B (3:08)

Neil John I really like this trial Because I think it demonstrates one of the areas of importance for intensive lifestyle modification. Remember, the look Ahead trial was stopped for futility in reaching its primary endpoint, which was a decrease in cardiovascular mortality. And some people have kind of said therefore the look Ahead trial did not work. It's important to look at some of these additional endpoints that were pre specified in the trial and diabetes is one of them. To be able to decrease by 15% the incidence of depression is a using lifestyle is a big deal. Remember other studies have shown that about 25% of people with diabetes suffer from depression. And when you have depression and diabetes, your outcomes are worse, your hemoglobin A1C is worse, you have a higher incidence of complications. And in fact a couple of trials have shown that when you have depression and diabetes compared to diabetes alone, you have higher mortality. So this trial, and we're going to be talking about depression in the next trial that we're going to review, really is very important. This trial particularly shows that attention to lifestyle, meaning specifically in look ahead diet with a goal of weight loss of I believe 7%, exercise greater than 150 minutes a week as a goal really has a substantial and measurable effect in improving mood, increasing quality of life and decreasing depression. Our next study is on depression in adults in the type 1 diabetes exchange clinical Registry. In the June edition of Diabetes Care we talked about in our previous article review the incidence of depression in patients with type 2 diabetes, but but in fact not a lot is known about the incidence of depression in type 1 diabetes, which is what this study looked at. This study looked at participants greater than or equal to 18 years of age who completed an eight item patient health questionnaire, the PHQ8, which is a validated reliable measure of current depression. Probable major depression was defined in four ways. A phq8 greater than 10 a a phq8 greater than 12 according to a diagnostic algorithm or as a continuous variable. A total in this population of 4.6 to 10.3% of participants were classified as probable major depression, depending on which parameter was used. Participants classified as depressed were more likely to be female, non white, race or ethnicity, to have a lower household income, lower education level, to exercise less often, to miss insulin doses, and to have one or more complications of neuropathy, nephropathy, treatment for retinopathy or cardiovascular and cerebrovascular disease. Hemoglobin A1C was higher in the depressed individuals versus the non depressed group. Occurrence of one or more diabetic ketoacidosis events occurred in 11% of the the patients who were depressed versus 4% who were not depressed. One or more severe hypoglycemic events occurred more often in the patients who were depressed, 18% of them versus non depressed, 9% of them over the past three months.

C (6:48)

John so I found this to be a very interesting article and the specific demographics of who was more likely to be depressed probably is not entirely different than the population in general. What I think is very interesting is how we're applying health care in the future. And I think, you know, as we work in systems right now that are kind of driven by people in hospitals and people being sicker, we don't have as many clear incentives to be proactive. I think as we move towards accountable care organizations and we're looking at people who have type 1 diabetes and people with type 1 diabetes who are three times as likely to have ketoacidosis, who are infinitely more likely to have episodes of hypoglycemia, that are more likely to skip doses of their medicines. Perhaps systems will now start looking at these folks and will screen them for depression. What I think will be a very interesting follow up study is if you identified these folks who have depression and you make interventions, be it psychotherapy, be it a combination of psychotherapy and medications, do you see that difference then in ketoacidosis? Do you see that difference in hospitalizations? Do you see that difference in diabetic complications? And as we kind of move forward to systems that we might have mental health folks on site, I think will be a very kind of interesting things. And I think this can certainly apply to both type one and type two diabetics, but certainly our type one diabetics are that much more at risk for kind of larger and more acute complications. Our next article is from the June edition of Diabetes Care and it looked at beta cell failure and type 2 diabetes, postulated mechanisms and prospect for prevention and treatment. So this paper was written by a group of experts who participated in a conference in October of 2013 to look at the question of beta cell failure. There are two major pathophysiologic abnormalities that underlie most cases of type 2 diabetes, insulin resistance and defects in pancreatic beta cell function. Progressive loss of beta cell function is central to the development and Progression of type 2 diabetes. Deterioration of beta cell function predates and predicts diabetes onset and progression has been found to be genetically determined and can be predicted with some accuracy. Although the current testing are cumbersome and not well standardized. A variety of interventions including weight loss, insulin Glitazones and anti inflammatory drugs can improve beta cell function temporarily with improvement of glucose control, but the outcomes are certainly of value to patients. Although there's a limited number of clinical studies that show improvement in beta cell function in type 2 diabetes, let alone an ability to reverse it, there is some thought with gastric bypass surgery that it might reverse beta cell dysfunction.

B (9:48)

Neil John, the reason why I thought that it would be helpful to talk briefly about this conference on preservation of beta cell function is it's an area that's talked a good deal about with regard to development of new pharmacologic therapies. One of the goals, of course when we think about drug intervention is to improve blood sugars, but the other goal is to and obviously to improve outcomes. But another goal is to do so by preserving beta cell function, and no one's fully figured out how to do that yet. Though there clearly, as you went over, are a lot of mechanisms that have input into preservation of beta cell function that range from genetics to epigenetics to different mechanisms of beta cell death. We've talked in a previous podcast about the use of early and aggressive insulin therapy in patients who have new onset type 2 diabetes and potentially its effect on preserving beta cell function in so doing hopefully diminishing the amount of time that someone has glucose excursions. There have been studies on TZDs with some effect on preservation of beta cell function and similarly with both classes of insulin rather Incretin, mon and their effect on preservation of beta cell function, though none of these interventions have been shown to have sustained improvement. It's an area to be aware of because we'll be hearing more about it with regard to interventions over the next few years. Currently past hearing about it, there really aren't direct interventions that we can have at this point. Our next article, also from the June edition of Diabetes Care, is on trends in the incidence of diabetes and pregnancy and serious perinatal outcomes. This was from a large population based study in Ontario, Canada from 1996 to 2010. The authors performed a population based cohort study on over 1 million women who delivered babies in Ontario, Canada between April 1, 1996 and March 31, 2010. Women were categorized as gestational diabetes 45,000 women, pregestational diabetes 13,000 or no diabetes approximately 1 million women. The age adjusted rate of both gestational diabetes and pregestational diabetes doubled from 1996 to 2010. The rate of congenital abnormalities declined by 23%, whereas the rate of perinatal mortality did not change Significantly. However, compared to women with no diabetes, women with pregestational diabetes and gestational diabetes faced an increased risk of congenital abnormalities, relative risk of 1.86 and 1.26, respectively, and perinatal mortality remained elevated in women with pregestational diabetes. John?

C (13:07)

So I love these studies from large nationalized healthcare systems because it really is a great way to look at a population. And it's not just people who presented to this hospital or that hospital. So I find these to be very exciting. A study with a million people, certainly stuff we can take away from that. So what are some of the things we found out? Well, diabetes is more prevalent in pregnant women over this period of time. Well, diabetes is probably more pregnant prevalent everywhere over that period of time. So that's not necessarily news. Overall, why are we more aggressive with our diabetic mothers? Well, we want better outcomes for babies. And over this period of time they found less congenital abnormalities. Even though there was more diabetes, there was less congenital abnormalities that were seen in the diabetic mother. So certainly some of the interventions, whether it's being seen more often, whether it's being treated with insulin, etcetera, Seem to have better outcome. What I found to be interesting is there really wasn't a whole lot of decrease in perinatal mortality. It's not an especially high number, but much higher in the child of a diabetic mother. So we really haven't made a huge difference with that. What I found to be interesting though is that the women who were pre diabetic tended to have more congenital abnormalities and tended to have a higher perinatal mortality than the diabetic mothers. So to me, this would really say that this is probably a group we need to start looking at. If these are two of the things that we really care about. We care about mortality and we care about decreasing congenital abnormalities even further. Perhaps we need to relook at what we're doing with this population. Perhaps they need to be seen more often, perhaps they need some interventions and need to not just go into the routine care of a pregnant woman. So I think this is a very large study that will help influence policy going forward. Our next article is also from Diabetes Care and this looked at healthy behavior change and cardiovascular outcomes in newly diagnosed type 2 diabetic patients. This was a cohort analysis of the addition Cambridge study. So this population based study was of 867 newly diagnosed diabetic patients who are between the ages of 40 and 69 years of age. The patients were assessed for their physical activity, their diet and alcohol consumption. At baseline and at one year, a composite primary cardiovascular disease outcome was examined comprised of cardiovascular mortality, non fatal mis, non fatal stroke, and revascularizations. The patients were followed for a period of 5 years. Cardiovascular risk was inversely related to the number of positive health behaviors changed in the first year after diabetes diagnosis. The relative risk for primary cardiovascular events in individuals who did not change any health behaviors compared with those who adopted three to four healthy behaviors, was fourfold higher.

B (16:18)

Neil John, I love this study because the issue here is we've known for years that if you intervene with intensive lifestyle modification patients with prediabetes, you have a great effect. You can decrease by two thirds the number of people going on to develop diabetes. That's from the Diabetes Complication and Prevention trial. But what we haven't really noticed once someone develops diabetes, do behavioral changes at that point help? The Look Ahead trial, which we mentioned earlier in this podcast, that was stopped based on futility for not reaching its primary endpoint of decreasing cardiovascular mortality, made us question whether it was worth addressing lifestyle strongly with the idea of decreasing cardiovascular outcomes when someone was already diagnosed with diabetes. But remember, the Look Ahead trial looked at people who already had established diabetes for a number of years. Number one and number two, and this is important, the Look Ahead trial in essence looked at the efficacy of the intervention, not necessarily of the behavioral change, because behavioral changes also occurred in both the control and intervention group. This looked at a free living group. Some people change their behavior, some don't, and I think it's very promising. I've had many patients who say, oh, now that I have diabetes, I know you've been telling me for years, diet, lose weight, exercise, but is it worth it now? Is the horse out of the barn? And this shows that the horse is not out of the barn so that it still makes a difference. What might be important here, though, is that people were assessed in the year after they developed diabetes and the year after they were given the diagnosis of diabetes, and their changes in behavior were measured at that point. And what that showed as you just went over, John, is that if you adopted three or four healthy behaviors, decreased your weight, improved your physical activity, stopped smoking, stopped drinking, that decreased by fourfold the risk of developing adverse cardiovascular outcomes. So that's a big deal. And it reinforces the fact that in patients who are newly diagnosed with diabetes, lifestyle intervention remains a cornerstone of the approach that we should have with patients. Our next article from June, Diabetes Care is on empagliflozin as add on to metformin in patients with type 2 diabetes. A 24 week randomized double blind placebo controlled trial. Patients with A1C levels of greater than 7% to less than 10% already receiving metformin greater than or equal to 1500 mg a day were randomized and treated with once daily treatment with empagliflozin 10 mg, empagliflozin 25 mg or or placebo for 24 weeks. The primary endpoint was a change in A1C level from baseline at week 24. In addition, there was an open label portion of this trial for patients who are entering the study with A1Cs greater than 10% at week 24. Adjusted mean change from baseline A1C was negative 0.13% in the placebo group, negative 0.7% with empagliflozin 10 mg and negative 0.77% with empagliflocin 25 mg. Empagliflozin significantly reduced mean daily glucose levels and systolic and diastolic blood pressures versus placebo. Adjusted change from baseline weight was negative 0.45 kg with placebo, negative 2 kg with empagliflozin 10 mg and negative 2.5 kg with empagliflocin 25 mg. Adverse events were similar across groups. Confirmed hypoglycemic adverse events were reported in 0.5%, 1.8% and 1.4% of patients receiving placebo 10mg and 25mg respectively. Events consistent with urine infections were reported in approximately 5% across groups and events consistent with genital infections. Usually mycotic infections were reported in 0%, 3.7 and 4.7% of patients, respectively. In the open label portion of the trial, looking at empagliflozin 25 milligrams in patients with A1Cs entering the trial greater than 10%. There was a decrease in A1C at 24 weeks of 3.2%.

C (21:21)

John so I think this is a very interesting article and I think what is kind of interesting is how I've come to evolve on my opinion of these classes of medicines. And originally when we first started seeing articles about these medications I viewed them kind of as a curiosity and there's going to be lots of urinary tract infections and lots of genital infections and who would necessarily want to take these medicines. And now as more and more papers are coming out. You know, it seems to be meeting some of the things that I'm going to look for in an add on medicine. So overall we're going to have about a 0.7 lowering of a 1C when we add this to metformin. And that seems comparable with some of the other things that we use as second line agents. Seems to be very well tolerated. The UTI thing really doesn't seem to be a whole lot different from placebo. There does seem to be an increase in the mycotic infections, doesn't seem to be a whole lot of hypoglycemia, doesn't seem to be a whole lot of other side effects that we seem to worry about. So I think this is an interesting add on. I think the curiosity to me is that patient who has A very high A1C who's not on other medications, adding this medicine in and only There were only 70 patients in that particular arm had a three point lowering of A1C and I'd be interested to see if this is actually studied in its own right in those patients who we see who have very high A1Cs that we think we're going to jump right to insulin. If maybe perhaps these medications for people whose diabetes is much poorly, more poor, poorly controlled, could be something that we're going to use earlier on.

B (23:06)

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. Sa.