C (6:10)

John so basically this study is looking at a low fat Diet versus a Mediterranean diet, as we learned from the Lyon heart trial, which had a 76% decrease in repeat cardiovascular events in a high risk population, put on a prudent Western diet versus a Mediterranean diet, found that the Mediterranean diet did so, so much better. And what we're finding in here, in the avenue of diabetes, yes, it does better. So a low fat diet that does not really look at car does not do as well as a Mediterranean diet, which is going to emphasize certain fatty acids, so monounsaturated fatty acids. So we're going to talk about olive oil, we're going to talk about nuts, we're going to talk about fruits, we're going to talk about fishes, and a lot of the things that are going to be very beneficial for our patients. So, yes, there are a lot of different diets that come and go. The Ornish diet, the Atkins diet, the Paleo diet. But I really think in so many studies, the Mediterranean diet really shows some prudence, probably for all of our patients. And even if you look at the French, the French, who might smoke at a higher rate than the United States, who might eat a fattier diet than the United States, in many ways have a lower risk of heart disease. And probably a little bit of that French paradox is having some red wine and having more of a Mediterranean diet than our diet of Big Macs and Coca Cola. Our next article is from Diabetes Care, and it looked at prandial options to advance basal insulin glargine therapy. Testing lixisenatide plus basal insulin versus insulin glulysine, either as a basal plus or basal bolus in type 2 diabetes. This was the GetGold Duo 2 trial. So in this particular study, patients were randomized to luxenatide once daily, insulin glulysine given either once or twice daily. They were both added to glargine with or without metformin. And the researchers tracked A1C reductions and weight loss. The areas that they were looking at was a 1C reduction with lixazenatide vs. Glu lysine in the once daily, the lixazenatide vs glu lysine in the thrice daily, and changes in body weight. The baseline characteristics between the two arms were similar. The patients had diabetes for an average of 12 years and had been on basal insulin for about 3 years. With glargine optimization, the A1Cs improved from 8.5 to 7.9 and with lixenatide down to 7.2, with blue lysine once a day down to 7.2 and with glu lysine down to 7.0. All the other CO primary endpoints were met. Symptomatic hypoglycemia and body weight were lower in lixazenatide versus the glu lysine patients, but they found more gastrointestinal events with the lixexenatide.

B (9:10)

Neil John this is another piece of evidence supporting the importance of GLP1s as in many ways a preferable next step after patients are not to goal on basal insulin alone One of the important gaps in care primary care is what to do with patients who are not to goal and this is over 50% of patients on basal insulin alone when used after oral therapy is no longer working. Typically what we used to do was go to basal bolus therapy at three times a day rapid acting insulin and then research showed that about 70% of patients could be controlled as well as they would be with basal bolus using only one rapid acting shot of insulin before the largest meal of the day. Nonetheless, it's a cumbersome approach because of issues with hypoglycemia and weight gain associated with the addition of rapid acting insulin. Therefore GLP1s have been looked at as an option to be used instead of one or three times a day rapid acting insulin added to basal insulin. This trial examined how GLP1, particularly lixisenatide worked when compared to either once a day or three times a day typical basal bolus therapy and it worked very well. So when we looked at as you went over lixisenatide instead of either once daily or three time daily rapid acting insulin and patients were not controlled to go on basal insulin alone. Lixisenatide had less weight gain and less hypoglycemia associated with it with the same outcomes with regard to A1C. So we've seen similar outcomes with other GLP1s, exenatide, albiglutide and elixisenatide showing that really GLP1s are emerging as the option of choice for patients who are not controlled to go on basal insulin alone, providing equal a 1c decrease with less hypoglycemia and without the weight gain that is typically associated with the addition of rapid acting insulin. Our next article from Diabetes Care is on text message support for weight loss in patients with a randomized clinical trial. In this trial the authors looked at both English and Spanish speaking patients with prediabetes and they were randomized to a control group which only received an invitation to Diabetes Prevention Program Classes in a defined curriculum or to the same classes augmented by text messaging. And in those text messages, they received messages adapted from the curriculum. For the full 12 months, mean weight decreased by 0.6 pounds in the control group and 2.6 pounds in the intervention group. 3% weight loss was achieved by 21% of participants in the control group, compared to 38% in the intervention group. JOHN so I think this is a.

C (12:35)

Very interesting study on two different effects, and I think one is the concept of the Hawthorne effect. So when anyone thinks we are observing them more closely, I think they're going to change their behaviors. And so in the group that really kind of felt that someone was kind of watching their weight loss and sending them text messages and things like that, I think that is going to have a bigger impact. I think the second is technology. And we are really faced with a crossroads here in medicine. So when you're looking at pushed versus pulled data, so the push data is we're sending people text messages with the same amount of information versus the pull data is they have to go to a class and attend a very good diabetes education class. So when we look at medicine as an industry, we have not really adapted to technologies quite the way that any other industry has. So once upon a time, banks had banker's hours and certainly now we do banking 24 hours a day. We do ATMs, we check our banking account online. And most of us can't remember the last time we were in a bank, which used to be something that we did every two weeks. So I think in medicine we are going to have to think about being more and more creative and using this amazing technology to get patients information that is going to change their behaviors that happen on a daily basis. Our next article is from Diabetes Care and it looked at predisposing factors for any and major hypoglycemia with saxagliptin versus placebo. And this is analysis from the SAVR TIMI 53 trial. So in this particular trial, patients with type 2 diabetes were randomized to saxagliptin or placebo and were followed for a medium of 2.1 years. There were over 16,000 patients in the study. And associations between any hypoglycemic event so that would be symptomatic or glucose measurement less than 54 or major hypoglycemia requiring extended assistance were analyzed with patient characteristics overall and by the treatment allocations that were given. So overall that they found that the patients had one at least hypoglycemic event 16% of the time and a major event 1.9% of the time. The patients who were allocated to saxagliptin versus placebo experienced higher rates of any hazard ratio of 1.16 for hypoglycemia and major hypoglycemia hazard ratio of 1.26. Hypoglycemia rates any or major or increased with saxagliptin in patients that were taking sulfonylureas but not in those taking insulin. The rates were overall increased with saxagliptin in Those who had a 1Cs at baseline under 7 but not those who had baseline a 1Cs greater than 7. They found that independent predictors of any hypoglycemia were as follows. Allocation to the saxagliptin arm a long duration of diabetes increased, updated A1C macroalbuminoria, moderate renal failure, sulfonylurea use and insulin use. Predictors of major hypoglycemia were allocation to saxagliptin, advanced age, black race, reduced bmi, long duration of diabetes, declining renal function, microalbuminoria and use of short acting insulin.

B (15:56)

Neil John Hypoglycemia has emerged over the last five years as a critical issue. We've known for as long as we've had glucose lowering agents about the short term effects of hypoglycemia that it can make someone feel bad, shaky, tachycardic, even pass out. But in addition to those short term effects, there's now robust evidence about long term negative effects of hypoglycemic episodes. And there's data showing that severe hypoglycemia is related to both decreased cognition over time, increased incidence of dementia and even increased incidence over three to five years of adverse cardiovascular outcomes, including cardiovascular death. So it's an area of critical importance for us all to pay attention to. It's not surprising that even a medication that has a low incidence of hypoglycemia, saxagliptin, when given in addition to other hypoglycemic agents, will cause some hypoglycemia. And it also is not surprising but important to recognize that that occurs more often when used in association with medications that have a high incidence of hypoglycemia, particularly the sulfonylureas. Also, of course we ought to be always careful about adding medicines when patients have low A1Cs to begin with. In this case, A1Cs less than 7 again showed a higher likelihood of hypoglycemia than when the medicine was started. In patients with A1Cs over 7 long duration of diabetes often is linked with less reserve and less ability to maintain homeostasis in the event of minor amounts of hypoglycemia. So the association there makes sense and also patients who had moderate or even severe renal failure. Because we know that many of the oral hypoglycemia are cleared renally and therefore or accumulate if used in patients with renal failure. It's a nice article that reminds us to pay attention to predictors of hypoglycemia. Our next article from Diabetes Care is on the association of weight loss maintenance and weight regain on four year changes in cardiovascular risk factors. The authors here looked at data from the Look Ahead trial, which was a large randomized trial of intensive lifestyle intervention compared to control in overweight and obese individuals with type 2 diabetes. In this study, the intensive lifestyle participants were grouped into six different categories according to weight change patterns. Category one was no weight loss. Category two was moderate weight loss 3 to 8% at both years one and four. Category three was large weight loss, 8 to 20% of body weight loss at years one and sustained through years four. Then category four was moderate weight loss at year one 3 to 8% but full weight regain by year four. The fifth category was a large weight loss initially and full regain of weight by year four and finally a large initial weight loss and partial regain of weight. And then they looked at these groups and compared the changes in cardiovascular risk factors, adjusting for baseline differences in medication use. Larger weight losses produced Greater improvement in A1Cs systolic blood pressure, HDL cholesterol and triglycerides at years one and four. Important here, there were no negative associations of losing and then regaining weight relative to not having lost weight at all. Moreover, those who had a large initial weight loss but full regain of weight still had greater improvements in A1C levels at year four than those with smaller or no initial weight loss.

C (20:02)

John so overall it's probably very hard for any of us to understand what resources we should be listening to when it comes to weight loss and weight gain and things like that. There are all these TV shows that like the Biggest Loser where people lose all this weight, and we certainly see things in television about how these people put all this weight back on and how horrible this is. So just looking at this particular study through our diabetic lens, certainly we found out for lots of studies that tighter control in diabetes early on leads to better things down the road than worse control up front. And I think this certainly goes with this, that if we can have that period of time, even if it is a fleeting period of time when people have lost weight and are doing better, that it does resonate down the line. And I think so. This is consistent with other things that we found in diabetes that if we can front load anything, be it weight loss, be it glycemic control, etc. That we will have some impact down the road that we might not necessarily expect. So certainly getting people to try to lose weight early, even if they put it on, is a good thing. And I think this study probably can be best summed up from Alfred Lord Tennyson. It's better to have loved and lost than never to have loved at all.

B (21:21)

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. It.