A quick look into the medicine cabinet of anyone sixty or older will likely reveal a statin. Primary prevention with high-intensity statins has substantially reduced the risk of atherosclerotic cardiovascular (ASCVD) events and all-cause mortality by improving cholesterol metabolism, providing a risk reduction that accumulates over a lifetime of statin use. Starting a statin at a younger age confers greater ASCVD benefit than starting a statin at an older age, as there is less cumulative atherosclerotic plaque formation.1 It stands to reason that young people, aged 20-39, may benefit from the early adoption of statins.
Currently, clinicians use the atherosclerotic cardiovascular disease (ASCVD) risk calculator, which calculates 10-year risk of major cardiovascular endpoints to guide statin therapy per 2018 American College of Cardiology/American Heart Association (ACC/AHA) recommendations. Statins are indicated for those who: (1) have a history of ASCVD events, (2) have severe hypercholesterolemia (LDL-C >190 mg/dL), (3) are aged 40-75 with diabetes and LDL-C >70 mg/dL, or (4) are age 40-75 and have 10-year risk of >20% or 5-19.9% with risk-enhancing factors.2 Young people, with few exceptions, are excluded from these recommendations due to the their low 10-year risk, even in the presence of risk factors. On its face, this is perfectly reasonable: younger people rarely have ASCVD events within 10 years and therefore statin initiation is unnecessary. Expand the scope to 30-year or lifetime risk, however, and things become more complicated.
First, we turn to the YOUNG-MI, a two-center registry of all myocardial infarctions (MI) from 2000-2016 in individuals aged 20-50 (n= 2097). Yang and colleagues wrote in 2020 that among the 431 MI patients under age 40, the most common risk factors for first-time MI were hyperlipidemia (90.7%), smoking (52.2%), hypertension (37.9%), and obesity (36.9%). Average LDL-C values in this group were 119.9 mg/dL and 92.9% had single or multivessel coronary artery disease (CAD).3 Risk factors for first-time MI in this population are similar to risk factors that underlie MI in older individuals, although most do not qualify for statin use per 2018 ACC/AHA recommendations. Note that these data are limited to an established ASCVD endpoint and do not consider those with similar risk profiles who may have ASCVD endpoints over the next 10 or 30 years.
Zeitouni and colleagues (2020) took it further. Their evaluation of a single-center Duke registry of young, first-MI patients using the 2018 Multisociety Cholesterol Guideline found that 46% and 56.7% of adults younger than 55 years (n= 2733) would have qualified for statin use per Class I and IIa 2018 and 2013 ACC/AHA recommendations, respectively.4 Among this population, only 2.7% were on a statin prior to their MI. The YOUNG-MI registry yields similar results: 51% were eligible for statin use per 2013 ACC/AHA recommendations and, including all under age 50, 12.5% were on a statin prior to MI.5,6 Eligible Duke registry patients (aged 40-55) had a median 10-year ASCVD risk of 6.4%, but a median lifetime risk of 33.9%. Note that 10-year ASCVD risk represents an underestimation of total population risk, as those under 40 (n= 415) were excluded.
Although these studies represented limited samples of a rare outcome, they provide important insights that may be generalizable to young people as a whole:
- Risk factors among young people are similar to those of older individuals. Some differences include an increased role of smoking, obesity, and family history of CAD among young people, while older people had an enhanced role of stage 3-5 chronic kidney disease, and personal history of CAD.4 Recognizing which risk factors and the relative contribution of risk factors to ASCVD endpoints can allow for early identification of at-risk patients and early intervention with statin treatment.
- Current recommendations miss a significant percentage of young people with known MI. Setting aside those with increased risk who do not have endpoints, current recommendations missed nearly half of those who already have had endpoints. Currently, 2018 ACC/AHA recommendations indicate statin use in those between 20-39 in the highest risk groups: longstanding diabetes with or without microvascular complications, albuminuria, eGFR <60 (Class IIb), and those with moderately high LDL-C (>160 mg/dL) or high LDL-C levels >190 mg/dL (Class I). More consistent screening can improve catchment of young people at risk. Additional discussions about expanding the scope of statin use might confer additional mortality benefits as this population ages, as there is a marked divergence between 10-year risk (6.4%) and lifetime risk (33.9%), per Duke registry findings. Limiting statin use to just those with 10-year risk ignores those who may benefit on the basis of lifetime risk.
- Young people with known ASCVD risk are undertreated. Per YOUNG-MI and Duke registry data, there is a notable gap even among those who qualify for statins (51% and 56.7% respectively) and those who were on a statin prior to MI (12.5% and 2.7%). Part of this stems from hesitancy to initiate medications, which is reflected in guidelines. The 2018 iteration of the ACC/AHA recommendations encourage physicians to prefer lifetime risk over 10-year risk and to use coronary artery calcium (CAC) scores to help guide therapy in young people, but prefers conservative treatment with lifestyle interventions to statins. A more aggressive approach for statin initiation, in addition to lifestyle interventions, may further reduce lifetime risk.
Our discussion thus far has been focused on young people with MIs with an extrapolation to long-term benefit of primary prevention. Estimating benefit of statin use for longer-term outcomes is challenging, due to the dearth of long-term outcomes data in younger populations. However, modeling studies bridge this gap and suggest a 30-year ASCVD risk benefit with early adoption of statins. An analysis of the NHANES database (2009-2016) modeled the estimated 30-year risk reduction from statin use in 3148 participants aged 30-59 years who did not qualify for statin use under 2018 ACC/AHA guidelines. Pencina and colleagues (2020), using two modeling methods, predicted a 51-71% reduction in premature ASCVD outcomes among patients between the ages of 30 and 39 when using a high-intensity statin for 30 years, corresponding to 1.4 million ASCVD events prevented in the US.7 This effect is even more impressive when considering that the study 1) considers only first ASCVD events and 2) limits statin use to only 30 years, despite evidence that shows an aggregating benefit of statin use with time.1 Modeling studies like these demonstrate a benefit to using statins early, for prolonged periods of time, and at high intensity. It also demonstrates that 30-year risk may be a more appropriate approach to ASCVD. While still theoretical, trialing the use of statins in young people beyond just those at highest risk may confer significant public health benefit.
A discussion about the benefits of statin use is nearsighted without including a conversation about side effects and costs. Statins have a well-characterized and minimal side-effect profile, as well as availability as low-cost generic drugs. Side effects are most frequently transaminase elevations and myopathy, with rarer side effects including necrotizing autoimmune myositis, new-onset diabetes (the JUPITER trial showed 25% increase in newly diagnosed diabetes, but ASCVD benefit regardless), hemorrhagic stroke (the SPARCL trial shows mildly increased risk of hemorrhagic stroke, offset by significant decrease in risk of ischemic stroke), and drug-drug interactions.8,9,10 Patient-specific tailoring of statin type can avoid many of these side effects.
Cost-effectiveness studies investigating the use of statins for primary prevention in those with modest ASCVD risk show a remarkable cost-saving effect in addition to a health/mortality benefit, an effect that is resistant to even the most adverse side-effect assumptions when using a 30-year treatment course model.11 Other limitations may include medication adherence, socioeconomic barriers, and patient education.
Statin use prevents or delays cardiovascular events in a group with the greatest risk of productive life years lost. While specific cutoffs and situational use of statins in young people must be established, loosening the criteria, recognizing the above identified risk modifiers, and encouraging early, liberal, and longitudinal use of statins can mitigate risk significantly. Blankstein and Singh offer insight on how to guide treatment. Focusing on risk factors, using modified risk scores, and employing lifetime/30-year risk instead of 10-year risk can guide statin initiation among young people. Adjusting recommendations for young people is within reach, easily achievable, and carries tremendous potential; it’s just a matter of doing it.
Akshay N. Pulavarty MPH, is a 1st year student at NYU Grossman School of Medicine
Peer reviewed by Michael Tanner, MD, associate editor, Clinical Correlations
Image courtesy of Wikimedia Commons, source: https://commons.wikimedia.org/wiki/User:Whispyhistory
- Leening MJG. Who benefits from taking a statin, and when? Circulation. 2020;142(9):838-840. doi:10.1161/circulationaha.120.048340 https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.120.048340
- Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APHA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. Circulation. 2019;139(25):e1082-e1143. doi:10.1161/CIR.0000000000000625 https://www.ahajournals.org/doi/10.1161/cir.0000000000000625
- Yang J, Biery DW, Singh A, et al. Risk factors and outcomes of very young adults who experience myocardial infarction: The Partners YOUNG-MI registry. Am J Med. 2020;133(5):605-612.e1. doi:10.1016/j.amjmed.2019.10.020 https://pubmed.ncbi.nlm.nih.gov/31715169/
- Zeitouni M, Nanna MG, Sun J-L, Chiswell K, Peterson ED, Navar AM. Performance of guideline recommendations for prevention of myocardial infarction in young adults. J Am Coll Cardiol. 2020;76(6):653-664. doi:10.1016/j.jacc.2020.06.030 https://pubmed.ncbi.nlm.nih.gov/32762899/
- Blankstein R, Singh A. Cholesterol guidelines. J Am Coll Cardiol. 2020;76(6):665-668. doi:10.1016/j.jacc.2020.06.055
- Singh A, Collins BL, Gupta A, et al. Cardiovascular risk and statin eligibility of young adults after an MI: Partners YOUNG-MI registry. J Am Coll Cardiol. 2018;71(3):292-302. doi:10.1016/j.jacc.2017.11.007
- Pencina MJ, Pencina KM, Lloyd-Jones D, Catapano AL, Thanassoulis G, Sniderman AD. The expected 30-year benefits of early versus delayed primary prevention of cardiovascular disease by lipid lowering. Circulation. 2020;142(9):827-837. doi:10.1161/CIRCULATIONAHA.120.045851
- Assessing severity of statin side effects: fact versus fiction. American College of Cardiology. https://www.acc.org/latest-in-cardiology/articles/2018/04/09/13/25/http%3a%2f%2fwww.acc.org%2flatest-in-cardiology%2farticles%2f2018%2f04%2f09%2f13%2f25%2fassessing-severity-of-statin-side-effects. Accessed February 22, 2022.
- Ridker PM, Danielson E, Fonseca FAH, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359(21):2195-2207. doi:10.1056/NEJMoa0807646
- High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006;355(6):549-559. doi:10.1056/NEJMoa061894
- Lazar LD, Pletcher MJ, Coxson PG, Bibbins-Domingo K, Goldman L. Cost-effectiveness of statin therapy for primary prevention in a low-cost statin era. Circulation. 2011;124(2):146-153. doi:10.1161/CIRCULATIONAHA.110.986349