Menopause Hormone Therapy is Not More Effective Than Statins

Why hormone therapy is not recommended for prevention of heart disease

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I’ve been asked a lot in the past couple of months about whether menopause hormone therapy (MHT) is more effective than statins at preventing heart disease. Like a lot. And I’m not the only one. I heard the same from many colleagues at the 2024 Menopause Society meeting. And it’s not just gynecologists who are seeing women misinformed about statins, hormone therapy, and heart disease. Family practice, internal medicine, and cardiology colleagues tell me that women are refusing statins because they have been led to believe that hormone therapy is superior at preventing heart disease. 

So I took to Instagram with two doctors who have more expertise on heart disease than me, Dr. Danielle Belardo, a preventive cardiologist who is on the board of the American Society of Preventive Cardiology, and Dr. Martha Gulati, Director of Prevention and Associate Director of the Barbra Streisand Women's Heart Center, Past President of the American Society of Preventive Cardiology, and author of the book, Saving Women’s Hearts. These ladies know their stuff. 

The full Instagram video is here, and I highly recommend listening, but I’ll cut to the chase. The short answer is no, menopause hormone therapy is not more effective than statins at preventing heart disease and menopause hormone therapy is not indicated for the prevention of cardiovascular disease. Also, statins work for women. Here is a clip with some salient points:

Coincidentally, the very next day after our Instagram live, The Menopause Society issued this statement, “The Menopause Society Statement on Misinformation Surrounding Hormone Therapy.” What did they say about heart disease? 

Based on existing science and clinical evidence, estrogen-containing hormone therapy is not recommended for primary prevention of cardiovascular disease or dementia in women who experience menopause at the average age.

Lately, when I refute a false claim about hormone therapy that I’ve seen on Instagram I get hit with two accusations. The first is that I am anti-menopause hormone therapy. This is absurd. I am very pro MHT for situations where it can help, but I don’t push it as a panacea because it isn’t. I am also honest about the data, but I understand, given how much hormone therapy is sold as a wonder drug, that sticking to the science could sound like a downer. I hear from women almost every day who use my book, The Menopause Manifesto, or this Substack to advocate successfully for MHT. While it’s anecdotal, I’ve yet to hear of one using my information accurately and being turned down by her health care professional.

The other false claim is, “No one ever says this,” which is a bizarre, albeit unsuccessful, attempt at gaslighting. Like, I made it up? Insert eye roll emoji. As multiple people have heard the claim about statins from their patients, and I’ve been asked about it multiple times on Instagram, someone is clearly saying it! While I don’t know the primary source of the “statin/hormones” claim or if there are a few or many, when I did a little digging, I found an video on Instagram from Dr. Mary Claire Haver, someone with a massive social media following, emphatically claiming that “hormone therapy is more effective at preventing cardiovascular death than a statin in women in menopause.” Here’s a screen grab from the video.

I can see how someone might hear this and believe that hormone therapy is more effective than statins. 

A Deeper Dive into the Evidence

I can find no randomized trials comparing statins with menopause hormone therapy for the primary prevention of cardiovascular disease, which is what we would need to support the claim that estrogen outperforms statins. There is quite a bit of data supporting the use of statins for women, which I have covered previously in this post, and the benefit of statins for women was specifically addressed at the 2023 Menopause Society Meeting, which I wrote about here. And of course, we covered statins in the Instagram live I linked to at the beginning of the post. Interestingly, there is a growing body of evidence showing that women who are on MHT and who also take statins have a lower risk of blood clots compared with women taking MHT without statins. So, this is an added bonus to your statin if you need to take one.

I asked Dr. Danielle Belardo what she thought of this clip and the claim about statins, and she told me that she thought it was dangerous and “misinformation.” The truth, which undoubtedly will receive exponentially fewer views on social media, is that the data for the prevention of heart disease with MHT is fraught with issues. Hence, MHT is not recommended for primary prevention of heart disease. Might a subgroup derive some benefit from some hormone formulations? Possibly, but which women, which hormones, what dose, what route of delivery, and how long must they take them? We can’t answer any of these questions with any certainty based on the existing studies. 

While animal studies and a lot of observational data suggest that MHT can be helpful for the heart, animal data doesn’t always translate to humans and observational data is fraught with issues. There actually are two randomized, double-blind trials (ELITE and KEEPS) that studied different formulations of estrogen early in menopause for the prevention of heart disease. They used surrogate markers for cardiovascular disease because too few women in this younger age group will have cardiac events. In KEEPS (the Kronos Early Estrogen Prevention Study), a randomized controlled trial of oral Premarin or a 50 mcg transdermal estradiol patch with cyclic progesterone versus placebo, there was no change in the primary endpoint with either hormone regimen versus placebo. Let’s restate that, no change with one of the most common regimens, a 50 mcg transdermal patch and oral progesterone. With ELITE (Vascular Effects of Early versus Late Postmenopausal Treatment with Estradiol), which evaluated oral estradiol and vaginal progesterone with placebo, there was a small difference in slowing the progression of carotid-artery intima-media thickness (CIMT), which is a good thing, but “no significant differences in post-treatment coronary-artery calcium and cardiac CT angiographic outcomes between the estradiol and placebo groups in either postmenopause stratum with a mean 6 years of follow up.” The meaning of the small improvement in CIMT is unknown, given the other markers showed no change.  

As Dr. Gulati said in the first video at the beginning of the post, while some forms of MHT do lower LDL in studies, that didn’t improve cardiovascular outcomes in studies. If a patient takes estradiol and their LDL decreases, we don’t know if that is the same effect as a statin lowering LDL because statins have pleiotropic effects. 

What about that 2015 Cochrane Review?

I’ve seen several people wave this around as proof that hormone therapy reduces cardiovascular events by 50%, so. let’s get into it.

This is a review of clinical trials of oral estrogen versus placebo, so it cannot be generalized to transdermal regimens. This is a very important point that almost always seems to be ignored. This review doesn’t include any data from KEEPS or ELITE, which were published a little later. While the overall conclusion for the Cochrane Review was “little benefit” from MHT for primary or secondary prevention of cardiovascular disease, much has been made of the subgroup analysis of women who started hormone therapy less than ten years after menopause. They had a reduced rate of coronary heart disease (which included death from cardiovascular disease and non-fatal heart attacks), with a relative risk of 0.52, but there was also an increased risk of blood clots, with a relative risk of 1.74. That second part is also often left out of the discussion.

However…

The authors had to combine data from trials with different oral estrogens and progestogens to do the sub-group analysis for those starting hormones within ten years of menopause. However, different hormones can have different effects, so lumping everything together may limit accuracy. One large study that was included, DOPS (the Danish Osteoporosis Prevention Study), has issues, including the fact that it was open-label, the control group was older, and it looked at data from a study designed to test a different hypothesis. This means we must be really careful about using DOPS to draw conclusions about protecting the heart. In fact, at the beginning of the Cochrane Review, the authors state that the results for women who start hormone therapy within 10 years of menopause are only “significant due to the DOPS 2012 trial, that has high risk of bias. We downgraded our confidence in the results of that metanalysis because, had the DOPS not been there, the metanalysis would not be significant.” Kind of an important point.  

Many Questions Need Answering Before MHT can be Recommended for Prevention of Heart Disease

While plenty of interesting hypotheses suggest estrogen might help, that hasn’t been well born out in rigorous studies, as the two randomized trials designed to look at primary prevention did not achieve their treatment goals–this is especially important as one of arm of KEEPS used the most common hormone regimen prescribed today, transdermal estradiol and oral progesterone.

It’s not even ideal to use the general term MHT when speaking about heart disease, because we shouldn’t lump all estrogens or progestogens together. Also, oral can have different effects than transdermal. The progestogen may have an impact, and of course, so might the dose. 

We can say with confidence that starting MHT within the first ten years after the last period or before age 60 does not create cardiac risk for women at low risk for cardiovascular disease, and that is important! Fantastic, even. We can also say that for women over age 60 and those at high risk of cardiovascular disease, there may be concerns about taking MHT. This is also an important conclusion, because we want to first do no harm.

More research is clearly needed to further understand the role of MHT and the heart and I am always open to what good, exciting, new science will bring. However, I think you can see from this discussion that there is no slam-dunk data suggesting MHT should be used to protect the heart. In fact, the actual clinical trials are underwhelming and people need to stop waving around that Cochrane Review. Also, if the data showed MHT was more effective than statins, MHT would, of course, be recommended in the guidelines in place of statins. Its absence from any guideline is proof the data isn’t there. And I’m not just talking about the Menopause Society guidelines, but also the cardiology guidelines as well. And no, it’s not a conspiracy to keep MHT from women funded by Big Statin. (Big Statin funds nothing because they are all low-cost generic drugs). Gynecologists and cardiologists are not shy about prescribing drugs! The claim that Big Pharma prefers statins over MHT is ridiculous on the face of it. Why? Because Big Pharma makes both of them anyway. 

If the evidence were clear that MHT were better than statins at reducing mortality from cardiovascular disease it would be in the guidelines. And it’s not as if the Menopause Society is trying to gatekeep hormones, they just believe women deserve science and robust evidence. And to make a universal recommendation for primary prevention we need robust evidence. And I think you can see from all the data that I have reviewed and from the explanation of the Cochrane Review why the Menopause Society Guidelines don’t currently recommend MHT to prevent heart disease. 

And please, let’s stop with the statin bashing. There are plenty of reasons to take MHT, and instead of scaring women unnecessarily about their hearts and statins, wouldn’t it be better to focus efforts on getting MHT to those who can truly benefit from it, but are having difficulty navigating the system? It may be less friendly to the algorithm, but it would certainly be a worthy goal.

References

The Menopause Society Statement Surrounding Misinformation About Hormone Therapy https://menopause.org/wp-content/uploads/2024/09/TMS-statement-on-HT-Misinformation.pdf

Cho L, Kaunitz AM, Faubion SS, Hayes SN, Lau ES, Pristera N, Scott N, Shifren JL, Shufelt CL, Stuenkel CA, Lindley KJ; ACC CVD in Women Committee. Rethinking Menopausal Hormone Therapy: For Whom, What, When, and How Long? Circulation. 2023 Feb 14;147(7):597-610. doi: 10.1161/CIRCULATIONAHA.122.061559. Epub 2023 Feb 13. PMID: 36780393; PMCID: PMC10708894.

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Davis JW, Weller SC, Porterfield L, Chen L, Wilkinson GS. Statin Use and the Risk of Venous Thromboembolism in Women Taking Hormone Therapy. JAMA Netw Open. 2023;6(12):e2348213. doi:10.1001/jamanetworkopen.2023.48213

Schierbeck L L, Rejnmark L, Tofteng C L, Stilgren L, Eiken P, Mosekilde L et al. Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial BMJ 2012; 345 :e6409 doi:10.1136/bmj.e6409

Boardman HM, Hartley L, Eisinga A, Main C, Roqué i Figuls M, Bonfill Cosp X, Gabriel Sanchez R, Knight B. Hormone therapy for preventing cardiovascular disease in post-menopausal women. Cochrane Database Syst Rev. 2015 Mar 10;2015(3):CD002229. doi: 10.1002/14651858.CD002229.pub4. PMID: 25754617; PMCID: PMC10183715.

Hodis HN, Mack WJ, Henderson VW, Shoupe D, Budoff MJ, Hwang-Levine J, Li Y, Feng M, Dustin L, Kono N, Stanczyk FZ, Selzer RH, Azen SP; ELITE Research Group. Vascular Effects of Early versus Late Postmenopausal Treatment with Estradiol. N Engl J Med. 2016 Mar 31;374(13):1221-31. doi: 10.1056/NEJMoa1505241. PMID: 27028912; PMCID: PMC4921205.

Miller, V. M., Taylor, H. S., Naftolin, F., Manson, J. E., Gleason, C. E., Brinton, E. A., … Harman, S. M. (2020). Lessons from KEEPS: the Kronos Early Estrogen Prevention Study. Climacteric, 24(2), 139–145. https://doi.org/10.1080/13697137.2020.1804545