Bempedoic Acid-- A medicine for a condition that may not exist
This is the third of my three-part series on the importance of control arms of trials
The Study of the Week finishes its three-part series on control arms. This one is a bit different than the past two columns in that the control arm will surely be used as a marketing force for a new cholesterol-lowering drug.
I will show you, in the fourth short chapter of this post, that you should have doubts regarding the nature of this condition.
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Chapter 1: Cholesterol plays a causal role in blood vessel disease—atherosclerosis in medical speak.
Stain drugs lower cholesterol and reduce the probability of future cardiac events. This class of drugs is one of the most studied interventions in all of medicine. The hundreds of studies on statins have shown a consistent 20-25% reduction in future events.
Statins are special in that not only do they reduce cholesterol, but they are known to have multiple other effects, such as reducers of vessel inflammation. We think these pleiotropic effects add to their efficacy in suppressing future events.
Chapter 2: At the recent American College of Cardiology sessions, we learned the results of a trial using a non-statin cholesterol reducing drug called bempedoic acid (BA). BA works in the same pathway as statins but does not affect muscle tissue.
You might wonder why we need another cholesterol-lowering drug. In blinded trials, patients stop taking statins at equal rates as they do placebo. And statins cost pennies.
Well, it turns out, that there is a phenomenon called statin intolerance.
Most people who start statins stop the drugs over the course of years. I borrowed this slide from Dr. James Howard, the primary investigator of a trial of statin intolerance, which I will tell you about in Chapter 4.
If you talk to any practicing clinician, they will testify that there are many patients who cannot take statins because of side effects, mostly muscle-related, but also brain related.
Yet, the picture above shows a puzzle: in blinded trials, the side effect profile is no different than placebo.
Chapter 3: Enter Bempedoic Acid
Steven Nissen, MD, from the Cleveland Clinic, presented results of the 14,000-patient CLEAR-Outcomes trial of BA vs placebo.
The major feature of this outcomes trial was that enrolled patients had to have statin intolerance. Half the group received the drug and half got placebo.
Bempedoic acid reduced LDL-C by about 15-20%. It also reduced hsCRP, a marker of inflammation, by a similar amount.
Over 40 months, bempedoic acid reduced the composite primary endpoint (heart attack, coronary revascularization, stroke, death from cardiovascular causes) by 13%. (HR 0.87 (0.79-0.96). Because the confidence intervals were less than 1.0, this was a statistically significant result.
That 13% relative reduction translates to a modest 1.6% lower absolute rate of events. Individual patients will see this differently. Some may say that 98.4% of the patients get the same result; but others, perhaps those who want to do everything to reduce cardiac events, will see a 1.6% reduction as worthy of taking a pill every day.
The Kaplan-Meier survival curves diverged over time, suggesting that the longer patients were exposed to the lower cholesterol level, the larger the effect.
Bempedoic acid reduced the individual endpoint of heart attack and stroke and coronary revascularization but did not reduce cardiovascular death or all-cause death.
Adverse effects deserve emphasis. Bempedoic acid predictably had no effect on muscle related complaints, but did associate with slightly higher rates of gout and gall-bladder disease.
Chapter 4: Uncertainties
The main issue is the matter of statin intolerance. For decades, doctors have tried to explain that true statin intolerance doesn’t exist—and patients should be counseled and re-started on another statin drug.
And a major study from the UK, led by Dr. James Howard, whose slide I used above, has shown that statins do indeed cause side effects, but it is not from the statin chemical, it is merely from taking a statin tablet.
That sounds weird, so let me briefly describe the SAMSON trial.
Howard and colleagues took about 100 patients who had stopped their statins because of side effects and enrolled them in 12-month trial wherein each patient received either 30 days of statin pills, statin placebos, or no pills. Each day the patients recorded their well-being on an app. (We call this an N-of-1 study, where patients are their own control.)
Sit down for the results.
Look at the bars. The average symptom score was best during the months of no tablets. But there was no discernible difference on the days/months in which patients took the placebo or real statin.
So the conclusion was that, yes, statins cause symptoms but it’s not from the statin, it’s from the act of taking the statin tablet. After the trial, about half of the previously intolerant patients successfully returned to taking statins.
Chapter 5: Now let’s predict what is going to happen…
Bempedoic acid will likely pass FDA muster. It has positive outcomes and reasonable safety. Though the degree of LDC-C reduction and degree of risk reduction is less than statins. It will surely be far more expensive than statins.
During the conference discussion, Dr. Nissen, the primary investigator of the CLEAR-Outcomes trial, mentioned that bempedoic acid can be combined with another non-statin cholesterol-lowering drug called ezetimibe. Ezetimibe has been found to have even more modest effects on cholesterol and future events. But the combination could provide up to a 40% reduction in LDL-C.
Later in the day, I was walking through the expo and came about a massive display, including an actual NASCAR adorned in ads for the combination drug, called Nexlizet. And it just so happens that the same company that makes bempedoic acid also sells Nexlizet.
My friend, electrophysiologist, and astute observer of medicine, Bogdan Enache, cheekily predicts the future.
The optimist side of me says, John, there are new cholesterol-lowering drugs available for statin intolerant patients. This is a good thing.
The pessimist side says that everyone knows that the empirical evidence clearly shows that statin intolerance really doesn’t exist, and if we were take time with patients, and use our skills as teachers, we could encourage patients to take less costly, more effective drugs.
SAMSON is one of the best trials of our generation. With enough public speaking, we might even be able to change norms. But none of that is likely to occur.
Instead, my cynical side predicts that it will not be long before pharma reps show up with free lunches in our offices.
Their talking points will be the high frequency of statin intolerance in the community, the compassion they deserve, and the good news that there are now excellent options for this unmet need.
This is all assuming that lowering cholesterol actually reduces heart attacks. As I understand it, having looked at some of the studies myself, it really only helps men over a certain age who have already had a heart attack, and even then the benefit is very slight.
Several years ago I fell ill in mid Autumn. I say “ill” because I developed all the nasty symptoms of fever including joint and muscle aches and a general lethargy – without actually having an elevated temperature. About three months into this, having been told by my PCP that it was likely a virus and that I should just wait for it to clear, I decided to investigate myself. I looked at all aspects of my life that might have been different enough to precipitate this illness. Among my various considerations was a new medication I’d started not long before this started. At that time, I simply did what my doctor suggested. After all, he knows best. I decided to quit that atorvastatin for a while just to see. Less than ten days later the “illness” lifted. To be certain, I waited a week longer and, still feeling fine, decided to re-challenge myself with atorvastatin. In less than a week I had my “fever” and “illness” back.
Now, you can tell me that my initially quitting the statin set me up for The Placebo Effect and that re-challenging myself set me up for The Nocebo Effect. OK. But you’ll not be able to tell me definitively that my initial “illness” was caused by Nocebo. I’d been innocently naive of side effect reporting at that time. I’m much more circumspect across the board now. Yes, ripe for all sorts of ‘cebos – with my eyes open.
Randomized Controlled Trials can tell researchers a great deal about the group-in-general that they have singled out for researching. They are not necessarily decisively informative concerning the unique issue(s) of any particular individual.
Having done further research and seeing that, for my niche, the absolute risk reduction is between 1% and 2%, and considering my “illness”, I forego any statins. Further, I forego other forms of cholesterol reduction.