ezetimibe selectively blocks absorption of LDL-C in the small intestine via inhibition of the critical Niemann-Pick C1 like 1 (NPC1L1) protein, causing the liver to increase clearance of LDL-C from the blood.^56,58 Ezetimibe is recommended by NICE (NG238 and technology appraisal TA385) in combination with statin therapy to provide greater LDL-C reduction.^3,86 It may be used as monotherapy or in combination with bempedoic acid (or another lipid-lowering therapy) or a statin.^3,79,86 RCT data showed that addition of ezetimibe to existing statin therapy was superior to statin treatment alone for both LDL-C lowering and HDL-C increase in adults with hypercholesterolaemia (P<0.001).⁷⁰ Subsequent patient-level analysis (>20,000 adults with CVD risk) revealed improvements in LDL-C, total cholesterol, non-HDL-C, ApoB, triglycerides and lipid ratios when ezetimibe was added to statin monotherapy, regardless of diabetes status, age, race and gender.⁷² Data from 17,830 people in a large US database showed that addition of ezetimibe to statin therapy (simvastatin, atorvastatin, rosuvastatin) increased the odds of attaining lower LDL-C (<1.8 mmol/L) by 2.6–3.2-fold, compared with titration of statin monotherapy.⁷¹ IMPROVE-IT, a large randomised CV outcome trial involving 18,144 people with acute coronary syndrome, demonstrated incremental reductions in LDL-C and improved CV outcomes with combination ezetimibe/statin therapy over a median follow-up of six years.⁵⁵ These data suggest that individuals who do not show adequate lipid lowering with statins alone may benefit from combination therapy, instead of simply increasing the statin monotherapy dose.^{13,23,53,55–58,70–72} In addition, the SWEDEHEART trial showed that early combination therapy with ezetimibe and a high-intensity statin provided greater absolute and relative reductions in major adverse CV events among individuals who had experienced a recent MI, compared with delayed initiation of ezetimibe/statin combination treatment.^59,60 Those who achieved the lowest non-HDL-C levels at two months and sustained these outcomes had the greatest reduction in risk during the study compared with individuals who showed a delay in lowering of non-HDL-C or those who never reached their non-HDL-C goal.⁵⁹ Individuals who had not received ezetimibe by 16 months post-MI had the greatest risk of experiencing another major adverse CV event and CV death.⁶⁰

Injectable monoclonal antibody therapies, evolocumab and alirocumab, bind to an enzyme called proprotein convertase subtilisin-kexin type 9 (PCSK9) involved in the breakdown of LDL receptors.^13,23,56 PCSK9 inhibitors (PCSK9is) extend the length of time that the LDL receptors are present at the cell surface, increasing uptake of LDL-C from the blood entering the liver.^13,23,56 These medicines need to be self-administered via subcutaneous injection every two weeks.^13,23,56 CV outcomes trials showed that, compared with placebo, PCSK9is reduced LDL-C concentration by up to 65%, when given alongside the maximum tolerated dose of high- or moderate-intensity statin, or when used with no statin or ezetimibe background therapy.^87–89 Major vascular events were also significantly reduced, compared with placebo (P<0.001).^87,88 Following cost/benefit analysis, NICE approved evolocumab and alirocumab for use only in specific clinical circumstances.^90,91 PCSK9is may be used in non-FH or mixed dyslipidaemia with CVD and high CV risk (defined as a history of acute coronary syndrome [e.g., MI, unstable angina requiring hospitalisation], coronary or other arterial revascularisation surgery, coronary heart disease, ischaemic stroke, peripheral arterial disease) only when LDL-C is persistently >4.0 mmol/L.^90,91 For very high CV risk individuals (defined as having recurrent CV events or CV events in >1 vascular bed [polyvascular disease]), PCSK9is can be prescribed only when LDL-C persists at concentrations >4.0 mmol/L.^90,91 People with primary heterozygous FH without CVD can be prescribed PCSK9is only when LDL-C is persistently >5.0 mmol/L, and those with heterozygous FH and CVD may be given PCSK9i therapy when LDL-C continues to be >3.5 mmol/L despite ongoing lipid-lowering therapy.^90,91

Inclisiran, a small interfering ribonucleic acid (siRNA)-based treatment, exerts a similar effect to evolocumab and alirocumab by blocking PCSK9 expression in the liver.^{12,13,23,30,56} It is given as a subcutaneous injection every six months.⁹² The ongoing ORION clinical trial programme has shown reductions in LDL-C of up to 50% among adults with ASCVD and raised baseline LDL-C concentrations (≥1.8 mmol/L), despite receiving the maximum tolerated statin dose (phase 3 trials: ORION-10 and ORION-11).⁹³ The phase 3 ORION-4 CV outcomes trial is due to complete later in 2026. Inclisiran is indicated in the UK for individuals with primary hypercholesterolaemia or mixed dyslipidaemia as an adjunct to diet and in combination with a statin/statin-based combination regimen when LDL-C goals have not been reached with the maximum tolerated statin dose, or alone/in combination with other lipid-lowering therapies in those who are contraindicated for or unable to tolerate statin therapy.⁹⁴ However, based on current evidence and cost-effectiveness estimates, NICE (TA733) supports the use of inclisiran as an adjunct to diet in adults in England with LDL-C concentrations persistently ≥2.6 mmol/L who are taking the maximum tolerated statin dose or other lipid-lowering therapies and have a history of CV events (acute coronary syndrome, coronary/arterial revascularisation procedures, coronary heart disease, ischaemic stroke or peripheral arterial disease).⁹²

Bile acid sequestrants, including cholestyramine and colesevelam, prevent reabsorption of bile acids and associated cholesterol from the stomach into the bloodstream.^13,23,56 To compensate for the shortfall, the liver uses hepatic cholesterol to synthesise more bile and increases LDL receptor expression resulting in a decrease in circulating LDL-C.^13,23,56 UK NICE guidelines do not recommend bile acid sequestrants for use as lipid-lowering therapy or in the prevention of ASCVD.³

Other treatments: targeting triglycerides

Fibrates (e.g., fenofibrate) activate the peroxisome proliferator-activated receptor alpha (PPAR-α), which regulates genes involved in the uptake of fatty acids in the liver and increases the breakdown of triglycerides in VLDL via upregulation of LPL expression.^23,56 Fibrates are not currently recommended by NICE as lipid-lowering therapy or for the prevention of ASCVD but may be useful in reducing triglyceride levels to lower pancreatitis risk.³

The mechanisms underlying the potential use of omega-3 fatty acids in decreasing the risk of CV events remain unclear.²³ Suggested pathways include their action in reducing synthesis of triglyceride-rich lipoproteins (e.g., VDL, IDL) and lowering inflammation.^23,95 Current NICE guidelines limit the use of omega-3 fatty acids (icosapent ethyl only) to individuals on statins with high CV event risk and raised fasting triglycerides (≥1.7 mmol/L).⁹⁵

Attenuating cardiovascular risk through lipid management

As highlighted already, a rapidly expanding evidence base clearly supports the role of LDL-C lowering in the reduction of risk for ASCVD and/or fatal and non-fatal CV events, such as MIs.^{13,14,23,38–65} It is important to note that some individuals will be predisposed to developing ASCVD due to their genetic background, the environment in which they have lived (e.g., exposure to second-hand smoke, growing up in poverty) or other factors, such as comorbidities (e.g., diabetes).^{12,13,27,30,96,97} This means that they have accumulated more endothelial dysfunction and arterial damage at an earlier stage of life and have a greater absolute risk of ASCVD/vascular events.^{12,13,27,30,96,97} Vulnerability will be higher in these individuals, even if they are able to lower LDL-C during adulthood to reduce their overall lifetime LDL-C exposure level.^{27,96,98–101} Early, intense and sustained lipid management is therefore critical for people with the greatest risk.^{12,13,27,30,96,98–101} In general, the higher inherent risk a person has for acute CV events, the lower their target LDL-C levels should be.^12,13,30

In the UK, the QRISK^® tool (QRISK^®2/QRISK^®3) is recommended to assess a person’s risk of CVD during the next 10 years, only in cases where there is no pre-existing CVD.^3,102 An individual presenting with an MI may have been scored as having a QRISK^®2/QRISK^®3 10-year risk of 7.5% prior to the event, which would be well below the defined level that triggers prescribing of lipid-lowering therapy (≥10%).^3,102

According to global data, approximately 60% of fatal and non-fatal CV events and 20% of all-cause mortality can be attributed to five modifiable risk factors (body mass index, systolic blood pressure, non-HDL-C, smoking, and diabetes).¹⁴ Data from a Swedish nationwide cohort demonstrated that around 75% of MIs occurred in people who were not taking lipid-lowering therapy in a population that was aged 55–69 years.⁵⁰ These data indicate that clinical practice should move away from the current focus on primary and secondary prevention, toward strategies that lower overall CV risk.^3,12,13,30

In addition, the impact of elevated triglycerides (>1.7 mmol/L) on CV risk and/or acute pancreatitis should not be underestimated, even when LDL-C levels are well managed. The NICE guidelines recommend that triglycerides should be measured alongside cholesterol parameters (non-HDL-C and LDL-C), with specialist referral for those who have elevated levels (>20.0 mmol/L or >10.0 mmol/L on repeat testing).³ Optimisation of other CV risk factors is endorsed, but NICE does not provide specific advice on how to address high triglyceride levels, other than sign-posting to their guidance on icosapent ethyl use in individuals using statins who have ASCVD.^3,95

Identifying high-risk groups

NICE and HEART UK endorse the use of the QRISK^® tool for CVD risk estimation in individuals aged 25–84 years, assuming that they do not already have ASCVD and are not taking statins.^2,23–25 Most primary care systems may not have been updated to allow easy access to the QRISK^®3 tool and continue to measure risk using the QRISK^®2 calculator. NICE has highlighted the potential for underestimation of 10-year CVD risk with the QRISK^®2 calculator and QRISK^®3 can underestimate CV risk in certain groups taking particular medications that cause dyslipidaemia (e.g., antipsychotics, corticosteroids, immunosuppressants) or those who have other underlying conditions (e.g., significant hypertriglyceridaemia [fasting triglycerides 4.5–9.9 mmol/L], severe obesity).^3,79 Use of a 10-year tool can also underestimate risk in younger people (aged <40 years) and the QRISK^®3-lifetime calculator may be more appropriate for these individuals.^3,103 ESC/EAS recommendations endorse the use of the Systematic Coronary Risk Evaluation 2 (SCORE2) and SCORE2-OP (older people; aged ≥70 years) calculators for estimation of risk for MI, ischaemic stroke, or fatal atherosclerotic CV event within 10 years in people without known ASCVD who are aged between 40–89 years.^12,13 The SCORE2 tool is available online and may help in assessing risk alongside the QRISK^® tools recommended by NICE.^3,102,103 Non-fasting non-HDL-C level is the parameter supported by NICE to guide dyslipidaemia management, while lowering of plasma LDL-C represents the main treatment target in the ESC/EAS guidelines.^3,12,13

Key factors that should alert HCPs to the likelihood of potential ASCVD and acute CV events include a diagnosis of type 1 diabetes, CKD, strong family history of CVD, high LDL-C levels, raised triglycerides, elevated Lp(a) levels, or evidence of disease on imaging.^3,12,13,30 As highlighted already, a growing number of other traditional and non-traditional lifestyle and environmental factors and comorbidities have been identified which can be associated with ASCVD onset and worsening.^2,6,12–22

Management of LDL-C levels in clinical practice: the lower, the better

NICE NG238 guidelines for primary prevention of ASCVD use a reduction in non-fasting HDL-C levels of >40% as the only target for statin therapy.^3,29 Secondary prevention recommendations are based upon LDL-C targets of ≤2.0 mmol/L or non-HDL-C ≤2.6 mmol/L.^3,29 These targets are conservative compared with those of the ESC/EAS and American recommendations as the UK guidelines incorporate cost-effectiveness calculations and are not prioritised according to CV risk.^{3,12,13,29,30,37,69}

The BEACON steering committee strongly advises that lower LDL-C levels should be targeted for those individuals with the greatest risk. The aim should be to drive LDL-C levels as low as possible, given that significant atherosclerosis will be present by the time treatments are initiated.¹⁰⁴ These perspectives are aligned with current ESC/EAS guidelines, which provide more stringent LDL-C treatment targets for higher risk groups compared with NG238, with target levels being <1.8 mmol/L for high-risk populations, <1.4 mmol/L for people with ASCVD and very high risk and <1.0 mmol/L for individuals with established ASCVD who have extreme risk and recurrent acute vascular events while taking maximally tolerated statin-based therapy (table 3).^12,13,30 People in each of these risk categories should also aim for an LDL-C reduction of at least 50% from baseline.^12,13,30

Evidence regarding the effectiveness of lower LDL-C targets has long been established.¹⁰⁵ Large-scale long-term studies and meta-analyses have revealed the sustained benefits of lipid-lowering therapies and incremental reductions in LDL-C with intensive treatment in reducing CV events over decades.^{38,55,106–109} Data suggest that, on average, the risk of major CV events will be lowered each year by approximately 21–24% for each 1 mmol/L decrease in LDL-C.^38,108,109 The benefits of effective LDL-C lowering are also believed to be cumulative, with additional reduction in risk observed over time when lipid levels are effectively maintained.⁶⁵ Mendelian studies examining ASCVD outcomes in people with genotypes conferring lower LDL-C levels indicated that lifetime risk of events could be reduced by 50–55% per 1 mmol/L reduction in LDL-C.^27,76,110

In 2012, the CTT Collaboration showed that, even in relatively low-risk populations (those with <10% chance of major vascular events over five years), each 1 mmol/L reduction in LDL-C was estimated to reduce the likelihood of a major CV incident by 11 events per 1,000 people over five years.^105,108 Yet, similar individuals would not receive LDL-lowering therapy under current UK guidelines.^{3,12,13,37,69} No evidence exists to suggest that any lower threshold for LDL-C represents an increased risk to health.^73,111,112 HCPs should feel confident that any support they provide to reduce a person’s LDL-C will likely benefit their long-term health outcomes. Assisting individuals in gaining an understanding of their own risk of ASCVD, based upon their lifestyle, environment and family history is essential in motivating them to take responsibility for modifiable factors within their control (e.g., diet, smoking, exercise) and helping them to make (and maintain) the necessary changes that will support enhanced long-term results. Interventions that address many of the lifestyle-associated risk factors will also help individuals to feel better/healthier overall, which can assist in maintaining engagement as they might not experience any difference in the way that they feel with lipid-lowering therapy alone, even if it is effective in reducing LDL-C levels.

Available treatment options for ASCVD prevention: what do UK guidelines advise?

Primary prevention of ASCVD

First-line treatment for primary prevention of ASCVD in the UK is typically initiated in primary care and will comprise statin monotherapy, usually atorvastatin (20 mg daily), with an increase in dose (up to 80 mg daily) if non-HDL-C is not lowered by >40% after 3 months.^3,79 People with CKD (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m² and/or albuminuria) may need a lower statin dose, depending on the statin selected (the prescribing information should be consulted before initiating treatment).^3,79 Ezetimibe (10 mg daily) will be added if the maximum tolerated statin dose fails to lower non-HDL-C by >40%.^3,79

Persistence and adherence with statins represents an ongoing challenge in the prevention of CVD and CV events.^{36,85,113,114} Perceptions and fears regarding tolerability issues can influence an individual’s motivation to take their statin medication as prescribed or to continue in the long term.^{36,85,113,114} As with all medications, some people may not tolerate statin-based regimens and can experience AEs, although NHS England has warned against labelling people as statin intolerant too quickly.⁸⁵ NHS England has published a statin intolerance algorithm (or pathway) to provide guidance on the recognition of risk factors for tolerability issues and appropriate approaches to reduce the occurrence of potential AEs.⁸⁵ Statin-associated muscle symptoms (SAMS) are a key reason for non-adherence or discontinuation, and true statin-related muscle toxicity (SRM) typically resolves when treatment is paused and reoccurs when a statin is reinitiated.⁸⁵ A spectrum of SRM exists and an individual may be able to continue their treatment if they consider symptoms to be tolerable.⁸⁵ Non-muscle-related side effects (occurring in up to 1 in 10 people) include gastrointestinal disturbance and asymptomatic increases in hepatic transaminases.⁸⁵ HCPs should be aware of the main risk factors for SRM and other potential tolerability issues, which include female sex, older age (≥75 years), frailty, history of muscle disorders or high creatine kinase levels, impaired renal or hepatic function, family history of statin intolerance and hypothyroidism.⁸⁵ Other factors, such as excessive alcohol consumption, high-intensity exercise, dehydration, vitamin D deficiency and potential drug-drug interactions should also be taken into account when considering potential statin tolerability issues.⁸⁵ Some people may be better able to tolerate their treatment on re-challenge with the same or a different statin (or with a dose adjustment) and an individualised approach that considers the risk versus benefit relationship must be adopted.⁸⁵

Where statins are contraindicated or not tolerated, ezetimibe (10 mg) monotherapy may be used first line, with the option to add bempedoic acid (180 mg) at 3 months if non-HDL-C or LDL-C reductions are not satisfactory.^3,79 NICE and NHS England recommendations suggest that specialist referral should be considered in cases where target non-HDL-C levels have not been achieved, despite maximum first- and second-line therapy.^3,35,79

Secondary prevention

High-intensity statin therapy, typically atorvastatin (80 mg daily), is recommended for adults with ASCVD, including coronary heart disease (CHD), angina, acute coronary syndrome (MI or unstable angina), revascularisation, stroke or transient ischemic attack (TIA) or symptomatic peripheral arterial disease.^3,79 Statin therapy should not be delayed while awaiting results or addressing modifiable risk factors.^3,79

Individuals who require additional LDL-C lowering efficacy may be prescribed ezetimibe or injectable therapies.^3,79 Inclisiran can be initiated (in people with LDL-C ≥2.6 mmol/L [in England]) and monitored in a primary care setting.^3,79 As already mentioned, PCSK9is are currently only recommended by NICE under certain circumstances in individuals with non-FH or mixed dyslipidaemia or primary heterozygous FH with/without CVD, according to different LDL-C concentration thresholds.^90,91 PCSK9is (alirocumab and evolocumab) need to be initiated by a secondary care specialist, with primary care HCPs continuing prescribing and monitoring once treatment has been established and confirmation that the person is tolerating therapy well.^3,79 Importantly, people who have elevated risk (including raised LDL-C levels) but remain below the LDL-C thresholds for inclisiran (≥2.6 mmol/L) or PCSK9i monoclonal antibody initiation (persistently >3.5–5.0 mmol/L, depending on CVD and/or FH status and level of CVD risk) will have limited access to these treatments under current NICE guidelines.^3,79

Leveraging combination therapy for improved outcomes

Updated NICE clinical guidelines for conditions, such as T2DM, recommend combination therapy from the start of treatment.¹¹⁵ For hypertension, combination therapy may be given when targets have not been met with the first-line medicine.¹¹⁶ The BEACON committee supports a similar approach for lipid lowering, using first-line combination therapy for appropriate people.

The evidence suggests that simply increasing statin therapy intensity may not be the most appropriate strategy in optimising lipid lowering.^55,57,74,76 Indeed, combination therapy, using a medium-intensity statin plus ezetimibe could provide greater reductions in LDL-C and studies indicate that this approach might support improved tolerability outcomes (figure 5).^55,57,74,76 The SANTORINI study showed that combination therapy with a statin plus ezetimibe or a PCSK9i plus an oral agent improved LDL-C lowering over one year across 14 European countries in people with high (N=2,033) or very high (N=5,173) ASCVD risk.⁷⁴ Despite a higher proportion meeting their LDL-C goal with combination therapy, compared with monotherapy, most participants in the study did not achieve their lipid-lowering target.^74,76 This highlights the challenges of achieving target LDL-C, even when treatment has been intensified.^74,76 IMPROVE-IT showed the benefits of adding ezetimibe to statin therapy to provide incremental improvements in LDL-C and CV outcomes, compared with statin monotherapy.⁵⁵ The RACING trial demonstrated non-inferiority with medium-intensity statin plus ezetimibe combination therapy, versus high-intensity statin treatment, regarding the three-year composite outcome of CV death, major CV events or non-fatal stroke in people with ASCVD.⁵⁷ A significantly lower proportion of participants discontinued or required a dose reduction due to tolerability issues with combination therapy, compared with high-intensity statin monotherapy.⁵⁷ The RACING study group reported similar results for the same primary composite end point in people who had undergone drug-eluting stent implantation.⁷⁷

Tailoring treatment appropriately so that each person is treated to a target LDL-C level, using medium- or high-intensity statin combination therapy with ezetimibe, has provided similar CV outcomes to high-intensity statin monotherapy.¹¹⁷ It is also known that doubling the dose of a statin is associated with an increase in LDL-C lowering of approximately 6%, due to non-linear pharmacokinetics, whereas adding a second medicine with a different mechanism of action is likely to provide additive LDL-C-lowering effect.^75,118

As discussed in the ESC/EAS and NHS England guidelines, the average reductions in LDL-C that may be achieved when using existing lipid-lowering options in combination are relatively well established.^12,13,30,79 Beyond combination therapy with existing oral therapies (statins, ezetimibe and bempedoic acid), individuals with the highest LDL-C (or non-HDL-C) levels may face further delays in reaching their lipid-lowering targets and optimising their health outcomes due to local commissioning arrangements or the need for specialist referral for injectable PCSK9is therapies.^3,79 These people have the greatest immediate need and rapid action is essential in preventing major CV events.¹²

The BEACON lipid-lowering algorithm and practical advice for consultations

Figure 6 shows the BEACON recommendations for lipid-lowering. The algorithm is based on current evidence and global guidelines and aims to help lower lifetime risk of ASCVD as well as fatal and non-fatal CV events. As many people who suffer acute CV events may be deemed below the threshold of risk according to non-HDL-C (NICE NG238) parameters, the BEACON committee recommends the ESC/EAS approach of attaining the lowest LDL-C levels possible.^12,13 However, a full lipid profile should be obtained from the start of management, with an enhanced profile requested where appropriate.^3,29 As highlighted already, fasted samples are not mandated by NICE but may be appropriate in some circumstances (e.g., potential hypertriglyceridaemia), and fasting status should be recorded.^3,29

At each stage, it is important that the person receiving treatment understands their current CV risk and the advice they have been given in terms of recommended medications and/or lifestyle approach. Box 1 provides a short summary of key points to consider and discuss during consultations about lipid lowering. Holistic management throughout the pathway should include ongoing advice and reinforcement of messaging regarding lifestyle factors such as healthy eating, physical activity, body weight or waist circumference measures, alcohol consumption and sleep improvement.^2,28 In addition, optimisation of management regarding any relevant comorbidities (e.g., diabetes, CKD) will be important in lowering ongoing CV risk.^2,28

Primary prevention

Initial consultation

• Primary prevention aims to reduce the risk of developing ASCVD or experiencing an acute CV event by addressing any evident modifiable risk factors (e.g., lifestyle, smoking) and reducing the potential harms posed by factors that cannot be modified (e.g., genetic/family history of FH).²⁸
• Where risk for development of ASCVD is suspected, use the QRISK^®3 (https://qrisk.org/) or QRISK^®3-lifetime calculator (https://qrisk.org/lifetime/), as appropriate, to assess the individual’s risk.¹⁰³ Remember that certain individuals will have an elevated residual risk due to family or medical history, their environment or lifestyle choices.^{27,96,98–101} It is also important to consider non-traditional risk factors, such as HIV, autoimmune or inflammatory conditions, metabolic disease (e.g., insulin resistance, MASLD/MASH) or hormone-related factors (e.g., PMOS, menopause, adverse pregnancy outcomes).^15–22
• In line with ESC/EAS guidelines, early, intense and sustained lipid management should be initiated for people with the greatest residual CV risk, including those with very high risk and LDL-C ≥1.8 mmol/L or high risk and LDL-C ≥2.6 mmol/L (despite optimisation of non-pharmacological measures, including dietary, lifestyle and environmental factors).^{12,13,27,30,96,98–101}
• Other CV risk factors beyond LDL-C levels should also be assessed, including smoking status, alcohol consumption, hypertension, high body mass index and/or waist circumference, diabetes status and renal function.³ Blood tests to examine transaminase levels and thyroid function should also be conducted.³
• If lipids are very high, (e.g., total cholesterol ≥7.5 mmol/L, LDL-C >5.0 mmol/L) common secondary causes of dyslipidaemia should be ruled out.
  • Secondary causes of pure hypercholesterolaemia (raised total cholesterol and LDL-C with normal triglycerides) include hypothyroidism, cholestatic liver disease, anorexia nervosa, nephrotic syndrome, pregnancy, extreme diets (e.g., ketogenic diet) and medications such as atypical antipsychotics, steroids and ciclosporin.²⁹ FH should be considered in these cases.²⁹
  • Secondary causes of mixed dyslipidaemia (raised total cholesterol, LDL-C and triglycerides) may include poorly controlled diabetes, metabolic syndrome, insulin resistance, obesity, excessive alcohol consumption, gout, renal disease, hypothyroidism, pregnancy, dietary causes and drugs such as atypical antipsychotics, steroids and ciclosporin, as well as beta-blockers, antiretrovirals, retinoids and oral oestrogens.²⁹
• Targets for LDL-C should be lower for people with elevated CV risk.^{12,13,27,30,96,98–101}
  • Provide diet and lifestyle advice for people with a CV SCORE2 <2% (https://www.escardio.org/guidelines/practice-tools/cvd-prevention-toolbox/score-risk-charts/) for 10-year risk of fatal and non-fatal CV events and untreated LDL-C <3 mmol/L.^12,13,30,119 Target LDL-C should be <3 mmol/L while QRISK^®3 remains <2%.^12,13,30
  • Discuss lipid-lowering therapy options (medium- or high-intensity statin) with individuals who have a calculated risk of 2–10% and untreated LDL-C >2.6 mmol/L.^12,13,30 Target LDL-C should be <2.6 mmol/L while QRISK^®3 remains between 2–10%.^12,13,30
  • Provide a strong recommendation for combination therapy with a high-intensity statin plus ezetimibe in cases where the calculated CV risk is >10% and untreated LDL-C >1.8 mmol/L.^12,13,30 Target LDL-C should be at least 50% lower than baseline and <1.8 mmol/L for individuals with high calculated CV risk (QRISK^®3 >10%), where possible.^12,13,30
• Hypertriglyceridaemia should be addressed:^3,37,79
  • Assess potential underlying causes, including lifestyle (e.g., diet, physical activity levels, excessive alcohol consumption), underlying conditions (e.g., obesity, T2DM, hypothyroidism), medications (e.g., beta-blockers, diuretics, corticosteroids) and genetic factors (e.g., FH).³⁷
  • Mild-to-moderate hypertriglyceridaemia (fasting triglyceride levels 1.7–10 mmol/L): discuss lifestyle adjustments that may improve triglycerides (e.g., diet, exercise).^{3,12,13,30,37,79} Repeat fasted blood tests when triglycerides are persistently >4.5 mmol/L and seek specialist referral for individuals with non-HDL-C concentrations >7.5 mmol/L.^3,79
  • Severe hypertriglyceridaemia (fasted triglycerides persistently >10 mmol/L): seek specialist advice. Urgent referral is required with fasted triglycerides > 20 mmol/L (when no evidence of excess alcohol use or poor glycaemic control). Individuals with severe hypertriglyceridaemia are at risk of acute pancreatitis.^3,37,79
• Discuss the benefits and risks of lipid-lowering therapy within the context of lifetime CV risk reduction.³
• Ensure that individuals who begin lipid-lowering therapy understand that treatment is a long-term preventative measure to maintain a lower risk of acute CV events, just as lifestyle interventions that promote and improve long-term CV health might (e.g., regular exercise, quitting smoking).¹²⁰
• Counsel on management of any common potential side effects associated with lipid-lowering medications and set the risks in context against the benefit of lipid-lowering therapy.^120,121
• Arrange for regular follow up and review to monitor ongoing lipid levels and assess treatment tolerability, outcomes and adherence, where monotherapy or combination therapy has been prescribed.^3,79

Follow up, treatment escalation and specialist referral

• While national guidelines state that lipid profile testing should be repeated at 12 weeks following initiation of treatment, the BEACON Committee suggests that testing within eight weeks may be appropriate.^12,29 Post-acute coronary syndrome, lipid profile must be checked within four to six weeks.^12,29
• Escalate treatment to optimise lipid lowering for those showing inadequate response to current therapy according to their calculated level of risk at baseline.^{3,12,13,30,79}
  • Discuss the benefits and risks of statin treatment when LDL-C is ≥3 mmol/L for individuals with baseline QRISK^®3 score <2%.
  • Strongly recommend combination therapy with a high-intensity statin plus ezetimibe when LDL-C levels are not reduced by ≥50% from baseline and/or when LDL-C rises above 2.6 mmol/L for individuals with a baseline QRISK^®3 score of 2–10%.

Secondary prevention

• Secondary prevention aims to avoid further worsening or progression of existing disease and damage after ASCVD diagnosis or an acute CV event.^2,28 Collaboration with secondary care and rehabilitation teams (where appropriate) should also aim to improve quality of life.^2,28
• Treatment for people with existing ASCVD will usually comprise a high-intensity statin plus a non-statin therapy with proven CV benefit and target LDL-C should be <1.4 mmol/L.^12,13,30,79
• Individuals with extreme risk, who have multiple or recurrent vascular events or CV events in more than 1 vascular bed (polyvascular disease) should aim for LDL-C to be <1.0 mmol/L.^12,13,30,79
• For people living in England, inclisiran injectable therapy may be initiated when fasting LDL-C ≥2.6 mmol/L despite maximum tolerated lipid-lowering therapy.^12,13,30,79
• PCSK9i therapy can only be initiated (by a secondary care specialist) in specific individuals according to NICE guidelines.^3,79,86,92
  • Primary non-FH/mixed dyslipidaemia: CVD and high risk (when LDL-C is persistently >4.0 mmol/L) or CVD and very high risk (with LDL-C that persists >3.5 mmol/L).
  • Primary heterozygous FH: without CVD (when LDL-C is persistently >5.0 mmol/L); with CVD and high or very high risk (when LDL-C levels persist at >3.5 mmol/L).

BEACON recommendations for improving lipid lowering in clinical practice

The BEACON steering committee believes that lipid-lowering standards in the UK should evolve to more closely reflect recommendations from the ESC/EAS.^12,13,30 In addition to the proposed BEACON algorithm, the recommendations summarised below aim to provide actionable advice on the ways in which HCPs can improve lipid management in their daily practice. There are many conflicting and misleading messages in the media regarding CV risk and the use of LDL-C-lowering medications, particularly concerning statins.^120,122 Box 2 provides information to help in addressing concerns that a person may have about lipid-lowering medications and dispel some of the most common myths. Box 3 provides links to key resources for HCPs and people with CV risk or dyslipidaemia.

1. In individuals who have an elevated 10-year or lifetime risk of acute CV events, education should be provided about the key processes within the body that drive ASCVD development. Information should be shared on the ways in which available treatments may work to prevent disease progression.
2. Many people who could benefit from lipid-lowering therapy are resistant to starting treatment due to negative media coverage about statins and their potential side effects. The risk of CV events needs to be placed in context (with evidence) to allow the individual to understand the potentially lifesaving importance of lowering their LDL-C so that they can make informed decisions about their treatment (and lifestyle modifications).
3. Help the person you are treating to understand that lipid-lowering treatment is a lifelong, and potentially life-saving, commitment to reduce their long-term risk of experiencing a CV event. Once treatment begins, it should be continued (unless tolerability issues arise).
4. Lipid targets must be based on the individual’s risk and combination therapy should be used as standard for appropriate people. The greater the CV risk, the lower the LDL-C target should be.
5. The person must be advised that, if they experience tolerability issues with their medicines, it will be possible to find an alternative agent that can be tolerated in most cases. Statin therapy is well tolerated in the majority of people.
6. Advise the person not to stop medication without a discussion with their GP or healthcare provider.

Key messages

• Atherosclerotic cardiovascular disease (ASCVD) remains a major cause of morbidity, mortality and health inequality in the UK. Atherosclerosis may begin in childhood and progress over a lifetime of exposure to ApoB-containing lipoproteins
• Risk assessment should consider lifetime risk (particularly in younger people), family history, comorbidities, triglyceride levels and other traditional (e.g., type 2 diabetes mellitus, overweight/obesity) and non-traditional (e.g., HIV, inflammatory bowel disease) factors
• Lowering of low-density lipoprotein cholesterol (LDL-C) is strongly associated with reduced risk of ASCVD onset, progression and worsening as well as risk of experiencing CV events
• People with the greatest baseline risk for ASCVD should be supported to achieve the lowest possible LDL-C levels through early, sustained intervention
• Combination lipid-lowering therapy, particularly using a statin plus ezetimibe (where appropriate), may help more people to reach LDL-C targets and should be discussed alongside approaches to lifestyle optimisation when making shared treatment/management decisions

Conflicts of interest

BB has received honoraria from Amarin, Aspire, AstraZeneca, Bayer, Boehringer Ingelheim, Chiesi, Consilient, Daiichi Sankyo, GlaxoSmithKline, Leo, Lilly, Menarini, MSD, Napp, Novartis, Novo Nordisk, Orion, Pfizer, Sanofi and Teva.

JC received honoraria/consultancy fees or research funding from Amgen, Sanofi, Daiichi Sankyo, Novartis, Akcea, Sobi, Ultragenyx, Verve Therapeutics, Menarini, Novo Nordisk, Astra Zeneca, Chiesi and Eli Lilly.

ET has received honoraria for services from Bayer, Daiichi Sankyo, Centre for Medical Development, Amarin, Morph consultancy, Royal Pharmaceutical Society, Soar Beyond, Novartis, Menarini, Novo Nordisk and YHPA.

WT: The Westcliffe Partnership has received funding from Abbott, AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol Myers Squibb, Dawn, INRStar, Medtronic, Oberoi Consulting, Pfizer, Roche, Sanofi-Aventis and Servier. WT has received funding from the following companies for provision of educational sessions, speaker fees, advisory and consultancy roles and travel grants to attend conferences: Abbott, AstraZeneca, Amarin Pharmaceuticals Ltd, Bayer, Boehringer-Ingelheim, Dexcom, Daiichi Sankyo, Eli Lilly, European Medtec, Menarini, Merck and MSD, Novartis, Novo Nordisk, Napp Pharmaceuticals Ltd, Roche and Sanofi. WT has also worked in a non-promotional capacity to support GP/PN education via MIMS, medical updates, DPC, DUK, Primary care health, PCDS and PCDE. WT is a Clinical Advisor to Gendius – AI remote management.

AP has received speaker fees and attended advisory boards for Amryt/Chiesi, Sanofi, and Ultragenyx. Educational grants were received from Menarini, Novartis and Sanofi.

DC has received honoraria/expenses from Amarin, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Menarini, Novartis, Novo Nordisk, Pfizer and Recordati. He has served on a consulting/advisory board basis for Amarin, AstraZeneca, Daiichi Sankyo, Menarini, Novartis, Pfizer and Recordati, and conducted funded research for AstraZeneca and Daiichi Sankyo.

MHC has received honoraria, research grants and educational support from Abbott, Daiichi-Sankyo, Boehringer Ingelheim, Lilly. Novartis, Sanofi, AstraZeneca, Novo Nordisk, Viatris, MSD and Menarini.

DBND has received honoraria/ project development fees from Sobi, Amgen, Daiichi-Sankyo, Recordati, Novartis, MSD, Lilly and Novo-Nordisk.

PFD has received speaker fees and fees for attendance at advisory boards from Amgen, Amarin, Arrowhead Pharmaceuticals, Besins Healthcare, Daiichi Sankyo, Novartis, Sanofi, Sobi and Ultragenyx. Financial support was received for travel and accommodation to attend national/ international conferences from Novartis, Amgen and Sanofi.

EH has received honoraria and consultancy fees from Novo Nordisk. Menarini, Daiichi Sankyo, Amgen, Amarin and Novartis.

JM has received honoraria from Daiichi-Sankyo and Menarini in relation to educational activities in the last year.

KKR has served on advisory boards, steering committees, or as a consultant or speaker for Abbott Pharmaceuticals, Amarin Pharma Inc., Amgen, AstraZeneca, Bayer Healthcare, Boehringer Ingelheim, Cleerly, CRISPR Therapeutics, CSL Behring, Dr. Reddy’s, Eli Lilly, Esperion Therapeutics, Kowa, MacLeods Pharmaceuticals, Mankind, Menarini International, NewAmsterdam Pharma, Nodthera, Novartis, Novo Nordisk, Pfizer, Sanofi, Silence Therapeutics, Vaxxinity, and Viatris. He reports roles related to trial leadership, oversight, or design for Eli Lilly, Esperion Therapeutics, Kowa, NewAmsterdam Pharma, Nodthera, and Scribe Therapeutics and also holds stock options in NewAmsterdam Pharma, PEMI31, and Scribe Therapeutics.

Funding

Journal supplement processing charges were also funded by A. Menarini Farmaceutica Internazionale SRL.

Medical writing and editorial assistance

This publication has been independently developed by the BEACON steering committee. Medical writing services were provided on behalf of the authors by Rebecca Down, PhD, at Copperfox Communications Limited and project management support was provided by Lisa Kelly at LKOTT Consulting Limited – Medical Communications. Funding for medical writing and project management support services was provided by A. Menarini Farmaceutica Internazionale SRL.

Authorship

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval for the version to be published.

Author contributions

All named authors critically appraised the data and associated analyses discussed in this paper and each conducted in-depth review of the manuscript content ahead of submission for publication.

Compliance with ethics guidelines

This article is based upon previously conducted studies and does not involve any new studies of human or animal subjects. Any studies discussed within the paper that included human subjects complied with the tenets of the Declaration of Helsinki of 1964 and subsequent revisions and used protocols that had been approved by relevant institutional review boards/ethics committees and included patients who had provided written informed consent.

Beverley Bostock
President Elect
Primary Care Cardiovascular Society, UK
Advanced Nurse Practitioner
Mann Cottage Surgery, Four Shires Medical Centre, Moreton-in-Marsh, Gloucestershire, UK
([email protected])

Jaimini Cegla
Consultant in Metabolic Medicine
Division of Diabetes, Endocrinology and Metabolism, Imperial College London, UK;
Lipids and Cardiovascular Risk Service, Department of Cardiology, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK

Emily Turner
Lead Pharmacist
Aire Valley Surgery and Guiseley and Yeadon Medical Practice, Leeds, UK

Waqas Tahir
GP Partner
Affinity Care, Bradford, UK

Alison Pottle
Consultant Nurse in Cardiology
Royal Brompton & Harefield Hospitals, Harefield Hospital, part of Guy’s & St Thomas’ NHS Foundation Trust, UK

Derek Connolly
Consultant Cardiologist
The Midland Metropolitan University Hospital, Aston University and Institute of Cardiovascular Sciences, University of Birmingham, Birmingham UK

Michael H Cummings
Professor of Diabetes and Endocrinology
Academic Department of Diabetes and Endocrinology, Queen Alexandra Hospital, Portsmouth Hospitals NHS Trust, Portsmouth, UK

Dev BN Datta
Consultant in Metabolic Medicine
Lipid Unit, University Hospital Llandough, Cardiff, UK

Paul F Downie
Consultant Chemical Pathologist
Department of Clinical Biochemistry, University Hospitals Bristol and Weston NHS Trust, Bristol, UK

Elizabeth Hughes
Consultant in Chemical Pathology and Metabolic Medicine
Sandwell and West Birmingham Hospitals NHS Trust, Birmingham, UK

Jim Moore
General Practitioner with Specialist Interest in Cardiovascular Medicine & GPSI Gloucestershire Heart Failure Service
GLOS Heart Failure Service, Gloucestershire Care Services NHS Trust, Brockworth, UK

Kausik K Ray
Professor of Public Health
Department of Primary Care and Public Health, Imperial College London, London, UK

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