Dr. Leahy: The ADOPT trial was a trial published in The New England Journal maybe three or four years ago and it’s kind of a modern day UK PDS, United Kingdom Prospective Diabetes Study, which was a study to give patients their first diabetes drug -- Type II diabetes -- and then follow them with time and actually see which drug was superior.  So, what was learned? 

Sulfonylureas can be effective, but they fail pretty fast.  They’re not the world’s greatest drugs.  Metformin did pretty well though it failed a little bit faster than the TZD and so the TZD was kind of interpreted to be the best and that’s how the trial was interpreted and written, though to be fair the differences between metformin and TZDs was modest enough that there’s an editorial in The New England Journal accompanying it and balanced weight gain, risk of congestive heart failure and cost of the TZD versus metformin and sort of decided maybe metformin was better.  

There’s a natural history to the disease and the natural history, we think, is related to beta cell failure.  So if beta cells continue to fail, you will no longer respond to this drug.  That’s the concept. 

So now we move into the question of durability of incretin drugs.  And the theory is they might have better durability because we know that they work on the islet cells to promote better beta cell function, i.e., more insulin secretion at a meal, better alpha cell function, i.e., less glucagon secretion at a meal and there’s this background in non-human systems, i.e., cells in animals, that you actually grow more beta cells that are thought to be healthy beta cells from these drugs.  That there is a GLP-1 physiology and probably GIP that promotes beta cells expanding in their mass -- a biology that is signaling paths that has been identified to all sorts of things.  And so the thought, and I keep saying thought or the speculation or belief -- these very touchy, feelly words -- the thought is that maybe these drugs will have better durability than what we have now. 

But if we talk about the ADOPT study, no one’s going to be able to comment on truly durability of effect of any of the incretin drugs until we get out five or more years.  And the second thing is you have to do a study that is carefully, carefully designed to compare the ongoing effectiveness of these drugs against other drugs like the ADOPT study.  So one of our problems now is the manufacturers of some of these drugs -- they’ve got groups of people who are on their therapy who choose to stay on their therapy, presumably because they work, and they follow them for a long time.  People can drop out if it stops working so they just keep reporting on the people who choose to stay in the study and the latest data we have is three years out. 

One of the GLP-1 receptor agonist drugs, exenatide, still works in a sizable number of people.  Not the five years that we need, or more, and not in a controlled trial with an active comparator so that you can say after five or six or seven years, well the people who were on the incretin drugs failed less than our other existing drugs, i.e., there seemed to be durability.  So I think the term durability is inappropriately used.  It’s thrown around a lot, saying that we know things we don’t know and, I think, for the incretin drugs there is hope that they might actually have a longer duration of effectiveness than what we’ve had before, but no data, no data that confirms that and we have to use them in the now, thinking about are they working for my patient now as opposed to thinking, well let’s put you in this drug and hopefully five years from now it will still be a good drug for you.