Sometimes summer rain is not such a bad thing, especially if it does force us inside temporarily and we manage to get something done we otherwise wouldn't have, or didn't miss something that we otherwise would have. Such was the case this week, when I reluctantly came inside from the dinner table on the terrace, but very happily ran into one of my favourite programs on CBC - "The Nature of Things", with David Suzuki.
The timing of this particular episode was very pertinent due to the recent FDA approvals for the newest class of cholesterol-lowering drugs known as PCSK9 inhibitors. This program was focused on cholesterol and it's association with heart disease, but perhaps rather unusually, the tone of the episode was more of a questioning nature, rather than simply selling the big pharma version of the story that we should essentially all be on a statin.
Dr. Beth Abramson, cardiologist and director of the Cardiac Prevention Centre of St. Michael's Hospital, and author of the book "Heart Health for Canadians" was up first, and she clarified that while cholesterol is (of course) an issue in heart disease, she emphasized that we are all individuals and it is our overall profile that determines our vulnerability to this disease. However, her tempered tone was not matched by Dr. Barbara Roberts, who is director of the Women's Cardiac Center at the Miriam Hospital.
Dr. Roberts, author of the book "The Truth about Statins", stated that the big statin clinical trials were all industry-sponsored trials, and said that "Industry-sponsored trials are four times more likely to report a positive result than non-sponsored trials." Additionally, she commented that statins given to healthy people (i.e. those who have not had a heart attack) only reduced the risk of a subsequent cardiac event in high risk men by a mere 1.5%. Further, she emphasised that even hardcore statin believers admit that 60-80% of all cardiac events are not prevented by statins. So what's the point here?
Dr. Roberts made the somewhat provocative statement that the only patient population who truly benefit from statins are middle-aged men who have had a heart attack, and she elaborated that beyond middle age it appears to be beneficial to have higher levels of cholesterol, which actually correlate with survival. Thus she claims that statins are essentially useful only for middle-aged men, and questions their use in women, period.
"The benefits of statins have been vastly exaggerated and the dangers have been vastly underplayed."
We then came to a question that particularly interests me, not least as it pertains to a project in our portfolio at AmorChem, which is examining the role of CD36 in the inflammation associated with cardiovascular disease. The salient point is that while, yes, there is no doubt that high levels of LDL-cholesterol are observed in direct association with heart attack and stroke, there is a clear stratification of patients who present with the disease in the apparent absence of cholesterol elevation - so what is going on?
The answer is of course, that cardiovascular disease is both a cholesterol problem and an inflammatory condition; rather shockingly to some, statins proved efficacy in a major clinical trial of almost 18,000 patients globally, even when those 18,000 people had very normal levels of cholesterol! The positive outcome can be summarised as 50% reduction in heart attack or stroke and 20% reduction in all-cause mortality. This was a game chamger, in that a cholesterol-lowering drug was that potent in patients whose cholesterol did not need lowering. The target that was identified to be lowered in response to statins in that study was of course CRP, a biomarker of cardiovascular inflammation.
But what about anti-inflammatory drugs that are not cholesterol-lowering in action? That's an excellent question, and it is being addressed in a major clinical trial being conducted currently in the USA and Canada - using an old arthritis drug which targets inflammation but has no effect on cholesterol levels in humans. Dr. Paul Ridker, a professor of medicine at Harvard Medical School and the Brigham and Women's Hospital in Boston, is examining the effect of methrotrexate, a drug that targets inflammation in arthritis, as a potentially novel agent for heart attack and stroke. The reasoning is underlined by the fact that otherwise healthy patients who have arthritis and who have taken methotrexate reportedly have lower occurrence of either heart attack or stroke, as an unexpected "side effect" or benefit of the drug.
It certainly is clear that we can have elevated cholesterol in humans, which leads to increased frequency of heart attack and stroke. Conversely, there are people with normal levels of cholesterol who still have high levels of heart attack and stroke, presumably due to a high inflammatory index. Obviously, the deadly combination of both negative factors is something that is likely to be involved in the worst cases of cardiovascular disease, and we need to impact them both in the western hemisphere.
But, as we know today, that's not the whole story either. There's another major player in this scenario, and it's not so much LDL, but rather it is its sister molecule, HDL. The benefits of HDL and it's role in reversing plaque build up were ratified by study of a small population in the town of Limone in Italy, whereby members of the population who have almost no HDL in their blood remain remarkably healthy - even in the case of certain patients with high LDL-cholesterol scores. The focus on this population by Dr. Cesare Sirtori, a professor of clinical pharmacology at the University of Milan, resulted from his intrigue at one male patient with an extremely elevated LDL level (he scored an 8.0!) and almost no HDL, but who appeared to be healthy.
Although the Mediterranean diet no doubt plays a role in preventing heart disease, Dr. Sirtori realized that it could not be the whole story, and his research showed that in this small town of largely inbred population, the residents had a mutation in a protein component of their HDL that de facto supercharged their HDL. Thus even with potentially deadly-low HDL levels, such people remained free of heart disease, which was and is a fascinating discovery. Dr. Steven Nissen of the Cleveland Clinic admitted to being totally skeptical at the hypothesis that HDL could reverse plaque built up over decades in patients during a mere six week infusion testing of a synthetic HDL, but also confessed to being "absolutely stunned" when it worked. Even though Pfizer picked up on the potential and seriously invested in the technology, it did not lead to a new drug.
Another promising discovery was made by the team of Dr. Stanley Hazen of the Cleveland Cliinic's Cellular and Molecular Medicine department who identified TMAO (trimethylamine N-oxide) in the blood of cardiac patients, which was determined to come from carnitine in our diet. This molecule is produced from red meat carnitine by bacteria in our stomach, and TMAO is now known to not only enhance cholesterol deposition in artery wall plaque, but also to prevent HDL from doing its job and exiting cholesterol out of plaque - a really negative double whammy! This novel biomarker holds promise as something else to measure to determine the overall cardiovascular health of invidivduals. A most worrying aspect of this segment in the story is that carnitine is often used as a dietary supplement by bodybuilders and athletes, and TMAO is also found in many of those energy drinks lining the shelf in the grocery store!
Notwithstanding all the discussion above about the true usefulness of statins, the cholesterol wars are only ramping up further with the imminent marketing of Praluent (Sanofi-Regeneron) and Repatha (Amgen) - two much-touted biologics that are PCSK9 inhibitors. These novel agents also target LDL, albeit by a distinct mechanism from statins, and only time will tell how successful (therapeutically and financially) these agents will become, and whether they do topple statins as the #1 drug of choice for lowering cholesterol. One disadvantage is that they are injectibles, which could impact patient compliance; this point is not lost on us and is in fact the crux of another project in our portfolio searching for oral small molecules targeting PCSK9.
Well, I better leave it there before I overstay my welcome. David Suzuki and "The Nature of Things" rarely disappoint, and this episode was no exception. Who would have thought that the hissing of early evening summer rain would have turned out so fascinatingly, and that rain did provide a rather calming backdrop soundtrack to an extremely provocative take on the cholesterol wars. Nature really did turn me on to the nature of things!
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