Drug Truths

A site devoted to teaching about drug discovery and development.

A Holiday Gift From Merck’s Ken Frazier

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These are quotes that a pharmaceutical R&D supporter like myself loves:

“The most sustainable strategy is innovation.”

“Science and translating science into medically important products has always been at the core of how (we) define ourselves in the world.”

“Science and innovation are in the DNA of the company.”

These sentiments don’t come from the head of a biotech company or a scientist who is the CEO of a pharmaceutical company like John Lechleiter at Lilly.  Rather, they come from Ken Frazier, Merck’s first-year CEO, a lawyer by training.  As reported by Christopher Weaver, Frazier defended his commitment at a recent breakfast hosted by The Wall Street Journal.  Frazier’s views, unfortunately,  aren’t embraced by Wall Street.  Merck’s stock has stagnated in Frazier’s first year whereas that of Pfizer has increased by about 25%, partially as a result of the latter’s commitment to slash its R&D budget.

Frazier has not been rash in crafting Merck’s research budget.  In fact, the combined R&D budget for Merck and its acquired company, Schering-Plough, was $8.6 billion in 2009.  If Merck not only kept this budget but rather increased it by 5% annually, it would project out to be almost $10 billion in 2012.  Instead, Frazier is planning on a spending about $8 billion on R&D in 2012 – still a hefty amount but meeting that goal requires cuts to the new combined R&D organization.  Nevertheless, Frazier is finding himself defending this spending to Wall Street critics.  His response?

“What we are really trying to do is run the company to create sustainable long-term value for our shareholders… The problem with R&D is that it’s not always consistent.  It’s not like engineering where you can incrementally innovate and make another version of the iPhone… If you look in the past, there have been other fallow periods for R&D, but over the long-term, science has always made progress.”

There are tremendous medical needs now facing people around the globe.  Alzheimer’s Disease (AD) is a problem that is getting worse as the population ages.  The societal costs are enormous.  There are a number of compounds that are in clinical development that are hoped to slow or even reverse AD.  The problem is that these clinical trials are long and expensive to run.  The same can be said for the clinical trials needed to discover and develop new treatments for many other diseases such as obesity, diabetes, heart disease and osteoporosis.  Gone are the days when one can simply show that a compound stops bone loss in an osteopenic woman.  Instead, long-term studies are needed to show that such a drug reduces fractures in this population.  Physicians, payers and regulatory agencies are requiring these types of studies before justifying prescribing such new medicines to patients.

Big pharmaceutical companies are the only organizations with the resources and talent to do this.  But substantial R&D budgets are required to capitalize on the exciting new opportunities being uncovered by genomics.  One can argue that the Mercks of the world are serving the national interest by making these large investments because, if they don’t do these studies, no one else will.  So kudos to Ken Frazier for having the courage to stand up to the R&D naysayers.  Perhaps his commitment to R&D will return Merck to the status of the World’s Most Admired company, a title they owned in the late 1980s.

Written by johnlamattina

December 20, 2011 at 9:30 am

Consultants Might Have More Credibility If They Had Their Facts Right

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Big Pharma often finds itself Wall Street’s whipping boy.  Why?  Analysts are looking for immediate answers from an industry built on proving–and disproving–hypotheses.  Unfortunately, the result is often misguided analysis, as happened last week when the firm Oliver Wyman issued a white paper  entitled “Beyond the Shadow of a Drought – The Need for a New Mindset in Pharma R&D.”

Before last week, I had never heard of Oliver Wyman, which describes itself as follows:

“Oliver Wyman is a leading global management consulting firm that combines deep industry knowledge with specialized expertise in strategy operations, risk management, organizational transformation and leadership development.”

Given my history in this field, I was eager to read this paper as this is a topic close to my heart.  Wyman’s analysis, however, was disappointing as it, for the most part, rehashes a lot of what has been discussed by others over the past few years.  What really surprised me, though, was that a number of the Oliver Wyman “insights” were based on misinformation.  One of these purported insights that particularly stood out to me was Wyman’s take on Pfizer’s torcetrapib program.

In order to better understand how off-base Wyman’s white paper is, it’s important to understand torcetrapib’s history.

As most people know, statins have revolutionized the treatment of heart disease.  They act by lowering LDL, the so-called “bad cholesterol,” and multiple long-term studies have shown that these drugs, in combination with diet and exercise, can effectively reduce the potential of heart attacks and strokes in patients with heart disease.  But many researchers have believed that lowering LDL is only addressing part of the heart disease problem.  Intriguing data have built up over the years showing that if one could effectively raise HDL, also known as “good cholesterol,” further progress could be made in reducing heart disease.

The problem that scientists have faced in this field is that not a lot is known about raising HDL and so trying to accomplish this feat in the laboratory has proven quite challenging.  An exception involves the emerging biology around a protein known as “Cholesteryl-Ester Transfer Protein (CETP).”  Back in 1990, a report in The New England Journal of Medicine described a Japanese family who, due to a genetic defect, didn’t produce CETP and as a result had very high HDL levels and low incidence of cardiovascular disease.  Because of this observation, a number of companies, including Pfizer, sought to come up with an inhibitor of CETP to test in heart patients.  The rationale was pretty simple: by inhibiting CETP, the new drug would raise HDL thereby mimicking the situation in the Japanese family who were born without this protein.  Theoretically, the CETP inhibitor would reduce heart disease maybe as well as statins.  In a dream scenario, the combination of statins and CETP inhibitors would reverse heart disease, enhancing the quality of life of hundreds of millions of people.

Finding inhibitors of CETP proved to be very challenging and most companies gave up.  Pfizer almost did as well.  But through hard work, creativity and a bit of luck, the CETP inhibitor torcetrapib was found.  It successfully cleared preclinical toxicology studies and entered clinical trials in 1999, eight years after the discovery program began.  The initial clinical results were astonishing.  Patients on torcetrapib had increases of HDL of 100% or more – an unprecedented finding.  Even better, torcetrapib also caused a modest decrease in LDL; however, when torcetrapib was added to Lipitor (atorvastatin), not only was the HDL elevation maintained, but LDL drops of 40 – 60% were seen.  The lipid remodeling that was achieved with this combination had never been seen with any therapy.

The combination of torcetrapib and atorvastatin (T/A) became a major focus not just for Pfizer but for the entire cardiovascular field.  As the early clinical data for T/A emerged, other companies that had previously given up their efforts in looking for CETP inhibitors jumped back in the hunt.  But although T/A uniquely modified the lipid profile of patients with heart disease, its ultimate value was not yet established.  The long-term benefits of altering heart disease with CETP inhibition were still hypothetical.  Furthermore, at the end of the Phase 2 studies, it was found that T/A caused a small, but reproducible increase in blood pressure.  However, based on the known association between atherosclerosis, blood pressure and cardiovascular disease, the large increase in HDL was expected to provide benefits that would be far greater than any harm caused by the small blood pressure increase.  To prove this, Pfizer had to carry out an extensive Phase 3 program which included a multiple year study in patients with heart disease with the hope of showing that patients with heart disease fared better on T/A than they did with Lipitor (atorvastatin) alone.  This was a pretty high hurdle.  Pfizer wasn’t content to test T/A versus a placebo; rather, it chose to test T/A against Lipitor, the premier statin that had a successful track record in reducing cardiovascular disease.

The Phase 3 program wasn’t cheap.  Overall, it was projected to cost $800 million.  But such an extensive and expensive plan was necessary.  Pfizer realized that even if this program was successful, T/A would be competing with generic statins such as simvastatin and eventually atorvastatin itself.  For physicians to be willing to prescribe T/A, for payers to be willing to pay for T/A,  and for patients to be willing to take T/A, the clinical program needed to show that it was a drug of clear value.

By now, most know of the result of the Phase 3 outcomes trial.  In late 2006, this study was halted by the Data Safety Monitoring Board (DSMB) responsible for overseeing the study.  The reason for halting the trial was an imbalance in all-cause mortality in the T/A patients as compared to those on atorvastatin.  In other words, T/A was not better than Lipitor alone; in fact, it was worse in reducing heart attacks and stroke.

This result stunned cardiologists around the world.  One of the more telling comments was from the renowned Dr. Steven Nissen of the Cleveland Clinic, who said: “These studies further demonstrate the great difficulty in developing therapies to disrupt the atherosclerotic disease process.”

So that’s the history.  Now here is the Oliver Wyman version of the story.

“Five years ago several companies—Pfizer, Merck, and Roche amongst others—were pursuing CETP inhibitors, an important new class of HDL-raising therapies.  Pfizer, with torcetrapib, was in the lead, and by combining the new agent with Lipitor, they had the opportunity to create an efficacy fortress and extend the significant value of their lipid therapy franchise.  But speed was of the essence if the combo was to launch before Lipitor lost exclusivity.  Despite having seen signals of increased hypertension in Phase II studies, Pfizer chose to move forward with a landmark 25,000-patient Phase III trial.  Unfortunately, the trial showed conclusively that torcetrapib increased cardiovascular events rather than reducing them.  In contrast to Pfizer, Merck chose to slow development of its CETP inhibitor, anacetrapib, to investigate the hypertension signal.  They proceeded only after they found that it appeared to be a torcetrapib-specific effect, and was not class-wide.  In results shared at the 2010 AHA, Merck showed that anacetrapib raises HDL by 138 percent, without the side effects of the Pfizer molecule.  What is this worth? Analyst (sic) currently project that anacetrapib will achieve peak sales ranging from $3 billion to $5 billion.”

Oliver Wyman uses this example to justify one of the tenets of its paper, which is, “speed kills” and that thoughtful, more deliberate clinical development processes are needed for pharmaceutical R&D to regain success.  Its analysts believe that rushing torcetrapib through clinical development was a mistake, that “overemphasizing speed leads to throwing good money after bad” and that it is “better to slow things down to get a perspective on a molecule.”  The implication is that Pfizer would have been far better off if it had taken the more thoughtful route used by Merck.  Unfortunately, Oliver Wyman doesn’t know what it is talking about.

As was stated above, it was generally believed that the dramatic HDL elevating effects of torcetrapib would be of far greater clinical importance than the relatively minor blood pressure elevating effects caused by torcetrapib.  Furthermore, the patients in this study were already on blood pressure lowering medications, thus their hypertension was being controlled.  This was not just Pfizer’s belief.  Some of the world’s leading cardiologists, like Dr. Nissen, were not only advising Pfizer on the torcetrapib program, but they were also carrying out the clinical trials.  Raising HDL was viewed as the “holy grail” in cardiovascular research.  Heart physicians around the world were anxiously awaiting the results from the torcetrapib studies.  It wasn’t a matter of going fast to maximize profits – this was state-of-the-art science.

When the torcetrapib trial was halted, everyone in the field was shocked.  Suddenly, the promise of CETP inhibition had evaporated.  Experts began to question whether raising HDL would have ANY benefit in patients with heart disease.  Merck, which had planned to launch their Phase 3 program at about the same time that Pfizer halted theirs, instead put their program on hold for a year as they tried to evaluate what to do.  Yes, anacetrapib didn’t raise blood pressure, but perhaps the CETP mechanism was flawed.   After a year of intense internal debate, Merck decided to go ahead with anacetrapib clinical studies, but in a slower fashion than they originally had planned.  Their first phase 3 trial, reported at the American Heart Association meeting in 2010, showed that anacetrapib can be safely administered to patients with heart disease for 18 months with dramatic HDL elevation and LDL lowering without undo consequences.  They are now running the crucial large scale Phase 3 outcomes study that, hopefully, will show that CETP inhibition can confer additional benefits in heart patients when compared to statin therapy alone.

But this remains a controversial field.  Interestingly, back in 2006, Pfizer had a compound with a similar profile to anacetrapib in Phase 2 studies when the torcetrapib results were found.  Clearly, Pfizer has chosen to get out of the CETP area of research and not advance this compound further, despite the sales projections, as quoted by Oliver Wyman, being made by analysts for the Merck compound.  Unfortunately, the torcetrapib results raised more questions than provided answers.  Perhaps the work being done by Merck and other companies will answer whether there is value in CETP inhibition.

The Oliver Wyman paper implies that rapid execution of clinical programs is done in a heedless and reckless fashion, and that is a fatal flaw which is contributing to the lack of Big Pharma success.  This is absurd.   I am not so naïve to think that being first to market is not factored into a company’s decision-making process.  But this is true for any company in any industry.  Oliver Wyman’s implications are misguided, at best, and seem to be based upon uninformed research that relies more upon popular opinion than on actual data.  Oliver Wyman is only the most recent offender.  Misinformed analysts have long heralded the death of Big Pharma.  Why?  Most of Wall Street’s doomsday scenarios are attributed to a lack of understanding about what actually happens in labs.  Ours is an industry in which we are tasked with proving scientific hypotheses, a challenge that is more often frustrating than it is gratifying.  The scientific aspect of what we do is so interwoven with Big Pharma’s economic concerns that there exists a tenuous relationship between scientists needing years to prove theory and analysts demanding results.  That there would be confusion and frustration is unavoidable.  What is avoidable, however, is the perpetration of misinformation by analysts unwilling or unable to do the necessary research to provide accurate insight.

Written by johnlamattina

December 13, 2011 at 1:10 pm

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Diet and Exercise Are Important – But Often Insufficient

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The stories are heartwarming.  A person is vastly overweight and finally decides to do something about it.  Through determination, hard work and a newfound discipline, this person loses 25, 50 or even 100 pounds, thereby changing his or her life.  Perhaps it is a woman who wants to have a child and is told that bearing a child would be life-threatening if she didn’t lose a significant amount of weight.  Perhaps it’s a man who has been ridiculed all his life who decides that he is tired of the verbal abuse.  You may have seen these scenarios played out on Dr. Oz or Oprah, or perhaps on the reality show, The Biggest Loser.  Seeing the changes in these people’s lives after such a physical transformation can be inspiring.

I am a big supporter of diet and exercise.  I once heard a doctor say that if you can somehow put the benefits of exercise in a pill, you’d have a wonder drug.  Yet, despite the obvious benefits and the importance of diet and exercise, recent studies suggest that for the majority of the obese population, just diet and exercise won’t be enough.

If you are worried about the obesity epidemic in the US, two recent New England Journal of Medicine articles might further concern you.  One is entitled “Comparative Effectiveness of Weight-Loss Interventions in Clinical Practice” (NEJM, 365;21, 1959 – 1968, November 24, 2011) and the other is  “A Two-Year Randomized Trial of Obesity Treatment in Primary Care Practice” (same issue, 1969 – 1979).  Essentially, these papers are similar in that they look at the effectiveness of different interventions in primary care practices by physicians who were trying to help their obese patients gain better control of their health.   On average, the patients in these studies had a body mass index (BMI)  of about 35 ( e.g., a height of 5’7” and a weight of 220 pounds) and had at least one cardiovascular risk factor (high blood pressure, plasma glucose, or cholesterol).  Both studies had control groups who received usual physician care.  In the behavioral intervention study, besides the control group, one group received additional face-to-face counseling and the other group received advice remotely (telephonic or email).  In the obesity treatment study, the control group was compared to those who received monthly lifestyle counseling and another group who received enhanced counseling plus meal replacements and weight-loss medications.

The good news is that in both studies, those patients who were getting enhanced treatment, be it extra counseling on behaviors, more frequent sessions with their doctors or physician assistants, or enhanced life-style counseling, all had sustained statistically significant weight-loss after two years.  The amount of weight loss wasn’t trivial – it was on the order of 5%.  Even if the counseling was done remotely, the results were meaningful.  Thus, extra time spent by primary care physicians and their associates can make a difference in helping their patients lose weight.

But the disappointing news is that even with the loss of 5% of body weight, these patients are still obese.  For the aforementioned person who loses 5% from their 220 pound frame, their new weight is 209 pounds and their BMI is 34 – still well in the obese range.  When you consider that the Center for Disease Control statistics for 2010 show that there are now 12 states where more than 30% of the adult population is obese, the loss of 5% body weight is just a small step to where we must get to in order to improve the nation’s health.

Obesity is a disease and its impact on the future health of the US cannot be trivialized.  Lifestyle changes are very important and can’t be minimized.  But for millions of Americans, this isn’t nearly enough.  Undoubtedly, the future for obesity treatment will necessitate a three-pronged effort that includes diet/exercise, life-style changes and new drugs.  For the latter, both the FDA and the pharmaceutical industry need to work together to help find safe and effective treatments to enhance a physician’s armamentarium to deal with this problem.

Written by johnlamattina

December 8, 2011 at 2:38 pm

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Is the Road to Big Pharma Success Slimming Down R&D and Focusing on Mini-Blockbusters?

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Today’s long awaited launch of the generic form of Lipitor, atorvastatin, has been the inspiration for a number of recent news stories.  One that particularly caught my eye is by Bloomberg’s Drew Armstrong entitled “Pfizer After Lipitor Slims Down to Push Mini-Blockbusters.”  The gist of the article is contained in the following line: “The next step will be rebuilding the world’s biggest drugmaker into a smaller, faster-moving company that focuses on development of biologic drugs and specialty medicines….”  The implication of this statement is that Pfizer previously had a strategy that was based on discovering compounds like Lipitor that would each generate annual sales of $12 billion and that Pfizer now realizes that this is a flawed plan and is going to get leaner and smarter.

If it was only so simple.

First of all, the original peak sales predictions for Lipitor were on the order of $700 – 800 million, as it was the fifth statin to reach the marketplace.  As discussed in this blog previously, the fact that it evolved into the biggest selling drug of all time was due to a “perfect storm” of great efficacy, excellent safety and the growing realization of needing to lower bad cholesterol (LDL) more than had been previously recognized.  Lipitor is a once in a generation product.  To base a company’s strategy on this luck is foolish – and it’s not what happened at Pfizer.

What is a mini-blockbuster?  Is it a compound that has sales of $750 – $1 billion?  Pfizer generated a number of these internally in the last decade: Chantix, Vfend, Geodon, Sutent, etc.  Interestingly, most analysts paid little heed to these compounds.  The general refrain was: “These are nice compounds, but none of them are Lipitor.”  Yet, many of these same analysts are now advocating this as the direction that Pfizer should take.

Will focusing on these biologics and specialty drugs make Pfizer “a smaller, faster-moving company” as the author suggests?  These drugs should be quicker to develop after all, right?  Not exactly.  A recent issue of the New England Journal of Medicine published an editorial titled “Therapy for Cystic Fibrosis (CF) – The End of the Beginning?”  (NEJM, 365;18, November 3, 2011) which discusses the truly outstanding research that led to the CF drug ivacaftor.  This is an important new medicine that will meet an important medical need.  It is also a specialty drug.  And this research STARTED in 1989.  A focus on specialty drugs doesn’t ensure rapid R&D programs – nor robust revenues.

Analysts give high grades to compounds in the company’s late stage pipeline, including tofacitinib for rheumatoid arthritis, criizotinib (Xalkori) for lung cancer and apixiban (Eliquis) for heart disease (which was co-developed with BMS).  All of these drugs are traditional small molecules and all resulted from extensive R&D programs.  In fact, the tofacitinib program began in 1993.  The predictions for peak sales of these compounds range from $1.5 billion for crizotinib to over $4 billion for tofacitinib and apixiban – not exactly “mini-blockbuster” numbers.  Pfizer also has important biologics in its pipeline, including the vaccine Prevnar, which is also on its way to being a blockbuster.  Pfizer’s portfolio is diverse; its problem is that with top line revenues of over $60 billion, it needs more of these great compounds.

There are a few lessons in all of this. First of all, predicting commercial success for a new medicine is always tenuous.  The biopharmaceutical industry has always been surprised, both positively and negatively,  by the performance of new drugs.  That is not going to change.  As I’ve written before, to say that you are going to focus on niche or specialty products is a prescription for disaster.  Such compounds can play a role in a company’s portfolio of products, but this shouldn’t be a driver for companies with sales of $25 – 60 billion.

Second, from a discovery research standpoint, the resources needed to come up with a new compound for clinical development differ little for a niche product or a projected blockbuster.  Admittedly, the development costs for a specialty products can be less, particularly for a so-called orphan disease for which there is no treatment and relatively few patients worldwide with the disease.  But a big pharmaceutical company’s portfolio should have a very limited number of such approaches if it is to thrive.

Finally, there is a view that there are fewer and fewer opportunities for major blockbusters.  I beg to differ.  A truly effective and safe drug to cause weight loss would likely have sales in excess of Lipitor’s.  The challenge in this field is clearing the high regulatory hurdle that exists for such a compound.  A new drug that can slow or reverse Alzheimer’s Disease would also have tremendous commercial potential as the incidence of this disease will surge over the coming years with the increasing life spans of people globally.  Heart disease continues to be a problem, and the obesity/diabetes epidemic will likely reverse the progress made in this arena over the past decade.  Will an agent that raises the good cholesterol, HDL, be a new breakthrough for treating cardiovascular disease?  If yes, major blockbuster status will be achieved here as well.  There also other major medical needs awaiting new, effective treatments.

You don’t build a business strategy on the hope of discovering $10 billion/year products.  You DO base it on having the most robust R&D organization possible.  And this leads to my final point.  Slimming down R&D isn’t the answer.  Rather focus, stability and resources are required for an R&D organization to thrive.

Written by johnlamattina

November 30, 2011 at 2:44 pm

Long-Term Benefits of Statin Therapy Again Confirmed

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For those who have heart disease, changes in diet and exercise are often not sufficient to reduce the risk of having a heart attack or a stroke.  Some type of medication is usually required for these patients to help them control their high lipid levels, particularly LDL, the so-called “bad” cholesterol.  As discussed recently in this blog, the usefulness of niacin, one of the drugs used for decades by heart disease patients, has been called into question.  Long-term outcomes studies with niacin are starting to show that niacin offers little, if any, benefit over statins, the relative newcomers to cardiovascular therapy.

As the industry evaluates the new information on the long-term usage of niacin, it’s natural to pose the same questions about statins.  Are their protective benefits maintained over many years of use?  Are patients exposed to these drugs for long periods susceptible to other diseases?  Over the past few years, studies have appeared showing that statins like Lipitor (atorvastatin) can, in fact, reduce the occurrence of heart attacks and strokes in patients with heart disease.  Now, a new study reported in The Lancet (November 23, 2011) from the Heart Protection Study (HPS) Collaborative Group offers further evidence for the value of this class of medicines.

The trial design was pretty simple.  This group of patients at high risk of heart attacks and/or strokes was given either 40 mg of simvastatin or placebo for slightly over 5 years, then post-trial follow-up occurred for another 5+ years bringing the duration of the study to 11 years.  Not surprisingly, those patients on simvastatin had an average decrease in LDL cholesterol of 40mg/dL and, more importantly, a decrease of 23% in major vascular events.  This benefit continued throughout the post-trial follow-up period.  Equally important was the fact that there was no evidence of “emerging hazards” (e.g., cancer) resulting from long-term simvastatin use.

The lead author of the HPS, Dr. Richard Bulbulia of the University of Oxford, commented: “All of those at increased vascular risk should start taking statins early and continue taking them long-term.”  He also commented that these results should provide reassurance to patients and physicians about the safety of statins and that the results should translate to other members of this class of medicines such as atorvastatin and Crestor.

The HPS has provided valuable results at a time when health care providers are struggling with increasing rates of obesity, diabetes and heart disease.  But this study is important for another reason.  Medications designed for controlling a chronic disease that patients will need to take for decades – not only heart disease, but also diseases like osteoporosis, depression or even cancer – will need this type of long-term outcome study, not just to provide patients and physicians with all-important risk-benefit data, but also to justify to payers the value of new medications.  These studies add time to the development of a new drug and greatly increase development costs.  But they are invaluable.

Written by johnlamattina

November 30, 2011 at 10:02 am

Does Niacin Still Have a Role in Cardioprotection?

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A number of years ago, I needed to address my rising cholesterol levels.  Despite being an avid runner with a Body Mass Index well within normal limits, my total cholesterol was 250 mg/dL and my LDL (“bad cholesterol”) was 140 mg/dL – both above recommended healthy levels.  Given that I have a family history of heart disease, I decided to seek medical treatment and, being a Pfizer employee, I visited my personal physician with the intent of getting a prescription for Lipitor.

Interestingly, my doctor was reluctant to do this.  This was the 1990s and Lipitor was new to the market.  He was not comfortable prescribing a drug that I potentially would take for the rest of my life without having seen more long term safety data.  Instead, he recommended that I take long-acting niacin, which is available over-the-counter at any pharmacy.

Niacin, also known as vitamin B3, is known to raise HDL, the so-called good cholesterol, by about 25% as well as modestly lower both LDL and triglycerides.  It has been used for decades to treat dyslipidemia based on results from the Coronary Drug Project (CDP).  Carried out in the late 1960s, the CDP study tested niacin vs. placebo in men who’d had a previous heart attack, over a period of five years.  Interestingly, niacin showed no difference from placebo in the death rate of the men in this study, but fewer patients on niacin had a non-fatal heart attack or stroke, by 26% and 24% respectively.  This study is the basis of the use of niacin in cardiovascular (CV) disease.

My experience with niacin was pretty typical.  There were modest reductions of both total cholesterol  and LDL (~15%), but these changes weren’t maintained over time.  But I also experienced the major niacin side-effect, flushing.  This irritation wasn’t minor.  The flushing was intense and was accompanied by itching and heat sensations.  Because of this side-effect, many patients refuse to stay on this medication despite its potential benefits.  After about a year, my physician took me off niacin and I started on Lipitor which was far more effective for me than niacin and which I tolerated very well.

So, why am I taking you on this stroll down memory lane?  A recent study reported in The New England Journal of Medicine (NEJM.org, 11/15/11), along with an accompanying editorial, call into question the value of using niacin to treat CV disease.  The AIM-HIGH trial, co-sponsored by the NIH and Abbott, looked at patients with established CV disease who were already on intensive statin therapy.  The goal of this study was to see whether adding niacin therapy provided any extra benefit.  The rationale for this was pretty sound.  Unlike statins, niacin can significantly raise HDL and further lower LDL.  Shouldn’t combining both modalities work better?  Surprisingly, it didn’t.  While the expected beneficial changes in terms of raising HDL did occur, adding niacin to intensive statin therapy was no different from adding a placebo in terms of preventing heart attacks, strokes or other adverse CV events.

The NEJM editorial accompanying the AIM-HIGH study results entitled, “Niacin at 56 Years of Age – Time for an Early Retirement?,” basically questions further use for niacin given the copious data with statins showing the superiority of these drugs in CV disease therapy.  This is causing some intense debate amongst cardiologists, who are unwilling to give up on niacin after this one study.  The defenders of niacin correctly point out that there are other long-term studies with niacin currently underway that will provide a more definitive answer to the value of niacin for treating heart disease.

Niacin is a medicine that has been used by physicians for 56 years.  Physicians take comfort in the fact that it has been around for so long and it has been taken by millions of people, so they know what the side-effects are.  Yet, niacin hasn’t been as intensively studied as newer classes of lipid modulating drugs.  It is now being subjected to the same type of scrutiny demanded by the FDA of new drugs.  I, for one, am looking forward to the completion of these studies.

As I have often written in this blog, decades of use does not ensure that a medicine is automatically safe and/or effective.  Industry detractors seem to forget that pharmaceutical companies are full of people that also need medicine.  I was my own case study in the effectiveness and risk-benefit profile of Lipitor versus niacin.  For me, Lipitor was the answer.  Whether or not that is also the case for others is a decision that a patient must make in consultation with his physician.  However, one thing is for certain: only long-term, well-controlled studies can provide assurance that a medicine is both safe and effective.

Written by johnlamattina

November 21, 2011 at 10:36 am

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Some Wisdom from Jane Brody

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“Some forms of ‘medicalisation’ may now be better described as ‘disease mongering’ – extending the boundaries of treatable illness to expand markets for new products.”

-Ray Moynihan, Iona Heath, David Henry in the British Medical Journal, 2002; 324:886-91.

Moynihan is one of the leading critics of the pharmaceutical industry.  He has a strong belief that the industry effectively invents diseases by the medicalization of conditions in such a way that convinces healthy people that they are sick.  One example used in the paper cited above is in the area of osteoporosis:

“Like high blood pressure or raised cholesterol levels, the medicalisation of reduced bone mass – which occurs as people age – is an example of a risk factor being conceptualized as a disease… Slowing bone loss can reduce the risk of future fracture – just as lowering blood pressure can reduce a person’s chance of a future stroke or heart attack – but for most healthy people, the risks of serious fractures are low and/or distant, and in absolute terms, long term preventive drug treatment offers small reductions in risk.”

Is bone-thinning a disease?  Of course not.  But, if you are a petite female of Asian or northern European background, bone thinning is the first sign of osteoporosis.  Unfortunately, when journalists like Moynihan make statements like this, it results in people ignoring health issues and taking the steps necessary to forestall diseases like osteoporosis.  Thus, it was refreshing to see Jane Brody’s recent article in The New York Times (November 1, 2011) entitled “A Reminder on Maintaining Bone Health.”

Brody believes that osteoporosis is under diagnosed because of a reluctance to get bone density tests and under treated because people avoid drug therapy for fear of side effects.  At age 60 she was found to have osteopenia, a condition characterized by low bone density but without frank osteoporosis.  She likens osteopenia to prediabetes or prehypertension.  At this stage, one doesn’t need to take drugs but lifestyle changes are recommended, such as regular weight-bearing and strength-training exercise, intake of calcium and vitamin D, smoking cessation and limited alcohol consumption.  However, people with osteopenia can benefit from drug therapy if they have already had a fracture.

But what about the safety of drugs for osteoporosis?  Brody does an excellent job in discussing the risk-benefit profile of bisphosphonates, the major class of drugs prescribed for this disease.

“On average, the bisphosphonates reduce the risk of a fragility fracture by 30 – 50%.  By comparison, the risk of the most talked about serious side effect – an atypical fracture of the femur, or thigh bone – is miniscule.”

What appealed to me about this article is the fact that an independent journalist from The New York Times has basically pointed out that bone loss is a real issue and needs to be treated long before symptoms arise.  Brody’s messages are pretty clear: monitor your bone health; at the first serious signs of bone loss you should make life-style changes; if your bone loss evolves into early osteoporosis, you should work with your doctor to identify the medicine best suited for you.  Unlike Moynihan’s minimization of a common disease of aging women and even some men, Brody has provided a thoughtful commentary on how best to approach bone loss.  It is great advice.

Written by johnlamattina

November 16, 2011 at 10:46 am

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