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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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March 22, 2013

Trouble for a Whole Class of Diabetes Drugs?

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Posted by Derek

The FDA has been turning its attention to some potential problems with therapies that target the incretin pathways. That includes the DPP-IV inhibitors, such as Januvia (sitagliptin) and GLP-1 peptide drugs like Byetta and Victoza.

There had been reports (and FDA mentions) of elevated risks with GLP-1 drugs, but this latest concern is prompted by a recent paper in JAMA Internal Medicine that uses insurance company data to nail down the effect. Interestingly, the Endocrine Society has come out with a not-so-fast press release of its own, expressing doubts about the statistics of the new paper. I'm not quite sure why they're taking that side of the issue, but there it is.

For what it's worth, this looks to me like one of those low-but-real incidence effects, with consequences that are serious enough to make physicians (and patients) think twice. At the very least, you'd expect diabetic patients on these drugs to stay very alert to early signs of pancreatitis (which is really one of the last things you need to experience, and in fact, may be one of the last things you experience should the case arise). And this just points out how hard the diabetes field really is - there are already major cardiovascular concerns that have to be checked out with any new drug, and now we have pancreatitis cropping up with one of the large mechanistic classes. In general, diabetic patients can have a great deal wrong with their metabolic functions, and they have to take your drugs forever. While that last part might sound appealing from a business point of view, you're also giving every kind of trouble all the time it needs to appear. Worth thinking about. . .

Comments (8) + TrackBacks (0) | Category: Diabetes and Obesity | Toxicology


1. simpl on March 22, 2013 11:42 AM writes...

This type of post-hoc studies are interesting for the hypotheses they throw up, rather than the percentages, or cause vs effect. They detect low-but-real effects when increase in cases >~double.
If I were a doctor, I'd really like to know about severity, also cases >64 years. It seems that many of the cases were in the first weeks of medication, so what should they be watching out for?
Knowledge of any dose dependency would also help, first to get to the causes, but also as metformin has been added to get better response, though it could easily be used to reduce the dosage of DPP4 inhibitors if that were worthwhile.
The safety needs clarification, anyway, because DPP4 inhibitors have potential for early treatment to avoid full-blown diabetes - like statins or aspirin in their time.

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2. petros on March 22, 2013 11:55 AM writes...

While concerns are understandable. it raises the issue as to whether it will become too risky (expensive) to try and develop any new drugs for the treatment of type II diabetes.

There is clearly a need for more than just metformin and sulfonylureas but are uncommon side effects just a pitfall that has to be accepted with other therapies?

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3. emjeff on March 22, 2013 2:46 PM writes...

This is a pretty small sample considering how large the T2DM population is. That may not stop the crusader rabbits at the FDA, though.

Some actual biological data which suggests why GLP-1 drugs are toxic is the first step. After that, prospective studies may be needed.

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4. Rev. Howard Furst on March 22, 2013 4:20 PM writes...

#3, hot off the press in Diabetes magazine's "online first" section is a report on substantial (40%) enlargement and dysplasia of exocrine pancreas and weird changes in islets, found during dissection of organ donors who had been receiving GLP-1 mimetics for diabetes. Could underlie all kinds of pancreatic mischief, including neoplasia over the long term.

"Marked Expansion of Exocrine and Endocrine Pancreas with Incretin Therapy in Humans with increased Exocrine Pancreas Dysplasia and the potential for Glucagon-producing Neuroendocrine Tumors"

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5. Jasonp on March 25, 2013 2:11 PM writes...

My fear is that these issues, combined with the crippling level of hypertension related clinical studies that have to be performed, will make this entire genre of drug discovery unfeasible at a time when the need is so high. You don't have adequate treatment if folks are still sick with met, sulfa and insulin. Yet there we are stuck.

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6. John C on March 28, 2013 6:19 PM writes...

How about doctors percribing (for type two)

1. 6 small meals a day instead of three big ones.
2. Weight loss program
3. Exercise program
4. Changing what is eaten. Low glycimic foods.
5. Education and follow up.
These five steps can do much more than any drugs out there and with no side effects.

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7. JeffB on April 8, 2013 9:43 PM writes...

Pardon the cynicism, but my endocrine colleagues were very slow to accept the problems with rosiglitazone, and many remain wedded to tight control despite continuing bad news from ACCORD (

It appears to be the zeal of the faithful, certainly not science.

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8. MICHAEL on April 23, 2013 4:35 AM writes...


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