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Diabetes Core Update
Diabetes Core Update July 2015
00:22:43
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 four 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. Skolmik.
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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 a novel drug, citagliflozin, which uses a novel mechanism, both SGLT1 and SGLT2 inhibition, published in Diabetes Care. Then, also from Diabetes Care, we discuss a position statement on diabetes self management, education and support, followed by discussion of an article from Clinical Diabetes on metformin and H2 receptor agonists or PPIs, their effect on B12 deficiency. Then an article on dapagliflozin's effect on glycemic control and cardiovascular risk in high risk patients. Then a discussion of an article published in Diabetes on the central effects of insulin detemir and its effect on decreasing food intake. Then an article from Diabetes Care on caloric restriction versus exercise and the effect on weight loss and insulin sensitivity. Our first study from Diabetes Care is on cigliflozin, a dual SGLT1 and SGLT2 inhibitor, as adjunct to therapy to insulin and type 1 diabetes. This study looked at a new class of agents, dual SGLT1 and SGLT2 inhibitors. The SGLT2 inhibitors we're very familiar with, they decrease glucose reabsorption in the kidneys. The SGLT1 receptor actually is responsible for absorption of glucose that's eaten from the intestines and this new mechanism interferes with both SGLT1 and SGLT2 receptors. This was an initial study treating 33 patients with citagliflozin, which is an oral SGLT1N2 inhibitor versus placebo in a randomized trouble blind trial assessing safety, insulin dose, glycemic control and other metabolic parameters for approximately one month in the citagliflozin treata group. The percent reduction from baseline in the primary endpoint of bolus insulin dose was 32%, accompanied by lower mean daily glucose measured by continuous glucose monitoring and reduction of 0.55% in A1C compared a placebo group.
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John so this is an interesting newer article. I think by now we're used to the SGLT2s and they certainly found themselves entrench now in our newer modalities for treating diabetes. But we really have ignored SGLT1. It has a fairly negligible effect in the kidneys. Only about 10% of the reabsorption that's done in the Kidney is by SGLT1. But here in the stomach we're seeing that impacting reabsorption can have an impact. I'm not completely sure with this product is what, you know, what we're seeing with regard to A1C reduction. How much of it is SGLT1 and how much is SGLT2? I'd be interested if there ever was a pure SGLT1 inhibitor. I think so this is something, you know, details to follow and we'll see if we're better off having selective inhibition. But we should remember that there is SGLT1 in the gut that does impact our homeostasis with glucose. There were two patients in this particular case who had DKA and these were folks who had type 1 diabetes. They all were folks who had very high sugars. I think it's important though, in May 15th, the FDA released a drug safety communication on SGLT2 inhibitors for diabetes. And in this particular series they had looked at folks over about a year and a half from 2013 to 2014 that there were 20 cases of ketoacidosis in folks with type 2 diabetes who didn't necessarily have the very, very high sugars that we associate dka. So I think this is an interesting article and I think we need to be mindful with our folks who we've started on the existing SGLT2 inhibitors that if something does not seem quite right, that certainly we should be assessing their acid base status. Our next article is From Diabetes Care, July 2015. This was a joint position statement of of the American Diabetes association, the American association of Diabetes Educators and the Academy of Nutrition and Dietetics and it looked at diabetes self management education and Support in type 2 diabetes. Diabetes self management education is the process of facilitating the knowledge and ability necessary for diabetes self care. Diabetes self management support refers to the support that is required for implementing and sustaining coping skills and behaviors needed to self manage on an ongoing basis. So in this position statement it really said how important it is to have supports in place for initial and ongoing care of our diabetic patients through nutrition education. And emotional health. The national standards they put forth for D.S.M.E. s the 10 standards. There should be internal structure, there should be external input, there should be access to care, there should be program coordination, there should be instructional staff in place, there should be a curriculum with a written set of guidelines. The care should be individualized, there should be ongoing support, there should be participant progress and quality improvement processes need to be in place.
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Neil John this is an important position statement because diabetes self management and education stands to benefit patients enormously. A number of studies have shown that the benefit with regard to something that's incredibly clear, a 1C reduction with using diabetes self management education and Support is between 0.5 and 2% benefit in A1C, which is to say it's the same as adding an additional medicine. The problem is we live in this incredibly busy world and patients have a hard time getting into diabetes self management education activities. It's recommended that patients go to them initially, when they're diagnosed and on an annual basis, as well as when there are significant changes in their status. But the reality is when this has been looked at, it's the minority of patients that actually go on to get diabetes self management education. In fact, under 10% of Medicare beneficiaries with diabetes get diabetes self management and education. And it's unclear whether that's because we as clinicians don't recommend it either often enough or with enough enthusiasm, or because the recommendations are there. But again, patients are busy and they never get there. One of the promises is a change to a medical home model that's occurring in many of our primary care offices, so that instead of getting a referral to go out to the diabetes educator who is somewhere else in town. Hopefully, as we integrate a medical home model, diabetes educators will be embedded in our offices, whether that's one session or multiple sessions a week. And it becomes easier to say to a patient, I'd like you to see our diabetes educator and just make an appointment on the way out and they come back to a place they're familiar with, they feel comfortable with. And it facilitates communication between the diabetes educator and ourself as the clinicians taking care of patients. So hopefully that will help. This is an important position statement, has a lot of pearls in it, but ultimately the main point is we need to somehow get patients to get diabetes self management and education training more often than they currently do. Our next article is from Clinical Diabetes and it's titled metformin with either histamine 2 receptor antagonists or proton pump inhibitors, a polypharmacy recipe for neuropathy via vitamin B12 depletion among individuals with diabetes, about 41% experience symptomatic GERD and 70% of those use oral antidiabetic medicines. This isn't surprising because patients with type 2 diabetes are often overweight and those are risk factors both for diabetes as well as GERD. The signs and symptoms of vitamin B12 deficiency can be mistaken for those with diabetic neuropathy. They include paresthesias, diminished vibratory sensation, diminished proprioception, loss of cutaneous sensation. So the potential for this combination to cause B12 deficiency and to cause neuropathy that may be confused with a diabetic neuropathy is important. B12 deficiency among individuals managed with metformin has been reported to occur at an incidence ranging between 5% and 36%. Individuals treated with metformin have lower B12 levels and worse diabetic neuropathy than individuals managed with medications other than metformin. In general, acid suppressors, including both H2 receptor antagonists and PPIs, have been documented to interfere with B12 absorption. Studies analyzing ranitidine have noted decreases in B12 in addition to H2 receptor agonists. Studies have noted an inverse correlation between duration of PPI therapy and B12 deficiency. Given that a lot of people are both on metformin and a lot of those people are on both PPIs and H2 antagonists, the potential for increasing problems with B12 deficiency is real. Monotherapy with either metformin and H2 receptor antagonist or a PPI can deplete vitamin B12. In a recent study, 22% of individuals in a non diabetic control group were found to be B12 deficient.
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John so I think this is interesting on several different points. So one is I don't think it was necessarily going to change our practice patterns to say we're not going to be using metformin because we're worried about vitamin B12 deficiency and ultimately neuropathy. I think it might change our practice and that people who are on metformin we might find ourselves in guidelines down the road that this is something that we are going to follow routinely in these patients just to see if, you know, we can have an early detection of a very treatable neuropathy. So I think that's one point. I think the second point is there's lots and lots of people on acid suppressing medications in the United States and it's really revolutionized ulcer prevention and treatment in the United States. And once upon a time they used to talk about potentially 15,000 deaths a year from NSAIDs, usually from GI bleeds. I think that's not our experience anymore and these medicines have been really so wonderful that we end up putting lots and lots of the population and if you look at various studies you'll see anywhere from 25 to 60% of the population has been on some acid suppressing medication. With the PPIs we have learned that it puts people potentially at increased risk for C. Difficile, it potentially puts people at increased risk risk for pneumonia, potentially puts people at increased risk for osteoporosis. And I think one of the problems is someone has some symptomatic gerd. We put someone on a medicine and then we leave them on that medicine forever and ever and we view them as fairly innocuous. But this potentially would raise a point that if we do have people on those medicines concomitantly, and there's often a lot of good reasons due to central adiposity, that perhaps these are folks that we do need to do some follow up vitamin studies just to see if they need to be supplemented. Our next article is from July edition of Diabetes Care that looked at dapagliflozin's effect on glycemia and cardiovascular risk factors in high risk patients with type 2 diabetes. This was a 24 week multi center randomized double blind placebo controlled study with a 28 week extension. There were over 900 patients who were randomized to receive either 10 milligrams of dapagliflozin or placebo in a double blind trial for four weeks followed by a 28 week extension. Patients were stratified by age, insulin use and time for the most recent cardiovascular event CO primary endpoints were changed from baseline A1C in proportion of patients achieving a combined reduction of A1C body weight and systolic blood pressure. At 24 weeks. The dabagliflozin group significantly reduced A1C, a decrease in 0.38 from baseline compared with a slight increase in the placebo group from baseline of about 0.08%. Significantly more patients met the three item endpoint with treatment with topagliflozin than with placebo 11.7 versus 0.9% respectively. Although 42% of the patients were over 65 years of age, similar results observed in both age stratified groups.
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Neil John this study essentially is reassuring. It shows that in a high risk group of people dapagliflozin does what you anticipate it to do, which is improve a 1C improve body weight and improve systolic blood pressure and that it has importantly no adverse cardiovascular effects. Clearly, for all diabetes drugs, the cardiovascular endpoints are important but are ultimately assessed in much larger studies than this one. A thousand patients, which seems like a lot of patients and is a lot of patients, isn't enough to provide full data on cardiovascular safety. But certainly because this was a high risk group, we find this paper very reassuring. Our next article is from Diabetes and is titled Insulin detymere is transported from blood to cerebral spinal fluid and has prolonged central anorexic action relative to NPH insulin. Insulin detemir reduces glycemia similarly to other long acting insulin formulations but causes less weight gain. Insulin signaling in the brain is catabolic, reducing food intake. The authors hypothesized that insulin detymere reduces weight gain relative to other insulins due to increased transport into the central nervous system or increased catabolic action within the brain. Transport of Denimr and NPH insulin into the cerebral spinal fluid was compared over several hours and following the administration of different doses peripherally in rats, cerebrospinal fluid insulin remained elevated significantly longer following insulin Detymir than following NPH when administered acutely into the third ventricle. Both Denimir and NPH insulin reduced food intake and weight at 24 hours and both food intake and body weight remained lower following dedomir than following NPH after 48 hours in direct comparison with another long acting insulin Insulin glargine Determir led to more prolonged increases in CSF insulin despite a shorter plasma half life in both rats and mice.
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John so in the upcoming months I think we're going to be seeing a lot of newer insulins that are coming down the pike and I think will be looking at ways to help differentiate one from another amongst clinicians. I think this is an interesting article with regard to thinking about, you know, overall how is glycemic control achieved in the brain with regard to other parts of the body? There was a Dr. DeFronzo who talked about the ominous octet and one of the eight parts of the ominous octet was the brain and satiety. And it's often mentioned that GLP1s can act there, but certainly insulins can act there as well impacting satiety and certainly that will control our intake of calories. So whether one particular insulin product might have a better control on satiety and therefore better control on weight gain might be interesting. Certainly we're not going to be injecting insulin into third ventricles on a whole lot of patients. But I think as we go forward and we look at the the whole array of insulins, we might differentiate one product with another product on how much it impacts one of these eight sites of hyperglycemia. In our last article is from the July edition of Diabetes Care and it looked at calorie restriction and matched weight loss from exercise independent and additive effects on glucoregulation and the incredin system overweight women and men. It has never been known whether calorie restriction has additive benefits to those from exercise induced weight loss. The researchers hypothesized that weight loss from calorie restriction and exercise improves insulin sensitivity more than match weight loss induced by either one alone and the incretin system might be involved in these adaptations. They looked at over 50 patients who were sedentary overweight men and women and they were randomized to have a 6 to 8% weight loss by using either calorie restriction exercise alone or a combination of the two. Glucose, insulin, C peptide insulin sensitivities and measurement of the incretin hormones were measured during frequently sampled oral glucose tolerance tests. They found that despite similar weight loss in all groups, insulin sensitivity index values increased twofold more in the groups that combined calorie restriction and exercise than in either group alone.
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Neil John I think this study emphasizes in a sophisticated way something that we either know or suspect, which is that both calorie restriction and exercise are good ways to lose weight and the best way is to do both. We know from a wealth of data, the most important study being the Diabetes Prevention Program trial, that calorie restriction and in that case weight loss of greater than 7% of body weight along with exercise. The recommended amount of exercise is 150 minutes a week. That's about 30 minutes of exercise five times a week. Not easy to do, but certainly achievable leads in a group of people with prediabetes to substantial decrease in progression to diabetes, actually a decrease of about 65% compared to usual care. So this study does underscore that while both diet and exercise are beneficial and optimal is using. 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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