Older fathers linked to genetic disease due to testicular tumours - Telegraph

By Chris Irvine
Published: 7:46AM GMT 26 Oct 2009

Researchers found that older men were more likely to have the benign tumours, known as spermocytic seminomas, which although harmless on their own, potentially passed on genetic mutations to their sperm, thereby increasing the chances of their offspring have health problems including autism or schizophrenia.

Professor Andrew Wilkie, from Oxford University, who led the study published in the journal Nature Genetics, said clumps of tumour-producing cells form in the testicular tissue which then produced the "germ cells".

“We think most men develop these tiny clumps of mutant cells in their testicles as they age,” he said. “They are rather like moles in the skin, usually harmless in themselves. But by being located in the testicle, they also make sperm - causing children to be born with a variety of serious conditions.”

It had long been believed that only women need worry about having children in later life, but a number of studies in the last 10 years have indicated that the quality of a man's sperm deteriorates as he becomes older. One particular study in Israel found that men who became fathers aged 40 or older were almost six times more likely to have a child compared with autism compared with men younger than 30. Another previous study found every additional five years increased the risk of a child have autism by 3.6 per cent.

"The major implication is for older fathers”, Prof Wilkie said. “We already knew that men in their 50s have a risk of having children with various individually rare genetic disorders — achondroplasia is a well known one — about tenfold higher than men in their early 20s.

“Adding all these risks together, the total additional risk is still only a fraction of per cent per cent because each of these disorders is rare.”

via telegraph.co.uk

Related Article

• Children of older parents at increased risk of autism

Posted via web from Jack's posterous

Number of UK children on antipsychotic drugs doubles - Channel 4 News

As many as 15,000 children and young people under the age of 18 were prescribed this medication last year. But these figures are only from GP surgeries and primary care trusts and do not include hospital prescribing, which suggests the true number could be far higher.

Astonishingly, no official data is kept on the number of youngsters being given anti-psychotics. This has only now been revealed after Channel 4 News commissioned a drug database company to collate them.

The investigation comes as the government announced that GPs could face jail if they are found to be "chemically coshing" elderly patients with dementia. But no mention was made of children and young people in the announcements.

Anti-psychotics are meant for patients with serious mental conditions such as schizophrenia, bipolar disorder and psychosis. But mental health experts now say that they would also appear, in some instances, to be being used to control children's behaviour.

If there is a doubling in the rate of children being given anti-psychotics that is a worry. My worry is that these drugs are being used for other purposes. Professor Tim Kendall

The investigation also found children are being left on the drugs for years at a time and are not being properly monitored, which is against best practice guidelines.

Professor Tim Kendall, who has been asked to write the first ever guidance on prescribing anti-psychotics to young people with serious mental illness, said that these findings are extremely concerning.

"As far as I am aware there is no evidence that there has been a doubling in the rate of psychosis so if there is a doubling in the rate of children being given anti-psychotics that is a worry," Prof Kendall said.

"My worry is that these drugs are being used for other purposes."

Family stories

And that would be appear to be what is happening. We have spoken to families whose children have been given the drug for attention deficit hyperactivity disorder (ADHD) and for autism.

The family of one young boy first prescribed an anti-psychotic when he was five for so-called "challenging behaviour" has subsequently been told that he was in fact in pain. The boy, now aged eight, is autistic and regularly banged his head against hard surfaces and lay on the floor kicking and screaming. But his parents said the anti-psychotics he had been on for three years had had no benefit at all.

Eventually he was seen by Professor Chris Oliver, of Birmingham University, who has been researching behavioural problems in children with autism.
His conclusion was that the young boy was most probably in pain - suffering from gastro-oesophageal reflux, more commonly known as heart burn. But because of his autism he was not able to articulate that he was physically suffering.

Anti-psychotics were developed in the 1950s and have been widely prescribed to adults since the 1970s. But they can cause, among other things, dramatic weight gain, diabetes and heart disorders. They can also leave patients with a Parkinson's disease-like tremor which does not stop even if they are taken off the medication.

via channel4.com

Posted via email from Jack's posterous

Overdiagnosis as a Flaw in Health Care

EARLY diagnosis has become one of the most fundamental precepts of modern medicine. It goes something like this: The best way to keep people healthy is to find out if they have (pick one) heart disease, autism, glaucoma, diabetes, vascular problems, osteoporosis or, of course, cancer — early. And the way to find these conditions early is through screening.

It is a precept that resonates with the intuition of the general public: obviously it’s better to catch and deal with problems as soon as possible. A study published with much fanfare in The New England Journal of Medicine last week contained what researchers called the best evidence yet that colonoscopies reduce deaths from colon cancer.

Recently, however, there have been rumblings within the medical profession that suggest that the enthusiasm for early diagnosis may be waning. Most prominent are recommendations against prostate cancer screening for healthy men and for reducing the frequency of breast and cervical cancer screening. Some experts even cautioned against the recent colonoscopy results, pointing out that the study participants were probably much healthier than the general population, which would make them less likely to die of colon cancer. In addition there is a concern about too much detection and treatment of early diabetes, a growing appreciation that autism has been too broadly defined and skepticism toward new guidelines for universal cholesterol screening of children.

The basic strategy behind early diagnosis is to encourage the well to get examined — to determine if they are not, in fact, sick. But is looking hard for things to be wrong a good way to promote health? The truth is, the fastest way to get heart disease, autism, glaucoma, diabetes, vascular problems, osteoporosis or cancer ... is to be screened for it. In other words, the problem is overdiagnosis and overtreatment.

Screening the apparently healthy potentially saves a few lives (although the National Cancer Institute couldn’t find any evidence for this in its recent large studies of prostate and ovarian cancer screening). But it definitely drags many others into the system needlessly — into needless appointments, needless tests, needless drugs and needless operations (not to mention all the accompanying needless insurance forms).

This process doesn’t promote health; it promotes disease. People suffer from more anxiety about their health, from drug side effects, from complications of surgery. A few die. And remember: these people felt fine when they entered the health care system.

It wasn’t always like this. In the past, doctors made diagnoses and initiated therapy only in patients who were experiencing problems. Of course, we still do that today. But increasingly we also operate under the early diagnosis precept: seeking diagnosis and initiating therapy in people who are not experiencing problems. That’s a huge change in approach, from one that focused on the sick to one that focuses on the well.

Think about it this way: in the past, you went to the doctor because you had a problem and you wanted to learn what to do about it. Now you go to the doctor because you want to stay well and you learn instead that you have a problem.

How did we get here? Or perhaps, more to the point: Who is to blame? One answer is the health care industry: By turning people into patients, screening makes a lot of money for pharmaceutical companies, hospitals and doctors. The chief medical officer of the American Cancer Society once pointed out that his hospital could make around $5,000 from each free prostate cancer screening, thanks to the ensuing biopsies, treatments and follow-up care.

A more glib response to the question of blame is: Richard Nixon. It was Nixon who said, “we need to work out a system that includes a greater emphasis on preventive care.” Preventive care was central to his administration’s promotion of health maintenance organizations and the war on cancer. But because the promotion of genuine health — largely dependent upon a healthy diet, exercise and not smoking — did not fit well in the biomedical culture, preventive care was transformed into a high-tech search for early disease.

Some doctors have long recognized that the approach is a distraction for the medical community. It’s easier to transform people into new patients than it is to treat the truly sick. It’s easier to develop new ways of testing than it is to develop better treatments. And it’s a lot easier to measure how many healthy people get tested than it is to determine how well doctors manage the chronically ill.

But the precept of early diagnosis was too intuitive, too appealing, too hard to challenge and too easy to support. The rumblings show that that’s beginning to change.

Let me be clear: early diagnosis is not always wrong. Doctors would rather see patients early in the course of their heart attack than wait until they develop low blood pressure and an irregular heartbeat. And we’d rather see women with small breast lumps than wait until they develop large breast masses. The question is how often and how far we should get ahead of symptoms.

For years now, people have been encouraged to look to medical care as the way to make them healthy. But that’s your job — you can’t contract that out. Doctors might be able to help, but so might an author of a good cookbook, a personal trainer, a cleric or a good friend. We would all be better off if the medical system got a little closer to its original mission of helping sick patients, and let the healthy be.

H. Gilbert Welch, a professor of medicine at the Dartmouth Institute for Health Policy and Clinical Practice, is an author of “Overdiagnosed: Making People Sick in the Pursuit of Health.”

via nytimes.com

Posted via email from Jack's posterous

Newer antipsychotics overused, U.S. study suggests - CNBC

CHICAGO - Although first approved to treat schizophrenia, new antipsychotic medications are increasingly being prescribed for a host of other uses, even when there is little evidence they work, U.S. researchers said on Friday.

The drugs, known as "atypical antipsychotics," have quickly eclipsed older-generation or "typical" antipsychotics and are increasingly used to treat conditions like bipolar disorder, depression and even autism.

"What we see is wide adoption for the use of these medications far beyond the evidence base to support it," said Dr. Caleb Alexander of the University of Chicago and a consultant for IMS Health, a company that collects data on prescription drugs.

He said more than half of all atypical antipsychotic prescriptions written in 2008 were based on flimsy evidence.

"We're talking millions of prescriptions a year for antipsychotics in settings where there is uncertain evidence to support them," said Alexander, whose study appears in the journal Pharmacoepidemiology and Drug Safety.

The drugs are not harmless, Alexander said in a telephone interview. They can cause weight gain, diabetes and heart disease and are far more costly than the older antipsychotics, which cause disorders such as involuntary movements.

Atypical antipsychotics accounted for more than $10 billion in U.S. retail pharmacy drug costs in 2008 -- nearly 5 percent of all prescription drug spending.

They include Johnson & Johnson's Risperdal, known generically as risperidone; Eli Lilly and Co's Zyprexa or olanzapine; Bristol-Myers Squibb and Otsuka Pharmaceutical Co's Abilify or aripiprazole; and AstraZeneca's Seroquel or quetiapine.

For the study, the team analyzed results of a physicians' survey conducted by IMS Health to determine which antipsychotics were being used and for what condition.

They found that antipsychotic treatment nearly tripled to 16.7 million prescriptions written in 2008 from 6.2 million in 1995. During that period, prescriptions for first-generation antipsychotics fell to 1 million from 5.2 million.

Although first approved for schizophrenia, antipsychotic drugs are also used to treat psychoses, bipolar disorder, delirium, depression, personality disorders, dementia and even autism. Although some of the atypical drugs have won U.S. regulatory approval for some of these uses, doctors are also prescribing the drugs for unapproved uses.

To assess the evidence for these so-called off-label indications, the team used effectiveness ratings from a drug compendium called Drugdex.

They found that antipsychotic use for indications that lacked Food and Drug Administration approval more than doubled to 9 million prescriptions in 2008 from 4.4 million prescriptions 1995, representing about $6 billion in spending nationwide.

Dr. Gregory Simon of the Group Health Research Institute, who was not part of the study, said he was especially worried about the increased use of antipsychotic drugs for bipolar disorder and depression.

"For bipolar disorder, we have no evidence that the atypical antipsychotics are safer or more effective than alternative treatments. They are certainly much more expensive. But use of the atypical antipsychotics has grown rapidly, displacing treatments that are less expensive and more well-established," Simon said in an e-mail.

For depression, the drugs are used to augment antidepressant therapy, but Simon said there are several other options, including switching to another antidepressant.

"Again, we have no evidence that adding an atypical antipsychotic is more effective than those other options, and it is the most expensive choice," he said.

Dr. Randall Stafford of Stanford University School of Medicine, who worked on the study, blames marketing by drug companies and a tendency for doctors to think newer is better.

"Physicians want to prescribe and use the latest therapies -- and even when those latest therapies don't necessarily offer a big advantage, there's still a tendency to think that the newest drugs must be better," he said in a statement.

via cnbc.com

Posted via email from Jack's posterous

Ex BMJ editor calls med journals "creatures of the drug industry"

Dr Richard Smith should know a thing or two about medical journals. He worked at the BMJ for over a quarter of a century!

Medical journals have become "creatures of the drug industry" rife with fraudulent research and packed with articles ghost written by pharmaceutical companies, the ex British Medical Journal editor has claimed.

In a highly critical book Dr Smith, who edited the BMJ for 13 years, said: "Medical journals have many problems and need reform. The research they contain is hard to interpret and prone to bias and peer review. The process at the heart of journals and all of science, is deeply flawed."

Here is an article in the JRSM which helps with the context.

Dr Smith, author of a new book entitled 'The Trouble with Medical Journals' and now chief executive of United Healthcare Europe, said the book was an honest analysis of trends in medical journal publishing and a frank account of his own experiences as editor of the BMJ.

He said: "It is increasingly apparent that many of the studies journals contain are fraudulent, and the scientific community has not responded adequately to the problem of fraud."He added: "I went away to Venice to write this book and I was rather taken aback by how negatively it turned out. When I put together all the evidence on journals I was surprised by the extent of the problems."

Dr Smith went on: "Medical journals have increasingly become creatures of the drug industry. The authors of studies in journals have often had little do with the work they are reporting."The use of ghost writers by pharmaceutical companies is rampant and many studies have conflicts of interest that are not declared."

He estimates that research fraud is probably common in the 30,000 or so scientific journals published throughout the world.The book, published by the Royal Society of Medicine Press, cites a number of dramatic cases of questionable research including Dr Andrew Wakefield's MMR paper published in the Lancet in 1998 that cast doubts on the safety of the triple vaccine which protects against measles, mumps and rubella.

The same journal published a study six years later concluding there was no evidence to support a link between MMR and autism.

Dr Smith says a study funded by Vioxx maker Merck and Co and published in the New England Journal of Medicine in 2000 failed to mention that three patients suffered heart attacks while using the now withdrawn painkiller.

And earlier this year, South Korean human cloning pioneer Hwang Woo-suk was fired from his professorship at Seoul National University following allegations he faked some of his research. The Trouble with Medical Journals examines the important relationships between journals and patients, the mass media, pharmaceutical companies, open access and the developing world.

Dr Kamran Abbasi, editor of the Journal of the Royal Society of Medicine, said: "Medical journals influence policy makers, doctors, and ultimately patient care, the best example is the MMR crisis. Richard Smith's book tells it like it is and the truth hurts — money can corrupt science and medical research."

Source

What are we doing to our children?

American children take anti-psychotic medicines at about six times the rate of children in the United Kingdom, according to a comparison based on a new U.K. study.

And with scant long-term safety data, it's likely the drugs are being over-prescribed for both U.S. and U.K. children, research suggests.

Among the most commonly used drugs were those to treat autism and hyperactivity.

In the U.K. study, there were 595 anti-psychotic prescriptions for children in 1992, or a rate of fewer than four children per 10,000 using the drugs. By 2005, 2,917 prescriptions were written, or a rate of seven children per 10,000 — a near-doubling, said lead author Fariz Rani, a researcher at the University of London's School of Pharmacy.

The study is in the May edition of the journal Pediatrics.

More

NYS Attorney General settles $181M deceptive marketing case with drug co. | Brooklyn Daily Eagle

via brooklyneagle.com

New York State Attorney General Eric Schneiderman on Wednesday announced a record $181 million settlement with Janssen Pharmaceuticals and its parent company Johnson & Johnson to resolve charges of improper marketing and advertising of the powerful anti-psychotic drugs Risperdal and Invega.

The settlement, joined by 36 other states and the District of Columbia, represents the largest multi-state consumer protection-based pharmaceutical settlement in history. New York will receive nearly $9 million.

In the complaint filed Wednesday in New York County Supreme Court, Attorney General Schneiderman charged that from 1998 through at least 2004, Janssen Pharmaceuticals engaged in deceptive and misleading practices when it marketed Risperdal, Risperdal Consta, Risperdal M-Tab and Invega for off-label uses.

As a result of the states' investigation, Johnson & Johnson agreed to change its marketing of Risperdal and Invega, and to cease promoting “off-label” uses of the drugs not approved by the U.S. Food and Drug Administration (FDA).

Off-label use refers to prescribing a drug for a condition other than what it’s been approved for, or to an age group other than that for which the drug was originally intended.

“Pharmaceutical corporations’ illegal promotion of drugs for off-label uses must stop. Consumers, including parents of children with serious mental disorders and vulnerable patients should be able to trust their doctor’s advice without fear that drug companies are manipulating their physician’s independent judgment,” Schneiderman said.

Risperdal is an anti-psychotic medication used to treat mental illnesses including schizophrenia, bipolar disorder and irritability associated with children and adolescents with autism.

Invega, which is derived from risperdone, is also marketed for the treatment of schizophrenia and bipolar mania.

The complaint charged that Janssen promoted Risperdal for unapproved uses, including dementia in elderly patients, schizophrenia and bi-polar disorder in children and adolescents, and depression, anxiety, obsessive compulsive disorder, conduct disorder, post-traumatic stress disorder and Alzheimer’s disease.

The other states that were part of Wednesday’s settlement are Alabama, Arizona, Colorado, Connecticut, Delaware, District of Columbia, Florida, Hawaii, Idaho, Illinois, Indiana, Iowa, Kansas, Maine, Maryland, Michigan, Minnesota, Missouri, Nebraska, Nevada, New Hampshire, New Jersey, North Carolina, North Dakota, Ohio, Oklahoma, Oregon, Pennsylvania, Rhode Island, South Dakota, Tennessee, Texas, Vermont, Washington, Wisconsin and Wyoming.

Posted via email from Jack's posterous

Psychiatrists: the drug pushers - by Will Self

Illustration by John Holcroft

A psychiatrist who once "treated" me used to recite this rueful little mantra: "They say failed doctors become psychiatrists, and that failed psychiatrists specialise in drugs." By drugs this psychiatrist meant drugs of addiction – and his "treatment" of me consisted of prescribing Temgesic, a synthetic opiate, as a substitute for the heroin I was more strongly inclined to take. So, he undertook this role: acting, in effect, as a state-licensed drug dealer; and he also attempted a kind of psychotherapy, talking to me about my problems and engaging with my own restless critique of – among many other things – psychiatry itself. Together we conceived of doing some sort of project on drugs and addiction, and began undertaking research. On one memorable fact-finding trip to Amsterdam, we ended up smoking a great deal of marijuana as well as drinking to excess – I also scored heroin and used it under the very eyes of the medical practitioner who was, at least nominally, "treating" me.

All of this happened more than 20 years ago, and I drag it up here not in order to retrospectively censure the psychiatrist concerned, but rather to present him and his behaviour as a perversely honest version of the role played by his profession. For what, in essence, do psychiatrists specialise in, if not mood-altering drugs? Or, to put it another way, what do psychiatrists have to offer – over and above the other so-called "psy professions" – beyond their capacity to legally administer psychoactive drugs, and in some cases forcibly confine those they deem to be mentally ill?

Psychiatry is undergoing one of its periodic convulsions at the moment – one that coincides with the publication by the American Psychiatric Association of the fifth edition of their hugely influential "Diagnostic and Statistical Manual of Mental Disorders" (DSM–5) – and I think we should all take the opportunity to join in the profession's own collective navel-gazing and existential angst. After all, while the influence of the talking cures is pervasive in oursociety – running all the way up the scale from anodyne advice dispensed on daytime TV shows, to the wealthy shelling out hundreds of pounds a week to pet their neuroses in the company of highly qualified black dog walkers – psychotherapy and psychoanalysis remain essentially voluntaristic undertakings; only psychiatry deals in mandatory social care and legal sanction. Besides, only psychiatry partakes of the peculiar mystique that attaches to medical care. We may dismiss the opinions of all sorts of counsellors and therapists, secure in the knowledge that their very multifariousness is indicative of their lack of overall traction, but psychiatry, dealing, as it claims, with well-defined maladies – and treating them with drugs and hospitalisation – exerts an enormous pull on our collective self-image. Just what the nature of this pull is, and how it has come to condition our understanding of ourselves and our psychic functioning, is what I wish to unpick.

Full-blown mental illness is an extremely frightening phenomenon to observe – let alone experience. And much of the debate that surrounds the efficacy of contemporary psychiatry is warped by the knowledge – lurking in the wings of our minds – that we wish to have as little as possible to do with it. We may understand rationally that psychosis isn't a contagion, yet still we turn aside from the street soliloquisers and avoid the tormented gazes of those being "cared for in the community". Arguably, the response of those who treated a trip to Bedlam to view the madmen and women as an entertainment had the virtue of at least being a form of contact. At their peak, mental hospitals such as Bedlam (and formerly known as "lunatic asylums") housed over 100,000 inmates, many of whom had been confined for behaviours that today would be regarded as lifestyle choices, such as socialism or sexual promiscuity. The hospitals were also dumping grounds for patients who we now know to have had organic brain diseases. It's sobering for those on the left to realise that the first politician to commit to their abolition was Enoch Powell. By the early 1990s many long-stay inmates had been returned to the outside world, but their lives were for the most part still grossly circumscribed: living in sheltered accommodation and visited by mental health teams, confined not by physical walls but by the chemical straitjackets of neuroleptic drugs.

An engraving of a bedridden patient at the New York City Lunatic Asylum Hospital in the late 1860s. Photograph: Stock Montage/Getty Images

Still, if you wish to visit Bedlam you can do so. The locked mental wards of our hospitals present a terrifying spectacle of seriously disturbed patients shouting, yelping, gurning and shaking – I know, I've seen them. And it's the much-repressed knowledge that this is going on that helps, I would argue, to prevent too much criticism of the psychiatric profession. Just as we are quietly grateful to prison officers for banging up criminals, so too we are grateful for psychiatrists and psychiatric nurses for providing a cordon sanitaire between us and flamboyant insanity. Yet while the regime under which those diagnosed with mental pathologies has changed immensely in the last half-century, the prognosis remains no better. Some say that it is manifestly worse, and that psychiatry itself is to blame. But the truth is that hardly anyone – apart from the professionals, whose livelihoods depend on it – can either be bothered to wade through the reams of scientific papers concerned with the alternative treatment regimens, or understand the different methodologies arrived at to assess competing claims.

Early in Our Necessary Shadow, his lucid, humane and in many ways well-balanced account of the nature and meaning of psychiatry, Tom Burns, professor of social psychiatry at Oxford University, makes a supremely telling remark: "I am convinced psychiatry is a major force for good or I would not have spent my whole adult life in it." This is a form of the logical fallacy post hoc ergo propter hoc("After this, therefore because of this"), and it seems strange that an academic of such standing should so blithely retail it because, of course, if we reverse the statement it makes just as much sense: "Having spent my whole adult life as a psychiatrist I must maintain the conviction that it is a major force for good." After all, the alternative – for Burns and for thousands of other psychiatrists – is to accept that in fact their working lives have constituted something of a travesty: either locking up or drugging patients whose diseases are defined not by organic dysfunction but by socially unacceptable behaviours. Burns has the honesty and integrity to admit that the major mental pathologies – schizophrenia, bipolar disorder, depression inter alia – cannot be defined in the same way as physical diseases, and he cleaves to the currently fashionable view of psychiatry as seeking to understand mental maladies through the tripartite lens of the social, the psychological and the biological. He also states that he sees the role of psychotherapy as central to the practise of psychiatry – and in this he dissents from the more mainstream "biological" model of treatment that has been in the ascendancy since the 1970s.

But what Burns cannot quite bring himself to do is give up thedrugs. In a 333 page book (complete with a glossary, a bibliography and an index), there are just three references to the most commonly prescribed psychiatric drugs: the SSRIs, or selective serotonin reuptake inhibitors (such as Prozac and Seroxat). When he does consider the SSRIs, he notes that they may indeed be overprescribed (as of 2011 46.7m prescriptions had been written in the UK for antidepressants), and in particular that they may be used to "treat" commonplace unhappiness rather than severe depression. What he doesn't venture near are the systematic critiques of antidepressants – and neuropharmacology in general – that have emerged in recent years. The work of Irving Kirsch, whose meta-analysis of SSRI double-blind trials revealed that in clinical terms – for a broad spectrum of depressed patients – SSRIs acted no better than a placebo, is something Burns doesn't want to look at. He also doesn't wish to examine too closely the underlying "chemical imbalance" theory of depression on which the alleged efficacy of the SSRIs is based, presumably because he knows that it's essentially bunk: no fixed correlation has been established, despite intensive study, between levels of serotonin in the brain and depression.

Antidepressant tablets. Photograph: Jonathan Nourok/Getty Images

I've swerved into consideration of antidepressants because I believe the exponential increase in their use is a function of the problem of legitimacy that psychiatry currently faces. Psychiatrists, of course, tell the public that the vast majority of these drugs are prescribed by general practitioners – not by them. But what has made it possible for someone recently bereaved or unemployed to have a prescription written by their doctor to alleviate their "depression", is, I would argue, very much to do with psychiatry's search for new worlds to conquer, an expedition that has been financed at every step by big pharma. Put bluntly: unable to effect anything like a cure in the severe mental pathologies, at an entirely unconscious and weirdly collective level psychiatry turned its attention to less marked psychic distress as a means of continuing to secure what sociologists term "professional closure". After all, if chlorpromazine (commonly known as Largactil) and other neuroleptics don't cure schizophrenia – any more than lithium "cures" bipolar illness – then why exactly do you need a qualified medical doctor to dole them out?

The proliferation of new psycho-pharmacological compounds has advanced in lock-step with the proliferation of new mental illnesses for them to "treat". As Ian Hacking observes in a review of DSM–5 in the current London Review of Books, the first DSM – published in 1952 – and its successor in 1968, were heavily influenced by the psychoanalytic theories then dominating psychiatry in the US. In 1980, with DSM–III there came a step-change. Hacking traces this to the efficacy of lithium in managing mania: "Now there was something that worked … clear behavioural criteria were necessary to identify who would benefit from lithium." James Davies begins his book, Cracked: Why Psychiatry Is Doing More Harm Than Good, with an examination of how these behavioural criteria were arrived at by the compilers of DSM–III and its subsequent incarnations. You may be thinking that all this is so much arcane knowledge – and wondering why we in Britain should be preoccupied by a diagnostic manual published in the US. But in fact the ICD (International Classification of Diseases) used by British doctors is compiled in the same way as the DSM – indeed most NHS psychiatrists favour the latter over the former. In the US it's simple: your insurance won't pay out unless you are diagnosed with a malady detailed in the DSM, but in Britain we have a less tangible – but for all that pervasive – form of socio-medical discrimination: no sick note – and no social benefits – unless what ails you conforms to the paradigms set out in DSM.

The focus of Davies's critique is that the criteria for what constitutes ADHD (attention deficit hyperactivity disorder), or autism, or indeed depression, are not arrived at by any commonly understood scientific procedure, but rather by committee: psychiatrists getting together and pooling their understanding of how patients with these maladies "present" (in the jargon). Under these circumstances it becomes somewhat easier to understand how the tail can begin to wag the dog: rather than arriving at a commonly agreed set of symptoms that constitute a gestalt – and hence a malady – psychiatrists become influenced by what psycho-pharmacological compounds alleviate given symptoms, and so, as it were, "create" diseases to fit the drugs available. This in itself, Davies might argue, explains why there are more and more new "diseases" with each edition of the DSM: it isn't a function of scientific acumen identifying hitherto hidden maladies, but of iatrogenesis: doctor-created disease. So, while it may well be general practitioners who do the doling out, psychiatrists are required to legitimate what they are doing and provide it with the sugar-coating of scientific authenticity. It's a dirty, well-paid and high-status job – but someone has to do it, no?

The vast number of "hyperactive" children in the US prescribed Ritalin is so well attested to that it's become a trope in popular culture – just like the SSRI-munching depressive. But these are our version of low-level "care in the community", the sad are becoming oddly co-morbid (afflicted with the same sorts of diseases) with the mad. Davies treads a familiar path in his critique of the influence of the multinational pharmaceutical companies on the structure and practice of psychiatry. If you aren't familiar with the fact that almost all drug trials are funded by those who stand to profit from their success then … well, you jolly well should be. You should also be familiar with the extent to which university research departments and learned journals are funded by those who stand to profit – literally – from their presumed objectivity. The money generated by the SSRIs in particular is vast, easily enough to warp the dynamics and the ethics of an entire profession, and indeed I would agree with Davies that it has in fact done just this. The sections of his book that deal in particular with the way big pharma has moved into markets outside the English-speaking world and effected a wholesale cultural change in their perception of sadness (rebranding it, if you will, as chemically treatable "depression"), simply in order to flog their dubious little blue pills, make for chilling reading.

Actually, Burns would agree with some of this critique as well; and recall, he's a psychiatrist who fervently believes that his profession has been, and continues to be, a force for good. Davies is a psychologist, and to the outsider the fierceness of his attack might be dismissed as part of a turf war among the psy professions (Irving Kirsch is a clinical psychologist as well). However, I don't think it helps anyone to see the current imbroglio as simply a function of late capitalism in its most aggressive aspect. I'm afraid I have to mouth the old lily-livered liberal shibboleth at this point and observe that, yes, we are all to blame; and our responsibility is just as difficult for us to acknowledge because we are largely unaware of it. We don't consciously collude in the chemical repression of the psychotic (and Davies produces quite convincing statistics to support the view that those with psychosis actually recover better if they aren't medicated at all), any more than we consciously collude in the fiction of depression as a chemical imbalance that can be successfully treated with SSRIs.

Instead, what both clinicians and patients experience is quite the reverse: we feel absolutely bloody miserable, we can't get up in the morning, we are dirty and unkempt, and we go along to our GP and are prescribed an antidepressant, and lo and behold we recover. My GP, who has just retired, and who is a wise and compassionate man who I absolutely trusted, told me that he prescribed SSRIs because they worked, and I believed him. That they worked because of the overpoweringly efficacious curative power we believe doctors and their nostrums to possess rather than because of any real change in our brain chemistry was beside the point for him – and I suspect it's beside the point for the vast majority of patients as well. By the same token, Burns is at pains to stress, contra-DSM, that the great strength and skill of the practising psychiatrist lies in being able to intuit diagnoses by empathising with patients. Diagnosis, for Burns, is an art form – not a science. By his own account I've little doubt that he's a good and effective psychiatrist who can make a real difference to the lives of those plagued by demons that undermine their sense of self. One of my oldest friends is a consultant psychiatrist who I've actually seen practising in just this way, with preternatural flair and compassion.

In both their cases, however, I feel about them rather the way I do about the last archbishop of Canterbury: I consider Rowan Williams to be a wise and spiritual man mostly despite rather than because of his Christianity; and I think many psychiatrists are good healers mostly despite rather than because of the medical ideology of mental illness to which they subscribe.

Interestingly there is one large sector of the "mentally ill" that Burns believes are manifestly unsuitable for treatment – drug addicts and alcoholics. He points to the ineffectiveness of almost all treatment regimens, possibly because the cosmic solecism of treating those addicted to psychoactive drugs with more psychoactive drugs hits home despite his well-padded professional armour. Elsewhere in Our Necessary Shadow he seems to embrace the idea that self-help groups of one kind or another could help to alleviate a great deal of mental illness, and it struck me as strange that he couldn't join the dots: after all, the one treatment that does have long-term efficacy for addictive illness is precisely this one.

Psychiatrists are notoriously unwilling to endorse the 12-step programmes, and argue that statistically the results are not convincing. There may be some truth in this – but there's also the inconvenient fact that there's no place for psychiatrists, or indeed any of the psy professionals, in autonomously organised self-help groups. Burns agrees with Davies that our reliance on psychiatry, and by extension, psycho-pharmacology, may well be related to our increasingly alienated state of mind in mass societies with weakened family ties, and often non-existent community ones. Surely self-help groups can play a large role in facilitating the rebirth of these nurturing and supportive networks? But Burns seems to feel that just as we will always need a professional to come and mend the septic tank, so we will always need a pro to sweep out the Augean psychic stables. I'm not so sure; psychiatry has been bedevilled over the last two centuries by "treatments" and "cures" that have subsequently been revealed to be significantly harmful. From mesmerism, to lobotomy, to electroconvulsive therapy, to Valium and other benzodiazepines – the list of these nostrums is long and ignoble, and I've no doubt that the SSRIs will soon be added to their number.

Sooner or later we will all have to wake up, smell the snake oil, and realise that while medical science may bring incalculable benefit to us, medical pseudo-science remains just as capable of advance. After all, one of the drugs that Irving Kirsch's meta‑analysis of antidepressant trials revealed as being just as efficacious as the SSRIs was … heroin.

http://www.theguardian.com/society/2013/aug/03/will-self-psychiatrist-drug-medication

Arkansas AG asks state Supreme Court to reconsider its tossing of $1.2B Johnson & Johnson Risperdal fine

LITTLE ROCK, Ark. - Arkansas Attorney General Dustin McDaniel asked the state Supreme Court on Monday to reconsider its decision tossing out a $1.2 billion judgment against drugmaker Johnson & Johnson, saying justices did "significant harm" to the state and broke from 170 years of precedent.

McDaniel filed a petition for rehearing over the high court's decision last month that the state misapplied the Medicaid fraud law in its lawsuit against New Jersey-based Johnson & Johnson and its subsidiary Janssen Pharmaceutical Inc. over the marketing of the antispyschotic drug Risperdal. McDaniel said last week that he would ask the court to revisit the ruling.

"The court's rejection of the state (Medicaid fraud) case does significant harm to the state and its citizens," McDaniel wrote in the filing. "It deprives the state of a critical tool to protect the integrity of the Arkansas Medicaid program and the vulnerable poor, sick and elderly who depend on Medicaid as a literal lifeline."

McDaniel said justices broke with years of precedent by ruling on grounds not previously raised in filings. Justices ruled that the state Code Revision Commission "substantively altered" the meaning of the Medicaid fraud law when it was codified and that it was originally intended to regulate health facilities. The commission is responsible for making technical corrections to state code.

McDaniel noted that the 1993 law remained unchanged for 21 years despite other amendments and attempted amendments by the Legislature over the years.

"By improperly transforming a well understood and accepted interpretation of the law, this court has arrogated to itself powers not conferred by the Arkansas Constitution or the General Assembly," he wrote.

The drugmaker said in a statement Monday that it didn't violate the Medicaid fraud law.

"After a thorough review of the case, the Arkansas Supreme Court agreed with our position. We believe that the record speaks for itself and are prepared to vigorously defend our position," the company said.

Risperdal was introduced in 1994 as a "second-generation" antipsychotic drug, and it earned Johnson & Johnson billions of dollars in sales before generic versions became available. The drug is used to treat schizophrenia, bipolar disorder and irritability in autism patients.

An Arkansas jury found the New Jersey-based companies liable in 2012. Pulaski County Circuit Judge Tim Fox then ordered the companies to pay $5,000 for each of the 240,000 Risperdal prescriptions for which Arkansas' Medicaid program paid during a 3 1/2-year span.

___

Follow Andrew DeMillo on Twitter at https://twitter.com/ademillo

http://www.canada.com/news/world/Arkansas+asks+state+Supreme+Court+reconsider+tossing+Johnson+Johnson/9711626/story.html?

Has pancreatic damage from glucagon suppressing diabetes drugs been underplayed? - BMJ

BMJ 2013; 346 doi: http://dx.doi.org/10.1136/bmj.f3680 (Published 10 June 2013)

Cite this as: BMJ 2013;346:f3680Article

• Related content
• Article metrics

1. Deborah Cohen, investigations editor

Author Affiliations

1. dcohen@bmj.com

Incretin mimetics have been called “the darlings of diabetes treatment” and they may soon also be licensed for treating obesity. But a BMJ investigation has found growing safety concerns linked to the drugs’ mechanism of action. Deborah Cohenasks why patients and doctors have not been told.

They’ve been touted as the “new darlings of diabetes treatment”—the biggest breakthrough since the discovery of insulin nearly a hundred years before. The so called incretin therapies—glucagon-like peptide-1 (GLP-1) agonists and dipeptidylpeptidase-4 (DPP-4) inhibitors—looked as if they might change the face of type 2 diabetes. Their dual action of switching on insulin and suppressing glucagon to help control blood glucose was the ultimate in diabetes care.

The promise of a Nobel prize for the investigators loomed large. Scientists had discovered a treatment that could potentially modify disease progression. Studies in experimental animals showed that GLP-1 caused a proliferation in new insulin producing β cells. The hope was that these new cells might be able to replace those that died off in the course of human diabetes.

Nor did the promise end there. GLP-1 acts on the brain to makes people feel less hungry and the more powerful drugs aid weight loss—rather than weight gain like many antidiabetic drugs before them.

Edwin Gale and Deborah Cohen discuss the science behind the story

It’s an effect companies are seeking to market in its own right. Spurred on by the US Food and Drug Administration’s willingness to license new obesity treatment, Novo Nordisk’s chief science officer Mads Krogsgaard Thomsen said last year that the “political establishment in the US now knows that behaviour change alone is not enough.”1

His company’s drug, liraglutide, is in the process of late stage clinical tests, which Thomsen says show promising results.

But an investigation by the BMJ suggests Thomsen’s confidence might be optimistic. Concerns held by some specialists about the potential side effects of GLP-1 drugs have emerged into the mainstream after both the FDA and the European Medicines Agency announced in March that they would launch a review into whether the drugs may cause or contribute to the development of pancreatic cancer.

As yet neither agency has reached any conclusions, but they are meeting to discuss the matter later this month. And, as this investigation has found, for the regulators it is not a new concern. Over the years, drug assessors have become increasingly concerned that the incretin drugs have the potential for unwanted proliferative effects.

Expert concerns

Concerns long held by some experts about the potential side effects of incretin mimetics have gathered momentum with three publications this year. An independent analysis of health insurance data published in February found that people taking exenatide and sitagliptin were at twice the risk of hospital admission for acute pancreatitis compared with people taking other antidiabetic drugs2—the absolute risk 0.6%. And in April an analysis of data from the US Food and Drug Administration’s adverse event reporting system showed an increase in reports for pancreatitis and pancreatic cancer in people taking incretin mimetics compared with those taking other antidiabetic drugs.3

The FDA and EMA have both confirmed to the BMJ that their own analyses also show increased reporting or signals of pancreatic cancer with incretin mimetics. But they emphasise that this does not mean the relation is causal.

Both agencies announced in March that they will review data from a study just published showing pre-cancerous and dysplastic changes to the pancreas in organ donors exposed to incretin mimetics.4

The evidence is fiercely contested, with manufacturers stoutly defending the safety of their products. Merck, for example, told the BMJ that independent observational studies and a meta-analysis of clinical trials involving 33 881 patients found no association between DPP-4 inhibitors and pancreatic cancer. Bristol-Myers Squibb says that “post-marketing data does not confirm a causal relationship between saxagliptin or exenatide and pancreatitis and/or pancreatic cancer” (see bmj.com for full questions and answers with manufacturers).

But a “Dear Doctor” letter from Bristol-Myers Squibb and AstraZeneca on the UK Medicine and Healthcare Products Regulatory Agency’s website says: “A review of reports of pancreatitis from post-marketing experience revealed that signs of pancreatitis occurred after the start of saxaglitpin treatment and resolved after discontinuation, which is suggestive of a causal relationship. Moreover, pancreatitis has been recognized as an adverse event for other DPP-4 inhibitors.”5 A spokeswoman for Boehringer Ingelheim told the BMJ: “Pancreatitis has been reported in clinical trials and spontaneous post marketing sources. Guidelines for the use of linagliptin in patients with suspected pancreatitis are included in the prescribing information of the treatment.”

The increasingly fractious debate among scientists and doctors was played out last month in the specialty journal Diabetes Care.

Experienced GLP-1 investigator, Professor Michael Nauck, head of the Diabeteszentrum in Bad Lauterberg, Germany, and a consultant to many of the manufacturers, argued that the published evidence against the drugs is weak. “The potential harms and risks typically refer to rare events and are discussed in a controversial manner,” he wrote.6 But a team of four academics from the US and UK (one an expert witness in litigation against one of the manufacturers) suggested that neither the safety nor the effectiveness of the class can be assumed. “The story is familiar. A new class of antidiabetic agents is rushed to market and widely promoted in the absence of any evidence of long-term beneficial outcomes. Evidence of harm accumulates, but is vigorously discounted,” they wrote in their response. 7

In the course of this investigation, the BMJ has reviewed thousands of pages of regulatory documents obtained under freedom of information and found unpublished data pointing to unwanted proliferative or inflammatory pancreatic effects.

The BMJ has also found that, despite published reports that indicated safety concerns, companies have not done critical safety studies; nor have regulators requested them. And access to raw data that would have helped resolve doubts about the safety of these drugs has been denied.

On their own, the individual pieces of unpublished evidence may seem inconclusive — increases in size and abnormal changes in animal pancreases, raised pancreatic enzyme concentrations in humans, reports of thyroid neoplasms, and pancreatitis in early clinical trials.

But when considered alongside other emerging and long standing evidence—such as concerns about the effect of GLP-1agonists on α cells first published in 19998; the presence of the GLP-1 receptor on cells other than the target pancreatic β cell; and increasing signals from regulatory databases2 9—a more coherent and worrying picture emerges, posing serious questions about the safety of this class of drug.

Problems in diabetic rats

These controversies might have stayed behind closed doors for much longer if Merck hadn’t approached the Larry L Hillblom Islet Research Centre at the University of California in Los Angeles (UCLA) in 2007.

Merck offered to fund Professor Peter Butler, chair of the laboratory, and his research team to study the effect of the DPP-4 inhibitor, sitagliptin on the β cells of rats that have been bred to develop diabetes similar to that in humans. Butler’s team designed the study; Merck provided the drug and advised them what dose to use. “I think they felt our [animal] model was nearer to type 2 diabetes than some of the other models they had studied and had available to them,” Butler said.

He agreed to take on the work, and his team, led by biologist Aleksey Matveyenko, gave the rats sitagliptin, metformin, or a combination of both drugs. During the 12 week study, the rats all seemed well. So Matveyenko was surprised to find abnormalities in the pancreases of the rats given sitagliptin. All were enlarged; one showed acute pancreatitis; and three out of 16 had acinar to ductal metaplasia, a pathological change thought to be a potential precursor of pancreatic cancer.10

As agreed, Matveyenko and Butler reported the results to Merck in a series of meetings in June 2008 before publishing their data the following year.10 In the course of these meetings, Butler told the company he was concerned about the safety implications of the animal studies. He offered to re-examine histological slides of pancreases taken from monkeys treated with sitagliptin, which Merck had collected as part of their preclinical study package, to see if these showed similar problems. His offer was not taken up.

The company and others did, however, act on Matveyenko’s rat study. The BMJ has learnt of a closed door meeting in June 2009, shortly after the study’s findings were published. It was held at the American Diabetes Association’s annual conference in New Orleans, which was supported by Merck. Delegates included regulators, doctors, and manufacturers with GLP-1 and DPP-4 drugs either on the market or in the pipeline. The meeting was sanctioned by the FDA, which sent Mary Parks, the director of the Division of Metabolism and Endocrinology Products, among others.

The BMJ has seen notes from the meeting, as well as one of the Powerpoint presentations. In it, a professor of digestive diseases (not named here to protect a source) said that the acinar to ductal metaplasia and chronic pancreatitis seen in the Matveyenko study could suggest an increased risk of pancreatic cancer. If the results turned out to be true, he said, the future of the drugs was in doubt; chronic pancreatitis can be subclinical for years before it shows up clinically. But this concern had to be balanced against the lack of data indicating similar effects in humans, he said.

The fact that the UCLA rats had diabetes might be seen as a strength of the research. But several speakers at the meeting dismissed Butler and Matveyenko’s rat model as being unreliable and, as reported in documents seen by the BMJ, suggested privately that their study should be aggressively pursued to show that the results were spurious.

Despite having collected the data under discussion and being at that time the editor of Diabetes (a journal owned by the American Diabetes Association), Butler was not invited to the meeting. Unaware that it had taken place, he contacted Robert Elashoff, a UCLA biostatistician and cancer epidemiologist, to discuss his concerns about the human relevance of their findings. Because companies control their clinical trial data, Elashoff thought the best way to see if there were any relevant safety issues would be to consult the FDA’s adverse event reporting system—where doctors and patients can log cases.

Regulator’s response

So with the help of Elashoff’s son, Michael, a former FDA drug reviewer, they checked the FDA’s adverse event reporting system for evidence of pancreatitis and pancreatic cancer in patients taking the drugs. They found an increase in the number of reports of pancreatitis and pancreatic cancer with sitagliptin and exenatide. They also found increased reports of thyroid cancer with exenatide. Up until this point, the FDA had notified doctors only about exenatide and pancreatitis—there had been no warnings about exenatide and thyroid cancer or pancreatic cancer, nor any warnings at all about sitagliptin and pancreatic disease. So they decided to contact the FDA to share their concerns.

On 14 September 2009, Butler, Robert Elashoff, and Matveyenko held a teleconference with Mary Parks and others at the FDA. They discussed the findings of the rat study and raised their concerns about the safety signals coming from the FDA’s database. They offered to work with the agency to try to find out more.

But the FDA did not seem enthusiastic. “The [response of the] FDA was quite surprising. They seemed to be defending the companies and defending the drugs. They were giving the exact same sound bites that the companies were giving,” Butler told the BMJ. “When we talked about the database showing a signal for pancreatic cancer, at that point the conversation was ended by the FDA.”

Shortly afterwards, on 25 September 2009, the FDA put out a safety alert for pancreatitis for sitagliptin. Others outside healthcare had taken swifter action. In October 2006, investment analysts from Bear Stearns had spotted the reports of pancreatitis associated with exenatide in the FDA’s database and warned investors.11 And in May 2009, London based pharmaceutical market analysts at Sanford Bernstein alerted its clients to safety concerns, based on its own review of the FDA database.12

What the manufacturers knew

Manufacturers too had spotted early signs of a link. In September 2008, Lilly convened a pancreatitis working group. Its aim was to establish the company’s “core medical beliefs for exenatide and pancreatitis” to get their external messaging correct. A presentation pointed to the mounting reports of pancreatitis in patients taking exenatide and the strengthening biological plausibility of exocrine pancreatic effects. While noting that diabetes itself increases the risk of pancreatitis, it drew attention to raised pancreatic enzymes and the fact that “several strong positive-rechallenge cases had been reported” (when a patient is taken off the drug and then put back on it gets the same symptoms).

It concluded, “While it is difficult to prove causal association between exenatide and pancreatitis, a causal association is likely.” An amended version seen by the BMJ, downgraded these concerns, taking out the words “causal” and replacing “likely” with suspected.

In a statement to the BMJ, Lilly said that it “evaluated data on an ongoing basis to ensure it adequately communicated the risks of Byetta [exenatide]. Lilly concluded that the FDA-approved labeling for Byetta appropriately communicated the potential risk of acute pancreatitis to health care providers.”

A month after the meeting with Butler, in October 2009, the FDA asked Merck to conduct a three month safety study in diabetic rodents treated with sitagliptin. The FDA had to repeat the request several times before Merck complied. The company eventually sent its results to the FDA earlier this year. These have not yet been published.

A spokesperson for Merck said it “shares data on an on-going basis with regulatory agencies around the world.” The FDA has told the BMJ that it deems this regulatory requirement to have been “fulfilled” and that “no regulatory recommendations were made based on our review of the study.”

The FDA also asked other companies with GLP-1 based drugs to do further safety studies, and the agency has provided the BMJ with copies of the resulting publications.

Amylin and Lilly published their results in 2012. Both articles state in their titles that there was no drug induced pancreatitis, and the companies use them to suggest an absence of harm from the drugs. However, both papers reported pancreatic changes.

In the Novo Nordisk study, the rats treated with liraglutide showed increased ductal proliferation and acinar to ductal metaplasia. One rat treated with exenatide had a “hemorrhagic pancreas” at necropsy with “moderate apoptosis-like necrosis, minimal inflammatory infiltration and slight hemorrhage/edema.”13 Although the pancreases did not increase in weight, the incretin treated rats had “significantly higher” levels of pancreatic amylase. Three of the liraglutide treated animals died from a “single erroneous dosing.”

A spokeswoman from Novo Nordisk told the BMJ, “Importantly, the study did not find any abnormalities in the pancreas associated with liraglutide treatment.”

In the Amylin study, amylase levels increased in the exenatide group but dropped back to the level seen in the control animals when the drug was stopped—a finding the company said was not toxicological [a damaging effect of the drug].”14

Effects of GLP-1

Meanwhile, Butler and his team wanted to understand what might be behind the safety signals they had detected. Their persistence has earned them a reputation for having an agenda against the drugs. Butler denies this allegation and says he has participated in teams to investigate both the potential benefits and unintended adverse effects of incretin mimetic drugs.

They suspected that GLP-1 receptors occur on pancreatic duct cells as well as pancreatic β cells—a fact the regulatory documents support and the medical literature confirms8 15—and that the hormone might have a proliferative effect.

To understand more about how GLP-1 agonists might affect people with diabetes, who are predisposed to pancreatic disease, they studied mice genetically predisposed to developing chronic pancreatitis and pancreatic cancer. The work was led by biologist Belinda Gier, who has since started working for Bristol-Myers Squibb.

These mice were given exenatide for 12 weeks. The researchers observed rapidly accelerated chronic pancreatitis and pancreatic dysplasia with an increase in lipase levels in those that had been treated compared with the controls. They found that the dysplastic areas (PanIN lesions) had the GLP-1 receptor.

In another study, Gier treated non-diabetic rats with the drug to examine the effects in the absence of pancreatic disease or diabetes. The pancreases of treated rats increased in weight compared with those of the untreated controls and showed hyperplasia in the exocrine pancreas. The researchers studied human tissue in vitro too. They found that GLP-1 induced proliferative signalling pathways.

According to Butler, this is the only study to look at the effects of the drugs in chronic pancreatitis. Proponents of the drugs question Gier’s methods, however, and companies have told the BMJ that they found no abnormalities in their preclinical studies. However, Gier’s work suggests that the way the pancreas is sectioned can affect the results. She found that, in healthy animals treated with the drugs, the histology was normal in the most accessible portions of the pancreas, the body and tail. “Methodological analysis of the entire pancreas . . . is necessary,” she wrote.

For the UCLA team, these findings suggested that the drugs have a proliferative effect, causing problems when superimposed on underlying disease. Its results were published in 2012.16

The team also published its review of the FDA adverse event database.9The paper presented data from 2004-09 on the frequencies of adverse event reporting associated with sitagliptin or exenatide for pancreatitis, pancreatic and thyroid cancer, and all cancers compared with those associated with four other diabetic treatments. It showed a sixfold increase in cases of pancreatitis with both exenatide (reporting odds ratio 10.68; 95% confidence interval 7.75 to 15.1; P<0 .0001="" 10.0="" 2.7="" 2.9="" 4.61="" 4.73="" a="" also="" and="" cancer="" exenatide:="" exenatide="" for="" fourfold="" in="" increase="" it="" odds="" p="0.004).</p" pancreatic="" ratio="" reports="" roughly="" showed="" sitagliptin:="" sitagliptin="" threefold="" thyroid="" to="" with="">

The authors highlighted the limitations of their study and advised that it should be interpreted with caution. Their methods were heavily criticised by industry representatives and medical societies—for example, for the lack of information about confounding factors such as obesity, alcohol consumption, smoking, and concomitant medications.17

But in April 2013, the US Institute for Safe Medication Practices published its own analysis, which reached similar conclusions. The institute reviewed data from the nationwide FDA Adverse Event Reporting System for patients taking incretin mimetics in the year ending 30 June 2012 and found 831 cases of pancreatitis, 105 of pancreatic cancer, and 32 of thyroid cancer.3

All five incretin mimetics, taken together, had rates of pancreatitis that were more than 25 times higher than in diabetic patients on other drugs (95% CI 15.9 to 41.8). For pancreatic cancer, results were mixed, with the GLP-1 agonists showing rates 23 times higher than for other anitdiabetic drugs (95% CI 5.7 to 95.1) and the DPP-4 inhibitors frequencies 13.5 times higher (95% CI 3.11 to 58.5). For the two other oral drugs, linagliptin and saxagliptin, there was only a single case each, with reporting ratios that were not significant.

Other independent sources have also corroborated the UCLA team’s FDA database analysis. Michael Elashoff presented the analysis at an American Statistical Association meeting in August 2012. Also presenting was William DuMouchel, chief statistical scientist at Oracle Health Sciences—a company that sells sophisticated computer analysis tools to regulatory authorities. Representatives from the FDA and some of the manufacturers attended too.

The BMJ has seen a copy of the Oracle presentation and spoken to DuMouchel. He reported a strong signal for pancreatitis for exenatide, sitagliptin, and liraglutide. For sitaglptin and exenatide there was also a signal for pancreatic cancer.

The BMJ also contacted WHO’s Uppsala Monitoring Centre—an independent foundation for the safe use of medicines—which collects adverse event reports from around the world.

Chief medical officer Pia Caduff told the BMJ that the centre had identified disproportionate reporting on pancreatic cancer with sitagliptin, exenatide, and liraglutide between 2009 and 2011 and for thyroid cancer with exenatide and liraglutide. However, there were only a handful of cases.

“Reports on these combinations have since then increased and together with the “human tissue study” hint at a possible causal association,” she said.

Legal action

Concerns about a link with pancreatitis has led to a lawsuit in California. Patients who have developed acute pancreatitis while taking exenatide are suing the drug’s manufacturer Amylin, now owned by Bristol-Myers Squibb. The lawsuit now includes relatives of people who have died from pancreatic cancer, and part of the case revolves around the interpretation of unpublished animal data. Lawyers acting for the plaintiffs asked to see pancreas histology slides from monkeys treated with exenatide in preclinical studies for market authorisation. The manufacturer refused: the slides were a commercial secret and had to be reserved for FDA access, it said.

However, a judge overruled the company, and Professor Clive Taylor, a pathologist from the University of Southern California, was asked to study the slides, though he was given only brief access under close supervision by staff at Charles River laboratories, the contract research organisation that conducted the monkey studies on Amylin’s behalf. Taylor looked at 96 slides from 48 animals. He pre-specified an algorithm for scoring the slides, was unaware of the doses received, and was handed the slides randomly one by one.

When Taylor returned home and analysed his findings, he found pancreatic intraepithelial neoplastic lesions in the treated animals, indicating chronic pancreatitis and pancreatic disease. The amount of pathological change in the treated animals was about twice that in the control animals.

“Well, if we were looking at human pancreas and saw those changes, I would say yes it’s a concern,” Taylor said in an interview with the BMJ and Channel 4’sDispatches. “These changes are associated with pancreatitis and even, perhaps, with pancreatic [neoplasia], pancreatic tumours,” he said.

The company’s pathologists disagree with Taylor’s interpretation—although they did not have a systematic way of scoring the slides. Taylor says the best way to resolve the difference of opinion is to make the slides available for further independent scrutiny. “As new information and new methods become available for looking at things, it seems to me that the right thing to do is apply that new information and those new methods to the material,” Taylor says. “There are other analyses that could be done. So far they have not, as far as I’m aware, been done.”

The company has refused to release the slides, and the judge has ruled that release would have to be at the request of the FDA.

The BMJ asked Bristol-Myers Squibb if it should allow independent experts access to the material for further analysis. It did not respond to this question.

Neither did it answer questions about whether it agreed with Taylor’s findings. A spokesman told the BMJ: “The available data from these [preclinical and clinical] studies, including the 91-day and 273-day monkey studies, were shared with regulators, including the FDA and EMEA [EMA].”

Neither the FDA nor the EMA has seen the Amylin monkey slides—they told the BMJthat they usually rely on the overall pathology report provided by the drug sponsor.

The FDA stated that the “pathology slides are the property of Amylin, and the FDA has not requested that Amylin have the slides re-evaluated by a pathology working group.” Taylor has sent the FDA his report and an agency spokesman has confirmed that it has received it. “The FDA has read Dr Taylor’s report and agrees that Dr Taylor’s interpretation differs from Amylin’s and the veterinarian pathologists that originally read the slides, but that the two parties are seeing the same type of histological changes.” The agency has not decided if an independent review would help. EMA has said it is able to request an additional review of the slides if it has concerns.

Taylor told the BMJ that the company pathologists who re-examined the slides had noted more pancreatic disease in those on the drugs but used different terminology for the changes.

Liraglutide in monkeys

The BMJ has learnt of other unpublished and disputed evidence from industry studies in monkeys. A study by Novo Nordisk reported results from monkeys treated with liraglutide for 52 weeks.18 The study, published in Diabetes in 2012, concluded an “absence of pancreatic structural changes in three species.”18

The paper has been used by the company to downplay concerns of pancreatitis and proliferative changes associated with their drug both at conferences and to the BMJwhen asked. However, it does not seem to present a complete picture of the 52 week study’s findings.

Through freedom of information requests, the BMJ has found that results that were not included in the published paper led regulators to raise concerns at the time of licensing the drug in 2008 and 2009. One of the EMA reviewers had noted that liraglutide had the “possibility of increased neoplasia perhaps through growth promotion (rather than a genotoxic effect).” The regulator also asked the company about a statistically significant increase in pancreatic weight in young healthy monkeys treated with liraglutide.

“Further investigations of the pancreatic tissues collected in the 52-week monkey study showed that the increased pancreatic weight was due to a 67% increase in absolute duct cell mass and 64% increase in exocrine cells when compared to the vehicle group,” an EMA reviewer said in 2008.“ Considering that concerns have been raised regarding the potential induction of acute pancreatitis following treatment with GLP-1 receptor agonists, the applicant is requested to evaluate the clinical relevance of this finding.”

In reply Novo Nordisk said the findings were due to the control monkeys having smaller pancreases. They also offered reassurance from a longer 87 week study, which they said did not show any effect on pancreas weight or any changes suggestive of inflammation or pancreatitis.

However, the pathology report obtained by the BMJ suggests that only the thyroid was processed for histology. The pancreases in the treated animals were also bigger. But the study was not set up to analyse organ weights and a source close to EMA said it was underpowered to detect anything but a large change given the spread of weights and the small numbers involved.

But the company disagree. A spokeswoman for Novo Nordisk stressed that a biological finding has to be reproducible and that is not the case with the 87 week study. “No dose-dependent significant increases [occurred] in any study but the 52 week [study],” she said.

Adding to the confusion a “human error” by a Novo Nordisk employee meant a graph to answer EMA’s concerns contained the wrong data so that it appeared to show no change at all. The EMA accepted the company’s explanation and did not ask to see the 52 week slides. It has since told the BMJ that its “interpretation of the 52 week monkey study is that there is no effect of liraglutide on pancreas weight.”

However, the FDA also had concerns about the 52 week study. Reviewers noted increased pancreatic weight in monkeys after 28 days of treatment. The toxicology reviewer believed these changes to be treatment related and suggested that the safety margin was low. An FDA spokesperson told the BMJ: “An expanded mass of exocrine and/or endocrine structures is also not equivalent to evidence of toxicity, but would merit investigation of causality if shown to be drug-related and dose-dependent.”

In fact the BMJ has uncovered an apparent dose-response relation in the Novo Nordisk data, which were obtained from the EMA. With increasing dose, the pancreatic weight and the exocrine component increased—although at the end of a four week recovery period (a period of not taking the drug), the pancreatic weights of treated monkeys were similar to those of control monkeys. Readers of Novo Nordisk’s publication in Diabetes were not given this information.18 The paper did make it clear that the sections were assessed unblinded to treatment.

A spokeswoman for Novo Nordisk said that the company thought the paper fairly represented its animal studies but noted that space constraints had prevented inclusion of some findings. “When publishing non-clinical data in a scientific journal, limitations on the article length do not allow for the inclusion of all study results,” she said, adding: “No macroscopic or microscopic changes were noted in any cell type in any of the monkey studies in the pancreas.”

Human pancreases

Even though the companies used a breed of monkey that is the closest proxy to humans, animals do not always accurately predict what will happen in humans. So earlier this year, a team of researchers from UCLA and the University of Florida decided to analyse the pancreases of human organ donors. Their findings, published in Diabetes, have prompted both US and European regulators to issue public statements about precancerous changes19 and to do further analyses. The FDA has confirmed that it has sent the team questions and plans to meet up.

Eight of the organ donors had type 2 diabetes and had been taking an incretin mimetic for at least a year (seven sitagliptin and one exenatide). Twelve other diabetic organ donors had been taking other classes of treatment. Fourteen non-diabetic organ donors were used as controls. The researchers matched the donors in the two treatment groups for sex and body mass index.

The pancreases in those who had taken incretin mimetics were on average 40% larger, with more precancerous changes. In addition, seven of the eight patients who had been treated with a mimetic had α cell hyperplasia, three expressed α cell derived microadenomas, and one had a grade 1 α cell derived neuroendocrine tumour that was “not appreciated in life.” These findings did not occur in the diabetic patients treated with other drugs or in the non-diabetic patients.

The researchers were not overly surprised. They viewed these findings as being entirely consistent with the drugs’ mode of action, glucagon suppression. Nor were they the first to find α cell hyperplasia associated with GLP-1 treatment. Long before the first incretin mimetic came on the market, published reports showed increased numbers of alpha cells in animals treated with a GLP-1 agonist.

In 1999, GLP-1 researcher Joel Habener and a team at Harvard found that exendin-4 (exenatide) induced an increase in α cells in rats. “It will be interesting to determine how sustained this increase in alpha-cell mass is during even longer-term administration of exendin-4,” they concluded.8 The BMJ asked Bristol-Myers Squibb about this finding. It did not answer the question.

At the behest of their ethics review board the UCLA/Florida team wrote to notify the FDA of the results of their study on human pancreases. The agency replied, “As you are aware, FDA shares your concern over the potential role these drugs may have on causing pancreatitis and/or pancreatic cancer and multiple nonclinical and clinical assessments have been required of sponsors of these drugs, including postmarketing requirements for those already on the market.”

However, the study has been criticised. A spokeswoman for Novo Nordisk told theBMJ: “The number of patients included in the study is small, and the groups are seemingly not well matched in relation to age at diagnosis, duration of diabetes, BMI [body mass index], and concomitant medication.”

Adverse event reporting

Many also argue that the value of evidence from regulatory databases is limited. Both the regulators and manufacturers point to ongoing post-marketing studies that will resolve the questions in years to come. Medical societies, such as the American Diabetes Association and the American Association of Clinical Endocrinologists, say that even the link to pancreatitis is controversial and question the evidence underpinning the safety concerns. In a recent statement, they said that patients should consult their doctor and that only adequately powered randomised controlled trials can really resolve this impasse.20 “New [randomised controlled trial] data [will be] available relatively soon which will allow physicians to definitively assess risks and benefits of this class of medicines,” a recent statement said.

But critics point out that the trials are done by the drug companies themselves. And Sonal Singh, assistant professor of medicine at Johns Hopkins University and drug safety researcher, whose database study published this year found increased rates of pancreatitis in exenatide and sitagliptin treated patients2 wonders what harm may be done while we wait for this level of evidence. “Safety signals can be dismissed on one limitation or another or you can find some other study which shows no risk. The other option is you can place a high bar for absolute certainty of risk or ask for such a long term study that years fly by and the patent expires,” he says. “The fundamental question is who bears the burden of the passage of time while these debates are settled?”

Responding to questions from the BMJ, the FDA said that adverse event reporting was most useful for detecting rare, serious, and unknown events but of limited value for assessing a known event or detecting events that have a high background rate in the population, such as pancreatitis or thyroid cancer.

However, the FDA has acted on such evidence before. It issued a safety alert in 2007 about pancreatitis linked to exenatide on the basis of 30 cases. In 2008 this was updated to include six cases of necrotising pancreatitis. In 2009, a similar warning for pancreatitis was issued for sitagliptin and, more recently, one for liraglutide—which also carries a black box warning for c cell originating thyroid tumours.

The EMA too has produced safety guidance for the incretin mimetics based on small numbers of cases of pancreatitis. But given that there are now hundreds of reports of pancreatic cancer—and the case reports have remained consistent or increased over many years— why no alert for this? Could it be because this class of drugs would not survive such a warning?

The BMJ asked the FDA about this seeming inconsistency. “Because of the time required for cancer to develop, it will always be difficult to apply spontaneous reports of cancer (any cancer) to drug exposure that began or occurred years before,” a spokesman said, adding that spotting disproportional reports in its safety database was not sufficient in isolation.

“FDA has conducted several reviews of pancreatic cancer in association with incretin mimetics and has not advanced a recommendation for labeling. It is important to note that neither a mechanism nor human cases need to be identified for labeling. For example, liraglutide and Bydureon [long acting exenatide] both have a warning for the potential for C-cell thyroid cancer based on rodent studies,” he said.

FDA official Curtis Rosebraugh said to an FDA committee convened to discuss the licensing of liraglutide that even if the drugs do cause pancreatitis the FDA would not remove them from the market but would “encourage awareness and early diagnosis.” He concluded that, “while many sponsors may responsibly introduce a drug into marketing, theirs is a profit-based business and the pressures to generate revenue are strong. Also, with most classes of drugs, there are similar drugs in development from competitors which places even more pressure to generate profit before there is more competition.”

Both the EMA and the FDA now acknowledge there is increased reporting of pancreatic cancer with incretin mimetics. But in a statement to the BMJ, the FDA said: “There has been no causal relationship established between exposure to incretin mimetics and pancreatitis, pancreatic cancer, and thyroid cancer.”

EMA said that it did not consider that current data support an increased risk of pancreatic or thyroid cancer with the products in question. “However the issue is under review at CHMP [EMA’s regulatory committee] and outcomes will be communicated when available,” a spokeswoman said.

While the debate continues about pathophysiology and mechanisms of action, questions remain about whether the companies and regulators have done enough to get to the bottom of these safety concerns. And have doctors and patients been adequately warned?

For Michael Elashoff, a former FDA drug reviewer who was part of the team expressing safety concerns in the recent journal debate, the implications are clear.

“These drugs are being used by hundreds of thousands or millions of patients and if the safety hasn’t been adequately studied then there’s a lot of people at risk of some very serious side effects of the drugs.”

What’s going on in the pancreas?

In a world where the prevalence of type 2 diabetes is increasing rapidly, finding new targets for therapy is a high priority for drug companies. The discovery by scientists in the 1970s and the then publication in 1993 by Michael Nauck of the double action of GLP-1 (glucagon-like peptide-1) provided just such a target.

GLP-1 is a hormone-like peptide released by the intestine in response to a meal; its functions include regulating insulin and blood glucose and slowing gastric emptying. In his study, Nauck found that GLP-1 both increased the insulin made in the pancreas and, by inhibiting the secretion of glucagon, reduced the glucose released by the liver. Excessive glucose release by the liver underpins the high circulating glucose that defines type 2 diabetes. Following secretion, GLP-1 is quickly inactivated by an enzyme, dipeptidyl peptidase-4 (DPP-4). The GLP-1 drugs are either analogues that are not inactivated by DPP-4, taken by injection (exenatide, liraglutide) or oral drugs that inhibit DPP-4 (sitagliptin, saxagliptin, and linagliptin).

The saliva of the desert dwelling Gila monster was the source for the first GLP-1 analogue on the market, exenatide. A heavy slow moving lizard, it eats once or twice a year, and uses the secretion of its salivary hormone exendin-4—which displays similar properties to GLP-1—to induce proliferation of its pancreas and gut to assimilate a meal. Some say this should have provided a valuable clue to the unwanted effects of raised circulating levels of a hormone that usually lasts for only minutes before it is broken down.

But now that most of the other treatments for type 2 diabetes are off patent, these are valuable drugs. Merck’s market leading drug sitagliptin generated about $4.1bn (£2.6bn; €3bn) in sales in 2012 with liraglutide’s 2012 sales of $1.7bn coming in behind. The profit margins mean there is much at stake for the companies and the organisations and doctors who depend on their support.

However, serious doubts about the wisdom of basing treatments on GLP-1 agonists have existed since the beginning. And the companies and regulators have, on reflection, had in their hands ample warning signs—and chance to resolve some of the emerging controversies.

In 2005, the New England Journal of Medicine published a study that showed pancreatic changes in patients who had a type of gastric bypass surgery called Roux-en-Y. The authors noted hypertrophy and hyperplasia of the islet cells, also affecting the cells in the pancreatic ducts. They thought this might be due to raised levels of the hormone GLP-1, which were known to occur after this type of procedure.21 (A later study on this type of surgery also showed a “pronounced” increase in α cell mass22).

Senior executives from Amylin and Lilly wrote to the New England Journal to distance their drug from the paper and to stress the lack of evidence of a pathological effect on the islets in animal studies. “A study of nine months’ duration in healthy cynomolgus monkeys at doses of more than 400 times those used in humans showed minimal-to-mild islet hypercellularity with no increase in islet size (data on file, Amylin Pharmaceuticals),” they said.

The suppression of glucagon by incretin mimetics was highlighted by companies in their drug licensing applications and was noted by regulators. Billions of dollars of sales later, after concerns have been raised about the safety of glucagon suppression and its effect on glucagon producing α cells, the extent to which they do this is being contested.

Butler and colleagues’ finding of α cell hyperplasia in humans taking GLP1 based drugs4 was not the first. In 1999 GLP-1 researcher Joel Habener and a team at Harvard found that exendin-4 (exenatide) induced an increase in α cells in rats.8

But evidence of α cell hyperplasia has come from multiple models and sources—including the companies themselves. Whether this is applicable to GLP-1 based treatments is subject to fierce debate.

Only last October, Professor Dan Drucker, a long standing consultant to many of the companies, gave a keynote lecture at European Association for the Study of Diabetes conference. “The therapeutic window for reduction of glucagon action to manifest beneficial effects for glucose control while avoiding enhancement of hepatic lipid storage, dyslipidemia, hepatocyte injury, and α-cell proliferation in diabetic subjects is unclear,” the official conference journal reported.23

Others in industry have previously highlighted the important role of glucagon suppression in the control of diabetes. In 2005 at a session entitled “GLP-1s: the new darlings of diabetes treatment” Jens Holst, scientific director of the Novo Nordisk Foundation for Metabolic Research at Copenhagen University and a long standing consultant to the company, told the American Diabetes Association annual conference that GLP-1 agonists were a powerful inhibitor of glucagon secretion, adding that he thought this would be “a very important action to diabetes patients.”

A spokesperson for Novo Nordisk acknowledged an effect on α cells but only from full not partial glucagon suppression. She told the BMJ: “Complete removal or blocking of the glucagon receptor, or important signalling components, have caused α cell hyperplasia. This is separate from the relatively modest lowering of glucagon secretion induced by GLP-1.”

The BMJ asked Drucker about this. In response he sent a copy of an article he had written in Cell Metabolism, but this did not describe α cell effects.24 Yet the BMJhas found that the companies were aware of the unwanted effects of the full and partial suppression of glucagon before the incretin mimetics came onto the market.

At the turn of the century, Holst, working with scientists from Novo Nordisk, reported that glucagon suppression in mice resulted in massive enlargement of the pancreas and the proliferation of α cells (α cell hyperplasia).25 They concluded that α cells appear not just in the islets but in the pancreatic ductal epithelium—something that Butler and colleagues found. Importantly, this effect did not require complete blocking of glucagon receptors or the stopping of glucagon production. Even a partial reduction in the hormone signalling resulted in α cell hyperplasia, as shown by Eli Lilly in 2004.26 The Lilly team acknowledged that they hadn’t seen any neoplasia; the studies up until that point had been short—only four months long. They suggested that both glucagon and its receptor must be functional in order to maintain a feedback loop that restrains α cell growth “but the exact nature of this feedback loop is unclear.”26

Over the years, evidence of the effects of modifying glucagon signalling has mounted. In 2009 Run Yu, codirector of the carcinoid and neuroendocrine tumour programme at Cedars Sinai Hospital in Los Angeles, published a report in patients with a rare condition causing deficiencies in glucagon signalling.27 He found α cell hyperplasia and neuroendocrine tumours.

“In type 2 diabetes glucagon plays a role but there is a price to pay with reducing it,” he told the BMJ.

Yu said that he had shared his view with certain companies after the study came out. Because of agreements with the companies, he was unable to say which they were.

He then did a study in mice with decreased glucagon signalling that was far longer than any conducted by the companies. He found that neuroendocrine tumours invariably developed after formation of α cell hyperplasia and eventually led to death. Yu concluded that glucagon suppression was not a safe way to treat diabetes.28 But whether this applies to GLP-1based therapies is still uncertain.

In the course of this investigation, the BMJ has looked at thousands of pages of regulatory documents from both the FDA and the EMA. There seems to be little discussion about the potential adverse effects of interfering with glucagon signalling on the α cell, even though the manufacturers spelt out —and the regulators noted—that glucagon suppression was one of the effects of the drugs. Michael Elashoff, a former FDA reviewer who has analysed the safety of the drugs, believes the regulators should have been more cautious in approving them.

“If some of the side effects can be anticipated in advance, then it seems incumbent upon the FDA to really force the companies to do real significant investigation of these potential side effects before the drug goes on the market and not leave it to experiment with actual patients taking the drug,” he said.

The FDA maintains that: “Long-term studies of incretin mimetics in rodents, dogs, and monkeys failed to demonstrate adverse pancreatic pathology or other toxicology reflective of a glucagon deficit that could be interpreted as a clear risk to human subjects.”

The BMJ asked the five companies who market incretin mimetics if they have ever studied the effects of glucagon suppression on the proliferation of α cells. Only Novo Nordisk responded to the question. It stressed that it had never seen α cell hyperplasia in any of its studies.29 30 31 “Alpha-cell hyperplasia is not mediated by the GLP-1 receptor,” a spokeswoman said. Behind the scenes, concerns also started to emerge about the potential inflammatory effects on the pancreas. Effects on pancreatic enzymes: Internal industry documents show that in 2005, one industry key opinion leader reported “extremely high” lipase levels in a patient taking exenatide. He was concerned that the company had missed signs of potential inflammation in its clinical trials.

Dennis Kim, then executive director at Amylin, wrote in an email that the doctor’s report was a “bit concerning” and confirmed that pancreatic amylase and lipase were not measured systematically in the company’s clinical trials.

The BMJ has found that companies have measured these enzymes for “safety issues,” but in many cases the data have not been reported in the published studies.

For example, in one Lilly funded trial comparing weekly exenatide with sitagliptin and two other diabetes treatments—insulin and pioglitazone—enzyme levels increased in a higher percentage of people taking incretin mimetics after 26 weeks of treatment.

Regulatory documents show the mean (SD) lipase concentration in the exenatide group increased from 42.0 (23.77) U/L on day 1 to 60.8 (38.39) U/L at week 26. Sitagliptin also increased lipase from 40.3 (21.3) U/L to 48.7 (30.7) U/L. The levels in the pioglitazone control dropped. However, when the trial was published in theLancet, these data did not make the final cut.32 The company did not say why when the BMJ put it to them. Neither did lead author, Richard Bergenstahl, answer the BMJ’s queries.

Earlier this year, the Lancet published another study funded by Eli Lilly and Amylin in which enzyme levels were measured but not reported.33 “Routinely measured concentrations of pancreatic lipase and total amylase varied in both groups and were not predictive of gastrointestinal symptoms,” the paper said.

The FDA says that the clinical value of routine amylase and lipase monitoring in asymptomatic patients is not clear. But pancreatologists, have told the BMJ that reporting enzyme levels is important because they may reflect a subclinical effect of the drug.

“Many large phase III trials report findings of significant biochemical abnormalities, even though the clinical significance may be uncertain at the time, and in this case where the drug is known to exert effects on the pancreas, I would find such information of value,” Thor Halfdanarson, a pancreatic surgeon, at the Mayo Clinic in Arizona said.

Indeed, writing in support of incretin mimetics in Diabetes Care last month, Michael Nauck said that the effect on pancreatic enzymes may be important.6“Effects of GLP-1 receptor stimulation on pancreatic enzyme synthesis, potential leakage into the circulation rather than direct secretion into pancreatic digestive juice, and a potential induction if a chronic inflammatory response need to be studied,” he said.

What happens to those who raise safety concerns

Those who have attempted to publish evidence on the possible harms of GLP1-based drugs have found that it can be difficult.

Butler and colleagues’ FDA database paper in Gastorenterology—which showed a sixfold increase in reports of pancreatitis with both exenatide and sitagliptin as well as increased reports of pancreatic and thyroid cancer4—was met with anger against the authors, particularly Butler. This was despite the paper being clear that their methods had limitations and should be interpreted with extreme caution. After the paper was published online, senior executives from Merck, manufacturer of one of the drugs in the study, and Novo Nordisk wrote to the editor ofGastroenterology to express their strong views.

Mads Krogsgaard Thomsen, the chief scientific officer for Novo Nordisk, likened the paper to the fraudulent Lancet paper by Andrew Wakefield and colleagues linking MMR vaccine to autism, in that it risked creating an unwarranted public health scare. He said that Novo Nordisk had drawn different conclusions from the data and asked the journal to “withhold the publication of Elashoff et al until it has been confirmed by an independent statistical analysis.”

Even attempts to discuss the Gastroenterology study and alert doctors of any potential implications proved problematic. Shortly after the paper was published online, the German Diabetes Society issued a statement written by Thomas Danne, a paediatric diabetologist in Hannover, on behalf of the society’s executive board.

It stated that new patients should be started on GLP-1 receptor agonists and DPP-4 inhibitors only in special circumstances and that all patients currently treated with these drugs should be informed about the findings to appear inGastroenterology.

But three days later the statement disappeared from the society’s website, only to be replaced by another. This said that Novo Nordisk’s letter to the editor ofGastroenterology—which the journal hadn’t published—said there was a “reporting bias,” which drew the quality of the published results into question. The executive board rescinded their initial recommendations and advised doctors not to change their current practice.

The BMJ has also learnt that Novo Nordisk has sent out scientific liaison officers to those who have raised concerns about their drug—although there is no evidence of intimidation. But now several of Peter Butler’s UCLA team and Michael Elashoff have been subpoenaed by Lilly in the relation to the lawsuit it is fighting with patients who have developed pancreatitis and pancreatic cancer while taking exenatide.

The request by Lilly’s lawyers for documents from Butler is particularly wide ranging. He has been asked for all published and unpublished data; all correspondence with authors pertaining to incretin mimetics when he was an editor; reviews he has done; and letters to journal editors. The subpoena also includes any communications to any media about GLP-1 studies.

Butler declined to talk about the subpoena when asked.

Novo Nordisk told Danish newspaper Berlingske that it has not been directly involved in the subpoena. However, a spokeswoman said that “it may be an industrial organisation (like Pharma) that is behind [it].”

Notes

Cite this as: BMJ 2013;346:f3680

Footnotes

• Competing interest: I have read and understood the BMJ Group policy on declaration of interests and have no relevant interests to declare.
• Provenance and peer review: Provenance and peer review: Commissioned; externally peer reviewed. (Editorial note: this statement has been amended since the article was originally posted. The original statement said that the article had not been externally peer reviewed, which was incorrect.).

References

1. ↵ 
   Hirschler B. Novo bets on high-price niche for obesity drug. Reuters 2012 Dec 11. www.reuters.com/article/2012/12/11/us-novonordisk-obesity-idUSBRE8BA0FM20121211.
2. ↵ 
   Singh S, Chang H-Y, Richards TM, Weiner JP, Clark JM, Segal JB. Glucagon-like peptide 1-based therapies and risk of hospitalization for acute pancreatitis in type 2 diabetes mellitus. JAMA Intern Med2013;17:534-9.
3. ↵ 
   Institute for Safe Medication Practices. Perspectives on GLP-1 agents for diabetes. 2013. www.ismp.org/QuarterWatch/pdfs/2012Q3.pdf.
4. ↵ 
   Butler AE, Campbell-Thompson M, Gurlo T, Dawson DW, Atkinson M, Butler PC. Marked expansion of exocrine and endocrine pancreas with incretin therapy in humans with increased exocrine pancreas dysplasia and the potential for glucagon-producing neuroendocrine tumors. Diabetes2013 Mar 22. [Epub ahead of print].
5. ↵ 
   Direct Healthcare Professional Communication on the association of saxagliptin (Onglyza) with serious hypersensitivity reactions and acute pancreatitis. www.mhra.gov.uk/home/groups/comms-ic/documents/websiteresources/con146917.pdf.
6. ↵ 
   Nauck MA. A critical analysis of the clinical use of incretin-based therapies: the benefits by far outweigh the potential risks. Diabetes Care2013 May 6. [Epub ahead of print].
7. ↵ 
   Butler PC, Elashoff M, Elashoff R, Gale EAM. A critical analysis of the clinical use of incretin-based therapies: are the GLP-1 therapies safe? Diabetes Care2013 May 6. [Epub ahead of print].
8. ↵ 
   Xu, G, Soffers DA, Habener JF, Bonner-Weir S. Exendin-4 stimulates both β-cell replication and neogenesis, resulting in increased β-cell mass and improved glucose tolerance in diabetic rats. Diabetes1999;48:2270-6.

   Abstract
9. ↵ 
   Elashoff M, Matveyenko AV, Gier B, Elashoff R, Butler PC. Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1–based therapies. Gastroenterology2011;141:150-6.

   CrossRefMedlineWeb of Science
10. ↵ 
    Matveyenko AV, Dry S, Cox HI, Moshtaghian A, Gurlo T, Galasso R, et al. Beneficial endocrine but adverse exocrine effects of sitagliptin in the HIP rat model of type 2 diabetes, interactions with metformin. Diabetes2009;58:1604-15.

    Abstract/FREE Full Text
11. ↵ 
    Bear Stearns. Type II diabetes: our thoughts on the GLP-1 opportunity. http://www.diabetologia-journal.org/files/BearStearnsReport.pdf .
12. ↵ 
    Bernstein Research. Novo, Lilly: GLP-1s, Byetta’s thyroid tumours in FDA adverse event database, real world tolerability, and expert interviews. Bernstein Research, 2009.
13. ↵ 
    Vrang N, Jelsing J, Simonsen L, Jensen AE, Thorup I, Søeborg H, et al. The effects of 13 wk of liraglutide treatment on endocrine and exocrine pancreas in male and female ZDF rats: a quantitative and qualitative analysis revealing no evidence of drug-induced pancreatitis. Am J Physiol Endocrinol Metab2012;303:E253-64.

    Abstract/FREE Full Text
14. ↵ 
    Tatarkiewicz K, Belanger P, Gu G, Parkes D, Roy D. No evidence of drug-induced pancreatitis in rats treated with exenatide for 13 weeks. Diabetes Obes Metab2012;15:417-26.

    Medline
15. ↵ 
    Koehler JA, Baggio LL, Lamont BJ, Ali S, Drucker DJ. GLP-1 receptor activation modulates pancreatitis-associated gene expression but does not modify the susceptibility to experimental pancreatitis in mice. Diabetes2009;58:2148-61.

    Abstract/FREE Full Text
16. ↵ 
    Gier B, Matveyenko AV, Kirakossian D, Dawson D, Dry SM, Butler PC. Chronic GLP-1 receptor activation by exendin-4 induces expansion of pancreatic duct glands in rats and accelerates formation of dysplastic lesions and chronic pancreatitis in the KrasG12D mouse model. Diabetes2012;61:1250-62.

    Abstract/FREEFull Text
17. ↵ 
    European Association for Study of Diabetes. Commentary on the publication by Elashoff et al [now deleted].
18. ↵ 
    Nyborg NCB, Mølck AM, Madsen LW, Knudsen LB. The human GLP-1 analog liraglutide and the pancreas: evidence for the absence of structural pancreatic changes in three species. Diabetes2012;61:1243-9.

    Abstract/FREE Full Text
19. ↵ 
    Cohen D. FDA is to assess data linking type 2 diabetes drugs with pancreatitis. BMJ2013;346:f1808.

    FREE Full Text
20. ↵ 
    AACE and American Diabetes Association issue joint response to published JAMA article. Press release, 26 February 2012. www.diabetes.org/for-media/2013/2013-aace-ada-jama-article.html.
21. ↵ 
    Service GJ, Thompson GB, Service FJ, Andrews JC, Collazo-Clavell ML, Lloyd RV. Hyperinsulinemic hypoglycemia with nesidioblastosis after gastric-bypass surgery. N Engl J Med2005;353:249-54. 

    CrossRefMedlineWeb of Science
22. ↵ 
    Rabiee A, Magruder JT, Salas-Carrillo R, Carlson O, Egan JM, Askin FB, et al. Hyperinsulinemic hypoglycemia after Roux-en-Y gastric bypass: unraveling the role of gut hormonal and pancreatic endocrine dysfunction. J Surg Res2011;167:199-205.

    CrossRefMedline
23. ↵ 
    Understanding incretin hormone action and the treatment of diabetes. MD conference. www.nxtbook.com/nxtbooks/md_conference_express/easd2012/index.php?startid=7.
24. ↵ 
    Campbell JE, Drucker DJ. Pharmacology, physiology, and mechanisms of incretin hormone action . Cell Metab2013; pii:S1550-4131(13)00150-2. [Epub ahead of print].
25. ↵ 
    Gelling RW, Du XQ, Dichmann DS, Romer J, Huang H, Cui L, et al. Lower blood glucose, hyperglucagonemia, and pancreatic alpha cell hyperplasia in glucagon receptor knockout mice. Proc Natl Acad Sci USA. 2003;100:1438-43.

    Abstract/FREE Full Text
26. ↵ 
    Sloop KW, Xiao-Chun Cao J, Siesky AM, Yan Zhang H, Bodenmiller DM, Cox AL, et al. Hepatic and glucagon-like peptide-1–mediated reversal of diabetes by glucagon receptor antisense oligonucleotide inhibitors. J Clin Invest2004;113:1571–81. 

    CrossRefMedlineWeb of Science
27. ↵ 
    Zhou C, Dhall D, Nissen NN, Chen CR, Yu R. Homozygous P86S mutation of the human glucagon receptor is associated with hyperglucagonemia, alpha cell hyperplasia, and islet cell tumor. Pancreas2009;38:941-6.

    CrossRefMedlineWeb of Science
28. ↵ 
    Yu R, Dhall D, Nissen NN, Zhou C, Ren SG: Pancreatic neuroendocrine tumors in glucagon receptor-deficient mice. PLoS One2011;6:e23397.

    CrossRefMedline
29. ↵ 
    Bock T, Pakkenberg B, Buschard K. The endocrine pancreas in non-diabetic rats after short-term and long-term treatment with the long-acting GLP-1 derivative NN2211. APMIS 2003;111:1117-24.
30. ↵ 
    Raun K, von-Voss P, Gotfredsen CF, Golozoubova V, Rolin B, Knudsen LB: Liraglutide, a long-acting glucagon-like peptide-1 analog, reduces body weight and food intake in obese candy-fed rats, whereas a dipeptidyl peptidase-IV inhibitor, vildagliptin, does not. Diabetes 2007;56:8-15.

    Abstract/FREE Full Text
31. ↵ 
    Cummings BP, Stanhope KL, Graham JL, Baskin DG, Griffen SC, Nilsson C, et al. Chronic administration of the glucagon-like peptide-1 analog, liraglutide, delays the onset of diabetes and lowers triglycerides in UCD-T2DM rats. Diabetes 2010;59:2653-61.

    Abstract/FREE Full Text
32. ↵ 
    Bergenstal RM, Wysham C, Macconell L, Malloy J, Walsh B, Yan P, et al. Efficacy and safety of exenatide once weekly versus sitagliptin or pioglitazone as an adjunct to metformin for treatment of type 2 diabetes (DURATION-2): a randomised trial. Lancet2010;376:4319.
33. ↵ 
    Buse JB, Nauck M, Forst T, Sheu WH, Shenouda SK, Heilmann CR, et al. Exenatide once weekly versus liraglutide once daily in patients with type 2 diabetes (DURATION-6): a randomised, open-label study. Lancet2013;381:117-24.

    CrossRefMedlineWeb of Science