Saxagliptin/Metformin Combo Pill Approved By FDA

The Food and Drug Administration (FDA) in the US has given approval for a combination pill featuring saxagliptin and extended-release (XR) metformin HCl to treat glycemic control in adults suffering from type 2 diabetes mellitus.


The combined pill, which is taken once a day, provides an alternative treatment for those nearly half of adult diabetes patients who are unable to control blood sugar levels . The approval was based on findings from two double-blind, 24-week, phase 3 clinical trials of saxagliptin and metformin immediate-release (IR), which were given as separate tablets, and compared with metformin IR alone.


Howard Hutchinson, chief medical officer at AstraZeneca, who developed the treatment, commented “Patients with type 2 diabetes in the United States can be taking four or five medications for various diseases and conditions, which can lead to complicated medication schedules. Kombiglyze XR combines two effective diabetes medications in a simple once-a-day dose for adult patients who need A1c reductions.”


The combination incorporates the complimentary mechanisms of saxagliptin, which is a dipeptidyl peptidase 4 inhibitor, with metformin, a biguanide . The therapy fights against the main defects in type 2 diabetes by increasing insulin secretion in a glucose-dependent manner, suppressing hepatic gluconeogenesis, and also helping insulin sensitivity.


As type 2 diabetes is a chronic, progressive disease with many factors involved in its development, patients often need more than one pill to treat the multiple defects associated with the disease.

Effectiveness Of Statins Is Called Into Question

As the world's most-prescribed class of medications, statins indisputably qualify for the commercial distinction of "blockbuster." At the zenith of their profitability, these medications raked in $26.2 billion a year for their manufacturers.

But in recent months the drugs' touted medical reputation has come under tough scrutiny.

Statins were initially approved by the US Food and Drug Administration for the prevention of repeat heart attacks and strokes in patients with high cholesterol who had already had a heart attack. And used for that purpose — called "secondary prevention" — the drugs are powerful and effective medications, driving down patients' risk of another heart attack or stroke by lowering their levels of LDL (or "bad") cholesterol.

Then physicians came to believe statins could also reduce the risk of a first heart attack in people who have high LDL cholesterol but are nonetheless healthy. This use of statins — called "primary prevention" — has driven the growth in the market for statins over the last decade.

Today, a majority of people who use statins are doing so for primary prevention of heart attacks and strokes. It is this use of statins that has come under recent attack.

"There's a conspiracy of false hope," says Harvard Medical School's Dr. John Abramson, who has cowritten several critiques of statins' rise, including one published in June in the Archives of Internal Medicine. "The public wants an easy way to prevent heart disease, doctors want to reduce their patients' risk of heart disease and drug companies want to maximize the number of people taking their pills to boost their sales and profits."

Heart patients and their physicians are not the only ones to pin their hopes on statins. The drug companies that brought statins to the market have explored the medications' benefits in prevention or treatment of such conditions as Alzheimer's disease, rheumatoid arthritis, prostate and breast cancer, kidney disease, macular degeneration and diabetic neuropathy. Although clear proof that statins could forestall or treat any of these diseases might bring in millions of new, paying customers, results have largely been mixed, inconclusive or disappointing.

In an ideal world, debate over the clinical virtues or vices of a drug would be long settled by the time the medication saw a meteoric rise in use. But in a healthcare system that relies on commercial incentives to spur drug development, prescription medications are a product like any other.

The FDA assesses drugs' safety and effectiveness for specific use; but its judgments are based on preliminary data, most of it generated by a drug company seeking approval for its product. Once the agency approves a drug for marketing, the company that makes it will move quickly and aggressively to expand the universe of patients taking its product.

Sometimes, by the time the deliberate pace of medical research and debate suggests that a drug is not all it's been cracked up to be, it's already become a bestseller. Statins, say some who study the relationship between medicine and the drug industry, seem to fit that pattern.

Statins appear to drive down the risk of heart attack or stroke by lowering the levels of fatty deposits circulating in the bloodstream. Research suggests that the drugs dampen inflammatory processes that can prompt deposits of plaque to break away from blood vessel walls and cause sudden blockages of arteries leading to the heart or brain.

And yet, the relationship between cholesterol-lowering and heart disease is not perfectly understood, and the precise role of inflammation in heart disease is also uncertain.

Statins certainly decrease rates of heart attack in people who have clear signs of cardiovascular disease, but it's not so clear they work that way in people who are healthy. In spite of that uncertainty, statins' use for primary prevention has skyrocketed.

That's the issue in the latest round of debate, which spilled onto the pages of the Archives of Internal Medicine in late June: whether statins prevent, safely and at a reasonable cost, the development of cardiovascular disease in people who are still healthy but are considered to be at high risk of a heart attack or stroke.

In the first of three studies published in the Archives last month, medical researchers found that, contrary to widely held belief, statins do not drive down death rates among those who take them to prevent a first heart attack.

A second article cast significant doubt on the influential findings of a 2006 study, called JUPITER, that has driven the expansion of statins' use by healthy people with elevated blood levels of C-reactive protein, a measure of inflammation. A third article suggested potential ethical, clinical and financial conflicts of interest at work in the execution of the JUPITER study and concluded the widely hailed trial was "flawed" and raises "troubling questions concerning the role of commercial sponsors."

"Tens of billions of dollars of revenue for the sponsor over the patent life of the drug were at stake in the JUPITER trial, as well as potentially millions of dollars in royalties for the principal investigator," wrote Dr. Lee Green of the University of Michigan Medical School in an editorial accompanying the trio of studies. "Doubtless, both sponsor and investigative team believe they made their design decisions for the right reasons," Green added. "But social psychology research provides abundant evidence that we human beings both respond strongly to self-interest incentives and firmly believe that we do not."

Statins still have ardent admirers, including cardiologist Steven Nissen of the Cleveland Clinic in Ohio. For many patients on a clear collision course with heart disease but not there yet, he said, statins make a difference. And even though recent studies question whether statins reduce heart attack deaths, Nissen added, many patients' lives are clearly improved by pushing a heart attack further into the future.

The stakes of this debate are big and continuing to grow (see related story, " Pinning down the side effects of statins"). As many as three-quarters of patients currently taking statins haven't yet had a stroke or heart attack; they have diabetes or high LDL cholesterol, conditions widely thought to put them at high risk of having one.

Those patients largely joined the ranks of statin consumers after 2001, when the US National Heart, Blood and Lung Institute adopted guidelines on the treatment of patients with high cholesterol.

The guidelines, updated again in 2004, suggested that as many as 36 million Americans should take statins — essentially tripling overnight the potential American market for the drugs. Of the nine experts involved in drafting the cholesterol treatment guidelines, the National Institutes of Health later acknowledged that eight had substantial financial ties to statin makers — links that may have predisposed them to view evidence of statins' benefit in its most positive light.

Said Abramson, the author of "Overdosed America: The Broken Promise of American Medicine": The best way to drive down the risk of developing cardiovascular disease in the first place is to exercise regularly, not smoke, drink in moderation and eat a healthy Mediterranean-style diet. But, he added, "this message gets drowned out by the commercial interests" of pharmaceutical companies who stand to benefit from increased sales.

Courtesy: Melissa Healy/LA Times

Diabetes Alert: Avandia May Be Banned In Europe

European regulators will decide by September if Avandia will be allowed to stay on the market there. The European Medicines Agency (EMEA) said on July 23 that it is still reviewing GlaxoSmithKline’s controversial diabetes drug, which has been linked to an increased risk of heart attacks.

Since 2000, the EMEA has contra-indicated Avandia for anyone with heart failure or a history of heart failure. Since then, use of Avandia, as well as Avandame (Avandia in combination with metformin) and Avaglim (Avandia in combination with glimepiride), has been further restricted several times by the EMA by new warnings and contra-indications on their use in patients with heart problems.

The EMEA initiated a new review of Avandia earlier this month on the request of the European Commission following publication of studies questioning the cardiovascular safety of the medicine.

In the US, a Food & Drug Administration (FDA) advisory panel took up Avandia last week. Since 2007, Avandia has borne a black box label – the FDA’s most urgent safety warning – regarding its heart attack risks. An FDA advisory panel met last week to consider further restrictions on the controversial diabetes drug.

According to a report in The New York Times, 12 of the panel’s 33 members voted that Avandia should be withdrawn; 10 voted that its sales should be restricted and the warnings on its label enhanced; 7 voted only to support enhanced warnings on the drug’s label; and 3 voted that the drug should continue to be sold with its present warnings unchanged.

The FDA is not required to follow the recommendations of such panels, but does so in most cases. However, the lack of unity among panel members in the case of Avandia makes it hard to predict what the agency will do, The Times said.

As I reported yesterday, the FDA has ordered GlaxoSmithKline to halt enrollment in a study called TIDE (Thiazolidinedione Intervention With Vitamin D Evaluation) over safety concerns. TIDE was designed to compare the long-term effects of Avandia with another diabetes drug called Actos.

Actos has not raised as many safety concerns as Avandia. For some time now, scientists inside and outside the FDA have opposed TIDE, saying it is unethical to compare Avandia, with its known cardiac risks, with a seemingly safer alternative.

Incidentally, India has already suspended all participation in the TIDE trial in the country. In India, at least 20 cities including Mumbai, Bangalore, Chennai and Hyderabad had enrolled over 150-200 subjects earlier this year for conducting these clinical trials, which are part of the global post-marketing studies to asses its safety risks.

According to The Boston Globe, the FDA said it halted recruitment in TIDE because it needs time to study new evidence of the Avandia’s risks. The agency is demanding that Glaxo update physicians and ethics oversight boards involved in the trial regarding all new safety information about the drug. The agency has not indicated how long the enrollment halt would last.

Diabetes: Safety Concerns Force FDA To Halt Enrollment For Avandia Trials

The FDA On July 21 ordered drug maker GlaxoSmithKline to stop enrolling new patients in a controversial clinical trial of its widely marketed diabetes drug, Avandia (rosiglitazone).

The clinical trial, called TIDE, was mandated by the FDA to assess safety risks of the drug, which is prescribed to treat type-2 diabetes.

But it has been highly controversial because Avandia has been linked in a variety of studies to an increased risk of heart attack and other adverse cardiovascular effects.

Critics, including one of the Food and Drug Administration’s own safety researchers, have said publicly that the trial should be stopped immediately, asserting that it is unethical to expose patients to risks that have been shown statistically to be quite real.

GlaxoSmithKline recently announced that India has already suspended all participation in the TIDE trial in the country.

In India, at least 20 cities including Mumbai, Bangalore, Chennai and Hyderabad had enrolled over 150-200 subjects earlier this year for conducting these clinical trials, which are part of the global post-marketing studies to asses its safety risks.

This development is significant in the wake of the fact that a total of around 2,000 diabetics were to be enrolled from India.

A debate has been raging on the blockbuster drug, Avandia since studies reported serious side-effects like heart attacks and strokes associated with its use, in 2007. It is widely-prescribed by doctors here in India, with 9-10 companies marketing it.

The country's drug controller general recently halted the trials, for which subjects were being enrolled since February, across various hospitals and clinics all over.

Dr Anoop Misra, director and head diabetes, Fortis Hospitals in New Delhi said: "This step taken by FDA of stopping this unethical trial is welcome, though belated. I hope further step of banning this drug is taken soon. I am also happy to note that DCGI (India) stopped this trial in India before FDA decision, and such efficient steps and regulations are required in India."

The FDA on its part said its action does not mean the drug will be removed from the market. But the agency is demanding that GlaxoSmithKline update physicians and ethics oversight boards involved in the trial regarding all new safety information about the drug.

It said the information "can be used’’ to update consent forms for new patients and current participants. Critics, including members of Congress, have said the current consent forms in use in the trial are inadequate given the extent of the scientific warning signs.

The potential dangers of Avandia have already discouraged enrollment in the trial.

The trial’s design called for global enrollment of 16,000 patients, with about a third in the United States. But the trial’s lead investigator, Hertzel Gerstein, of McMaster University in Ontario, Canada, said last week only about 1,120 patients had been recruited worldwide, because of the widespread safety concerns.

By a vote of 20 to 12, an FDA advisory panel last week recommended that the drug be permitted to remain on the market. But half of the members who voted to keep it on the market also supported strong restrictions on prescribing, including education programs about the risks for doctors and patients, which specialists predict will dramatically cut into GSK sales figures.

GlaxoSmithKline said in a statement that new enrollment in the trial would be stopped "pending FDA review of recommendations from its Advisory Committee meeting July 13-14. Patients already enrolled may continue in the trial."

"This pause in enrollment will give clinical trial investigators and patients time to learn about the data presented to the FDA Advisory Committee and the Committee’s recommendations," said Dr Ellen Strahlman, GSK’s Chief Medical Officer. "We are committed to working with the FDA in the best interest of diabetic patients."

Avandia, which was approved for the market in 1999, was prescribed 2 million times by US doctors in 2009. It was once the largest-selling drug in its class, with more than $3 billion in global sales. It sold around $1 billion in 2009, with half of that revenue in the US.

Killer Drug Gets Safety Certificate From FDA - GSK Claims "Victory"

This week the US Food and Drug Administration voted not to ban GlaxoSmithKline's diabetes drug rosiglitazone (brand name Avandia). Their vote has been reported as a victory for the company. I don't think so: this saga tells an ugly story about our collective medical incompetence.

Rosiglitazone was first marketed in 1999. From the outset it was a magnet for disappointing behaviour. That first year Dr John Buse discussed an increased risk of heart problems at a pair of academic meetings. He was silenced. GSK made direct contact, then moved on to his head of department.

Buse felt pressured to sign various legal documents and after wading through documents for several months, in 2007 the US Senate committee on finance released a report describing the treatment of Dr Buse as "intimidation".

In 2003, the Uppsala drug monitoring group of the World Health Organisation contacted GSK about an unusually large number of reports associating rosiglitazone with heart problems. GSK conducted two internal meta-analyses of their data in 2005 and 2006.

These showed the risk was real, but although both GSK and the FDA had these results, neither made any public statement, and they were not published until 2008.

Why then? In 2004 GSK were caught ‑ famously - hiding data showing side effects of the antidepressant paroxetine in children: a court settlement required them to post all clinical trial results voluntarily on a public website.

Using this data source, cardiologist Prof Steve Nissen and colleagues published a landmark meta-analysis in 2007 showing a 43% increase in the risk of heart attack on rosiglitazone. People with diabetes are already at increased risk of heart problems.

The FDA found a similar risk in their own calculations, but voted in 2007 to keep the drug on the market. This is not insane: diabetes is tricky, 300 million people have it worldwide, a great many die from it, and rosiglitazone is unusually good at controlling blood sugar. Lots of dangerous drugs are kept on the market and then used less frequently, in extreme circumstances.

A consensus algorithm from the American Diabetes Association and the European Association for the Study of Diabetes, meanwhile, unanimously recommended against rosiglitazone. Although annual sales for rosiglitazone fell, they still remained over $1bn (£650m). Concerns continued to mount. So did the bad behaviour. In 2007, Nissen caught GSK out discussing a copy of his unpublished paper, which they had obtained improperly.

Then on 28 June this year Nissen published an updated meta-analysis of 56 trials in over 35,000 patients. Again it found an increased risk of heart problems. GSK's response to all this has been like the responses you get from homeopaths.

There are seven trials since 2007, they said, showing no excess risk: fine, except there are 56 which collectively do show an excess risk. There is this other meta-analysis, they said, which looked at 164 trials: fine, except it's published in a fairly obscure journal, and it looked at trials lasting more than four weeks, when the others set the bar at trials over 24 weeks, because a heart risk takes time to develop.

In any case, this other meta-analysis is not brilliant for GSK's case, since it points out that the company denied access to data from six trials which we know to have taken place. There is no excuse for companies withholding data from academics and doctors. But most revealingare the deep-rooted flaws this story exposes in our rather ad hoc systems for gathering, analysing, and disseminating evidence on risks and benefits of treatments.

This drug has been on the market since 1999, and it has seen billions of dollars of sales every year. There has been plenty of real patient experience of this treatment, but we have failed to capture it for analysis. Most of the trials included in these meta-analyses were not specifically designed to look at heart problems, and so the data on these is unpredictably inaccurate.

In an ideal world, for every patient, wherever possible, we could be gathering anonymised outcome data and comparing this against medication history. In an ideal world, wherever there is genuine uncertainty about which treatment is best, a patient would be randomised to one treatment, and their progress monitored. In an ideal world, these notions would be so embedded in our notion of what healthcare looks like that no patient would be bothered by it.

This isn't fanciful, or difficult, or disproportionately expensive. Instead we have a hotchpotch of incomplete monitoring systems and unforgivable secrecy.

Courtesy: Ben Goldacre/The Guardian

Diabetics' Deaths: Glaxo to Pay $60 Million in Avandia Settlements

FDA regulators urged Glaxo to withdraw Avandia from the market in 2008 because it was causing 500 avoidable heart attacks a month but Glaxo officials sought to intimidate doctors who criticized the drug

GlaxoSmithKline Plc is said to have agreed to pay about $60 million in the first settlements of lawsuits alleging the company’s Avandia diabetes drug causes heart attacks and strokes in some users, people familiar with the accords said (reports Bloomberg).

Glaxo, the UK’s biggest drugmaker, agreed to resolve more than 700 Avandia suits filed by three attorneys, including Houston-based plaintiffs’ lawyer Mark Lanier and Philadelphia- based litigator Sol Weiss, the people said. The settlements come as Glaxo is scheduled to face its first Avandia trial in state court in Philadelphia in July.

The settlement works out to about $86,000 for each case, less than the average $500,000 per case forecast by Gbola Amusa, an analyst at UBS AG in London. While more than 4,000 Avandia lawsuits already have been filed, the company faces at least another 9,000 claims over the drugs that haven’t yet been filed under an agreement with Glaxo, the people familiar with the settlements said. Such “tolling” agreements are common in US mass-tort cases.

“We take the $86,000 per case liability as a key positive and look for more insights on other potential settlements,” Amusa said in a note to clients today. “We continue to believe science favors Avandia’s place in the US market.”

Glaxo officials yesterday declined to comment on the settlements. They said the company continues to prepare for trials over Avandia scheduled for this year.

“GlaxoSmithKline stands by Avandia and is fully prepared to defend any litigation,” Bernadette King, a company spokeswoman, said in an e-mailed statement.

Regulators approved Avandia for sale in the US in 1999 and the medicine generated annual revenue of $3 billion by 2006, including sales of a combination of Avandia and another drug.

Avandia was the world’s best-selling diabetes pill before safety concerns emerged. Sales plunged after a May 2007 report in the New England Journal of Medicine linked the drug to a 43 percent increased risk of heart attacks, prompting US and European regulators to order Glaxo to strengthen its warnings.

Last month, Glaxo reported first-quarter profit that beat analysts’ estimates. The reserves budgeted for legal matters for the quarter increased by 210 million pounds ($312 million) because of “the progress we are making toward settlement of existing cases,” according to an April 28 statement.

The settlement may reduce Glaxo’s liability in the cases from initial estimates ranging from $1 billion to $6 billion, UBS’s Amusa said. “Settlement implies liability at or below the low end of our $1 billion to $6 billion range,” Amusa said in today’s note.

The Food and Drug Administration is reviewing Avandia’s safety profile and will present its findings to an advisory committee in July, officials said in a March 30 letter to two U.S. senators who released a critical report about the drug.

London-based Glaxo’s decision to settle cases before they come to trial will save the company time, money and embarrassment, said Richard Nagareda, a Vanderbilt University law professor who teaches classes on mass-tort law.

“It sounds like they’ve beaten down the price on these cases to the point that there isn’t that much benefit from taking them to trial,” Nagareda said in an interview.

Status Conference

Lanier, who won the first jury verdict against Merck & Co. over its withdrawn painkiller Vioxx in 2005, resolved more than 500 Avandia cases, the people said. Weiss, who was among a group of plaintiffs’ lawyers who negotiated a $3.75 billion settlement of suits over Wyeth’s diet drugs in 2000, resolved more than 200 Avandia cases, the people added.

Weiss announced at a status conference last month in Philadelphia Common Pleas Court that he had earlier settled his Avandia cases slated to be tried there, the people said.

Ted Oshman, a Manhattan-based plaintiffs’ lawyer, also settled a number of cases, the people said. None of the three attorneys returned calls for comment on the accords.

Glaxo officials contend former Avandia users who suffered heart attacks can’t link them to the drug and the drugmaker didn’t hide the medicine’s health risks.

Glaxo is “confident that when courts and juries look at actual clinical data, the manner in which we communicated with the FDA and physicians and our openness in posting studies on our website, the facts will support our position,” King, Glaxo’s director of product communications, said in the e-mail.

Andrew Witty, Glaxo’s chief executive officer, said in an interview last week that he was confident about Avandia’s “risk-benefit profile” and the company’s handling of the drug.

“The only thing I ask for is that qualified scientists with the right evidence and data calmly look at the information,” he said. “The company’s done all the right things in terms of sharing that data with the regulators and working with the regulators to update the label.”

Glaxo’s officials also are in settlement talks with attorneys for other former Avandia users, such as Los Angeles-based plaintiffs’ lawyer Mark Robinson and Manhattan-based litigator Benedict Morelli, the people said.

Robinson helped win a $4.9 billion jury verdict in a case against General Motors Corp. in 1999 over exploding fuel tanks in passenger cars. Morelli won a $22.5 million verdict against a Wyeth unit last year in a case over a polio vaccine.

In their Avandia suits, consumers contend Glaxo officials refuse to take the drug off the market even though studies have shown it poses an increased risk of heart attack and stroke compared with competing medicines.

A report by two US senators in February noted FDA regulators urged Glaxo to withdraw Avandia from the market in 2008 because it was causing 500 avoidable heart attacks a month.

The report, by Senators Max Baucus and Charles Grassley, also said Glaxo officials sought to intimidate doctors who criticized the drug. Dr. John Buse, a University of North Carolina Medical School professor, gave presentations highlighting Avandia’s risks, the senators said.

Glaxo officials complained to Buse’s supervisor and threatened to take legal action over the statements, the report said. Buse later agreed to stop criticizing the drug, according to the report.

Glaxo officials rejected the senators’ contentions that it concealed safety information about Avandia or used improper marketing tactics. They said the report contained “errors of fact, omission and inference and shouldn’t have been published.”