Introduction

Welcome to this discussion among endocrinologists/diabetologists in which we will review information presented at the 2007 ADA annual meeting and discuss up-to-date treatment practices for diabetes. We will ask you to comment on specific pharmacotherapies including exenatide (Eli Lilly's Byetta®) and sitagliptin (Merck's Januvia™). We will also inquire about your opinion regarding medications and other technologies that are in the developmental stage. Panel Intelligence discussions are enhanced when you, as a panelist, not only respond to the posted questions, but also reply to comments made by our moderator and your fellow panelists. We look forward to a lively and interactive discussion. Please note: In your participation on this panel, Panel Intelligence expects and requires that you comply with the terms of the Consultant Confidentiality Agreement to which you previously agreed. If you have any questions about the terms of that agreement, please review them through the link provided on your Panel Intelligence home page after you've logged in.

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Please review abstract about exenatide  (Appendix A)

Q1: Exenatide

Please review the attached abstract about exenatide. Please describe your experience with exenatide over the past year. Have your outcomes been consistent with those seen in the abstract? If not, how have they differed? Please describe the strengths and weaknesses of the medication from your perspective. How do you anticipate that the use of exenatide will change in the next year? The next three years?

Panelist 6: I might have missed this but did the abstract report on the placebo experience? My guess would be that they gained weight, had worse control, etc. but it would be important to see that comparative data in order to gauge the byetta effect. I have about 18mos experience with patients on Byetta. About 3/4 stick with it (at significant cost) while 1/4 drop it d/t GI effects. Most seeking it are women concerned with weight gain on traditional therapy. Weight loss in my experience has been similar (2-3kg usually fairly quickly). I have not noted the sustained weight loss effect but many of my patients have gone on to needing insulin which confounds the question. I still see it as niched to about 2.5% of my patients. I don't really see that changing in the next 3 years.

Panelist 2: The abstract is just the yearly presentation of their open label study. There is no control group. As always, they do not state the number of dropouts. Actually, by year 2 there was a 50% dropout rate. These were for loss to followup and such. So, as in all studies of this type, the people doing well are there and the ones who did not are gone! Have used a lot of exenatide in the past year - it is the standard second drug after metformin for me, at least for most patients. It is not really possible to compare to the abstract, other than to say, the patients who are doing well on it long term are doing well on it long term. The ones who are not are not taking it! It will probably decrease in use when the qd meds are out.

Panelist 7: Presumably there is a control group. The authors should have reported changes in weight, HbA1c, and FPG in this group for comparison. It is difficult to judge the importance of these results without this information. The continuing weight loss in encouraging but if it plateaus at around 5 kg this will not have much effect on the problem of obesity in persons with diabetes. These effects are not dramatic but I would expect exenatide use to increase since it is a novel treatment and therefore of potential use in persons with diabetes refractory to other therapies.

Panelist 2: There is no control group. It is open label extension.

Panelist 8: My experience with exenatide (E) in T1D (majority of my patients) is limited. While a significant proportion of T1D patients would benefit from E, their already intensive insulin therapy is barrier to E use. I'd welcome a dual delivery insulin pump that would allow for E bolusing. I'd rather see this development than a more widespread use of slow release GLP-1 analogues or DPP4 inhibitors in T1D.

Panelist 1: As per previous responses, open label extension data are not always robust. Regardless, my ongoing experience is extremely favorable. Few dropouts and continued wt. loss in most, but not all. patients. Considerably better response than with Januvia. One reviewer commented on use n T1D - never tried.

Panelist 1: This question has already been responded to and recorded despite system claims to the contrary.

Panelist 9: I have a more limited experience with this medication - maybe 1 -1.5 yrs. My experience shows that ~20-25% drop use of exentide, either within a short time of onset of use because of nausea. Others stop taking it after a longer period of use when they see they they have not lost a lot of weight (the initial impetus for use was weight loss). Generally A1c goes down 0.5-0.8% not 1% as the authors say for those who stay on the med for a long (> 6 months) time.

Panelist 5: The abstract does mirror much of my clinical experience with Bytetta. Most of the patients i have used it in has been as an add on to one or two oral agents and in the vast majority this has resulted in improvement in HBA1c ranging from 0.5 to up to 2.0 depending on the initial baseline. About 50% of my patients have had at least 5% sustained weight loss, some have had much more and even in those who have been weight neutral the HBA1c improvement has often still occured. I anticipate exenatide slowly moving to more earlier use in the treatment algorithm and it may ultimately have a role in diabetes prevention among subjects with pre-diabetes.

Panelist 3: I am concerned about the claims of long lasting benefits and weight loss when this is a highly selected group of "responders". This is not good science. Yes, there are good responders to all drugs but identifying them is difficult

Panelist 10: My exerience is generally consistent with the puiblished trial results. I guess 10% can't tolerate. It doesn't have super efficacy in part because the duration is short- very weak fasting glucose effect. short term utilization will stay constant, but long term this will be displaced by long acting GLP-1 agonists.

Panelist 11: Unfortunately, our formulary at the VAH where I work has not included this drug on the formualry, therefore I have no personal experience with the drug. However, I can comment given my interactions with my colleagues. The acceptance of the drug in the endo community has been high among my colleagues. Surprisingly, the necessity for twice daily injection and the early onset nausea has not been an impediment for our patients. The continuous weight loss and continuing effectiveness over long periods has been especially appealing. The general experience has been consistent with the abstract. It is important to note that success in long standing type 2 patients with failing beta cells will not be accomplished. I anticipate that there will be continued acceptance over the next several years but the availability of the LAR preparation and DPP IV inhibitors will cut into the number of individuals on this drug.

Panelist 9: Our formulary is also limited. My experience is that it is particularly overwieght women seeking the medication. Taking 2 shots a day or even 3-4 shots a day matters not as long as they have the perception / illusion that they will lose weight

Other uses of exenatide

The following suggested potential uses of exenatide were mentioned in the discussion: • The use of a dual delivery pump containing insulin and exenatide for patients with type 1 diabetes. • The use of exenatide in patients with glucose intolerance/pre-diabetes What are your opinions of these clinical scenarios? Would you consider using exenatide in these situations? Would you recommend that further studies be conducted in these areas?

Panelist 10: The use in prediabetes might be a bit of a stretch. The experience with diabetes prevention trials has been abysmal in terms of persistance of patients on drug. Ranging from ~50% to 70% with Xenical and Metformin. I would expect less with Byetta. The idea of coadministration is interesting. It could get around the peak effect which I think leads to nausea and would have more durable effects. Presumably the effects in patietns with T1DM would be exclusively due to glucagon suppression.

Panelist 6: I think it would be a tough sell to offer in pre-diabetes. Metformin would be my choice (and I'm sure my patients'). Hadn't really thought about a dual-action pump. Might be interesting but certainly niche.

Panelist 2: As far as pump - using symlin makes more sense. There is no need for the beta cell action as patient is on insulin. Symlin gives same effect. For prediabetes - AFter studies - sure. But, shots at that point are a stretch - though would give it cover for those who use it for weight loss.

Panelist 11: It is unlikely that in the face of almost complete destruction of the beta cells that the primary efficacy of exenatide would be demonstrated. However, the supression of glucagon, decrease in appetite and slowing of gastric emptying might be adjunctive to insulin infusion, but this is highly speculative. It has not been demonstrated that islet neogenesis is possible in far advanced immunological destruction. In impaired glucose tolerance in individuals at risk for type 2 diabetes the likelihood of benefit is high in prevention or delay of diabetes.

Panelist 7: Research would have to demonstrate a role for exenatide in prediabetes. We would be talking about a DPP-like study. Very expensive and hard to do. I don't have an opinion about the dual delivery pump. Again, if data supported its use, I would consider it.

Panelist 1: DM1 - bolus short acting insulin would be much easier to use than a dual hit with 2 different agents. Poor prognosis. Pre-diabetes: doubt if injection therapy has a ghost of a chance - especially wothout data indicating a future beneficial effect on either small or large vessel vascular disease.

Panelist 4: It is being used by some practitioners for prediabetes-I think we need to wait for data

Panelist 8: both applications sound reasonable (I proposed the former)

Panelist 5: I am not very convinced on the utility of continuous infusion of exanatide via a pump for type 1 diabetics. I think the greater utility in this settign would be to have a dual delivery pump containing symlin which has virtauuly all the salutary effects asssociated with exenatide and is already approved for use in type 1 diabetes. As regards the potential utility of Byetta in pre diabetes i feel it does have considerable potential here especially since it is associated with weight loss, and a beta cell preseravatory effect.

Symlin® (pramlintide)

One panelist mentions the use of Symlin with insulin. Please describe your current use of Symlin. Which patients receive the therapy? Please comment on its efficacy. Is it well-tolerated?

Panelist 6: Have not been using it much at all. Rarely use it to help with difficult to manage hypoglymcemia in type I's close to goal.

Panelist 2: Use is some Type 1 with the short acting insulin - but that means 7-8 + shots per day. It can help a little, but not great. On the other hand have been starting to Use in Type 2 with lantus and no short acting insulin and it works great - much easier than premeal insulin. It is about to get FDA approval for this.

Panelist 10: we have used it in some patients with T1DM but more wit T2DM. Seems well tolerated with effects on appetite and works as adjunctive therapy with insulin to control blood sugars. We don't have a lot of patients on this combination.

Panelist 1: No experience.

Panelist 9: I have never used it. given that people who could benefit from it are taking 4 shots a day - the addition of 3 more shots is cruel and unusual punishment.

Panelist 11: Pramilinatide is a synthetic amylin and is useful in slowing gastric emptying and inhibiting postprandial glucagon. It is useful in the intensively controlled insulin using diabetic. It is most useful in attaining additional postprandial glycemic reduction especially in type 1 patients. We helped develop the use of this drug at my former university but I have no recent experience with this therapy.

Panelist 7: No experience.

Panelist 5: We use symlin quite frequently in our type 1 population and less so amon our type 2s (where exenatide is the preferred incretin). Many of our type 1 that use it have pumps so that in fact they only have to do three injections. It has generally been associated with not only a 0.5-1 unit HBA1C drop in our hands but also a variable reduction in total insulin requirement as well as reduction in glycemic swings. For the vast majority of subjects we have on it..it is well tolerated. The main issue with our type 1s has been to reduce insulin doses when starting it to prevent development of hypoglycemia.

Panelist 9: Should this be used in type 1? No, there is no endogenous insulin production. Use in "pre-diabetes" - for this to happen we will need a sea change in thinking about glucose disorders - ie that newly diagnosed DM is an end stage disease not an "early" disease and that it would make sense to "prevent" newly diagnosed DM in high risk people. Given the expense of byetta and the "needle" associated with its use for someone without clinical DM - I, for one, cannot see this happening any time soon.

Exenatide LAR

There was a paucity of abstracts about exenatide LAR at ADA. Why might explain this lack of data? Have there been changes in exenatide LAR’s development status?

Panelist 10: The trial is in progress as far as I am aware and probably they didn't have any opportunity to analyze data. I haven't heard of any delays.

Panelist 6: I thought the LAR trials had not been completed yet. I have not heard anything to date.

Panelist 2: The trials continue - it is just not ripe.

Panelist 11: As far as I know, data are to be presented in Europe. Development seems to be on line.