NEWZLETTER 09
www.diabetesheartcare.com
Dr.V.K.Gujral
What is in a cigarette
Diabetes Drugs Must Now Clear Cardiovascular Hurdle, Says FDA
December 18, 2008 (Silver Spring, Maryland) — The Food and Drug Administration is now recommending that all new drugs developed for the treatment of type 2 diabetes show that they do not increase the risk of cardiovascular events.
The recommendation is included in a new guidance document issued this week by the agency and emerges after concerns have been raised about the cardiovascular safety of drugs in this field, especially the thiazolidinediones (TZDs), including rosiglitazone (Avandia, GlaxoSmithKline). The new standard is effective immediately and affects all drugs and biologics currently in development.
Last July, the Endocrinologic and Metabolic Drugs Advisory Committee voted overwhelmingly in favor of requiring sponsors to conduct long-term clinical trials or provide equivalent evidence ruling out an unacceptable cardiovascular safety risk. Based on that two-day meeting, the FDA is now asking sponsors for more stringent clinical trials that collect data on cardiovascular end points, as well as studies that include real-world patients likely to be seen in clinical practice.
"To obtain sufficient end points to allow a meaningful estimate of risk, the phase 2 and phase 3 programs should include patients at higher risk of cardiovascular events, such as patients with relatively advanced disease, elderly patients, and patients with some degree of renal impairment," the FDA states in the guidance document. "Because these types of patients are likely to be treated with the antidiabetic agent, if approved, this population is more appropriate than a younger and healthier population for assessment of other aspects of the test drug's safety."
The report, from the Center for Drug Evaluation and Research (CDER), recommends that sponsors establish an independent cardiovascular end points committee to prospectively assess cardiovascular events during all phase 2 and phase 3 trials. These events should include cardiovascular mortality, MI, and stroke and can include hospitalization for acute coronary syndrome, urgent revascularization procedures, and possibly other end points.
Glycemic control, as measured by changes in glycated hemoglobin levels, remains an acceptable primary efficacy end point for approval of drugs to treat hyperglycemia, the agency states. Studies, however, will likely be longer and more expensive, in order to provide sufficient data on cardiovascular risk for these new therapies.
In a briefing with reporters yesterday, Dr Mary Parks, director of the division of metabolism and endocrinology products, said the FDA has sent out more than 100 letters to drug companies informing them of the recommendations. The new guidance applies to all unapproved drugs, but the agency is working on another guidance document to evaluate the cardiovascular safety of drugs already approved.
In addition to showing cardiovascular safety, the agency is asking companies to provide comprehensive data collection that will allow for appropriate meta-analyses to be performed at the time of their completion. The document is nonbinding, meaning companies are not required to follow the new guidelines, although the FDA guidance is "suggested or recommended."
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Food and Drug Administration. FDA announces new recommendations on evaluating cardiovascular risk in drugs intended to treat type 2 diabetes. December 17, 2008. Available at: http://www.fda.gov/bbs/topics/NEWS/2008/NEW01928.html.
10-DEC-2008
Diabetes drugs double women's fracture risk
Long-term use of a popular class of oral diabetes drugs doubles the risk of bone fractures in women with type 2 diabetes, a study reports.
According to researchers at Wake Forest University School of Medicine who reviewed 10 previous drug trials, for every 20 women in their 70s with type 2 diabetes who took thiazolidinediones -- rosiglitazone (brand name Avandia) and pioglitazone (brand name Actos) -- for at least one year, one of them has a chance of suffering a fracture. In women in their mid-50s, the figure equals one fracture in every 55 women. That's more than double the normal risk for those age groups.
The research appears online in the Canadian Medical Association Journal this week. About 14,000 patients were involved in the studies analyzed by study co-author Sonal Singh, assistant professor of internal medicine at Wake Forest, and his colleagues.
The same increase in fractures was not found in men, Singh says, though the reason was not determined.
In 2006, almost 4 million people in the USA took the drugs for diabetes, and Singh estimates about half were women.
He says the fracture risk and the previously reported cardiovascular risks of the two drugs call the modest blood-sugar-lowering benefits of the class of drugs into question.
John Buse, president of medicine and science for the American Diabetes Association and medical professor at the University of North Carolina-Chapel Hill, says the ADA recommends other drugs, such as oral metformin, as the first treatment options for people with diabetes. But as with the class of drugs in the Wake Forest study, he says the pros and cons have to be weighed patient by patient as well.
"There are some people who just can't take metformin because it makes them vomit or have diarrhea," he says.
No drug is without risks, Buse says. "There's not a single drug that has no consequence. I mean, insulin can kill people from hypoglycemia, and yet its widely recognized to be of benefit to people with diabetes," Buse says.
Says study co-author Curt Furberg, professor of public health sciences at Wake Forest: "You always weigh the good effects and the not-so-good effects."
He points out that researchers now know that the drugs increase the risk of heart failure and the risk of fractures in women. The Food and Drug Administration ordered black box warnings last year on both drugs' labels against their use in patients with advanced congestive heart failure. Avandia has been shown to increase the risk of heart attacks as well.
Rimonabant Has Been Associated With Five Deaths in the UK
June 5, 2008 — The cannabinoid antagonist rimonabant (Acomplia, Sanofi-Aventis) has been associated with five deaths in the UK since its launch there in mid-2006, according to new data from the UK's Medicines and Healthcare products Regulatory Agency (MHRA) [1].
Rimonabant was approved throughout the European Union in June 2006 for the treatment of obesity, but Sanofi-Aventis withdrew its approval application in the US last year after an FDA advisory committee unanimously recommended nonapproval of the drug, citing a "clear" signal of neurological and psychiatric side effects. In June 2007, psychiatric adverse drug reactions were reassessed by the European Medicines Agency, leading to new contraindications in patients with major depressive disorder or those taking antidepressants. Suicidal ideation and aggressiveness were added as adverse reactions to the prescribing information, and it was recommended that rimonabant should be stopped if a patient develops depression.
The latest information on adverse reactions reported with rimonabant recorded on the MHRA website (covering the period from launch of the drug until May 9, 2008) notes that there have been five fatal events associated with this drug. These are classified as two deaths due to cardiac disorders, one classified as "general," one as death due to infection, and one due to psychiatric disorders (suicide).
Sanofi-Aventis confirmed these figures for heartwire and noted that three of the deaths were in fact of cardiac origin (two MI and one sudden death), one was the result of an infection, and one of psychiatric causes. A company spokesperson commented that it was not surprising to see cardiac deaths in a patient group that has cardiac risk factors and that none of the deaths had been causally linked to rimonabant.
Of the 2123 total number of adverse reactions reported, 974 were classified as psychiatric disorders, 241 were classified as nervous-system disorders, and 229 were gastrointestinal disorders.
More information on the type of adverse reactions being reported with rimonabant is given in the May issue of the MHRA's Drug Safety Update, which covers the period until the end of January 2008. At this point there had been four deaths recorded as being associated with the drug--one suicide, two MIs, and one sudden death of unknown cause. There had been 1971 individual reactions received at this time point in the UK, 423 of which were serious, the report states.
It notes that the most common adverse reactions were psychiatric disorders (44% of the total), and the most common psychiatric reactions were depression and related disorders of mood, of which 52 reactions involved suicidal and self-harming thoughts or behaviors. The MHRA says that depressive reactions remain a source of concern. Until the end of January 2008, there had been 211 reports of depression and related mood disorders, and of those for which a time to onset was available, one-third occurred within the first week of starting treatment with rimonabant, and almost half occurred within the first two weeks. Of these 211 patients, 20 were receiving concomitant treatment with antidepressants and 36 were reported to have a history of depression or suicidality, although rimonabant is contraindicated in patients with ongoing major depression or those taking antidepressants.
Other reported suspected adverse reactions, which are not currently in the product information for rimonabant and have been identified as new safety signals, include hypoglycemic reactions (seven reports), which the MHRA says may be due to inadequate monitoring of blood-glucose control in patients who have managed to reduce calorie intake without appropriate adjustment of glucose-lowering medication; paranoia (15 reports); rash; tremor (14 reports); and headache (40 reports).
The MHRA also notes that the UK, Germany, and France are the highest consumers of rimonabant worldwide and that from launch until the end of 2007, the total amount of rimonabant dispensed in the UK equates to about 21 000 patient-treatment-years.
Rimonabant is indicated in Europe for use together with diet and exercise to reduce weight in adult patients who are obese, with a body-mass index (BMI) >30 kg/m2, or who have a BMI >27 kg/m2 and also have other risk factors, such as type 2 diabetes or dyslipidemia. The RIO series of clinical trials showed that showed that roughly one-quarter of obese subjects randomized to rimonabant lost 10% of their body weight after one year, while half of subjects lost about 5% of their original body weight. These losses were greater than those achieved on placebo.
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Medicines and Healthcare products Regulatory Agency. Drug analysis print. Drug name: Rimonabant. June 3, 2008.
TRANS FAT is a deadly silent Killer !!
The Recommended intake is Zero !
