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Diabetes Core Update
Diabetes Core Update June 2016
00:22:55
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 Diabetes...
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- [00:04]
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 Skolnick, 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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B
We have another excellent issue this month, beginning with an article from Diabetes Care on lipid lowering therapy and cardiovascular outcomes in patients with type 1 diabetes, then an article on glucose variability and exenatide versus rapid acting insulin, followed by an article from Clinical Diabetes on new insulin therapies, a focus on Glargine 300, then a discussion of the addition of liraglutide to insulin in type 1 diabetes, then an article from Diabetes Care on breaking up sedentary time and the effects on carbon cardiometabolic parameters, and finally a review of the gut and glucose homeostasis. Our first article is from Diabetes Care on the association between use of lipid lowering therapy and cardiovascular disease and death in individuals with type 1 diabetes. In this study they used propensity score analysis for treatment with lipid lowering therapy calculated from 32 baseline clinical and socioeconomic variables on a large cohort of patients. They estimated the risk of acute mi, stroke, coronary heart disease and cardiovascular and all cause mortality in individuals who were and were not on lipid lowering therapy. A total of 24,000 individuals were included from 2006 to 2008 with type 1 diabetes without a history of coronary disease and were followed until December 31, 2012. 18,000 were untreated and 5,300 were treated with lipid lowering therapy. The mean follow up was six years. What they found was the hazard ratio for treated versus untreated was as follows cardiovascular death 0.6 all cause death 0.56 fatal and non fatal stroke 0.56 fatal and non fatal acute MI 0.78 fatal and nonfatal coronary heart disease 0.85 and fatal or non fatal cardiovascular disease in general 0.77 John so one of the.
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Things that interest is interesting is the ADA recommends all folks with type 1 diabetes over the age of 40 be put on a statin. I think that makes a whole lot of sense. In this particular trial the treated population were in their early 50s. The folks that were untreated were in their 30s and certainly there would be some ethical questions to look at a high risk population and not necessarily treat them. So the untreated population turned out to be in their 30s and what we found is there, there was a significant level of improvement with putting that untreated population on a statin. And I was always kind of curious about that age of 40 because some people might be diagnosed with type 1 diabetes at 7 years of age and could have had diabetes for 30 plus years by the time they hit 40. So whether this is going to move the bar on that age that we're going to start using a statin. Statins pretty well tolerated with a lot of generic statins are a lot less expensive. So I could certain see based on a study like this that we moved that bar from the age of 40 to a lower age. Our next article is from Diabetes Care and it was glucose variability in a 26 week randomized comparison of mealtime treatment with rapid acting insulin versus a GLP1 agonist in participants with type 2 diabetes at high cardiovascular risk. So our A1C is associated with diabetes complications but does not reflect glycemic variability. Glycemic variability might worsen outcomes by inducing inflammation, oxidative stress and cardiac arrhythmias. This trial tested whether a GLP1 receptor agonist based regimen can reduce this variability in cardiometabolic risk factors while maintaining a similar A1C level. After a run in on metformin and basal bolus insulin, 102 participants were randomized to be in the metformin basal insulin arm or randomized to axenatide before the two largest meals of the day. They were followed through continuous glucose monitoring to look at variability. Hypoglycemia weight risk markers and cardiac arrhythmias were assessed. The endpoint was changing glucose coefficients of variation from baseline to 26 weeks. At randomization, the mean A1C was 7.3 and 7.4 in the two arms. The glucose variability was very similar in the two arms at baseline. At 26 weeks, A1C levels were similar 7.1 versus 7.2, whereas the variability improved in the GLP insulin group. There was no difference in hypoglycemic events. There were changes in body weight. A decrease in 4.8 in the GLP1 arm versus a gain of 0.7 kilos. There were some changes in AST and serum amyloid ratios.
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Neil John we know that over time, as patients have diabetes for longer periods of time, they have increased variability of glucose, meaning basically the excursions of glucose after eating are much greater than that for people without diabetes. We also know that for people on basal insulin, while basal insulin is obviously incredibly helpful at lowering a 1C, it works primarily or more on fasting glucose than on post prance glucose. And what this trial shows is that a short acting GLP1 exenatide decreases the postprandial glucose excursions. We know that and thereby decreases glucose variability. So those are all important things. What we don't know though is that even though it's suspected that increased glucose variability leads to inflammation and may be correlated with important outcomes end organ damage, we actually don't have good data now that shows that decreasing glucose variability improves those outcomes. That's the linchpin here. That would at some point be incredibly helpful and important if we're going to make the leap from saying short acting GLP1 agonists like exenatide that this trial clearly shows decreases glucose variability actually leads to improved outcomes. Nonetheless, this is an important study and shows the effect of exenatide on decreasing glucose variability, which brings glucose control closer to normal for patients with long standing diabetes. Our next study is from Clinical Diabetes on advances in insulin therapy. A review of new insulin glargine 300 units per milliliter in the management of diabetes. The use of long acting insulin analogs has contributed in important way to improvements in diabetes management over the past decade. Recently, newer basal insulins have been developed that have even longer durations of action with less variation in blood glucose control. And with these there's been a trend toward reduction in nocturnal hypoglycemia. These new basal insulins include insulin Deglodex and new insulin Glargine 300 units per milliliter. This article concentrates on insulin Glargine 300 units per ML. Glargine 300 is a new formulation of insulin glargine that delivers the same number of insulin units as Glargine 100, but in one third of the injection volume. The pharmacokinetic and pharmacodynamic studies have shown that after injection, Glargine 300 is released more gradually from the subcutaneous depot than Glargine 100, giving Glargine 300amore consistent pharmacokinetic profile and importantly A prolonged duration of action beyond 24 hours. Glargine 300 was approved by the FDA in early 2015. The main studies of Glargine 300 were in the addition clinical trial program. The primary endpoint in all the studies was non inferiority for a 1C change from baseline in month six and the main secondary endpoints in the Trials with type 2 diabetes was the percent of participants with greater than 1 nocturnal confirmed or severe hypoglycemia from week 9 to week 6. Data from the four studies of glargine 300 in people with type 2 diabetes have shown similar reductions in A1C compared to glargine 100 and a decrease in the amount of the secondary endpoint of nocturnal and severe hypoglycemia. There was also less weight gain with Glargine 300 than with Glargine 100 in one of the trials and there was weight loss in another trial. In type 1 diabetes, treatment with Glargine 300 and Glargine 100 led to similar reductions in A1C over a six month period. Looking at safety, clinical trials of Glargine 300 have not highlighted any unique adverse events arising from the use of this new formulation. There was no evidence of increased injection site reactions for 300 compared to 100.
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John so anytime we have a new novel agent, I think we need to think about how this fits in. So what I think would be the advantages of this 300 unit long acting glargine. Well, one is I think it has a longer half life. So I think we have a lot of people who are on Glargine right now that are receiving two doses in a day. I'm hopeful we'll be able to using this product use once a day. I think we have people who have more hypoglycemia risk and if this indeed has a lower hypoglycemia risk, I think that's a huge safety issue. I think we have people who have insulin resistance who are receiving more than 100 units a day of Glargine. You know, you can't fit more than 100 units in a standard syringe. So I think for those folks, I think it's going to be a very good product and I think it's kind of going to be very interesting. What are the downsides to it? So I think when we think about safety, I think if we have people who are used to drawing up a product that is 1/3 as strong, we really need to educate people on that the volumes are going to be smaller. So that eye test, am I taking enough insulin? Needs to be important and I think use of pens and things like that can help control a little bit of that. But people who are using that eye test based on volume, I am worried kind of safety wise with that. But I think this is an exciting product and we'll see what happens with it. Our next article is from Diabetes Care and it looked at the addition of liraglutide to insulin in patients with type 1 diabetes. A randomized placebo controlled clinical trial for 12 weeks, the researchers investigated whether the addition of three different doses of liraglutide to insulin in patients with type 1 diabetes resulted in significant reduction in glycemia, body weight and insulin dose. The researchers randomized 72 patients to forearms, placebo and three separate doses of liraglutide. All the patients had type 1 diabetes and they were followed for 12 weeks. What they found that in the 1.2 milligrams and 1.8 milligram groups the mean weekly reduction in average blood glucose was significant when it was not found to be significantly changed in the 0.6 mg liraglitude in the placebo group. In the 1.2 mg liraglutide group, the A1C fell significantly by 0.78. Why it did not in the 1.8 mg group and the 0.6 mg group, glycemic variability was reduced. In the 1.2 mg group only. The total daily insulin dose fell significantly only in the 1.2mg and 1.8mg liraglutide groups. There was a 5 kilo weight loss in the two higher dose groups. Overall, liraglutide led to higher gastrointestinal adverse events and there was more time spent in hypoglycemia.
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Neil John this is an interesting trial and it raises the question first, when I saw the title, why would I think a GLP1 would be effective in type 1 diabetes? Because incretin mimetics essentially work by enhancing insulin secretion in a glucose dependent manner after eating. So what the trial essentially showed I'm going to focus on one piece here was that in the 0.6 and the 1.8 milligram group there was not a change in A1C but in the 1.2 milligram group there was a significant improvement in hemoglobin A1C. Why might that be? Well, with 18 people in each arm. It's not surprising that the groups were inconsistent with regard to a number of parameters, one being BMI. Two milligram group had a significantly higher BMI 33 than the other three groups where the BMI was 26 to 28. It may be that liraglutide has a greater effect in patients with type 1 diabetes who are overweight by virtue of the very significant weight loss that you get with GLP1s and perhaps with that weight loss decreasing some insulin resistance even in obese patients with type 1 diabetes. I think this is an area where there will be more study and there will be more to come. Our next article is from Diabetes Care on the benefits for type 2 diabetes of interrupting prolonged sitting with brief bouts of light walking or simple resistance activities. The goal of this study was to determine whether interrupting prolonged sitting with brief bouts of intense walking or simple resistance activities improves postprandial cardiometabolic risk markers in adults with type 2 diabetes. In a randomized crossover study, 24 inactive, overweight, obese adults with type 2 diabetes with an average age of 62 years underwent the following 8 hour conditions on 3 separate days with 6 to 14 days in between uninterrupted sitting which was the control group, sitting plus three minute bouts of light walking every 30 minutes and sitting plus three minute bouts of simple resistance exercises composed of half squats, calf raises, gluteal contractions and knee raises every 30 minutes. Compared with the control group that just sat. Both activity break conditions significantly attenuated the area under the curve for glucose and for insulin and C peptide.
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John so I think this is a very interesting study when you look at the 20th century when we were mostly a manufacturing economy that workers who had problems was often musculoskeletal. I was working on a factory and I'm doing one particular thing all day so I would develop a problem with my wrist or elbow or shoulder. Now that we've become mostly a service economy and large number of the US employed population are sitting, feeding some type of computer or answering a phone all day. Perhaps the new OSHA related diagnoses are not so much musculoskeletal but are metabolic. So are we. Is obesity and diabetes an offshoot of what we've created as an economy? So certainly there are people who are being fairly ingenious to look at this. You could go on any kind of online site and there's a whole assortment of treadmill desks where you can kind of stand and kind of walk one, one and a half miles an hour as you do your thing, you can. I just saw last night on television a desk that kind of pops up as a standing desk. So I think certainly if we are in the workforce and we have employees who are sitting all day, that maybe we do need to encourage people that every 30, 45 minutes they should get up from their desk, walk around the office and move on from things to kind of help with their own health. We've seen in plenty of studies over the years that small little exercise things, parking your car further away, walking one flight of steps do make a difference. And I think we're seeing this very modest, small study that perhaps for the average worker, having something that people get up and move about regularly might lead to healthier workers in the long term. Our next article is from Diabetes Care and it looked at the role of the gut in glucose homeostasis. The function of the GI tract is to play a major role in the regulation of of postprandial glucose profiles. Gastric emptying is a highly regulated process which normally ensures a limited and fairly constant delivery of nutrients, glucose to the proximal gut. The subsequent digestion and absorption of nutrients are associated with the release of a set of hormones. This feeds back to subsequently regulate gastric emptying and regulates release of insulin, resulting in down regulation of hepatic glucose production and deposition of glucose in insulin sensitive tissues. So overall, to think about the incretin effect, we will have different responses to intravenous and oral glucose. So through the use of hormones, different loads of oral glucose will basically result in a normal system for the same amount of glucose getting into the bloodstream, whereas if you're using it intravenously, it'll be dose dependent. So this incretin effect, if healthy, will try to keep a regular steady state of insulin depending on what we are eating. And this is the incretin effect. So overall, how does the gut respond to an intake of food? Well, it responds differently. If something is taken in intravenously versus something that is orally. So if I'm giving someone intravenous glucose, there's going to be a dose response curve seen. If I'm giving someone subsequent larger amounts of glucose orally and someone has an intact system, there's going to be a fairly consistent amount of glucose that's going to be presented to the small intestine and this is called the incretin effect. And this is impacted by the two incretin hormones, GIP and GLP1. So we are set up to have a fairly steady state of glucose kilocalories per minute that it's finding its way into the gut. We get into the gut and then we have an SGLT1, not an SGLT2, but an SGLT1 that helps transport glucose through the system. We then get to the liver and as we know, the liver is really one of the main targets for insulin action in the postprandial situation. So hepatic glucose production is effectively shut down where hepatic glucose uptake is enhanced. However, a considerable part of absorbed glucose passes through the liver, so there is a rise in plasma glucose concentration. So simultaneously the glucose uptake in tissue expressing GLP transporters or glut, increases the function as increased glucose concentration. Normally after glucose ingestion, secretion of glucagon falls, which together with rising glucose and insulin concentrations, accounts for a decrease in hepatic glucose production.
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Neil John, that's a nice overview of the importance of the incretin system in regulating glucose homeostasis. It really is a pretty complicated area and for those of us who take care of diabetes, the change from the old days where we thought that diabetes type 2 was just a product of insulin resistance and not enough insulin, to the current thinking with the ominous octet where diabetes is a product of effect of the brain, liver, gut, alpha cells, beta cells, adipose tissue, muscle and kidney, has really made it more and more challenging for us in primary care to wrap our heads around what's going on. But it's really important too, because as you really well pointed out, two new classes of agents, DPP4s and GLP1 receptor agonists, are intimately involved in facilitating glucose homeostasis in patients with diabetes through their effect on the incretin system in the gut. And it's incumbent upon us who take care of patients to really do our best to understand these increasingly complex systems, because that understanding directly relates to our comfort in using these incredibly potent and important medicines for our patients. 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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Sa.