Eradicating Atherosclerosis: Should We Start Statins at Younger Ages and at Lower LDL-Cs?

Abstract

Purpose of review:

Given increasing burden of cardiovascular disease, we review the literature for earlier initiation of statin therapy, at younger ages and lower low density lipoprotein cholesterol (LDL-C) levels, with the goal of preventing the development of atherosclerosis prior to clinical events.

Recent findings:

There is rising prevalence of dyslipidemia among younger adults. Although guidelines offer recommendations for adults over 40, there is little guidance for management of younger adults with moderately elevated LDL-C levels. Earlier and more aggressive statin use may slow progression, or even halt atherosclerosis, and may likewise be beneficial and cost-effective on a population level.

Summary:

Further research is needed to define the exact age and LDL-C level at which to start statin therapy. Until then, more detailed risk stratification with lab testing and imaging should be used to identify younger adults at highest risk.

Introduction:

Atherosclerotic cardiovascular disease (ASCVD) is common, increasing in prevalence, and represents the leading cause of morbidity and mortality worldwide [1]. It is the result of a lifelong process of atherosclerosis which is initiated by the accumulation of atherogenic lipoproteins within the arterial wall. Reduction of low-density lipoprotein cholesterol (LDL-C) is a mainstay of ASCVD prevention as there is proven effectiveness in reducing ASCVD events commensurate with the degree of LDL-C reduction achieved [2, 3].

Current guidelines emphasize reduction of LDL-C in middle-aged and older adults with either elevated 10-year risk of ASCVD events or anyone with established ASCVD [4, 5]. While this strategy has been effective at reducing rates of ASCVD events in older adults, clinical events also occur at younger ages, with approximately half of all ASCVD events occurring before the age of 65, and one-quarter of new-onset ASCVD events in men occurring before the age of 55 [6]. Current guidelines for cholesterol management in adults 20-40 years old without familial hypercholesterolemia (FH) or established ASCVD are not clear, prompting the clinician to ask: How aggressively should we lower LDL-C in younger adults, what are our treatment strategies, and when should we start? Herein, we review the potential benefits and risks of early statin initiation with a focus on clinical considerations.

Prevalence of Elevated Cholesterol in Younger Adults

Hypercholesterolemia, defined by the World Health Organization (WHO) as total cholesterol ≥ 190mg/dL, has a global prevalence of 39% (37% in males, 40% in females) in adults aged 18 years and older as of 2008, the most recent WHO estimate [7]. In the United States, the burden of dyslipidemia is high even among younger patients. Data collected from 2015-2018 revealed that 8.5% of men and 4.9% of women aged 20-34 years had serum total cholesterol greater than or equal to 240 mg/dL or were taking cholesterol-lowering medications. In those aged 35-44 years, 18.2% of men and 8.9% of women had hypercholesterolemia [8]. Among U.S. children and adolescents in 2011-2014, 7.4% had elevated total cholesterol above 200 mg/dL, though interestingly, the pattern of sex difference was reversed, with 8.9% of girls vs 5.9% of boys being affected. The same analysis showed a higher prevalence of hypercholesterolemia among non-Hispanic black and non-Hispanic Asian children compared to non-Hispanic white and Hispanic children, a trend reflected by data in the adult population [9].

The prevalence of dyslipidemia in US adults over age 20 declined for two decades following approval of the first statin in 1987. While the overall prevalence of total cholesterol greater than or equal to 240 mg/dL declined from 19.6% in 1988-1994 to 12.1% in 2011-2014, this trend has since plateaued over the last decade with a prevalence of 11.5% on the most recent estimate by the U.S. Centers for Disease Control and Prevention in 2015-2018 [8]. Data on U.S. adults older than age 20 from the National Health and Nutrition Examination Surveys (NHANES) demonstrated a similar pattern in age-adjusted mean serum Apo B concentrations, which declined in women from 94 mg/dL in 2005-2006 to 91 mg/dL in 2013-2014 where it has plateaued. In men, Apo B declined from 98 mg/dL in 2005-2006 to 93 mg/dL in 2011-2012 but has since increased to 95 mg/dL in 2013-2014 [10]. Thus, while population-level dyslipidemia was previously decreasing, this beneficial trend has halted in recent years.

Current Guideline Recommendations

There is a paucity of clinical guidance for younger adults (20-40 years old) with LDL-C levels that are elevated, such as above 130 mg/dL, but less than 190 mg/dL. Current major society guidelines for the management of dyslipidemias prioritize pharmacologic LDL-C lowering for ASCVD risk reduction in middle-aged and older patients, those with established ASCVD, and those with particular high-risk comorbidities such as diabetes or FH, but they provide less clear recommendations for the management of mild-moderately elevated LDL-C in younger patients.

The most recent American College of Cardiology (ACC)/American Heart Association (AHA) guideline on the management of blood cholesterol recommends consideration of statin initiation for patients over age 40 who have a calculated 10-year ASCVD risk of 5%-7.5% and additional risk factors, or 10-year ASCVD risk >7.5% (Table). For patients 20-39 years of age, the ACC/AHA guidelines recommend screening for traditional cardiovascular risk factors every 4-6 years. Within this group, assessment of lifetime ASCVD risk is emphasized over 10-year risk, as the pooled cohort equations are not validated for use in this age group. There are no specific recommendations for interventions based on lifetime risk score, but its use is encouraged to promote lifestyle modification. Within the 20-39 year-old population, the guidelines do provide a class IIa (moderate) strength recommendation for consideration of statin therapy for those with LDL-C greater than or equal to 160 mg/dL in the presence of additional risk-enhancing factors, such as a family history of early ASCVD [4, 11]. This recommendation, which is based on moderate-quality (Level B-R) evidence, aims to identify and treat patients whose elevated LDL-C and family history is more likely to represent genetic hypercholesterolemia and who would benefit the most from early statin therapy [4, 11].

Table 1:

Current Guideline Recommendations for Cholesterol Management of Adults and Young Adults

Age Group	ACC/AHA [4]	ESC/EAS [5]	NLA [12, 13]
20-39 years without FH or DM
Risk Assessment	Assess 30-year or lifetime risk using pooled cohort equations (not graded)	Assess lifetime risk or relative 10-year risk (not graded)	Assess lifetime risk (not graded)
Treatment Recommendations	Emphasize lifestyle modification (not graded) Consider medical therapy if family history of premature ASCVD and LDL-C ≥ 160mg/dL (not graded)	Lifestyle recommendations, stop smoking and SBP < 160mmHg (Class 1) Lipid-lowering therapy not considered unless FH or other specific disorders (not graded)	No age-specific treatment recommendation. Statin therapy first-line for all-comers who have an indication for treatment.
20-39 years with FH
Risk Assessment	No specific recommendation	High Risk: FH without other risk factors Very High Risk: FH with ASCVD or another major risk factors	No age-specific recommendation. Recommend against risk assessment in those with LDL-C ≥ 190mg/dL
Treatment Recommendations	Maximally tolerated statin therapy for those with LDL-C >190mg/dL (Class I) Ezetimibe (Class IIa) if less than 50% reduction in LDL-C despite statin (Class IIa) Bile acid sequestrant if less than 50% reduction on ezetimibe and statin (Class IIb) PCSK9i if >30yrs old, heterozygous FH and LDL-C > 100mg/dL on ezetimibe and statin (Class IIb)	Patients with FH at very-high risk consider ≥ 50% LDL-C reduction and use drug combination if goals not achieved (Class IIa)	No age-specific recommendation. Consider 50% reduction in cholesterol with any intervention.
20-39 years with DM
Risk Assessment	Consider risk enhancing factors: prolonged duration of disease (≥ 10 years of T1DM or ≥ 20 years of T2DM), albuminuria, eGFR < 60mL/min/1.73m2, retinopathy, neuropathy, ABI < 0.9 (Class IIb)	Moderate Risk: Patients with T1DM < 35 yrs old and T2DM < 50 yrs old if DM for < 10 yrs without other risk factors High Risk: DM without target organ damage, or DM ≥ 10 years, or another risk factor Very high risk: DM with target organ damage, 3 major risk factors, or early onset T1DM of long duration	High risk: DM and 0-1 other major ASCVD risk factor Very High Risk: ≥ 2 other major ASCVD risk factors or evidence of end organ damage
Treatment Recommendations	May be reasonable to initiate statin therapy if any of the above conditions met (Class IIb)	High Risk: LDL-C reduction ≥ 50% and goal < 55mg/dL (Class I) Very High Risk: LDL-C reduction ≥ 50% and goal < 70mg/dL. Statin therapy may be considered in patients ≤ 30 yrs old with T1DM and T2DM if end organ damage or LDL-C > 2.5mmol/L (as long as pregnancy not planned) (Class IIb)	No age-specific treatment recommendation. High risk: moderate or high intensity statin (Class A) Very High Risk: moderate or high intensity statin, with LDL-C goal < 70mg/dL

T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; ABI, ankle brachial index; eGFR, estimate glomerular filtration rate; FH, familial hypercholesterolemia; DM, diabetes mellitus

Similarly, the most recent European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guidelines on management of dyslipidemias advocate for individualized risk-based consideration of statin therapy for patients aged 40-69 using the revised Systematic COronary Risk Evaluation (SCORE2) prediction algorithm for estimation of 10-year ASCVD risk. Although the SCORE cardiovascular risk chart does not offer a 10-year risk prediction for those under 40 years, the ESC/EAS guidelines include a separate figure to illustrate relative cardiovascular risk for younger individuals. This chart emphasizes substantial changes in relative risk with increasing cholesterol and blood pressure levels, targeted to a younger population in whom absolute risk might be low, but relative risk potentially high. The ESC/EAS guidelines recommend diet and lifestyle interventions for younger patients at elevated cardiovascular risk, but do not offer specific guidance for medication use in those under 40 years of age without FH or diabetes [5].

The National Lipid Association (NLA) Dyslipidemia Recommendations also provide little guidance for management of elevated LDL-C in young adults with LDL-C less than 190 mg/dL [12, 13]. The NLA recommendations for statin therapy are similarly based on ASCVD risk estimation. Statin therapy is always recommended for those with LDL-C greater than 190 mg/dL regardless of age, but for young adults with LDL-C less than 190 mg/dL and no major ASCVD risk factors, such as diabetes, smoking, hypertension, or family history of early ASCVD, statin therapy is not recommended [12, 13].

The lack of detailed recommendations for younger adults with moderately elevated LDL-C has contributed to low statin use among this population despite some being at increased ASCVD risk. A recent prospective study of patients presenting with acute myocardial infarction (MI) found that fewer than half of all patients younger than age 55 presenting with MI would have been eligible for statin therapy prior to presentation per ACC/AHA guidelines [••14]. This recommendation was reflected in the pattern of statin use in the same group of patients, who despite having higher average LDL-C than those older than 55 years, were significantly less likely to be prescribed a statin. Additionally, this group of younger patients with a median 10-year ASCVD risk of 6.4% made up 41% of all clinical events in the study compared to 35% events occurring in those aged 55-65 with median 10-year risk of 11.6%, and 24% of events in those aged 66-75 years with median 10-year risk of 19.6% [••14].

Individual Benefits of Early Statin Therapy

Potential benefits of early, aggressive LDL-C lowering include decreased progression of atherosclerosis, decreased lifetime exposure to LDL-C, and potential plaque regression.

Apo B lipoproteins lead to atherosclerosis and clinical events

Atherosclerosis begins early in life, and its course is determined by cumulative Apo B lipoprotein exposure and the presence and degree of risk-enhancing factors [15, 16]. While traditional risk factors, such as hypertension, diabetes, obesity, metabolic syndrome, and smoking influence the rate of atherosclerosis progression by predisposing the arterial intima to abnormal penetration and retention of Apo B lipoproteins, overwhelming evidence from clinical intervention, observational, and genetic studies has conclusively demonstrated the primary causal role of Apo B lipoproteins and associated LDL-C in the development and progression of atherosclerosis [15]. Additional studies have demonstrated the rate of atherosclerosis progression is directly proportional to cumulative exposure of the arterial intima to Apo B lipoproteins [2, 15-•18].

Atherosclerosis can begin in childhood

Atherosclerosis leads to the clinical manifestations of ASCVD, such as coronary artery disease, cerebrovascular disease, and peripheral vascular disease, which become common in middle and older age and represent the end-stage manifestations of lifelong atherosclerotic disease. While clinical events are uncommon prior to middle-age, autopsy studies have documented the presence of early atherosclerotic lesions in children and more advanced disease in young adults with the severity of disease correlating with both ante-mortem and post-mortem LDL-C and total cholesterol concentrations [19, 20]. Additionally, studies have demonstrated serum concentrations of LDL-C measured in childhood and young-adulthood consistently predict future risk of ASCVD [17, •18, •21] or surrogate measures of preclinical atherosclerosis [•21-24], and more recent studies provide evidence that elevated levels of LDL-C in childhood and young-adulthood disproportionately enhance future ASCVD risk compared to adult levels of LDL-C [25, 26]. The impact of childhood exposure to elevated LDL-C in accelerating ASCVD is exemplified by patients with FH who experience lifelong exposure to profoundly high concentrations of LDL-C and suffer clinical events in young-adulthood if left untreated. Alternatively, patients with genetic alterations causing lifelong low serum LDL-C are nearly completely protected from clinical ASCVD [27], a finding repeated by mendelian randomization studies [28].

Apo B (and LDL-C) lowering with statin therapy improves CV outcomes and reduces plaque progression

Given the overwhelming evidence that cumulative exposure of Apo B lipoproteins determines the course of atherosclerosis progression, early initiation of LDL-C lowering therapy has the potential to dramatically reduce the burden of atherosclerotic disease. Despite recent expansion in the pharmacologic armamentarium of LDL-C lowering therapies, statins remain the first-line therapy due to their demonstrated effectiveness at reducing LDL-C and ASCVD risk, low cost, and acceptable side-effect profile [29]. Statins reduce LDL-C concentration via inhibition of the rate-limiting step of cholesterol synthesis leading to upregulation of LDL-receptor and increased hepatic clearance of Apo B lipoproteins [30].

In adult primary and secondary prevention populations, ASCVD risk reduction attributable to statin therapy correlates with the degree of LDL-C reduction and the length of treatment, reflecting the cumulative reduction in Apo B exposure resulting from their use [2, 15, 31]. Similar results were noted in children with FH for whom statin therapy significantly reduced progression of preclinical atherosclerotic disease and clinical events [32-34]. While the utility of statins in reducing risk of ASCVD events is well-established, studies using coronary intravascular ultrasound to assess plaque burden have demonstrated cessation of non-calcified plaque progression and in some cases, plaque regression with statin use [35, 36]. Evidence of more dramatic plaque regression has been demonstrated in patients achieving remarkably low LDL-C concentrations when treated with a combination of statin and PCSK9 inhibitor [37, 38]. While multiple studies have demonstrated regression of non-calcified plaques with reduction in LDL-C, calcified plaques, representing more advanced lesions, appear less amenable to regression once established [35, 39]. This suggests the optimal timing to initiate therapy in young patients with elevated LDL-C is prior to the development of calcified plaques in order to prevent their development and associated persistent ASCVD risk.

Population Benefits of Early Statin Therapy

With rising worldwide rates of childhood obesity and metabolic syndrome expected to lead to increased prevalence of ASCVD, earlier initiation of statin therapy has the potential to reduce the population burden of ASCVD and improve outcomes for those at highest risk [40]. Wider distribution and earlier initiation of statin treatment may also decrease disparities in longer-term ASCVD outcomes in populations with higher ASCVD risk. India, for example, carries a high rate of premature coronary artery disease compared to the global population – with median age for first presentation of acute myocardial infarction of 53 years, compared with 63 years for that of Western Europe and Asia [41]. Dyslipidemia (specifically high ratio of apolipoprotein B to apolipoprotein A1) has been identified as one of the primary drivers of this increased cardiovascular risk among younger South Asian individuals [41]. High cholesterol is common among young adults in India, with rates as high as 39% in urban males, and 23% in urban females. Earlier, targeted intervention has potential to decrease the disproportionate burden of ASCVD among these high-risk groups [42].

The management of ASCVD utilizes tremendous financial resources, and its financial impact is only expected to rise. The U.S. healthcare system for example, spent $126 billion on healthcare related to ASCVD in 2015, and costs are expected to more than double to $309 billion by 2035 [43]. Given their ubiquity and low cost, early initiation of statin therapy to prevent costly complications of ASCVD is a potential strategy to address the rising financial impact of ASCVD. Data on the financial effects of statin therapy in adults younger than age 40 is limited, but a recent analysis of the hypothetical financial impact of statin therapy in young adults found earlier statin initiation would be cost effective in preventing or delaying ASCVD events [•44]. Using a computer simulation model populated with NHANES data, this study evaluated the financial impact of statin therapy when applied to simulated populations of young adults aged 18-39 years irrespective of estimated ASCVD risk and found that statin treatment for patients with LDL-C >130 mg/dL was highly cost-effective in young men and intermediately cost effective in young women [•44]. Considering an estimated 26.3 million young adults in the U.S. who do not have a diagnosis of ASCVD have an LDL-C ≥ 130mg/dL, this analysis suggests that earlier initiation of statin therapy in this group may have the potential to significantly blunt the predicted rise in cost associated with clinical ASCVD.

Potential Risks of Early Statin Therapy

Since approval of the first statin, lovastatin, in 1987, statins have proven to be safe and well-tolerated overall [45]. Although no long-term safety data exist for their use in children and young adults, the evidence accumulated from their use in adults over the last 35 years does not suggest harm with long-term use [29, 34, 46-48]. Similarly, 10-year follow up data on the safety of statins initiated in children with FH at an average age of 13 also found no evidence of adverse effects [33]. Additionally, there appears to be no lower limit to safe reduction of LDL-C concentration as demonstrated by patients with genetic variations leading to hypo-functioning proprotein convertase subtilisin/kexin 9 (PCSK9) who have persistently low LDL-C for the duration of their life without identifiable negative effects [27].

Statin-associated muscle symptoms (SAMS) occur in 7-29% of individuals prescribed statin therapy and are a common cause of statin non-adherence or discontinuation [49]. Despite the prevalence of SAMS, randomized control trials have found no significant difference in the rates of muscle symptoms among those receiving statin or placebo [46]. SAMS are suspected to be related largely to the nocebo effect, in which the act of taking the medication, rather than the statin itself, causes harm [50]. SAMS are generally more common among older individuals, as advanced age (greater than 80 years) has been identified as a risk factor for statin intolerance, and there is little evidence to suggest that SAMS would be a barrier to statin use in a younger population [51].

In the young adult population, the potential for pregnancy is also an important consideration prior to statin initiation. Statins have classically been withheld from patients who are pregnant or attempting to become pregnant due to their “Pregnancy Category X” designation attributed to a theoretical risk for teratogenesis [52]. This designation was removed by the United States Food and Drug Administration in 2021 after review of relevant data failed to show evidence of statin-related birth defect. The revised FDA guidance now recommends continuation of statins in patients who may become pregnant, but stopping therapy during pregnancy and breastfeeding in all but those at highest risk of ASCVD [52, 53].

Alternative paradigms for LDL-C Reduction

The current paradigm of statin initiation based on estimated 10-year ASCVD risk starting at age 40 misses an important opportunity for early intervention – when the potential for risk reduction is greatest. To eradicate atherosclerosis, the goal of statin therapy should be to reduce LDL-C to a level sufficient to halt the progression of atherosclerosis before the onset of clinical or subclinical disease. To this end, more research is desperately needed to determine the most appropriate age and LDL-C concentration at which statin initiation should be considered. Based on current evidence, it is very likely we should be treating patients at significantly younger ages and lower LDL-C concentrations, though the exact numbers remain unknown.

Alternative paradigms for management of elevated LDL-C must be considered to facilitate earlier identification and treatment of patients at risk for future ASCVD, even if their current absolute risk is low (Figure). One such paradigm others have proposed emphasizes early intensive lowering of LDL-C/Apo B for a duration sufficient to induce plaque regression and stabilization in order to restore the normal vascular biology of the arterial intima, thus reversing the underlying pathophysiologic process of atherosclerosis. Proponents of this strategy have suggested an initial three-year period of high-intensity LDL-C/Apo B lowering therapy targeting a serum LDL-C of 20-40 mg/dL, which could be followed by additional periodic retreatments approximately every decade to maintain low plaque burden [54-56]. This approach has the potential benefit of reducing the burden of daily medication adherence and minimizing potential safety concerns of continuous lifelong LDL-C lowering therapy [54]. Additional research is needed to determine the optimal treatment duration required to induce sufficient plaque regression as well as the optimal interval between periods of treatment [54].

Figure 1:

Alternative Paradigms for Lipid Management in Young Adults.

Interest has also grown in the application of gene editing to permanently alter cholesterol regulatory genes, negating the need for future pharmacologic therapy. Gene-editing tools based on CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats-CRISPR associated protein 9) and CRISPR base editors have the ability to permanently alter the genome of target tissues and have become an area of intense interest due to their potential for treating monogenic diseases [57]. A preclinical study in primates using CRISPR base editors targeting the PCSK9 gene resulted in a 90% reduction in serum PCSK9 and 60% reduction in serum LDL-C after a single infusion and was durable for at least 8 months [58]. This research resulted in the development of the CRISPR base editor construct VERVE-101 targeting the human PCSK9 gene, which was recently approved for a first-in-human Phase 1 clinical trial and has the potential to produce similar results as were seen in nonhuman primates [59].

A more traditional, and perhaps more immediately feasible, approach is to employ additional risk stratification tools to better identify young patients most likely to benefit from early statin treatment. Although risk estimation can be challenging in younger adults for whom absolute risk may appear low, there are several lab- and imaging-based tools that may be useful. First is the use of 30-year ASCVD risk models to guide statin initiation. Retrospective application of these models demonstrated significant improvement in prediction of clinical events leading to earlier statin utilization and reduced ASCVD risk in younger patients [60, 61]. Estimation of lifetime ASCVD risk is an additional method of risk stratification whose current use is limited to guiding therapeutic lifestyle interventions in those whose 10-year risk is low, but is not recommended to guide initiation of statin therapy [4]. One limitation of these models is their development using data from the primarily White Framingham and Framingham Offspring cohorts, limiting their validity across diverse populations [61].

Quantification of coronary artery calcium (CAC) via computed tomography is useful in identifying patients at elevated cardiovascular risk by providing direct evidence of atherosclerotic heart disease through visualization of calcified plaques. CAC burden is strongly predictive of future ASCVD events independent of other risk factors [•21]. In 40-75 year-old patients, CAC testing is recommended by the most recent ACC/AHA primary prevention guidelines for patients at intermediate 10-year risk (7.5%-20%) to provide additional risk stratification and guide pharmacotherapy and lifestyle interventions [11]. In this middle-aged and older population, the absence of CAC can be reassuring, and is sometimes referred to as the “power of zero” [62]. However, in younger patients who have had less time to develop advanced calcified plaques, the absence of CAC should be interpreted with caution [•21, 22, 63]. CAC imaging techniques are limited to the identification of calcified plaques and unable to identify early atherosclerotic lesions that are not yet calcified [•21, 54]. This could result in potential underestimation of risk, which is of particular concern in younger patients who are less likely to have advanced calcific lesions. Indeed, in one recent study evaluating the ability of CAC to predict obstructive coronary artery disease (CAD) defined as luminal stenosis > 50% in adults over age 18, the predictive value of CAC varied by age, being least predictive in patients younger than age 40 and most predictive in those over age 70 [••64]. This study actually found obstructive CAD to be more prevalent in those with CAC = 0 in patients younger than age 40 with 58% of those with obstructive CAD having CAC = 0 [••64]. Therefore, while the presence of CAC in younger patients is highly predictive of future ASCVD, a CAC score of zero must be interpreted with caution in this population.

However, if CAC is present in younger individuals, its ability to predict future ASCVD events is stronger than in older patients [••64, 65]. Even very low CAC scores (<10) in young adults are associated with significantly increased risk of future cardiovascular events and mortality [•21, 22, 66], and risk rises with increasing CAC. One study of patients with an average age of 40 years who were followed for 12.5 years demonstrated a 2.6 times greater risk for clinical ASCVD events in patients with CAC 1-19 compared to CAC = 0, a 5.8 times increased risk for those with CAC 20-99, and those with CAC >100 were at 9.8 times greater risk [22]. Another study found that 34.4% of a group of patients aged 30-50 years had CAC > 0, and patients with CAC > 100 were at 10 times greater risk of cardiovascular mortality than those with CAC = 0 [65].

Lipoprotein(a) [Lp(a)] is a low-density lipoprotein whose Apo B component has been linked via disulfide bridge to apolipoprotein(a) [67]. Evidence from observational, mendelian randomization, and genome-wide association studies has shown that elevated Lp(a) is associated with increased risk for ASCVD independent of LDL-C, though the precise mechanism by which Lp(a) imparts increased risk is unknown [67, 68]. Lp(a) levels are 80-90% genetically determined and remain stable over the lifetime, and measurement of Lp(a) can help to identify underlying genetic risk [67, 68]. While Lp(a) levels do not typically respond to statin therapy, statin treatment in those with elevated Lp(a) is associated with decreased ASCVD risk, which is thought to be due to optimization of risk associated with LDL-C reduction rather risk mediated by Lp(a) itself [68]. Although no targeted therapies are available yet for the treatment of elevated Lp(a), several are currently in development [69]. Lp(a) testing is recommended by the ESC/EAS guidelines in those with established ASCVD to inform risk stratification and treatment intensity [5, 68]. ACC/AHA guidelines currently provide no recommendation for routine Lp(a) measurement, though Lp(a) elevation above 50 mg/dL or 125 nmol/L is considered a risk-enhancing factor for ASCVD [4, 68]. Measurement of Lp(a) in young adults gives insight into underlying genetic risk and early identification of its elevation, and early identification of its elevation should prompt a more aggressive approach to LDL-C reduction.

Finally, polygenic risk scores have the potential to identify patients at elevated risk for dyslipidemia and have the unique advantage of being predictive at an early age when the potential benefits of treatment are greatest. There have been significant advancements over the last several years in the development and validation of polygenic risk scores for prediction of ASCVD, but the evidence for their clinical utility remains limited [70, 71]. Polygenic risk scores have demonstrated modest improvement in predictive capacity in the adult population compared to standard risk assessment and were predictive of statin response in certain subgroups [70, 72]. Although polygenic risk scores have been shown to improve identification of children at elevated risk for dyslipidemia in adulthood, further research is needed to clarify their role in risk stratification [72].

Conclusion:

Despite tremendous recent advances in our ability to modify risk of ASCVD, the optimal way to manage adults 20-40 years old with elevated LDL-C but without FH is still unclear. Given the rising prevalence of cardiovascular disease, earlier and more aggressive cholesterol management may be beneficial, not only to halt the progression of atherosclerosis, but also decrease downstream cardiovascular events. Further research is urgently needed to clarify in which younger adults we should aggressively lower LDL-C, at what ages, at what levels of LDL-C, and with what therapies.