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.
Findings
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.
Nice write up John.
You left out the absolute risk reductions for statins and only mentioned the relative risk reductions.
All cause mortality was mentioned in your article for BA, but I didn’t see it for statins.
I think we all know this is a ploy to make billions more on a drug that doesn’t touch all cause mortality.
I look at it like getting flood insurance in a mountain that has no water, but neglecting to do anything to prevent a fire that starts on the mountain because all the trees and brush are kindling.
Have you looked deeper into the mechanisms of cholesterol and heart disease to see that it is not a direct causal link but instead associated with heart disease? Changing the diet/lifestyle factors often change the cholesterol numbers and the insulin resistance and metabolic inflammation that is more the primary cause of heart disease.
But Big Pharma and their FDA buddies them wouldn’t have billions to make and power to control if the truth about cholesterol really came out.
Hello, I am deeply shaken by this post. It has been established that statins have close to no effect for primary prevention (vast majority of thise who are prescribed statins,) and a modest one in secondary prevention. The effect is due to anti-inflammatory action and not lowering of cholesterol, (the effect is observable before cholesterol goes down). Also, for the cholesterol hypothesis to work, multiple ad hoc side hypothesis are necessary which does not reflect well on the central one !!! Very bad science indeed...Dr Malcolm Kendricks has proposed a simple and biologically plausible mechanism that can explain why rate of hearth disease goes up in various diseases and contexts that do not have any connexion between them . He has a blog and has published many books, namely The plot tickens. He has a very deep knowledge and respect of the scientific method. It's a must and fun read for every cardiologist.