Byetta Takes a Beating as Feds Question Its Safety; Defender Chides FDA for Bureaucracy and Bad Science

David Kliff of Diabetic Investor asks, “Has the FDA ever heard of something called a statistically relevant sample size or incidence rate? Do they understand the concept that patients with diabetes are at an increased risk of pancreatitis?”

| Aug 28, 2008

Byetta has had a tough past few days. A lawsuit by a Virginia man alleges that the drug caused his life-threatening bout of severe pancreatitis, and there are rumblings from the U.S. Food and Drug Administration that it may force Byetta's makers to attach a "black box" warning to its container and packaging-a stern, highlighted caution about potentially dangerous, even fatal, side effects. 

Both events indicate that the glow may be coming off Byetta (exenatide), which has been hailed since its introduction in 2005 as one of the most powerful and effective type 2 diabetes treatments ever developed, thanks to its weight reduction and A1c percentage-lowering capabilities.

But even as some try to make the case that Byetta might be linked to severe pancreatitis that has led to two deaths, the drug's makers and proponents have taken the FDA to task for allegedly misusing statistics and taking an overly cautious approach.

What Has Been Happening

Virginian Victor Deleon's lawsuit against Amylin and Eli Lilly, Byetta's co-marketers, is seeking restitution for damages from pancreatitis he says was brought on by his use of the drug. Deleon, who was hospitalized for pancreatitis last December, alleges that the companies failed to adequately test and monitor Byetta's potential side effects or to state them forcefully enough on the drug's warning labels.

Deleon came down with the disease, a painful inflammation of the pancreas that can lead to internal bleeding and even death, just weeks after the FDA ordered Amylin and Lilly to provide stronger cautions to prescribers and users that Byetta could be a factor in the onset of pancreatitis.

At the time, the FDA was responding to reports that Byetta usage was suspected in the onset of 30 cases of pancreatitis. Even though that number was miniscule when compared to the number of Byetta users-conservative estimates say 700,000-the form of the disease being reported, hemorrhagic pancreatitis, was more severe than the normal affliction. In hemorrhagic pancreatitis, unlike normal pancreatitis, acute inflammation destroys pancreatic cells and can lead to a patient's death.

On August 18, some time after it had directed Amylin and Lilly to beef up Byetta's warning labels, the FDA announced that it had received news of six more cases of possibly Byetta-related pancreatitis, including two of which the patients had died. As result, the agency indicated that it is considering asking for a "black box" warning label on Byetta that spells out potentially fatal side effects from taking the drug.

Byetta's Defenders Weigh In

Amylin and Lilly weighed in on the controversy on August 26, 2008. In a teleconference with news media, the companies said that since 2006, the prescribing information for Byetta has included information about pancreatitis. "The companies were aware of the pancreatitis cases referenced in the alert, as well as others, and previously reported these cases to the FDA," they said in a press release that preceded the conference.

The co-marketers also pointed to a recent study that said patients with type 2 diabetes run nearly three times the risk of developing pancreatitis as those without diabetes.

David Kliff, publisher of the Chicago-based Diabetic Investor newsletter, mounted a blistering attack on the FDA, questioning its statistics and competence in the matter. He cited the FDA's August 18, 2008, statement that there was no indication of causation between acute pancreatitis and Byetta and that the events were "rare and uncommon."

"Has the FDA ever heard of something called a statistically relevant sample size or incidence rate?" Kliff asked in an e-mail update on the controversy to his subscribers. "Do they understand the concept that patients with diabetes are at an increased risk of pancreatitis?"

He accused the agency of being "hypersensitive to any possible issue after Rezulin, Avandia, and Vioxx-just to name a few of the agency's more recent blunders. Rather than fully investigate and follow their mission to use evidence-based medicine, the FDA overreacted."

He called the agency's actions "careless" and said that the people who will be hurt the most are diabetes patients and their physicians. "Once again government bureaucrats drop the ball and it lands where it does the most damage. Even if the FDA did the unthinkable and actually issued some sort of statement clearing Byetta, the mercury is already out of the thermometer. They cannot undo the numerous press reports on their action or change public perception."

Kliff said he considers it "highly unlikely" that the FDA will require a black box warning for Byetta.

Other Woes: A Threat to Byetta LAR and  Questions About Weight Loss Effects

Aside from theoretical links between Byetta and pancreatitis, another potential problem for the drug is whether its users can sustain the often significant weight loss many of them enjoy once they begin using it. The Financial Times of London quotes an article from Pharmawire, "Amylin's Byetta: physicians remain skeptical of drug's real-world benefit," in which some researchers question the drug's weight-loss efficacy beyond a year or two.

However, other doctors and scientists quoted in the article say that a current study that hints at Byetta's loss of weight-control effectiveness is based on too small a sample. They say it will take more than the three and one-half years the drug has been on the market to ascertain its real usefulness as an agent in long-range weight loss.

Possible Effects on Byetta LAR

The suspicions lodged against Byetta by the FDA may come to bear against its long-term version, Byetta LAR, a once-weekly injection that is now in late-stage FDA-approved trials.

Although Amylin has reported no cases of pancreatitis associated with Byetta LAR, a potential problem with the drug is that its active agent remains in patients' systems long after they have ceased taking it. If that agent were later proven to be a causal factor in the onset of pancreatitis, it would have a dampening effect on the long-term drug's marketability.

What Are the Odds?

If a link can be established between Byetta and pancreatitis, what are your chances of developing the disease if you are currently one of the 700,000 people taking the drug?

If the 36 reported cases of pancreatitis reported to the FDA can be linked to the use of Byetta, it means that out of 700,000 people taking the drug, 1 in 19,444—5/1,000ths of 1 percent—have come down with the condition.

(If you use David Kliff's figure of "nearly 800,000" Byetta users, the number of people who may have come down with pancreatitis because of using the drug is 1 in 22,222.)

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Categories: A1c Test, Byetta, Diabetes, Diabetes, Food, Type 2 Issues, Weight Loss


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Comments

Posted by Anonymous on 28 August 2008

I am going to continue to use Byetta. It works very well for me and keeps my blood glucose at a good level. I have been using it for over two years and have not had an A1c of over 5.2 during that time; it is currently 4.9. The risk of pancreatitis seems very small compared to the benefit I get from Byetta.

Posted by Anonymous on 28 August 2008

I took Byetta for about 6-8 months along with 70/30 insulin. I became increasingly sick on my stomach the longer I used the drug. I did lose some weight, but I believe it was because I did not feel all that good while taking Byetta. It also seemed that my food did not go down like it should and that is just sat in my stomach for longer periods of time. I eventually quit taking Byetta and began feeling okay and not so sick on my stomach anymore.

Posted by Anonymous on 29 August 2008

I have been using byetta now for a year and haven''t had nothing except lowered blood sugar and lost about 20 lbs. this stuff is great.

Posted by Anonymous on 29 August 2008

I tried to use Byetta for six months and never was so sick in my life! My whole quality of life was affected by this med. I did lose 10 lbs but it was not worth this type of living which,for me, was non-living.
I must add that I had to use chemo for breast cancer several years before and was not as sick as I was with Byetta!

Posted by Anonymous on 29 August 2008

I was diagnosed with type 2 diabetes in August 2007. After being put on 2 Byetta injections a day and the only side effect was severe nausea for ONLY the first week. I stuck it out and actually in the end Byetta ended up being my LIFE SAVER. Byetta does curb your appetite so you don't eat as much. So after being on Byetta only 7 months I had a 50 lb weight loss. Exactly one year after a type 2 dabetes diagnosis I am now 64 lbs lighter. Take NO MORE Byetta and have a perfect A1C and no longer am considered as having diabetes. Not that I am saying Byetta takes your diabetes away. It helped me in the weight loss though that I had severely needed to get my blood sugars back to within a normal range again. THANK YOU TO BYETTA!! It saved my life.

Posted by Anonymous on 29 August 2008

1:20,000 is based on known reported cases.

We know that not all cases are reported. For example digoxin toxicity has been the most common cause of hospitalization yet only 30 cases a year are reported to the the FDA. That is an extreme case where a toxicity is well known however when there is a lot of publicity as in the present case the reporting rates will go up (which they probably haven't yet with Byetta). Even after they go up comparison of published cases with FDA reports (e.g. Lilly's Oraflex) as well as FDA's internal estimates indicate that 10% or less of cases are reported.

That means that the true incidence is not 1 in 20,000 but really more than 1 in 2000.

David Kiff may have knowledge of basic statistics but he clearly has no knowledge of pharmacoepidemiology and reporting rates.

I'd also like to know what are the extent of his financial conflicts.

Posted by cmack on 29 August 2008

Why is ther no information on what the symptoms woudl be if indeed Byetta was causing Pancreatitis?

Posted by Anonymous on 29 August 2008

I really felt good on byetta. My BS dropped and it was a great appetite suppressor. Then a month later I went into the ER because of severe gastral problems.(I thought I was having a heart attack) Was terrible, would not clear up and had to go off the only type2 diabetes drug that worked for me. UGH! Why can't the drug mfg get it right?

Posted by Anonymous on 29 August 2008

I have tried to use Byetta for 2 years. The entire time it made me sick. I had foot surgery in March 2008. The byetta dosage resulted in increased nausea, and my taste and desire for food decreased. I lost 10 lbs but felt like hell the entire time. I have decided to stop the byetta because I honestly think it was causing my health to deteriorate and reach a point that I was not going to live. No medication is worth that affect!

Posted by Anonymous on 29 August 2008

Under "What are the odds?" - this is a meaningless exercise without including what the incidence of pancreatitis is in people with type 2 diabetes who are not using exenatide. It is like stating that "2% of people who eat carrots die of stomach cancer". that sounds pretty serious unless you have the stomach cancer rates of those people who don't eat carrots (say 2.5%). A little more critical analysis on the author's part please.

Posted by Anonymous on 29 August 2008

This is absolute nonsense. People on Byetta also grow get skin cancer, grow old, get divorced, and get fired from their jobs. What you want to know (and what nobody is talking about) is whether type 2 diabetic patients on Byetta are more likely to develop pancreatitis than type 2 patients not taking Byetta. As far as I know, there isn't a shred of evidence to suggest that this is the case.

Posted by Anonymous on 29 August 2008

I have been taking it for about 8 months now. I have had wieght loss of about 15 lbs and some nausa. I find that if I inject in my stomach or butt that it's not felt as much, also if I inject just before a meal it's not as bad. The loong I wait to eat after an injection the more chance i have of feeling nausa come on. I also feel bad if I eat a high carb meal, so it makes me eat better. I have never experianced any of the gut problems or pain. I wll continue to take Byetta and my Meformin. My ranges are from 90 to 120 and don't go over 135 after eating and that's a spagetti dinner!!

If your taking byetta and feeling sick, try injecting it in your butt and eating within 15 min after your injection. Worked for me!!

Posted by Anonymous on 29 August 2008

I have been on Byetta for over a year. The first week, I had some nausea but nothing since. My a1c's plummeted from 10 to 5.9 in two months, and I have lost 35 pounds. Byetta's saving my life! If diabetics naturally have a higher incidence of pancreatitis even without Byetta, I feel that the risk of taking Byetta is justified. It's got to be better than kidney failure, heart disease, losing limbs, etc. What about those risks?

Posted by Crobin59 on 29 August 2008

Byetta worked well for me during the 9 months that I used it. I had no nausea or abdominal pain and my A1C dropped to below 6 for the first time since I was diagnosed in 2004...But then, my hair started falling out and the Byetta was the only thing new in my regimen. There's nothing on the package, in the formulary, in the PDR, or the website that lists hair loss or alopecia as a side effect, but when I Googled Byetta and hair loss, I got lots of hits. I stopped taing the Byetta and my hair stopped falling out and has finally started growing back. Fortunately, other meds have kept my A1C in check, but I've gained weight. If Byetta were my only choice, I'd just have to wear a wig, because it works!

Posted by Anonymous on 30 August 2008

I have been on byette for nearly 30 days and have experienced very little side effects. The positives are better BS, may hunger has significantly been reduced and I have eliminated two of 6 medications saving $140 days quarterly. I look forward in testing my A1C in 60 more days. Tommorrow, I move to a 10 mcg injection, hoping the good continues.

Posted by Anonymous on 1 September 2008

I have been using Byetta for a year and have lost about 35 pounds. The nausea was hard to take initially, and now I only have nausea periodically. The weight loss is a blessing and worth feeling nauseated every now and then. I do not believe there is enough information to determine the over-all safety of the drug. I feel this bears more research and documented results comparable to other drug issues.

Posted by tujunga1 on 4 September 2008

I've been on Byetta a year now and it has been well worth any risks there might be! In the last last year or two I've dropped 81 lbs and have lost my sleep apnea - another dangerous co-morbidity for diabetics. I feel a lot better and look a lot better. The Byetta probably has helped me drop a good 50 or the total lost 81 lbs. I only had minor nausea with this at each step ( going on the 5mcg a week of nausea, going up to the 10 mcg about 2-3 days). Ny A1C has dropped form 7.8 to 6.7 and if I'd eat a bit more wisely, I'd probably see it go lower - my problem, not the drug's.

I think it's a great help to me, but many people may not be able to use it as we all have slightly different metabolisms and sensitivities. I think it's the best thing to come along in the 10 years since my Type 2 diagnosis and plan to continue on untill I either lose all of the weight (another 50lbs is my goal) or lose my symptoms of the Type 2. I'll take the chance on the Pancreatitis. I hope that anyone who is really sick on this drug will talk to their doctors as I would think you'd have some pretty good indication something's wrong. I've had friends with Pacreatitis, and they were pretty sick. Any early intervention by your doctor could be a real lifesaver. I figure if you are having any problems, question your doctor!

Posted by Diabetes Health Editor on 12 September 2008

Response from the author...

"Under "What are the odds?"" posted by Anonymous on 29 August 2008 asks for "a little more critical analysis on the author's part, please"

...Patrick Totty wishes to respond:

Anonymous makes a good point. It was a misstatement to say “what are the odds?” when we don’t know what the odds are for developing pancreatitis among type 2s who don’t take Byetta. I revised the language simply to say that if the 36 cases cited by the FDA can be linked to Byetta, one out of 19,444 users developed the condition.

Posted by Anonymous on 21 September 2008

hi, i'm kimberly ha. the reporter who wrote the Pharmawire article. Thanks for referencing my article.

you can email me at kimberly.ha@pharmawire.com

i'm still investigating the effects of byetta and pancreatitis.


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