Type 2 diabetes drugs: risks w/o benefit

Yet another study, this one conducted in the U.K, has shown that the oral drugs typically prescribed for people with type 2 diabetes are killing some of them; and many more have suffered heart attacks and congestive heart failure while on the drugs. Ironically, these are the very conditions that the drugs are intended to prevent. The British Medical Journal recently published findings from a 15-year database of more than 91,000 people with type 2 diabetes. The drugs they were taking—Avandia, Actos, Glucophage, and Amaryl—will be familiar to Americans. This is the eleventh published study to acknowledge the fact that oral hypoglycemic drugs are associated with an increased risk of serious harms. This one shows that some are riskier than others.

For those of you who are on one of these drugs, I provide access to the new study and leave it to your doctor to explain. I want to move on to the larger issue of why doctors continue to prescribe these dangerous drugs and how they got on the market in the first place. That last point is more easily addressed. Drugs most often receive FDA approval on the basis of what researchers call surrogate endpoints, for example, blood sugar levels are controlled, blood pressure or cholesterol is lowered, etc. The studies are usually too short in duration to prove what matters most to the people taking the drugs—i.e., they cut the chances of heart attack, stroke, etc.

I put the question of why doctors continue to prescribe these drugs in the face of so much proven danger to Nortin M. Hadler, MD, whom I consider the informed-skeptic-in-chief on this topic. Dr. Hadler is a professor of medicine and microbiology/immunology at the University of North Carolina, Chapel Hill. He is the author of two books, each with excellent sections devoted to type 2 diabetes (see below). Of course, the place to start questioning Dr. Hadler is the very definition of type 2 diabetes, which has been expanded over the years to include more and more people.

Dr. Hadler had a ready answer, “I don’t think America realizes how much input industry has on the medical organizations and their thought leaders who are involved in writing these definitions and treatment guidelines. Several of these entities are so heavily underwritten as to be almost wholly owned subsidiaries of the pharmaceutical industry. Professional meetings have much more the tone and the feel of the marketplace than they do of the academy. And all of this happened in the last 20 years.

“There are several pharmaceutical industry-supported medical groups that compete to establish standards of care for type 2 diabetes and related conditions. Some endocrinologists believe that type 2 diabetes, obesity, high blood pressure, and high cholesterol—all cluster together because they are parts of a single metabolic syndrome, which responds poorly to the treatment of its components. Others argue strenuously for the treatment of one or the other components [of metabolic syndrome]. Rather than choosing meaningful effectiveness as their battle cry, they are more interested in turf wars. The cardiologists are averse to this metabolic syndrome notion and want to pull out cholesterol and maybe hypertension as the most important risk factors to treat. The Endocrine Society and the American Diabetes Association finally got together and came out with their definition of type 2 diabetes and guidelines for lowering blood sugar.

“All of this is driven by the belief that if we normalize cholesterol or blood sugar we will improve longevity and decrease the incidence of blindness, kidney failure, stroke, heart attacks and leg ulcers. The thought leaders are so convinced of their belief that they focus on treating the blood sugar and to question whether they are treating the patient seems unnecessary. Their shortsighted efforts are rewarded with renown by the pharmaceutical industry. Almost all the thought leaders are heavily involved in drug trials where they are paid for studying the drugs. And almost all are vying for a place on the committees that set treatment guidelines.

“We now have three randomized controlled trials of oral hypoglycemic drugs in the treatment of type 2 diabetes and based on these three, we doctors cannot offer any meaningful assurance whatsoever that taking these drugs will decrease the likelihood of having a stroke, death before your time, amputation, renal failure, blindness. Anybody who tells you otherwise is exercising firm beliefs in the face of the evidence. They are wont to argue that oral hypoglycemics might have proven effective if we had done a bigger and/or longer trial. Such an argument is on the thinnest of ice. The available trials are impressive for their duration (measured in over a decade for two of the trials) and their size. Little of importance, if anything, has been missed.

“Maybe it’s time to address the other aspect of the metabolic syndrome that is too long and too often ignored. Most people who fall into the metabolic cluster are facing serious socioeconomic challenges in our society for which type 2 diabetes is one surrogate measure and for which pharmaceuticals are irrelevant.”

When I asked Dr. Hadler about metformin, the oldest and some doctors believe the safest diabetes 2 drug, he was unmoved by the British study that showed it to be effective at reducing the risk of heart attack, stroke, etc. “When you look carefully at that study, you will see the finding [of effectiveness] was not statistically significant [which means it could be due to chance].” As someone who has done an in-depth assessment of this landmark study, called the United Kingdom Prospective Diabetes Study, Dr. Hadler states, “…we doctors cannot offer any meaningful assurance whatsoever that taking these drugs will decrease the likelihood of having a stroke, death before your time, amputation, renal failure, blindness.”

Dr. Hadler is the author of The Last Well person. How to stay well despite the health-care system and Worried Sick. A prescription for health in an overtreated America, each has a strong section on type 2 diabetes. He appears frequently on National Public Radio.

For More Information:
Type 2 diabetes is largely due to lack of exercise and poor eating habits. See our 2008 interview with Dr. Steve Blair on the importance doing at least one-half hour of brisk walking five or more times a week. And to learn how to eat well and lower your risk of type 2 diabetes and other chronic conditions, read Michael Pollen’s new book entitled, “Food Rules.”

If you would like to know more about how the pharmaceutical industry brings the thought leaders around to its way of thinking, read Our Daily Meds by former New York Times business reporter Melody Petersen.

Maryann Napoli, Center for Medical Consumers(c)

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How good is Tamiflu?

The antiviral drugs Tamiflu (generic name: oseltamivir) and Relenza (zanamivir) are getting renewed attention now that the flu season is upon us. Both are in the same drug class called neuraminidase inhibitors. Because Tamiflu dominates the market for antivirals, it is named throughout this article but the findings are generally applicable to both drugs.

The benefit once you get the flu: Roche Laboratories had to conduct two trials to get FDA approval for this indication. The studies showed that Tamiflu, reduced the duration of the seasonal flu by a little more than one day…but only when taken within 40 hours of the onset of flu symptoms. This benefit, however, is limited to those with influenza A or B. The two trials had a combined total of 1,355 people who were randomly assigned to take 75 mg Tamiflu or a placebo, twice daily for five days. At the start of the trials, all participants were proven to be infected with influenza A. In time, more studies were published and all were reviewed for a recent issue of Lancet Infectious Diseases. This review found Tamiflu shortened the duration of influenza by 13 hours for healthy people and by 18 hours for high-risk people. Tamiflu costs between $5 and $10 a pill, depending on where it is purchased.

Problems with the above: When flu symptoms develop, you are not likely to know whether you have influenza A or B; nor will there be much time for laboratory confirmation. (The test is highly inaccurate anyway.) Chances are high that you don’t have influenza A or B because both are relatively rare, representing less than 10% of the 200 or so circulating viruses. What’s more, the symptoms are indistinguishable from the other 90% of circulating viruses that cause what is known as influenza-like illness. H1N1, or swine flu, is an influenza A virus, which is why this drug is allowed to be marketed for seasonal as well as H1N1 influenza. (The yearly seasonal vaccines are also aimed solely at influenza A and B viruses.)

Benefit when trying to prevent the flu: In the Roche-sponsored trials for this purpose, healthy unvaccinated adults, aged 13 to 65 years, took 75 mg Tamiflu once daily for 42 days during an outbreak of influenza in their community. 5% of the people taking a placebo got the flu, compared with 1% of those taking Tamiflu. In healthy children, aged 1 to 12 years, taking 30 mg or 60 mg (depending on the child’s weight) Tamiflu once daily for ten days, 17% of those taking the placebo got the flu, compared with 3% of those taking Tamiflu. As for Tamiflu’s ability to reduce complications, see Postscript below.

Resistance: “Emergence of drug-resistant influenza viruses after treatment has been reported, particularly in children in Japan, where the dosing schedule is different [i.e., more aggressive] from that used throughout the rest of the world,” according to a report in the February 15, 2009 issue of Clinical Infectious Diseases. The authors of this report also found that resistance to Tamiflu is more likely to occur in H1N1 influenza A [swine flu] than in other influenza A or influenza B viruses.

Revised CDC recommendations: On September 22, 2009, the CDC updated its recommendations to physicians, stating that Tamiflu should be reserved for high risk populations like pregnant women and babies. “Most healthy persons who develop an illness consistent with influenza, or persons who appear to be recovering from influenza, do not need antiviral medications for treatment or prophylaxis.” In other words, now that antivirals have shown some resistance, not to mention marginal effectiveness, the CDC says these drugs should be reserved for people at high risk for flu-related complications.

History: Tamiflu was approved by the FDA in 1999 for the treatment of influenza A and B. About four years ago when the avian flu was the threat, several governments, including that of the U.S., started stockpiling Tamiflu. In the U.S. government’s case, the stockpiling was for the military. Just since the emergence of swine flu in Mexico last spring, J.P. Morgan, the investment bank, estimated that governments have placed new orders for antiviral drugs of $3billion, despite the fact that this flu season looks like it will be relatively mild. Initially, Roche was required by the FDA to state in the drug’s label that Tamiflu’s efficacy in the treatment of influenza in people with chronic cardiac disease and/or respiratory disease had not been established. This disclaimer appears again in the updated 2008 FDA-approved label for Tamiflu because Roche still has not tested its drug for this high-risk population that needs it the most. [The drug label is the package insert that comes with medications and reprinted in the Physicians’ Desk Reference. The label is written by the drug company and then negotiated and approved by the FDA.]

Unanswered questions: Why haven’t the government-customers for Tamiflu leaned on Roche to prove its drug is effective in treating people with chronic cardiac disease and/or respiratory disease? What incentive does a company have to develop a better drug when it can make a billion dollars selling a barely effective drug like Tamiflu to the U.S. government each year?

Risks: Years after Tamiflu went on the market, reports surfaced that Tamiflu-treated people with influenza had experienced delirium and abnormal behavior, leading to injury and even death. Most of the cases occurred in children and in Japan where this drug was used excessively. Influenza itself (without Tamiflu) can be associated with a variety of neurologic and behavioral symptoms such as hallucinations, delirium, and abnormal behavior. In 2008, the FDA and Roche revised the label for Tamiflu accordingly. Nausea is a common side effect of Tamiflu.

Other antiviral drugs to avoid: In 2005 the Lancet published a study showing that influenza A viruses had developed resistance to Symmetrel and Flumadine and other antiviral drugs in a class called amantadine. These drugs were widely prescribed before 2005.

Postscript, added December 8, 2009
The British Medical Journal announced the publication of an updated review of all studies related to Tamiflu effectiveness, concluding, “There is no clear evidence that the antiviral drug most commonly used against influenza – oseltamivir (Tamiflu) – prevents complications like pneumonia in healthy people [who who become ill with influenza]. …Yet such claims have been a key factor in decisions to stockpile these drugs as part of global pandemic preparedness plans.” The review is described as part of a joint investigation by the Cochrane Collaboration, the British Medical Journal, and [BBC] Channel 4 News.

And this addendum December 7, 2010: See this new website for an excellent explanation of the benefits and risks of Tamiflu.

Maryann Napoli,Center for Medical Consumers(c)

Steroids alone best choice for Bell’s palsy

Bell’s palsy is defined as the abrupt paralysis of the facial nerve, resulting in an inability to control facial muscles on the affected side. The good news is most people recover without treatment; the bad news is that up to 30% do not recover completely, often suffering facial pain, psychological trauma, and facial disfigurement. A meta-analysis of all trials that have compared the standard treatments for Bell’s palsy—steroids plus anti-viral drugs or steroids alone—was published recently in the online version of the British Medical Journal (BMJ). It concluded that steroids are the better choice and there is no benefit to adding anti-viral drugs.

It was not so long ago that steroids were shown to be better than no treatment at all. The first such trial was published in 2007 in the New England Journal of Medicine. Within 72 hours of the onset of Bell’s palsy symptoms, the participants were randomly assigned to treatment for 10 days with steroids, or an anti-viral drug (acyclovir), or both, or with placebo. Steroids alone proved to be the best in terms of decreasing permanent facial disfigurement (96% of those taking steroids recovered completely at 9 months, compared with 77% on the placebo).

Although this study should have put an end to the addition of anti-viral drugs like acyclovir (brand name: Zovirax), it didn’t. Perhaps this new study will change doctors’ prescribing practices. Eudocia C. Quant, Department of Neurology at Massachusetts General Hospital in Boston, and colleagues found six trials that had compared the two treatments in a combined total of 1,145 people with Bell’s palsy. Although the researchers identified steroids alone [e.g., prednisone or prednisolone] as the better choice, they left the door open for the possibility that future research might find the newer anti-viral drugs do have some benefit.

Maryann Napoli, Center for Medical Consumers(c)

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What about the negotiated drug discounts?

President Obama just gave a powerful speech about health care reform, but notably absent was something crucial to people on Medicare—that is, giving the government the power to negotiate discounts for prescription drugs. Other industrialized countries use the power of numbers to reduce their drug costs. In our case, it would be the 44 million Medicare enrollees. The U.S. pharmaceutical industry would have us believe that the European countries are getting a free ride because our high drug costs are paying for innovation in new drugs, something that supposedly occurs only in the U.S. This view has gone unchallenged by the mainstream media.

Donald Light, PhD, the Lokey visiting professor in comparative health care at Stanford University, has recently taken up this issue in the academic journal Health Affairs. He analyzed the new drugs discovered between 1982 and 1992 and concludes that Europeans have discovered more important new drugs, dollar for dollar, than Americans. When Dr. Light was asked to elaborate by e-mail, he said that the greater share of U.S. research funds go to what’s called me-too drugs or drugs that offer little or no advantage over existing ones. “Only 1 in 7 new drugs offer significant clinical advantages for patients,” he added.

Unfortunately, only excerpts are available from the subscription-only Health Affairs analysis and the recent Lancet editorial that supported Dr. Light’s findings. You may, however, read the entire 2005 article on the same topic, co-authored by Dr. Light, “Foreign free riders and the high cost of U.S. medicines.” Read also the pharmaceutical industry’s rebuttal and the authors’ reply in the Rapid Responses at the end of the article.

Why no mention of drug discounts in President Obama’s speech? Representative Henry A. Waxman (D-CA) answered the question before the speech in an interview with our local public radio station. “The White House made a deal with the pharmaceutical industry that is not in the interest of senior citizens,” said Waxman. “The drug manufacturers poured money into an ad campaign promoting health care reform in return for not allowing Medicare to negotiate drug discounts. The industry anticipates windfall profits from the 47 million new customers [the formerly uninsured]. ” He went on to explain the deal industry made with the White House and one of the key Congressional committees [the one headed by Senator Max Baucus] regarding the “doughnut hole,” which is the $2,700 point where Medicare stops paying for drug coverage and people must pay out of pocket for the next $4,000 until coverage kicks in again. The drug industry agreed to give discounts, but here’s the catch…only for the brand name drugs, i.e., the most expensive drugs. “The pharmaceutical industry got just what it wanted,” said Waxman.

Maryann Napoli, Center for Medical Consumers(c)

Anemia drugs hasten death in some cancer patients

For seven years Johnson & Johnson ran deceptive ads on prime time TV and in magazines with this recurring theme: A cancer patient cannot continue working because of debilitating fatigue due to chemotherapy. The ads told people in similar circumstances to ask their doctors about Procrit, which always quickly put an end to the fatigue. There is no published evidence to support the cure-for-fatigue claim, according to a 2007 press briefing at the FDA. Eventually, the agency required warning labels for Procrit, Aranesp, and Epogen —- all drugs widely prescribed to treat anemia in cancer patients. Warning label refers to the black box warning that appears in the 20 or so pages of information that comes with the drug (sometimes). The warnings for Procrit, Aranesp, and Epogen now list a higher incidence of potentially fatal blood clots, heart damage and increased tumor growth.

Now they can add “decreased survival” to the list. This week, the Cochrane Collaboration, the independent, international organization that evaluates research, published a meta-analysis of the information generated by the care of nearly 14,000 cancer patients entitled, “Anti-anemia drugs shorten survival for some cancer patients.” This meta-analysis is co-authored by Maryann Napoli, Center for Medical Consumers. For background on how their drugs came on the market and how financial incentives encouraged oncologists to overprescribe them, see her testimony on this topic before the FDA’s Oncologic Drug Advisory Committee in 2007 and one year later in 2008.

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FDA’s Warning System for Drug Adverse Reactions

It’s a well-acknowledged fact that it takes years for all of the harms about a drug or medical device to emerge. The Food and Drug Administration regularly publishes a list of drugs and other medical products whose prescriber labeling and/or patient information has been updated with new warnings. The Medwatch Program is the FDA’s Safety Information and Adverse Event Reporting System/a>>. It provides a list organized by the severity of the drug’s risk and describes the specific nature of the label changes, for example, a new black box warning. If you see a drug of interest on the list, just click on the product name in the left hand column and you can see the new warnings and cautions about the product’s use.

Arthur A. Levin, MPH, Center for Medical Consumers©

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Blood Pressure Drugs for All at High Risk, Whether or Not Blood Pressure is High

The typical doctor visit starts with blood pressure measurement, and everyone with a high reading is told to come back again in three months. If blood pressure remains high, one drug or more is the next step, and then three-month follow-up visits continue indefinitely.

A team of British researchers wants to radically change this scenario. Blood pressure lowering drugs should be prescribed to anyone who is at high enough risk to benefit from treatment, whatever their reason for being at high risk and regardless of whether they have high blood pressure or not. What’s more, the British researchers want to change the traditional doctor-visit focus from: has your blood pressure gone down and stayed down? to: is your drug therapy causing any adverse effects?

All blood pressure drugs can dramatically reduce the risk of heart attack and stroke; and all are virtually interchangeable, say the British researchers. Therefore, any tailoring to the needs of the individual would be based on whether the drugs cause adverse effects. Fewer doctor visits would be the result, as well as fewer adverse drug reactions, many of which are currently caused by doses that are too high. Eliminated is the uncertainty many doctors have about which drugs to prescribe and who should be treated.

The proposed radical shift in thinking about blood pressure drugs appeared online last month in the British Medical Journal. Malcolm Law and colleagues based their proposal on an in-depth analysis of the data from 147 blood pressure drug trials published between 1966 and 2007. The trials had a combined total of nearly a half-million participants, aged 60 to 69 years.

Law and colleagues base their conclusions on these trials that compared people with and without heart disease given drugs or a placebo; people with normal blood pressure and high blood pressure (hypertension) with and without drug therapy.  All five classes of blood pressure drugs were represented, as well as differing doses.

Here’s what they found: Any one of the main classes of blood pressure drugs given at the standard dose will reduce the incidence of fatal and non-fatal heart attack by about 25% and stroke by about 33% and heart failure by about 33%. These reductions held up, say Law and colleagues, whether or not the people had heart disease and whether or not they had high blood pressure.

Of course, you would want to know what your risks are for each heart problem if you don’t take any drugs so you can get a clearer idea of what the risk becomes once you do. The British researchers did the math for you based on older people living in England and Wales. At age 65, the risk of having a heart attack (fatal and non-fatal) in the next ten years is about 10% in men and 5% in women. If they go on blood pressure drugs at half dose, the risk in men goes down to 5.4% and in women to 2.7%.

Adverse effects will be minimized with low-dose combination therapy. Cost is dismissed because four of the five drug classes are off patent, and the fifth (angiotensin receptor blockers) will be off patent by the end of this year. “It is difficult to defend the widespread practice of tailoring treatment. The case for individualizing blood pressure lowering disappears with low dose combination therapy based on three drugs; the greater efficacy compared with selective monotherapy or dual therapy avoids the need to choose between drugs,” wrote Law and colleagues.

Some exceptions were found to the all-drugs-are-equally-effective finding. For example, beta blockers [some brand names: Tenormin, Toprol] have an edge over other drugs when given after a recent heart attack; and calcium channel blockers are less effective than other drugs in the risk of heart failure but they had a greater stroke prevention effect than other drugs. Some drugs should be avoided in pregnancy.

Two of its co-authors, Malcolm R. Law and Nicholas J. Wald, made headlines six years ago when they proposed something similar in concept called the polypill. The polypill combines three blood pressure drugs at half the standard dose, a statin, folic acid, and aspirin. At the end of their new research paper, Law and Wald acknowledged that they had “competing interests” (i.e., conflicts of interest) because they hold patents “on the formulation of a combined pill to simultaneously reduce four cardiovascular risk factors, including blood pressure.”

Their research paper is bound to reignite a worldwide debate among doctors about the use of drugs for prevention. What’s needed now is the release of all data used in the new meta-analysis of blood pressure lowering drugs so that an additional critical analysis can be conducted by a team of researchers without competing interests.

There may be strong reasons against the idea that the benefits outweigh the risks for everyone on blood pressure drugs. For starters, the implication that adverse drug effects are banished with low doses has already been disproved in low-dose aspirin studies. No matter how low the dose in these studies, the cases of gastrointestinal bleeding are higher in the people taking low-dose aspirin than in the people taking a placebo. This is true of the Women’s Health Initiative in which the study participants were taking only 100 mg aspirin every other day.

For more information
The May 19, 2009 issue of the British Medical Journal “Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomized trials in the context of expectations from prospective epidemiologic studies.”

Maryann Napoli, Center for Medical Consumers© June 2009

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Oral vs. Standard Chemotherapy To Prevent Recurrent Breast Cancer

Older people are underrepresented in clinical trials, a problem that is particularly acute where it concerns breast cancer. This is a disease that strikes women who are average age 63 years at diagnosis; and the overwhelming majority of deaths occur over the age of 65 years. A new study fills an important information gap about adjuvant drug treatment for older women with breast cancer. It also clears up lingering questions about oral vs. intravenous (IV) chemotherapy.

In 1998, Xeloda (capecitabine) became the first oral chemotherapy drug to be approved by the FDA for metastatic breast, i.e., late-stage cancer that has spread beyond the breast. Xeloda is produced by Roche Laboratories, which partly funded this study, published last month in The New England Journal of Medicine.

Two Questions Asked

Can Xeloda benefit women at earlier stages of breast cancer? How does it compare with standard chemotherapy? These questions were answered by the new study, led by Hyman B. Muss, MD, University of Vermont, Burlington, and conducted at many academic medical centers in the U.S. and Canada.

After their initial treatment for breast cancer, the 600 study participants were randomly assigned to Xeloda or one of two standard IV chemotherapy regimens (One known by the acronym, CMF—cyclophosphamide, methotrexate, and fluorouracil, or another regimen that combines cyclophosphamide and doxorubicin). The participants had been diagnosed with breast cancers that ranged from stage I through stage IIIB.

First, the researchers looked at the number of participants who were recurrence-free at 3 years. It was 68% of the women in the Xeloda group and 85% of the women in the IV chemotherapy group.

When the researchers looked at overall survival, IV chemotherapy again proved better than Xeloda. The survival rate at three years was 86% for the women in the Xeloda group versus 91% for those in the IV chemotherapy group. Two women in the Xeloda group died of treatment-related complications.

Although IV chemotherapy came out on top regarding recurrence and survival, it was worse when it came to side effects. Twice as many women in the chemotherapy group suffered moderate to severe toxic effects, such as nausea and vomiting (64% vs. 33%). More women on IV chemotherapy (38%) could not complete the six cycles of treatment because of severe toxic side effects, compared with 20% who could not finish the six planned cycles of Xeloda.

The greatest benefit to taking Xeloda was shown for the women in this trial who had hormone-receptor negative tumors. This is consistent with the results from earlier research conducted at Oxford University.

The new study provides more fodder for the contentious issue of drug costs. Both private and public health plans in the U.S. are requiring patients to pay more out of pocket for cancer drugs. Many plans, including Medicare, will reimburse for IV drugs, but not for oral drugs. This leads some cancer patients to suspect that they are being steered away from the newer and better oral drugs for cost-saving reasons.

News Flash:
A cancer patient on Xeloda was detained by U.S. immigration officials because his fingerprints had mysteriously disappeared, according to May 26, 2009 Annals of Oncology online. The drug can cause chronic inflammation of the palms or soles that can over time eradicate finger prints.

Maryann Napoli, Center for Medical Consumers(c) June 2009

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Heartburn Drugs Overused In Hospital Patients Not at Risk for Stress Ulcers

Acid-reflux drugs like Nexium and Zantac, which suppress stomach acid, are among the most widely prescribed in the country. Their use has been steadily increasing among hospital patients, often for indications that have no supporting scientific evidence. Between 40% and 70% now receive some version of these acid-suppressive drugs, also known as proton pump inhibitors (PPIs), during a hospital stay. A new study, published last month in the Journal of the American Medical Association, found that they have a higher incidence of pneumonia than hospital patients not given these drugs.

The study was led by Shoshana J. Herzig, MD and colleagues who analyzed the medical records of all patients who where admitted to a large, urban, academic medical center in Boston from 2004 through 2007. To be included in this study, the patients had to be at least 18 years of age and hospitalized for three or more days, but not admitted to the intensive care unit. The study included nearly 64,000 patients, 52% of whom were given one of two classes of acid-suppressive drugs—PPI (e.g., Nexium, Prevacid, Prilosec) and histamine2 receptor antagonist (e.g., Pepcid, Zantac).

Of the hospital patients who received the acid-suppressive drugs, 4.9% developed pneumonia while in the hospital, compared with 2% of the people not given the drugs. PPIs were more likely than H2 receptor antagonists to be prescribed and to cause an increase in pneumonia. After taking into account that the drug-treated people may have been sicker at the time of hospital admission, the researchers estimated that the people given acid-reflux drugs had a 30% increase in their risk of pneumonia compared with those not given the drugs.

Although hospital patients frequently are given acid-reflux drugs for preventive purposes, Dr. Herzig and colleagues say that the drugs are approved by the FDA only for people at high risk for developing stress ulcers.

This study builds on the results of earlier acid-reflux drug studies that found people on these medicines have a higher incidence of hip fracture, community-acquired pneumonia (i.e., pneumonia that occurred outside of a hospital), and diarrhea associated with Clostridium difficile.

Maryann Napoli, Center for Medical Consumers© June 2009

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The Marketing of Osteoporosis

How a risk factor (bone loss) became a disease (osteoporosis) by Maryann Napoli. Originally published in American Journal of Nursing, May 2009

Nurses probably get the same question I often get as a consumer advocate.  Should I be on this drug? You’re asked because you’re seen as the expert or simply a knowledgeable friend.  In fact, it’s a valid question not only to ask but also to look beyond the prescribing health care provider for answers.

In the name of prevention, millions of Americans have accepted the idea that it is reasonable to treat a risk factor (e.g., high cholesterol, bone loss) as if it were a disease. Think back to the 1990s when virtually all menopausal women were advised—pressured, according to accounts that came my way—by their gynecologists to go on hormone therapy to prevent heart disease and hip fractures.

More people should question the wisdom of going on long-term drug therapy. Often the magnitude of the risk factor has been overestimated; or the danger of the disease itself may be exaggerated by people trying to sell us something—like a drug you must take for the rest of your life.

Osteoporosis provides an excellent example of how the pharmaceutical industry begins creating a market for a new prevention drug years before it is approved.  The disease has become a major health concern for older women, though it was unknown to the general public until the early 1980s when the drug industry-led awareness campaign began.  It used to be that osteoporosis was not diagnosed until a fragility fracture had occurred.[1]

But a new definition, one based on bone mineral density, was established in 1993 at a World Health Organization meeting of osteoporosis researchers.  Its ostensible purpose was to determine the global prevalence of osteoporosis, but this meeting is where the definition of osteoporosis was radically changed.  What had been simply a risk factor (bone loss) became a disease (osteoporosis), complete with an arbitrary cutoff (bone density more than 2.5 standard deviations below the normal bone mass in young women).[2]

Overnight, the market for bone drugs had been expanded. Years after that WHO meeting, I would learn that it was sponsored by several pharmaceutical companies.² Hormone drugs were the standard preventive treatment at the time of the meeting, but three years later the first non-hormonal drug for bone loss—alendronate (Fosamax)—was launched.

Getting symptom-free women to accept drug therapy requires scarey statistics that imply the danger period starts right after menopause, leaving the impression that hip fractures, the most disabling consequence of osteoporosis, often occur soon after the hot flashes are over.  Here’s one stat you would see often: 24% women, aged 50 and over, die within a year of a hip fracture.[3]  And here’s one you don’t see often: over 90% of the hip fractures occur in people over 70 and the average age is 80.[4]  Elderly men have hip fractures, too, but the early marketing of alendronate was all about the ladies.

How Predictive are Bone Scans?

In the initial phase of the industry-funded osteoporosis awareness campaign, the scan known by the acronym DEXA was advised for women at the time of menopause. Scanning caught on in a big way, especially after Merck, the maker of alendronate, began financing the installation of DEXA machines in doctors’ offices.[5]  Nothing creates drug customers faster than getting people to be routinely scanned.

Unfortunately, scanning is not good at predicting which women in their early 50s will have a hip fracture at age 80. This was known in 1997 thanks to a report from the British Columbia Office for Health Technology Assessment, which—to my knowledge—is the first to reveal industry sponsorship of that 1993 WHO meeting where osteoporosis was redefined.[6]

Unfortunately, the report had no effect on U.S.testing guidelines, but consumer advocate Barbara Mintzes, Universityof British Columbia, summed up the situation nicely, “Bone mineral density testing is a poor predictor of future fractures, but an excellent predictor of start of drug use.”[7] Merck’s ads aimed at women did not even mention alendronate, they simply said, “Ask your doctor whether a bone density test is right for you.”  Sure, low calcium/vitamin D intake, scatter rugs, poor muscle strength, certain medications, impaired vision were given lip service as contributing factors to osteoporotic fractures, but loss of bone density always seemed front and center.

How Good is the Drug?

In the initial phase of DEXA promotion, many women in early middle-age, with low bone density but no history of fracture, were put on alendronate, despite the fact that the drug was tested only in elderly women with vertebral fractures. The results, even for this supposedly high-risk elderly group, were not impressive. In the Merck-sponsored three-year trial that received Food and Drug Administration approval, hip fractures occurred in 1% of those on alendronate, compared with 2% of those on a placebo. [8] (A “50% reduction in hip fracture” is the accurate, though misleading, way these results were often portrayed.)

Here is where the nurse/advocate can serve as a sounding board for patients deciding whether to go on drug therapy, helping them consider questions like:  Are you similar in age and fracture history to the women in this trial? What does that 1% fewer hip fractures mean to you? Let’s compare that 1% benefit with the 1.5% risk for a alendronate-induced esophageal ulcer found in this trial? Consider what happened to the study participants who did not take alendronate (98% of the untreated women—i.e., the placebo group—did not have a hip fracture).  The “script” for this discussion is the drug’s official FDA-approved label and the Physicians’ Desk Reference where the trials that won FDA approval are described.

When alendronate was put to the test for elderly women with bone loss but no vertebral fractures, the four-year trial showed that the hip fracture rate was no different for the drug-treated participants than it was for the women taking a placebo.In short, the drug is good at improving bone density but not so good at reducing hip fractures. This did not stop other drug companies from introducing their own alendronate knockoffs—risedronate, ibandronate, pamidronate, etidronate and zoledronic acid.  All are in the same drug class called bisphosphonates.  In an example of how long a drug has to be on the market before the full picture of harm is known, the FDA reported early this year that all bisphosphonates carry the risk of severe and sometimes incapacitating musculoskeletal pain.[9]

Drug Ad Campaign Misled Doctors

Why younger rather than elderly women became the likely recipients of a bisphosphonate prescription is no mystery.  Merck’s initial ads aimed at physicians encouraged it.  A multi-page glossy ad campaign that ran frequently in Annals of Internal Medicine featured a thin fortysomething white woman with a crumbling ancient stone column in the background.  “Don’t wait for a fracture… No matter what her degree of osteoporotic bone loss…” [10]  I wrote to the editor-in-chief of Annals, pointing out that alendronate had no proven benefit for women in early middle age.  Never got a reply, but Annals stopped running the ad about six months later.  Still, the message had already gone out, there and elsewhere—early middle age is the appropriate time to start fracture prevention with alendronate.  From the drug industry’s point of view, the younger customer is far more desirable than, say, the  elderly nursing home resident with a limited remaining lifespan in which to take drugs.

Today, women in the osteoporosis drug ads are usually in their early sixties.  The guidelines for bone density measurement currently recommend bone mineral testing not begin before age 65 (or 60 in some high-risk cases)[11], but now there’s a bigger problem.   Researchers have known, at least since 2000, that bone strength or bone quality are better predictors of hip fracture than bone density.  In 2001, the National Institutes of Health redefined osteoporosis as a combination of bone mineral density and bone quality. But there is no test for bone  quality or bone strength. ¹

It’s going to take time for the word to get out.

How relevant is this story to other drugs people take to treat a risk factor?  In a word: very.  Three-fourths of all Americans on cholesterol-lowering statins, the country’s top-selling drugs, do not have heart disease and are thus far less likely to benefit than people who do. [12]  (Statins are terrific at lowering cholesterol, but much less impressive at reducing the risk for heart attack[13]—sound familiar?)  The thresholds for high cholesterol[14] and high blood pressure were lowered several times over the years, each time making millions more people eligible for drug therapy. ⁵ 

Drug ads and industry-sponsored “education” programs are no longer the only major sources of biased information. Industry funding compromises the directives of non-profits like the American Heart Association and the American Cancer Society, as well as the experts who write treatment guidelines. [15]  One example of the latter: eight of the nine doctors who served on the 2004 government committee that expanded the guidelines for cholesterol-lowering drug therapy had financial ties to statin companies.[16]

More than ever, nurses must be knowledgeable advocates for their patients. You may be the last of the independent health professionals.

For More Information:

Added May 19, 2012: New take on bone density retesting.  and  Warning on bone drugs:  Stop after 5 years.

http://courses.washington.edu.bonephys    Web site of bone physiologist and osteoporosis researcher Susan Ott, MD, Associate Professor, Department of
Medicine, University of Washington.  Mostinteresting section: “When [drug] studies don’t give clear answers.”  Definitely take the quiz. (Accessed June 12, 2008.)

 

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[1] Cheung, AM and Detsky, AS. “Osteoporosis and Fractures: Missing the
Bridge?” JAMA. 2008;299(12):1468-1470.

2 Kazanjian A, et al. Normal bone mass, aging
bodies, marketing of fear: bone mineral density screening of well women. University of British Columbia Centre for Health
Services and Policy Research. British Columbia Office of Health Technology Assessment BCOHTA  98:10C Sept 1998. http://www.chspr.ubc.ca/files/publications/1998/bco98-10C.pdf  (AccessedJune 13, 2008.)

[3]
National Osteoporosis Foundation. www.nof.org
(Accessed June 5,
2008)

[4]
Love S.M. with Lindsey, K.  Dr. Susan
Love’s Menopause & Hormone Book.  New York: Three Rivers
Press, 2003.  P.109

[5]
Moynihan R and Cassels A. Selling
Sickness: How the world’s biggest pharmaceutical companies are turning us all
into patients. New York: Nation Books, 2005 page 142.

[6]  Kazanjian A, et al.  Bone Mineral Density Testing: Does the
Evidence Support Its Selective Use in Well Women? 1997 British Columbia Office for Health Technology
Assessment, University of British Columbia.  http://www.chspr.ubc.ca/files/publications/1998/bco98-07C.pdf   (AccessedJune 5, 2008)

[7] Mintzes, B. Direct to consumer advertising is medicalising normal human experience. BMJ 2002;324:908-911.

[8]Physicians’ Desk Reference, 59^th edition 2005, page 2051.

[9] FDA Alert: Bisphosphonates (marketed as Actonel, Actonel+Ca, Aredia, Boniva, Didronel, Alendronate, Alendronate+D, Reclast,
Skelid, and Zometa). Posted Jan 7, 2008. http://www.fda.gov/medwAtch/safety/2008/safety08.htm#  (AccessedJune 12, 2008.)

[10] Napoli M. Alendronate: A new drug with an ad campaign that encourages misuse.   HealthFacts. July 1996.

[11] Agency for Healthcare Research and Quality. U.S. Preventive Services Task Force. Sept 2002. http://www.ahrq.gov/clinic/uspstf/uspsoste.htm
(Accessed June 13, 2008.)

[12]
Abramson J, et al. Are Lipid-Lowering Guidelines Evidence-Based? Lancet. 2007
Jan 20;369 (9557):168-9.

[13]
Carey J. Do cholesterol drugs do any good? Business Week, Jan 17,2008.
(Accessed onlineJune 16, 2008.)

[14]
Center for Science in the Public Interest. http://www.cspinet.org/integrity/press/200409231.html
(Accessed June 6, 2008).

[15]
Lenzer
J. Education and debate:  Alteplase for
stroke: money and optimistic claims buttress the “brain attack”
campaign.  BMJ 2002;324:723-729.  http://bmj.bmjjournals.com/cgi/content/full/324/7339/723#B14
(Accessed June
13, 2008.)

[16] National Cholesterol Education Program. Third Report of the Panel on Detection, Evaluation, and Treatment of high blood cholesterol in adults (Adult treatment panel III) 2004. http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3upd04_disclose.htm                    (Accessed June 6, 2008).