B (3:09)

Neil John, this is a really important article and I think presents us with a very difficult clinical dilemma. So, as you said, weight regain after weight loss is very common. In fact, when we look at most studies of dietary and lifestyle interventions, what we see is that the majority of people lose weight consistently for about six months. And then if we look at the mean, people begin to regain weight from six months to two years. If you look at that data in more detail, it turns out that about 25% of people continue to have weight loss over time, but about 3/4 of people do have significant weight regain. What does that mean for us? Clinically, it's absolutely clear that weight loss leads to improvement in cardiometabolic risk factors as well as a decreased incidence of diabetes. But this study shows us, and we've heard this before, that weight cycling, where we lose weight, then gain weight, actually increases the risk of diabetes. And here has a ratio 1.3, it increases the risk of diabetes by 30%. So the dilemma that we have is that we advise people to lose weight knowing fully that about three quarters of them, if they're successful, will regain that weight. What do we do with that information? I think to me what it means as a physician advising patients is that we need to have significant long term buy in and that the decision to embark on lifestyle modification is not a decision to be excited about this over the next one to three months, but a decision to make long term plans to be committed to sustained lifestyle changes. Because if not, our advice to lose weight might actually backfire and increase someone's risk of diabetes. So the discussions about lifestyle have to occur not over one visit, but over a few visits. The decision to embark on lifestyle modification should be one that with it comes a long term commitment and on our end, repeated office visits helping patients to sustain the motivation that's necessary to make long term changes. Our next study is on the efficacy and safety of the once weekly GLP1 receptor agonist albiglutide versus sitagliptin in patients with type 2 diabetes and renal impairment from Diabetes Care. This was a phase 3, randomized, double blind, multicenter, 52 week study. The primary endpoint was a change in a 1C from baseline at week 26 in patients with renal impairment. Patients had either mild, moderate or severe renal impairment defined as greater than or equal to 60, up to 89 milliliters per minute, 30 to 59 and 15 to 29. Baseline demographics were similar across treatment groups and renal impairment was similar across treatment groups. The overall mean age was 63 years, a BMI of 3, 30 and an A1C of 8.2. The duration of diabetes for these patients was approximately 11 years. A1C change from baseline at week 26 was significantly greater for albiglutide than it was for sitagliptin, a decrease of 0.83% versus a decrease of 0.52%. Results of safety assessments were similar across groups, though the incidence of gastrointestinal side effects was greater for oviglutide than it was for sitagliptin.

C (7:05)

JOHN so having patients of ours that are going to have CKD2 to CKD4 is a fairly common incidence in folks who have diabetes. And oftentimes we're stuck with what to do. And certainly metformin is going to be our workhorse, oral diabetes medicine. But certainly as people's kidney functions get worse, there's less comfort in using it and probably less safety in using metformin. So then we have to turn to other classes. The sulfur phono ureas are not always a great idea, especially glyburide in folks who have decreased renal function, because that might hang around for a long, long time and cause hypoglycemia. So we have to turn to some of the other agents. So for the glitazomes, sometimes with the ability to retain fluid with them, they might not be the greatest of choice either. So we're going to look at some of these new incretin based therapies. The DPP4s have been medicines that are safe to use in, in folks with renal impairment up to CKD4. I think we're also going to be cautious and depending on the drug you use, you're going to have to adjust the dose. So in this particular study they looked at sitagliptin and they gave people dose adjustments based on what the renal function. This new GLP1 receptor agonist that was approved in April by the FDA. Albiglutide is a medicine that can be given weekly and in this particular study they started at a dose and they did not base the dose based on someone's renal function. They kind of titrate it up to get better effects. So overall, what do we see that the medicine seemed to do? Both groups of medicines seem to do well, although there seemed to be a more robust reduction in A1C in patients who are long standing diabetics in the GLP1 receptor agonist arm versus the DPP4. So I think this is a medicine that you could use safely. My only kind of takeaway question with the study is there weren't tons of people in E group who had CKD4. So you know, I'm not sure I wouldn't be watching those folks a lot more closely but a newer medicine that is part of our armamentarium for using our diabetics who have impaired renal function. Our next article is from Diabetes Care and It looked at GLP1 receptor agonist or bolus insulin with optimized basal insulin in patients with type 2 diabetes. This was a 30 week open label multi center randomized non inferiority trial of 627 patients who were begun on 12 weeks of insulin optimization at the beginning of the study. For the patients who were not gotten to goal, they were randomized to either axenatide twice a day or thrice daily mealtime Lispro that was titrated to their premal glucose level. Both were added to insulin glargine which was given at a mean of 61 units per day and metformin at a mean of 2 grams per day. The patients in the two groups had A1Cs that ranged between 8.2 and 8.3. At 30 weeks post randomization the mean A1C changes were non inferior for exenatide compared with lispro with having A1C levels that decreased from 1.1 to 1.13 weight decreased with exenatide and increased with Lispro. So there was a loss of 2.5 kilos in the exenatide group and there was a gain of 2.1 kilos in the Lispro group. More patients reported treatment satisfaction and better quality of life with azenatide than lispro, although a larger proportion of patients with azenatide experienced treatment emergent adverse effects, most of these being GI side effects. The axenatide resulted in fewer nocturnal hypoglycemic episodes but much more GI adverse events than lispro.

B (10:57)

Neil John, I think this is another exciting article about the GLP1 receptor agonist class of agents. I want to step back for a minute and talk about some of the articles we've reviewed over the last few months because this is emerging and I don't get excited easily, but this is emerging as a incredibly exciting class of agents. Over the last few months we've looked at and reviewed studies from diabetes care on albiglutide versus lispro. We've looked at dulaglutide versus sitagliptin, we've looked at obiglutide versus sitagliptin versus glimepiride and in all of these studies the GLP1 agonist has done as well or better than the agents that it has been compared to in terms of efficacy in decreasing a 1C. We also earlier this year reviewed the FDA analysis that was discussed in February's issue of the New England Journal of Medicine about safety concerns. And According to the FDA's analysis, the concerns about pancreatic cancer, while it will continue to be watched, don't currently have merit. There's no indication of a significant safety signal. So what we're seeing here is a class of agents where there's an increasing plethora of studies showing that it has both efficacy better than competing agents. And I think excitingly here in the study you reviewed as efficacious as insulin, as add on bolus insulin, but yet has attributes which distinguish it from insulin and those main attributes are a lack of hypoglycemia, as we saw in this study and others, and importantly weight loss. Most of our type two diabetics are overweight. We tell them they need to lose weight, but then we're often in the position of giving them an anabolic hormone, insulin, that really stacks the deck against them that makes them gain weight. The difference in weight in this study was remarkable, losing about 5 pounds on the GLP1 receptor agonist and gaining about 5 pounds on bolus insulin for a 10 pound weight difference, which I think most of us would say is an important weight difference. So we're really seeing here in this study and others We've reviewed the GLP1 receptor agonist class of agents emerging as an extremely powerful and attractive class of agents with both efficacy as well as a lack of weight loss and hypoglycemia. Our next study from Diabetes Care is on reduced testing frequency for glycated hemoglobin A1c and its association with deteriorating diabetes control. In this study, the authors examined repeat A1C tests over 400,000 tests in almost 80,000 patients from 2008 to 2011 processed by three United Kingdom clinical laboratories, examine the relationship between retest interval and the percentage change in A1C, as well as the proportion of patients who showed an A1C rise. The data showed that the optimal testing frequency required to maximize the downward trajectory in A1C was four times a year, particularly in those with an initial A1C of greater than or equal to seven, which is consistent with our current guidelines. Testing at three monthly intervals was associated with a 3.8% reduction in A1C compared with a 1.5% increase in patients who only had their A1C tested annually. Testing more frequently than every three months provided no additional benefit compared with annual monitoring. Three month testing was associated with halving of the proportion of patients showing a rise in their A1C.

C (15:05)

John so I thought this was interesting from a public health standpoint. One of the great things about seeing any study that comes from the United Kingdom is they have such a large pool of inclusive data. So it's really terrific to look at a large healthcare system and A1Cs a little bit of the Heisenberg principle. I think if we're kind of looking at something, it probably is going to change it a little bit. So I think anything that we do that we're going to monitor a little bit closely, I think we're going to do a little bit better. And probably if you looked at people who went to the dentist four times a year versus the people who went every three years, you would probably find much better oral health. So I don't think in taking this away that I'm going to suddenly be testing my patients with diabetes who have mean a 1Cs of 7.34 times a year. I think it's a good reminder though that the patients who aren't coming in regularly, they're probably their glycemic control is not as good as I think it is and I probably need to have good mechanisms in place to make sure my patients are at least getting twice a year a 1Cs. And my patients who I really want to enact change and I want to get their level slower, probably checking a 1Cs more frequently makes a lot of sense. Our last article is from Clinical Diabetes and it looked at an evaluation of the current type 2 diabetes guidelines where they converge and diverge. The study looked at recommendations from five governing bodies that give recommendations for the management of diabetes and they were the American Diabetes association, the ada, the World Health Organization, the who, the American association of Clinical Endocrinologists, the aaca, the Indian Health Service, IHS and Center for Medicaid and Medicaid Services, or cms. They identified consistencies and discrepancies among the guidelines for non pregnant adults with type 2 diabetes in the areas of screening, diagnosis, management and prevention. The ADA, WHO and IHS guidelines recommended that adults be evaluated for type 2 diabetes if they are overweight, meaning a BMI greater than or equal to 25 and have one of the following risk factors first degree relatives with diabetes, women who delivered a baby weighing greater than £9, a diagnosis of hypertension, diagnosis of polycystic ovarian syndrome, a history of gestational diabetes or ACANTHOSIS nigricans. Under CMS guidelines, diabetes screening is covered benefit for individuals who have been diagnosed with hypertension, hyperlipidemia, impaired glucose tolerance or impaired fasting glucose or those who are obese having a bmi greater than 30. Screening is also a covered benefit for individuals with at least two of the following risk factors age greater than 65, overweight, BMI greater than 25 but but less than 30, family history of diabetes, history of gestational diabetes, or delivery of an infant greater than 9 pounds. One major difference among the guidelines is that the ADA, AACE, and IHS guidelines include an A1C greater than 6.5 as diagnostic criterion for type 2 diabetes where the WHO and CMS guidelines do not. For management, all five sets of guidelines are in agreement that patients can benefit from medical nutritional therapy and diabetes self management education. For medical management only, the ADA guidelines specifically recommend initiating metformin therapy at the time of diagnosis for patients and whom it is not contraindicated. The AAC guidelines recommend several medications that can lower fasting plasma glucose and postprandoglucose, but it does not prioritize which medicine should be initiated first at the time diagnosis. In addition to starting glucose lowering medications that affect glucose metabolism, the ada, who, ace, and IHI guidelines also recommend initiating aspirin therapy. The ada, aace, and IHS guidelines also recommend that patients begin taking a statin regardless of their baseline lipid levels unless contraindicated. For target glycemic control, the ADA, WHO, and IHS guidelines recommend an A1C of less than 7. The AACE guidelines recommend an A1C less than 6.5. A comparison of the blood pressure, blood glucose, and lipid targets recommended in the ada, who, A, ce, and IHS guidelines are listed in the paper and are all fairly equivalent. In patients with chronic diseases, immunization should be kept up to date to minimize the risk for complicating infections. The ada, IHS guidelines recommend that patients living with diabetes have an annual flu shot. The pneumococcal vaccine and hepatitis vaccination series are also recommended. These recommendations overlap with current recommendations from the cdc. In addition, the CDC and IHS recommend that patients living with diabetes be immunized with zoster and a tetanus vaccine for prevention to prevent people with diabetes prediabetes from progressing to type 2 diabetes, the ADA, WHO, ACE, and IHS guidelines suggest lifestyle interventions such as physical activity for at least 150 minutes a week and smoking cessation. The ADA and AACE recommendation of starting metformin when prediabetes is identified, but criteria for initiating this therapy differ between the two sets of guidelines.

B (20:40)

Neil John it's interesting. Even in this age of evidence based medicine where we have lots of information, lots of data, there's still differences among the different guidelines because the evidence is often incomplete. The guidelines are still important though, and I'm reminded of a story of an army platoon that was lost in the Alps when one of the soldiers found deep in his backpack a map. They made it down and when they got down to base camp they were asked how did you find your way to base camp? And they said, well, we found a map in the backpack. When one of these soldiers looked again at the map, turned out that it was for a different part of the mountain chain. And the lesson there, and the saying that has come from that is any map will do. And the important thing when we look at differences in the different guidelines isn't always what the small differences are, but rather that you adhere to some set of guidelines. Any map will do that. When we have direction, we'll continue to check patients, we'll continue to advise patients, and that itself eclipses the minor differences in the guidelines. Next thought, where are the important differences in these guidelines? I think there are three important differences that rise to the top. One is the difference between the American Diabetes association and the AACE's recommendations for A1C targets American diabetes is less than 7. AACE is less than 6.5. The less rigorous target comes from data from the ACCORD study that intensive treatment didn't yield a better benefit. But it's important not to lose the American Diabetes recommendations that for younger patients who are healthy with no comorbidities, a more rigorous A1C control may be beneficial. Next, what medicine to use first? The AACE is more lenient in individualization and choices with regard to first medicine versus Metformin in the ada, although I think we'd often use Metformin first when given full choice. And lastly in this article there was mention of blood pressure goals using the old goal of 130 over 80. But in fact the current ADA guidelines recommend that for patients with diabetes our blood pressure goals and this was also in last year's JNC8 guidelines is simply 14090 the same as it is for everyone else. But it's important, as I said, the differences are less important than the similarities and we often care of patients before following clear guidelines. 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.

C (23:55)

SA.

B (24:21)

Sam.