Primordial prevention and population health

The first step in the public health approach to ASCVD prevention is to change the milieu that promotes risk factor development as early as possible [19]. While primary prevention is about treating risk factors to prevent ASCVD, primordial prevention is avoiding the development of risk factors in the first place. It begins with changes in lifestyle, environmental and social conditions to prevent risk factor development from birth. Many risk factors have their origins early in life since this is the time when lifestyles are formed. Whilst genetics may be considered the ‘loaded gun’, environment and lifestyle effectively ‘pull the trigger.’ Many of these changes require policy changes, affordable healthy life choices and improvements in health literacy. Population level changes at a time of maximal developmental plasticity offer the best hope of setting individuals on a more favourable trajectory long-term towards better cardiovascular health. Recommendations regarding this remain the same as in the 2017 Roadmap; public health interventions should incentivise a healthy lifestyle. These can simply be put as keep physically active, an important necessity as many jobs have a sedentary nature, avoid tobacco use, maintain ideal body weight for ethnicity, reduce salt consumption and where feasible adopt the traditional Mediterranean-type diet with substitution of monounsaturated and polyunsaturated for saturated fat [20, 21]. In particular, plant-based foods should be encouraged and incentivised [22, 23, 24]. Specifically, these approaches should focus on children or young adults, that is, start as early as possible when it comes to primordial prevention.

Primary Prevention

Future approach: Lifetime risk estimation

The main implication of the cumulative exposure hypothesis is that maintaining low levels of LDL-C throughout life reduces cumulative exposure to the number of lipoprotein particles that become trapped within the artery wall over time, thus slowing the rate at which atherosclerosis develops and delaying the age at which the underlying plaque burden is large enough to increase the risk of having an acute ASCVD event. However, to maximize the benefit of reducing plaque burden by reducing cumulative exposure to LDL-C, it is also necessary to reduce exposure to other causes of arterial wall injury that increase the risk of having an acute event at all levels of plaque burden. Therefore, the cumulative exposure hypothesis suggests that the most effective way to reduce the lifetime risk of ASCVD events is by reducing cumulative exposure to LDL-C to slow atherosclerotic plaque progression, while also reducing cumulative exposure to other causes of arterial wall injury including elevated blood pressure, diabetes, and tobacco smoking.

Very long-term prospective follow-up of the Framingham Heart Study demonstrates that persons who maintain low levels of LDL-C and blood pressure throughout their lives have a very low lifetime risk of atherosclerotic cardiovascular events [30]. The PDAY risk score based on the relationship of risk factors to measured atherosclerosis in 15–34 year-olds strongly predicts premature ASCVD [31]. In addition, Mendelian randomization studies demonstrate that persons who are naturally randomized to genetic variants associated with lower lifetime exposure to LDL-C have a substantially lower lifetime risk of ASCVD [32, 33]. The same observation is true for BP. The latter studies agree closely with the 80% reduction in cardiovascular morbidity and mortality observed in Finland over the past 40 years [34]. Beginning in the 1970s, Finland initiated a coordinated public health programme to reduce cardiovascular morbidity and mortality by reducing exposure to saturated fats to lower plasma cholesterol levels, and by discouraging the practice of preserving meat with cured salts to lower blood pressure levels [34]. Over the following 40 years, this programme resulted in a reduction of 1.5 mmol/L (58 mg/dL) in the population mean level of total cholesterol, an 8.7 mmHg reduction in the population mean level of systolic blood pressure (SBP), and a corresponding 80% reduction in cardiovascular morbidity and mortality. Assuming that most of the total cholesterol reduction was due to reduction in LDL-C in response to lower consumption of saturated fats, the magnitude of this reduction in cardiovascular morbidity and mortality is nearly identical to what would have been predicted by long-term exposure to the same magnitude of lower LDL-C and SBP in Mendelian randomization studies, thus providing powerful real-world evidence to support the cumulative exposure hypothesis.

Although some guidelines have referenced the value of lifetime risk [25, 35, 36], current clinical practice does not focus on lifetime risk [37], or on reducing cumulative exposure to the causes of ASCVD. Instead, current clinical practice guidelines recommend both informing the decision to initiate LDL-C lowering therapies, and titrating the intensity of those therapies, based on a person’s estimated short-term risk of developing an acute cardiovascular event over the next 10 years (29). However, short-term risk estimating algorithms are mathematically dominated by age because acute atherosclerotic cardiovascular events tend to occur later in life after a person develops a substantial underlying atherosclerotic plaque burden. As a result, informing the decision to initiate LDL-C lowering therapy based on short-term 10-year risk has the practical effect of inviting us to wait until a person develops a large atherosclerotic burden before initiating therapy to lower LDL-C to slow the progression of atherosclerosis.

Indeed, current clinical practice guidelines explicitly focus on using pharmacologic therapy to lower LDL-C to prevent atherosclerotic cardiovascular events among persons with a high estimated 10-year risk of experiencing an acute ASCVD event; and on intensification of pharmacologic LDL-C lowering therapies to achieve even lower LDL goals among persons who have already experienced an ASCVD event. Achieving these more intense plasma LDL goals almost always require the use of two or more pharmacologic LDL-C lowering therapies. Recent advancements in embedding causal inference and causal effects into artificial intelligence and machine learning algorithms (‘causal AI’) permit an estimation of the effect of lower LDL-C or systolic blood pressure (SBP) in discrete time-units of exposure, conditional on previous cumulative exposure to account for the amount of plaque burden and arterial wall injury that has accumulated prior to the initiation of interventions to lower LDL-C or SBP. This method allows an estimate of the benefit of lowering LDL-C, SBP or both beginning at any age (and extending for any duration of time) on the risk of developing an acute atherosclerotic cardiovascular event. Studies using these causal AI methods suggest that there is a stepwise increase in the reduction in the risk of atherosclerotic cardiovascular events for each decade earlier that LDL-C lowering is initiated [32] (Figure 3).

These studies suggest that modest sustained reductions in LDL-C beginning earlier in life are associated with a lower risk of ASCVD events at all ages as compared to more intense LDL-C lowering started later in life. Indeed, these studies suggest that ‘residual risk’ of experiencing an acute ASCVD event despite intense LDL-C lowering initiated later in life may be explained by the extent of the plaque burden that accumulates prior to the initiation of LDL-C lowering therapy. Although aggressive LDL-C lowering initiated later in life can slow (or perhaps even arrest) plaque progression, the plaque burden that accumulated prior to the initiation of LDL-C lowering still persists and may disrupt the subsequent formation of a thrombus overlying the disrupted plaque, obstructing blood flow and leading to an acute cardiovascular event. As a result, reducing the cumulative exposure to LDL-C as a strategy to slow the progression of atherosclerotic plaque may both substantially reduce the lifetime risk of ASCVD and substantially reduce the residual risk of acute atherosclerotic events if implemented globally.

Familial hypercholesterolemia

Familial hypercholesterolaemia is an autosomal co-dominant condition which results in life-long elevations in LDL-C from birth leading to premature cardiovascular disease (from age 30 in men and age 40 in women) and premature deaths. Heterozygous FH (HeFH), results when an individual inherits one affected gene from a parent. Several recent studies have emerged that should inform future public health strategies directed towards early case finding and initiating treatments early in the life course.

The global prevalence of HeFH is 1:311 and is present in all WHO regions at similar levels [38]. However, the frequency in communities with founder effects is higher, being as high as 1:70 [39]. Even though it affects every WHO region, there is little data from as many as 130 countries, meaning that HeFH may not even be recognised and is thus a missed opportunity. The FHSC (Familial Hypercholesterolemia Studies Collaboration) global registry demonstrated that HeFH diagnosis globally occurs in the fourth decade of life with only 2.1% diagnosed before the age of 18 years, with age of diagnosis in the Asia-Pacific region worst, underscoring the need for system-wide changes enabling early diagnosis [40]. At diagnosis, 17.4% had coronary artery disease (CAD), 2.1% stroke and 5.2% peripheral arterial disease with 11.3% having premature CAD [40] consistent with data suggesting that among patients with premature CAD the prevalence of FH could be as high as 1:17–25 [38].

The lack of widespread availability of genetic testing means that the commonest method of diagnosis globally is using clinical criteria with ~75% using the Dutch Lipid Clinic Network criteria (DLCN) [40], consisting of biochemical measurements, physical examination and family history. Women are diagnosed several years later than men and are less likely to have CVD at diagnosis. This means that contributions (from premature ASCVD) to the DLCN score will be absent, making LDL-C, physical examination and family history even more important, to even consider a diagnosis of FH in women. Furthermore, with increasing age, metabolic causes of elevated LDL-C become more common. As the prevalence of risk factors such as hypertension, diabetes and increased BMI increase with age (40), if patients with FH are identified earlier there is a greater chance that unhealthy lifestyles and other behaviours might be avoided reducing the likelihood of lifestyle associated risk factors later in life. Treatment beginning in adolescence dramatically reduces premature myocardial infarction and death in this condition [41]. Case finding through screening in childhood (as discussed later) is attractive for multiple reasons, not least because LDL-C is less likely to be influenced by metabolic disorders in this age group, increasing the likelihood that elevated cholesterol has a genetic basis.

Though cholesterol lowering treatment is effective, most adult patients with HeFH will likely require at least two therapies. The FHSC registry demonstrates that less than 3% of patients achieved LDL-C levels of < 1.8 mmol/L (70 mg/dL). At present, though statins are generally used, ezetimibe is only used in about 24.6% and PCSK9 monoclonal antibodies (MAbs) in 3%. As patients with HeFH usually have an LDL receptor (LDL-R) mutation, the normal gene can be upregulated with statins and LDL-R lifecycle enhanced with therapies that lower free PCSK9. In this regard inclisiran with twice yearly dosing may be convenient offering similar efficacy to MAbs which require dosing every two weeks, when added to statins in genetically confirmed HeFH [42].

Homozygous FH (HoFH) occurs in approximately 1:300 000. Affected individuals have extreme elevations in LDL-C – typically > 13 mmol/L (500 mg/dL) – and manifestations of ASCVD or aortic or supra-aortic stenosis before the age of 20 which is invariably fatal by aged 40 if untreated [43]. Those affected carry two affected genes in pathways related to cholesterol metabolism. Recently available data on HoFH from 38 countries showed that the average age of diagnosis was 12 years, with average LDL-C levels of 14.7 mmol/L (570 mg/dL) and with 9% already having evidence of ASCVD or aortic valve disease at diagnosis [44]. There are significant differences in how patients are treated between high- and low-to-middle-income countries which impacts health outcomes. Patients in high-income countries (HICs) had LDL-C levels on treatment of ~4 mmol/L (155 mg/dL) and were more likely to receive newer therapies with four or more drug combinations than in non-high-income countries. The latter by contrast mostly use two drug combinations and had on treatment LDL-C levels of about 9 mmol/L (350 mg/dL). The average age of first cardiovascular event in low-middle income countries was at 24.5 years and at 37 years in high income countries. Cardiovascular risk related to high-LDL-C in part could be attenuated with an earlier age of diagnosis as well as using four or more lipid lowering treatments, including apheresis. Notably, as many of these patients have severely diminished LDL-R function, hence traditional therapies that work through the LDL-R pathway like statins, ezetimibe and PCSK9 inhibitors may not achieve the magnitude of LDL-C lowering necessary to reduce atherosclerosis progression. This necessitates the need for newer therapies that are independent of the LDL-R like lomitapide and evinacumab. These therapies are currently extremely expensive but potentially lifesaving.

Secondary Prevention

As the risk of recurrent ASCVD events and progression of atherosclerosis is highest in individuals with pre-existing or prevalent manifestations of ASCVD, pharmacological interventions for cholesterol lowering need to be initiated without formal risk estimation. This means statins usually of high potency (with the aim to achieve at least 50% reduction in LDL-C) are used irrespective of untreated cholesterol levels rather than starting at low doses and titrating up. This is particularly important among those who experience an acute atherothrombotic event and are at greatest risk of further events [45]. Just as with primary prevention, among ASCVD patients, risk varies considerably [46, 47]. As more recent global guidelines have recommended lower cholesterol goals for these patients, it is now clear that this inevitably means that statin-based monotherapy will not help the majority of patients reach lower LDL-C levels. For instance, the new ESC/EAS 2019 goals of <1.4 mmol/L (55 mg/dl) are likely to be achieved by only ~1/5 individuals and with only ~1/2 achieving goals of <1.8 mmol/L (70 mg/dl) [48]. Globally there is an underutilisation of combinations of lipid lowering treatments [48] which are inevitably necessary in order to achieve the new recommended cholesterol levels. Although newer add on therapies are available, their cost and uncertainties in everyday practice as to who benefits most when healthcare resources are scarce have impacted their widespread use. In this regard, estimation of 10-year risk with the SMART risk equation is globally the most validated tool for assessing absolute risk and thus allows estimation of absolute benefit [46, 49]. A schematic shows how among 13 patients with ASCVD, risk varies based on demographics and co-morbidities, Absolute benefits of anti-coagulants depends upon the starting global risk. The absolute benefits of further LDL-C lowering through PCSK9 lowering therapies depends upon the global risk as well as on the treatment levels of LDL-C, for instance on statins and how much further it is lowered by adding on non-statin lipid lowering therapies eTable 4. The SMART tool provides up to 10-year quantitative assessments of risk and potential benefit and is available as an online tool. Where this is not available, simple qualitative tools like the TIMI Risk Score for Secondary Prevention (TRS2P) in those with established ASCVD, have been shown in several studies to differentiate by a factor of three between those at very high risk from those at much lower risk and who derive greater absolute benefits from further cholesterol lowering [26, 50].

Pharmacological lipid lowering therapies

Triglycerides

Triglyceride (TG) elevations often reflect the spectrum of lifestyle related metabolic dyslipidaemia. Hence, weight loss, diabetes control, alcohol reduction and carbohydrate reduction are important means to lower TG levels. If TG levels fall, the cholesterol within TG rich lipoproteins will also fall. Most guidelines recommend more intensive non-HDL-C or apo B lowering for patients with high triglycerides for reasons discussed earlier, due to an absence of clear benefit from therapies such as fibrates in individual contemporary trials although meta analyses suggest some benefits in the high TG/low HDl-C phenotype [12]. However, among patients with high TG the use of icosapent ethyl resulted in significant reductions in CV events despite only modest TG lowering suggesting that any clinical benefit may be through non-lipid related pathways [64]. Some guidelines now recommend high dose icosapent ethylicosapentethyl as a potential option to reduce CV risk among high-risk patients (ASCVD or diabetes and multiple risk factors) with TG (1.5–5.6 mmol/L or 135–499 mg/dl) and on statin therapy [26, 29].

Lipoprotein(a) and Lp(a)

Lipoprotein (a) should be measured at least once in a person’s lifetime. Management of individuals with high Lp(a) currently focuses on control of other major risk factors to reduce ASCVD risk [65]. Lipoprotein apheresis is often used to reduce severe elevations in Lp(a) and more modest reductions of about 20–30% are achievable through PCSK9 directed therapies [66]. To what extent Lp(a) lowering with these therapies confers additional benefit beyond the LDL-C lowering is uncertain although post-hoc analyses using post randomisation changes suggest there may be benefit [67] from PCSK9 mAbs from Lp(a) lowering independent of the LDL-C lowering effects. Trials focused on specifically lowering Lp(a) by 80% or more with RNA based therapies are ongoing to evaluate this.

Who was surveyed?

In July and August 2021, the WHF conducted an online consultation of all WHF members using snowball sampling to include regional members as well as national representatives (Figure 4, Panels A–F). This online survey included questions on clinical practice as well as questions on the roadblocks and solutions which had been identified in the original WHF Cholesterol Roadmap. In total, responses were collected from 38 countries. The highest number of responses were collected in the WHO Region for the Americas, followed by the European Region. Respondents predominantly worked in an urban setting with 40% working in public hospitals, 23% in private hospitals and 18% in outpatient clinics only. Other work settings included government organisations, research organisations and NGOs. Seventy percent of the respondents were cardiologists, followed by lipid specialists, endocrinologists, nurses, nutritionists, researchers, and health advocates. The specialities represented in part reflect WHF membership, but perhaps also point to major barrier in ASCVD prevention, namely healthcare systems focused on treating disease based in secondary and tertiary care rather than in primary care with a focus on preserving health. Furthermore, those surveyed may represent the best-case scenario of practitioners who are engaged and up to date with cholesterol management and ASCVD prevention.

Which guidelines are used by WHO region

Overall, most respondents recognize that they follow an ASCVD prevention guideline to manage LDL-C. Broadly by WHO region, the European and African WHO regions relied mostly on the ESC/EAS guidelines, the Eastern Mediterranean and the Western Pacific WHO Regions on the ACC/AHA guidelines, and the picture was more contrasted in the WHO Region for the Americas and the Southeast Asia Region (details in Supplementary Appendix). Overall, across WHO income regions the ESC Score charts were the most commonly used. The WHO has published CVD risk prediction charts for each WHO region. Hence prior roadblocks such as the absence of risk tools for regions not studied in ESC or ACC/AHA risk calculators such as Africa or Latin America should not be obstacle. Prior uncertainty about the accuracy of risk prediction tools potentially which may have resulted in no risk prediction tool being used whatsoever, or when used over/underestimation of risk can now be overcome.

Perceptions about lipid lowering therapies and cholesterol

Clinician and patient perceptions about the need or effectiveness of therapies could be an impediment to better management of cholesterol and ASCVD risk. An important finding is that 93.9% of the respondents reported initiating lipid lowering therapy based on ASCVD risk irrespective of the conditions leading to increased ASCVD risk. Only 12.2% reported initiating therapy based on cholesterol levels alone. This trend was seen in all WHO income regions (Figure 4, Panel A). Overall, around 27% of respondents are uncomfortable with prescribing high potency statins. Notably, 60% of the respondents from LMICs reported being uncomfortable prescribing high potency statins. Conversely, in HICs 65% reported being fully comfortable with the use of high potency statins (Figure 4, Panel B). This represents a significant barrier to tackling ASCVD globally as the majority of the global population reside in LMIC. Across income regions, approximately 25% of the respondents felt somewhat or highly uncomfortable with lowering LDL-C ‘too much’. A minority of respondents felt uncertain about how and when to use combination therapies. Given the low use of combination therapies globally, this suggests that there is a wide gap between self-reported awareness of what to use and when to use combination therapy and correct application.

Patient perceptions collated from respondents suggest that two-thirds of the respondents felt that their patients were convinced about the benefits of lowering cholesterol and around 20% felt that patients were not convinced about these benefits. Similarly, around 60% felt that patients were convinced about the safety of cholesterol lowering medications. However, among LMICs, 70% of the respondents were unsure or felt this was not the case. Finally, 80% of the respondents in low-income countries (LICs) felt that patients find it hard to understand the risk of ASCVD (28% in HICs) (Figure 4, Panel C). Taken together much more work is needed to improve health literacy including a greater need for patient/public engagement as well as shared decision making. Limitations of our survey merit consideration. In particular, the sampling may not be fully representative as some surveyed did not respond and the ‘perception’ of physicians about patients were considered instead of patients being asked directly.

Availability and access to different lipid lowering therapies

High-intensity statins and ezetimibe were reported to be available by most responders independent of WHO income region. In LICs, 40% of the respondents pointed to the lack of availability of fixed dose statin/ezetimibe combinations, and 60% reported that PCSK9 inhibitors were not available. In LMICs, the lack of availability of ezetimibe was reported by 20% of the respondents, and the corresponding figure for fixed dose statin/ezetimibe combination therapies and for PCSK9 inhibitors was 40%. This was not an issue in upper-middle income countries (UMICs) and HICs (Figure 4, Panel D). One possible barrier for adequate LDL-C lowering was that 75% of the respondents in LICs reported that fixed dose statin/ezetimibe combination therapies and PCSK9 inhibitors were not registered. Respondents from LMICs reported issues with registration for all medications, but to a lesser extent. In UMICs, lack of registration of PCSK9 inhibitors was reported by only 10% of the respondents.

Regarding access to lipid lowering therapies in LICs, none of these four treatments (high- intensity statins, ezetimibe, fixed dose combinations or PCSK9 inhibitors) were reported to be universally prescribed freely in the public sector. In LICs, 50% of respondents reported that high intensity statins could be freely prescribed with 75% approximately answering that ezetimibe, fixed dose combinations of statins/ezetimibe and PCSK9 inhibitors cannot be freely prescribed. Taken together improving availability and access of high-intensity statins and ezetimibe as a basic minimum standard would alleviate a major obstacle to care in LICs. Only HICs reported that, apart from PCSK9 inhibitors, lipid lowering therapies could in most cases be prescribed freely in the public sector (Figure 4, Panel E). A similar trend emerged regarding the insurance coverage for most private patients without significant co-payment in HICs (Figure 4, Panel F). There was a strong gradient among country income categories regarding payments by patients, with the smallest patient participation in HICs. In LICs, most drugs were reported to be paid for by the patient or to have a large co-payment (apart from PCSK9 inhibitors which are largely unavailable).

The link between wealth and health and the vicious cycle has never been clearer. Health systems in LICs and LMICs must recognise the public health benefits of cholesterol lowering and consider prevention and preventive strategies as an investment rather than an expense. In this regard they must provide statins as essential medications without the burden for cardiovascular health being placed on patients who can least afford to pay for these vital therapies. Novel ways of working to share the cost of investment through multi-stakeholder engagements such as public/private partnerships, NGOs, philanthropy and other approaches may help to initiate change in LICs and LMICs which can then be sustained by member nations.

Attainment of cholesterol goals and patient adherence to treatment plan

In the recent survey performed by the WHF, across WHO regions overall, 44% of the respondents reported that 51–75% of patients achieved LDL-C control, 28% reported that 25–50% achieved LDL-C control, and 19% that more than 75% achieved LDL-C control. By comparison, only 11% felt that less than 25% of patients achieved LDL-C control. Separating regions by income, worryingly in LICs, only 20% of the respondents reported that 51–75% of patients achieved LDL-C control, whilst 40% reported that less than 25% of patients achieved LDL-C control. This correlates with findings from a recent study which found that, in a range of LMICs, statins are used by about one in ten eligible people for the primary prevention of cardiovascular diseases and one in five eligible people for secondary prevention [68]. A limitation of these data is that it is unclear which specific goals respondents are aiming to achieve. Given the data in the rest of the world that untreated cholesterol levels are similar across regions, use of more simplistic and pragmatic approaches such as initiation of more potent statin regimens from the outset per se or initiation of fixed dose potent statin ezetimibe combinations may improve barriers in implementation. Globally, 51% of the respondents reported that 51–75% of patients adhere to their treatment plan, 25% reported that more than 75% of patients adhere to treatment, and 26% said that less than half of the patients adhere to treatment. The proportion of respondents reporting that patient adherence was less than 50% amounted to 60% in LICs and to 42% in LMICs. As discussed previously significant roadblocks remain surrounding health literacy in LICs and LMICs. Concerted efforts will be required at the level of government or health care policy to address this.

The second part of the survey focused on a series of roadblocks solutions which had been identified in the original WHF Roadmap on Cholesterol [5]. Overall, the roadblocks previously identified persist and the prior observed gradient across countries by income category remains. Notably, across all WHO income categories, the lack of awareness surrounding FH among both the general population and physicians, as well as barriers to diagnosing and effectively treating FH have not been overcome and remain the most significant barriers to managing this inherited cholesterol disorder. In LICs and LMICs, lack of access to facilities, and awareness about the importance of ASCVD risk factor screening, and adherence to treatment, among both physicians and patients, were still reported to be significant roadblocks. Conversely, in HICs, access and awareness did not apply for the majority of respondents, although implementation was far from ideal.

Future solutions

Regarding the possible solutions to overcoming roadblocks identified in the previous Roadmap, most remained relevant. Most participants agreed that screening campaigns for dyslipidaemias and FH were needed. The ideal scenario would be for universal cholesterol screening before the age of 18 and ideally in the first decade of life, which would also offer opportunities for child parent screening which has been suggested to be cost effective [69, 70]. This approach is supported by observation that among non-index cases, diagnosis of FH occurred at a younger age and CVD was far less prevalent at diagnosis [40]. Additionally, preventing obesity has to be an integral part of public health policy as it will prevent metabolic lipid disorders and diabetes both of which increase ASCVD risk.

If cholesterol measurements including Lp(a) become more readily available and costs fall, universal cholesterol screening before the age of 18 and ideally in the first decade of life may be the ideal time window not only to establish a diagnosis of an inherited lipid disorder but also to establish treatment. Patient advocacy has a key role to play with policy makers, as shown in Europe, to set the public health policies needed globally [71, 72]. Where government institutions have implemented these at scale, such as in Slovenia, this can become a beacon of best practice [73]. For children, establishing a diagnosis of FH offers opportunities to initiate early and maintain favourable lifestyles when other lifestyle related CV risk factors are largely absent, potentially helping sustain behaviours into later life. As physicals signs of hypercholesterolaemia are likely to be absent in children establishing a diagnosis of FH will rely largely on LDL-C levels and thus the availability of testing. With recent advances in genomics, monogenic or polygenic contributors to cardiovascular disease could aid early decision-making.

Potential solutions for healthcare systems should include the available, scalable, low-cost genetic testing which could cover inherited dyslipidaemias (FH and high Lp(a)). For dominant and co-dominant traits this further offers an opportunity for reverse-cascade testing. Although newer treatments are expensive and may not be available in many LMICs, combinations of potent statin regimens and ezetimibe as single pill especially if initiated early through screening/case finding, may offset therapeutic costs related to case finding later in the life-course where atherosclerosis and clinical disease are much more advanced. For FH patients with characteristics suggesting higher risk of ASCVD, proposed algorithms may help guide further intensification of treatment [43]. However, for HoFH, due consideration should be given to pricing of contemporary potentially life-saving therapies inevitably required for this condition. Moreover, regulators and industry should ensure early paediatric testing of these therapies and their availability in LMICs will be needed, as it is here that the global burden of HoFH lies.

Clinical practice guidelines to prevent cardiovascular events focus on recommending pharmacologic therapy to lower LDL-C among persons with advanced atherosclerosis. Moreover, combinations of pharmacologic therapies to more intensely lower LDL-C among persons with a history of ASCVD events, are designed to be implemented in resource-rich HICs. Therefore, these guidelines may not be optimal for implementation in resource-limited LMICs. Indeed, adopting this strategy to prevent ASCVD events in LMICs could exacerbate healthcare inequities because these countries are unlikely to be able to afford expensive combinations of therapies required to achieve very low LDL-C targets, thus potentially leading to worse outcomes among persons in LMICs following an acute cardiovascular event. Instead, a more effective strategy for LMICs may be to proactively prevent ASCVD events by reducing cumulative exposure to LDL-C, the main cause of atherosclerosis. Lifetime cumulative exposure to LDL-C can be reduced by maintaining modest long-term reductions in LDL-C beginning earlier in life with diet or the combination of diet and low-dose generic LDL-C lowering therapies. Indeed, maintaining modest long-term reductions in LDL-C beginning earlier in the atherosclerotic disease process is likely to be more effective at preventing the lifetime risk of ASCVD events, and substantially less expensive, than focusing on more aggressive pharmacologic LDL-C lowering started later in life and therefore later in the atherosclerotic disease process. However, significant barriers must be overcome to effectively prevent ASCVD events by reducing cumulative exposure to the causes of atherosclerosis and other forms of injury to the arterial wall in in LMIC countries (Box 2).

Finally, simplified, easily implemented CVD guidelines, adaptation of risk profiling for specific regions and use of point of care testing was felt by survey respondents to be of value in improving implementation of best care. Furthermore, programmes including trained community health workers for risk evaluation could be of value in LMICs [74]. Shared decision making with patients could be enhanced through better health literacy. This will require the continuing need for public health awareness campaigns [75] aimed at increasing societal understanding about the causes of ASCVD, and its prevention including overcoming misinformation about the safety and efficacy of life saving treatments such as statins. Healthcare systems should think about preserving health rather than treating disease, which means considering prevention as an investment for the future rather than an expense. This will require greater availability and affordability of lipid lowering drugs, multi-professional teams and use of new technologies which are scalable to improve patient adherence like text messaging. As well as the public, continued education and dissemination of some of the key concepts about lifetime cumulative exposure to cholesterol, safety of cholesterol lowering and cholesterol lowering treatments will be needed, given the uncertainty within the present survey about limiting the number of statins to avoid misconceptions surrounding dose and cholesterol lowering efficacy as well as the potential utility of a polypill. A list of minimum requirements by country income status is shown in Table 2.