C (4:22)

Sean so the Mediterranean diet is a very exciting thing and certainly there are scores of diet books that are written, but this is really the one that stands out as really having such a difference now in diabetes. And this is the longest trial ever done on the Mediterranean diet as well as cardiovascular disease. The term Mediterranean diet is a little bit of a misnomer in that there is such disparate countries and such disparate diets that live around the Mediterranean that this was really based on a Cretan diet. They found that men and women from Crete had a relatively low incidence of heart disease, but ate a diet that was not necessarily low in fat. And it was first described really in the 40s and 50s, but really did not become popularized to the 1990s in the Lyon heart trial. And looking at people who already had had a cardiovascular event being on a Mediterranean Diet had a 70% decrease in a repeat cardiovascular event. So certainly for heart disease we know that a Mediterranean diet can make a big difference. And here for people with diabetes, certainly a diet, this particular Mediterranean diet trial also had low carbohydrates as part of it. But a Mediterranean diet can certainly be very, very powerful in preventing diabetes from happening. And certainly from what you know about cardiovascular disease, it certainly is a diet that is has a lot of benefits in that arena as well. So certainly I think if we're recommending people to learn something about a diet, I think maybe to stay away from the more trendy book based diets and really get some information on the Mediterranean diet might be really helpful for our patients. Our next article is from Diabetes Care and it looked at patient preferences for non insulin diabetes medicine. A systematic review, an evidence based synthesis of patient preferences for the management of hyperglycemia is needed in doing so the Researchers looked at 2,800 titles of original research and found 10 articles that met inclusion criteria for a systematic review of patient preferences. The studies were all conducted between 2007 and in 2012. The key attributes that the researchers looked at were those associated with patient preferences included treatment benefits, meaning glycemic control and weight loss or control the treatment burden, how hard it was to administer, how often you have to take it in cost and various side effects which might be weight gain, GI effects and hyperglycemia. Various clinical and quality of life related factors influence patient preferences for non insulin diabetes medicine. Treatment efficacy with regard to glycemic control and weight loss control and the risk of treatment related hypoglycemia and GI effects were the most important drivers of patient treatment selections. Further work is needed in this area to determine what might be the best medicines in patient size Neil John I.

B (7:23)

Really like this article because it puts front and center the issue of patient preference, and I also like the way they've organized a discussion about patient preference into benefits to be derived from medicines, the burden of taking the medicines, and the side effects of the medicines. If you think about it, probably more than any other area of medicine, diabetes control is related to patient adherence. We have great medicines and we have over eight to 10 different classes of medicines to choose from. And over the last five years there's been increased emphasis on personalizing care and individualization of therapy. We've talked about that in previous podcasts, but what that really means is having a discussion with patients about what are the attributes of the medicines that we're considering putting them on. Because remember, currently, adherence to medications for patients with diabetes only runs between depending on what medicine and what study you look at. Depending on 50% to 80% of medicines are taken that we prescribe if we can have patient buy in, if the patient cares more about GI side effects, for instance, than they do hypoglycemia. And we believe that that's a reasonable judgment. Prescribing a medicine that minimizes GI side effects is important because, as C. Everett Koop once said, patients get no benefit from medicines they don't take. So attention to patient preference enhances patient adherence, and their algorithm for how to look at patient preference, I think is a helpful one. Our next article is on musculoskeletal complications in type 1 diabetes. The development of periarticular thickening of the skin on the hands and limited joint mobility, which is called chiroarthropathy, are associated with diabetes and can lead to significant disability the objective of this study was to describe the prevalence of this malady in the well characterized diabetes control and complications the DCCT trial and examined risk factors as well as the effect of therapy. This cross sectional analysis was performed in over 1200 participants in year 18 of 19 after an average of 24 years of follow up. Chiroarthropathy, defined as the presence of any one of the adhesive capsulitis, carpal tunnel syndrome, flexor tenosynovitis, dupuytren's contractures or a positive prayer sign were assessed using a targeted medical history and standardized physical examination. These endpoints were present in 66% of subjects and associated with age, sex, diabetes duration, skin intrinsic fluorescence, hemoglobin A1c Neuropathy and retinopathy and was not related to intensity of treatment.

C (10:33)

John so you know once again another study that shows people that have long term diabetes have a complication and I think for years we've known that people have diabetes are more likely to have carpal tunnel and I don't think that's a reach and I think if any of us were taking an exam and saying which of these is associated with carpal tunnel, I think we would all get carpal tunnel. I think it's surprising that things like trigger fingers and certainly dupuytren's contractures for years I think we knew had some association with diabetes. It is significant, statistically significant that people who have better A1Cs have less of this, but it really does not look, at least in this particular study, that having a better A1C is super duper protective. So I think this is going to be one of the things we're certainly going to encounter in our folks who have had diabetes for a while and it's going to be more common. We're going to treat them appropriately. I certainly think there are much more important life threatening reasons to encourage people to have better glycemic control than preventing trigger fingers and carpal tunnel. But certainly when people have these complications we certainly can explain why they might be having them. Our next article is from Clinical Diabetes and it looked at clinical considerations for insulin pharmacotherapy and ambulatory care. Part 1 Introduction and Review of Current Products and Guidelines with the availability of four distinct types of synthetic and analog insulin products, initial dosing and titration may vary depending on the regimen selected and patient specific characteristics. This article is the first of a two part review of the use of insulin in the ambulatory care setting. Insulin pharmacotherapy can be divided in four types based on the pharmacodynamics and pharmacokinetic parameters. Insulin products on the US Market include rapid, short, intermediate and long acting products as well as some pre mixed formulations. Furthermore, insulin therapy can be characterized as either basal or bolus therapy. Basal therapy includes long and intermediate acting insulin products used to mimic physiological insulin secretion in the absence of food and the rapid and short acting insulin products constitute bolus therapy which is used to mimic the secretion of insulin from the pancreas in response to food. Each unit of insulin, regardless of the type, has an equal effect in lowering blood glucose. The human insulin analogs Lispro, glutisamine, glargine and Detymir have been chemically altered via recombinant DNA technology. These chemical alterations chain the amino acid sequence of the insulin protein, thus adjusting the pharmacokinetics and pharmacodynamic parameters. The most common route of administration of insulin is by the subcutaneous injection. Patients administering insulin through subcutaneous injection have the option of using insulin pens or vials with syringes to inject insulin. Pump therapy provides a constant infusion of insulin. Three sets of guidelines relating to the therapeutic management of type 2 diabetes is used in clinical practice. These include the Standards of Medical Care by the American Diabetes association, the European association of the Study of Diabetes and an update from the American association of Clinical Endocrinologists which was released in 2011. Recommendations from these guidelines serve as a foundation for creating an individualized patient centered treatment regimen for patients with type 2 diabetes. Self monitoring blood glucose is also imperative to help and detect, appropriately manage and appropriately manage hypoglycemia, which is a major risk and a limitation for insulin therapy. For patients who suffer from severe hypoglycemia, short term relaxation of glycemic targets with a tapering of insulin therapy may be appropriate, especially in light of recent data suggesting potential associations with cognitive impairment and mortality. Basal insulin alone is generally the initial insulin of choice when added to pharmacotherapy regimen, thus allowing for uniform insulin coverage over the course of a day. In most patients, a single injection of a basal insulin is initiated, a low dose of 0.1 to 0.2 units per kg per day after initiation. Titration is described in the guidelines as addition of one to two units of basal insulin to the daily dose made once or twice weekly for elevated fasting glucose readings. The guidelines go on to recommend that as patient nears their glycemic control goals, dose modifications should occur less often and generally consist of fewer additional units of insulin. When basal insulin is not sufficient to maintain glycemic control, bolus insulin therapy with short acting or rapid acting insulin just before meals is recommended. Available guidelines provide vague recommendations for the dosing range for bolus insulin. Providers should be aware that when a patient's daily dose of basal insulin becomes greater than 0.5 units per kilogram per day, the need for intensification with bolus insulin increases. When the total daily dose of basal insulin nears 1 unit per kg per day, the addition of bolus insulin is generally required to achieve glycemic control. The guidelines suggest initial prandial insulin with a single dose just before the meal that contains the largest carbohydrate contents for that particular day. The combination of both long acting basal insulin and rapid acting mealtime insulin is described as basal bolus therapy in most guidelines. The AACE also favors long acting basal insulin to target fasting glucose as the initial insulin therapy in most situations with Glargine or DEDOMRE preferred for the same reasons described previously. The AAC guidelines are also in agreement with both the ADA guidelines in recommending initiation with 0.1 to 0.2 units per kg per day of basal insulin analog generally equating to approximately 10 units daily. The 2013 algorithm and consensus statement divide dosing recommendations for the initiation of basal insulin based on whether patients have an A1C greater than eight or less than eight. For those who have an A1C greater than 8, a higher weight based dose of 0.2 to 0.3 units per kg per day is recommended as opposed to the standard 0.1 to 0.2 units per kg per day. The 2013 AACE publications provide specific guidelines in insulin titration based on either a fixed or variable methodology. The fixed methodology option suggests titrating basal insulin by two units every two to three days. If the variable methodology is preferred, titration is based on fasting blood glucose levels with four units added for fasting readings greater than 180, two units added for fasting readings of 140 to 180 and one unit added for fasting readings between 110 and 139. Unlike the ADA guidelines, the ACE guidelines recommend specific dosing instructions for prandial insulin initiating at 5 units before meal representing approximately 7% of the basal insulin dose. Furthermore, the 2013 guideline and consensus statement recommend for patients with a total daily dose 0.3 to 0.5 units per kilogram per day, 50% of that dose should constitute the prandial insulin analog when initiated. The updated algorithm discusses dose increases every two to three days based on percentages when a rapid acting analog is used. The preandual dose should be increased by 10% for postprandial glucose levels greater than 180. And finally, the 2013 guideline discusses the initiation of GLP1 receptor agonists or DPP4 inhibitors as alternative to bolus insulin for prandial control.

B (18:23)

Neil John that was a nice overview of insulin therapy. And while we do a lot of insulin therapy because a lot of our patients simply aren't controlled on two or three oral hypoglycemic agents, it remains an important issue in primary care because many primary care physicians are uncomfortable 1 starting insulin and 2 knowing what to do after not having good control simply on basal insulin. To me, the important highlights of what you just went over are essentially when to start basal insulin and that's simply when someone isn't controlled on two to three oral hypoglycemic agents or when their A1C is over 10% on presentation or on one or two agents and then starting basal insulin. The the algorithm that I like actually is and you went over all of the choices, I'll just share the ones I like with our listeners. I like starting with 10 units that's in package insert for one of the basal insulins and having patients check their fasting sugars for two to three days in a row. If it remains above 140, increase by two units and continue doing that until the fasting blood Sugar is below 140. It's simple, straightforward and in my experience patients are able to adhere to that pretty easily and comply with that regimen. And then a reminder that when a patient's A1C is elevated but their fasting blood sugars are controlled, we then need to think about adding bolus doses of insulin. Or when, as you said, we're using more than 0.5 to 1 unit per kg, we ought to think about bolus therapy. In my experience, the easiest thing is to start with one meal a day. That will control about 70% of people who will be controlled on three meals a day. Starting bolus insulin with the largest meal of the day A couple of months ago we reviewed a study saying you can start it with breakfast, it doesn't have to be the largest meal of the day. Start with 5 units and again make it simple, increase by 1 or 2 units every few days for post prandtl Sugars greater than 180 and I like what you said at the end about option for postprandial control of sugars being using one of the newer agents, a DPP4 or GLP1. And as we'll hear in an article that we'll do later in this podcast, there is room for perhaps SGLT2s that were not discussed in this article, but as supplemental addition to insulin in patients who aren't controlled on insulin 11 our next article is on improved glucose control with weight loss, lower insulin doses and no increased hypoglycemia with empagliflozin added to titrated multiple daily injections of insulin in obese patients with inadequately controlled type 2 diabetes. This study investigated the efficacy and safety of the SGLT2.2 inhibitor empagliflozin added to multiple daily injections of insulin in obese patients with type 2 diabetes patients inadequately controlled on multi dose insulin plus or not including metformin with average BMI of almost 35. An average insulin dose of 92 units were randomized and treated with once daily empagliflozin 10 mg, empagliflozin 25 mg or or a placebo for 52 weeks. Insulin dose was to remain stable in weeks 1 to 18, adjusted to meet glucose targets in week 19 to 40, then stable in weeks 41 to 52. The primary endpoint was change from baseline A1C at 18 weeks. Secondary endpoints were changes from baseline and insulin dose, weight and A1C at week 52. Results showed an adjusted mean change from baseline A1Cs of negative 0.5 for placebo versus negative 0.94 and negative 1.02 for empagliflozin 10mg and empagliflozin 25mg respectively at week 18. At week 52, further reductions in insulin titration resulted in changes from baseline and A1C of negative 0.81 minus 1.18 and negative 1.27 with placebo empagliflozin 10 and empagliflozin 25mg respectively with final A1Cs of 7.5, 7.2 and 7.1 respectively.

C (23:33)

John so another interesting article about the SGLT2 inhibitors. So these non insulin dependent medications clearly by the study can be used with insulin and can get you about a point lowering of a 1C. So I think that's exciting. They decrease weight. So when you're putting people on insulin instead of increasing your insulin and potentially increasing the weight you put on people, this will decrease the weight. I think some of the early concerns about urinary tract infections were once again borne out in the study that there really isn't a significant change in urinary tract infections, genital mycotic infections still in this study kind of follows other studies of this and other drugs that there's an increased rate with that. So certainly I think that these are some medicines that provide some of the things we really like. We like medicines that will have patients lose weight. We like some medicines that can be used in concert with insulin and the safely can. We like some medicines that don't cause some hypoglycemia and hopefully the side effect profile will be fairly well tolerated. So I think these are some medicines that clearly more and more studies are showing more and more places that this will be kind of part of our diabetes toolbox. Our last article is from Diabetes Care and it looked at exposure to persistent organic pollutants, relation with abnormal glucose metabolism and visceral adiposity. The contribution of persistent organic pollutants or POPs to the pandemic of type 2 diabetes and obesity has been assumed but remains speculative. The researchers in this study looked at glucose tolerance in a group of normal weight and obese individuals. Fat distribution was assessed with abdominal CT scanning, determining of subcutaneous adipose tissue and visceral adipose tissue. Selected PCBs were measured in the serum and the subset of obese individuals who underwent bariatric surgery. The POPs were also measured in their adipose tissue. Among the obese participants, serum and adipose tissue's level of pops were significantly correlated to glucose levels during oral glucose tolerance test. Pop's levels were significant predictors of abnormal glucose tolerance tests. Adipose tissue levels of the PCPs were significant predictors of diabetes. Serum level PCBs were inversely related to BMI, but serum and adipose tissue levels of all the POPs were positively related to the amount of CT determined VAT and cat, suggesting an important role for visceral fat compartment in the POP dynamics.

B (26:24)

Neil John what I find interesting about studies like this and potentially scary is the authors conclude our findings further sustain the theory that exposure to environmentally relevant levels of PCPs may exert both a diabetogenic and obesogenic effect. The problem is that's the only take home point that people remember. And maybe that's true, maybe this suggests it. But I think what's probably even more important, and you and I both have run our journal club over many years with the residents and the thing that we always emphasize is are there fatal flaws in studies and do the studies support the author's conclusion? And here the authors themselves acknowledge that huge issue with that conclusion. And what the authors say, and I don't think this can be emphasized enough, is that this is a cross sectional study and that given the lipophilicity of organic solvents, the detected relationships might simply reflect increased adipose mass in individuals, and increased adipose mass retains PCBs and other organic chemicals. So that it actually might not be a causal effect, but simply that people who have a tendency toward diabetes, who are more obese, will have a Greater amount of PCBs and other organic chemicals in their fatty tissue. So we want to be careful if we hear from our patients about this concern that one this was a cross sectional study and actually might not mean anything, and two if it does, the degree to which these sort of chemicals probably contribute to diabetes, if at all, is probably a great deal less than many of the known contributors, the largest two of which are lack of exercise and increased levels of obesity secondary to poor diets. For more information and links to the article articles that we discussed in this issue, just go to www.diabetesjournals.org. until next week, keep listening and keep learning. Sa.