After Cracking Metformin Code, Scientist Makes Breakthrough Discovery That Points The Way To New Class Of Diabetes Drugs

HDAC inhibitors may provide a novel way to cut excessive blood glucose levels at the source

RESEARCHERS have uncovered a novel mechanism that turns up glucose production in the liver when blood sugar levels drop, pointing towards a new class of drugs for the treatment of metabolic disease, the Salk Institute for Biological Studies announced in a press statement today.

In a uniquely collaborative study, the scientists have found evidence ‒ published in the May 13, 2011 issue of the journal Cell‒ that a group of enzymes, or proteins, currently under investigation for the treatment of cancer could potentially also work as a treatment for type 2 diabetes. This is significant because it not only portends a new treatment for diabetes, but it also could mean that a new treatment has already gotten through the costly and lengthy early stages of drug development.

The Salk discovery revolves around enzymes called histone deacetylases, or HDACs, which help the liver produce sugars when blood glucose runs low after prolonged periods of fasting, particularly at night. After a meal, insulin “instructs” muscle cells to store this glucose and turns off sugar production in the liver. In patients with type 2 diabetes, however, the body effectively doesn’t “listen” to insulin, and the liver keeps producing sugar.

Dr, Reuben J. Shaw

"These exciting results show that drugs that inhibit the activity of class II HDACs may be worthwhile to be pursued as potential diabetes drugs," said lead author Reuben Shaw, an assistant professor in Salk’s Molecular and Cell Biology Laboratory.

Up to this point, all experiments had been performed in cultured cells but the researchers were really interested in whether class II HDACs controlled blood glucose in mouse models of diabetes. Strikingly, suppression of all three HDACs simultaneously restored blood glucose levels to almost normal in four different models of type 2 diabetes.

"The key will be to specifically block HDACs involved in glucose control," said Shaw, "but the fact gluconeogenesis takes place in the liver makes this task easier as most drugs sooner or later travel to the liver once they hit the bloodstream."

"Our results predict then that some of those drugs, probably not the same ones that work on cancer but some of the ones that are sitting on the shelf that maybe weren’t effective for cancer but in fact hit these enzymes, that they could be potential therapeutics for diabetes," said Shaw. "That means that the time from this initial discovery until the time that this can be tested in the clinic is much shorter."

Ronald Evans, a professor in Salk’s Gene Expression Laboratory, said that while this discovery is novel, scientists have long noticed a link between cancer and diabetes, particularly because the risks of both diseases are increased in obese patients. This discovery -- that suppressing HDACs can treat diabetes as well as cancer -- is a way of turning this theory into a potential treatment.

"We know that along with increased weight and obesity there is an increased risk of cancer. We also know that cancer cells undergo a profound metabolic change and so the cancer metabolism has become a very big area (of study)," Evans said.

"So for those of us who study metabolism and study cancer, the link between these two seemingly separate areas, actually at the level of the genome, happen to work with several common pathways," he continued, "because they’re both dealing with either consuming energy, which is what happens with cancer, or storing energy, which is what happens with obesity."

Currently, metformin (Glucophage, Glucophage XR, Glumetza, Fortamet, Riomet), an oral biguanide anti-diabetic drug, is the most widely prescribed agent for treatment of type 2 diabetes. The drug mainly works by lowering glucose production by the liver, and thus lowering fasting blood glucose. Although metformin – approved in the United States in 1994, and in Europe prior to that – has been used for many years, its mechanism of action is not well understood.

"Metformin is originally derived from a plant found in Western Europe called 'French lilac' or 'Goat's Rue' because goats didn't like to eat it. They steered clear of the plant because it contains a compound that acts to naturally lower blood glucose in animals that eat it ‒ to prevent them from eating it again," Shaw explained.

Does Periodic Fasting Lower The Risk?

A few years ago, Shaw discovered how metformin helps insulin to control glucose levels: It binds to a "metabolic master switch" known as AMPK that blocks glucose production in the liver. Trying to identify novel targets of AMPK that might be relevant to diabetes, Maria Mihaylova, a graduate student in the Shaw laboratory, focused her efforts on a family of HDACs known as class II HDACs. They function as negative regulators of gene activity by stabilizing the tightly coiled structure of DNA in chromosomes, making it inaccessible to proteins that transcribe DNA.

Working closely with Ronald M. Evans and his team, Mihaylova found that inhibiting class II HDACs shut down genes encoding enzymes needed to synthesize glucose in liver. "We identified class II HDACs as direct targets of AMPK in a bioinformatics-based screen, but we didn't know which genes they might regulate in liver since they weren't even known to be found there," said Mihaylova.

In collaboration with her colleagues in Marc Montminy's lab, a professor in the Clayton Foundation Laboratories for Peptide Biology, and like Shaw and Evans a member of the Center for Nutritional Genomics at the Salk Institute, Mihaylova discovered that HDACs themselves associated with the DNA regulatory elements controlling the expression of the glucose synthesizing enzymes, but they only flocked there after she had treated cells with the fasting hormone glucagon.

"In response to the glucagon, chemical modifications on class II HDACs are removed and they can translocate into the nucleus," she explains. There, they bind to FOXO, a key metabolic regulator, which had been shown previously to be shut down by insulin.

"It came as a big surprise that FOXO is activated by glucagon," explains Shaw. Further experiments confirmed that the genetic suppression of class II HDACs in liver cells led to an increase in acetylated FOXO, which now can neither bind DNA nor activate the genes encoding glucose-synthesizing enzymes.

A parallel study, led by Montminy and published in the same issue of Cell as Shaw's paper, shows that in fruit flies, FOXO not only controls the expression of a fat-digesting enzyme but is activated by a glucagon-like hormone in a manner similar to human FOXO.

"The central circuitry of how animals regulate metabolism in response to fasting and feeding is conserved from fly all the way to man emphasizing the importance of class II HDACs in coordinating how different hormones direct the creation and use of glucose," says Shaw, who is a co-author on Montminy's paper.

Shaw next plans to test whether these glucose loving HDACs may also play roles in certain forms of cancer as well.

Source: Salk Institute for Biological Studies

Diabetes: “Welchol Added to Existing Diabetes Therapy Achieves Better Glucose Control”

WHEN used in combination with certain antidiabetes medications, colesevelam effectively lowers HbA1c levels in adults with type 2 diabetes, reports Endocrine Today. Colesevelam was approved by the FDA in 2008 for use in combination with metformin (Glucophage), sulfonylureas (Amaryl, DiaBeta, Glucontrol)) and insulin to improve glycemic control in adults with type 2 diabetes.

Harold Bays, MD

Although originally developed as an agent to lower LDL, data from three clinical trials demonstrated that colesevelam (Welchol, Daiichi Sankyo) improved glucose levels in adults with type 2 diabetes, Harold Bays, MD, medical director and president of the Louisville Metabolic and Atherosclerosis Research Center in Kentucky, said during a session of the American Association of Clinical Endocrinologists 20th Annual Meeting in San Diego this week.

Compared with placebo, when added to metformin, insulin and sulfonylureas, colesevelam led to 0.5%, 0.6% and 0.8% reductions in HbA1c levels, respectively, he said. “We did one set of clinical trials with metformin-based therapy, insulin and sulfonylureas…What’s really interesting when we look at the data is that, while these are somewhat different agents, reductions in HbA1c were remarkably similar,” Bays told the audience.

To further evaluate the efficacy of colesevelam, researchers conducted a pooled post-hoc analysis of the three pivotal studies of the drug in patients with type 2 diabetes. In total, the number of patients in the treatment group increased to 355. Results indicated that when added to metformin-based therapy, colesevelam significantly reduced cholesterol levels, improved glycemic parameters and exhibited a good safety profile.

“We found almost exactly what could be anticipated from the original trials,” Bays said. “Data showed reductions in HbA1c, fasting glucose levels, LDL, non-HDL and a nonsignificant increase in HDL and moderate increases in triglycerides.”

Colesevelam was also generally well-tolerated, Bays said. A moderate increase in constipation was the most notable side effect, with 10% to 13% of patients experiencing constipation vs. 2% to 3% in the placebo group. Other common adverse events included nausea, dyspepsia and nasopharyngitis (common cold). In studies involving pediatric populations with heterozygous familial hypercholesterolemia, adverse reactions included nasopharyngitis, headache, fatigue, increases in creatine phosphokinase, rhinitis and vomiting.

Prescribing information for colesevelam recommends against use in patients with a history of bowel obstruction, triglyceride levels greater than 500 mL or with a history of hypertriglyceridemia-induced pancreatitis. Bay emphasized that strict adherence to these indications is important for preventing adverse events and use of clinical judgment.

“We cannot look to these clinical trials for blanket safety information for all patients,” Bays said. “The results are only applicable to those patients who were administered the drug in keeping with the study populations.”

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.

Metformin Code Cracked

Scientists in Scotland have used samples taken from 20,000 patients in Tayside to help make a breakthrough in the treatment of diabetes.

Academics from the Biomedical Research Institute at Dundee University played a key role in establishing how the drug metformin actually works.

Metformin has been used worldwide for more than 50 years by people with Type 2 diabetes but scientists have never known exactly how it helped sufferers.

The development means the scientists may now be able to develop the drug to help extend its use.

The team at Dundee used the clinical data of patients with diabetes, linked to donated blood samples from the Tayside area.

They identified a gene that helps to show how the body works with and makes use of metformin, which has been shown to protect against heart, eye and kidney disease in those with the metabolic disorder. It is also recognised as holding benefits against cancer, but scientists have never been able to explain why.

The condition usually affects overweight people and is caused by too much glucose, a type of sugar in the blood. It differs to Type 1 diabetes, which is an insulin-dependent condition usually diagnosed in childhood.

Around 228,000 people are thought to suffer from both types of the disorder in Scotland.

Dr Ewan Pearson and Professor Colin Palmer were among the researchers at the university who were able to determine how well metformin worked.

They identified an area of chromosome 11, which includes a gene called ATM (Ataxia Telangiectasia Mutated), that altered how people responded to metformin. This was also found by researchers in Oxford.

“ATM is a gene that is known to be involved in the DNA damage response system of cells, a mechanism that if faulty can lead to the development of cancer,” Dr Pearson said.

“In one of the largest studies of its kind, we have used the genetics of drug response, otherwise known as pharmacogenetics, to investigate how metformin works.

“We were expecting to find genes involved in blood-sugar regulation so the finding that ATM is involved in metformin response was unexpected.”

Although the ATM gene has been widely studied by cancer scientists, no-one has previously thought it had a role in how this commonly used diabetes drug worked.

Dr Pearson added: “Our finding therefore draws together mechanisms that protect against cancer and lower blood sugar, suggesting a new area for diabetes drug development.”

The research was funded by the Wellcome Trust and Diabetes UK and is published in the journal Nature Genetics.

Professor Peter Donnelly, who leads the Wellcome Trust Consortium at Oxford University and was a lead investigator in the study, said: “We have shown how useful genetics can be in shedding light on how drugs work.

“In addition, this study is the first to robustly identify a gene to be involved in how metformin works, and is there- fore an important first step towards understanding how an individual’s genes can affect the way they respond to treatment.”

Diabetes UK has awarded Dr Pearson further funding to continue the research using new genetic techniques on 8000 people with Type 2 diabetes.

Dr Iain Frame, director of research at leading health charity Diabetes UK, said: “This study is a great example of how research can produce unexpectedly exciting results.

“The benefits for people with Type 2 diabetes may not be immediate but any research that increases our knowledge of how effectively drugs work in different individuals is hugely important.

“This is why Diabetes UK is funding Dr Pearson to continue this important line of research and this is likely to have significant impact in the future for people with Type 2 diabetes and the costs involved to the NHS in treating Type 2 diabetes.

“An added bonus of this work is that the researchers have also discovered that this gene is involved in protecting the body against cancer.”

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.

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