Statin Absolute vs Relative Risk

One of the arguments you hear online is that the absolute risk reduction in heart attacks or death is very small. They will say that statins only reduce the risk of death by 1.1%. They argue that this small reduction is not worth the possible side effects of the medication.

Even if we were to accept this at face value, think about scale. Hundreds of millions of people around the world qualify for a statin. A 1% absolute reduction applied to that many people means millions of lives. That's a lot of lives saved.

But the bigger problem is that the "1%" number itself is misleading. Let me show you why, with the charts redrawn so they're easy to read.

Medical note: This article is for general education and is not a substitute for advice from your own doctor. Never stop a statin on your own.

Key takeaways

• Absolute risk reduction is the difference in percentage points between two groups. Relative risk reduction is how much of the risk went away. Both are true. They just answer different questions.
• Absolute numbers from short trials look tiny because trials only last a few years. The benefit of lowering LDL grows every year you stay on treatment: 12% fewer events in year 1, 29% by year 7, for the same LDL drop.
• Heart disease risk comes from LDL multiplied by years of exposure. Lower, earlier and longer is better.
• In the 4S trial, simvastatin cut deaths from 12% to 8% in people with heart disease, about 1 death prevented for every 30 people treated for 5 years.

The chart the medfluencers love

Figure: heart attack deaths in the Lipid Research Clinics trial, drawn on a full scale (left) and zoomed in (right). Redrawn from Lipid Research Clinics Program. JAMA. 1984 (Results).

The medfluencers love this example. In the 1984 Lipid Research Clinics trial, 3,806 men with high cholesterol were given cholestyramine or a placebo for about 7 years.

• The left side is how they draw it. On a 0 to 100% scale, 98.0% vs 98.4% of men did not die of a heart attack. The bars look identical.
• The right side is the same data, zoomed in. 2.0% of the placebo group died of a heart attack, compared with 1.6% on cholestyramine. That is a 0.4% absolute reduction, and a 24% relative reduction in heart attack deaths.

They use this small absolute reduction to deny that there is any benefit, or to minimize the 24% relative reduction. This is flawed and dishonest thinking. When the graph is drawn on a 0 to 100% scale, you can't even see a real difference.

And look at the drug they picked. Cholestyramine lowered LDL only about 12.6% more than placebo. Even so, if you gave it to millions of people, you would still save thousands of lives.

The biggest problem is that they use this example to deny the benefit of statins, which lower LDL far more and have shown much larger reductions in heart attacks, strokes and deaths. In the 4S trial of 4,444 people with heart disease, 12% of the placebo group died over 5.4 years, compared with 8% on simvastatin: a 30% lower risk of death, or about 1 death prevented for every 30 people treated. But they still insist on using a weak, decades-old drug to make broad statements.

This gains them a large online following among the anti-cholesterol crowd, which supports their speaking careers, book sales and supplement sales. It's dishonest and harms the public, especially the younger people who will live with the consequences for decades.

Absolute Risk Is Artificially Lower

Another problem with using absolute risk reduction is that, in a short study, it is artificially low.

Let's imagine a trial where the intervention is to quit smoking at age 45. You take 10,000 smokers and tell half of them to quit. You follow them for 5 years, until they are 50. In that five-year span, maybe 3% of the smokers develop lung cancer and 2% of the quitters do. That's a 1% absolute reduction but a 33% relative reduction.

Is it plausible to conclude that quitting smoking only reduces your risk of lung cancer by 1%? Of course not. Five years is far too short, and it would be unethical to keep people smoking long enough to find out. But we don't have to guess. We have the real lifetime data.

Figure: cumulative risk of dying of lung cancer by age 75 in UK men, by the age they stopped smoking. Redrawn from Peto R, et al. BMJ. 2000 (Results).

• The pink bar is men who kept smoking: a 16% chance of dying of lung cancer by 75.
• The other bars are men who quit. Quitting at 60 cut that to 10%, at 50 to 6%, at 40 to 3%, and at 30 to 2%.
• The earlier you stop the exposure, the bigger the gap. Over a lifetime, quitting at 30 cut the risk by 14 percentage points, not 1.

The area under the curve, your lifetime exposure to cigarette smoke, is what drives the risk. Scientists call it the AUC. LDL cholesterol works exactly the same way.

Absolute vs Relative Risk In Lipid Lowering

The same applies to cholesterol lowering therapy. JUPITER, for example, was designed to test rosuvastatin (Crestor) for up to 5 years. The benefit was so large that the trial was stopped early, after a median of just 1.9 years. Once a treatment is clearly saving lives, it's no longer ethical to keep half the people on a placebo. That means trials end before the absolute benefit has had time to grow.

I highly recommend watching Dr. Gil Carvalho's video on YouTube explaining the difference between absolute risk reduction and relative risk reduction. He is an MD and PhD and a great educator. His channel contains many other evidence based topics around cardiometabolic health.

Video:
https://www.youtube.com/watch?v=vRRD8nXEyGM

Figure: percent with a cardiovascular event by age 55, by quarter of LDL exposure between ages 18 and 40. Redrawn from Domanski MJ, et al. J Am Coll Cardiol. 2020 (Central Illustration).

A study in the Journal of the American College of Cardiology showed this principle directly. Researchers followed 4,958 young adults from the CARDIA study, who were 18 to 30 when they enrolled, and added up their LDL exposure over the years.

• Each bar is a quarter of the group, from the lowest LDL exposure (left) to the highest (right).
• By age 55, 2.6% of the lowest-exposure group had a heart attack, stroke or other cardiovascular event, compared with 8.6% of the highest-exposure group, more than three times as many.
• Every extra 100 mg/dL-years of exposure raised risk about 5%. And the same exposure built up at a younger age raised risk even more.

The longer you are exposed to elevated levels of apoB, LDL particles, or their stand-ins like LDL cholesterol and non-HDL cholesterol, the more likely you are to have a cardiovascular event, and the sooner.

Absolute Risk Increase As Time On Therapy Increases

Figure: relative reduction in major cardiovascular events per 1 mmol/L (39 mg/dL) lower LDL, by year of treatment. Redrawn from Wang N, et al. Circ Cardiovasc Qual Outcomes. 2022 (Results).

A 2022 analysis of 21 randomized trials of statins, ezetimibe and PCSK9 inhibitors, with 184,012 patients, looked at the benefit year by year. Its conclusion:

"The benefits of LDL-C lowering do not seem to be fixed but increase steadily with longer durations of treatment. The results from short-term randomized trials are compatible with the very strong associations between LDL-C and cardiovascular events seen in Mendelian randomization studies."

• Each bar is one year of treatment. For each 1 mmol/L (38.6 mg/dL) lower LDL, major cardiovascular events fell 12% in year 1, 20% by year 3, 23% by year 5 and 29% by year 7.
• The whiskers are the margin of error. Year 7 has the widest one because fewer trials ran that long.

And the effects keep compounding. The area under the curve shrinks in your favor every year your LDL stays low.

The higher you start, the more you gain

Figure: estimated reduction in lifetime coronary heart disease risk from keeping LDL 50% lower for life. Redrawn from Ference BA, et al. J Am Coll Cardiol. 2018 (Table 1).

Another very well done article, by Dr. Brian Ference and colleagues, showed that the absolute benefit of lowering LDL is much greater than short trials suggest, and that it grows with time. These estimates are based on genetic studies, which show about a 54% lower risk for each 1 mmol/L of lifelong lower LDL.

• Each row starts at a different LDL and cuts it in half for life.
• Starting at 250 mg/dL and cutting it to 125 lowers lifetime risk of coronary heart disease by about 92%.
• Starting at 100 mg/dL and cutting it to 50 still lowers it by about 65%.

Those with the highest starting LDL benefit the most from a 50% reduction over their lifetime. But everyone benefits.

Same LDL, different risk

Figure: concept redrawn from Ference BA, et al. J Am Coll Cardiol. 2018 (Figure 4). Illustration; ages approximate.

This chart shows that people retain LDL particles in their artery walls differently, even at the same LDL level.

• The dashed line is the average person with an LDL of 125 mg/dL, building plaque at a steady rate.
• The pink line is someone who retains more LDL particles. Same LDL, but plaque builds much faster, and heart attack risk starts rising around age 25.
• The light blue line is someone who retains fewer. Their risk doesn't start rising until around 62.

Your genetics can make a huge difference in the age of your first heart attack, and you can't tell which line you are on. That's why keeping LDL low matters for everyone.

Cumulative LDL Cholesterol Exposure Increases Risk

Figure: lifetime LDL exposure (LDL multiplied by age) for three people. Concept and threshold from Ference BA, et al. J Am Coll Cardiol. 2018 (Figure 5); lines calculated.

Here is the math. Your cumulative LDL exposure is your LDL multiplied by the years you've lived with it. In Dr. Ference's model, the risk of a heart attack starts to rise once you cross about 5,000 mg-years.

• The grey line is an LDL of 120 for life. You cross 5,000 mg-years around age 42.
• The pink line is an LDL of 80 for life. You don't cross it until around 62.
• The dashed line starts at 120 and drops to 80 at age 50. The climb slows, which in the paper means about a 25% lower risk of a heart attack. But the exposure already built up from 0 to 50 doesn't go away. If they had started earlier in life, the benefit would have been much greater.

The LDL you were born with

Figure: typical LDL cholesterol across life. Concept redrawn from Ference BA, et al. J Am Coll Cardiol. 2018 (Figure 3); curve approximate.

Babies are born with an LDL around 60 mg/dL. By adulthood, most people are at 120 or higher. Everything above that baseline, the pink area, is acquired exposure that adds up year after year.

This is why I stress primordial prevention: keeping LDL low before plaque ever starts. Once your LDL is above about 60 mg/dL, on a long enough time horizon, your odds of developing plaque and heart disease keep rising.

Read the full article, it's free access:
https://www.jacc.org/doi/pdf/10.1016/j.jacc.2018.06.046

The fine print

• Relative and absolute risk are both real. Absolute risk reduction depends heavily on your starting risk and how long you're followed. That's exactly why a 2-to-5-year trial understates a lifetime of benefit.
• The lifetime estimates are modeled. Dr. Ference's numbers come from genetic studies (Mendelian randomization), not from a trial that followed people for 50 years. The 2022 trial analysis shows the trial data are moving in the same direction.
• The smoking data are from UK men at 1990 rates. The lesson about exposure over time is the point, not the exact numbers.

What I tell my patients

1. Don't judge a treatment by a 5-year absolute number. Ask what it does over 20 or 30 years.
2. Know your LDL or apoB, and get a one-time Lp(a).
3. Reduce saturated fat, increase fiber, and take your medications if you need them. These move the needle most.
4. Then: do cardio, lift weights, reduce stress and improve sleep. And don't smoke.
5. If your LDL is high, treat it early, even in your 20s and 30s. Lower, earlier and longer is the goal.

Frequently asked questions

What is the difference between absolute and relative risk?
Absolute risk reduction is the difference between two groups in percentage points, for example 2.0% vs 1.6%, or 0.4%. Relative risk reduction is the share of the risk that went away, in that example 24%.

Do statins only reduce risk by 1%?
No. That number comes from short trials in lower-risk people. The benefit grows every year you stay on treatment, and it's much larger in people at higher risk. In people with heart disease in the 4S trial, simvastatin cut deaths from 12% to 8% in about 5 years.

Why do short trials make statins look weak?
Because heart disease builds over decades. A trial that lasts 2 to 5 years catches only the start of the benefit, and the best trials are often stopped early because the benefit is so clear.

The bottom line

Next time someone tells you statins only reduce your risk by 1%, remember: that's a short-term absolute number from a short trial. Heart disease is driven by LDL multiplied by years. The benefit of lowering LDL compounds every year, and the earlier you start, the more you gain.

Related Statin & Medication Posts

• Do Statins Really Only Add 4 Days?
• Do Statins Work Over Age 65?
• Statins and Cholesterol Treatment in Older Adults
• Do Statins Reduce All Cause Mortality?
• No One Has Side Effects From Statins!
• Dr. Alo's Dietary Guidelines

Still have questions? Stop Googling and ask Dr. Alo.

You've read the science, but applying it to your own life can be confusing. That's exactly what the Heart 2 Heart VIP Community is for. You can ask me questions directly, join live video calls where we talk through your labs and situations like this one, and get physician-level guidance based on your actual numbers.

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Dr. Alo

References

1. Lipid Research Clinics Program. The Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in incidence of coronary heart disease. JAMA. 1984;251(3):351-364. doi:10.1001/jama.1984.03340270029025.
2. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344(8934):1383-1389.
3. Peto R, Darby S, Deo H, et al. Smoking, smoking cessation, and lung cancer in the UK since 1950: combination of national statistics with two case-control studies. BMJ. 2000;321(7257):323-329. doi:10.1136/bmj.321.7257.323.
4. Vineis P, Alavanja M, Buffler P, et al. Tobacco and cancer: recent epidemiological evidence. Journal of the National Cancer Institute. 2004;96(2):99-106. doi:10.1093/jnci/djh014.
5. Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein (JUPITER). New England Journal of Medicine. 2008;359(21):2195-2207. doi:10.1056/NEJMoa0807646.
6. Domanski MJ, Tian X, Wu CO, et al. Time course of LDL cholesterol exposure and cardiovascular disease event risk. Journal of the American College of Cardiology. 2020;76(13):1507-1516. doi:10.1016/j.jacc.2020.07.059.
7. Wang N, Woodward M, Huffman MD, Rodgers A. Compounding benefits of cholesterol-lowering therapy for the reduction of major cardiovascular events: systematic review and meta-analysis. Circulation: Cardiovascular Quality and Outcomes. 2022;15(6):e008552. doi:10.1161/CIRCOUTCOMES.121.008552.
8. Ference BA, Graham I, Tokgozoglu L, Catapano AL. Impact of lipids on cardiovascular health: JACC Health Promotion Series. Journal of the American College of Cardiology. 2018;72(10):1141-1156. doi:10.1016/j.jacc.2018.06.046.