B (4:00)

Neil John I always like when I see head to head trials of medications that are on the market. This is a common problem patients who are not adequately controlled on two first line medicines, metformin and sulfonylurea and then the question comes up pretty commonly in the office what do you do next? Both these classes of agents are on the map as a what next choice? Canagliflozin, currently the only SGLT2 inhibitor on the market approved last March and acetagliptin, a DPP4 inhibitor. Both of those are reasonable choices and a good way to look at what to use when we choose our medicines is to reflect back on the American Diabetes association statement about treatment of hyperglycemia where they said we ought to think about individualizing therapy according to five criteria. The effect of the medicines on weight, efficacy, hypoglycemia, side effects and cost. Both of these medications are around the same cost side effect wise there were more yeast infections in the canagliflozin group. Both of these classes of medicines as shown in this study have a low incidence of hypoglycemia. Where there was a difference here between the two medicines, there was a slightly better profile for weight loss with canagliflozin. Remember the SGLT2 and inhibitors work by allowing glucose to be excreted or not reabsorbed in the urine. So you're losing calories through that loss of glucose in the urine. There was a slightly better effect on weight with the canagliflozin group and with regard to efficacy, canagliflozin came out ahead by about 0.3 percentage points. I think the truth is we continue to look to individualized therapy according to those criteria and canagliflozin here was a little more effective and had a little better effect on weight. I think they're both on the map as add on agents. Our next study is from Diabetes Care and it is a randomized trial of continuous subcutaneous delivery of exenatide by the IT CA650 system versus twice daily axenatide injections in metformin treated patients with type 2 diabetes. The ITCA650 system is a miniature osmotic pump system that's designed to deliver continuous subcutaneous release of exenatide at a precise predetermined rate for up to 12 months after a single placement. It is about the size of a small matchstick and it's inserted subcutaneously in the abdominal region similar to the way that for instance the old Norplant devices used to be inserted. This study was a 24 week open label phase 2 study in type 2 patients inadequately controlled with metformin. In stage 1, 155 patients were randomized to 20 or 40 micrograms per day delivery by the ITCA 650 system or exenatide bid at a dose of 5 to 10 micrograms. Stage 2131 individuals randomized to either 20, 40, 60 or 80 micrograms a day by the subcutaneous system change from baseline for hemoglobin A1C. Weight and fasting plasma glucose were evaluated at weeks 12 and 24 and the results showed that the hemoglobin A1C was significantly lower in all groups after 12 and 24 weeks. Not surprising. The mean change in A1C from mean baseline of 7.98% was minus 0.98, minus 0.95 and minus 0.72% for the 20 and 40 microgram per day subcutaneous system and the BID exenatide group respectively. Between 63 and 50% of subjects achieved A1C levels less than 7.

C (8:19)

John so this certainly has a James Bond type quality to it. And I guess James Bond has probably been around long enough that he maybe has diabetes by now, but a very, very kind of cool thing to think, geez, I'm going to put some medicine under your skin and it's going to stay there for six to 12 months and it's going to bring your A1C down a point and a half. That said, you know, we're old enough to remember, you know, the, the trials and tribulations with the Norplant delivery system and certainly I think a lot of those were related to removal. When you put the Norplant in, it certainly became encased and oftentimes you found that you had not really put them all in on the same level that you thought you had, and often there seemed to be one that was hard to remove. So I think something that would be a delivery system that's a single entity to take out would be far easier than other things. So I think this is interesting and certainly would be interested in learning more as we get closer to things like this. And I think patient tolerability might be pretty good. When you think you're going to compare I'm going to take and do a 20 minute procedure in the office twice a year as opposed to I'm going to stick myself with a needle twice a day and I'm going to get just as as good care. So I'm intrigued and more to follow. Our next article is from the September edition of Diabetes, and it looked at antipsychotic induced insulin resistance and postprandial hormone dysregulation independent of weight gain or psychiatric disease. The atypical antipsychotic medicines have been revolutionary in their treatment of mental illness, but have become stigmatized by metabolic side effects, including obesity and diabetes. Although the mechanisms underlying these metabolic defects are not well understood, it is assumed that the initiating pathophysiology is weight gain, secondary to centrally mediated increases in appetite. To determine if the atypical antipsychotics have detrimental metabolic side effects independent of their weight gain or psychiatric disease, the researchers administered olanzapine or aripiprazole or placebo for nine days to 10 healthy subjects under controlled inpatient conditions while maintaining activity levels prior to and after interventions. The researchers conducted a meal challenge and a euglycemic hyperinsulinemic clamp to evaluate insulin sensitivity and glucose disposal. They found that olanzapine, an AAP highly associated with weight gain, causes significant elevation in postprandial insulin. GLP, like peptide 1 and glucagon, coincident with insulin resistance compared with placebo. Aripiprazole, an AAP that's considered metabolically sparing, induces insulin resistance but had no effect on postprandial hormones.

B (11:13)

Neil John I think this is an important issue because currently over 5 million people in the United States are on this class of medicines. Accounting for a class of Drugs that has over $17 billion in sales each year. And it's a class of medicines that provides a very, very important beneficial effect to those who really need it, but also a class of medicines which have begun to be prescribed to groups of people, particularly children and the elderly, where the indications for benefit are less clear and the potential therefore for side effects even greater. So it's important to understand one of the main side effects, which is hyperglycemia, in more detail. It's also a group of patients often that are prescribed this medicine that aren't very good at complying with lifestyle modification to offset any of the adverse effects on glucose. What this study basically showed is that it's not just the weight gain associated with antipsychotics that cause hyperglycemia, but it's a direct effect of the, of the compounds on causing insulin resistance. I think we're going to see more research into this area and we've already seen more careful prescribing in individuals for whom there are less clear benefits. Again, I think we'll hear a lot more about this over the next few years. Our next article is from the September edition of Diabetes Care and is on adding once daily Lix eisenatide for type 2 diabetes inadequately controlled by established basal insulin. This was a double blind, parallel group placebo controlled trial of 495 individuals with established basal insulin therapy but inadequate glycemic control who were randomized to lixisenatide 20 micrograms or placebo for 24 weeks. The mean duration of diabetes in this group was 12 and a half years and the duration of insulin use was a little bit over three years. Insulin dosage was on the average 55 units a day. And baseline A1C was 8.4 with Lix Esenatide. The placebo corrected change of A1C from baseline was negative 4% and the mean A1C at the end was 7.8%.

C (13:46)

John so, you know, this is another in kind of the GLP1 family of medicines, there's an add on medicine. It had some reduction of a 1C. It really doesn't seem super duper exciting when you look at the numbers as an add on agent on what it really did to A1Cs, this particular product. Sanofi, who makes this product, had withdrawn it from the FDA to do some further testing. So it was really, I think, going to resubmit this drug in 2015. So, but I think just, you know, what you use as your second or third agent, you kind of have to weigh the risks and benefits and what are you going to get out of this particular medicine? So the GLP1 medicines can be very effective as add medicines to people on insulin. Our next article is from the September 2013 edition of Diabetes Care and looked at secular changes in the age specific prevalence of diabetes among US adults from 1988 to 2010 as part of the NHANES trial, this study looked at over 22,000 adults for three different periods, 1988 to 1994, 1999 to 2004 and 2005 to 2010. Diabetes was defined by the researchers as having self reported diagnosed diabetes or having a fasting plasma glucose level greater than 126 or an A1C greater than 6.5. The number of adults with diabetes increased 75% from 1988 to 1994 up to 2005 to 2010. After adjusting for sex, race, ethnicity and education level, the prevalence of diabetes increased over the two decades across all age groups. Younger adults had the lowest absolute increase of diabetes prevalence of 1% followed by middle aged adults 35 to 64 at 2.7%, older adults at 10%. All of these were statistically significant. Comparing 2005 to 2010 and 1988 to 1994, the adjusted prevalence ratios by age group were 2.3, 1.3 and 1.5 for younger, middle aged and older adults respectively. After additional adjustment for body mass index, weight to height ratio and waist circumference, the adjusted prevalence ratio remains statistically significant only for adults over 65 years of age.

B (16:12)

Neil John While these results are not surprising, they remain important. There's an epidemic of obesity and diabetes occurring in this country. Currently the obesity rates, what is it? About a third of adults are obese, another third are overweight and those numbers are increasing. And if you look at the statistics, there's about a 10 year lapse between the increase in obesity and then the increase in diabetes. And this study basically shows a 75% increase in the prevalence of diabetes over the last 20 years. Projections of diabetes currently are such that of every three infants born this year, one of those three will develop diabetes at some point during their lifetime. Last month we reviewed an excellent paper on the socio demographic influences to diabetes and the paper talked about things like less people walking to work, walking to school, the effect of increased calories, about 400 extra calories a day that the average American eats now versus 20 years ago, the influences of food deserts in the city. There are so many different influences that ultimately create an obese nation and in turn this incredible increase in diabetes. The answers are going to ultimately lie in less calories, more exercise. How we'll get there is anyone's guess. Our last article for this issue is from the September edition of Diabetes Care on Rapid improvement in diabetes after Gastric bypass surgery. Improvements in diabetes after Roux en Y Gastric bypass surgery often occur within days of surgery. A lot has been discussed about what the origin of that improvement is, ranging from surgically induced hormonal changes and the restrictive post operative diet as proposed mechanisms. This study evaluated the contribution of caloric restriction versus surgically induced changes to glucose homeostasis and weight loss. Their method was that they took patients with type 2 diabetes who were planning to undergo a roux en Y procedure and there were two study periods, one six weeks before surgery involving a 10 day inpatient day in which patients served as their own control for the period after surgery. The pre surgery period consisted of diet alone. The post surgery period matched all aspects of the diet except of course, patients had had the roux en y procedure. Results showed of the 10 patients who completed the study, the average age was 53, the average BMI was 51. The average duration of diabetes was a little over 7 years. Patients lost 7.5 kg during the pre surgery period versus 4 kg during the post surgery period. Their daily glycemia was more improved in the pre surgery period than in the post surgery period.

C (19:26)

John so gastric bypass and certainly we've talked about bariatric surgery in this forum and talked about it having an 80 some percent chance of curing diabetes. And so what is so magical about having a gastric bypass? Well, maybe that people take in less calories and and I know it's revolutionary to actually think that people eating less calories and losing weight can actually have a big effect on their diabetes, but certainly this proves that it does. The the problem is free will is a great burden and these folks were kind of hospitalized and kind of kept in a controlled environment and watched what they ate and certainly maybe we wouldn't need to be setting up bariatric centers all over the country if we could actually get people to eat less and lose weight.

B (20:19)

For more information and links to the articles that we discussed in this issue, just go to www.diabetesjournals until next week. Keep listening and keep learning. It.