Nearly six out of seven participants have been men, mainly because men develop heart disease earlier and make up a greater share of heart patients. Perhaps not surprisingly, they are less informative about the effects of statins on women. Many studies simply combined data for men and women, and others didn't include enough women to permit statistically significant conclusions.
Hoping to get more definitive answers, researchers from the University of California at San Francisco and the University of North Carolina combined and re-analyzed the data for women in several major statin studies.
Writing in the Journal of the American Medical Association May 12, , they offered these conclusions:. Statins reduce the risk of cardiovascular events in women who already have heart disease. Statins reduce the risk of fatal heart attacks in women with cardiovascular disease. However, both groups had a similar risk of death from all causes. It's not clear whether statins reduce the risk of cardiovascular events or cardiac death in healthy women with high cholesterol.
Should not be taken by pregnant women, heavy drinkers, or people with active or chronic liver disease. Should be used with caution by those taking gemfibrozil, cyclosporine, clofibrate, erythromycin, or niacin. Can increase the effect of warfarin. Statins should be taken only when cholesterol remains high despite lifestyle changes reducing dietary fats, losing excess weight, and exercising more.
Many people have been on these drugs for many years, and we are beginning to discover that they may do more than lower cholesterol. For example:. They may reduce breast cancer risk. There's some evidence from the Women's Health Initiative WHI and other studies that certain statins protect against breast cancer. They may reduce gallstones. A report from the Nurses' Health Study indicates that statin use might help prevent gallstones from forming, particularly in women who have diabetes.
They may slow cognitive decline. More than 3, participants in the Cardiovascular Health Study — an NIH-sponsored observational investigation of women and men ages 65 or older — were given cognitive tests annually for seven years. The test scores of those who were taking statins declined less from year to year.
They may reduce C-reactive protein CRP. In several studies, statin use has been associated with a reduction in CRP, the inflammatory marker that is emerging as a risk factor for heart disease. An ongoing study — Justification for the Use of Statins in Primary Prevention — is testing whether a newer statin, rosuvastatin Crestor , can reduce heart attack risk in men and women with normal LDL cholesterol but elevated C-reactive protein levels.
All drugs have side effects, and statins are no exception. But their side effects are widely known, and, for the most part, mild. They include the following:. Muscle problems. Statins commonly cause muscle pain myalgia. Rarely, statin use can lead to rhabdomyolysis — severe muscle deterioration, with the release of muscle proteins into the blood.
If that happens, the kidneys can fail, overwhelmed by the task of removing those proteins from the body. Fatal rhabdomyolysis occurs in only about one person per million using the currently approved statins. Statin users who experience muscle pain should be given blood tests to check their levels of creatine kinase CK , an enzyme released in muscle breakdown.
For simple myalgia without elevated CK levels, it may help to switch to a different statin. Liver toxicity. Long-term statin use has been associated with elevated blood levels of liver enzymes.
Statin users should have their blood checked regularly, and if liver enzyme levels reach three times normal, the statin should be replaced with a different type of cholesterol-lowering drug. If you're pregnant or plan to become pregnant. Rumor—and that is all that we have to this day—had it that some of the dogs treated with mevastatin developed intestinal tumors. So in the fall of , Sankyo halted its trials.
Knowing that only a methyl group distinguished lovastatin from mevastatin, Merck, too, immediately halted its testing on people, recalling all outstanding samples from clinical investigators and notifying the U. Although only a few patients had received lovastatin, and only at low doses, Merck still advised the physicians who were conducting the trials to check very carefully for signs of cancer in their subjects. Merck then set out to determine the exact nature and extent of the problems that Sankyo had seemingly encountered.
Failing to track down any solid evidence of harm, P. As he was to relate years later in his autobiography coauthored with historian Louis Galambos of Johns Hopkins University , Vagelos took aim at getting to the bottom of the problem by making a business proposition to Sankyo: "If you help us solve this problem, we'll share Mevacor [trade name for lovastatin] with you in Japan, and you can share your second-generation product with us when you're ready.
Apparently, their bosses at Sankyo saw it as bad for business. Knowing Sankyo's concerns over the tumors that mevastatin allegedly induced, and given the general lack of cooperation that they encountered in Japan, Merck executives didn't know what to do with lovastatin. Their ultimate decision proved to be a wise one.
Instead of pursuing a drug to treat the general population, they focused their efforts on the small fraction with a condition called heterozygous familial hypercholesterolemia, which afflicts approximately 1 in people. In this genetic disease, a person carries two different copies of a gene, hence the term heterozygous. One copy works normally, and one does not. The possession of one aberrant copy of the gene in this autosomal-dominant disease is sufficient to cause problems because of a deficiency in the cellular receptors responsible for the removal of circulatory LDLs.
As a result, people with this disease have a severe elevation of LDLs, and they typically develop cardiovascular disease between the ages of 30 and 40 if left untreated. Figure 6. The liver makes two forms of cholesterol: low-density lipoproteins LDLs light blue and high-density lipoproteins HDLs dark blue a.
Next, receptors orange can capture LDLs from the circulatory system and return them to the liver. The use of statins b blocks HMG-CoA reductase, which diminishes the production of both forms of cholesterol. With fewer LDLs manufactured in the liver, fewer enter the blood.
In addition, the reduced level of LDLs in the liver triggers the expression of receptors that pull even more LDLs from the blood, which further decreases blood LDL levels. Remarkably, statins increase the level of HDLs in the blood, but the mechanism remains controversial.
Regardless, the increase in HDLs further enhances the cardio-protective benefits of statins because the HDLs ferry cholesterol from other tissues, including artery walls, back to the liver for excretion, which further diminishes blood LDL levels.
Since Sankyo had already used mevastatin on similar patients with some favorable results, the case was compelling: After all, people with hypercholesterolemia faced a great and certain danger, whereas the cancer potential of mevastatin remained only speculation. For this reason, many of the clinicians involved in the early trials of lovastatin urged Merck to continue.
Merck, therefore, did what had to be done: It presented all of its data to the FDA and sought approval for further studies on patients with this condition. The FDA consented, and Merck's clinical trials on lovastatin resumed in The early results suggested that this compound dramatically reduces LDL levels with few side effects.
The company continued its work, moving through the drug-development process. By , the FDA approved Mevacor alias lovastatin for use in patients whose cholesterol levels could not be adequately controlled by diet or by using other drugs, such as inhibitors of the intestinal resorption of cholesterol derivatives or absorption of the parent compound from dietary sources.
Despite the FDA's approval, Merck still faced a fundamental question: Although it was clear that statins decreased the level of blood LDL-cholesterol, did these drugs necessarily protect against cardiovascular disease? To find out, Merck sponsored the Scandinavian Simvastatin Survival Study the "4S study" for short , which was completed in In a group of patients diagnosed with "moderate" hypercholesterolemia defined at the time as a total blood cholesterol level of milligrams per deciliter , 2, patients received a placebo, and 2, took simvastatin, a second-generation statin from Merck produced by the synthetic modification of lovastatin.
The results of this study, a milestone in cardiology and evidence-based medicine, were conclusive. The group of patients taking simvastatin not only showed statistically significant decreases in total blood cholesterol and LDL cholesterol of 25 and 35 percent, respectively, but also a 42 percent decrease in death rate. These stunning results and the successful trials with Mevacor drew other pharmaceutical companies into the statin market.
Sankyo, for instance, eventually teamed up with Bristol-Myers Squibb to distribute and sell a derivative of mevastatin with increased efficacy, pravastatin marketed as Pravachol. Although Sankyo and Merck both originally isolated valuable statins from natural sources, their later efforts were directed at manufacturing them synthetically. In the early s, Merck filed a patent that showed that some of the complexities of the fungal metabolites were superfluous and could be eliminated without compromising biological activity.
Figure 7. LDL receptors—shown here as a crystal structure—in the liver are often defective in heterozygous familial hypercholesterolemia, a genetic disease that causes very high levels of blood LDLs. People with this disease usually develop cardiovascular disease by the age of Merck first tested lovastatin on patients with heterozygous familial hypercholesterolemia to show that it diminishes blood-LDL levels. Merck then sponsored the Scandinavian Simvastatin Survival Study on patients with "moderately" high blood-cholesterol levels, and it showed that simvastatin—another statin from this company—diminished blood-LDL levels by 35 percent and decreased the death rate by 42 percent.
Image courtesy of Lawrence Berkeley National Laboratory. Roth, then a year-old postdoc in the chemistry department at the University of Rochester, started tinkering with statins, exploring their synthetic chemistry. In the spring of , he succeeded in synthesizing one of the fungal statins that Endo and Kuroda had isolated a few years before. Within only two years, Roth found himself heading up an scientist atherosclerosis group at Parke-Davis Pharmaceutical Research.
And while they made remarkable progress in fabricating their first synthetic HMG-CoA-reductase inhibitor, this was scuttled when they were notified that Sandoz AG, a Swiss drug company that is now part of Novartis, had obtained a patent for the very same compound.
Parke-Davis was left with no other option but to turn its efforts toward what started out as a second-tier drug called atorvastatin—now known better by its trade name, Lipitor. Did this mean that the market was already saturated? According to Ron Winslow, later writing in the Wall Street Journal , the decision Parke-Davis made arose from economic rather than scientific considerations. Second, the statin market looked likely to grow into one of the biggest pharmaceutical boons of all time.
In short, if Parke-Davis could capture even a small piece of the action, Lipitor could become the company's best seller. These considerations were to be the tipping point. Parke-Davis moved the compound into clinical trials to show that doses of Lipitor of 10 milligrams and 80 milligrams per day decreased LDL-cholesterol levels by 40 and 60 percent, respectively.
These were decreases in LDL-cholesterol levels that beat every other available statin—at any dose—by at least 40 percent. With the niches for statin drugs quickly filling up, Parke-Davis wanted to get Lipitor to customers as soon as possible. To do that, the company needed to convince the FDA that Lipitor should be put on the fast track for approval, a privilege reserved for products that address an "unmet medical need.
Figure 8. Lipitor top is a statin called atorvastatin, which was developed by Parke-Davis later purchased by Pfizer. To find that need, Parke-Davis used a version of Merck's earlier technique. Parke-Davis contacted two South African doctors who were treating a group of young patients with the homozygous form of familial hypercholesterolemia.
This is where an individual has not just one but two copies of the disease-causing gene. Characterized by cholesterol levels of milligrams per deciliter or more, children with this condition typically suffer a heart attack or undergo bypass surgery before or soon after entering their teens.
Because these doctors had previously tried Merck's Zocor trade name for simvastatin with little effect, these children faced a grim prognosis. With very little to lose they agreed to try Lipitor. The blood cholesterol levels of the children in the trial started to come down within a month. One child with an untreated blood cholesterol level of 1, milligrams per deciliter achieved a new steady state of Others with somewhat lower untreated levels achieved milligrams per deciliter.
Having at least gone some way toward meeting this unmet medical need, Lipitor received a priority review from the FDA. To get a similarly fast and favorable "review" from customers, Parke-Davis made an equally strategic marketing decision: They elected to co-market Lipitor with Pfizer.
At the time, , Pfizer was the fifth most-profitable pharmaceutical company, renowned for its acumen in sales and marketing, but also a company that lacked a statin of its own.
Disadvantages would seem to be inevitable when entering a market late in the game, but if there is an advantage to be had it is that the latecomer has ready access to the competitor's products to test against their own. To set off Lipitor from other statins, Parke-Davis and Pfizer therefore commissioned a head-to-head trial—called the CURVES study—of comparative-dose efficacies of Lipitor atorvastatin against four other statins in patients with hypercholesterolemia.
Lipitor won hands down. For example, at a dose of 10 milligrams per day, it lowered LDL cholesterol by 38 percent, which was significantly better than what patients experienced with equivalent doses of fluvastatin 17 percent , lovastatin 29 percent , pravastatin 24 percent and simvastatin 28 percent. Lipitor captured 18 percent of the statin market over the next 18 months, in large part through Pfizer's sales prowess—making it second only to Merck's Zocor, which had 37 percent.
In one case, though, even Congress believed that Pfizer's marketing of Lipitor went too far. In January , Pfizer launched a Lipitor-advertising campaign centered on Robert Jarvik—known for developing the Jarvik artificial heart.
As Stephanie Saul wrote in the February 25, , issue of The New York Times : "[T]he campaign had come under scrutiny from a Congressional committee that is examining consumer drug advertising and has asked whether the ads misrepresented Dr. Jarvik and his credentials. Although he has a medical degree, Dr. Jarvik is not a cardiologist and is not licensed to practice medicine.
Jarvik as an accomplished rower gliding across a mountain lake, but the ad used a body double for the doctor, who apparently does not row. As of March Lipitor's patent is due to expire, at which point it will face competition from generic versions. In this eventuality, Pfizer will need more than sheer marketing power to replace Lipitor's revenue stream. Akira Endo's decades-old adventure continues.
In the mids, the U. Heart Protection Study—sponsored by the U. These subjects were considered at high risk of cardiovascular disease because of factors such as diabetes, but their physicians did not consider them candidates for statin therapy because their blood LDL-cholesterol levels were within the normal range.
Nonetheless, this study put these people on either 40 milligrams per day of simvastatin or a placebo for an average of 5. The results were impressive. In those individuals with diabetes but no obvious arterial disease who were put on simvastatin, the risk of a heart attack or stroke decreased by about 20 percent. Rory Collins, who together with Richard Peto, headed this study, estimates that up to 20 million people worldwide would be eligible for statin therapy.
On TheHeart. Other work shows the potential for still broader applications of statins. In April , for example, Beatrice A. Golomb, a professor of medicine at the San Diego School of Medicine and director of the University of California, San Diego's statin study, and colleagues reported that statins lower blood pressure.
Learn more. Show navigation Hide navigation. Sub menu. History in medicine: the story of cholesterol, lipids and cardiology Vol. Petra M. Topic s : Lipids. Introduction Checking lipid values and prescribing lipid-lowering drugs is core business for cardiologists.
History The word cholesterol consists of chole bile and stereos solid , followed by the chemical suffix -ol for alcohol. Figure 1. Chemical structure of cholesterol. Lipoproteins In , Michel Macheboeuf suggested that circulating lipids exist in complexes with proteins: this was the discovery of lipoproteins [10, 13]. Figure 2. Dorothy Crawford Hodgkin More research into lipids, lifestyle and atherosclerosis In the early s, it became clearer for some that there was an association between lipoproteins and cardiovascular disease CVD [13].
Epidemiological studies In those exciting times, large population studies were born, and epidemiological evidence was gathered. Dietary interventions When epidemiological evidence presented an association between diet and congenital heart disease CHD , the first dietary intervention studies were initiated. Figure 3. History of lipid-lowering drugs Before reaching the lifechanging era of cholesterol-lowering drugs in the s, other options were tested.
Nicotinic acid Nicotinic acid Niacin was first synthesised by Albert Ladenburg in [8]. Resins The Dow Chemical Company developed cholestyramine as a water softener.
Other substances In the s, by serendipity, it was found that, whilst removing a part of the thyroid as anti-anginal therapy! Newest-generation medication In , ezetimibe was introduced Schering-Plough , an intestinal cholesterol absorption inhibitor. Important pharmaceutical trials The first results of the Coronary Primary Prevention Trial which started in were published in [22]. Conclusion Every cloud has a silver lining.
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The early years of lipoprotein research: from discovery to clinical application. Ose L. Tidsskr Nor Laegeforen. Brown WV. From the Editor-in-Chief. J Clin Lipidol. Thematic review series: the pathogenesis of atherosclerosis: an interpretive history of the cholesterol controversy, part III: mechanistically defining the role of hyperlipidemia.
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