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Diabetes Core Update
Diabetes Core Update January 2016
00:21:25
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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- [00:04]
Sam
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.
- [00:38]
Dr. Neal Skolnick
Thank you. It's a pleasure to be here.
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Sam
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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Dr. John Russell
Thank you. I'm looking forward to going over this week's articles.
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Sam
And now for the articles.
- [00:56]
Dr. Neal Skolnick
We have another excellent issue this week, beginning with an exciting article on stem cell Transplants for type 1 diabete published in Diabetes Care. Then an article on lifestyle modification for the prevention of gestational diabetes, followed by an article on alligliptin, a DPP4 and its effect on the development of atherosclerosis. Then an article on a novel insulin peg Lispro insulin, followed by an article that discusses and looks at depression, stress levels and its effect on cardiovascular outcomes in patients with diabetes and those without diabetes. And finally, a really interesting article on the effects of prolonged sitting on glucose metabolism. Our first article, which really is amazing, is on umbilical cord mesenchymal stromal cells with autologous bone marrow transplantation in established type 1 diabetes. A pilot randomized controlled open label clinical study to assess safety and impact the goal of this study was to determine the safety and effects on insulin secretion of umbilical cord mesenchymal stromal cells plus autologous bone marrow mononuclear cell stem cell transplantation without using immunotherapy in established type 1 diabetes. Between January 2009 and December 2010, 42 patients with type 1 diabetes were randomized through to receive supraselective pancreatic artery canalization or standard care, with the canalization delivering the stem cells that we just discussed. At one year, metabolic measures improved in the treated patients. The area under the curve for C peptide increased 105% in 20 of the 21 responders, where it decreased 7% in control subjects. A1C decreased by 13% in the stem cell transplant group to 7.5. In the treated group it increased 1.2% to 8.7. Daily. Insulin requirements actually decreased by about a third only in the treated group, with no change found in the control group.
- [03:35]
Dr. John Russell
John the hockey great Wayne Gretzky used to say, I don't care where the puck is, I care where the puck is going. And certainly stem cell research with regard to diabetes certainly seems a place where the puck is going. We've got 3 million type 1 diabetics in the United States and certainly finding a stem cell an to production of insulin would certainly be a game changer for them. And this research is going on on so many different levels and there's so many different questions that need to be answered. The term stem cell goes back to the 1860s. We've been looking at this in the United states since the 1950s and probably in earnest since the 1980s with regard to using stem cell as a treatment modality, an answer to a problem. So there is research going on in the production of beta cells, there's research going on for stem cells that produce beta cells and alpha cells. And how these stem cells are going to be delivered I think is going to be a question how these stem cells are going to be produced and how we can have these stem cells exist in a way that has them not being attacked by our innate immune system. So this is the first, I think of many, many papers to come and I think we're going to see some exciting things coming in this avenue of research. Our next article is from the January edition of Diabetes Care and it looked at gestational diabetes prevention, the finished gestational diabetes prevention trial. So in this trial there were 293 women that either had a history of gestational diabetes or a pre pregnancy BMI of greater than 30 that were enrolled in the study at under 20 weeks gestation. They were randomly assigned to either an intervention group or a control group. The subjects in the intervention group received individual counseling on diet, physical activity and weight control from trained study nurses and had one group meeting with a dietitian. The control group received standard antenatal care and the diagnosis of gestational diabetes was made on a two hour glucose tolerance test between 24 and 28 weeks gestation. Of the 269 women included in the analysis, the incidence of gestational diabetes was 13% in the intervention group and 21% in the control group. After adjustment for age, pre pregnancy bmi, previous gestational diabetes status and the number of weeks gestation, gestational weight gain was lower in the intervention group by half a kilo and women in the intervention group increased their leisure time, physical activity more and improved their dietary quality compared with women in the control group.
- [06:08]
Dr. Neal Skolnick
Neil John this is an important study. We live in an age where approximately 60% of the population of women who are becoming pregnant are either overweight or obese, and 15% of women who are pregnant develop gestational diabetes. The impact of gestational diabetes is large. Roughly 10% of those women go on to develop type 2 diabetes in the year or so after delivery. And over the 10 years after delivery, up to two thirds of those women go on to develop type 2 diabetes. The impact of gestational diabetes does not stop with the woman alone, but their children have a higher risk of developing type 2 diabetes and actually have impaired glucose metabolism at a higher rate early on in childhood. So the need to do something is large. This study was modeled after the classic study, the DPPT trial or the Diabetes Prevention Program trial, which used lifestyle modifications, I.e. diet and exercise, to decrease the rate of progressing from prediabetes to diabetes by approximately 60%. That trial was then replicated in the finished Diabetes Prevention Program study. Now we see the finished gestational Diabetes Prevention study. And what's interesting about this study is also its protocol, which, as you went over, is not that intensive. And even at a protocol that was not incredibly intensive, the effect we see is a decrease of approximately one third in the development of gestational diabetes. What does this tell us? How does this inform us? I think what it tells us is that we can do something. When patients come into their pregnancy either overweight or obese, they very simply should be enrolled or should be encouraged to carry out an intensive lifestyle modification program. And now there is good hard evidence that that intensive program can make a substantial difference. Remember, this doesn't take away the importance of primary prevention and regular diet and exercise in order to decrease the number of people who are coming in either to their pregnancy, either overweight or obese is the area that likely will yield the biggest benefit. But when people are coming in either overweight or obese, this is an important protocol. Our next study is titled allogliptin A DPP4 prevents the progression of carotid atherosclerosis in patients with type 2 diabetes. The current study investigated the effects of alligliptin, a DPP4 inhibitor, on the progression of carotid atherosclerosis in patients with type 2 diabetes. They looked at 341 patients with type 2 diabetes who were free of cardiovascular disease and entry and recruited at 11 clinical units and randomly allocated treatment to alagliptin. 172 people or conventional treatment, 169 people. The primary outcome was changes in the mean common and maximal intima media thickness of the carotid artery measured by carotid artery echo during a 24 month treatment period. What they showed was that alligliptin treatment had a more potent glucose lowering effect than the conventional treatment, a decrease of 0.3% in A1C without an increase in hypoglycemia. The changes in the mean intimal thickness of the carotid arteries was significantly greater a decreased thickness after alligliptin treatment than after conventional treatment. It decreased in the alligliptin group and slightly increased in the control group.
- [10:17]
Dr. John Russell
John so I'm not completely sure what to make of this study. So carotid intimal thickness studying is something that has a United States preventive task force D rating. So we're looking at a surrogate marker that we're encouraged not to do necessarily in patients. And we see this particular technique used in a lot of statin trials because people do not necessarily want to do do intravascular ultrasounds. People don't necessarily want to do cardiac catheterizations to see the effect of statins. So this particular DPP4 showed some decrease in carotid intimal thickness. But in both groups, in both the control group and the treatment group, less than 50% of the folks were on a statin. So I probably would use this particular DP4 like you would use the other DPP4 and I would be very, very aggressive in getting any of your diabetic patients who are over the age of 40 to be on a statin. Our next article is from the January 2016 edition of Diabetes Care and it was a randomized trial comparing basal insulin, PEG lispro and insulin glargine in patients with type 2 diabetes previously treated with basal insulin. So in this trial that took place over 52 weeks, patients were randomized to either peg lispro 307 patients or Glar's gene 159 patients. It was an open label treat to target study and patients were randomized. The primary endpoint was a change in A1C from baseline to 26 weeks. At 26 weeks, the reduction in A1C was superior in the Peg Lispro group with a decrease of 0.82 versus 0.29 in the glargine group with the PEGLISPRO that was maintained at 52 weeks. More PEGLISPRO patients achieved an A1C under 7% and the PEGLISPRO versus glargine, the nocturnal hypoglycemia rate was 60% lower. There were more patients who had the lower A1C that did not have nocturnal hypoglycemia and total hypoglycemia rates were lower. Also at 52 weeks, triglycerides and transaminases were higher in the PEG list. Pro Group vs Glargine Liver fat content assessed in the subset of patients increased from baseline with Peg Lispro versus Glargine with stable levels maintained between 26 and 52 weeks.
- [12:36]
Dr. Neal Skolnick
Neil John this is an interesting new insulin. Peg Lispro has a greater effect on the liver than on the peripheral tissue and by virtue of that effect has a lower rate of hypoglycemia, a prolonged length of action and greater efficacy than traditional basal insulin. Nonetheless, it also had significant side effects, a small number of patients having increased LFT's though none of them having an effect on the liver to cause increased bilirubin which would be high's law. Remember that would be an important signal and also a number of patients having increased fatty deposition greater than 10% in the liver due to those side effects and potential adverse effects. Lilly announced early in December that it would suspend the drug development program for Peg Lispro. On reflecting on that we really live in an exciting age with regard to drug development. Drug development presents enormous challenges and with that comes responsibility and carefulness that companies have in the decisions about whether or not to move ahead with their drug development program. Tens of millions of dollars must have been spent on that development and early on in drug development. Companies simply don't know whether there will be adverse effects and at what point if there are to continue to pursue their development program to understand better those adverse effects or whether to suspend the program. Lilly in this case with regard to PEG Lispro, after a lot of early clinical trials and then phase three trials, decided in December to suspend the drug development program for peglisprom. Our next study is on the consequences and comorbidities of elevated stress and or depression symptoms in cardiovascular outcomes in diabetes. The objective of this trial was to evaluate the impact of comorbid depressive symptoms and or stress on adverse cardiovascular outcomes in individuals with diabetes compared to those without diabetes. The investigators examined the relationship between baseline depressive symptoms and or stress in adults with and without diabetes and then looked at cardiovascular outcomes including stroke, MI card and cardiovascular death over approximately six years. There were a total of 22,000 adults of whom approximately 4,000 had diabetes with a mean age of 64 years. Elevated stress and or depressive symptoms were More common in subjects with diabetes 37% versus 30% in fully adjusted models reporting either elevated stress or depressive symptoms was associated with a significantly increased incidence of stroke, an increase of about 57% and cardiovascular death 53% in individuals with diabetes, but not in those without diabetes. The combination of both elevated stress and depression in patients with diabetes was associated with a higher incidence of cardiovascular death over a doubling of cardiovascular death than either behavioral comorbidity alone, which increased cardiovascular death by about 50%. And it was higher than those with both elevated stress and depressive symptoms without diabetes, where the increase in cardiovascular death was approximately 30%.
- [16:26]
Dr. John Russell
John, I find this to be a very interesting study and how to apply this. Well one of it will be would be interesting in a follow up study. If you take this cohort of folks who have diabetes and depression and you treat their depression, does their cardiovascular risk factors decrease? And I think that would be very interesting. And perhaps our diabetic patients should all be screened in the office with a, with an instrument like a phq2 where you can ask two questions to see if someone has some depression to see if you should do a PHQ9 screening test in the office to see does this person have some depression? And can I, can I work on this? I think the interesting thing probably would be almost applying that ATP3 model to these particular patients. You know if you had a patient who has just diabetes, perhaps they're LDL, you'd want it 100. Perhaps if someone has depression and diabetes you would aim for an LDL of 70. So I think it's interesting, I think this lends for some more investigation but I think we should be looking at all the different things that influence our diabetic patients and certainly depression is a large part of the population in general as well as specifically our diabetic patients. Our next article is from Diabetes Cancer and it looked at breaking up prolonged sitting with standing or walking and its attenuation on the postprandial metabolic response in postmenopausal women. So this study of 22 overweight obese dysglycemic postmenopausal women with a mean age of 66 had each woman participate in two of the following treatments. Prolonged unbroken sitting for seven and a half hours or prolonged sitting broken up with either standing or walking at a self perceived light intensity of 5 minutes for every 30 minutes the incremental area under the curve for glucose, insulin, non esterified fatty acids and triglycerides were calculated for each treatment condition. The following days all participants then underwent a seven and a half sitting protocol. Compared with a prolonged bout of sitting. Both standing and walking significantly reduced the glucose area under the curve when compared with prolonged sitting. Insulin was reduced for both activity conditions of standing and walking. Both standing and walking attenuated the suppression of the non esterified fatty acid. Compared with prolonged sitting, there was no significant effect on triglycerides. The effects on glucose, both standing and walking and insulin walking only persisted into the following day.
- [18:54]
Dr. Neal Skolnick
Neil John, it's really interesting. We used to think of physical fitness as being attached just to exercise, but there's this whole new area emerging that links sedentary time to cardiovascular risk and that's become apparent in epidemiologic studies. And the study that you just went over gives us the physiologic correlates, the effect on glucose metabolism that explains at least some of the epidemiologic link that we've seen between increased sedentary time and poor cardiovascular outcomes. This becomes more and more important as we live in a society where more and more workers spend much of their day sitting rather than walking around. And we've thought for a long time that we could take care of that by making sure that we get enough exercise. The recommended 150 minutes per week of moderate to vigorous exercise. But what has become apparent, and the term that is used is the exercise and couch potato, is that separate from the amount of exercise you do, you still need to take time during long periods where you might be sedentary to get up, as was described in this study, about every half hour to stand, to walk just for five minutes to offset the negative effects of prolonged periods of sitting. 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
Sam.