Christopher Labos, MD, CM, MSc

DISCLOSURES | March 19, 2025

15187

00:0008:45

This transcript has been edited for clarity. 

Okay, everyone. Get ready. We’re going to have a fight about statins, again. If you’re the type of person who likes fighting about whether Betamax was better than VHS, you’re going to love this! This is On Second Thought.

We love arguing about cholesterol. It’s all some people live for. In fact, so much so that some of the anti-cholesterol crowd have also become antivaxxers because — I guess, in for a penny, in for a pound? This is not new, though, and people have been pushing an anti-cholesterol message for years.

In 1989, The Atlantic published a cover called The Cholesterol Myth. It said lowering your cholesterol is next to impossible with diet, often dangerous with drugs, and it won’t help you live longer. And you don’t have to search online for long before some “health bro” tells you to eat six raw eggs for breakfast because cholesterol will make you strong. Probably saw the movie Rocky too many times, I don’t know. 

The problem with trying to talk rationally about cholesterol is that this debate has been going on for decades. I have a much longer written piece about the cholesterol debate on Medscape, so you can go check that out. But basically, the cholesterol skeptics were not really wrong in the 1960s, 1970s, and 1980s.

The diet studies and the epidemiological studies were suggestive, but they were hardly definitive. And had you been there, you probably would have said the same thing. Plus, the drugs that we had to treat cholesterol, like cholestyramine, aren’t really used today because, frankly — they sucked.

So, the Atlantic cover was not really wrong. Diets are hard, and most of them are unsustainable for long periods of time because people are human and not cybernetic androids (at least, not yet). And the medications were terrible. But then the statin era began, and the publication of the 4S trial really showed impressive cardiovascular benefits. That should have ended the cholesterol debate. Except it didn’t. 

That’s partially because people don’t like to change their minds (look at social media) and partially because people became so entrenched in their positions during the 70s and 80s that people couldn’t forget the vitriol that had been lobbed against them. And some people just didn’t keep up with the data. 

Before we get to the main point, statins do reduce major cardiovascular events. They do reduce mortality. They have been studied in women. They have been studied in older populations. And (get ready for the real controversial point) a lot of statin side effects, especially the myalgias, are the result of the nocebo effect.

The other thing that really bugs me is that statins aren’t the only medications for cholesterol out there, anymore. In the 1990s, it was statins or nothing, but that’s not really true anymore. I’ll acknowledge, ezetimibe is not the most potent thing and it’s a big ask for somebody to inject themselves regularly with a PCSK9 inhibitor, because people don’t like needles. I mean, we learned that during COVID, didn’t we? 

I’m not delusional. We’re not going to start first-line therapy with the more expensive injectable medications when cheaper oral medications exist. But we can at least agree that it’s a bit silly to keep arguing over statins when the issue should be about lowering cholesterol? Because that is the point: the cardiovascular benefit depends entirely on how much you lower cholesterol. Whether you do it with fibrates, or niacin, or statins, or PCSK9s — the mechanism doesn’t matter. It’s the final cholesterol result that makes the difference. Granted, you don’t get much bang for your buck with fibrates or niacin (and I don’t use them for exactly that reason). The point is, lower cholesterol.

It doesn’t really matter how you do it. 

So why are people still arguing about statins? It’s come up again because of the new PREVENT risk calculator. If you’re in primary care, it probably is a bit confusing that we keep switching from Framingham Risk Score to the pooled cohort equation to the new PREVENT risk calculator. Let’s set that aside for now. 

Yes, people argue about whether they overestimate or underestimate risk in some populations, but predicting the future is hard — which is why I’ve never won the lottery and have to keep making these videos to buy groceries. However, you do need a way to identify low-, medium-, and high-risk individuals. I don’t think anybody really wants to pick a fight with me about treating high-risk populations; it’s the low-risk populations that get everybody all hot and bothered. So, do we treat them? 

Here’s the two issues. One, does lowering cholesterol in primary prevention patients improve outcomes? And two, is it cost effective? Because those are very different questions. To the first point, does cholesterol matter in primary prevention? Well, yes — yes it does. When you meta-analyze all the statin trials that have been done over the past 20-30 years, you get pretty clear linear associations. But with secondary prevention, the slope is greater. If you lower cholesterol by 1 mmol/L (yes, I’m using SI units, get over it), the cardiovascular lowering effect is greater in secondary prevention than in primary prevention. This makes sense, as the sickest patients always benefit most from therapy. Antibiotics are life-saving for somebody with sepsis and are far less impressive if you just have a urinary tract infection; but they work for both patients. 

So, do statins and cholesterol reduction work in primary prevention? Yeah! You have a few different reports that you can draw on here: There was the Cochrane review in 2013 and the USPSTF review in 2016, and they both showed a benefit. Now, everybody likes to claim that those reports did not show a mortality benefit to statin use in primary prevention. But go back and read those papers — they both showed a reduction in all-cause mortality. Not a big reduction, but there was a reduction. 

Let’s look at the USPSTF review. Absolute risk reduction with statins for all-cause mortality was 0.4%. It’s not zero. Whenever somebody claims that statins don’t reduce mortality, feel free to call them a liar. An absolute risk reduction of 0.4% is a number needed to treat (NNT) of 250. That’s obviously not impressive, but it’s not that terrible either. Remember, a NNT of 250 over 1-6 years. Primary prevention is long-term: It’s not a race, it’s a marathon. Apply this to a whole population over many years and that mortality benefit starts adding up. 

Also, proving all-cause mortality benefit is hard because people are much less likely to die from heart attacks, now. We have defibrillators, stents, and much more effective medications, so mortality has gone down. You can’t show a mortality benefit in a population that isn’t going to die, but you are preventing heart-related clinical endpoints. Heart attacks, strokes, and even getting a stent are no longer considered very high-risk. Look at the clinical benefit for composite cardiovascular events, and the absolute risk reduction is 1.39%. That’s a NNT of 72 over 1-6 years. I think that’s pretty good, all things considered. 

Here we get to the second, more contentious question: Is it cost-effective? That kind of depends on you. Can we really put a value on a human life? I mean, yes, insurance companies do it all the time. Obviously, we’re not going to put everybody on statins. That would not be cost-effective. But where do you want to draw the line? How “low” is low-risk? How “high” is high-risk? That is largely a subjective question. As everybody argues about which risk prediction formula to use and whether the thresholds should be drawn, remember: We’re basically arguing about who has the better compass, not whether the earth is round.

Statins do work, even for primary prevention. Is the number needed to treat good enough? If you want to know what I think — yes. You get more benefit in higher-risk patients than in lower-risk patients (and eventually we need to stop arguing about how to define those things), but heart disease rates are going down because we have become more aggressive about anti-smoking policy, blood pressure targets, and diabetes treatments. We see less heart disease because we are more aggressive in controlling risk factors than we were a generation ago. 

Now, there’s something called the population paradox: Small benefits to an individual can have a huge impact when applied to a whole population. Is an NNT of 72 good enough? Well, statins aren’t free, but they are pretty cheap given that they’re all generic now. They have side effects (like all medications do), but a lot of those side effects are due to the nocebo effect. They aren’t going to cause cancer, dementia, or turn your brain to mush. 

Some people are making good faith cost-effectiveness analyses, and some are whack-a-doodle pseudoscience zealots that have drunk the Kool-Aid and think statins are killing everyone.

Either way, cholesterol is a cardiovascular risk factor and you can’t deny that it exists. Is your patient at high enough risk to justify treatment? I leave it for you to decide. But statins do work — don’t let anyone tell you otherwise. For Medscape, I’m Christopher Labos.