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Diabetes Core Update
Diabetes Core Update December 2015
00:25:17
Diabetes Core Update is a monthly podcast that presents and discusses the latest clinically relevant articles from the American Diabetes Association’s four science and medical journals – Diabetes, Diabetes Care, Clinical Diabetes, and...
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A
Welcome to the American Diabetes Association Diabetes Core Update, where we will regularly keep you up to date on the latest clinically relevant articles from the American Diabetes Association's core science and medical journals Diabetes, Diabetes Care, Clinical Diabetes and Diabetes Spectrum. Joining us for this program are Dr. Neal Skolnik, who is a Professor of Family Medicine at Temple University School of Medicine and Associate Director in the Family Medicine Residency Program at Abington Memorial Hospital. Welcome Dr. Skolnick.
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Thank you. It's a pleasure to be here.
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And Dr. John Russell, who is a Professor of Family Medicine at Temple University School of Medicine and Director in the Family Medicine Residency Program at Abington Memorial Hospital.
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Thank you. I'm looking forward to going over this week's articles.
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And now for the articles.
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We have another excellent issue this month, beginning with an article on SGLT2 inhibitors in type 1 diabetes published in Diabetes Care. Then an article on dulaglutide versus insulin glargine in patients already on metformin and glimepiride, then an article on SGLT2 inhibitors, their history from bench to bedside, followed by a discussion of depression in youth with diabetes, then reviewing an article on inhaled insulin vs insulin aspart in patients with type 1 diabetes, then an article on the importance in insulin NPH of resuspension before injection and its effect on pharmacokinetics and pharmacodynamics of the insulin and finally a discussion of a symposium on the microbiome and diabetes. Our first study is titled Efficacy and Safety of Canagliflozin, an SGLT2 inhibitor as ADD on to insulin in patients with type 1 diabetes. This study looked at the safety and efficacy of canagliflozin as add on to insulin in patients with type 1 diabetes. Remember, SGLT2s are currently FDA approved in type 2 diabetes but have been used off label in patients with type 1 diabetes. This was an 18 week double blind phase 2 study that randomized 351 patients with a 1Cs of 7 to 9% on multiple daily insulin injections or insulin pumps to canagliflose in 100 or 300 milligrams or a placebo. The primary endpoint was the proportion of patients achieving at week 18 both an A1C reduction from baseline of greater than or equal to 4% with no increase in body weight. More patients had both a 1c reduction greater than or equal to 4% and no increase in body weight with canagliflozin 100 and 300mg vs placebo week 18 41% vs 14% with a significant P value. Both canagulaflos and doses provided reductions in A1C body weight and insulin dose versus placebo. Over the 18 weeks there was an increased incidence of ketone related adverse effects including specific adverse effect of diabetic ketoacidosis 4.3% with canagliflowsin 106% with canagliflozin 300 and none in the placebo group.
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John so you know I think this is a pretty important paper. So you know the holy grail would possibly be combining an insulin therapy with a non insulin based therapy and the SGLT2s would seem to make lots and lots of sense. This clearly points out the the whispers that we had heard about this ketoacidosis that happens with SGLT2. Not only does it happen, it happens a pretty significant amount of time. So 4 and 6% compared to placebo and type 1 diabetics. I would view this at this point as a class effect and I would be very slow to use an SGLT2 inhibitor in someone with type 1 diabetes for this risk of ketoacidosis and the positive effects were modest at best. So certainly the juice is not worth the squeeze. Our next article is from Diabetes Care and it looked at the efficacy and safety of Once weekly dulaglutide vs insulin glargine in patients with type 2 diabetes on metformin and glimepiride. This study compared the efficacy and safety of the once weekly GLP1 receptor agonist dulaglutide versus daily insulin glargine that were both combined with the maximally tolerated doses of metformin and glimepiride in patients with type 2 diabetes. In this study that took place over 78 weeks, they randomized 810 patients who had baseline mean A1C's of 8.1 to two different doses of dulaglutide or glargine. The change from baseline A1C was minus 1.08 in the higher dose and minus 0.76 in the lower dose of dulaglutide. The patients who got glargine had a decrease in a 1C of 0.63. There were statistical criteria for superiority met with the higher dose of dulaglutide and non inferiority for the lower dose. More patients on the higher dose achieved an A1C less than 7. Body weights decreased with both groups of dulaglutide and increased with the glargine. The total hypoglycemia rates were lower with dulaglutide. The severe hypoglycemic events was minimal in both groups. Increases in pancreatic enzymes were observed for dulaglutide. The incidence of nausea was much higher in the higher dose of dulaglutide. The medium dose of dulaglutide also was higher than baseline glargine. There was also a higher incidence of diarrhea.
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Neil John this is a nice study in that it looks at a GLP1 in addition to metformin and glimiparide. Remember that sulfonylureas are still used as the main agent after metformin in about 60% of patients who are on a second agent. So this is a very common scenario and this study adds to the EV on the efficacy and benefits of GLP1s as a third line agent as an add on agent after oral hypoglycemic agents need something else when comparing the GLP1 to insulin we of course see again that there is weight loss instead of weight gain and there's low incidence of hypoglycemia. In this study there was actually increased efficacy. So this further supports the recommendations of GLP1s as an option instead of insulin as add on to oral hypoglycemics as was articulated very nicely in the Medical Management of Hypoglycemia article this past January 2015 by Silvio and Zucchi and really gives us lots of options about how to treat patients with A1Cs that are not sufficiently controlled on one or more oral hypoglycemia agents. When it comes to choices of injectables. Our next article is on sodium glucose CO transporter inhibitors their effects on renal and intestinal glucose transport from bench to bedside. This interesting article gives a historical perspective on the SGLT2 inhibitors which have over the last few years become a commonly used agent in type 2 diabetes. It turns out that these were discovered over 200 years ago from isolation of a chemical known as fluorezine which was found in apple tree bark that inhibited sodium glucose cotransporters 1 and 2 and it took over 200 years from the discovery of fluorescein to the first medications inhibiting SGLT2s for the treatment of diabetes. SGLT1 is expressed at high levels in the intestine, also expressed in the kidney, heart and skeletal muscle, while SGLT2 is expressed almost exclusively in the kidney. Renal SGLT2 expression is increased in patients who are hyperglycemic who have diabetes as well as in rodent models with type 2 diabetes. In the 1930s, work showed that there is a maximum capacity for renal tubular glucose transport and nearly all filtered glucose is reabsorbed when plasma glucose is below a threshold. But when it gets above a threshold, it begins to spill into the urine. That's why before we had the ability to check point of care blood sugars, we would dip urines. In the early 70s, it was demonstrated that glucose resorption occurred in the proximal tubule and it was demonstrated that it occurred through two distinct sodium dependent glucose transport systems, SGLT1 and 2. Importantly, in subjects with type 2 diabetes treated with SGLT2 inhibitors, the urinary glucose excretion rate is high when plasma glucose is high, but it diminishes as plasma glucose approaches hypoglycemic levels, which suggested that the development of this class of agents would give a low risk of treatment induced Hypoglycemia. Since both SGLT 1 and 2 existed in the kidney, there was also a suggestion that there might be greater glucose control with dual inhibition than just SGLT2 inhibition. SGLT1 is essential for intestinal glucose and galactose absorption and represents the primary mechanism of glucose and galactose uptake from the lumen into the body. Inhibition of SGLT1, though, can lead to significant diarrhea. Although that original chemical, fluorezine, was known to increase urinary glucose excretion and was demonstrated to completely inhibit renal glucose absorption in the 1930s, the potential for using increased glucose excretion as a means to regulate plasma glucose wasn't demonstrated until the 1980s. In the 1980s, there was pursuit of selective SGLT2 inhibitors with improved properties. The first publication demonstrating the potential of a selective SGLT2 inhibitor as treatment for diabetes in rodent models appeared only in 1999. Since then, there's been an incredible amount of research and there's now three FDA approved SGLT2 inhibitors. Dapagliflozin, canagliflozin and empagliflozin.
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John so I think we're seeing kind of more residual from the kind of the 1880 kind of bark run where we kind of discovered aspirin from bark, we discovered quinine from bark, and we discovered the fluorescence from bark. So the SGLT2s certainly are becoming entrenched in our care for folks with type 2 diabetes. We talked earlier in the issue today that we really are careful to use it with people with type 1 diabetes. But I certainly think this is going to be in the mix of the medicines that we use. After metformin. And I think, you know, I think we're just starting to see the tip of the iceberg of this medicine that's probably our oldest known medicine in the category of diabetes, which Neil kind of went over the history. So the category of our oldest diabetes medicine is now one that we're finding new and interesting ways to incorporate into our patients care for type 2 diabetes. Our next article is from Diabetes Care and it looked at depressive symptoms in youth with type 1 or type 2 diabetes. This was the result of the Pediatrics Diabetes Consortium Screening Assessment of Depression in Diabetes study. To evaluate the frequency of depressive symptoms and the diagnosis and management of depression in youth with either type 1 diabetes or type 2 diabetes. The Pediatric Diabetes Consortium looked at type 1 and type 2 diabetes registries. They conducted the Children's Depression Inventory Self Report short version in 261 youths with either type 1 diabetes or 339 use with type 2 diabetes who were all aged between 10 and 17 years of age. They found the symptoms of depression were identified in 13% of the type 1 diabetics, in 22% of the type 2 diabetics. Of these youths, only 4% of the young folks with type 1 diabetes and 9% of the folks with type 2 diabetes were treated by a therapist within the prior 12 months. Depressive symptoms were associated with lower family income and obesity in the type 1 diabetics, but not in the type 2 diabetics.
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Neil John, this is important because this expands the information that we have about depression in patients with diabetes and adults to the pediatric population. We know that an adult's depression is important. It affects in patients without diabetes about 10 to 12% of the population. And two years ago, the United States Preventive Service Task Force suggested that we should be screening for depression routinely in patients with diabetes. As is true of many chronic diseases, the incidence of depression is about twice as high, 20 to 25%. So this is a real issue for many of our patients with diabetes. You might ask, why is it important? Well, other studies have shown a relationship between showing that patients who are depressed and have diabetes have poorer A1C control, poor adherence to medications, diet and exercise. And in fact, one study showed in adults higher mortality in patients who had depression and diabetes. This shows that the incidence of depression is significant in a pediatric population as well and that most of the patients with depression and pediatrics are not identified. So this increases our awareness to ask about symptoms of depression in children with diabetes and to then, of course, address it. Our next study is on inhaled technosphere insulin compared with injected prandial insulin and type 1 diabetes. The goal of this study was to compare the safety and efficacy of technospheric insulin and insulin aspart in patients with type 1 diabetes. It was an open label non inferiority trial comparing change in A1C from baseline to week 24 of prandial technosphere insulin inhaled with that of subcutaneous Aspart, both with basal insulin in patients with type 1 diabetes and A1Cs from 7.5 to 10. The mean change in A1C in the inhaled insulin patients was negative 0.21 from baseline and that was non inferior to that found with use of aspart patients, negative 0.4% from baseline. More aspart patients achieved a 1Cs less than 7. Rather 31% versus 18%. Inhaled insulin patients had a small weight loss minus 0.4 kg compared to weight loss gain plus 0.9 kg for aspart patients. Inhaled insulin patients had a lower hypoglycemia event rate than aspart patients, 9.8 versus 14 events per patient months. Cough, generally mild, was the most frequent adverse event with inhaled insulin 32% versus 2% with Aspart, leading to discontinuation in 5 of patients.
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John since the discovery of insulin in 1922, we have been looking for ways to give insulin delivery short of giving it a needle. And certainly figuring out a way to do it without having to cause a little pain for the patients I think is a little bit of the holy grail of diabetes research. So certainly how we treat hypothyroidism, if we had to give someone a needle to replete their thyroid would probably seem much different than the simplicity we have with giving people oral levothyroxine. So in this particular study I found to be very interesting. So we have had kind of go rounds with inhaled insulin before, but if I remember it was a very large cumbersome thing that really wouldn't fit into the middle of someone's workday. This new product is kind of a small, elegant thing that someone could keep in their pocket or locker and kind of use a little bit of insulin before a meal at work or at school. I think really seems like it would work really well. I was impressed that it didn't have weight gain. In fact it had some weight loss. I think at the end of the day we'll be very interested in patient satisfaction. So certainly someone kind of having to give themselves an injectant of a short acting insulin outside the home doesn't seem to me to be too user friendly. So if there is something someone can keep in their pocket, cover their meal and have good patient satisfaction with it, this might be something that we'll be using in our patients. Our next article is from Diabetes Care and it looked at the pharmakinetics and pharmadynamics of NPH insulin in type 1 diabetes. The importance of appropriate resuspension before subcutaneous injection Crystalline NPH insulin comes in two phase solution with either a solvent or a rapid acting insulin in the premixed formulations and needs adequate mixing for complete resuspension before injection. The aim of the study was to establish the pharmacokinetics and pharmacodynamics after the injection of appropriately resuspended versus non resuspended NPH insulin. So to look at both the pharmacokinetics and pharmacodynamics they were assessed after subcutaneous injection of the NPH insulin at a steady state by a pen that was either resuspended, meaning that the pen was kind of turned up and down 20 times or non resuspended and the pen was maintained in a fixed position either horizontally or vertically with the tip up or tip down. They looked at 11 subjects with type 1 diabetes, a mean age of 31 who had an average A1C of 7.2 compared with the resuspended NPH. The non resuspended NPH insulin had profound differences in both pharmacokinetics and pharmacodynamics with either a reduced amount of insulin with when the pen was horizontal or when the tip was up or increased when the tip was down. Of plasma insulin concentrations, the duration of the NPH insulin action was shorter in the folks who had the tip up but longer in the folks who had the tip down compared with the resuspended insulin.
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Neil John, it really reminds us of the importance of details in medicine administration and to me reminds me of the importance of having patients see a certified diabetes educator to go over the details of how to use their medicines. This was amazing. A large difference in insulin delivery depending on whether patients suspended their medicines, resuspended their medicines correctly and I suspect on reflection about this study because it took about a minute and 30 seconds of shaking the pen prior to insulin administration. I suspect many of my patients don't completely do that who are on NPH insulin and this is a nice reminder for me to remind them to do this on a regular basis. Next we are going to discuss an article that reviewed A research symposium on diabetes and the microbiome. Several lines of evidence suggest that the microbiome may influence the development of type 1 diabetes. Probiotic treatment of mice modifies the course of type 1 diabetes and increased use of antibiotics in humans correlates with the increased incidence of diabetes. The literature shows varying effects of probiotics and antibiotics on type 1 diabetes and that was reviewed during this symposium. The risk for and progression of type 2 diabetes is clearly affected by genetic influence, but most of that influence is small compared to environmental influence. Increasing evidence that was reviewed during the symposium suggests that the microbiome host interactions may be one of the environmental factors that influence type 2 diabetes risk and progression. Several studies have linked the intestinal bacterial environment to metabolic health in mice that did not have bacteria in their gut. The transfer of bacteria from lean humans can prevent adverse effects of transfer bacteria from obese humans. This evidence suggests that manipulation of the microbiome could actually influence type 2 diabetes treatment. In other studies reviewed here, antibiotic treatment and strains prone toward metabolic derangement improved insulin resistance, lowered blood glucose and led to improvement in glucose signaling. Another study showed that the gut microbiome is incredibly complex and is an ecology that is composed of hundreds or even thousands of interactive species. The transfer of adult male gut microbes into immature females elevated in one study, testosterone production, blocked islet cell inflammation and autoantibody production and actually protected animals from type 1 diabetes. We know that obesity is a major contributor to type 2 diabetes risk and that alteration in energy balance can promote weight loss or weight gain. And this symposium also reviewed the relationship between the gut microbiome and obesity. Colonization of the gut in bacteria free mice through fecal transplant led to weight gain, and the degree of weight gain was depending on the weight of the donor, with greater weight following transplants from obese mouse or human donors and less weight when the transplants were from lean donors.
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JOHN so this is really some wild stuff when you think, you know, that the number of cells we have in our body, our skin cells, our heart cells, our muscle cells, are so dwarfed by the number of cells of the microbiota that kind of makes up us. And I think it's very interesting and I think on a very kind of practical level, you know, we need to think of what are the day in and day out things that are affecting our flora. You know, do we need so much antibiotics in our meat products and all the things that we buy? Do we need to be very judicious in the antibiotics that we're giving people in an ambulatory level for things that don't make any difference, such as acute bronchitis. So can we be more judicious in not killing off good microbiota by things that we don't really need to do? I think going forward in the future to think that this might be a targeted way to treat diseases is really kind of mind blowing. It's a little bit scary. It seems like I've seen enough sci fi movies that kind of started this way where someone wanted to change things. So, you know, I think we need to be smart about doing some of these things, but it certainly seems to be a new frontier that is just opening up.
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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.
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Sam.