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Diabetes Core Update
Diabetes Core Update 8/10/2013
00:18:35
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 Diabet
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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 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 from Diabetes on expansion of both exocrine and endocrine pancreas with incretin therapy in humans, as well as increased potential for dysplasia and the potential for glucagon producing neuroendocrine tumors. Then we have a point counterpoint published in Diabetes Care on the benefits of and the risks of incretin therapy. And finally, the last article that we'll review in this issue is on exercise training and its effect on quality of life in individuals with type 2 diabetes.
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Our first article is from Diabetes, the July 2013 edition. This study looked at the expansion of exocrine and endocrine pancreas with incredin therapy in humans with increased exocrine pancreas, dysplasia, dysplasia and the potential for glucagon producing neuroendocrine tumors. In this particular study, the researchers looked at postmortem studies of pancreases in patients with diabetes treated with incredin therapy. Diabetics not treated with incredin therapy and age match controls with eight folks in the first group, 12 in the second and 14 in the third.
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Okay.
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Overall, the researchers found that there was a 40% increase in pancreatic mass in the diabetic patients who were treated with incredin therapy. There was an increase in exocrine cell proliferation and dysplasia. The pancreas and diabetic treated with incredin therapy were notable for alpha cell hyperplasia and glucagon expressing microadenomas and a neuroendocrine tumor. The beta cell mass was reduced by 60% in those with diabetes, yet there was a six fold increase observed in incretin treated subjects although they continued to have diabetes endocrine cells. CO staining for insulin and glucagon were increased in diabetic compared with non diabetic control subjects and markedly there was a further increase by incretin therapy. So overall, in conclusion, the incretin therapy in humans resulted in a marked expansion of the exocrine and endocrine pancreatic compartments and the former being accompanied by increased proliferation and dysplasia.
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Neil John, this is a potentially critically important article. On the one hand, there's a bit of excitement, more than a bit of excitement about the fact that incretin therapy may increase pancreatic mass. And I think early information about that made people think that perhaps it could actually, actually reverse diabetes. Because as we saw in this article, pancreatic mass in patients with diabetes compared to normal controls, pancreatic mass is smaller, but it's larger than those treated with incretin therapy. The problem is that one that increased pancreatic mass doesn't necessarily mean that it's functional mass because other studies have not shown a reversal of diabetes with increname therapy. More importantly though, is the study's implications about safety of incredin therapy. One, because there's increase in alpha cell mass which surrounds ducts and ductal hyperplasia, it gives some underlying pathophysiologic mechanism for the reports of an increased incidence of pancreatitis with this of medicines. Now that increased risk of pancreatitis is not solidly confirmed in the literature. It's been recognized as a possibility, is currently being monitored for because we know that diabetics in general have an increased rate of pancreatitis. But this would lend some underlying pathophysiologic reasons why that might be so. More important is the findings of microscopic dysplasia and microadenomas in pancreases from patients who had died for other causes, from other causes, but who had their pancreas analyzed after being on incredin therapy. And this is potentially a very important signal to pay attention to. And we'll have to watch more because the question is ultimately going to be at what point does this become concerning enough? And we don't know whether these microadenomas simply are there or whether they will progress to cancer. And we don't know whether incretin hormones are actually not necessarily cancerogenic, but may be similar to what estrogen is in breast cancer. If there's a tendency toward breast cancer, estrogen may increase that tendency. And people who have a predilection toward developing microadenomas or might have microadenomas that never become clinically relevant. Does this class of medicine suddenly increase the progression of microadenomas onto cancer? We don't know at this point, but this adds to the current state of the art and it raises some concerns for which currently there isn't a clear conclusion.
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Next we're going to review two point counterpoint articles that were in the July issue of Diabetes Care looking at the safety of incredin based therapies. Glucagon, like peptide based therapies, have many actions. The GLP1 increases insulin secretion, inhibits glucagon release and delays gastric emptying. GLP1 receptors are not just pancreas based but are also found in thyroid, bone and renal tubules in the pancreas. GLP receptors are expressed in the pancreatic duct and isolates. It is possible that the exocrine proliferation from the GLP can be related to pancreatitis from causing ductal occlusion. In both observational and epidemiologic studies there has shown increased rate of acute pancreatitis in diabetic populations. There were increased cases of pancreatitis in the first year with azenatide and with other GLP1 based therapies. But overall the main concern is not just pancreatitis but but the implication stemming from pancreatitis. Meaning does the pancreatitis lead to cellular changes that leads to dysplasia? There's a Significant database for GLP1 receptor and DP4 inhibitors of cancers of the pancreas. So overall the question that remains is is there low level pancreatitis that is happening from ductal hyperplasia that leads to potentially leads to pancreatic neoplasia? And the question in the negative for these medicines is this another diabetic medicine that was rushed through market that had safety concerns that emerged post hoc that even when safety concerns are being initially raised that they are being discounted and not taken seriously as they should be?
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Neil the second part of this point counterpoint article by Michael Nouk discusses that the benefits outweigh the potential risks. In this part of the article he talks about the fact that there are signals that have suggested some effects of the incretin class of medications, particularly with regard to pancreatitis, pancreatic cancer and thyroid carcinoma and he critically looks at those signals and weighs them against known benefits, particularly with regard to pancreatitis. An initial article showed an odds ratio around 1 but with wide confidence intervals. Then another article showed an actual tenfold increase in pancreatitis in patients using exenatide or sitagliptin. This exception to these studies that are out there was based on an analysis of the United States Food and Drug Administration Adverse Event Reporting System. The concern that is raised about this system is that once people are alerted to the fact that pancreatitis might be occurring with incretin medications that it might lead to some reporting bias of pancreatitis in people who are on incretin medicine medicines. A recent case control study reported a higher odds ratio for the risk of hospitalization for a diagnosis of pancreatitis in patients taking incretin based medications. The concern though that's raised in this article is that there wasn't in that trial and in others that reported pancreatitis clarity about how the diagnosis was made. And while we know that pancreatitis is more common in all patients with diabetes compared to those who don't have diabetes, it also turns out that there are mild elevations of amylase and lipase levels in patients with diabetes that might be misinterpreted as representing pancreatitis. So his feeling was that it can't be taken as fact that chronic stimulation of the GLP1 receptors that occurs with any incretin mimetic induces acute or chronic inflammatory responses that are in fact pancreatitis. The next issue that he looks at is pancreatic cancer and there's acknowledgement that there's early evidence that there might be an increase, as we talked about in our first article of dysplasia and microadenomas. But the context that this is looked at in this article is that these are potential risks and that they're not necessarily an actual threat to patients until they are proven as such. With regard to thyroid carcinoma, it's clear that GLP1 receptor agonists have the potential to induce proliferative changes in rodent thyroid cells and that GLP1 receptor expression is there in human thyroid. But it's not clear that and there aren't reported cases of a direct causation of incredin mimetics causing thyroid cancer in humans. On the positive side, this article discusses cardiovascular risk factors and outcomes with incredibimetics. There are a number of studies that have looked at cardiovascular outcomes. None of them are large enough to have conclusive evidence of a positive or negative effect, but they suggest not reaching statistical significance that there might be a benefit and that benefit might be derived from a reduction in systolic blood pressure of about 2 to 5 points and a better outcome with regard to body weight with incredibly mimetics than with other diabetes medicines. Regarding the properties of incredin based medications as anti diabetic drugs, the author goes on to say they're effective in lowering glucose and avoid the problems with some of the other classes of glucose lowering medications, particularly problems with hypoglycemia and weight gain, and may have positive benefits on aspects of cardiovascular profiles. That's known effects regarding issues related to potential short term induction of acute and long term risk for chronic pancreatitis and eventually pancreatic cancer, the author feels that the data at hand does not convincingly prove that those risks are clear risks and that the thyroid cancer risk issue is also unresolved. So concludes the author and I'll quote from his last paragraph. While the benefits expected are proven from using incredibly based medications seem to be substantial and address risks central to patients with type 2 diabetes, the potential harms and risks typically refer to rare events and are discussed in a controversial manner.
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John so in summary we've looked at very important classes of medicines and I think we do not want to lose the pros or the cons and the overall kind of take away points from this. So when you're looking at the incredin based therapies, I think some of the things we need to remember are a lot of the good things that come from it. So these are medicines that do not cause hypoglycemia, these are medicines that cause weight loss. These are medicines that do pretty well in how they interact with other medicines. There needs to be some adjustment for renal coverage for the renal dosing for these but overall pretty well tolerated. They decrease blood pressure by about 2 to 5 millimeters of mercury which is comparable to some of the differences that we saw in the all hats study. And overall they are more durable than the sulfonylureas. And looking at the GLP medicines you can get perhaps a two point decrease in an A1C with that and exenatide can be given once a week. So clearly some very positive things from these categories. I think the negatives from the two categories is certainly there can be GI side effects. Withdrawal happens of the medicines in about 3 to 8%. The pancreatitis issue I think is an issue that I think we have to keep our antenna up for. Overall I think we need to wait for more studies to definitively look the cancer issues, especially the cancer of the pancreas, much more than the thyroid cancer and a couple points of heart rate probably is not an overall huge increase. But I think the overall takeaway point that we should have is diabetes is a top 10 killer in the United States. And it would be in an ideal world we wouldn't have to give people any medicines. And every one of the medicines we're going to give people for diabetes carries its own bag of hammers. And suddenly I think we're finding some new things from these classes of medicine that at least we need to be cognizant of as data comes in. Our last article is from the July 2013 edition of Diabetes Care and this study looked at exercise training and quality of life in individuals with type 2 diabetes. This randomized controlled trial, which was part of the Heart D trial, Health Benefits of Aerobic and Resistant Training and individuals with type 2 diabetes, was a nine month exercise study that compared the effect of aerobic training, resistance training or a combination of resistance and aerobic training versus a non exercise control group on hemoglobin A1Cs in sedentary individuals who had type 2 diabetes. Overall, the sample had a higher baseline quality of life compared to the United States national norms. The Quality of Life Physical Component Scale and the General Health subscale were improved by all three exercise training conditions compared with the control group. The resistance training group had the most beneficial changes in bodily pain, whereas physical functioning was most improved in the aerobic and combined conditioning group. The changes in the mental component score did not differ between the control group and any of the exercise groups. The combined training condition group had greater gains than the aerobic training condition group in the mental component score, mental health and greater gains in vitality compared with a control group.
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Neil John, I like this study and the reason why I like it is we know that exercise yields a benefit in terms of reduction of a 1C. We know that from studies like the Diabetes Prevention Program trial that it yields a benefit in decreasing the progression from prediabetes to diabetes. We've seen in other trials that exercise has a positive effect in ameliorating depression. It's nice now to see clarity that it has a generalized good effect on quality of life in patients with diabetes. We know that patients with diabetes score lower in quality of life indexes in general than patients without diabetes. What do we really care about? We care about how we feel day to day and I think the take home point here is important. Parsing out which is better aerobic or resistance exercises. If you're going to start an exercise program it probably makes sense to do some aerobic exercise and some resistance exercises in order to yield the greatest benefit and that benefit will accrue in many areas, including how you generally feel about your life, which is what Quality of Life Indexes. 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.