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Diabetes Core Update
Diabetes Core Update October 2016
00:23:16
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 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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A
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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C
Thank you. I'm looking forward to going over this week's articles.
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A
And now for the articles.
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B
We have another exciting issue this month, beginning with an article discussing Lorcaserin's effect on food cues as she shown by functional mri. Then a discussion of an article from Diabetes Care on combination therapy with empagliflozin and metformin, followed by an article that looks at once monthly axenatide, then an article from Diabetes Care that looks at pioglitazone in patients with prediabetes after a cva, decreasing the risk of eventual development of diabetes, then an article on the effects of bed rest and decreasing muscle strength and increasing insulin resistance in patients, and finally an article on the use of basal insulin along with GLP1 receptor agonists. Our next study is on the metabolic effects of fatty acid enriched diets compared to carbohydrates enriched diets in patients with type 2 diabetes, published in the August edition of Diabetes Care. Dietary interventions in patients with type 2 diabetes are important as an approach to care. While a healthy diet is critical, there's still uncertainty about the optimal macronutrient composition. In this study, the authors performed a meta analysis comparing diets high in monounsaturated fatty acids to diets high in carbohydrates or to diets that had polyunsaturated fatty acids on metabolic risk factor outcomes in patients with type 2 diabetes. The authors identified 24 studies over 1400 participants comparing high monounsaturated fatty acid diets to high carb diets and four studies comparing two high polyunsaturated fatty acid diets. When comparing high monounsaturated fatty acid diets to high carb diets, there were significant reductions in fasting plasma glucose, triglycerides, body weight and systolic blood pressure, along with significant increases in hdl. When high monounsaturated fatty acid diets were compared to high polyunsaturated fatty acid diets. There were significant reductions in fasting plasma glucose.
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C
John so basically this study is looking at a low fat diet versus a Mediterranean diet. As we learned from the Lyon Heart trial, which had a 76% decrease in repeat cardiovascular events in a high risk population, put on a prudent western diet versus a Mediterranean diet, found that the Mediterranean diet did so so much better. And what we're finding in here in the avenue of diabetes, yes, it does better. So a low fat diet that does not really look at carbs does not do as well as a Mediterranean diet, which is going to emphasize certain fatty acids. So monounsaturated fatty acids. So we're going to talk about olive oil. We're going to Our next study is from Diabetes Care and it looked at an initial combination of empagliflozin and metformin in patients with type 2 diabetes. This study randomized over 1300 drug naive patients who had A1Cs between 7.5 and 12% overall. The mean baseline was around 8.6 to 8.9. The patients were randomized for 24 weeks to either empagliflozin 12.5 mg twice a day and metformin 1000 mg twice a day, empagliflozin 12.5 mg twice a day and metFormin 500 mg twice a day, empAgliflozin 5 mg twice a day and metFormIn 1000 mg twice a day empagliflozin 5 mg twice a Day, metFormin 500 mg twice a Day or monotherapy with empagliflozin at either 25 mg or 10 mg daily or monotherapy with metformin at 1000 mg twice a day or metformin 500 mg twice a day. The primary endput was the endpoint was change in baseline A1C to the end of the study of 24 weeks. At 24 weeks the reduction of A1C was minus 1.9 to minus 2.1% with the metformin and empagloflos in twice daily regimens. The empagloflows in once daily regimens was minus 1.4 and the decreases of 1.2 to 1.8 with metformin twice daily regimens. Reduction in weight at 24 weeks was significantly greater with empagliflozin plus metformin at the twice daily regimen from a loss of 2.8 to 3.8 kg than with the metformin twice daily regimens which show a decrease of 0.5 to 1.3 kg. All of these were statistically significant. The adverse event rates were similar across all groups and no hypoglycemic adverse events required assistance.
- [05:58]
B
Neil John, I think this is really an interesting and important study because remember, it occurs in the context of roughly half of all patients now on oral agents who are not controlled to goal, and it occurs in the context of an enormous amount of clinical inertia that we've discussed on previous podcasts. In fact, in an article that we previously discussed about three years ago in Diabetes Care, we talked about the fact that it takes almost two years for patients who are not controlled on an initial oral antidiabetic medicine to get a second medicine added after they are no longer at their target a 1C. The reason that's important, of course, has to do with other things that we've discussed, metabolic memory and the legacy effect that when someone spends a good portion of their years with diabetes up above their target, essentially with poor glucose control, and we then get them back into control, they still have adverse consequences from those years where they were not in control. So the idea of having better control early on that is more sustainable is very important here. What we're seeing is that we have better efficacy with EMPA plus metformin than we do with metformin alone. And we in addition get more weight loss and a bit of a decrease in blood pressure as well. And that's also occurring in the context of the cardiovascular study, the EMPA REG study that showed for patients with existing coronary disease that empagliflozin has a beneficial effect on decreasing cardiac endpoints. So it may be that we're moving toward an era where more aggressive control early on with combination therapy, thereby decreasing the amount of clinical inertia and the amount of time out of control, decreasing the consequences by metabolic memory and the legacy effect of periods of time where you're out of control. Keeping people in good control early on with combination therapy is the beginning of what may become a new paradigm of care. So I think this is really a very exciting study that we're likely to use on into the future. Our next study from Diabetes Care is on the efficacy and safety of multiple doses of axenatide once monthly suspension in patients with type 2 diabetes. This study investigated the efficacy and safety of multiple exenatide once monthly suspension doses of exenatide containing microspheres compared to the reference dose of axenatide once weekly microspheres in aqueous solution. In this phase 2 randomized controlled single blind study, 121 adults with type 2 diabetes and A1Cs from 7.1 to 11 were randomized to subcutaneous axenatide 2 milligrams weekly or exenatide 5, 8 or 11 milligrams given once a month for 20 weeks. The primary endpoint was change in A1C at baseline. The mean age of the patients was 50 years of age. Their A1C mean was 8.5%, fasting plasma glucose mean 184 and body weight was 98 kilograms. At week 20, A1C reductions were negative 1.54% with azenatide once weekly and negative 1.29%, 1.07% and 1.66% and negative 1.45% with exenatide 5, 8 and 11 micrograms monthly, respectively. There were no significant differences in A1C reductions among the exenatide once monthly suspension doses. Weight decreased with all treatments.
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C
John I'm very excited by this and I think if we're looking at that cohort of patients out there who, you know, an injectable medicine might work, but really they're not interested in an insulin, they're not interested in giving them a shot every day, they're afraid to give themselves a shot, and even something weekly might be problematic. You could imagine something that you could give once a month that perhaps you have that friend, that visiting nurse, you come into the office and you get bring your medicine and during your visit we give you a shot in the office once a month. So suddenly all these people who really couldn't bring themselves to give a shot, no matter how elegant the delivery device is, suddenly we can capture them. So in looking at the study, of course I want to look what's the downside? What's going to be the catch? And I would be thinking, boy, if we're going to give you this medicine for a month, oh my goodness, the adverse events is going to be worse and it wasn't. So I'm really excited that suddenly we could perhaps use a different delivery system. And maybe this isn't going to apply to everyone, but there are those people who need that help, but maybe they can't get that help once a week. And once a month would be something that certainly someone's primary caregiver, someone's endocrinologist could participate in the delivery system of this medicine, which works very well. Our next article is from Diabetes Care and it looked at the prevention of diabetes with pioglitazone in insulin resistant patients with cerebrovascular disease. So in this study, a total of over 3,800 patients with a recent ischemic stroke or TIA who had no history of diabetes who had fasting plasma glucose under 126 in insulin resistance by homeostasis model were randomly assigned to pioglitazone or placebo. Surveillance for diabetes onset during the trial was accomplished by periodic interviews and annual fasting plasma glucose testing. After one year, the measurement of insulin resistance and fasting plasma glucose decreased to 4.1 in 95 in the pioglitazone group and rose to 5.7 in 99 in the placebo group. Over a median study of 4.8 years, diabetes developed in 73 or 3.8% of the participants assigned to pioglitazone compared to 149 or 7.7% who were assigned to the placebo group. So a hazard ratio of 0.48. The effect was predominantly driven by those with impaired fasting glucose. So fasting plasma glucoses that were greater than 100 were elevated. A1Cs Neil John I think this is.
- [12:55]
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A very exciting study and combined with the portion of this study called the IRIS study that was reported earlier this year in the New England Journal becomes something that actually for me is changing my practice. So the New England Journal article from this past spring showed that in patients essentially with prediabetes who had a TIA or small cva, use of pioglitazone decreased the combined endpoints of recurrent stroke or heart attack by 25%. That's pretty impressive. Very impressive. Now this study that you just went over shows that in addition, for a group of patients who have prediabetes, it decreases by half their progression to diabetes. I think that that gives us an important benefit. It's likely decreasing progression to prediabetes through its effect on beta cell preservation, which has been shown in other studies. So that for pat fit essentially the group included in this study, patients who are post CVA or TIA with prediabetes, I don't see any reason not to have as one of the medicines added after that event to use pioglitazone. Our next article is titled One week of Bed Rest Leads to Substantial Muscle Activity and Induces Whole Body Insulin Resistance. Published in Diabetes, this study looked at 10 healthy young males with an average age of 23 and a BMI of 23 who were put to one full week of absolute strict bed rest. Prior to and after bed rest, their lean body mass and quadriceps cross sectional area were assessed as well as the VO2 peak. Remember, VO2 peak represents the maximum oxygen consumption which is a reflection of aerobic physical fitness. They assessed leg strength as well as well as whole body insulin sensitivity. What they found was that bed rest resulted in a 1.4 kilogram decrease in lean body mass, which equated to a 2.5% decrease in lean body mass. They saw a 3% decline in quadriceps total area. The VO2 peak as well as the repetition maximum for their muscles declined by 6% and 6.9% respectively. And bed rest induced a 30% decrease in whole body insulin sensitivity.
- [15:48]
C
John so I think this is an interesting study. For years when I've been rounding in the hospital, I've been telling patients and their families that you lose about 2% of your muscle mass every day you lie in bed. And this reinforces this. And, and I think some of that data was some older studies that I think I it was passed along to me, but I never read the original study. So this reinforces that to me. One, it's a little hard though overall to extrapolate from something that's going to happen to males in their 20s that we can expect for our 70, 80, 90, 100 year old patients with regard to muscle mass. But I still think it's going to hold true that that 2% per day is going to go a long way. But the other thing I think is interesting is this insulin resistance. So sometimes we have people in the hospital and we think, boy, we're going to bring them in the hospital, we're going to control their diet, their sugars are going to be better and oftentimes they're worse. And I think that would speak to that. And that level of insulin resistance, as they pointed out in the article, is equivalent to 30 to 40 years of aging of our pancreas. So that short time in the hospital can have reverberations with people getting back home or getting to a skill nursing facility and requiring insulin where maybe they didn't require it when they came into the hospital. So I do think we need to be mindful of this as normal physiology. So when people are sent to rehab their back or their knee or their hip after some time in the hospital, we might need to rehab their pancreas a little bit. And I think we need to be mindful just as it's going to take a little bit time. And I think in this particular study, it's at least 12 weeks to get a lot of this muscle mass back. After weeks, it might take a little while for the insulin resistance to go away as well. Our last article is from Diabetes Spectrum and it looked at basal insulin use with GLP1 receptor agonists and this is a wonderful review article for those of you who are interested. So I'm going to break it down a little bit and the authors really did a wonderful job. So one of the reasons that basal insulin and GLP receptor agonists will be good is how complementary they are. So when we look at the mechanism of action, basal insulin augments basal insulin increases glucose disposal and decreases hepatic glucose production. Our GLP1 receptor agonists increase glucose dependent insulin secretion from the pancreas, decrease glucose dependent secretion of glucagon, slows gastric emptying and increases satiety. With regard to glucose, our basal insulin is primarily going to lower our fasting plasma glucose. With our GLP1s, the short acting agents primarily lower postprandial glucose. The longer acting agents will lower both postprandial glucose and fasting plasma glucose. For weight, basal insulin increases weight. Our GLP1 will decrease weight. The main adverse effect for insulin will be Hypoglycemia. For the GLP1 receptor agonists, it's GI issues nausea, vomiting, diarrhea, but has a low risk of hypoglycemia. For administration of insulin, our basal insulin will be given subcutaneously once or twice a day, where our GLP1s can be given once or twice daily, up to once weekly, as we heard earlier in the podcast, perhaps coming once monthly. So looking at that, there seems to be some complementary abilities for these medicines. Now, looking at some of the clinical evidence they brought up, they talk about a meta analysis from 2014 that described 15 studies with over 4300 patients in which a GLP1 receptor agonist was added to basal insulin therapy or vice versa. In patients with type 2 diabetes, there was an additional reduction of A1C of 0.44% and a decrease of weight of 3.2 kg. The combination therapy did not increase the relative risk of hypoglycemia. So overall the studies demonstrated efficacy with regard to A1C lowering body weight reduction with the basal insulin plus the GLP1 receptor agonist compared to using basal insulin plus prandial insulin. So overall, the authors concluded that patients receiving a GLP1 receptor with basal insulin was a good idea and they concluded that twice Daily axenatide was a reasonable alternative to prandial insulin for patients with type 2 diabetes with suboptimal glycemic control despite glargine therapy.
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B
Neil John the concept of combination therapy with basal insulin and a GLP1 is really an incredibly exciting thing and there are currently two different formulations that are under FDA review insulin degladec with liraglutide and insulin glargine with lixisenatide. The reason why it's exciting has to do with context. If we look at patients who are on insulin alone nationwide, only about 30% of them are controlled to goal. In the best research studies on basal insulin alone, only about 50% of patients are control to goal. And it's a group of patients in whom it is of course very important to get them closer to goal. The use of combination medicine and perhaps in the future in co formulations that are available as one single injection allows, as you really nicely went over discussed in the study, increased efficacy compared to either basal insulin alone or GLP1 alone. But it does so while mitigating the adverse weight effects of adding additional insulin. So typically with basal insulin we have an increase in weight. With a combination of basal insulin and the GLP one we tend to decrease weight. It also does so at no it has better efficacy and there's no increased risk of hypoglycemia. And finally, when compared to the GLP1s alone, there really is much less in the way of GI side effects. So using this as a combination potentially allows us an opportunity to have better efficacy with less side effects than we would have using either one alone. That begs the question of where might this fit in? And I suspect it will fit in very nicely. Nicely for patients who are not controlled on either two or three oral medications, oral anti diabetes medications, or for patients. And for patients who are not controlled on either a basal insulin or a GLP1 alone. For more information and links to the articles that we discussed in this issue, just go to www. Diabetes journals.org until next week. Keep listening and keep learning.