Dr. Leahy: Incretin hormones have a biology that far, far is outside simply regulating islet function.  GLP-1 receptors are in most of the tissues of the body and when you give GLP-1 in pharmacological amounts a lot of things happen.  Perhaps one of the most interesting and one of the ones which has helped define a favorable clinical profile of the GLP-1 drugs is there are GLP-1 receptors in the feeding centers of the brain and either in animals or humans when you give GLP-1 therapy there is a satiety affect.  There’s probably an effect also on actually optimizing glucose regulation and peripheral tissue somewhat, i.e., improving insulin sensitivity and the bottom line is that people lose weight. 

Now the fact that sulfonylureas are associated clearly not with weight loss and maybe weight gain is just sort of a different biology because they don’t have an affect on feeding that anybody knows and then this issue of weight gain it’s sort of a generic issue with many diabetes drugs not simply sulfonylureas.  Part of it we’ve argued for years is that if people are hyperglycemic enough that they spill glucose in the urine if you now give a therapy, any therapy -- insulin would be another clear prototype -- and drop their blood sugars below a renal threshold then they now hang on to more calories they eat and it’s like they’re eating more even though they’re not.  So that’s one issue and that has been legitimized by research for many years. 

But the second issue is that there is this feeling that drugs that promote insulin secretion are potentially associated with weight gain maybe because of risks of lows, maybe a patient essentially just eats to try and avoid lows especially during the day when they’re physically active.  There is this sort of background behavioral biology people think about with these kinds of drugs that may promote some weight gain. 

So the actual mechanism we could argue about it doesn’t really matter.  There is a clear sort of defining profile of drug effects -- GLP-1 receptor agonists for the most part are associated with weight loss, certainly many patients.  The DPP-4 incretin drugs probably not more associated with weight stability, not drugs we think about with weight gain.  And drugs like sulfonylureas and probably insulin in many patients associated with some modest weight gain.