Transcription
Are statins really helping women's hearts? Statins are drugs that lower cholesterol, and millions of women take them every day. But here's the problem. For women, cholesterol isn't the best way to measure heart risk. The real driver is insulin resistance. The root of diabetes, high blood pressure, and belly fat. As a matter of fact, statins can actually make insulin resistance worse, raising your risk of type 2 diabetes. So, if you want to protect your heart, the answer isn't just lowering cholesterol, it's improving your metabolic health.
This is lecture 117 of the metabolic classroom. Looking to improve your own metabolic health? Visit insuliniq.com for courses, coaching, consultations, and a 10-day free community membership trial. to dive deep into the science behind metabolic health, become an insider at benbickman.com, where you'll enjoy my exclusive content, add free podcasts, live stream Q&A access, and more.
Welcome to another episode of the metabolic classroom. I'm Benjamin Bickman, a biomedical scientist and professor of cell biology. If you're new, this is the podcast that's a bit of a mini lecture and I am always hoping to explore some aspect of human metabolism in a way that hopefully helps you live a healthier life. Today I'm discussing a timely and even controversial subject and that is statins and women's health. During the course of the mini lecture, we're going to explore what statins are and then hopefully in an unbiased approach explore some of the pros and cons of their use. I am going to admit focus a bit more on the downsides because that seems to be something that is all too often overlooked in conventional care. And I also want you to learn why metabolic factors like insulin resistance might actually be far more important for understanding a woman's risk for heart disease than traditional cholesterol markers. So I am in a way imagining someone listening to this and maybe she has been told that she has high cholesterol and thus needs to be on a statin. That happens surprisingly often. I am going to cast a little bit of doubt on that approach.
Okay, first of all, let's just begin with a definition. What are statins exactly? Statins are a class of a prescription medication designed to lower cholesterol levels in the blood. They do this by inhibiting the actions of an enzyme that's found in many, many places throughout the body, many cells, but most famously in the liver. And that enzyme is HMG COA reductase. Now, why do I point out the liver? because it's the liver that's actually making cholesterol to be released and sent into the blood. Whereas, say if the muscle is making cholesterol, it's holding on to it. It's not packaging it out. Now, when this enzyme gets blocked, which is again what statins do, it's going to reduce the amount of low density lipoprotein cholesterol or LDL, sometimes LDLC or just LDL. This is often referred to as the bad cholesterol that circulates in your bloodstream. Of course, cholesterol is cholesterol. There's no difference regardless of how it's carried, but typically when they talk about LDL cholesterol, they're talking more about the particle that's carrying it. And we'll come back to that in just a bit.
Statins are widely prescribed, especially for people who appear to have a risk of cardiovascular disease based on blood markers. And then the idea is that if you lower these markers, most famously LDL cholesterol, then you can prevent the buildup of plaques in your arteries, which is then in turn going to reduce the chance of heart attacks or strokes. Now, it sounds pretty straightforward, right? Certainly everything I've said is the dogmatic view that is widely embraced, but as we'll see, the story gets more complicated, and I submit its even more complicated in women.
So, let's talk about gals and the use of statins for what's called primary prevention. That is women who haven't yet had a cardiovascular event like a heart attack or stroke. The evidence here is mixed. Some metaanalyses suggest that statins can reduce the relative risk of major events by about a third. So maybe some kind of 30% reduced risk. Now remember that is a relative change and this is in women without prior heart disease. So that's roughly similar to men. But when we drill down, the absolute benefits are often small to the point of negligible, to the point of nothing, and there's no clear reduction in overall mortality. One systematic review and a metaanalysis specifically on statins for primary prevention in women found no significant impact on cardiovascular mortality. In other words, while statins might prevent some events, they don't necessarily extend life expectancy in the group and the benefits may be overstated for women relative to the consequences that are not so positive.
So, the negative risks or negative outcomes. Now, to be fair, as much as I am going to spend the next length of the mini lecture highlighting some of the concerns I have, that's not to say the data is are overwhelmingly negative. There are some positives to be noted uh if only perhaps by reaching a bit and overextending perhaps. But a 2022 meta analysis reviewed 27 trials and they found that statins reduced all cause mortality by about 15 or so percent in women for primary prevention. A 2012 meta analysis of a large cohort, 170,000 or so participants, it showed similar event reduction. And in fact this case in men and women but the relative risks translate to tiny absolute changes and in women specific trials like the Jupiter trial 2010 uh while uh elevated or C reactive protein elevated women so women with higher levels of CRP saw some benefits overall mortality wasn't budged.
Now, one of the main rationes for prescribing statins in general is to target elevated LDL cholesterol and even to a degree efforts to try to use statins to lower apo lipoprotein B, often called apo B. Apo B has become the darling biioarker in cardiology and cardiovascular research. There is tremendous enthusiasm to put it mildly for it as a supposed gold standard of cardiovascular risk. The idea is here simple. The more apo particles you have, the more atherogenic particles circulating in your blood. Now that is to be distinguished from LDL cholesterol. LDL cholesterol is attempting to measure the amount of cholesterol that is being carried on the LDL particle. Apo B is in fact a measurement of the particle itself. So that's the difference between them. But here's a problem. When you actually look at outcomes in women, LDL and APOB are remarkably weak predictors of heart disease. In the women's health study tracking over 28,000 women for more than two decades, LDL cholesterol was associated with only a 1.4fold increase in risk per standard deviation. Now again, this is all relative. APOB did a little better, a 1.9fold, but even that effect quickly faded with age. So, as the women got older, that had less and less relevance. Now, compare that with the hype around APOB, and it's clear to me that the enthusiasm has far exceeded the evidence. So, again, just to put those in perspective, LDL cholesterol was associated with a 1.4fold increased risk. Apo Better at 1.9.
Now, what about inflammation? Just a moment ago, I mentioned how there's studies to show that statins are appear to be more effective in women who come into it with elevated C reactive protein. Well, even inflammatory biomarkers like C reactive protein showed up to of about a 1.8fold dissociation with premature events. So that's stronger than LDL and on par with APOB. But to put all of this bluntly, the markers that statins appear to be designed to improve or what they're marketed to improve are barely moving the needle in women. So so much attention is spent on LDL cholesterol, even C reactive protein nowadays, most especially APOB. And yet they appear to have a marginal statistical statistically significant relationship with a heart event. In fact, I can't help but recall my old mentor helping me understand the difference between something being statistically significant versus meaningful. I suspect this is an instance where he would say, "Well, sure, it's statistically significant, but is it meaningful?"
Now, maybe we would say it is, but if those modest changes are meaningful, well, hold on to your seats because let's contrast that with markers of metabolic health. In the same study, the differences that they found are staggering. The differences between these lipid markers and metabolic markers. So in the same study, diabetes increased risk of heart disease by more than 10fold. So it was a 1.9 change. Now it's a 10.7fold change. So dramatically higher. Metabolic syndrome, which of course is insulin resistance. Of course, so is diabetes. It's that's type two diabetes. Metabolic syndrome carried a six-fold increase. Hypertension was 4 and a half and obesity was about the same, four and a half. And perhaps most striking, the lipoprotein insulin resistance score LPIR. This is uh considered to be the most direct measure of insulin resistance but it is once again just a big algorithm of various lipids but very well connected to other markers of insulin resistance like those measured through a hypoglycemic uh in uh you a uglycemic hyperinsulinemic clamp. So the clamp technique has been used to validate the LPIR score and that was tied to once again about a 6 and a halffold increased risk in women. So if those modest numbers of of the lipids LDL at 1.4 four or so uh APO B at 1.9. If those are meaningful and people want to focus on them, then you cannot justify overlooking things like diabetes. Again, that was more than tenfold uh 10.7 hazard ratio rather than 1.9 which was Apo B. And again, metabolic syndrome 6.1, obesity, hypertension four and a half, four and a half. So we need to be honest then if if we're claiming that the lipid markers matter in women which again is the priority in the topic today then we have to admit that the metabolic markers matter far more and these are not subtle differences. These metabolic markers crush the predictive power of LDL and APOB.
What's more, other large cohorts confirm it. The Framingham Offspring study found that insulin resistance increased risk nearly twofold while insulin sensitivity was powerfully protective. Importantly, the effects these effects what they find with insulin resistance hold even after adjusting for things like LDL cholesterol and smoking. So if you just level the playing field with lipids, insulin resistance continues to have an effect. To me, the takeaway based on the evidence is unmistakable. In women, lipids are weak. Metabolic dysfunction is strong. And of course, that's all to say predictors of heart disease. And and maybe we would even say contributors to heart disease to be more precise and may be fair. LDL and APOB appear to be very minor players while insulin resistance and its consequences like type 2 diabetes, metabolic syndrome dominate the risk landscape. And again, it's not even close.
Now, in the midst of all of this data, looking at statins and the markers that appear to matter most, there is a an unfortunate irony. Statins zealously lower LDL, a weak predictor, very weak predictor, especially in women. But they also zealously increase insulin resistance, the very risk factor that appears to be the strongest driver of heart disease. So the tragedy and irony is that by targeting a weak marker like cholesterol while exacerbating a meaningful one like metabolic syndrome and insulin resistance, statins might be trading one risk for another, particularly in primary prevention where benefits are slim. So that is to say a woman who's never had an event, a cardiovascular event before.
And speaking of these risks, let's talk about that a little more now. The cons and starting with type two diabetes. Statins have been consistently linked to higher incidence of new onset type two diabetes. And this effect appears particularly pronounced in women. In fact, in post-menopausal women, for example, statin use has been associated with a 48% increased risk of developing diabetes. Even after adjusting for factors like age and and BMI, you know, so even the bigger body, this is not a minor effect. Remember, type two diabetes itself is a massive risk factor. It increased the likelihood of a woman having a cardiovascular event by more than 10 times. So, it matters. And that increased risk of type 2 diabetes could potentially offset any apparent cardiovascular benefit from lowering statins in women.
I think now the mechanisms behind this seem to involve statins impairing insulin sensitivity as well as beta cell function which then can contribute to higher blood glucose levels. One pathway is through reduced levels of GLP-1, the now famous hormone that helps regulate blood glucose and of course promotes weight loss. I need to credit Nick Norwitz here. I wouldn't have seen this paper without him pointing it out, but a 2024 study showed that statins can aggravate insulin resistance by reducing GLP1. Interestingly, and I won't get into the specifics. I actually addressed this in a research review that you can go listen to for you insiders. I discussed the entire paper, but they found that it was microbiome dependent. In fact, in their research, they found that statins had unfortunate and unhealthy changes in the microbiome, which led to a significant drop in GLP-1, which in turn exacerbated insulin resistance. And if they could keep the microbiome in check, then they were able to protect the GLP-1 and prevent the insulin resistance as a result of the statins.
Now beyond GLP-1 several other mechanisms can explain some statin induced insulin resistance and metabolic complications. So first statins are known to deplete a molecule called co-enzyme Q10 or CoQ10. This is an electron carrier that is crucial for mitochondrial function. A 2013 review notes that this reduces ATP production in beta cells which in turn impairs insulin secretion potentially by uh 10 to 20% in highdose users. That's a pretty significant drop. Second, there is an inflammosome activation. So a paper in the journal diabetes found that statins trigger the NLRP3 inflammosome which can then promote inflammation and if it persists damage the beta cells and I've described previously how inflammation is one of the cardinal causes of insulin resistance. And then third a 2023 paper finds that statins can suppress glucose uptake into tissues by inhibiting glute 4 transllocation. Glute 4 being that doorway that opens on the surface of certain cells like fat cells and muscle cells to allow the glucose to come in.
So a lot of that is directly metabolic and tying it statin use to diabetes. But beyond diabetes, statins are associated with other health risks that appear to disproportionately affect women. For example, muscle issues such as myalgia, like muscle pain or weakness are reported much more frequently in women on statins. And this is in fact one of the reasons women discontinue statins more than men because they experience some of these more painful side effects more than men. In fact, some evidence suggests that women are about twice as likely as men to experience these muscle specific symptoms which can range just from mild muscle aches to severe complications like rabdomiolysis which is the muscle actually getting destroyed. Uh and adding to this a paper in 2024 notes that muscle pain can affect up to 25% of women which is about double than what you see in men. And even beyond the muscle, brain fog is another problem. A recent survey of 170 people found that 75% reported issues with memory or attention deficits and linked to statin use. And women were really over represented in this group. And uh women also are more likely than men to report having depression because of the use of statins.
Now I need in the in the interest of being clear here there is evidence of a different sort where a 2025 paper suggests that statin use actually reduced the risk of dementia by 14%. That's a relative reduction. Um but that was not uh they didn't split that out by sex. And so there could still be a sex-based um problem here that would make women have a little more pause than compared to their male counterparts. I think very much that the risks compound in women in part due to just smaller bodies, lower body weight, which may be taking a dose of statin that is a little much for that smaller body, but also perhaps some hormonal changes. And that allows me to transition into always a favorite topic. I love discussing hormones. As a professor who teaches a graduate course in endocrinology, I find the topic endlessly fascinating. And in women, it is endlessly much more complicated, if you will, than in men when it comes to hormones.
Now, let's first discuss menopause. As estrogen levels drop, women become more susceptible to some metabolic changes because estrogen, the main estrogen estradiol is allows a woman to be a metabolic superhero. Um, but what happens when that's gone uh because of menopause? Well, then statins may exacerbate the situation, make it even worse. So, as much as she is experiencing changes due to the loss of estrogen, statins appear to compound that loss. Studies consistently show that it's the post-menopausal woman who experiences that up to almost 50% increased risk of developing type 2 diabetes. And this is not something seen in premenopausal women. That's important. something I didn't note previously that that dramatic increased risk of type two diabetes appears to be a post-menopausal problem. But of course, it's the post-menopausal woman who's more concerned with heart disease.
Now, it's not just a matter of menopause because this and discussing hormones and women makes me want to make you aware of a critical warning particularly with pregnancy. Statins are contraindicated during pregnancy and breastfeeding due to potential risks to the fetus. Now, this is overwhelmingly from animal studies. Animal studies have long and convincingly suggested that statins can cause birth defects like central nervous system problems or skeletal malf forations. And that's because it interferes with cholesterol synthesis, which is a molecule of life. You have to have cholesterol. Now there's some human very recent human data to that looked at women who were accidentally taking statins through their first trimester which appears to be the most sensitive time and they did not report an increased risk of congenital anomalies. Even still, the animal data has been so convincing and sobering that the FDA recommends an absolute hard stop with statins at least a few months before a woman attempts to conceive and then avoiding them entirely during pregnancy and even lactation. So, if you are of childbearing age and interested in childbearing, all the more reason to be exceptionally cautious with these drugs.
To wrap this up, while statins I think have a place in medicine and can offer some protection against cardiovascular events, the cons, especially for women and especially in the instance of primary prevention, deserve some serious consideration. Remember the predictive power and indicative power of LDL and APOB in women to to indicate heart disease risk is exceptionally weak and needs to be contrasted with the remarkably robust role of insulin resistance and type two diabetes. these metabolic markers. To me, this suggests very strongly that we really ought to prioritize lifestyle interventions that improve metabolic health over some reflexive prescription of statins just based on a less meaningful marker like LDL cholesterol and even APOB. Now to address this I think most prudently I think things like resistance training generally a lower carb or smart carb diet and then trying to avoid you know stress management which I know is a vague thing but just something as simple as optimizing sleep habits I think can really start to address some of the root causes and allow you to address the main risk without the side effects that would come from the drug.
Now, if you are on the drug, and of course, I'm not a health care uh professional. I'm not your clinician. I'm just your friendly neighborhood scientist. I think there are still some strategies that you could explore to help offset the side effects of statins. And this would just be some targeted supplementation to help support muscle and metabolic health. I would say the most evidence-based option is going to be CoQ10. So actually getting a CoQ10 supplement usually in the order of about 100 to 300 or so milligrams daily and this is going to allow you to replace what you may be making less of because remember statins are stripping the body's ability to make cholesterol and CoQ10 is made from cholesterol. Speaking of made from cholesterol, also vitamin D. So vitamin D3 I think is another important one. Uh and it's one you want to monitor and make sure you're not getting low. And beyond those two, which I think are relevant, omega-3 fatty acids can lower inflammation and help with blood lipids on their own, magnesium may be helpful, especially for muscle aches and pains. And then alpha lipoic acid can also just act as a bit of an antioxidant, especially if you are getting some CoQ10 problems uh in your mitochondria. It's very likely that those are now mitochondria producing much more oxidative stress and less ATP than they were before. So you want to try to squatchch or resolve that oxidative stress.
Now with these supplements having been described, please understand that there is evidence to support them. Otherwise, I wouldn't mention them. But uh there there it's a limited upside and I think there may be some synergy with all of them. Nothing is really going to totally undo the effects, but again I only share that comment as just a note of caution. Not that I'm giving any prescription and again I'm not giving any kind of medical advice because I know this is an incredibly charged topic and one that many people feel very strongly about. My thoughts just lean more on just show me the raw data more than anything.
Thanks for joining me in the metabolic classroom. I hope that you feel like you've learned something valuable from this mini lecture. If you did enjoy it, please subscribe, leave a review, and maybe share this with someone you know. a gal who's on a statin. Not that we want her to stop, but we want her to consider both sides of the story in the event she hasn't heard it. Until next time, more knowledge, better health.
Looking to improve your own metabolic health? Visit insuliniq.com for courses, coaching, consultations, and a 10-day free community membership trial. To dive deep into the science behind metabolic health, become an insider at benbickman.com, where you'll enjoy my exclusive content, add free podcasts, live stream Q&A access, and more.