Cholesterol Statins Part 2 Part 3
Statins were quickly dubbed the “miracle drug” and were transformed into the world’s bestselling drug category. Lipitor, manufactured by Pfizer, has been the world’s bestselling pharmaceutical drug from 2002 to 2010, amassing over 12 billion dollars in sales in 2010 alone. In second place is AstraZeneca’s Crestor, with sales of 6 billion dollars in 2010. There are many studies done on the cholesterol-lowering drugs, the statins. Let’s review a few.
There are at least two statin trials that have shown a relationship between cholesterol lowering and survival, one that directly contradicts mainstream dogma.
In the PROSPER trial, which involved high-risk, elderly subjects, the higher survival rates in both treatments and control groups were seen among those with the highest LDL cholesterol. In the Japanese lipid intervention trial, a six-year study of over 47,000 patients treated with simvastatin, those with total cholesterol levels of 200 to 219 had a lower rate of coronary events than those whose levels were above or below this range. The lowest overall mortality was seen in patients whose total and LDL cholesterols were between 200 and 259 and 120 and 159. The highest death rates in the studies were observed among those whose cholesterol levels were below 160.
How statins really work:
Statin drugs exert their lipid-lowering effect by blocking 3-hydroxymethylglutaryl coenzyme A reductase, an enzyme in the liver that is involved in early stages of cholesterol synthesis. Statins inhibit the synthesis not only in cholesterol but in a whole host of important and immediate metabolites including, but not limited to, mevalonate pyrophosphate, and other pyrophosphates.
Inhibition of these compounds means that statins exert a plethora effect unrelated to cholesterol lowering.
We shall discuss these later, but below are numerous examples of how these lipid independent effects can indeed impact positively on the cardiovascular system.
1. Impairment or reversal of atherosclerotic plaque formation. Statins reverse or impede the progression of atherosclerosis in rabbits without any accompanying change of the serum cholesterol.
2. Improvement in arterial function. In elderly, diabetic patients, the statins increased dilatation of the brachial artery only after three days before any changes in cholesterol occur. There were also other studies that showed improvement in arterial function prior to any drop in cholesterol. Long-term improvements in arterial functions by statins are also unrelated to the degree of cholesterol reduction.
3. Anti-clotting effects. Statins have been shown to reduce blood platelet production of thrombo__ that encourages blood clotting. These effects were not seen in the older drugs that lowered total LDL cholesterol that bound cholesterol, such as the fibrates and cholestyramine. Studies have shown that there is reduced platelet reactivity before significant reduction in LDL cholesterol.
4. Anti-inflammatory effects. Statins markedly reduce both measures of inflammation and atherosclerosis despite little changes in serum cholesterol. In humans, statin therapy produces significant reductions in C-reactive protein, a marker of inflammation. This statin-induced reduction in CRP is not correlated with any decrease in LDL cholesterol.
5. Anti-oxidant effects. We know that free radical damage plays a great role in the development of atherosclerosis. In animal studies, statins decrease oxidative stress, even where cholesterol levels remain unchanged.
6. Inhibition of the migration and proliferation of smooth muscle cells that is seen during atherosclerotic plaque formation. This phenomenon occurs independently of lipid lowering.
7. Prevention of atherosclerotic plaque rupture. In patients with symptomatic carotid atherosclerosis, 40 mg per day of pravastatin reduced the lipid and oxidized LDL cholesterol but increased the collagen content of plaque as compared to control substance. These changes are commensurate with those seen in stable plaques that are less prone to rupture. In one experiment, simvastatin significantly increased serum cholesterol levels, but induced a 49% reduction in intraplaque hemorrhage and reduction in calcification, both markers of advanced unstable plaque. These factors appear to be independent of cholesterol reduction.
8. Prevention of cardiac hypertrophy. Statins prevent cardiac hypertrophy, as demonstrated in mice. This benefit occurred despite changes in serum cholesterol.
9. Increased nitric oxide activity. Nitric oxide plays a substantial role in maintaining healthy arteries. Crestor in a study was shown to increase nitric oxide by over 50% without reducing plasma cholesterol levels.
From the preceding studies, it is shown that statins exert a multitude of favorable cardiovascular effects independent of cholesterol reduction.
Nonetheless, many doctors continue to claim that the LDL cholesterol reductions largely explain the low coronary mortality seen in some statin trials. Increasing aggressive statin therapy is now being heavily promoted, on the basis that greater reduction in LDL cholesterol will lead to more favorable coronary mortality outcomes, although some of the following studies failed to support this.
The PROVE-IT trial was randomized for patients hospitalized with acute coronary events to 40 mg of pravastatin or 80 mg of Lipitor daily. The study followup continued for two years and the high-dose Lipitor group enjoyed a 30% reduction in mortality and a 28% reduction in overall mortality, but in review of the study the PROVE-IT trial not only tested two different statin dosages, but two different statins. The variables were not controlled.
The A2Z trial showed that again all cause mortality decrease was not statistically significant, high-dose versus low-dose statin. It showed that there was no guarantee that LDL cholesterol reductions were responsible for the trend toward lower mortality on the high dose. C-reactive protein values became significant.
In many studies, there is no difference in overall mortality rates, high dose versus low dose.
The New England Journal of Medicine published a study in 2005 and the data found that patients who have a low CRP level after statin had better clinical outcomes than those with a higher CRP, regardless of the resultant level of LDL cholesterol. They found atherosclerosis regressed in patients with greater reduction in CRP levels, but not in those with the greatest reduction of LDL levels.
In another study, the PRISM study, the effects on statins on coronary events was evaluated for 1600 patients with proven coronary disease and a history of chest pain. After thirty days, statins significantly reduced mortality and the incidence of nonfatal myocardial infarctions compared to patients who did not receive statins.
The need for revascularization and length of hospitalization were also decreased, BUT the benefits were independent of cholesterol reduction. Total cholesterol levels were similar between treatment groups in both studies.
Because atherosclerosis heart disease and inflammatory ailments, it is hardly surprising that reductions in inflammatory markers such as CRP are accompanied by significant reductions in atherosclerotic progression.
In 2006, the American Medical Association Archives in Internal Medicine featured a pool analysis of thirteen randomized control trials, comparing intensive statin therapy with control group (no statins or low-dose statins are usual care in patients hospitalized with acute coronary syndrome). The results were analyzed over 24 months, with a 19% reduction in composite end-points of overall cardiovascular events, but this reduction was INDEPENDENT of LDL cholesterol reduction.
The author acknowledged the importance of statins’ pleiotropic effects and stated “There is no significant evidence that reduction in LDL cholesterol explains the beneficial effects.”
Who’s in the statin studies?
When questioned about the safety concerns of statins, drug companies constantly point out the low evidence of adverse side effects in control randomized trials.
They are trying to say that statins are safe, effective, and extremely well-tolerated, but I don’t agree. Why don’t I agree?
Because when researchers recruit participants for statin clinical trials, they are carefully screened for, and exclude, a wide range of individuals, including women of child-bearing age, those with a history of drug or alcohol abuse, poor mental function, heart failure, arrhythmia and other cardiac conditions, liver and kidney disorders and other serious diseases, and hypersensitivity to statins. Thus, the disparity between the widespread real world prevalence of side effects of statin use and the low prevalence of side effects in clinical trials is hardly surprising.
This sort of careful screening is par for the course in clinical trials, so it is little wonder that 51% of prescription drugs are subsequently found to have adverse side effects not detected prior to regulatory approval. Many studies have shown that side effects are more prevalent than we think. The results of the ALLHAT study, published in 2002, provide more evidence that statin side effects are more frequent. By the sixth year of the study, 23% of people on pravastatin had stopped taking the medication.
Statins in cancer:
In 1996, the Journal of the American Medical Association published an extensive review of the research studying the link between cholesterol-lowering drugs and cancer. It stated “All members of the two popular classes of lipid-lowering drugs, fibrates and statins, can cause cancer in rodents, in some cases at levels of animal exposure close to that prescribed to humans.
The author recommended lipid-lowering drug treatments, especially with fibrates and statins, should be avoided except in patients at high short-term risk of coronary heart disease. In the PROSPER trial, they found a 25% increase in newly diagnosed cancers among elderly individuals treated with pravastatin; while there were twenty less deaths from coronary heart disease and stroke in the treatment group, there were 24 more deaths from cancer.
In the 2006 study by Japanese researchers, there was increased incidence of lymphoma and myeloma among statin users. Knowing that statins exert immune-suppressive effects, the examination association between statin use and development of lymphoid malignancies in the case-controlled study. There was found to be a 224% higher frequency of statin use among patients with lymphoid malignancies compared to control.
In the CARE trial, breast cancer, another readily detectable malignancy, developed in twelve women from the treatment group, but only one woman with control, a highly significant difference.
Statins and impotency:
If rhabdomyolysis, cognitive dysfunction, potential kidney failure, possible increase in birth defects, cancer, and heart failure were not bad enough, recent added literature shows an adverse statin side effect of erectile dysfunction. Studies in the UK researchers noted statins associated with erectile dysfunction and impaired libido. Investigations in the Netherlands found significant reductions in testosterone, providing the clue as to why statins can interfere with sexual capacity. These widespread cases of decreased testosterone have been commonplace, since the statins decrease cholesterol, which is a precursor to testosterone therapy.
To maintain the lipid-lowering effects, statins must be administered on a lifelong basis. To establish belief that statins promote muscle damage, cognitive dysfunction, birth defects, heart failure, and carcinogenicity in rodent studies and increased cancers in human trials warrant extreme caution. Given the complete lack of data on the effects of decades of statin administration, users can consider themselves part of a massive experiment in progress, the outcome of which is largely unknown. Warnings for statins used to be limited to high-risk patients where dramatically shortened life expectancies may override any concerns about long-term effects, but things have now changed. Only time will tell what the final outcome will be.
Also important is to see if you are absorbing question from your food or you’re making it and deliver these are tested I perform and all my patients.
In my opinion, after review of the literature, I have stopped my use of statins. I had been on statins for almost thirty years. Over the years, I was on Mevacor, Pravachol, Lipitor, and Crestor. Due to the review of literature, I am now maintaining a strict diet with Nutritionals, niacin, sterols, and red rice yeast. I hope this information has been practical and informational and may better help you decide what to do.
In addition I have found with detoxification and a good diet the cholesterol can be regulated and optimal ranges
Dean Silver, M.D.