B (5:15)

Neil John this is a pretty startling and frankly pretty scary set of data. We've known for years that patients with type 2 diabetes have a higher instance of cognitive impairment and eventually dementia than patients who don't have diabetes. And we know from a subset of the ACCORD trial that in that group of patients, the tight versus usual control that was looked at in the ACCORD trial didn't lead to different outcomes. But the data isn't there to the same degree with type 1 diabetes. The fact that 28% of patients with type 1 diabetes by middle age, or a number that's five times higher than that in the average population, suffer from identifiable cognitive impairment is scary. And in fact, when they looked at that, this is the same number of people over 25% that in a non diabetic population, the average 85 year old cohort actually has of cognitive impairment. What's really interesting though is the breakdown of which patients with type 1 diabetes were at higher risk. And it really does appear to be patients who did not have as good control for a long period of time. So it was those who had a 14 year average, a 1C greater than 7.5%, those who had proliferative retinopathy, those had polyneuropathy and an abnormal ankle brachial index. And so really what do you do with this information? What this information really makes you want to do is even harder and more so than before. Work with our type one diabetics, have this information conveyed so that patient with type 1 diabetes knows about this as another reason to really be meticulous in the care of patients with type 1 diabetes and try to achieve as good sugar control as is safely possible. Our next two papers are on euglycemic diabetic ketoacidosis, a potential complication of treatment with sodium glucose cotransporter 2 or SGLT2 inhibitors. And the second of the two papers is on diabetic ketoacidosis and related events in the Canagliflozin type 2 diabetes clinical program. Let's first go over the first paper on euglycemic diabetic ketoacidosis with SGLT2 inhibitors. This trial was basically started because one of the authors noticed an unusual case, a case of DKA with normal blood sugars, and then contacted some of her colleagues who in turn said that they also had seen cases like this. And so they put together a case series and reported them. They identified 13 episodes that occurred in nine individuals of euglycemic DKA, that is DKA with normal blood sugars. Seven of those were in type 1 diabetics and two in patients with type 2 diabetes from practices across the United States. Absence of significant hyperglycemia in these patients delayed recognition of the emergent nature of the problem and delayed appropriate treatment with insulin. Let me give one example of these nine cases. Patient number two was a 58 year old man with type 2 diabetes who received canagliflozin without any insulin, who was admitted for an elective sigmoid colectomy and was discharged on his original dose of canagliflozin, 300 milligrams a day. Five days after discharge he was readmitted with severe abdominal pain, vomiting, hyperventilation and poor oral intake. Initial lab studies showed a sodium of 133, an anion gap of 17, a glucose of 150, a bicarb of 10 and a creatinine of 1.1. Lab studies 15 hours later on the same day showed a glucose of 164 and serum osmolarity of 3. During the next 24 hours his blood sugars ranged from 150 to 180. Because of his recent colectomy, he underwent an exploratory lap that was unrevealing after other etiologies of anion gap acidosis were excluded. He was treated for euglycemic DKA with IV insulin and fluids and had resolution of his acidosis. This type of story with patients coming in not identified as being in dka, needing insulin because of normal blood sugars and then getting better once the diagnosis was thought of and they received insulin and were treated like DKA is repeated throughout the different case descriptions, again most of them in patients with type 1 diabetes on both insulin and SGLT2s, but a couple of the cases in type 2 diabetics. The next study on diabetic ketoacidosis and related events in canagliflozin's type 2 diabetes clinical program looked at all serious events of DKA and related events from the 17,596 patients in randomized studies of Canagula flosin through 11 May 2015. Serious adverse events of DKA and related events were reported in 12 patients. That's 0.07% including 4, 6 and 2 treated with tenagliflozin, 100, 300 milligrams and a comparator respectively. Corresponding incidence rates were very small, 0.5, 0.7 and 0.2 per thousand patient years respectively. Most patients with DKA and related events had blood Sugars greater than 300 at presentation of DKA, were on insulin and had DKA precipitating factors, including some with latent autoimmune diabetes of adulthood.

C (11:32)

Sean wow. So that was a lot of information and I'm going to give you my take on how I think we need to apply that. So certainly when we see any new class of medicine we are going to see some post marketing issues that arise and certainly we're not going to know what to expect when medicines come out. So the second paper that looked at canagliflozin and DKA in type 2 diabetics, their takeaway point was a lot of these folks had type 1 diabetes and probably shouldn't have been on canagliflozin in the first place. And their overall incidence of decay was probably about 1 in 1100, 1 in 1200 patients. And they all had very high sugars. And I think most of us as clinicians, if we had someone with very high sugars, a low bicarb, we would be thinking potentially that this person could have DKA and not a reach for that. The first paper kind of, you know, a group of endocrinologists saying hey, we're seeing something that doesn't make a whole lot of sense. Have you seen that as well? I'm not sure most of us as the average clinician would leap to think that someone had a euglycemic dka. And I think this is a nice warning point for all of us in this new class of medicine that this is something new we need to be looking at. I also think in the first paper it, it also many of these cases seem to happen in a post operative period. So one of the things I might think about is really having folks off my SGLT2 inhibitor, maybe a week or 10 days, much like an aspirin, to really allow that to get out of someone's system before they're going to the operating room. And we all know so many different variables are changing when someone goes to the operating room and when we have folks on these new medicines. I think we need to be mindful of this and perhaps there's some additional testing we need to see when a patient just doesn't feel well. Emergency room that we really want to look to say, you know, does this person have an increased anion gap? Does this person have some findings that are go along with acidosis? Do I need to get a ph? Do I need to be more aggressive with my insulin and fluids? Not necessarily less aggressive with the insulin which seems in the, in the first paper which happened with a lot of people. So I think this is some interesting things. I think a lot more details will follow in the upcoming months. Our next article is from Diabetes Care and it looked at energy balance after sodium glucose CO transport to SDLT2 inhibition. In this particular study, 86 patients with type 2 diabetes with an average A1C of 7.8 and a GFR an average of 89 received empagliflozin 25 mg a day for a 90 week period with frequent assessment of body weight. GFR and fasting blood glucose time dependent GFR was calculated as the product of GFR and fasting. Plasma glucose time dependent glycosuria was estimated from previous direct measurements. The Relationship of calorie to weight changes was estimated using a model of a human energy metabolism that simulates the time course of weight change for a given change in calorie balance and calculated corresponding energy intake changes. The researchers found at week 90, the weight loss averaged a decrease of 3.2 kilogram plus or minus 4 kilogram, which correlated to a medium calorie deficit of 51 kilocalories per day. However, the observed calorie loss through glycosuria was found to be 200 kilocalories a day and was predicted to result in a weight loss of somewhere around 11.3 kilos. So what happened to the lost weight? Patients lost only 29% of the weight loss predicted by their glycosuria. This model that the researchers came up indicated that the difference was accounted for by an increase in calorie intake of 269 kilocalories per day.

B (15:33)

Neil John, this is really interesting and I think many of us have wondered for a while why that weight loss that you see in the first few months of taking an SGLT2 inhibitor seems to plateau and not continue, even though we know the glucocuria continues. What this study shows, which is really remarkable, I mean, they measured the amount of calories being lost in the urine and where it was made up, and what it shows is that only a third of the predicted weight loss that one would predict from the amount of glucose that's actually lost in the urine occurs by the end of the year. Where it's made up is increased intake. Potentially it might also be made up by increased activity. We don't know that. But basically the mechanisms for weight loss and maintaining a current weight are complex and occur often beyond our recognition. The SGLT2s don't have the additional quality that the GLP1s have of increasing satiety. So that it seems that when we use an sg, the practical consequence of this, I think clinically, is that when we use an SGLT2, if we want to maximize the amount of weight loss attached to it, we really need to emphasize behavioral interventions and diet. And if we can use both diet along with SGLT2s, that's a powerful combination that potentially improves both a 1Cs and facilitates continued weight loss. The next study from Diabetes Care is titled Results from a European Multi Center Randomized Trial of Physical Activity and or Healthy Eating to Reduce the Risk of Gestational Diabetes. In this trial, pregnant women at risk for Gestational diabetes with a bmi greater than 29 from nine European countries were invited to undertake a 75 gram oral glucose tolerance test before 20 weeks of gestation. Those who did not have gestational diabetes were randomized to either a healthy eating group, a physical activity group, or a healthy eating plus physical activity group. Women received five face to face and four optional telephone coaching sessions based on the principles of motivational interviewing. A gestational weight gain of less than 5 kg was targeted. Among the 150 trial participants, 32% developed gestational diabetes by 35 to 37 weeks of gestation and 20% achieved a gestational weight gain of less than 5 kg. Healthy eating women had less gestational weight gain and lower fasting glucoses than those in the physical activity group. No significant other differences between the healthy eating plus physical activity and the other groups were observed.

C (18:40)

Jaunt so some years back the governor of Oregon decided he was going to put together a health plan and in this health plan they listed a little less than 700 diagnoses. And in order what was the most cost effective thing for spending money on? And what they found in the Oregon health plan was the thing that was most effective for spending money on was prenatal care. So pre dental care is so important. Diabetes in pregnancy is certainly an issue we would like to avoid. And my takeaway point from this study and they did interventions for folks after they were 20 weeks pregnant. My takeaway point from this particular study is let's find the folks who have a bmi greater than 29 at the start of their pregnancy and start making some interventions with regard to diet and exercise at the beginning of their pregnancy so they don't develop gestational diabetes. And I think that probably wouldn't cost a whole lot of money, a whole lot of resources, and certainly would be fitting for us trying to prevent some diseases and preventing some diseases in some very benign ways with diet and exercise.

B (19:52)

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