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: 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

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