Heart disease, caused by plaque on artery walls, is the leading cause of death for both men and women. Plaque buildup is also a major cause of stroke, which the CDC lists separately from heart disease as the fourth leading cause of death for women and fifth for men. In turn, plaque is caused by too much cholesterol. It develops over decades without symptoms before it finally ruptures to cause things like heart attacks (see the schematic below from this paper).
Autopsies on American soldiers killed in the Vietnam war and Korean War – generally young, physically fit men – found that about half of them already showed signs of heart disease. Studies using modern medical imaging techniques have confirmed that many healthy adults with well-controlled cholesterol levels already show signs of plaque buildup.
Fortunately, we’ve made huge progress towards preventing heart disease, though many people don’t seem aware. Google searches for a cure for cancer are 43 times as high as those for a cure for heart disease. But cancer is really many different diseases that are far more diverse than plaque buildup on artery walls. In this post I’ll try to convince you that we’ve made great progress towards a cure for heart disease and that one of our most well understood tools – statins – is underutilized.
Scientists first connected cholesterol to heart disease in 1910, when they found that the aortas of people with heart disease had 20 times as much cholesterol as those of healthy people. In 1939, a doctor discovered large families whose members shared unusually high levels of blood cholesterol and early heart attacks. By the 1960s, doctors had figured out the genetic basis for the condition. With two forms, people with the worse kind have cholesterol around 800 mg/dl and can have heart attacks as early as five years old. People with the less bad kind have cholesterol around 300 to 400 mg/dl and can have heart attacks in their 30s. A series of observational studies like the Framingham Heart Study and the Seven Countries Study verified that even at more typical levels, LDL cholesterol is correlated with higher risk of heart disease.
The cholesterol in your blood comes both from cholesterol you eat and cholesterol produced by your liver, although more comes from your liver. Your liver produces cholesterol because it is a crucial ingredient in building cell membranes. Statins inhibit an enzyme your liver uses to produce LDL cholesterol.
The first statin was discovered in the early 70s. Research on statins started in petri dishes, then advanced to mice, hens, dogs, and monkeys. Finally trials advanced to humans with genetically elevated cholesterol, the patients with the most to gain from an effective treatment. From there, statin research progressed to people who had already experienced events like heart attacks and eventually people who were just considered high risk for heart disease. After a series of setbacks and false starts, lovastatin became the first approved statin in 1987.
Long-Term Benefit of Statins
A 2009 meta-analysis of five randomized trials including 31,000 patients treated for an average of five years found huge benefits of statins across a range of patient groups. The studies found an average decrease in LDL cholesterol of 28%. Major coronary events like heart attacks fell by 31% and death from heart disease fell 29%. In other words, everything related to heart disease fell by about a third. Deaths unrelated to heart disease and stroke were unchanged, so overall mortality fell by a smaller – but still gigantic – 21%.
Further studies compared different doses of statins and found that higher doses decrease both cholesterol and the risk of heart disease even further. A 2010 meta-analysis of 26 trials with 170,000 patients compared statins to placebo as well as high-intensity to low-intensity found that every reduction in LDL cholesterol of 40 mg/dL brought a 20% reduction in the risk of death from heart disease, with no sign of a lower bound on healthy LDL levels. (The lowest cholesterol group they considered was that with baseline LDL below 77 mg/dL. Newer drugs have pushed LDL cholesterol down much further and still find no limit to the health benefits of decreasing it.)
Very Long-Term Legacy Benefit of Statins
The simple model we use to understand heart disease – plaque builds up over decades until it ruptures – suggests that the longer you take a statin, the greater the benefit should be. And if you stop taking a statin you should retain a benefit. Five of the large, long-term trials of statins ended around the 90s, giving us the chance to see what happened to people from those trials decades later. After these studies ended their subjects were left to their own devices to take statins or not. People from the treatment and control groups ended up taking statins at similar rates after the end of their studies. What that means is that these follow-up studies tell us what happens a decade or two after you finish a five-year course of treatment with statins, called a legacy benefit. It’s not exactly the same as asking what happens if you take a statin for 20 years, but it’s still useful.
Results of this decades-long follow-up partially support but also complicate this simple model of heart disease. Two of the five studies looked at people who already had symptomatic heart disease, what’s called “secondary prevention”. The other three were “primary prevention” studies of people who were just at above-average risk of heart disease. Roughly speaking, the secondary prevention studies found no legacy benefit of statins, but the primary prevention studies did. Keep in mind that all these studies found large benefits while the subjects were taking statins.
One explanation of these mixed results is that for people who already have significant plaque, all a statin does is prevent that plaque from rupturing. Then, as soon as the patient stops taking the statin, the probability of a heart attack quickly goes back to what it was before. But for people who are still healthy, taking a statin slows or stops their steady march towards heart disease. Once they stop taking a statin that march resumes, but they’ll forever be behind where they would have been if they had never taken a statin.
A 20-year follow-up of one trial found a surprising benefit for heart failure, with a giant 35% reduction in hospitalizations. Heart failure – the inability of the heart to pump sufficient blood – is caused by the heart becoming too weak or too stiff. It’s typically viewed as somewhat separate from the plaque buildup statins prevent. The authors of this study speculate that the other heart problems statins prevent typically cause a cascade of problems ending in heart failure. The result was so unexpected, none of the other trials even looked for this effect. Heart failure happens so late in life there may still be information to learn about heart failure from even longer follow-up of the other trials.
The most commonly cited side effect of statins is myopathy, a broad category of muscle problems, but most often general muscle pain. One survey found that 25% of current statin users experienced muscle pain.
Reports of muscle pain following statin treatment are a serious problem, but not for this reason you might think. This side effect is mostly, if not entirely, not a result of taking a statin. In randomized trials, the rate of muscle pain in the treatment group exceeds that in the control group by one patient per 10,000 patient-years of treatment. One meta-analysis found no increase at all. Even if this side effect is real and happens to you, it’s nothing to worry about. If the pain comes, it typically happens within the first few weeks or months of treatment and ends shortly after treatment is stopped.
The real problem is how many people stop or never start taking statins because they believe statins cause muscle pain. The same survey I mentioned above found that 60% of former statin users believed their treatment had caused them muscle pain.
Why do so many people believe statins have a side effect that’s nearly non-existent in randomized trials? The evidence points to a strong nocebo effect. Media reports widely mention muscle pain as a result of statin therapy, so as soon as patients taking statins feel muscle aches, they blame the statin. The authors of one of these large, long-term blinded studies followed up with “open label” treatment. That is, they continued the study in exactly the same way except that they told people if they were receiving the statin. During the blinded period, reports of muscle pain came from almost exactly 2% of patients in both the treatment and control group. After they were told whether they were taking a statin or the placebo, though, there were 40% more complaints of muscle pain from patients on statins.
A delightful study recently demonstrated just how unrelated these muscle pains are to statins. The researchers coordinated with doctors at 50 sites and waited for patients on statins to say that they wanted to stop taking the drugs because they were feeling muscle pain. Then they asked those patients to join a study where they would spend one year alternating between a statin and a placebo every two months without knowing when they were on the statin. At every two month treatment change, the patients filled out a survey about their muscle pain. There was no meaningful difference in reports of muscle pain between the treatments.
Type 2 Diabetes Risk
So what stops us from giving statins to everyone? Type 2 diabetes (T2D).
A meta-study found that statins, compared to placebo, increase the relative risk of T2D by 9% over an average of four years of treatment. But the baseline risk was low enough that for each 255 people treated with statins for four years, only one extra person would get T2D.
The mechanism for the increased T2D risk is unclear. The authors of the meta-study suggest that some people might simply die before being diagnosed if they don’t take statins. Another idea is that a non-fatal heart attack scares people into a healthier diet, reducing their T2D risk.
This study of medical records for 80,000 people who were not on statins found that people with naturally low LDL had double the risk of T2D as people with a more typical LDL. So it may be that achieving low LDL levels increases risk of T2D whether the cause of the low LDL is statins or something else.
Whatever the cause, the increased risk of T2D is more than offset by the decreased risk of heart disease. One of the worst consequences of T2D is a rough doubling of heart disease. In fact, 80% of diabetics will eventually die of CVD. So the main way to balance the increased risk of T2D against the heart disease benefits of statins is by calculating the net effect on heart disease. Even for patients who start treatment with a five-year CVD risk below 10%, the direct benefit of statins on heart disease is more than 50 times larger than the increase in heart disease by way of T2D.
So if statins stop progression towards heart disease with virtually no side effects, should everyone start taking them in their 20s? I think the answer is “maybe.” Most doctors might say “no,” but the truth is we haven’t run long-term trials of statins in healthy thirty-somethings, let alone twenty-somethings. Every time scientists run a large, long-term study of more powerful statins or statins in a lower-risk population than they previously considered, they keep finding new benefits.
The US Preventive Services Task Force – a government agency that makes widely respected recommendations for these sorts of things – recommends that adults from 40-75 years old and a 10-year heart disease risk of 10% or more, according to their calculator, take a statin. But the main reason for these limits – why not people under 40? over 75? – is a lack of studies, not evidence of harm. There’s a significant chance that studies in new groups would find that even more people would benefit from statins. I’m a 32-year-old type-1 diabetic and my doctor already prescribed me a low-dose statin to stop me from developing heart disease when I’m older. Most people who are already included in these expert recommendations don’t take statins, though. It would be a huge public health win to get all those people on a proper dose of statins.