Diabetes Management: Metformin Gets Highest Marks in New Study

The cost of managing diabetes is going up all the time. And while pharmaceutical companies are doing a great job trying to develop new drugs, the overriding profit motive is sometimes prompting them to cut corners or suppress information that may prove to me inimical to their bottom line. A case in point is Avandia, which is now banned in many countries but still prescribed in the US, but with many caveats.

However, the safety of most diabetes drugs are time-tested — insulin was discovered in the early 1920s, and two of the other most commonly prescribed, metformin and sulfonylurea, have been around since the 1950s. Indeed, these drugs have five characteristics physicians look for in diabetes medications: few potential complications, safety, tolerability, ease of use and a low cost. (See my earlier post 'Look to Older, Longer-Studied Treatments here.)

It’s not surprising that Metformin, in combination or alone, remains the top choice for first-line treatment of type 2 diabetes because it demonstrates the best risk-benefit profile vs. other diabetes drugs, according to new data.

Most importantly, the newer drugs, which have no generic options, are significantly more expensive than older ones. One hundred metformin pills cost about $35.57, or 35 cents a pill, while 30 Januvia pills (a DPP-4 inhibitor) cost $192.52, or $6.42 a pill — nearly 18 times as much. Ask any diabetic and he’ll tell you why he shudders at the thought of taking the newer medication, especially if it’s out of pocket.

According to the new study, metformin, that has been around for more than 15 years, works just as well and has fewer side effects than a half-dozen other, mostly newer and more expensive classes of medication used to control the chronic disease, new Johns Hopkins research suggests.

In their report ‒ published online March 14 in the journal Annals of Internal Medicine ‒ the Johns Hopkins team found that metformin, an oral drug first approved by the US Food and Drug Administration (FDA) in 1995, not only controlled blood sugar, but was also less likely to cause weight gain or raise cholesterol levels.

“Metformin works for most people. It’s cheaper, there’s a generic form — it’s tried and true,” says study leader Wendy L. Bennett, M.D., M.P.H., an assistant professor in the Division of General Internal Medicine at the Johns Hopkins University School of Medicine. “Our study shows that even though there are all these newer drugs, metformin works just as well and has fewer side effects.”

The team looked at several popular classes of oral diabetes medication — metformin (sold as Glucophage, Fortamet and others), second-generation sulfonylureas (Amaryl, Glucotrol and more), thiazolidinediones (Avandia and Actos) and meglitinides (Starlix and Prandin) — and added two new classes of drugs, dipeptidyl peptidase-4 (DPP-4) inhibitors (Januvia and Onglynza) and glucagon-like peptide-1 (GLP-1) receptor agonists (Byetta and Victoza), which are given by injection.

Results indicated that most medications used as monotherapy yielded comparable decreases in HbA1c (about one absolute percentage point on average throughout the course of a study). Metformin alone, however, lowered HbA1c more than DPP-4 inhibitors alone, and any type of combination therapy reduced HbA1c by about one absolute percentage point more than monotherapy.

Weight loss with metformin was a mean 2.5 kg more vs. TZDs and sulfonylureas. Other data also showed that combination metformin and GLP-1 agonists induced greater weight loss than other combination therapies, but the researchers said evidence supporting this finding was weak.

When compared with pioglitazone, sulfonylureas and DPP-4 inhibitors, metformin also significantly lowered LDL. Further, the drug decreased triglycerides and moderately raised HDL.

The researchers reported that sulfonylureas raised the risk for hypoglycemia four-fold vs. metformin monotherapy. Combination treatment with metformin and a sulfonylurea also had a six-fold higher risk for hypoglycemia than combination metformin and TZDs.

Analysis of other adverse events revealed that risk for congestive heart failure was higher with TZDs than with sulfonylureas. Risk for bone fractures was also higher with TZDs than with metformin alone or metformin combined with sulfonylurea. Diarrhea, however, was more commonly associated with metformin than with other medications.

“Although the long-term benefits and harms of diabetes medications remain unclear, the evidence supports use of metformin as a first-line treatment agent,” the researchers wrote.

The study is an update of Hopkins research published in 2007 that also showed there were advantages to metformin. New classes of medication for adult-onset diabetes have been approved by the FDA since then, and Bennett and her colleagues wanted to know if the newer drugs were any better than the older crop.

The research team also looked for the first time at the efficacy of two-drug combinations to treat the chronic disease, which has become increasingly common with more than one-third of diabetes patients needing multiple medications.

Researchers found that while two drugs worked better than one in those patients whose blood sugar remained poorly controlled on a single medication, there were also side effects associated with adding a second medication.

“Diabetes is an enormous public health problem, and patients have difficult decisions to make about what medications they should be taking,” Bennett says. “Our study provides good information comparing drugs and can be used to inform those decisions.”

Bennett and her colleagues reviewed 166 previously published medical studies that examined the effectiveness and safety of diabetes drugs, as well as their impact on long-term outcomes including death, cardiovascular disease, kidney disease and nerve disease.

No drug or combination of drugs was shown to have an advantage in improving long-term outcomes, Bennett says, primarily because there weren’t enough long-term studies, particularly of newer medications.

While most drugs reduced blood sugar similarly, metformin was consistently associated with fewer side effects. Though metformin is associated with increased risk of gastrointestinal side effects, Bennett, an internist, says she finds many of her patients can overcome them by starting with a low dose and taking it with meals, though patients with severe kidney disease may avoid it.

The sulfonylureas and meglitinides were associated with increased risk for hypoglycemia, or dangerously low blood sugar levels. The thiazolidinediones increased risk of heart failure, weight gain and fractures. In September 2010, the FDA placed restrictions on the use of Avandia because of concerns that the drug increases the risk of heart attack.

While the drugs all reduce blood sugar levels, Bennett says more research is needed into whether they actually improve outcomes for diabetics in the long run. It remains an open question as to whether patients with type 2 diabetes who have their blood sugar controlled by medication will reduce their chances of having complications associated with the disease, including eye, kidney and nerve diseases, she says.

“Some of the drugs haven’t been on the market long enough to study the long-term effects or even some of the short-term rare side effects, so we need longer studies in patients who are at highest risk for complications” she says.

Diabetes Alert: Avandia Warnings Updated To Reflect Restrictions on Use

GlaxoSmithKline has finalized an update for the warning label and medication guide of their diabetes drug Avandia, which includes information on new FDA required restrictions on use and concerns about potential heart problems with Avandia.

In a press release issued Monday, the company said that the changes will affect all rosiglitazone-based drugs; including Avandia, Avandamet and Avandaryl.

The labels and guides will note that Avandia is only available to patients who are already taking the drug or who have failed to control their diabetes with other medications. It also includes an updated black box warning that notes that clinical trials show a “statistically significant” increased risk of myocardial infarction and notes that trials have indicated that Takeda Pharmaceuticals’ Actos, a competing drug, does not appear to carry the same risks.

Avandia (rosiglitazone) was first approved in the United States in 1998 to treat type 2 diabetes by helping control blood sugar levels. The drug has been used by millions of diabetics, but sales plummeted following the concerns about potential Avandia heart risks.

In September 2010, the FDA determined that the black box warning added in 2007 was not enough and issued stronger warnings about Avandia and restricted use. The agency determined that only patients who have failed to control their diabetes through every other available medication should be given access to the medication, and ordered the drug’s maker, GlaxoSmithKline, to develop a risk evaluation and mitigation strategy (REMS) to make sure the drug is adequately restricted. The decision came after an FDA advisory committee narrowly voted this summer not to issue an Avandia recall.

GlaxoSmithKline said in its press release that it continues to work with the FDA on developing a REMS program.

The drug maker faces thousands of Avandia suits filed by people who allege that they suffered an injury as a result of the drug maker’s failure to adequately warn about the risk of heart problems.

A number of Avandia settlements have reportedly been reached by GlaxoSmithKline in an effort to resolve the Avandia litigation.

Diabetes Alert: Actos Linked To Bladder Cancer

After Avandia, it is now the turn of Actos to be linked to life-threatening conditions. On September 17 the United States Food and Drug Administration announced it is reviewing the link between use of the diabetes drug Actos or pioglitazone and elevated risk of bladder cancer among patients with type 2 diabetes mellitus who were using the medication.

The FDA said an analysis of data collected during a 5-year period from an ongoing 1o-year observational study conducted by the manufacturer, Takeda Pharmaceuticals North American Inc in San Diego showed overall there was no significant association between use of Actos and increased risk of bladder cancer among diabetes mellitus patients. Apparently, those who used Actos were 20 percent more likely to be diagnosed with the cancer, but the increase was deemed statistically insignificant.

The FDA acknowledged the risk of bladder cancer was found significantly higher among those who had either been using Actos for more than two years or had had a highest accumulative dose of this medication.

The health regulator did not say how higher the risk it was among those patients at risk. Instead, it advised doctors should continue following the current recommendations to prescribe Actos and patients would take the drug as prescribed. If they have any concern or worry, they should talk to a medical professional.

At this time, the agency stressed it has not concluded that it is Actos that caused the increase in the risk of bladder cancer among patients who either used the drug for more than 2 years or those whose accumulative intakes of this drug over the years were the highest.  It will inform the public of further information on the safety issue when it has become available, probably within a few months.

Based on the information released by the FDA, it is possible that Actos increases the risk of bladder cancer among the diabetes mellitus patients, a health observer suggested.

The FDA cited preclicnical carcinogenicity studies of Actos saying male rats receiving doses of the drug that were equivalent to what diabetes patients receive were at higher risk of bladder cancer.  Also, two 3-year controlled clinical studies of Actos showed patients who used Actos were at higher risk of bladder cancer compared to those who used other medications.

The FDA said these data have been included in the Actos drug label as precautions. But it does not mean that Actos as the cause increases the risk of this malignancy.

The health observer, who did not want to be named, cautioned the patients included in the analysis took Actos for a period between 0.2 and 8.5 years.  He said although the overall risk was not significant higher in the whole population, the risk differed among individuals. That is why those who had taken the Actos for more than 2 years and those who had highest accumulative doses were at greater risk.

Actos was approved July 15, 1999 as an adjunct to diet and exercise to control blood sugar in adults with type 2 diabetes mellitus.  Studies suggest Actos does not increase as much heart risk as its competitor known as rosiglitazone or Avandia, which is made by GlaxoSmithKline.  Rosiglitazone was found twice as likely to suffer heart attack as Actos.

One type of heart risk - heart failure - has been recognized by the FDA, which in Aug 2007 required a boxed warning, the highest grade of warning, to alert patients and medical practitioners that pioglitazone may cause or exacerbate heart failure in certain patient populations.

Red meat, processed meat, soft drinks, eggs, fruit juice, and arsenic in drinking water have been associated with an increased risk of type 2 diabetes mellitus, while coffee consumption, brown rice, vitamin d, exercise, plant-based diet, omega-3 fatty acids, garlic, fish, turmeric, micronutrients like selenium, vitamin e, vanadium, and chromium, soy products, Mediterranean diet, L-carnitine, and black tea may help reduce the risk or actually prevent the disease.

Thank you David Liu

Diabetes: Look To Older, Longer-Studied Treatments

The safety of most diabetes drugs are time-tested — insulin was discovered in the early 1920s, and two of the other most commonly prescribed, metformin and sulfonylurea, have been around since the 1950s. Indeed, these drugs have five characteristics physicians look for in diabetes medications: few potential complications, safety, tolerability, ease of use and a low cost.

But newer, "high-tech" drugs such as Avandia (Rosiglitazone Maleate) – branded differently outside the US market (e.g. Windia in India) - are different. Avandia landed with a splash on the market 11 years ago and quickly became the top-selling diabetes drug in the world. It's used by Type 2 diabetics to help improve blood sugar control in a different way than most other diabetes medications. Instead of causing the body to make more insulin, it works to use what is naturally made more efficiently.

But when studies began to link it to an increased risk of heart attacks and strokes, its fortunes quickly reversed. Now an advisory panel to the US Food and Drug Administration has recommended that the drug be slapped with stricter warnings and increased supervision.

That doesn't mean diabetes patients taking Avandia should necessarily stop. Or that there are no options for those who choose to do so. Far from it. Rather, it offers a lesson in how medications are prescribed for Type 2 diabetes, which accounts for 90% to 95% of the 23.7 million diagnosed diabetes cases in the US alone.

As with high blood pressure and cholesterol, there is no silver-bullet, cure-all medication for either type of diabetes, said Daniel Einhorn, president of the American Assn. of Clinical Endocrinologists. Treatment for Type 1 (in which the body produces no insulin) largely amounts to taking insulin and maintaining a healthy lifestyle. But treatment for Type 2 (in which the body does not produce enough insulin or is resistant to what is produced) often includes a combination of drugs, which can produce varying results among different patients or even in the same person over a number of years.

Neither doctors nor their patients have to wade through the offerings on their own. They have a long history of data on which to draw. Avandia's rapid rise and fall highlights the importance of knowing what to expect.

Other Treatments

To improve medication management for diabetics, professional associations such as the American College of Endocrinology and the International Diabetes Center have created charts detailing how and when to prescribe the drugs based on myriad factors, including a patient's weight, fitness level, health conditions, other medications and ability to control blood glucose levels.

"Doctors can take many paths down the road, but the road maps give you advice," Einhorn said. "They like the ability to choose a plan for patients, but many are kind of glad to have the guidance of general principles."

The charts provide information on target glucose levels, potential side effects and benefits of the drugs, and suggestions on when to add new medications.

When first diagnosed with Type 2 diabetes, most patients are advised to regulate blood sugar with exercise, diet and stress management. If that fails, the first medication that they receive is usually metformin, said Sanjay Kaul, a cardiologist at the Cedars-Sinai Heart Institute and member of the FDA's Avandia panel.

Metformin has the five characteristics physicians look for in diabetes medications, Kaul said: few potential complications, safety, tolerability, ease of use and a low cost.

"Metformin is preferred by professional societies as the treatment of first choice for diabetic patients," he said. "It is relatively safe, without side effects, well tolerated, weight neutral and inexpensive. And evidence shows it may save lives."

It decreases the amount of sugar (glucose) the body takes from foods and the amount of glucose produced by the liver. About 15% to 20% of diabetes patients cannot tolerate the drug because of gastric side effects or kidney problems, said Richard Bergenstal, president of medicine and science for the American Diabetes Assn. and executive director of the International Diabetes Center.

When first starting diabetes medications, some patients experience side effects such as water retention. These are usually seen within a week or so, and three months is sufficient time to see if a drug is affecting glucose reduction, Bergenstal said.

If a patient can't tolerate the drug or it doesn't decrease blood sugar adequately, a second medication is typically added to the regimen. About a dozen categories of drugs are available in the second class of medications, Bergenstal said, but four of them make up about 90% of prescriptions.

One group is sulfonylureas (such as Amaryl, or glimepiride), which help the pancreas release more insulin. A second is DPP-4 inhibitors (such as Onglyza, or saxagliptin). DPP-4 is an enzyme that blocks the secretion of the hormone GLP-1, which stimulates the release of insulin. The third is GLP-1 agonists (such as Byetta, or exenatide), which mimic the actions of GLP-1. And lastly, thiazolidinediones (such as Avandia, or rosiglitazone, and Actos, or pioglitazone), which increase the body's sensitivity to insulin.

If patients still don't meet their target glucose levels, a third medication is added to the regimen. This could be another of the drugs not used in the second tier, background insulin (long-acting, which stays in the bloodstream for 24 hours) or a thiazolidinedione. If patients continue to have problems, the fourth, and final, level of treatment is insulin therapy.

Patient-Specific Help

But doctors can, and obviously should at times, move beyond the guidelines. Among the most important factors in doing so are patient preferences and needs.

Treatments should not just be safe but manageable over the long term. That often amounts to a limit of one or two doses a day, Einhorn said. Further, they should be as effective as possible so patients aren't forced to monitor glucose too frequently.

Many patients don't want to give themselves shots and look at insulin as "the end of the road," so doctors may try to avoid insulin when possible, Bergenstal said. Others may need to lose weight, so doctors might choose drugs less likely to cause weight gain.

"Knowing your patient is really critical," he said. "As much as we put algorithms out … if you match them to patients' best preferences, you will get the best outcome."

And monitoring is crucial — both of the patient and of the drugs on, and coming to, the market, as the troubles with Avandia so aptly highlighted.

"Even when a drug gets approved for sure, maybe 5,000 people have taken it, so now we have 1 million who will be using it," Bergenstal said. "We have to have good surveillance and be willing to change our mind and modify things."

Even after a drug is approved by the FDA, doctors and medical associations gather data to see how it affects patients before relying on it too heavily, he said. Sometimes the data are inconclusive, as with Avandia — even the FDA panel that waded through numerous studies could not decide if there was enough of a cardio risk to pull it from the market.

This is where physicians help decide the risks and benefits to their patients, Kaul said. When an FDA advisory committee meeting was held in 2007 to look at Avandia studies, physicians had already started curtailing the use of the medication, he said. The market share of thiazolidinediones that year was essentially split 50-50 between GlaxoSmithKline's Avandia and its competitor, Takeda Chemical's Actos. Avandia's market share is about 10% now and "rapidly shrinking," Kaul said.

"Physicians have already decided what to do with Avandia," he said. "They use their clinical judgment and are obligated to protect patients from potentially harmful therapies."

Thank you Tammy Worth/latimes.com

Drugs Cannot Treat The Underlying Cause of Diabetes!

If you or someone you know is diabetic and taking medication for it, please understand that you cannot successfully treat the underlying cause of diabetes with drugs.

Avandia - the controversial drug that is linked to increased incidents of heart attacks (see my earlier posts) - works by making diabetes patients more sensitive to their own insulin, helping to control blood sugar levels.

In fact, most conventional treatments for type 2 diabetes utilize drugs that either raise insulin or lower blood sugar. Avandia, for example, lowers your blood sugar levels by increasing the sensitivity of liver, fat and muscle cells to insulin.

But you must understand that diabetes is NOT a blood sugar disease you may have been led to believe.

Type 2 diabetes is actually a disease caused by insulin resistance and faukty leptin signalling, both of which are regulated through your diet.

Conventional treatment, which is focused on fixing the symptom of elevated blood sugar rather than addressing the underlying disease, is doomed to fail in most cases.

Type 2 diabetes is virtually 100 percent avoidable, and can be effectively treated without medications in about the same percentage of cases.

Leptin, a relatively recently discovered hormone produced by fat, tells your body and brain how much energy it has, whether it needs more (saying "be hungry"), whether it should get rid of some (and stop being hungry) and importantly what to do with the energy it has (reproduce, upregulate cellular repair, or not).

In fact, the two most important organs that may determine whether you become (type 2, insulin resistant) diabetic or not are your liver and your brain, and it is their ability to listen to leptin that will determine this.

How is this done?

Well, that's the kicker. The only known way to reestablish proper leptin and insulin signaling is through a proper diet and exercise!

There is NO drug that can accomplish this, but following these simple guidelines can help you do at least three things that are essential for successfully treating diabetes: recover your insulin/leptin sensitivity, help normalize your weight, and naturally normalize your blood pressure.

As an aside, none of these will drastically raise your risk of a heart attack the way Avandia will … and in fact will have only positive benefits on your heart and your entire body:

• Severely limit or eliminate sugar and grains in your diet, especially fructose which is far more detrimental than any other type of sugar.Finding out your nutritional type will help you do this without much fuss. While nearly all type 2 diabetics need to swap out their grains for other foods, some people will benefit from using protein for the substitution, while others will benefit from using more vegetable-only carbohydrates. Therefore, along with reducing grains and sugars, determining your nutritional type will give you some insight into what foods you should use to replace the grains and sugars.
• Exercise regularly -- a must for anyone with diabetes or pre-diabetes. Typically, you'll need large amounts of exercise, until you get your blood sugar levels under control. You may need up to an hour or two a day. Naturally, you'll want to gradually work your way up to that amount, based on your current level of fitness.
• Avoid trans fats
• Get plenty of omega-3 fats from a high quality, animal based source.
• Get enough high-quality sleep every night.
• Optimize your Vitamin D levels. Recent studies have revealed that getting enough vitamin D can have a powerful effect on normalizing your blood pressure and that low vitamin D levels may increase your risk of heart disease.
• Monitor your fasting insulin level. This is every bit as important as your fasting blood sugar. You'll want your fasting insulin level to be between 2 to 4. The higher your level, the worse your insulin receptor sensitivity is.

So please remember that a drug will never treat the underlying cause of type 2 diabetes the way these lifestyle changes will.

It looks like Avandia is set to go the way of Vioxx, which was also pulled from the market after killing 60,000 people. You don't need to wait for the red tape to be removed to start looking out for your own health.

(Adapted from an article in Mercola.com) 

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

Diabetes: Avandia Drug Trial Unethical And Dangerous

The Canadian physician whose research escalated safety concerns about the Type 2 diabetes drug rosiglitazone (marketed as Avandia) is urging the US Food and Drug Administrationto call a halt to a major international trial designed to compare the safety of Avandia against another diabetes drug in the same class.

Dr David Juurlink, chief of clinical pharmacology and toxicology at Sunnybrook Health Sciences Center in Toronto, was the lead author of a 2009 study that found that compared to elderly diabetics taking a drug called pioglitazone (marketed as Actos), those taking Avandia were about 30% more likely to suffer heart failure or death.

On Tuesday, Juurlink joined with Dr Sidney Wolfe, director of health research for the consumer watchdog group Public Citizen, in calling a further clinical trial pitting the two diabetes drugs against each other "unethical" and "dangerous."

In 2007, the FDA issued two separate safety warningson Avandia and required the drug's maker, GlaxoSmithKline, to post "black box" warnings on the medicine's patient instruction sheet indicating the drug might put patients taking it at higher risk of ischemic heart attack or heart failure. The agency also ordered GSK to conduct a post-marketing safety trial of Avandia.

That planned trial is expected to draw from sites in 14 countries, including a number of newly-added developing countries such as Pakistan, India, Latvia, Chile, and Mexico, and to enroll 16,000 subjects. Called the TIDE trial, or Thiazolidinedione Intervention in Vitamin D Evaluation, was the subject of Tuesday's appeal from Juurlink and Public Citizen.

In fact, both drugs have been tagged with safety issues: In addition to raising rates of cardiovascular events, the class of Type 2 diabetes drugs known as thiazolidinediones (or TZDs) have been linked in studies to higher rates of edema, macular edema, bony fractures, anemia and acute liver injury. Older diabetes medicine such as metformin and sulfonylurea are widely believed to be safer alternatives.

At the same time, the drugs are widely used and have many defenders in the care of Type 2 diabetes.

But extensive financial ties between the drug companies that make the medicines and many of the clinicians and researchers who have defended them have prompted some to ask whether the safety debate has been tainted by industry influence.

There is scant evidence that the proposed clinical trial will yield more reliable evidence of Avandia's relative safety profile than existing research has done, Juurlink and Wolfe wrote in a Tuesday letter to FDA Commissioner Margaret Hamburg. Nevertheless, it will expose "thousands of high-risk patients with diabetes to a drug with an unfavorable safety profile and clinical advantage over its comparator," they wrote.

The "price of definitive proof" of the drug's safety hazards, they added, "will almost certainly be measured in the lives of study subjects who have been incompletely informed about the risks and benefits of participation" in the trial, they added.

Thank you Melissa Healy

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.”