The fall of the statins

I hold no stocks in statin manufacturing, neither I get paid under any form by any of these industries. This is my own clinical opinion supported by peer-reviewed published evidence.

We do not deserve statins same as we did not deserve the discoveries that sat on a shelf or in a drawer for 50 years after their discovery until we, as a society, were finally ready for them. Cold truth! Check out the history of the integrated circuits, the old story of penicillin, or even metformin.

Nearly a decade ago, while researching the impact of metformin treatment on tumor development and metastasis in patients diagnosed with diabetes and breast cancer, I was fortunate to work with very motivated people. Research pays badly, sometimes not at all. Yet, students stick around to investigate intriguing ideas. It is the magic of being there, in the middle of the story, when the discovery happens. We surely failed, 9 out of 10 times. However, once in a blue moon, if we didn’t give up, the extraordinary feeling of seeing it with your own eyes for the first time ever did happen. And you know what? Nobody ever wanted to be paid to experience that! Actually, people will pay themselves decades of life and sacrifice dozens of guilty pleasures to only live that feeling ONCE…

We had sleeping bags under our desks and rarely worked 8 hours shifts. Looking back, I wouldn’t change a damn thing: it was fantastic! The projects were totally out-of-the-box while the data was intriguing and unveiling. What more can one ask for in research?? That day, chatting over coffee, one of my students asked: “What if it’s not only metformin? What if it’s more than one drug that influences cancer outcomes? What if it’s cholesterol drugs too?“. We weren’t sure about either but had a vague suspicion that metformin and insulin sensitizers played a role in counteracting tumor development. Could have statins improved insulin resistance in patients with diabetes? Nobody knew. Until that day we had one big project: TYBRES (The impact of TYpe 2 diabetes mellitus drugs on Breast cancer REcurrence and Survival). It was that exact day that CHOLBRES got born. Named on the spot by the student that raised that first question, the CHOLBRES study (The impact of CHOLesterol drugs on Breast cancer REcurrence and Survival) was a blasting one week adventure and the trigger of several controversies. We were the very first ever to point at the statins and ask: are they, in fact, insulin sensitizers? If so, can they improve diabetes outcomes? Can they prevent tumor development?

CHOLBRES was born on a Sunday (yeah, we were in the lab on Sunday!). Monday morning we submitted an official amendment request for the clinical protocol (to also gather cholesterol treatment info). It wasn’t a big deal but one couldn’t move a finger without the Institutional Board Approval. On Tuesday, my group interviewed 4 new student volunteers from the incoming 3rd doctoral year in pharmacy. We all were contagiously excited about our in-progress work and – sure thing! – by lunch, our team had +4 members on-board. The following Sunday night, at midnight, was the deadline for the late-breaking science submission to present at the American Association for Cancer Research international conference. You better believe it, the discussion that we could submit data for an AACR presentation originally came as a joke as the study amendment wasn’t even approved yet!

Anyhow, we took it way too serious and before we knew it we discussed how many patients we had (hundreds) and how to split the data collection responsibilities between the members of the now bigger team. The impossible was actually quite possible… To submit the presentation proposal by Sunday night, I needed one day to write it. The statistician needed one day to analyze the data. So, the entire data collection had to end by Friday. It was the end of the business day on Tuesday and my email inbox just got a new message: our amendment received approval to expand the treatment information collection! We were jumping and clapping like children having promised a new toy. Then we had that deep quiet realization of what that meant: we had Wed, Thu, and Fri to collect ALL the data double-blinded, cross verify and validate all the results. Our excitement suddenly seemed scary. We couldn’t afford to sleep… at all.

Nobody cared. Most of us didn’t go home or slept for 72 hours in a raw (that was before we found out that lack of sleep was carcinogenic in humans!). My sleepless turn came over the weekend for the final verification/valiation on Friday and the writing of the final proposal on Saturday night and Sunday. Surprising, the big day wasn’t Sunday, but Saturday evening when all of us couldn’t keep still waiting for the final analysis results. I still remember our first normal meal after that crazy adventure. On Saturday I reserved a gazebo in the garden of one of our local restaurants and took everyone out for an early and long dinner. It must have surely been caffeine effect but none of them seemed tired at all. Each and every one was sweating excitement! All were ready to do it all over again in a heartbeat. Other colleagues of mine were advertising positions paid with hard dollars and recruitment took many months to assemble an effective team. Ours got assembled literally in a week and came all for free, stuffed with enthusiasm at the max capacity. Wow! I felt blessed.

My phone rang in the middle of a project joke at our dinner table. It was the statistician. The look on my face must have been self-explanatory as they all stopped talking trying to hear our conversation. Breast cancer patients with diabetes lived longer if using cholesterol drugs. Of all, using a statin provided the best outcomes. I found myself sharing my thoughts:

Guys, statins do modify cancer outcomes in diabetics… It’s not only the cardiovascular outcomes that they improve, it may be recurrence too… Holy crap, all diabetics should be on a statin because all are at higher risk for cancer!” 

This time was silence around the table. Suddenly, the realization that we may have had a great tool that we weren’t taking advantage of counterbalanced the excitement that we could now send a presentation proposal for AACR. If the data we were holding was true, then guidelines had to change sooner than later!

I sent the proposal that Sunday at 11:59pm. Monday morning we were all digging for all the available clinical data on statins. We had to understand the risks vs. benefits. What we found out was stunning: statin pleiotropic effects were reported as early as two decades earlier. There was clear evidence that statins would have prevented cardiovascular events and cancer. With what I know today, I feel that we lost 3 decades and millions of lives by not promoting statins use in patients with diabetes sooner. Our investigation found that statins were safe enough to even become over-the-counter drugs! There was, in fact, at least one FDA application for a statin to gain over-the-counter status. Interestingly, given other competitor statin brands, the request has not been approved DESPITE the safety and efficacy issues being fundamentally resolved. I was sadistic enough to go through the entire 500+ pages file to understand the grounds on which lovastatin did not receive OTC status. the best I could find was the lack of additional benefits that OTC access could provide for the population (meaning additional to the benefits of being prescribed). Right! Like preventing cardiovascular disease and cancer in patients with diabetes wasn’t quite enough.

The year after we witnessed the American Heart Association changing the guidelines to recommend the use of cholesterol drugs – “preferably a statin” –  regardless of cholesterol levels, in all patients with diabetes mellitus over the age of 40 having a risk factor for cardiovascular disease. The same year, the JUPITER study demonstrated that rosuvastatin prevented cardiovascular events in patients with normal low-density lipoproteins and C-reactive protein over 1.5mg/L (a considerable large part of diabetes and pre-diabetes population). JUPITER was stopped early because the statin benefits were so dramatically better than placebo that was unethical to continue giving placebo! That moment we knew that in just a few years, receivers of the statin under JUPITER were about to benefit from cancer preventative effects.

So, I jumped on a flight to Wilmington to meet with the JUPITER study team. No, AstraZeneca did not pay for my trip nor my stay. It was me initiating that conversation because I thought that rosuvastatin’s ability to prevent cancer and metastasis was overwhelming. Our CHOLBRES data stunned the audience. They thought they had a great drug, but did not expect to be that good! That discussion triggered more investigation into the JUPITER post-study data and there was a clear cancer-related benefit.  However, FDA rejected the claims since the study was not originally designed to evaluate cancer outcomes (my personal opinion: nasty!). There was something else that JUPITER reported. They reported more diabetes diagnoses during the course of the study. Although authors explained that the population had a CRP>1.5mg/L and it was more likely to develop diabetes, the statins’ gossip began to spread.  We have a track record of failing to see true value when we see it and that applies to statins too.

Guess what? Then the anti-statin grassroots movement started. There was a pipeline of new cholesterol class drugs about to be placed on the market, thus the old good friends – statins – now most of them generic and CHEAP had to be placed under a bad light to make room to the new expensive options about which we didn’t know a damn. We were so bitter about it… AHA kept solidifying the guidelines promoting statin use in diabetics but then the stupid, irresponsible published science stroke (because we get this too every now and then).

I recall going mad over a JAMA paper reporting more diabetes diagnoses in patients receiving a statin. The paper did not evaluate the background comorbidities and original risk for diabetes; they did not account for that risk in the analysis!!! It wasn’t statins that caused diabetes, the cases were at a high risk for diabetes, to begin with (likely pre-diabetic!) simply because they required a statin. It was likely a suboptimal statin regimen that enabled the diabetes diagnosis later on. This was the crappiest paper that was about to discredit statins and prescribers were about to become reserved in prescribing them to a population that desperately needed them!! Of course, I ended up writing a letter to the editor spelling out the reasons for which that wasn’t true science. I wasn’t even the only one, it was quite a few of us. Unexpected, they published all our comments! Then all of a sudden, all but one comment were removed from the online version of the article. That irritated me badly. However, I kept a copy of the actual website print back when the comments were still accessible. Check it out here. In the following years, many patients refused statin treatment especially if the LDL levels were normal. On one hand, the patients did not understand the context and, on the other hand, many prescribers were on the fence themselves being unclear about the controversy. Having seen the actual data in my own hands, I felt both sad and helpless. In a way it was tragic. How tragic? I’ll tell you in 10-15 years when we can assess the consequences…

Until then, remember these few things about statins:

  • Patients with type 2 diabetes mellitus over the age of 40 having one risk factor for cardiovascular disease (ie smoking, overweight, family history etc.) require a statin regardless of LDL levels. This is primary prevention for cardiovascular events and adds cancer-related benefits if a patient is diagnosed with cancer.
  • A man over the age of 50 or a woman over the age of 60 having a risk factor for cardiovascular disease  (ie smoking, overweight, family history etc.) and a CRP level over 2mg/L is eligible for rosuvastatin regardless of LDL levels and regardless of being or not diagnosed with type 2 diabetes mellitus.

I am passing this forward because people are still dying despite safe, effective, and cheap prevention treatment being available and this is heartbreaking. Do all statins provide the same benefit? We went further and identified two of them to be the best: pravastatin and rosuvastatin. The groundbreaking data was presented this fall by one of my students representiing my group at the annual meeting of the American Association of Clinical Pharmacists. I’ll tell you more about that story later. Stay healthy!

PS. Yes, AACR accepted our presentation that year! The data was subsequently accepted for publication too.

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Dr. Alice

I teach people how drugs work, when they are needed, and why. My expertise as a pharmacist and researcher allows me to determine whether taking or not taking a drug will pose any risk given all current circumstances that apply at this moment. Many times we don't know unless we try, but other many times walking the extra mile pays off giving in return more wonderful moments and more to give to others.

3 thoughts on “The fall of the statins

    1. Did you have any muscle pain throughout these 20 years of using statin? If not, then nothing to worry. My first guess would be that consistent muscle pain would surely lead to the treatment interruption. Hard not to notice muscle wasting (rhabdo) because it hurts and it also leads to urine color changes (darker brown). Do check your cholesterol and C-reactive protein levels every year and make sure to take the statin as prescribed. Last, not least, these 20 years prove the promised cardiovascular event prevention and that is wonderful for you – many more years to come!

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