Avandia – More Questions than Answers / Januvia safety questioned/Finally some good news for Abbott

Avandia – More Questions than Answers / Januvia safety questioned/Finally some good news for Abbott

The markets haven’t opened yet and already it’s been a busy day in the diabetes world. Leading the way today is the Congressional hearing on Avandia (you can watch the hearing at www.oversight.house.gov the hearing is set to begin at 10am EST). Prior to today’s hearings the New England Journal of Medicine released three editorials and one article on Avandia. This collection of information unfortunately creates more questions than answers regarding Avandia’s safety.

In the article “Rosiglitazone Evaluated for Cardiovascular Outcomes- An Interim Analysis” the authors took an early look at the data from the ongoing RECORD trial. The authors concluded “Our interim findings from this ongoing study were inconclusive regarding the effect of rosiglitazone on the overall risk of hospitalization or death from cardiovascular causes. There was no evidence of any increase in death from either cardiovascular causes or all causes. Rosiglitazone was associated with an increased risk of heart failure. The data was insufficient to determine whether the drug was associated with an increase in the risk of myocardial infraction.”

In one editorial “The Record on Rosiglitazone and the Risk of Myocardial Infraction” By Bruce Pstay, M.D., Ph.D. and Curt D. Furberg, M.D., Ph.D. the authors state;
“Although the limitations in design and conduct of the RECORD trial argue for a cautious interpretation of its findings, the results of risk of myocardial infraction (hazard ratio, 1.16; 95% CI, 0.75 tom 1.81) are nonetheless compatible with those of the meta-analysis. This overlap between the 95% confidence intervals for the trial and the meta-analysis is substantial.”

The authors go on – “Thus, even with the findings from the RECORD trial included, the possibility of a benefit in terms of risk of myocardial infraction remains remote, and there is still significant evidence of harm.” “Rosiglitazone, however, appears to be associated with an increase rather than a decrease in the risk of myocardial infraction.”

David M. Nathan, M.D. added in his editorial “Rosiglitazone and Cardiotoxicity – Weighing the Evidence” – “Unfortunately, this interim analysis, performed after a mean 3.75 years (about 60% of the planned 6-year duration of the study), fails to provide exculpatory evidence.” More from Dr. Nathan:

“It is reasonable to ask whether physicians should feel comfortable using a drug that might have an 8% excess risk of sever cardiovascular disease or death from cardiovascular causes. Given the other choices of therapy available, including pioglitazone, which has limited clinical trial data suggesting a protective cardiovascular effect (albeit in a study that has been criticized for its design and its analysis, the answer should be no.”

Dr. Nathan concludes “The jury may still be out with regard to the cardiotoxicity of rosiglitazone, but when it comes to patient safety, “first, do no harm” should outweigh any presumption of innocence.”

Finally Jeffrey M. Drazen, M.D., Stephen Morrissey, Ph.D. and Gregory D. Curfman, M.D. write in their editorial “Rosiglitazone – Continued Uncertainty about Safety” –
“In short, this means that there is continued uncertainty about the cardiovascular safety of rosiglitazone.”

In all the editorials the authors question whether GlaxoSmithKline (NYSE:GSK) has been forthcoming with all the available data on Avandia. The FDA is also taken to task. In the Psaty, et. al. editorial the author’s state, “The main limitations of the meta-analysis are the quantity of the available data. The responsibility for limited availability of high-quality data resides primarily with the manufacturer (GlaxoSmithKline) and also perhaps the Food and Drug Administration (FDA).” The authors go on, “By October 2006, the product labels in Europe were revised to include this information. The U.S. product label still does not identify ischemic cardiovascular disease as an adverse reaction in the general population of patients with diabetes. Why did the FDA not make this information public in a timely fashion?”

For their part the FDA said yesterday they will convene a meeting of outside experts on July 30th to discuss Avandia and similar drugs. The FDA did not state specifically what the phrase “similar drugs” meant but to Diabetic Investor this can only mean on thing, the agency also wants to take a look at Actos.

The FDA could have another problem on their hands with the newest drug used to treat type 2 diabetes; Januvia. In an article that appeared on worstpills.org it states patients should not use Januvia for seven years. According to the article “Clinical study participants who took the drug experienced an increase in creatinine, a chemical found in blood. Elevations in creatinine are often an early indicator of kidney problems.” Sidney Wolfe, director of the health research group at Public Citizen, stated “individuals with type 2 diabetes should wait seven years before taking Januvia.” He added, “they should not be human guinea pigs and risk being harmed by adverse effects associated with Januvia that may be magnified with time, as they were with Avandia.”

The article also brings up a concern addressed by Dr. Nathan namely that FDA approved Januvia too quickly and did not adequately analyze the drug.

The article concludes “We call this our “Seven Year Rule,” and it based on a study we co-authored in the May 1, 2002 Journal of the American Medical Association. This study found that one-half of all new drug safety withdrawals occurred within two years of their FDA approval. One-half of all black box warnings, the strongest type of safety warning the FDA can request, and drug safety withdrawals combined occurred within seven years of new drug approvals – thus the Seven Year Rule.”

Diabetic Investor has been one of the few, perhaps the only publication prior to today’s article on worstpills.org that has raised the question over Januvia. Merck (NYSE:MRK) has been marketing Januvia as an effective treatment for type 2 diabetes with the primary benefit being that the drug has fewer adverse events than existing medications. Based on patient and physician interviews we have called into question just how effective Januvia really is as the results appear less than robust. In earlier email alerts we also warned that Januvia’s safety profile is unknown. Quite frankly there just wasn’t enough data to conclude that Januvia is safe to use on a long-term basis.

Given the attention surrounding Avandia it would come as no surprise when more physicians come forward with concerns over Januvia. This also puts physicians in rather uncomfortable position when advising their patients on whether or not to switch from Avandia to another medication. No matter what the FDA decides to do with Avandia, physicians must consider the legal ramifications of their advice. Based on all available data the safest route is to switch patients off Avandia. However, that creates a quandary of just where to go next. Does this concern over Januvia eliminate the drug as an option? Can they simply switch patients to Actos with confidence that the drug does not have the same cardiovascular concerns as Avandia? Will concerns over possible long term side effects cause physicians to pause when prescribing Byetta?

Diabetic Investor sees the situation playing out as follows; first there is just too much risk for physicians to continue prescribing Avandia therefore prescriptions will continue to decline. Next, until further data becomes available Actos will likely become the primary replacement option for Avandia. Both Januvia and Byetta will also see their prescriptions accelerate. In an interesting twist physicians will also begin a dialogue with patients about the possibility of moving towards insulin. An unfortunate consequence will be even lower patient compliance with their current therapy regimen. Patients are more confused than ever and have few independent resources they can go to when looking for answers. As we have said repeatedly patients want a simple answer to a complex question and they want it yesterday.

It is unclear at this point what action the FDA will take. The agency is in a difficult situation and really has only one truly safe option which is to place a black box warning on Avandia as they investigate further. It’s likely since Actos is from the same family of drugs the FDA will take another look at Actos as well. At this point it’s doubtful the agency will do anything in regards to Januvia as there just isn’t enough evidence one way or another. This could change in a hurry should more physicians come forward with concerns.
Lastly, the agency will likely change the parameters for the drug approval process.

As we said before the real losers here are the millions of patients who want to know if the medications they take each and every day are safe.

In news that is likely to be lost in all the other diabetes news, Abbott (NYSE:ABT) has received approval for their Navigator continuous glucose monitoring system from European regulators. This is welcome news for Abbott as they are still waiting for the FDA to approve Navigator here in the U.S. While this is welcome news for Abbott nothing has really changed for the company. Their conventional blood glucose monitoring business continues to struggle. They have yet to announce what plans, if any, they have regarding the insulin pump market. Previous statements appeared to indicate the company would be entering the market, although more recent statements indicate they may be reconsidering. Finally even if the FDA approves Navigator tomorrow, the device is well behind Medtronic (NYSE:MDT) and Dexcom (NASDAQ:DXCM) who are gaining valuable market experience with their already approved products.

On second thought the company is probably delighted this news will not gain attention as it will only reinforce something Diabetic Investor has been saying for some time, when it comes to diabetes Abbott is letting history repeat itself. Years ago Abbott bought Medisense and basically ran the company into oblivion. To reinvigorate their diabetes franchise they went out and bought Therasense. While they haven’t completely ruined Therasense the outlook is not promising. Based on their history in diabetes Diabetic Investor is confident they will complete the job and ruin Therasense as well.

David Kliff
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