C (4:31)

John so it's very interesting. So as long as we've been studying diabetes, we've certainly been searching for a cure. So when Banting and Best discovered insulin, they really discovered a treatment and maybe a causality, but they certainly did not discover a cure. And despite all of the advances we've made in diabetes over the last 80 to 90 years, we really haven't discovered a cure. The authors were very cautious to not use a term cure, but to use the term remission. But if you're five years out from your surgery and you really have not gone back to needing diabetic medicines, you probably could talk about this as a cure. So what would be the problem of suddenly recommending a bariatric surgery to all the diabetics who are between 30 and 35? Well, one is the cost to American society. One quarter of all the people that have diabetes in the United States would fall into this mild diabetes category. So we're going to be doing an awful lot of stuff surgeries, and these surgeries were the roux en wise. This was not a study that said doing the gastric band or some kind of more simplified maneuver would certainly achieve this. But I certainly think that this is an interesting thing to think about because getting a four point decrease in someone's A1C is very, very powerful and a lasting four point decrease. And really these were folks that have been diabetics for a long time. And to actually think that somehow you're going to be able to bring their diabetes and their hypertension under control is really magnificent. I guess we will see as we go forward. Are we going to keep lowering this range? But certainly diabetes is a disease that carries great, great morbidity and mortality with it and our procedures, as we've seen when gastric bypass first came out, I used to quote to patients about a 1 to 2% mortality rate and I think now those numbers are down in the, you know, the 1 to 2 per thousand range or 1 to 2 per 2000 range. So certainly the procedure has gotten safer and probably is a safer procedure in someone who has mild obesity, as you would in these instances is going to be a better surgical candidate. Our next article is from Clinical Diabetes, the summer edition, and it looked at once weekly glucose lowering therapy for type 2 diabetes exenatide once weekly a glucagon like peptide 1, a GLP1 receptor agonist, is the first and only glucose lowering therapy indicated for once weekly administration with diet and exercise to improve glycemic control in patients with type 2 diabetes. Several GLP1 receptor agonists are available for use in the United States, including exenatide twice daily, liraglutide once daily and exenatide weekly. Exenatide weekly has been shown to provide continuous glucose control by gradually releasing the axenatide, which is the same active ingredient in the exenatide that's given twice daily. This is achieved by giving it subcutaneously in microspheres. The exenatide containing microspheres, which are about the diameter of a human hair, are made of the same material as dissolvable sutures and release exenatide by diffusion during degradation. Regular weekly administration of exenatide has been shown to result in consistent azenatide concentrations, although the peak efficacy is not attained immediately after two injections, the plasma concentration of exenatide reaches the therapeutic range to affect fasting glucose and there is a steady state plasma concentration after six to seven weeks. The clinical effectiveness and tolerability of exenatide weekly were demonstrated in six randomized active control trials with a total of over 3,000 patients in which the A1C reductions over approximately six months ranged from minus 1.3 to minus 1.9. In patients who had baseline A1C values between 8.3 and 8.5. Direct comparative trials showed that A1C reductions with axenatide weekly were significantly greater than A1C reductions with sitagliptin pioglitazone exenatide twice daily or insulin glargine, but significantly less than with liraglutide in type 2 diabetic patients already using one or more glucose lowering therapies. Exenatide weekly has been shown to reduce a 1C in combination with metformin or in combination with a thioglitazone or sulfonylurea but has not been studied in combination with basal insulin. In an extension trial, patients continuing on azenatide weekly for up to three years demonstrated sustained mean A1C reductions of minus 1.6 and weight reductions of minus 2.3 kg in the randomized controlled trials. Weight loss with azenatide weekly was similar to that of axenatide twice daily or metformin and significantly greater than that of sitagliptin, pioglitazone or insulin glargine and slightly but significantly less than that of liraglutide. Exenatide weekly has been demonstrated to improve blood pressure and lipids in addition to A1C and body weight. The average systolic blood pressure reductions of -6.2 millimeters of mercury were demonstrated in a pooled extensive data at 52 weeks. The most frequent adverse events observed with the weekly exenatide were transient GI effects such as mild to moderate nausea. The incidence of spontaneous reported nausea was 14 and 26% for exenatide weekly versus 35 and 35.4% for the exenatide twice daily. Most nausea occurred within the first two weeks of treatment and only 1% of patients discontinued the drug because of GI effects. The GI events associated with exenatide weakling may be less frequent than with exenatide twice daily and because the gradual increase in exenatide concentration approximates a dose titration. In the trials of exenatide weekly there were no events of major hypoglycemia. Injection site reactions were observed more frequently with exenatide weekly than with exenatide twice daily 7.1 versus 2.6%. Axenatide weekly is renally excreted, so it's contraindicated in patients with severe renal impairment. Axenatide weekly is not indicated for the use in patients with current diagnosis or a history of pancreatitis and is contraindicated for patients with a personal or family history of medullary thyroid carcinoma or the Men syndrome type 2.

B (11:17)

Neil John this is a helpful review of medicine that is new on the market that we're just beginning to get experience with. This really fits into our management. If we look at the recent consensus statement that we reviewed in our last podcast and which we had a discussion with the chairman of the committee on a special podcast also last month. This really fits in as a second line agent very nicely with regard to efficacy, ease of use, a low risk of hypoglycemia. It has weight loss associated with it, though it does have high cost. So those are the things that we'd want to take into account in the mix when we're making a decision about what to use. After someone no longer has a 1C control on metformin, its efficacy clearly is fairly impressive, with a decrease of a 1C of about 1.5. Weight loss is clearly advantageous 2 1/2 kg, and it was interesting also to see its effect on LDL cholesterol, decreasing LDL cholesterol by about 7%. It was also interesting to me to have clarified in this review that it doesn't kick in immediately, as some of our other hypoglycemic medications do, that it takes six to seven weeks to achieve a steady state concentration, and with that comes some forgiveness in dosing. If someone forgets to give themselves the medicine, they can give themselves that dose, the missed dose, up to four days later. All in all, it's a nice overview of a medicine that adds in a substantial way to our armamentarium. Our next article is from the summer edition of Diabetes Speaker Spectrum on improved disposable insulin pen devices, providing an alternative to vials and syringes for insulin administration. The background here is simply that insulin therapy is acknowledged to be underused in the United States, and one of the reasons for underuse is the barriers to initiation and adherence to insulin therapy and the difficulty in use of insulin. Insulin pen delivery devices may help address some of those problems. Those devices include the Solostar by Sanofi Aventis, the Flexpen by Novo Nordisk, and the Quickpen by Eli Lilly. They're generally easier to use, more convenient, and have improved medication adherence compared to traditional vial and syringe delivery. However, despite those advantages, actually their acceptance and use in the United States has been slow, lower than other parts of the world. The development of insulin pens during the past decade has really simplified the administration of insulin, and it's increased both lifestyle flexibility and actually gives greater dosing accuracy. If you look first at older patients, nearly half of all patients with type 2 diabetes are over 65 years of age and are an important group that often find it difficult to manually and visually draw up insulin syringes from vials. This has actually been studied and there is it's been shown that there's poor dosing, reproducibility and there's inaccuracies in vial and syringe delivery, and that problem is greater for older than it is for younger adults. In patients greater than 60 years of age, it's been demonstrated that the majority of patients found the functioning of the insulin pen easy to understand and preferred it for feedback future treatment over the conventional vial and syringe method. Insulin pens have also been studied in children and adolescents, and in those groups have similarly been found to be useful. Ease of use is an important criterion for patients who are insulin naive to promote early acceptance of insulin therapy and to overcome the barriers to initiation and adherence to insulin therapy, as well as fears of therapy. Ease of use in this group seems to be helpful. In fact, greater patient confidence and dose accuracy has been reported with the original flex pens and the quick pen when they were compared to the vial and syringe devices. In general, the required injection forces are lower for disposable insulin pens than they are for the traditional method of giving insulin. Unfortunately, insulin pens are used by less than 10% of the United States insulin users. The downside, of course, of pens is that they are about 25% more expensive than syringes and vials. The question, though, remains that if it leads to increased adherence, it might end up being a net savings for for the health system.

C (16:33)

JOHN so I think this is one of those issues that can be summed up with it being pennywise and pound foolish. So we found a device that works better that when you look at countries where there's one payer that people who are paying for the medicines are also paying for the hospitalizations have kind of realized that if people won't take their insulin, won't use insulin, they're more likely to have more morbidity down the line. So if we can figure out a way that you and I can teach someone simply in our office to start insulin, and I certainly don't think this is going to be for all our patients on insulin. But it's a nice way to get people started in a very simple way of things. And I think people are so overwhelmed with the whole rigmarole of drawing up vials, and certainly it lends itself much more readily for someone to make an error if they're drawing things up themselves than if they're dialing to a number that's 22 or 44 or whatever it would be. So I think this makes a whole lot of sense. I think one of the things for us, if we are new to the pens, just to remember you have to order your needles separately. Our next article is from the June edition of Diabetes Care and it looked at beta cell function preservation after three and a half years of intensive diabetic therapy. To assess beta cell function after three and a half years of intensive therapy with insulin plus metformin versus triple oral therapy in patients with metformin, glyburide and pioglitazone, the researchers randomized 58 patients with treatment naive newly diagnosed type 2 diabetes. All patients were started off with insulin and metformin for a three month lead in period and then they were randomized to either insulin therapy or triple oral therapy which included glyburide, metformin and pioglitazone. Beta cell function was assessed using a mixed meal challenge test at randomization at 6, 12, 18, 30 and 42 months. The completion rate at three and a half years were 83% in the insulin group and 72% in the oral therapy group. There was good compliance in both group. Beta cell function was preserved at three and a half years after diagnosis with no significant change from baseline or difference between the two groups as measured by the area under the curve of C peptide or the ratio of C peptide to glucose. Excellent glycemic control was maintained in both groups. The end of the study A1C was 6.35 in the insulin group and 6.59 in the oral therapy group. The weight did increase in both groups over time from 102 to 106 in the insulin group and 100.9 to 110 in the oral therapy group. There was no significant difference between the groups overall for weight and the hypoglycemic events decreased significantly over time but did not differ between the two groups.

B (19:33)

Neil John, I find this study very interesting and very provocative because I think most of us are satisfied when we have a patient with new onset diabetes to get their A1C to go, whether we determine that goal to be less than 6, 7 or less than 6.5 or as near to normal as possible. But very few of us really try to achieve completely normal blood glucose levels and probably use the data from ACCORD which showed that tight control didn't yield a better outcome than average or not quite as tight control in the group at large and even in the group that had diabetes for a relatively short period of time. We should be careful not to generalize the ACCORD data to patients who truly are new to therapy because ACORD was not patients who are new to therapy. So the results of ACCORD really don't apply to patients who are essentially drug naive with newly diagnosed diabetes which this study looks at here. Patients had initial run in of insulin, which I don't think most primary care physicians are going to do, nor would it be recommended at this point. And then very aggressive therapy not to achieve just a 1Cs that are to goal, but essentially normal a 1Cs and by so doing over a three and a half year period of time essentially had normal beta cell function. What does that mean in terms of take home points? I think there are a couple one we need to be very careful about therapeutic inertia Therapeutic inertia refers to waiting to increase therapy too long, staying still inertia when someone's A1C goes above goal and patients tend to have a great deal of time with a 1Cs that exceed goal before changes are made. That's point number one. Point number two, this is going to be very this issue of beta cell preservation is going to be very interesting to follow and see as more data comes out on it how aggressive we really should be in patients who are new to therapy. Our next article is from Diabetes Care, published online two weeks ago and it's a scientific statement from the American Heart association and the American Diabetes association on non nutritive sweeteners, their current use and health perspectives. We're going to cover this relatively briefly and and encourage you to tune in to a special podcast that we're going to have where we'll be talking with the co chair of the Committee, Judith Wiley Rosette and discuss the scientific statement in more detail. Non nutritive sweeteners are currently used by about 15% of the United States population and their use is generally intended to lead to weight loss. In substituting non caloric sweeteners for sugar based or caloric sweeteners, the question here is whether or not it's effective. The statement did not address issues of safety because safety has already been weighed in on and the non nutritive sweeteners have been deemed safe through FDA analysis. For non nutritive sweeteners to actually contribute to weight loss, it is not as simple as simply substituting something without calories for sugars that have calories, but rather there has to be no compensatory increase in caloric intake later in the day. And in fact it turns out that most studies show that there's between a 15 to roughly 30% compensatory increase in caloric intake, thereby offsetting some of the decrease or replacement of calories that occurs when a person doesn't eat a sugar based soda, juice or food. The effect of non nutritive sweeteners on body weight has actually been Inconsistent in both controlled and observational studies with some studies showing that there is weight loss and some studies showing an actually negligible effect on weight loss. With regard to effect on diabetes and glycemic Response, there were four randomized trials that varied from one to 16 weeks in duration and there was no significant differences found between the effects of non nutritive sweeteners and various comparisons such as sucrose starch or placebo on standard measures of glycemic response.

C (24:29)

John so certainly these artificial sweeteners are really ingrained in the fabric of our society and people have different preferences. There's the pink packet people and the blue packet people and the yellow packet people and people have their preferences. The use of saccharin dates back to the 1870s when it was first discovered became in more widespread use during World War II when there was a sugar shortage. In the 1970s there was question whether it was linked to bladder cancer in very very high doses. That was withdrawn in the year 2000. There were other questions with NutraSweet that there might be some cancer links and that certainly had been withdrawn as well. So I think the safety of these things in moderation is fine and I don't see any study that's really shown long term problems. One of the questions clearly is if I decide I'm not going to drink my soda that has 140 calories in it because I'm going to have a diet soda that has zero calories in it, am I then going to replace that 140 calories with chips or something else? And really with weight loss, it's math. It's how many calories in versus how many calories you burn out. So certainly this is a way for people to not take in all those liquid calories which seem clearly to be linked with weight gain. And you know, a lot of the sodas we drink have about 12 calories per ounce them, but they're not a panacea as well. I think we need to look at other things in our diet and if we're having a big double cheeseburger but we're having a diet soda with it, perhaps we're missing the point.

B (26:10)

So that's all of the articles for this week and until next week. Keep listening and keep learning.