Yet another drug that medical researchers hoped would be a godsend for people at high risk of cardiovascular disease has bitten the dust before it even hit the market, its major pre-licensing trial, which had enrolled over 12 000 patients at high risk for serious cardiovascular problems in 540 health centres around the world, abandoned by the drug’s manufacturer due to poor results.
And yet the lesson just doesn’t seem to sink in – manipulating biomarkers with drugs doesn’t actually cause people to become healthier; it just results in them dying prematurely with good-looking numbers.
The latest drug to induce this sense of déjà vu is called evacetrapib, a name that rolls trippingly off the tongue. It was developed to treat people with elevated cholesterol who can’t take statin drugs such as Lipitor because of the muscle pain and damage they cause.
(Not to mention the fact that for most of the people to whom they’re prescribed – those in the ‘primary prevention’ category which means they haven’t yet had a heart attack but have elevated cholesterol which puts them at risk of one – they reduce the risk of having a heart attack by only 2.3%, and of dying by less than 1%, which is pretty underwhelming for drugs that have raked in billions of dollars for their manufacturers.)
Statins work by inhibiting an enzyme called HMG-CoA reductase, which controls the very first step of cholesterol synthesis. Problem is, it’s also the first step in the synthesis of coenzyme Q10, a vitamin-like substance which helps cells generate energy. This may be one mechanism by which statins cause muscle pain and damage.
Evacetrapib has a completely different mechanism of action to statin drugs: it’s a cholesteryl ester transfer protein (CETP) inhibitor, which works by pulling cholesterol out of HDL particles so it can be dumped into bile and excreted from the body.
And the recently-cancelled trial showed that it worked extremely well at manipulating cholesterol fractions: those taking evacetrapib saw their LDL (‘bad’) cholesterol drop by an average of 37% and their HDL (‘good’) cholesterol rise by 130% (i.e. more than double).
Problem was, these changes in biomarkers didn’t translate to the results that actually matter to patients. There wasn’t a damn bit of difference between those taking the drug and those taking placebo in rates of cardiovascular death, heart attack, stroke, coronary artery bypass surgery or hospitalisation for chest pain due to unstable angina.
What’s the point of taking a drug that gives you pretty blood-work, but doesn’t protect you against disease? Answer: there isn’t one, which is why evacetrapib’s manufacturer, Eli Lilly, pulled the plug on the clinical trial and has abandoned the drug.
What fascinates me about the whole debacle is that evacetrapib was actually the third drug in its class to have a clinical trial cancelled due to poor results. Torcetrapib, the first CETP inhibitor to be developed, had its major pre-licensing clinical trial terminated early by its manufacturer, Pfizer, when it was found to increase HDL cholesterol by 60-100%, lower LDL by up to 20%… but raise the risk of dying from either cardiovascular or other causes. Oops.
Then Roche canned its contender in the CETP inhibitor contest, dalcetrapib, after it was found to be ineffective at preventing death from coronary heart disease, nonfatal heart attack, ischemic stroke, unstable angina, or cardiac arrest.
Despite these disappointing results, cardiologists were pretty worked up about the potential of evacetrapib (Dr Peter Libby, a Harvard cardiologist, avowed that “All of us would have put money on it,” – and I imagine some of them did), and appeared flummoxed when it failed to show the expected benefit. The study’s principal investigator, Dr Stephen Nicholls, who also happens to be deputy director of the South Australian Health and Medical Research Institute in Adelaide, expressed his consternation at the unexpected results:
“We had an agent that seemed to do all the right things. It’s the most mind-boggling question. How can a drug that lowers something that is associated with benefit [i.e. LDL] not show any benefit?… we’re trying to understand how a drug that seems to do all the right things in terms of blood cholesterol levels doesn’t then translate into reducing clinical events.”
Newsflash, Dr Nicholls: Health comes through healthy living. You can’t drug a person into wellness. You can’t compensate for the health-destroying effects of the Western diet, laden with artery-clogging and inflammation-generating animal products, refined carbohydrates and oils, by giving people drugs.
Dr Paul Thompson, a cardiologist at Hartford Hospital, allowed himself to peek at the truth when he mused
“It may be that the LDL level is less important than how it gets changed,”
but then distanced himself from the implications of his statement by adding
“But we don’t know that.”
Well, it depends what you mean by ‘know’. It’s been known for decades that people have naturally low cholesterol, blood pressure, triglycerides or any number of other risk factors, because they have earned their good numbers through healthful living, also enjoy protection against cardiovascular disease.
For example, males in areas of rural China where a diet low in animal products and overall fat kept average cholesterol levels at 3.3 mmol/L, had a nearly 17-fold lower risk of dying from coronary artery disease than American men, while Chinese women had a nearly 6-fold lower risk (bearing in mind that women have a far lower risk of heart disease than men throughout most of their lives).
The sad reality is that medications constitute a permission slip for people to continue their self-destructive lifestyle practices while being lulled into a false sense of security that the magic pill will save them: A US study found that statin users increased their intake of calories and fat, due to the false reassurance that the drug provides.
We’re way past due for doctors to grow up and stop putting childish faith in drugs for the treatment and prevention of condition that are universally acknowledged to be lifestyle diseases, and to treat their patients like adults too. When was the last time your doctor sat you down and explained your choices to you fully and honestly:
“Well, Mr/Ms Jones, you have a disease that was caused by your poor dietary habits and lack of exercise. If you want to recover from this disease, you will have to eat a diet consisting mostly or entirely of minimally-processed plant foods and get regular exercise. If you do this, you will probably make a full recovery and go on to live a long, healthy life. If you do not wish to change your way of life, I can prescribe drugs to you. They will make your blood-work look better, but will have very little effect on your risk of dying prematurely from your disease. They will also have side-effects that may seriously impair your quality of life. Now, you tell me which course of action you’d like to take.”
Never had this conversation with your doctor? I’m not surprised. But interestingly enough, some medical academics are waking up to the pointlessness of targeting risk markers such as high cholesterol, rather than the risky behaviours that cause them. Dr Rita Redberg, the editor of JAMA: Internal Medicine, commented in an editorial that
“Focusing on cholesterol levels can be distracting from the more beneficial focus on healthy lifestyle to reduce heart disease risk.“
But until the day comes when doctors have such conversations with their patients (if it ever does!), you need to take responsibility for your own health.
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