Jupiter? A Lot of Gas. Much Remains Hidden.
Statins — if they are putting a smile on your face, you most likely work for the pharmaceutical industry. Patients taking them for any longer periods are most certainly not smiling.
Statins are in many ways quintessential pharmaceuticals. As most pharmaceutical drugs, statins interferes with and suppresses important biochemical pathways in the body. They are marginally effective in terms of disease prevention (about 1% absolute risk reduction) but portrayed as a wonder drugs.
SIDE EFFECTS
Because of the mode of action, long term use is expected to create numerous serious side effects, but since studies usually are only a few years long, these potentially devastating side effects will be prominent only after a longer period of time, especially when they have been prescribed to large sections of the population.
So why do we not hear reports of statin users keeling over en masse? When the noticeable side effects grow more and more unpleasant, most people stop taking them. This saves them from being hit with serious effects such as rhabdomyolysis, ALS or kidney failure.
If you ask the patients taking statins how they would rate statins, you get consistently low ratings because of the associated side effects. For example, in one online database, Crestor received a rating of 1.9 on a scale of 1 to 5. Lipitor get a 2.1 rating.
Patients describe the experienced side effects and give the drug a rating. They also submit any comments they may have. The comments on average go something like this:
I am so happy I found this website. I have had devastating muscle pains and muscle loss, memory problems, hair loss, panic attacks and depression. My life has been completely wasted. I had to quit my job. I felt like a zombie. My doctor told me it has nothing to do with the statins and told me to keep on taking them, but after coming here, finding out that I am not alone, I have stopped taking the drug and my problems have rapidly abated. If I try statins again, the problems come back. I feel so much better now, the only problem is that my kidneys seem to be permanently damaged. I will need dialysis or a transplant. The prescribed statin quickly and dramatically lowered my cholesterol levels but it also completely ruined my quality of life. I will never take statins again. They robbed me of my mind and ruined my health permanently.
Most of the sporadic positive ratings are positive mostly because the statin did manage to reduce the cholesterol levels, not because the patient has experienced an increased quality of life.
The small risk reduction provided by statins seems not to be a result of their cholesterol lowering action, but this fact is not widely advertised of course. The fact that low cholesterol levels are associated with a long list of problems including a higher risk of violent death is usually not mentioned either.
IMPRESSIVE UNDERREPORTING
If you ask the pharmaceutical industry, they tell you that statins are very well tolerated and have very low rates of side effects. How does this add up?
The short answer is: your doctor isn’t listening. Studies have shown that when patients report statin side effects to their doctors, they are most likely to deny that this has anything to do with the medication, even if the side effect is a well known adverse drug reaction. If you report a less well known statin side effect such as memory-loss, depression, or aggression, this has a very low chance of being reported as an adverse drug reaction. :
Eighty-seven percent of patients reportedly spoke to their physician about the possible connection between statin use and their symptom. Patients reported that they and not the doctor most commonly initiated the discussion regarding the possible connection of drug to symptom (98% vs 2% cognition survey, 96% vs 4% neuropathy survey, 86% vs 14% muscle survey; p < 10−8 for each). Physicians were reportedly more likely to deny than affirm the possibility of a connection. Rejection of a possible connection was reported to occur even for symptoms with strong literature support for a drug connection, and even in patients for whom the symptom met presumptive literature-based criteria for probable or definite drug-adverse effect causality.
Jerry Avorn, a professor at Harvard Medical School and the author of “Powerful Medicines: The Benefits, Risks and Costs of Prescription Drugs” claims there is a horrendous underreporting of side effects and that a whopping 90% to 99% of serious side effects are not reported.
And statins are advertised as wonder-drugs with very few side effects, creating a mindset that cause most reports from patients to be immediately dismissed.
Regarding effects on the mind; memory loss, depression and aggressive behaviors, the divide between official drug information and the real world experiences of patients seems particularly wide.
STATINS, A RECIPY FOR SCRAMBLED BRAINS
Cognitive side effects aren’t even listed on the patient information sheets for Lipitor, for instance.
Well, you might say that if there are no studies that document these cognitive side effects, I should not expect it to be listed on the patient information sheets. True, but there are studies.
Independent UCSD researchers report that memory problems are the second most common side effect after muscle aches. The UCSD Statin Study group, headed by Beatrice A. Golomb, MD, PhD, has been researching the risk-benefit balance of statins and they consistently find effects on moods and memory besides the well known muscle symptoms. This might include patients who were irritable, hostile or exhibited short tempers, road rage and homicidal impulses. They have also encountered patients developing temporary amnesia and cognitive problems leading to the loss of their employment.
So why are there so few studies documenting these effects? Most trials are performed with the aim of documenting the benefits of the drugs tested, they are not designed to identify these less well-defined cognitive effects. Many studies also exclude patients who experience side effects in pre-trial tests, leading to low rates of reported side effects in the trial itself.
How are these cognitive effects ever going to be properly registered as adverse reactions if they almost always are interpreted as normal features of old age by doctors that believe statin drugs are side-effect-free gifts from the pharmaceutical gods? Still, even though these cognitive effects are very rarely reported, hundreds of Medwatch drug adverse reports actually have managed to reach the FDA. The problem is that the FDA is not reporting their data back to the medical community.
COMPLETE MEMORY LOSS
Duane Graveline MD MPH, Former NASA Astronaut, Former USAF Flight Surgeon has personal experience of these effects and wrote about them in his books “Lipitor, Thief of Memory” and “Statin Drugs Side Effect.” He suffered from transient global amnesia after being put on Lipitor and was found by his wife in a confused state, walking around aimlessly in the yard outside their home, unable to recognize his home or his wife.
This effect is not rare. It is not only common but inevitable. Muldoon says 100% of statin users have cognitive dysfunction if one uses sensitive enough testing. The reason is that our sole source of brain cholesterol so vital to memory function, is from our glial cells. The effect of all our statins on the hippocampal glial cells is quite predictable — inhibition. Need I say more? Some 40% of my 6500 reports from statin victims are cognitive in nature.––– Duane Graveline
Pfizer, the manufacturer of Lipitor, says the drug has been tested in 400 clinical trials and racked up 145 million patient years of experience. They claim the data “do not establish a casual link between Lipitor and memory loss.”
Well that speaks volumes about Pfizer. The pharmaceutical companies are aware of the problem, but they are not in a terrible hurry to investigate. On the contrary, it is business as usual; they will do all they can to bury the evidence, disregarding the consequences of such a strategy.
Cognitive problems, rage and homicidal tendencies, well that rings a bell. For fifteen years, Ely Lilly managed to hide the nasty little fact that Prozac had a suicide risk twelve times higher than other antidepressants.
SILENCE IS GOLDEN
The usual response of the pharmaceutical companies to health professionals that dare to speak out is to scare them into submission. Luckily, not all are easily scared.
Orli Etingin, vice chairman of medicine at New York Presbyterian Hospital, declared the following about Lipitor at a recent luncheon discussion:
This drug makes women stupid.
Dr. Etingin, is the founder and director of the Iris Cantor Women’s Health Center in New York. He told the story about a patient in her 40s, who could not concentrate or recall words. Tests could not identify the problem, but after she stopped taking Lipitor, the symptoms vanished and when she resumed, the symptoms returned.
“I’ve seen this in maybe two dozen patients”, Dr. Etingin said later, adding that they did better on other statins.
MODE OF ACTION
Why would we expect to see effects on the brain and nervous system from statins? Statin drugs work by an enzyme that enables the liver to make cholesterol, and cholesterol is absolutely vital for the brain and nerves.
Besides inhibiting the manufacture of cholesterol, statins also inhibits CoQ10-production since it is part of the same pathway, the mevalonate pathway. The way it works is that the statin inhibits the enzyme HMG-CoA reductase which is the rate-limiting enzyme of the mevalonate pathway.
Is this a good thing? No, it is disastrous.
This system is essential for our survival. The activity of this enzyme could be said to be a requirement for metabolic fitness. Inhibiting the enzyme HMG-CoA reductase is similar to inducing old age and decrepitude, which fits very well with the way the unfortunate patient feels after being on statins for a while.
Inhibiting CoQ10-production is a recipe for premature aging and death and has serious implications for muscle and nerve health. This is something that Duane Graveline the Former NASA Astronaut unfortunately also has experienced. He was not only hit with several bouts of very serious memory loss; after stopping all statin drugs, he did not fully recover and after a while it dawned on him that his progressing weakness fits the symptoms of a dreaded disease that has been identified by the WHO as a possible side effect of statin treatment; ALS – Amyotrophic Lateral Sclerosis, which usually is considered unfailingly lethal.
THE JUPITER STUDY
In light of this, let’s take a look at the new celebrated study of Crestor: The Jupiter Study. Here is what the authors say themselves in the study:
In this trial of apparently healthy persons without hyperlipidemia but with elevated high-sensitivity C-reactive protein levels, rosuvastatin significantly reduced the incidence of major cardiovascular events.
The disinformation starts as early in as at the fifth word of the sentence: “apparently healthy persons.” They were not at all healthy! If you read the study, you see they had high blood sugar, roughly 80% were overweight or obese and more than 40% had metabolic syndrome.
The lead author Paul M. Ridker was asked the question, “There has been some discussion here at the AHA about this population, the apparently healthy men and women in this trial, with people saying they really weren’t all that healthy, 41% metabolic syndrome, blood pressure maybe a little higher than optimal. I’d like you to respond to that, how healthy are these people, are they patients?”
And he responds in this interview:
RELATIVE RISK REDUCTION, ABSOLUTE DECEPTION
Compared to placebo, the group treated with Crestor had about half the chance of having fatal event in the form of a heart attack, stroke, or cardiovascular disease. This 50% risk reduction sounds really impressive, doesn’t it? That’s because they choose to present the risk reduction in relative terms — that is; the change of risk expressed as a percentage of the original risk. The real (absolute) risk reduction in the Jupiter trial was 0.9%. The results suggest you reduce the risk of having an event from 1,8% to 0,9% if you take the drug for 1.9 years.
WHAT ARE THE REAL SIDE EFFECT RATES?
What they usually fail to tell you is that you now have a high (absolute) risk of experiencing some form of side effect from the drug. How high? For statins in general the range goes from around 1% to up to 90% depending on whom you ask and what you are measuring. The industry says 1% or less but that has nothing to do with reality.
Doctors frequently judge the rate to be around 10-15% from their own experience with patients on statins, but then you have to take into account that they normally explain away a substantial part of the side effects, instead classifying them as effects of old age, so the real figure is higher.
Some claim it is around 30%. One trial found an astounding 90% side effect rate. In that study, as many as half of the events were considered serious, but the authors for some reason chose not to comment on this high rate.
JUPITER IN THE MEDIA
Let’s get back to the Jupiter trial. It has been described like this in the media:
Cholesterol-lowering statin drugs are already blockbuster medicines taken by 30 million people around the world. Now it turns out you still might need them if you have normal cholesterol. ––– Scientific American
But, was a more realistic interpretation is: The trial shows that for the very small and unusual group of people who are overweight and have a high CRP but still have low or normal cholesterol levels, there is a reduced chance of having a stroke or heart attack. But there seems to be an increased risk of having a FATAL infarction.
If you look at the numbers you see that the Crestor group had a higher number of fatal infarctions; nine instead of six, which is 50% higher if you would like to use deceptive relative percentages. The Crestor group had a lower number of fatal strokes, though, three instead of six.
If we can trust the results. Why should we not?
According to Mark Hlatky, a Stanford University health-policy professor, the study was poorly controlled and excluded people with diabetes and uncontrolled high blood pressure.
Also, there are surveys of clinical trials has shown that studies funded by drug companies have a very high chance of showing that the drug is effective whereas studies of the same drug that are not funded by the industry have a much lower chance of demonstrating the drug to be effective.
What do we know about Crestor?
The FDA finally approved Crestor in August 2003 after delays caused by safety concerns. AstraZeneca marketed Crestor as a “super statin”, lowering cholesterol much more aggressively than other statins, which no doubt was a good marketing strategy back then, but now the Vytorin debacle has shown that lowering LDL cholesterol excessively is not a magic formula for success. Baycol, which also is a super statin, was withdrawn from the market because its side effects.
Crestor has been called the worst cholesterol drug on the market. Why? A study by the American Heart association found Crestor have 6.8 times the number of adverse effects as Lipitor and 2.2 times as many as Merck’s statin Zocor.
The consumer group Public Citizen has put Crestor on its “DO NOT USE” list, saying it is “possibly worse than BAYCOL.” Public Citizen and its Health Research Group directed by Dr. Sidney M. Wolfe, has a track-record of correctly predicting the withdrawal of drugs such as BAYCOL, Propulsid, and Rezulin long before they are actually withdrawn.
It is a doomed drug. It is not going to survive. [...] The renal toxicity, high rate of cases of rhabdomyolysis compared with other statins and lack of unique benefit are compelling reasons to remove rosuvastatin from the market before additional patients are injured or killed.––– Dr. Sidney M. Wolfe
OK, lets have a look at the adverse events (Table 4), in particular, those events that occur more frequently in the treatment group: Newly diagnosed diabetes: +54 cases, Hepatic disorder +30 cases, Renal disorder +55 cases, Rhabdomylosis +1, Myopathy +1, Muscular weakness, stiffness, or pain +46, Creatinine, >100% increase from baseline +6.
Although some of these raise concern, it must be considered a surprisingly low number of adverse events, in total 193 out of 8901 which amounts to 2%.
IMPRESSIVE DROP-OUT RATES
This begs the question; Why did a whopping 25% stop taking the drug during the trial? That’s 2225 people who decided they didn’t want to continue.
A substantial number of these drop-outs must be expected to be side effect related. Muscle aches is a frequent complaint, and the rates reported in this study does not at all seem credible.
If we say just half of the drop-outs are side effect related and we assume there was only one side effect per person, we get an adverse event rate of 12,5%, more than six times higher than reported. Is this an accurate prediction of what would happen if Crestor was let loose on a rampage among unsuspecting members of the general population?
Well, no, it is just guesswork and we are not taking into account that the pre-trial screening of study participants must have weeded out a large number of sensitive individuals, so you could expect the real world side effect rate to be even higher.
PREMATURE TERMINATION
But wait, there is more. The study was only allowed to run for 1.9 years, allegedly because it would be unfair to have the participants in the placebo arm to go without Crestor. [Insert roll-of-eyes here].
Isn’t it likely that there would be a continually rising rate of serious adverse events as the study progressed? It seems very convenient to terminate the study early after 1.9 years instead of letting it run the planned 4 years. It certainly is convenient for the sponsor of the study, Astra-Zeneca – the manufacturer of Crestor, and very convenient for the lead author who happens to be a co-inventor of the patent for the CRP-test used in the study.
The authors themselves acknowledge the possible problems inherent in lowering cholesterol as aggressively as was done in the Jupiter trial:
In this trial, myopathy, hepatic injury, and cancer did not occur more frequently with rosuvastatin than with placebo, despite the fact that LDL cholesterol levels below 55 mg per deciliter were achieved in half the participants receiving rosuvastatin (and LDL cholesterol levels below 44 mg per deciliter in 25%). Since the median follow-up of subjects was 1.9 years, we cannot rule out the possibility that the rate of adverse events might increase in this population during longer courses of therapy.
Yes, how true.
The aim of the study from Astra-Zeneca’s perspective seems to be to expand the use of Crestor to a large segment of the population, but is it really a good idea to unleash a super-statin with a high rate of adverse events based on a 1.9 year long prematurely halted study sponsored by the manufacturer?
The track record of data manipulation and trickery that we have seen from pharmaceutical companies over the years should cause even people wearing extremely rose-colored sun-glasses to be a little suspicious of this study.
The premature cessation of Jupiter study could be seen as a sign that Astra-Zeneca is well aware of the long term risks associated with Crestor, causing them to end the study to avoid the embarrassment of having the number of deaths in the Crestor arm of the study overtake the number of deaths from all causes in the placebo arm.
Is there any signs of such a trend in the data? Have a look at this graph from the study:
I rest my case.
And have a look at the lower curve. That’s the real data. The real difference is that small! In the upper curve the difference between the treated and untreated group is magnified to make it easier to see.
ANOTHER FRAUD?
You would hope that the costs of compensating victims of pharmaceutical fraud would be high enough to discourage trickery and data manipulation in the pharmaceutical industry. Is that true? The legal aftermath of the Vioxx fraud would be a good indicator.
In the Vioxx cases that went to trial between 2005 and 2007 where Merck was accused of fraud, causing the death of hundreds of thousands people, the company prevailed in 11 out of 16 trials. This tells us how hard it is to persuade juries that pharmaceutical companies knowingly defrauds regulators, doctors and patients, even when there is corroborating insider information from governmental agencies.
If it makes financial sense to downplay risks and hide data, should we really be surprised if Crestor turns out to be a seed that produces bitter fruit?
You could wish for a world in which the righteous reap the sweet fruit of their uprightness, where the wicked reap the bitter fruit of their wickedness and the innocent are protected.
Unfortunately, in the real world there is little protection for the innocent and the pharmaceutical companies seem to enjoy all the fruits they are reaping.
For now.
- www.AskAPatient.com Crestor Rating ¶
- www.AskAPatient.com Lipitor Rating ¶
- Golomb, Beatrice A.; McGraw, John J.; Evans, Marcella A.; Dimsdale, Joel E.Physician Response to Patient Reports of Adverse Drug Effects: Implications For Patient-Targeted Adverse Effect Surveillance, Drug Safety, Volume 30, Number 8, 2007 , pp. 669-675(7). ¶
- Healy D, Herxheimer A, Menkes DB (2006) “Antidepressants and Violence: Problems at the Interface of Medicine and Law.” PLoS Med 3(9): e372 doi:10.1371/journal.pmed.0030372 ¶
- Duane Graveline, My Statin Story ¶
- The Jupiter Trial: Paul M Ridker et al., Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein, N Engl J Med. 2008 Nov 20;359(21):2195-207. Epub 2008 Nov 9. ¶
- Pedersen TR, Faergeman O, Kastelein JJ, Olsson AG, Tikkanen MJ, Holme I, et al. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA 2005;294: 2437-45. ¶
- Bekelman JE, Li Y, Gross CP. Scope and impact of financial conflicts of interest in biomedical research: a systematic review. JAMA 2003;289: 454-65. ¶
- Joel Lexchin, Lisa A Bero, Benjamin Djulbegovic, Otavio Clark, Pharmaceutical industry sponsorship and research outcome and quality: systematic review, BMJ 2003;326:1167-1170 (31 May), doi:10.1136/bmj.326.7400.1167 ¶
