C (4:42)

John so albiglutide was FDA approved this winter, kind of early spring. So this is a weekly GLP1. So looking at these two studies, this behaves like other GLP1s. It is fairly efficacious in regard reducing A1Cs. It certainly does not have hypoglycemia, it has weight loss and it has some nausea, vomiting, GI symptoms at a much higher rate than the other medicines we use for diabetes. So this looks like it will be a once weekly medication that will be kind of part of our toolbox and very effective. I think the second study is very surprising. So I think if we were going to say if we are going to be using a basal bolus approach with insulins and we're going to compare it with a basal once weekly GLP1, we'd certainly expect the basal bolus to be much more effective. And these really weren't even equally effective. The GLP one was more effective. So certainly if you ask our patients would you rather do something every Sunday versus take three shots a day, you know, on top of your basal insulin? You could really see that people would want to do this. And also you see, you know, you could take a medicine that's going to help you lose weight weight versus taking more insulin that's going to make you put on weight. So I think this is a very exciting study for this newer medicine. I think we're going to look later at the other glp, one agent that is waiting for FDA approval and I think when you start lining up these weekly medicines, if you can start looking and saying this one is more effective than that one, I think might be the clinical question that we might even talk about later in the show. Our next article is from Diabetes and it looked at Metformin pharmacogenomics, Current status and future directions Emerging evidence reviewed at this workshop indicates that genetic variation may be one of the most important determinants of an individual's response to metformin. The overall objective of the Workshop on Metformin Pharmacogenomics, which was sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases, was to assess the state of the field of metformin pharmacogenomics and identify key gaps and opportunities in scientific knowledge to further the understanding of metformin's clinical responses. Overall, metformin has a maximal effect that's exhibited at 2 grams per day. Most sequence side effects associated with metformin are GI, with over half of the patients being able to tolerate the maximum daily dose. However it's reported that 5% of patients are unable to tolerate any dose. In the UK PDS trial it was demonstrated that the overall risk of diabetes related death and other negative endpoints were reduced with metformin. Reduction of cardiovascular related deaths in patients on metformin in comparison with patients on other anti diabetic medicines with similar level of glycemic control was confirmed in its meta analysis. Metformin is not metabolized in the liver or kidney but rather excreted intact in the urine. The half light of the drug measured in the plasma is between 4 and 8 hours on individuals without renal dysfunction and the clearance exceeds glomerul filtration rate which is consistent with tubular secretion. Metformorin's primary reaction is through its insulin sensitizing effect in the liver resulting in a decrease of hepatic glucose output mainly through inhibition of gluconeogenesis. So looking at some of the genomics in the recent treatment options for type 2 diabetes in adolescent and youth, the Today study adolescents appear to have high metformin failure rates when compared with similar intervention studies in adults. The first and only genome wide association trial which was the GWAS trial which was conducted in metformin treated patients thus far in the Diabetes Audit and Research in Scotland, the DART study looked at 10,000 patients with diabetes and 8,000 control patients who had EMR information. Of these, 3,200 metformin treated patients underwent genotype testing. The study found considerable inter individual variation in metformin response, with some patients experiencing lowering of their A1C by close to 4%, while other patients exhibited no change or substantial increase in A1C after treatment from the study. The strongest association with metformin response was found in a variant lying in a region on chromosome 11 containing 7 genesis. One potential candidate gene is the ATM gene, which may regulate enzymes involved in the response to metformin. The largest diabetes prevention trial, the dpp, and its extension into the DPP outcome study looked at metformin and its ability to prevent diabetes. There was a variability seen in the ability of metformin to prevent diabetes. A candidate gene analysis had been reported with several variants in genes showing a nominally significant effect on the response to metformin. Of particular note were variations in genes in various pathways, supporting the relevance of the pathway in metformin's clinical action. In summary, 12 genes have been associated with glycemic control by metformin and the most reproducible associations have been known in the transporter genes. There appears to be a strong desire among patients and physicians to use pharmacogenomic guidance to help select medications in use. However, uptake in the real world is slow. In a recent survey of US physicians, only 13% of physicians reported having ordered or recommended a pharmacogenomic test in the previous six months and only 29% of physicians reported that they received graduate or postgraduate training in pharmacogenomics.

B (10:30)

Neil John, this is an interesting study and clearly, or an interesting review, and clearly this issue of individual variation is important. What happens for our patient in front of us gets lost in mean data that we see. So the UK PDS trial showed an average decrease in A1C with metformin of 1%, but that doesn't say what individual patients did. And in the other study that you reviewed and nicely went over, some patients lost 4% on their A1C while other patients actually increased their A1Cs a little bit. Some patients, 5% of patients can't tolerate metformin at all. And clearly, as this review indicated, there seems to be some relationship between response to medicine, medicines, side effects and different genomic templates. The problem is, while we'd all like a test that could tell us who's going to respond to metformin and how much they're going to respond, I think the bottom line for US clinicians is that this is interesting, will likely someday be important, but still is relegated to that future world of ideas that that really is not ready for implementation with our patients in the office. Our next article from Diabetes Care is on statins and the risk of diabetes. This article looked at a cohort of over 100,000 residents of the Italian Lombardi region who were newly treated with statins during 2003 and 2004. Patients were then followed from the index prescription of a statin until 2010. During this period, patients who began therapy with an antidiabetic agent or who were hospitalized with a main diagnosis of type 2 diabetes were identified. Adherence to statin medication was measured by the proportion of days covered with statins in their large database. Results showed that during Follow up, over 11,000 cohort members experienced the outcome of developing diabetes. And compared to patients with very low adherence to statins, those with low, intermediate and high adherence to statin therapy had hazard ratios of 1.12, 1.22 and 1.32. Or with high adherence, that 1.32 means essentially 32% increase in the likelihood of developing diabetes.

C (13:09)

JOHN so I think this is a little bit interesting. I don't think this is kind of breaking any new ground. We learned in the Jupiter trial that if you put people on a high dose statin in that particular trial, they used rosuvastatin, a certain percentage of folks will go on to have diabetes. And in this particular study they looked at a fairly homogeneous population and they found, yes, that people who were put on statins and people who were put on more potent statins were more likely to develop diabetes. And if this wasn't a statin medicine, if this is one of the other classes of anti lipid medicines which have all had kind of a pretty bad couple years with regard to outcomes, maybe you would say this might change what you do. But certainly we have volumes and volumes and volumes of data that statins make people live longer. And I think the fact that they come away with in this particular study is you would treat 250 patients for four years to have one new case of diabetes. Yet if you stop doing statins, you would certainly kind of lose that 20% protection that you've really seen across the board with all the statin trials. So certainly I think this would. The number I would remember is 250 patients treated for four years, one new case of diabetes. When the patients come in, because patients see this stuff in commercials and patients go online and they come in here and say, I don't want to take this medicine because it's going to cause diabetes, but it certainly would be throwing the baby out with the bathwater. Next up we have three articles from Diabetes Care and they look at the new GLP1 receptor agonist dulaglutide. The first trial looked at efficacy and safety of dulaglutide monotherapy versus metformin in patients with type 2 diabetes. So in this particular 52 week study which was double blinded, patients were randomized to subcutaneous dulaglutide at two particular doses or metformin. The 800 patients had a 1Cs that were greater than 6.5 but less than 9 1/2 and they were also treated with diet and exercise alone or low dose oral hypoglycemic medicine monotherapy at 26 weeks the change from baseline A1C was a decrease in 0.78 in the higher dulaglutide dose and a decrease in 0.71 in the lower dulaglutide dose. The metformin had a decrease of 0.56 so both doses were found to be superior to metformin. There was a greater percentage of patients who reached their A1C targets. There was no severe hypoglycemia reported in the dulaglutide doses. Overall, there was more cases of nausea and vomiting in the dulaglutide. Most common side effects were nausea in the dulaglutide patients, diarrhea in the metformin patients, but overall there was not a great amount of difference between the two medicines. With regard to overall GI side effects. The trial looked at the efficacy and safety of dulaglutide versus sitagliptin after 52 weeks in patients with type 2 diabetes. This multicenter double blind parallel arm study randomized over 1,000 patients with a mean baseline age of 54 years and mean a 1C of 8.1 were randomized to two separate doses of dulaglutide, the same as in the previous trial, sitagliptin 100mg a day or placebo. The patients were followed for 52 weeks. The mean A1C changes at 52 weeks was a decrease in 1.1 A1C in the higher dose of dulaglutide, a decrease in 0.87 in the lower dose of dulaglutine, a decrease in 0.39 in the sitagliptin. Both the dulaglutide doses were superior to sitagliptin. No events of severe hypoglycemia were reported the mean weight changes at 52 weeks were greater in the dulaglutide with a decrease of 3 kg at the higher dose and 2.6 kg at the higher dose compared with the sitagliptin which had a loss of 1.5 kg. The most common side effects once again in this GLP1 receptor agonist study were GI symptoms which were much more common of nausea, diarrhea and vomiting. The third trial looked at the efficacy and safety of dulaglutide when it was added on to pioglitazone and metformin versus axenatide in patients with type 2 diabetes. This 52 week multicenter parallel ARM trial randomized patients to two different doses of dulaglutide, exenatide or placebo. The patients were also treated with metformin and pioglitazone. The patient's mean baseline A1C was 8.1. The change from baseline to primary endpoint was a decrease in a 1C of 1.5 for the higher dose of dulaglutide, decrease in 1.3 in the lower dose of dulaglutid, a decrease in 0.99 for exenatide and 0.46 in placebo. Both dulaglutide doses were superior to placebo at 26 weeks and axenatide at 26 and 52 weeks. At 26 and 52 weeks total hypoglycemia incidence was lower in patients receiving dulaglutide than in those receiving exenatide. No dulaglutide patients reported severe hypoglycemia. The most common side effects once again were GI adverse side effects. The higher dose of dulaglutide seemed to have a higher side effect profile than exenatide. The lower dose seemed to have a lower incidence of GI side effects than the axenatide.

B (18:55)

Neil John, I think this set of articles along with the earlier set of articles, articles on albiglutide are incredibly exciting. This class of agents, the weakly GLP1 receptor agonists, really are emerging as both powerful and having a low incidence of hypoglycemia. So just to review what you just discussed, dulaglutide versus metformin dulaglutide has better A1C control dulaglutide versus sitagliptin a DPP4 inhibitor dulaglutide has Better A1C control and I think very excitingly or interestingly in a head to head trial with another weekly GLP1 receptor agonist, weakly exenatide dulaglutide has better A1C control. Earlier we heard about albiglutide, another GLP1 receptor agonist and we saw it compared to two other agents or a few other agents actually in the first study you talked about compared with both placebo sitagliptin and glamiparide showing improved A1C control. And in a fairly mind boggling study, head to head against three time a day lispro and patients who weren't adequately controlled on glargine, better A1C control with better weight control associ with it than lispro. I think it's obviously a class of medicines that we're just going to get used to using, but at least from this published data in this month's Diabetes Care on a large number of patients, I think the article you just mentioned on dulaglutide, the first article had over 1,000 patients, the second over 800, the third over 1,100 large numbers of patients. Well done trials. Impressive results, head to head with a number of different medications. An exciting class to begin to get experience with. The last article that we're going to be reviewing this month is from Diabetes Care on the first randomized trial comparing two patient driven approaches to initiate and titrate prandial insulin, lispro and type 2 diabetes. This trial looked at subjects 18 to 85 years of age on basal insulin plus an oral antidiabetic drug for greater than three months who had a 1Cs between 7 and 12%. Once optimized on insulin glargine, subjects were randomized to one of two self titration algorithm groups adjusting lispro either every day or every three days for 24 weeks. Baseline A1Cs were similar in the two groups, approximately 8.5%. Both algorithms every day and every three day adjustments had significant and equivalent reductions in A1C from the baseline, approximately a reduction of 1% A1C and the incidence and rates of hypoglycemia were similar for the two groups.

C (22:15)

John so in this particular study I think points out a couple things. One is that there's a lot of different ways to skin a cat and the other thing is two very tight control regimens both work the same. You know, comparing changing every one day to every three days both seem pretty intense as opposed to changing once a week or a little less often than that. So they both seem to work pretty well. I think anytime we can empower our patients to be part of the decision making process about their own disease is clearly patient centered, and it's clearly what we want to do for our patients.

B (22:56)

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