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Diabetes Core Update
Diabetes Core Update May 2014
00:22:50
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]
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. Skolnick.
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B
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 a really great issue this month, starting with the use of anti diabetic drugs in the United States. An overview of published in Diet Diabetes Care, then a study that looked at second line agents for glycemic control, also in Diabetes Care, followed by predictors of metabolic healthy obesity in children from Diabetes Care, then an article from Diabetes on the risk of cardiac arrhythmias during hypoglycemia, followed by another article from Diabetes, an intriguing one on microbiologic gut flora possibly causing obesity, published in Diabetes and finally from Diabetes Care, an article on the relationship between alcohol and vascular complications and mortality in patients with type 2 diabetes.
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Our first article is from the March edition of Diabetes Care and looked at use of anti diabetic drugs in the United States between 2005. The researchers wanted to examine market trends for antidiabotic drugs, so through the use of several established databases, they looked at the prescriptions that were dispensed from US retail pharmacies from the period of 2003 to 2012. Since 2003, the number of adult anti diabetic drug users increased by 43% to 18.8 million users. Metformin use almost doubled to up to 60.4 million prescriptions dispensed in 2012. Among the newer antidiabetic drugs that were released between 2003 and 2012, the DPP4 inhibitor sitagliptin had the largest share with 10.5 million prescriptions. Rosiglitazone use plummeted to less than 13,000 prescriptions dispensed in retail or mail order pharmacies in 2012. In looking at metformin use, about 45% metformin use was for monotherapy between 33.4 and 48.1% of sulfonylurea DPP4 thioglitazones GLP1 analogs was not accompanied by metformin.
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Neil John, this is an important article and I think has a number of important points contained within it. Point number one is simply that use of anti diabetic drugs increased by the number of users increased by 43% to 18.5 million people in 20002012 compared to 2003. Point number two is that use of metformin doubled over that almost 10 year period. That's important because metformin clearly is the recommended first line agent by the American Diabetes Association. That leads to point number three, which is about a third to almost 50% of use of other agents was not with concomitant Metformin. And it reminds us to think about fundamental one, to think about using Metformin first. But also we don't know if a lot of that use was due to intolerance to metformin, particularly GI side effects which we've all seen in many of our patients, leading to point number four which is that we still see a lot of use of sulfonylureas. I personally think this is a good thing. They're medicines that many of our patients can afford easily. They're on the phone $4 medicine list in many large pharmacies and an important group of medicines, even though as side effects they can cause weight gain and have a higher incidence than other medicines of hypoglycemia. And then the increased use of important new agents, particularly the DPP4s and the GLP1s that they have advantageous qualities, the lack of weight gain or actually weight loss, low incidence of hypoglycem. Clearly we're seeing a lot of that usage. It'll be interesting whenever the next rendition of this study comes out in perhaps five years, what the uptake of the SGLT2s will be. And finally the fact that the medical community really does respond importantly and quickly to safety concerns. And we see a dramatic drop in the use of TZDs with almost disappearance of use of Rosiglitazone in about half of the use currently as there was 10 years ago in pioglitazone due to presumably concerns about cardiovascular issues in bladder cancer. So this gives us a nice overview of the lay of the land of prescribing of anti diabetic drugs. Our next article is from diabetes care titled second line agents for glycemic control for type 2 diabetes are newer Agents Better? In this article the authors developed and validated a new population based glycemic control model that Simulates natural variation in a 1C progression. They compared treatment intensification of metformin monotherapy with sulfonylureas, DPP4 inhibitors, GLP1 agonists or insulin. Outcome measures included life years, quality adjusted life years, mean time to insulin dependence and expected medication cost per quality year of life from diagnosis to first diabetes complication, either ischemic heart disease, MI CHF, stroke, blindness, renal failure or amputation or death. Results showed that according to their model, all regimens resulted in similar life years and quality adjusted life years regardless of glycemic control target that was assessed. But the regimen with sulfonylureas incurred significantly lower cost per quality adjusted life year and resulted in the longest time to insulin dependence.
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John so I thought this was an interesting study. I'm not always sure what to do with these studies that look at quality adjusted life years and you see different dollars for things that it's not really clear what the perspective is for this. Overall I think what it would say is the sulfonylureas are still a good class of medicines to use. They're affordable for a lot of folks and a lot cheaper than a lot of the other add on agents. If you look at the quality adjusted life years between sulfonylurea and the most expensive regimen, it was probably about $150 a year which doesn't seem like kind of a night and day difference in dollars. And the difference between people moving on to insulin was somewhere about three to four months. So overall, you know, it's not an earth shattering improvement. And I think when you think that the sulfony areas are much more likely to cause hypoglycemia than either the DPP4s or the GLP1s, I think you know that increased potential safety and we're going to talk about hypoglycemia and EKGs later in the program. So I'm not completely sure what that hundred and fifty dollars is worth. I'm not sure if that three month delay in getting to insulin is really a significant one or not. And all the attendant costs once we are more worried about hypoglycemia with people or buying more test strips etc, etc, So I think the sulfonylureas, you know, are good. I think all the second line agents beyond metforminol all have some warts on them and I think, you know, coming back to what the ADA says is we really should individualize our care for our patients. Our next article is from the February 2014 edition of Diabetes Care and it looked at predictors of metabolically healthy obesity in children. This cross sectional study included children between 8 and 17 years of age who had BMIs that put them in the 85th percentile or greater. They all were enrolled in a multidisciplinary pediatric weight management clinic from the period of 2005 to 2005 2010. They were followed with various demographic, anthropometric, lifestyle and cardiometabolic data through the medical record review. Participants were put in either a metabolically healthy or metabolically unhealthy obesity group according to two separate classifications. One was based on insulin resistance and the other was based on cardiometabolic risk factors which included blood pressure, lipids and glucose. The prevalence of metabolically healthy obesity and insulin resistance was 31% and metabolically healthy obesity and cardiometabolic risk factors was 21%. Waist circumference and dietary fat intake were independent predictors of metabolically healthy obesity. Of insulin resistance, moderate to vigorous physical activity was the strongest independent predictor of metabolically healthy obesity with cardiometabolic risk.
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Neil John I think this article is a good one to discuss because it introduces, for people who haven't heard it before, the term metabolically healthy obesity. It's a term that was coined about 15 years ago but has received increased attention recently as a way of parsing out how to direct our largest efforts. Among the large proportion, currently a third of the United States population, that's obese. So the idea here is that those who are both obese but also metabolically unhealthy, that is who have insulin, either have insulin resistance or cardiometabolic risk factors, should receive more vigorous attention with regard to weight loss. Whether or not that ends up being an important concept we don't know because there aren't follow up studies. In adults, about 40% of those who are obese fall into the metabolically healthy category. Here what we're seeing is it's also an important category for children. So about a third of children fall into the metabolically healthy category. Interestingly, who falls into that category depends how you define it. So of those who were so if we look at metabolically healthy, there was only about a 50% correlation between those who were defined as healthy by not having insulin resistance or by not having metabolic risk factors. What I also think is important here though is what influences metabolically healthy obese versus those who are unhealthy and the two modifiable risk factors that seem to come out as you mentioned, are dietary fat intake influencing insulin resistance and physical activity as being an independent predictor of metabolically healthy with regard to cardiovascular risk factors. So this may prove or may not prove long term to be an important concept, but it's one that's helpful to be aware of as it's become more common in the literature. Our next article is from Diabetes titled Risk of cardiac arrhythmias during hypoglycemia in patients with type 2 diabetes and cardiovascular risk. In this study, 25 insulin treated patients with type 2 diabetes and a history of cardiovascular disease or two or more risk factors underwent simultaneous continuous interstitial glucose and ambulatory electrocardiogram monitoring. Frequency of arrhythmias, heart rate variability and markers of cardiac repolarization were compared between hypoglycemia and euglycemia and between hyperglycemia and euglycemia matched for the time of day. There were 134 hours of recording at hypoglycemia, 65 hours at hyperglycemia, and 1,258 hours of euglycemia. Bradycardia and atrial and ventricular ectopic counts were significantly higher during nocturnal hypoglycemia compared with euglycemia. Arrhythmias were more frequent during nocturnal versus daytime hypoglycemia. Excessive compensatory vagal activation after a counter regulatory phase may account for bradycardia and associated arrhythmias. QT intervals corrected for heart rate greater than 500 milliseconds and abnormal t wave morphology were observed during hypoglycemia in some participants. Hypoglycemia, frequently asymptomatic and prolonged, may increase the risk of arrhythmias in patients with type 2 diabetes and high cardiovascular risk.
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John, this was a pretty amazing study, I think, and there certainly have been other studies before that have talked about EKG changes with hypoglycemia, but to me this was kind of a real time study and they hooked people up to a halter monitor and had continuous glucose monitoring and just kind of sat back and looked to see what happened. So what have we learned over the last, you know, four or five years? Well, I think we've certainly learned that tighter control in older folks with diabetes often leads to an increased mortality rate. And this might explain that, you know, having a prolonged QTC maybe doesn't matter as much if you're a, you know, 17 year old type 1 diabetic, but certainly if you're an older patient and you have a prolongation of your qtc, you're much more likely to be on some medicines that impact that. Some of the other studies that have looked at this have also found that people with autonomic neuropathy are more likely to succumb to this problem. And oftentimes the blood pressure problems or the EKG problems that we see often occur more often overnight. So if a older diabetic patient has a cardiac dysrhythmia and dies in the night, no one really knows why. They just say, well, cardiovascular, it's a cardiovascular equipment risk equivalent and someone just died. So certainly this would be another thing to me to say, maybe I need to be a little bit more careful in putting our older patients who are at risk for arrhythmias, people who might already have a prolonged QTC, in situations where they're going to have hypoglycemia. Maybe I'm going to be more careful in people who have a history of autonomic neuropathy. And just to be mindful that hypoglycemia again is a risk, we've seen multiple studies in the last year that have shown that people who have hypoglycemia significant enough to take them to an emergency room are at increased risk for some mortality down the line. And I think now we have some information on what causes it. Our next article is from diabetes, the January 2014 edition, and it looked at the replication of obesity and associated signaling pathways through the transfer of microbiota from obese prone rats. So in this particular study, the researchers looked at the difference in the gut flora of obese prone and obese resistant rats and examined the contribution of this flora to both the behavioral and metabolic characteristics during obesity. They found that the obese prone rats display a distinct gut flora compared to obese resistant rats that were fed the same high fat diet. The transfer of this flora from obese prone but not obese resistant rats to germ free mice replicated the characteristics of the obese prone phenotype which was reduced intestinal and hypothalamic satiation, signaling, hyperphagia, increased weight gain and adiposity and enhanced lipogenesis and adipogenesis.
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Neil John I think this is a mind boggling article and if you think about it, years ago, not that many years ago, it would have been hard to believe that peptic ulcer disease could be linked to a bacteria. H. Pylori what this study is essentially doing is using Koch's postulate, the idea that you can isolate an infectious agent from one source and then take it and infect another uninfected source and reproduce the symptoms and does that with regard to obesity, the fact that they took obese. Now it's clear that obesity is a multifactorial illness and I can comfortably say illness or disease because this past year the AMA declared that obesity is a disease. It is also at the same time a risk factor for lots of other diseases, including importantly diabetes. But what these authors did that is truly unique is looked at whether or not there can be a relationship between gut flora and transference of gut flora to uninfected, in this case rats and reproduce, things that would lead to obesity and in fact cause weight gain. Those things that led to obesity with changing of flora included increased gut permeability, increased inflammation, increased signaling and decreased satiety. So this is an area to watch and I'm excited about the idea and excited to see if this will be replicated in other studies and if it in fact will end up being an important mechanism by which people become obese. The next study is titled the Relationship between Alcohol Consumption and Vascular Complications and Mortality in individuals with type 2 diabetes. Published in Diabetes Care, this study looked at the effects of alcohol use among participants in the advanced trial. During a median of five years of follow up, 9% of patients in the trial died, 10% experienced a cardiovascular event and 10% experienced a microvascular complication. Compared with patients who reported no alcohol consumption, those who reported moderate consumption had fewer cardiovascular events about 17%, fewer, less microvascular complications about 15% and lower. All cause mortality 13% lower. The benefits were particularly evident in participants who drank predominantly wine with a decrease in cardiovascular events of 22%. All cause mortality of 23%. Compared to patients who reported no alcohol consumption, those who reported heavy consumption had dose dependent higher risks of cardiovascular events and all cause mortality.
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Sean so this is something I think we've been kind of dancing around for many years and speaks a little bit to the French paradox and that the French smoke at a higher rate and often eat kind of creamier foods, yet have a lower cardiovascular disease rate than we do here in the United States. And people have often postulated that it is due to their alcohol consumption. Other studies like the Leon Heart Trial that looked at a Mediterranean diet that showed a significant decrease in cardiovascular re events compared to a standard cardiac diet. It becomes very hard for us to recommend alcohol to patients because certainly we see the amount of mortality and morbidity that alcohol causes in many, many patients lives. It's not completely clear what the mechanism of action is that's happening from the consumption of alcohol, it doesn't really have an appreciably huge impact on our lipids. In fact, when we drink too much alcohol, it increases our triglycerides. So whether it's a little bit of the anti inflammatory effect, whether it is a slight increase of the hdl, but certainly people having one or two drinks a day for a man or one drink a day for a woman certainly could have some cardiovascular benefits. This particular study said that wine did so much better. Other studies really have not broken this down to different things, but certainly wine has been around for as long as people have been around, and it makes people happy. It makes many religious ceremonies go better and sweetens life. So drink up.
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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. Sa.