Statins in Young Adults: Is Early Treatment Ready for Prime Time?

Table of Contents

• Key Points
• Background: Why This Debate Matters
• The Case for Starting Statins Early
• Uncertain Benefits: What We Still Don't Know
• Uncertain Harms: Potential Risks of Lifelong Statin Use
• Uncertain Costs: Is This Affordable Medicine?
• The Bottom Line: What Should Patients Know?
• Study Limitations
• Frequently Asked Questions
• Source Information

Key Points

• Current guidelines recommend statins for young adults only if LDL stays very high after lifestyle changes.
• Early statin use might prevent plaque buildup, but no long-term trials prove it prevents heart attacks decades later.
• Rare serious statin risks include rhabdomyolysis, myopathy, neuropathy, and a small increased diabetes risk.
• If diabetes risk accumulates over 50 years, excess risk could approach 5%, meaning one extra case per 21 treated.
• Experts recommend incremental guideline expansion to high-risk 30-year-olds, not broad use in low-risk young adults.

Background: Why This Debate Matters

Heart disease remains the nation's leading killer, and cholesterol — specifically low-density lipoprotein (LDL), the "bad" cholesterol — is a major culprit. But when should treatment begin?

Currently, young adults under 35 years of age who do not have an exceedingly rare genetic disorder such as familial hypercholesterolemia are at very low short-term risk for coronary heart disease (CHD). The 5- to 10-year risk of having a heart attack or dying from heart disease in this age group is minimal.

Because of this low short-term risk, current guidelines from the National Cholesterol Education Program's Adult Treatment Panel are conservative. They recommend drug therapy with statins for young adults only if cholesterol levels remain very high after a trial of lifestyle modification — meaning diet, exercise, and weight management are tried first.

But this issue of the Journal of the American College of Cardiology features two companion articles by Steinberg and Forrester that press for earlier and more aggressive treatment with statins, particularly for young adults with high lifetime risk. Their reasoning rests on three pillars:

1. Atherosclerotic (plaque) damage to coronary arteries from nonoptimal lipid levels starts accumulating early in life — even in childhood and young adulthood.
2. This damage could be prevented or slowed with statin therapy.
3. Preventing the accumulation of atherosclerotic damage should lead to much lower rates of cardiovascular disease later in life.

This "cumulative damage hypothesis" is compelling. But the authors of this commentary, Drs. Mark Pletcher and Stephen Hulley from the University of California, San Francisco, warn that expanding statin therapy to include millions of healthy young adults is a "high-stakes proposition" that requires careful examination of the potential benefits, harms, and costs.

The Case for Starting Statins Early

Several lines of evidence support the idea that earlier cholesterol control could provide dramatic protection against future heart disease.

The "20% to 40%" problem. When statins are started in middle-aged and older adults, they reduce the risk of heart attack and other CHD events by only 20% to 40% compared with placebo in randomized, blinded trials. That's meaningful, but far from complete protection. Why isn't it better? By the time most people start statins in their 50s or 60s, decades of atherosclerotic damage have already accumulated.

The genetic "experiment of nature." In striking contrast, people with genetic variations in the pro-protein convertase subtilisin/kexin type 9 (PCSK9) gene — a gene that controls expression of the LDL particle receptor — have naturally low LDL cholesterol levels throughout their entire lives. These individuals experience an 88% relative risk reduction in coronary heart disease. That's nearly total protection, achieved simply through lifelong low LDL exposure. This suggests that reducing lifelong cumulative exposure to LDL via statins started early in life might provide far more complete protection than the partial benefit seen when treatment begins later.

The CARDIA study. The authors' own research from the CARDIA (Coronary Artery Risk Development in Young Adults) cohort shows a very low prevalence of coronary calcium — a marker of atherosclerosis — in middle-aged people who have maintained low LDL cholesterol levels since they were in their twenties. This finding directly supports the notion that keeping LDL low from a young age prevents plaque buildup.

Statins can halt existing disease. Additional evidence shows that statins can arrest and even reverse atherosclerosis in middle-aged and older populations, and they clearly reduce atherosclerotic disease early in life in specific settings, such as children with familial hypercholesterolemia.

Uncertain Benefits: What We Still Don't Know

Despite the compelling logic, there is no hard evidence from long-term randomized trials demonstrating that starting statins in young adulthood actually prevents heart attacks decades later. And there are several reasons to be cautious.

Statin benefits may not equal genetic benefits

Statin-mediated LDL reduction may not be equivalent to genetically mediated LDL reduction. When statins are started in middle-aged and older populations, CHD event prevention begins quickly — within 1 to 2 years of starting therapy. This rapid effect suggests that part of statin efficacy comes from plaque stabilization, anti-inflammatory effects, and other short-term "pleiotropic" mechanisms that are not directly related to halting the long-term progression of atherosclerosis. To the extent that these short-term, non-atherosclerotic mechanisms drive statin benefits, early treatment may not provide the expected degree of benefit compared with waiting until later in life, when CHD events usually begin to occur.

Starting at 30 might be too late

The suggestion to start statins at age 30 may not be early enough. Atherosclerotic changes are evident very early in life — studies like the Bogalusa Heart Study have documented early plaque formation in children and young adults. After three decades of exposure to nonoptimal LDL levels, initiating statin therapy at age 30 might provide only modest incremental improvement in atherosclerosis reduction and long-term CHD event protection.

The adherence problem

Even if guidelines recommend statins for young adults, will people actually take them? Two major barriers stand in the way. Physicians often fail to follow prescribing guidelines, and patients frequently fail to take their medications as prescribed. These are substantial problems even among older adults at high risk, and the situation is worse at younger ages. The same problem has been documented with efforts to control hypertension (high blood pressure) in young adults.

The authors note that mounting efforts to improve adherence to existing guidelines for patients at moderate to high short-term risk is probably a more efficient, immediate, and noncontroversial public health strategy than expanding prescribing guidelines into younger age groups — although the two approaches are not mutually exclusive.

Uncertain Harms: Potential Risks of Lifelong Statin Use

Statins are relatively safe medications and only occasionally cause side effects. But "relatively safe" over a decade of use is different from "safe" over 5 or 6 decades of continuous use starting in early adulthood.

Known side effects and their rates

Here is what is currently known about statin side effects, based on large observational and post-marketing studies of middle-aged and older adults:

• Rhabdomyolysis (severe muscle breakdown that can cause kidney failure): The most serious side effect, although exceedingly rare. It occurs at a rate of 3 to 4 per 100,000 person-years of treatment, with 10% of cases being fatal.
• Clinically significant myopathy (muscle pain or weakness accompanied by elevated creatine kinase levels): Occurs at an excess rate of about 11 per 100,000 person-years in statin users.
• Minor muscle pain (myalgia): Commonly reported by statin users, but notably, this symptom appears to be just as common in people randomized to placebo as in those randomized to statins in controlled trials — meaning the "muscle aches" may partly reflect what people expect to feel, not what the drug actually does.
• Elevated liver enzymes: Persistently elevated serum levels of alanine aminotransferase (ALT, a marker of liver stress) occur at an excess rate of about 70 per 100,000 person-years. However, no firm evidence links statin use to liver damage, and rates of liver failure in statin users are indistinguishable from background rates in the general population.
• Peripheral neuropathy (nerve damage causing numbness or tingling in the hands and feet): Reported at a rate of 12 per 100,000 person-years.

Diabetes risk: a new concern

A surprising new finding is the significant increase in diabetes incidence associated with statin use. A meta-analysis of randomized trials found an excess rate of about 1 in 255 persons taking statins for 4 years developed new-onset diabetes. While this risk is small, the concern is what happens over a lifetime.

Here is the alarming math: if diabetes risk continues to accrue at the same rate (about 1 per 1,000 person-years of treatment), then the excess cumulative risk for diabetes after 50 years of treatment — for example, from age 30 to 80 — would approach 5%. That translates to a number needed to harm of about 21, meaning one extra case of diabetes for every 21 people treated for 5 decades.

Similarly, if the annual rate of statin-associated rhabdomyolysis does not decrease after the first few years but instead continues unabated or even increases with longer-term exposure, treatment over several decades could produce a much higher cumulative risk for this life-threatening condition than we currently see in routine practice.

What about cancer, depression, and suicide?

Early concerns about increased rates of cancer, suicide, or depression associated with low cholesterol levels or statin use have not been substantiated by large meta-analyses, longer-term follow-up (10 years) from several clinical trials, and other recent studies. This is reassuring news.

Special considerations for young adults

There is no known reason why statins should be more toxic in young adults than in older adults. But young adults are physiologically different. It would not be surprising if myopathy or minor muscle pain turned out to be more common in younger patients, or if young adults were susceptible to some yet-undiscovered adverse effect.

Women of childbearing age face a unique concern. Statins are not considered safe to take during pregnancy or breastfeeding. This complicates any effort to extend statin prescribing to young women who may become pregnant, and it requires careful counseling about contraception for women who start statins in their 20s or 30s.

The quality-of-life question

Taking a statin every day for many decades may also affect self-image by "labeling" a person as less than healthy. It could induce excessive worry about future heart disease, or otherwise dampen quality of life. This is likely to be especially important for young adults who might otherwise have no regular contact with the medical world.

When substantial levels of this "disutility" (a term researchers use for the negative value placed on being on daily medication) are present and persistent, they can outweigh the benefits of statin therapy — benefits that are remote in time and therefore subject to "discounting" (the psychological tendency to value current experiences more highly than distant future events). The good news is that disutility may wane over time as patients become accustomed to taking a pill daily, and education about the real benefits of statins can substantially reduce — or even reverse — this effect.

Uncertain Costs: Is This Affordable Medicine?

With the increased availability of low-cost generic formulations, the cost of statins has become less of a limiting factor — but questions remain.

One cost-effectiveness analysis found that treating all persons age 35 years and older with LDL levels of 130 mg/dl or higher would become cost-saving (meaning the savings from prevented heart attacks and related care would outweigh the cost of the medication) when the price of statins falls to $0.10 or less per pill.

Per-pill costs in this range are currently available through large discount retail chains. However, prices at traditional retail pharmacies are often substantially higher, even for generic formulations.

Several scenarios could make a major initiative to prescribe statins to low-risk young adults expensive and not cost-effective:

• If very low statin prices cannot be universally accessed by the public
• If average prices rise significantly
• If high-cost brand-name formulations are used instead of generics
• If the added cost of starting statins earlier in life is not sufficiently offset by enhanced reductions in heart attack rates

There is also a population-level math problem. Even if early statin therapy significantly reduces risk in high-risk young adults, the overall impact on national heart disease rates may be limited, because many heart attacks actually occur in the more numerous lower-risk people. To truly "unseat coronary disease as the nation's leading killer" — the goal envisioned by Forrester — would require a dramatic expansion of treatment guidelines and excellent adherence. Such an expansion would expose many more people to the uncertain benefits, harms, and costs of lifelong statin therapy.

The Bottom Line: What Should Patients Know?

The Adult Treatment Panel IV Committee — the body responsible for updating national cholesterol guidelines — must weigh these uncertainties against mounting evidence supporting earlier statin use. The report was due in early 2011, and the authors offer a thoughtful framework for the decision.

Option 1: Wait for more research. Waiting before expanding statin prescribing guidelines is a reasonable option. The ideal randomized trial — randomizing 20-year-olds to statins or placebo and following them for 50 years — is essentially impossible because of the decades-long follow-up required. But several other research approaches are feasible and useful:

• Further observational research on long-term effects (both harms and benefits) of statin therapy
• Confirmation of the genetically mediated lifelong cholesterol-exposure findings
• Randomized trials to explore short-term effects of statins in young adults
• Studies to improve adherence to guidelines among both physicians and patients
• Modeling studies to quantify uncertainty and simulate projected effects of different statin prescribing strategies

Option 2: Expand guidelines in a targeted way. If the committee decides to expand treatment guidelines, the authors endorse a careful, incremental approach. They suggest considering statins for younger persons starting at around age 30, but only for those with risk factors that convey high lifetime risk — as opposed to 10-year risk — for coronary heart disease.

Treating high-risk persons who have more to gain in the long run increases the likelihood that treatment will eventually result in net benefit for patients. This approach would have a relatively limited population-level impact at first, but it would avoid exposing millions of low-risk young adults to lifelong medication with uncertain benefits.

The authors emphasize that important research on long-term effects should proceed regardless of how guidelines are formulated. They conclude that a dramatic expansion in statin prescribing is "best approached incrementally by future guidelines."

Study Limitations

This article is a commentary — an expert opinion piece — not a clinical trial or a systematic review. Its conclusions reflect the authors' interpretation of existing evidence. The authors have no conflicts of interest to disclose.

Key limitations of the evidence base they describe include:

• No long-term randomized trials have tested statins started in young adulthood and followed through middle age.
• Long-term safety data beyond 10 years of continuous statin use are limited.
• Rates of rare adverse events come primarily from observational studies of middle-aged and older adults, and may not apply to younger populations.
• The diabetes risk estimate (1 in 255 over 4 years) comes from a meta-analysis of trials that were not designed to assess long-term diabetes risk, and extrapolating that risk over 50 years is speculative.
• Cost-effectiveness projections depend heavily on assumptions about medication pricing, adherence rates, and the degree to which early LDL reduction translates into long-term event prevention.

Frequently Asked Questions

Should healthy young adults start taking statins to prevent heart disease?

Current guidelines recommend statins for young adults only if cholesterol remains very high after trying diet, exercise, and weight management. Some experts argue for earlier use, but uncertainty remains about long-term benefits and risks. A careful, individualized discussion with a doctor is important before deciding.

What are the potential benefits of starting statins early in life?

Early statin use might prevent plaque buildup in arteries, potentially reducing future heart attacks. Evidence supporting this comes from genetic studies showing people with lifelong low LDL have an 88% lower heart disease risk. However, no long-term trials prove starting statins in your 20s or 30s prevents heart attacks decades later.

What are the risks of taking statins for decades starting in young adulthood?

Statins are relatively safe, but long-term use over 50 years is not well studied. Rare risks include rhabdomyolysis, myopathy, peripheral neuropathy, and elevated liver enzymes. Newer concern is a small increased risk of diabetes, which may accumulate over time. Unknown effects in younger people cannot be excluded.

How much does statin therapy increase the risk of developing diabetes?

A meta-analysis of randomized trials found one extra case of diabetes for every 255 people treated for 4 years. If this rate continues, the added risk over 50 years could approach 5%, meaning one extra case for every 21 people treated. This estimate is speculative because long-term data are limited.

Should I worry about muscle pain from statins?

Minor muscle pain is commonly reported with statins, but in controlled trials it occurs just as often with placebo, suggesting expectation may play a role. Serious muscle breakdown called rhabdomyolysis is very rare, at about 3 to 4 cases per 100,000 person-years of treatment.

What should a young adult do if they have high cholesterol?

Lifestyle changes such as diet, exercise, and weight management are the first step. Statins are recommended only if cholesterol remains very high after a trial of lifestyle modification. Before starting, discuss your personal heart disease risk, potential benefits, and possible risks with your healthcare provider.

Source Information

Original Article: "Statin Therapy in Young Adults: Ready for Prime Time?"

Authors: Mark J. Pletcher, MD, MPH, and Stephen B. Hulley, MD, MPH, from the Department of Epidemiology and Biostatistics and the Division of General Internal Medicine, Department of Medicine, University of California, San Francisco.

Journal: Journal of the American College of Cardiology, Vol. 56, No. 8, 2010, pages 637–640. Published by Elsevier Inc. on behalf of the American College of Cardiology Foundation.

DOI: 10.1016/j.jacc.2010.05.018

Note: This patient-friendly article is based on peer-reviewed research. It is intended for educational purposes and does not constitute medical advice. Patients should consult their healthcare provider about whether statin therapy is appropriate for their individual risk profile.