In the end I knew that statins would be overthrown. Their time, like the dinosaurs would come to an end. I also knew it would be nothing to do with me, or any of the other critics. Nor would it have anything to do with the fact that their terrible burden of adverse effects finally came to light.
No, it would be because their patents ran out, which meant that the big pharmaceutical companies could not make eye-watering profits from them anymore. Inevitably, therefore, they would be replaced. Indeed, for years I have watched, with varying degrees of amusement, the unending efforts to unearth the ‘new’ statins. The wonder drugs to be taken by everyone, for the rest of their lives. The ones that will make billions for the pharmaceutical companies, and several millions for the key opinion leaders promoting them.
Steven Nissen had a go with apoA-1 Milano. This is a little story you may want to look up on Wikipedia. Basically, a small village was found in Italy (near Milan) where people had very low rates of heart disease, and they also had very low levels of HDL ‘good’ cholesterol.
Turning science on its head, it was therefore decreed that their HDL must be especially ‘good’ at preventing heart disease. [Rather than accept that HDL had bugger all to do with heart disease]. So attempts were made to synthesize their form of HDL, then inject it into patients. This was done in small scale clinical studies.
So brilliantly did Nissen sell the results of these studies that a start-up company called Esperion, which funded the trials, was sold to Pfizer for over a billion dollars on the back of the results. If you want to find out more, the HDL synthesized was called ETC-216, not apoA-1 Milano.
This is what Steven Nissen had to say about the trials.
“The fact that you can actually pull major amounts of plaque out of the artery in five or six weeks is an epiphany,” Nissen says. H. Bryan Brewer, chief of the molecular disease branch at the National Heart, Blood & Lung Institute, adds: “Quite to everyone’s surprise, this indicates that we might be able to be much more successful in a shorter period of time than we thought possible.”
By golly it all sounds very exciting, does it not. Pulling significant amounts of plaque out of artery walls, in six weeks! This is quite amazing, what a brilliant drug. In truth, though, that quote was from 2003. Has anything since happened since to this magical plaque munching HDL? Is it now on the market, saving lives? Well, as you ask, the answer is no.
However, several other HDL raising agents have also been developed in the last few years. Unfortunately, they also raised the risk of heart attacks and strokes – then disappeared. Torcetrapib, dalcetrapib, anacetrapib…. A yes, anacetrapib, not quite gone yet.
‘Anacetrapib has a knock-your-socks-off effect on HDL and a jaw-dropping effect on LDL,” said Chris Cannon in an AHA press release. He also said “The lipid effects are jaw dropping in both directions,” Yes, indeed, they were. Although I am not sure that ‘jaw dropping’ and ‘knock your socks-off’ are truly scientific terms.
But then Forbes ran this headline on the 22nd October
‘Merck Heart Drug Runs Into New Worry.’ 1
As an aside, you can find out far more about drugs in development by reading Forbes magazine than you will ever get from the scientific journals.
Anyway, I wouldn’t bet the house on anacetrapib as I suspect it will soon follow the other ‘trapibs’ into an early grave. But never mind, Lilly has yet another HDL raising agent waiting in the pipeline, evacetrapib. What is it with these unpronounceable names, and why don’t these companies just give up? However, perhaps this one has a better shot than most, because as Steven Nissen said of dalcetrapib…
“Dalcetrapib was always a long shot,” said Steven Nissen, chairman of cardiovascular medicine at the Cleveland Clinic. “The worry all along was that it wouldn’t have enough effect to produce a benefit,”
Then, as he went on to say of evacetrapib
“We got everything we could hope for from this drug, and maybe more,” remarked study co-author Steven Nissen, adding that “we are going to move evacetrapib forward as rapidly as possible” into a late-stage trial.” Gosh, he is running a study on evacetrapib too. He was also lead investigator for Torcetrapib2.
That Steven Nissen, what a busy chap he is? Wasn’t he the one who said about the new cardiovascular prevention guidelines. “The evidence was never there” for the LDL targets, he said. Past committees “made them up out of thin air,” he added. Why yes, I think he was.
Anyway. They have tried raising HDL…fail. They have tried a different way of lowering LDL using ezetimibe. It lowered LDL, and has had absolutely no effect on cardiovascular disease…fail. They have tried combing different HDL raising agents with statins….fail.
You know, you might even begin to think that raising HDL wasn’t that good an idea. Billions have been thrown this target, everything has miserably failed. It is also interesting that LDL lowering agents, other than statins, have failed to have any impact on cardiovascular disease. Has this had any effect on the lipid hypothesis? You must be joking.
Given this litany of disastrous drugs trials, why do I now believe that statins are about to be overthrown? What agents could be out there that are going to sweep them into the dustbin of history.
Clearly it cannot be an agent that lowers LDL even more than statins. Can it? Well, Steven Nissen has recently said the following about LDL lowering. This quote is in connection to new drugs being developed3.
“….it matters how you lower cholesterol, not just by how much.”
It matters how you lower cholesterol, not just by how much….. Interesting. Well, if cholesterol does cause heart disease, then it doesn’t really matter how you lower it, does it? The only question is, by how much? Or is Steven Nissen trying to say something else?
As a further aside, if you want to know where the really big bucks are being spent in cardiovascular research, and what is in the pipeline, all you need to do is follow Steven Nissen’s pronouncements. He is the weather vane. You don’t need to be a weather man to know which way the wind is blowing.
…… (to be continued)
1: http://www.forbes.com/sites/matthewherper/2013/10/22/merck-heart-drug-runs-into-new-worry/
2: http://online.wsj.com/news/articles/SB10001424052702304363104577389353232022644
Dr. Malcolm Kendrick 
That is so bizarre it makes my head spin. It’s absolutely appalling. However I’m beginning to wonder if I was onto something with my anagrams. These unreal sounding names appear to be nearly palindromic but only in the way they sound just as odd when read backwards. Is is a marketing ploy?
Dalcetrapib biparteclad
Torcetrapib bipartecrot
Anacetrapib bipartecana
excuse me, it’s just the statin after-effects speaking.
Craig.
Quote: “You don’t need to be a weather man to know which way the wind is blowing.” …And you don’t need to be a medic to recognise that some drugs kill! When one reads that there are more deaths in hospitals owing to error or mistake than there are on the public highways then could the message be that whatever ails one, then go a long walk along the centre carriageway of the motorway. Okay, this might not effect a cure but it sure will increase one’s chances of survival!
Meanwhile the poor old patient is simply a pawn in the game of life…
How about this for a really smart idea?
Cholesterol Drug From Trash Seen Preventing Heart Attack
Is it now blowing some PCSK9 inhibitors our way?
Could be
One man went to munch
Went to munch a statin
Sometime shortly after lunch
Went to much a statin.
Two men went to munch
Went to munch their statins
Two men, one man, and his dog
Went to much their statins.
Ooooooh, three men went to munch
……
Ahoy, Dr K. Scandiwegian wisdom?
http://healthimpactnews.com/2013/sweden-becomes-first-western-nation-to-reject-low-fat-diet-dogma-in-favor-of-low-carb-high-fat-nutrition/
I wonder why we are in the front in Sweden with our LCHF (Low Carb High Fat) grassroot movement. Around one quarter of the population is today “carb-consious”. Authorities are seriously concerned – a good sign!
Was it just by chance that a handful of people set this off with the GP Doctor Annika Dahlqvist as the key figure? Why didn’t it happen in UK with a much more severe obesity problem to start with?
Hi Dr.K,
I think you’re missing a “closing” italic symbol somewhere in the article, as the bottom bit, after the italic quotes , is still in italics!
if it’s written in html it will be a tab me thinks!
Great article again, I don’t know how you find the energy.
Regards
I read the article and first saw ‘their patients ran out’. I bet that’s happening now too.
Neurologist Dr David Perlmutter published his book “Grain Brain” in the USA in September. This book is based on the Low Carb, High Fat, Statins Are Bad principle. Already it’s a number one New York Times bestseller. I don’t know how it got there so fast, but he did get public exposure on Fox television. That certainly seems to be the way to get to the public.
Here’s a very interesting take on statins and prescribing in general: http://www.pulsetoday.co.uk/views/blogs/statins-statins-everywhere/20005125.blog
You may need to register to read it, but it is free. I also highly recommend Copperfield’s blog -he used to do a column in the Tiimes. Wonderful!
Thanks
Articles in the press today saying “cholesterol fuels breast cancer” and saying statins can help reduce the risk: http://www.bbc.co.uk/news/health-25142026 They are certainly doing their best to make people take statins for one reason or another !
Off label prescription, gotta find somewhere to dump excess production as the fatted calf lumbers ever nearer the cliff edge.
There is this study showing raising Vitamin d level to 40ng/ml =100nmol/l reduced cancer incidence by 77%.
The cholesterol molecule they are talking about here is 27HC which is in the same biosynthesis pathway as Vitamin D3.
I doubt it will possible to prevent 27HC production without having effects elsewhere in the system including Vitamin D production.
We should also consider the reasons why 27HC is produced? There is a theory it’s a natural defence mechanism to prevent the formation of new fat cells.
#Anne
I learnt of a study recently on breast cancer and statin use; It didn’t seem to have been as well publicised as the ‘cholesterol fuels breast cancer’ study. It found that 10 year use of statins was linked to almost a doubling of the risk of breast cancer [1]. Given that result, the whole issue of prescribing statins to older women is extremely questionable especially since they have never been proven to be beneficial to women.
On another topic I found that a 2008 study that showed that cholesterol depletion inhibited insulin secretion from pancreatic beta cells, this could give an explanation for the link between statin use and diabetes [2]. I haven’t done a full literature search but it didn’t take long to find another study indicating the same thing [3]. There was an interesting letter in 2011 to QJM entitled – ‘Statin-induced diabetes: perhaps, it’s the tip of the iceberg’
I like to know the reason why things happen and the mechanism, so knowing why statins can be linked to type 2 diabetes I find useful.
(1) Long-term statin use and risk of ductal and lobular breast cancer among women 55 to 74 years of age.
Authors McDougall JA, et al
Cancer Epidemiol Biomarkers Prev. 2013 Sep;22(9):1529-37. doi: 10.1158/1055-9965.EPI-13-0414. Epub 2013 Jul 5.
http://www.ncbi.nlm.nih.gov/m/pubmed/23833125/
(2) Inhibition of Cholesterol Biosynthesis Impairs Insulin Secretion and Voltage-Gated Calcium Channel Function in Pancreatic β-Cells
Fuzhen Xia, Li Xie, Anton Mihic, Xiaodong Gao, Yi Chen, Herbert Y. Gaisano and
Robert G. Tsushima
http://endo.endojournals.org/content/149/10/5136.full
(3) Cholesterol Biosynthesis Pathway Intermediates and Inhibitors Regulate Glucose-Stimulated Insulin Secretion and Secretory Granule Formation in Pancreatic β-Cells
Miho Tsuchiya, Masahiro Hosaka , Tomohisa Moriguchi, Shaojuan Zhang,
Masayuki Suda, Hiromi Yokota-Hashimoto, Kazuo Shinozuka and Toshiyuki Takeuchi
http://endo.endojournals.org/content/151/10/4705.short
(4) Statin-induced diabetes: perhaps, it’s the tip of the iceberg
M.R Goldstein, L. Mascetelli
http://qjmed.oxfordjournals.org/content/104/2/174.short
@Anne
See this study that shows high cholesterol significantly reduces the risk of breast cancer http://healthydietsandscience.blogspot.co.uk/2012/10/high-cholesterol-reduces-risk-of-breast.html
Yes, the statin studies are all enormously biased. People with high cholesterol levels are less likely to get cancer, including breast cancer. People with high cholesterol are put on statins. People on statins are found to be less likely to die of cancer, including breast cancer. Conclusion (of an idiot), statins protect against breast cancer.
That would be a lovely example on the perils of correlation, to use in an introductory stats course. The example I was weaned on was the correlation between the price of tobacco in Havana and the salaries of ministers of religion in New England.
‘The perils of correlation’ may be the title of a future book, starring Dick Dastardly, and Muttley – no doubt.
One of my favourites in this realm is Uffe Ravnskov’s linear, very strong, relationship between the local taxes in the Stockholm area and risk for heart disease. The higher the taxes the higher the risk for heart failures.
Seems probable!
Oh yes, I knew that David. I was simply pointing out what is happening in the statin/cholesterol world. The pharmaceutical companies won’t give up their statins if they can help it 😦
I have been struck by the level of stupidity on this issue that I’ve seen on blogs. I particularly cherish one commenter who started “I know that correlation doesn’t imply causation” but then rather spoiled the effect by saying “but the degree of correlation in this case is so high that it must imply causation”.
Annnnnd now that cholesterol is on the verge of being given the green light (or conveniently ignored altogether as it probably should have from the start) they’ve miraculously found another reason to malign it and keep up the statination…
Just Google away on [ cholesterol 27HC breast cancer ] keywords, I have no idea at this stage whether the claims are legit, but basically every news outlet is saying a metabolite of cholesterol CAUSES breast cancer. We’ll see.
Oh, never mind – I didn’t read the comments section before posting… #facepalm
Hi there, I log on to yolur blogs on a regular basis.
Your writing style is awesome, keep up the good work!
Pfizer bought Esperion for a billion $ in order to protect Lipitor’s 12 billion dollar yearly revenue, effectively burying Apo A1 Milano for 14 years
Apo A1 Milano reduced atheroma volume for the first time in history of mankind a mind boggling 4% in 5 weeks of treatment in a study with 125 patients double-blind, randomized, placebo-controlled multicenter pilot trial comparing the effect of ETC-216 or placebo on coronary atheroma burden measured by intravascular ultrasound (IVUS)
So according to you sir:
“By golly it all sounds very exciting, does it not. Pulling significant amounts of plaque out of artery walls, in six weeks! This is quite amazing, what a brilliant drug. In truth, though, that quote was from 2003. Has anything since happened since to this magical plaque munching HDL? Is it now on the market, saving lives? Well, as you ask, the answer is no.”
So you are suggesting that because the drug could not hit the market yet, for the obvious reasons already stated, the drug is useless and doesn´t deserve further consideration?
What kind of scientist are you? never crossed your mind that Pfizer did bury the drug in order to protect it’s multi billion revenue treating cronic patients, instead of effectively curing them in a couple of years?
There are hundreds of different types of “HDL” lipoproteins sir! you are way out of your depth! please read and stop embarrassing yourself and endangering your patients!
http://www.health.harvard.edu/newsletter_article/hdl-the-good-but-complex-cholesterol
I pitty your patients sir, what a disgrace, sorry excuse of a “doctor”
Just have to ask, out of curiosity, is the negative “PR” and shilling against Apo A1 Milano paid, or is it good old arrogant incompetence?
Have a nice day “doc”!
If you are going to comment on my site I have three rules. One, no advertising. Two, nothing that is incomprehensible. Three, no personal insults. You have broken rule three, but I have put your comment up anyway. I think you will find that your comment says a great deal about you, and little of relevance about me. Perhaps you should ask a friend to check things you write, before you send them off. You may also wish to pay some heed to good old UK libel laws.