New Major Study Pans Statins

New Major Study Pans Statins

A major study panned the use of statins. Pfizer has done an excellent job of keeping the results out of the Journals and Press (a couple of minor articles were all I could find doing a search 11/11/8, in http://scholar.google.com).

"The meta analyses of primary prevention clinical trials show statistically significant benefits for men but not for women"

"A study showing Pfizer Inc.'s (PFE) cholesterol drug Lipitor was no better than a fake pill in slowing artery thickening has raised questions about the imaging technique used in that trial - and in a previous study that caused sales of rival drug Vytorin to fall."

CNNMoney.com at http://money.cnn.com/news/newsfeeds/articles/djf500/200807031304DOWJONESDJONLINE000719_FORTUNE5.htm

New Pfizer Lipitor Study Could Fuel Cholesterol-Drug Debate

July 03, 2008: 01:04 PM EST

A study showing Pfizer Inc.'s (PFE) cholesterol drug Lipitor was no better than a fake pill in slowing artery thickening has raised questions about the imaging technique used in that trial - and in a previous study that caused sales of rival drug Vytorin to fall.

The results of the so-called Cashmere study were unexpected because previous studies have shown that Lipitor, the world's best-selling prescription drug, reduces the risk of heart attacks and cardiovascular events.

"The question is not the agent in this study because we know Lipitor works," BMO Capital Markets analyst Robert Hazlett said.

Instead, Hazlett said it raises questions about the reliability of the study's imaging technique when used in certain patient populations. Hazlett recently discovered the study's results on the Web site clinicalstudyresults.org and issued a research note about the trial Thursday.

Interestingly, the new Lipitor data provides ammunition to defenders of rival cholesterol drugs Vytorin and Zetia, which are marketed by a joint venture of Merck & Co. (MRK) and Schering-Plough Corp. (SGP). The Cashmere study's design used the same imaging technique as the "Enhance" study of Vytorin, which showed Vytorin was no better than the statin drug simvastatin at slowing artery thickening.

Merck and Schering-Plough have defended Vytorin's effectiveness in lowering bad cholesterol levels, but prescription volumes for both Vytorin and Zetia have plummeted since Enhance results were released in January. Vytorin is a combination of Zetia and simvastatin.

In both studies, patients at the start of the trial had relatively low artery disease burden, possibly because of prior treatment with cholesterol drugs. That could help explain why the study drugs were unable to show a significant benefit as measured by an imaging technique known as carotid intima-media thickness, or CIMT, a noninvasive ultrasound test.

Merck recently discontinued a separate CIMT trial of an experimental cholesterol drug, MK-524A, saying the imaging technique wasn't appropriate for the study's patient population.

One key difference between Lipitor and Vytorin, however, is that there are still no data proving that Vytorin reduces the risk of heart attacks more than simvastatin alone, whereas Lipitor's benefit in that regard has been proven in past trials. A large trial designed to test Vytorin's effect on outcomes is several years away from completion.

Spokespeople for New York-based Pfizer couldn't immediately be reached Thursday morning.

Lipitor is crucial to Pfizer's fortunes. It generated $12.7 billion in sales last year, roughly one-fourth of total company revenue. Lipitor sales have been under pressure mainly because of the 2006 introduction of generic versions of simvastatin, which was previously a blockbuster drug for Merck under the brand Zocor.

Also, Pfizer recently halted television ads for Lipitor following criticism that the doctor featured in the ads wasn't licensed to practice. Pfizer recently agreed to settle patent litigation that is expected to keep generic Lipitor copycats off the U.S. market until 2011.

The Cashmere study evaluated the effect of Lipitor on CIMT in nearly 400 post- menopausal women with moderately high levels of bad cholesterol. Roughly half were given an 80-milligram dose of Lipitor - the highest available dose - daily for up to 12 months, and the other half took a fake pill, or placebo. Patients' artery thickness was measured at the beginning and end of treatment by CIMT tests.

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New York Times, The Diabetes Dilemma for Statin Users By ERIC J. TOPOL, Published: March 05, 2012 http://mobile.nytimes.com/article?a=920989&f=28⊂=Contributor

San Diego, Calif.

We're overdosing on cholesterol-lowering statins, and the consequence could be a sharp increase in the incidence of Type 2 diabetes.

This past week, the Food and Drug Administration raised questions about the side effects of these drugs and developed new labels for these medications that will now warn of the risk of diabetes and memory loss. The announcement said the risk was "small" and should not materially affect the use of these medications. The data are somewhat ambiguous for memory loss. But the magnitude of the problem for diabetes becomes much more apparent with careful examination of the data from large clinical trials.

Statins have been available since the 1980s but their risk of inducing diabetes did not surface for nearly 20 years. When all the data available from multiple studies was pooled in 2010 for more than 91,000 patients randomly assigned to be treated with a statin or a sugar pill (placebo), the risk of developing diabetes with any statin was one in every 255 patients treated. But this figure is misleading since it includes weaker statins like Pravachol and Mevacor - which were introduced earlier and do not carry any clear-cut risk. It is only with the more potent statins - Zocor (now known as simvastatin), Lipitor (atorvastatin) and Crestor (rosuvastatin) - particularly at higher doses, that the risk of diabetes shows up. The cause and effect was unequivocal because the multiple large trials of the more potent statins had a consistent excess of diabetes.

For those statins, the higher the dose, the more diabetes, though we don't have enough data yet to say with precision at which dose excess diabetes showed up for each drug. What we do know is that diabetes showed up. The numbers increase to one in 167 for patients taking 20 milligrams of Crestor, and up to one in 125 for intensive statin treatments involving drug strategies to markedly lower cholesterol levels. Let's just round this off and say that one in every 200 patients treated with any of the three most potent statins will get the side effect of diabetes. That's quite a conservative number because diabetes was not even being carefully looked for in most of the trials. And we have data for only 5 years of treatment; it might be worse with longer statin therapy.

More than 20 million Americans take statins. That would equate to 100,000 new statin-induced diabetics. Not a good thing for the public health and certainly not good for the individual affected with a new serious chronic illness.

If there were a major suppression of heart attacks or strokes or deaths, that might be justified. But in patients who have never had heart disease and are taking statins to lower their risk (so-called primary prevention), the reduction of heart attacks and other major events is only 2 per 100. {That number of MI prevented depends on which study is used. Others fail to find for moderate risk population no benefit.—jk} And we don't know who the 2 per 100 patients are who benefit or the one per 200 who will get diabetes! Moreover, the margin of benefit to risk is quite narrow.

What should people who are taking statins do? If they are prescribed for someone who has already had heart disease or a stroke, the benefit is overriding - no changes are suggested. But in the vast majority of people who take statins - those who have never had any heart disease - there should be a careful review of whether the statin is necessary, in light of the risk of diabetes and the relatively small benefit that can be derived. Beyond that, a dose reduction or use of a less potent statin should be considered on an individual basis.

We need to find out why statins cause diabetes and, ideally, through genomics we could determine who is at risk for this important side effect. But to date nothing has been done to sort this out - despite the fact that the market for statins is well over $20 billion per year. There are thousands of blood samples sitting in company freezers around the world that could potentially provide the answers.

The announcement, medication label change and health advisory by the F.D.A. were long overdue, and have brought this important public health issue to light. The information that we have does not support that this is a "small" problem unless one considers more than 100,000 new diabetics insignificant. The problem of statin-induced diabetes cannot be underplayed while the country is being overdosed.

Eric J. Topol is a cardiologist at the Scripps Clinic, a professor of genomics at the Scripps Research Institute and the author of "The Creative Destruction of Medicine."

The second article I found

2004 about the start of the CASHMERE study

Fundamental & Clinical Pharmacology, Volume 17, #1, Pages 131-138, Jan 27, 2004

ABSTRACT

Carotid intima-media thickness (IMT) measurement is a noninvasive method used for quantification of early stage of atherosclerosis. Data suggest that the combination of statin and hormone replacement therapy (HRT) might be useful in reducing the early progression of atherosclerosis in postmenopausal women. The main aim of the study is to compare the effects of 12-month therapy with atorvastatin (80 mg/day), HRT (oral 17β-estradiol 1 or 2 mg/day, plus cyclic dydrogesterone 10 mg) alone and their combination vs. placebo on the progression of carotid IMT by using a high-definition echotracking device. The secondary objectives are to assess the effects of the treatments vs. placebo on arterial stiffness, lipid profile and C-reactive protein. The CASHMERE trial is an European randomized study with a 2 × 2-factorial design, double blinded for atorvastatin and prospective randomized, open blinded endpoint evaluation (PROBE) method applied to HRT. The investigators can adjust the dose of estradiol at any time during follow-up if necessary. A total of 800 postmenopausal women with mild hypercholesterolemia and with no previous history of cardiovascular disease will be included and followed up by their physicians [general practitioners (GPs) or gynecologists] for 1 year. The CASHMERE trial is the first randomized clinical trial to examine the effects of a statin alone or combined with HRT on the structure and the function of carotid artery as early markers of atherosclerosis in postmenopausal women with mild hypercholesterolemia. The results are expected for 2007.

More major studies, pan statins, this time for women

Statins and Adverse Cardiovascular Events in Moderate Risk Females: A Statistical and Legal Analysis with Implications for FDA Preemption Claims

Theodore Eisenberg
Cornell University - School of Law

Martin T. Wells
Cornell University - School of Law

May 21, 2008

Date posted: May 25, 2008 ; Last revised: July 18, 2008

Abstract:
This article presents: (1) meta analyses of studies of cardioprotection of women and men by statins, including Lipitor (atorvastatin), and (2) a legal analysis of advertising promoting Lipitor as preventing heart attacks. The meta analyses of primary prevention clinical trials show statistically significant benefits for men but not for women, and a statistically significant difference between men and women. The analyses do not support (1) statin use to reduce heart attacks in women based on extrapolation from men, or (2) approving or advertising statins as reducing heart attacks without qualification in a population that includes many women. The legal analysis raises the question whether Lipitor's advertisements, which omit that Lipitor's clinical trial found slight increased risk for women, is consistent with the Food, Drug, and Cosmetics Act and related Food and Drug Administration (FDA) regulations. The analysis suggests that FDA regulation should not preempt state law actions challenging advertising that is not supported by FDA-approved labeling. Our findings suggesting inadequate regulation of the world's best-selling drug also counsel against courts accepting the FDA's claimed preemption of state law causes of action relating to warnings and safety. Courts evaluating preemption claims should consider actual agency performance as well as theoretical institutional competence. Billions of health care dollars may be being wasted on statin use by women but the current regulatory regime does not create incentives to prevent such behavior.

http://papers.ssrn.com/sol3/papers.cfm?abstract_id=1137248

From the 35 page paper:

QUOTE FROM AD:

LIPITOR significantly reduced the rate of coronary events [either fatal

coronary heart disease . . . or nonfatal MI . . .] . . .. Due to the small number

of events, results for women were inconclusive.8

This express acknowledgment of “inconclusive” results for women contrasts with the

cardioprotective claims, not qualified by gender, in Pfizer’s advertising. Nor does the label or the advertising disclose that the key clinical trial of Lipitor found a modest increased risk of heart problems in women.9 The nondisclosures continued even after a discussion of relevant statin studies concluded that the existing literature provides no “significant evidence to back up the claim that statin therapy reduces the risk of CHD in women without heart disease”10 and despite well-documented calls for statin use to be refocused toward those for whom clinical evidence of benefit exists.11

The possibility remains that cardioprotection claims for women might be based on extrapolation from results for men. Recent meta analyses of statins’ effects for women have yielded conflicting results. Walsh and Pignone’s thorough study finds that cholesterol lowering drugs did not reduce CHD death or non-fatal myocardial infarction (NFMI).12 But Thavendiranathan et al. appear to report greater cardioprotection for women than men.13 Neither study assessed outcomes separately for men and women, thereby leaving unanswered the question whether cardioprotection claims for women might reasonably be extrapolated from results for men. Our meta analyses assess random control trials (RCTs) that report statins’ effects for men and women. The outcome of interest is CHD death and NFMI. Consistently with Walsh and Pignone, for women without pre-existing heart disease or diabetes, we find no evidence that RCTs support the claim that statins reduce CHDNFMI. Instead, we find a statistically significant difference between outcomes for men and women. This undermines basing cardioprotection claims for women on extrapolation from men’s results.

. . . A substantial portion of the multibillion dollar statins market may include users for whom no clinical study supports statins outperfoming a placebo. Billions of health care dollars maybe saved by more prudent approvals, marketing, and policing of statins and other drugs.

9 Peter S. Sever et al., Prevention of coronary and stroke events wuth atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations,in the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm (ASCOT–LLA): a multicentre randomised control trial, 361 Lancet 1149, 1155 (2003).

10 John Abramson, Overdo$ed America: The Broken Promise of American Medicine 139 (2005).

12 Judith M.E. Walsh & Michael Pignone, Drug Treatment of Hyperlipidemia in Women, 291 JAMA 2243 (2004). Similar conclusions are reached in a Russian study. D.V. Preobrazhenskii et al., Hypercholesterolemia in Men and Women of Various Age. Part II. The Problem of Efficacy and Safety of Statins, 47 Kardiologia 75 (2007).

Those who have a financial interest in the outcome manipulate the results, Major study finds that all 37 journal articles positive effects over stated; the average was 32%. Statins cause erectile dysfunction, cognitive imparement, and cancer.

Lipitor (2011) lifetime sales $131 billion, tops all drugs. Plavix at $60 billion is second.

STATINS CANCER Link

52% short term

LA Times, Health section, July 21, 2008 -- excerpts

Vytorin, the combination drug (simvastatin (better known by its commercial name Zocor) and ezetimibe--known as Zetia) prescribed to lower cholesterol, sustained another blow today, when the author of a major clinical trial announced that the medication had failed to drive down hospitalization and death due to heart failure in patients with narrowing of the aortic valve. In the process, researchers in Norway detected a significant blip in cancers in the 1,800 subjects they followed

Today's findings suggested something more ominous: the incidence of cancer -- and of dying of cancer -- was significantly higher in the patients taking Vytorin. Altogether, 67 patients on placebo developed cancer during the trial. Among subjects on Vytorin, 102 developed cancers of various kinds.* This is the second adverse press—the first being in March 08, when the ENHANCE trial found that Vytorin fared no better than a placebo at reducing plaque buildup on the walls of patients' arteries.* *

Comments by jk

Simvastatin (Zocor) is off patent. Thus in a scramble for profits a combination drug (on patent) was introduced. Direct to consumer market cost $155 in 07—mainly TV ads.

* The pressing issue is that since the development of Statins, the very first animal studies in the 60s it has been known that Statins increase the incidents of cancer. However, nearly all studies done thereafter have not included cancer.

* Several studies have failed to find a reduction in the build of plaque, even thought the statins including Zocor, reduce LDL and cholesterol. Few studies include the principle reason for taking a statin, namely a reduction in the death rate. Claims for such reduction probably entail a failure to control the contravening variable, aspirin usage. Given a pile of evidence, including the very mechanism of plaque formation, which involves inflammation process, I must conclude that the use of statins is highly suspect. Given the harm done including cognitive impairment, weakness, and cancer, if my skepticism is born out, the harm done by statins as a course of treatment will far surpass that of VIOXX which killed over 200,000 people world wide by accelerating atherosclerosis.

EXTENDED RELEASE NIACIN IS A SAFER, AND A MORE EFFECTIVE WAY TO LOWER MI RISK!