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Diabetes Core Update
Diabetes Core Update Spetember 2016
00:25:48
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 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. Skolmik.
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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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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 excellent issue this month, beginning with an article on gastric bypass reducing symptoms as well as hormonal responses to hypoglycemia from Diabetes Care, as well as our next article on lipohypertrophy and its effect on insulin absorption in diabetes care, hyperglycemic effects on patients with type 1 diabetes and cardiovascular outcomes, then a discussion of a new medication, lixielan, a titratable fixed ratio combination of lixisenatide, a GLP1 receptor agonist and an insulin glargine, followed by a discussion of an article on gastric bypass versus medical management, and finally an article that looks at clinical inertia and the time to increasing treatment when patients fail initial metformin therapy. Our first article from Diabetes Care is on gastric bypass reducing symptoms and hormonal responses in hypoglycemia Gastric bypass surgery, one of the most common bariatric procedures, induces both weight loss as well as having significant metabolic effects. The authors note that they have observed anecdotally that gastric bypass patients have lower glucose levels and have had frequent asymptomatic hypoglycemic episodes, so decided to study this in a systematic manner. They subjected patients before and after gastric bypass surgery to hypoglycemia and examined symptoms as well as hormonal and autonomic nerve responses in 12 obese non diabetic patients. They looked at these patients both before and then 23 weeks after gastric bypass surgery using a hyperinsulinemic hypoglycemic clamp model. The Idenberg hypoglycemia symptom delta scores during clamp were attenuated from 10 before surgery to 5 after surgery. There were also marked post surgical reductions in glucagon, cortisol, catecholamine and sympathetic nerve responses to Hypoglycemia. In addition, GLP1 and GIP rose during hypoglycemia, but less so post versus pre surgery.
- [03:22]
C
John so I think this is an interesting study and as we're going to talk about in this particular edition, we're going to talk about both about hypoglycemia and gastric bypass in different articles. Hypoglycemia is something we should be very worried about in our patients and certainly it's been something that's been in a lot of the literature. Certainly we're going to be thinking about bariatric surgery for our patients who have a certain level of obesity concomitant with diabetes. So this particular article would tell me that folks who've had a gastric bypass are at increased risk for having hypoglycemia, that it probably has some incretin kind of based methodology for why it happens. And I think we need to be mindful and if we have had someone who has had a gastric bypass, I think we need to be smarter about the medicines that induce hypoglycemia. Our insulins probably not a whole lot of room for giving folks sulfonylureas who've had a gastric bypass. So I think we should really try to rule them out as medicines. But I think we should be mindful. Just like when we have patients who are on beta blockers, one of the things that we always learned about beta blockers is it blunts the hypoglycemic symptom effects that people are going to have. So I think we need to be mindful of this. And especially if people are having asymptomatic hypoglycemia who are doing things like driving, climbing ladders, etc. I think we need to be a little more mindful and maybe take our foot off the gas a little bit in achieving glycemic control in these patients. Our next article is from Diabetes Care and it was insulin injection into lipohypertrophic tissue, blunted and more variable insulin absorption in action and impaired postprandial glucose control. So this crossover study of 13 patients with type 1 diabetes who received abdominal injections of insulin lispro into either lipohypertrophic tissue that had been confirmed by examination and ultrasound or normal adipose tissue. On day one, a euglycemic clamp was performed with two injections each into the lipohypertrophic tissue and the normal adipose tissue. And on another day, one Injection per region was given before a standardized mixed meal of 75 grams of carbohydrates, all in randomized order. Compared with normal adipose tissue, the lipohypertrophic tissue reduced insulin absorption and effect, but increased intrasubject variability. Postprandial blood glucose concentrations were 26% higher in the lipohypertrophic tissue and maximal concentrations of blood glucose occurred later in time. Hypoglycemia occurred numerically less frequently with the lipohypertrophic injections 2 versus 6. But profound hypoglycemia only occurred with a lipohypertrophic tissue injection in the two patients.
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B
Neil John this is an incredibly important topic that I don't think most of us in primary care think about. A lot patients know about it though. Lipohypertrophy are those nodules that can be felt under the skin in patients who have injected insulin for a long period of time. On pathology, they're composed of a lot of fibrous tissue infiltrating normal adipose tissue and most importantly less capillaries, so less vascularity than normal adipose tissue. And because of that there's less absorption, as shown in this study, of insulin and even more importantly, that absorption is variable over time in the same person and variable in different people. This is important primarily due to this variability because when you have a patient who's coming in who one doesn't seem to be responding at all to increasing doses of insulin, we ought to think about lipohypertrophy and make sure that they go back and see the diabetic nurse educator and talk about details about how to rotate their site of injection and how to avoid injecting into those nodules. In addition, it's potentially dangerous because if sometimes they're injecting into a nodule and having poor absorption, they risk severe hyperglycemia as seen in a couple of patients in this study with glucose in the three hundreds. But then if the next day they're injecting into normal adipose tissue, that same injection might cause significant hypoglycemia. So when you're seeing large day to day variability in patients or unexpected responses or non response insulin that's being used, it's something that is important to think about, to check for and often to consult with our diabetic nurse educator colleagues to give patients just good clinical advice on how to avoid injecting into those nodules. Our next study is titled A Population Based Study of All Cause Mortality and Cardiovascular Disease in Association with Prior History of hypoglycemia among patients with type 1 diabetes. This study included two nested case controlled studies with age and sex matched control subjects and using sampling methods performed separately within a cohort of 10,000 patients with type 1 diabetes in Taiwan. Patients had a history of severe hypoglycemia, were identified during the first year, then during years 1 to 3 and then years 3 to 5 before the occurrence of the study outcomes. Prior severe hypoglycemic events within one year were associated with higher risk of all cause mortality and cardiovascular disease. The adjusted odds ratio was 2.7 and 2.0, respectively. Events occurring within 1 to 3 years and 3 to 5 years before death were also associated with adjusted odds ratios of 1.9 and 1.6.
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C
John so again, another article about the dangers of hypoglycemia. I think what's interesting about this article, certainly we are well aware of the increased mortality that goes with hypoglycemia in our senior citizens and we learned about that in the accord in advance and still that holds true and so many studies that we look at, but this was mostly a study of younger people with type 1 diabetes and certainly there were deaths from hypoglycemia in this large cohort and lots of ages and it was a little more common in the over 50 population, but it was certainly happening throughout all the age groups. So I think it's something that we should be concerned about hypoglycemia in our younger patients, not just of our older patients. A second takeaway point is it was done in Taiwan. So it's mostly a homogenous population that may or may not be representative of everyone we take of, but I certainly think it's something that we should be thinking about. A third thing is this study did not have a 1Cs in it. It was not part of the Taiwanese kind of approach to diabetes in the study. So we cannot correlate were the people who were dying from hypoglycemia what was the A1C baseline of that? We did learn that the people who were more likely to die were much more likely to have some kind of diabetic complication, retinopathy, neuropathy, cardiovascular disease. So and also we learned that having previous episodes of hypoglycemia, even if it was four or five years ago, did put you at an increased risk going forward. So what I would take away from the study is our type 1 diabetics, we need to be mindful of hypoglycemia, even if we have not figured out the mechanism that leads to people dying. I think we need to be mostly mindful of our diabetics who had a severe episode of hypoglycemia, especially recently but anywhere in the last five years, and our type one diabetics who have other complications associated with their diabetes. Our next article is from Diabetes Care and it looked at the efficacy and safety of lixolan, a titratable fixed ratio combination of lixazenatide and insulin. Glargine versus insulin Glargine and type 2 diabetes inadequately controlled on metformin metformin monotherapy so in this particular study there were 160 patients in two separate arms. One of the groups received once daily lixolan and the other group received glargine insulin for 24 weeks. The Lixolan and Glargine were started at 10 units and 5 units respectively of the two parts, the Glargine and the Lixoxenatide versus 10 units of Glargine respectively and the patients were titrated based on the Glargine 100 requirement according to fasting plasma glucose. Results the primary objective of the study was to test non inferiority of lixolan in reducing a 1Cs and if that was met statistical superiority was tested. Secondary objectives included looking at body weight changes, hypoglycemia and safety. The baseline characteristics of the mean age of the two groups was a mean age of 57 years, duration of diabetes 6 to 7 years and BMIs of 32 at week 24. The A1C was reduced from 8 at baseline to 6.3% in the Lixolan group versus 6.5 in the Glargine group. This established statistical non inferiority and superiority of lixolan. The lixolan improved two hour postprandial plasma glucose versus glargine. Body weight was reduced in the lixolan with a loss of a kilogram versus a gain of a half a kilogram with the glargine with no increase in hypoglycemic glycemic events. In each group the incidence of nausea and vomiting was low with the Lixolan being 7% and 5% respectively.
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Neil John this is a really exciting new class of medicines when you think about it. Current guidelines suggest that for patients who are not responding to two or three oral hypoglycemic agents we can consider injectable therapies either GLP1 receptor agonist or basal insulin. There are problems though with each of those choices. With basal insulin, of course there's difficulty with hypoglycemia and with significant weight gain that is of great concern to patients with GLP1 receptor agonists. The main difficulty is GI side effects. By combining the two agents in a fixed ratio titratable combination, they were able to mitigate many of the difficulties with each one of the injectables alone. So instead of having weight gain as you do with insulin, Lixielan here had weight loss. There was no increased hypoglycemia even though there was better efficacy with lixielan versus insulin alone, so that it really offers a very effective, very potent option that mitigates some of the most difficult side effects of either medicine alone. This went up. This particular combination was up in front of the FDA Advisory committee in May and had a vote that was significantly in favor of approval and is currently as of August up in front of the full FDA and we'll know whether or not it's approved as one of a new class. There are two out there, one of a new class of combination GLP1, basal insulin combination medicines and fixed ratio combinations that will offer additional options for us and our patients. The next article is titled Durability of addition of Roux En y gastric bypass to lifestyle intervention and medical management in achieving primary treatment goals for uncontrolled type 2 diabetes in mild to moderate obesity A randomized controlled trial, the authors compared three year achievement of American Diabetes association composite treatment goals an A1C less than 7%, LDL cholesterol less than 100 and systolic blood pressure less than 30 after two years of intensive lifestyle medical management intervention with and without Roux En Y gastric bypass at the beginning of the study with one additional year of usual care. A total of 120 adult participants with a BMI of 30 to 40 and an A1C greater than 8% were randomized to two treatment arms where they got either directly into intensive lifestyle and medical management or into the gastric bypass group and then lifestyle and medical management. They were then followed for 24 months and 36 months. At 36 months, the triple endpoint goal was met in 9% of lifestyle medical management patients and 28% of gastric bypass patients 10% and 19% lower than at 12 months. Mean A1C values at three years were 8.6% and 6.7%. No lifestyle medical management patient had remission of diabetes at 36 months where 17% of gastric bypass patients had full remission and 19% had partial remission, meaning full remission is off of all medicines with a normal A1C. Lifestyle Medical management patients used more medications than gastric bypass patients. A mean of 3.8 medicines versus 1.8 medicines. Percent weight loss was approximately 6% in the lifestyle group and 21% in the gastric bypass group. Over three years, there are 24 serious or clinically significant adverse events in the lifestyle group versus 51 with gastric bypass.
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C
John so I found this to be a very interesting article and some of the points are, so they looked at a population between, with BMIs between 30 and 40, and guidelines are not necessarily going to have our patients between 30 and 35 BMIs going to surgery. So it looked at a population that might be a little bit lighter with regard to their BMIs for the people that were sending to surgery. And I think we kind of lost the overall takeaway of this article in really being fixated on this triple aim of having someone's A1C reduced someone's lipids, their LDL under 100 and their hypertension, their, their systolic blood pressure under 130. So if, if I could wave a wand and do the surgery and I never touched someone's lipids and I never touched their blood pressure, I could live with that if I could get 50 to 60% of the people to have a 1Cs going from the 8s down into the 6. So I don't really want to lose that point. And we have really great statins, so getting someone's LDL under 100 might talk a little bit to that. Therapeutic inertia. And patients suddenly think, I don't need to take any of our medicines. And remember, not all of our medicines and all of our LDL production is necessarily related to our dietary intake. There's a hepatic component of that. So just like we have patients who have bariatric procedures who still have their OSA. Remember, about 25 to 30% of people will still have their OSA even if they lose a significant amount of weight. We're going to have people who are still going to necessarily need to be on their statin. So as we are kind of winnowing down their med list, we probably are going to think about leaving that statin in there. And oftentimes these populations have had diabetes for a while, so suddenly they've lost the weight. I don't think they're completely out of harm's way with regard to atherosclerosis. So I think keeping their LDL on their LDL in check with a statin makes a whole lot of sense and people might still need their anti hypertensive. So I don't think the triple aim is this horrible takeaway point. I think one of the points is people sure did a lot better at year one than they did at year three and I think sometimes we take our eye on the off the ball a little bit and I think it's kind of human nature to do really better up front when we're really enthused about things. And I think we all slip back and we heard in last month's edition that even having some early success really is a much better thing than never having success at all. So I think we should be excited about that. Perhaps we are going to look at our patients who have lower BMIs for being quicker to have them have a gastric bypass. But the other takeaway point for these patients overall is these folks had a lot more serious diabetes in that 30 to 35 range. That's 60% of the people were taking insulin already. So this isn't the person who has a BMI of 32 who's got 500 of metformin that we should be sending to the surgeon. But I certainly think of our diabetics who have higher A1Cs despite being on maximal medications whose BMIs are under 35. We really should consider this in the future as a therapeutic option. Our last article is from Diabetes Care and it looked at the intensification of diabetes therapy and time until a 1C goal attainment among patients with newly diagnosed type 2 diabetes who fail metformin monotherapy within a large integrated health system. So in this particular study, the Electronic Health Record at the Cleveland Clinic was used to identify patients with newly diagnosed type 2 diabetes between the years 2005 and 2013 who failed to reach an A1C goal after three months of metformin monotherapy. A time dependent survival analysis was used to compare the time until an A1C goal attainment in patients who receive early intensification of therapy within 6 months of metformin failure or late intensification. The analysis was performed for A1C goals of 7, 7.5 and 8. Treatment was intensified early in 62, 69 and 72% of patients with poor glycemic control defined with A1C goals of 7,7.5 and 8, respectively. The probability of undergoing an early intensification was Greater with higher A1C categories and the time until A1C goal attainment was shorter among patients who received early intensification regardless of their A1C goal.
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Neil John this study raises the issue of clinical inertia, which is really a critical issue for all of us. We know that over 50% of patients with diabetes don't attain their A1C goals and we know that it can take a long time to intensify therapy. A study that we reviewed in 2013 on this podcast talked about in a cohort of 80,000 patients that were followed after failing a single medicine, usually metformin, it took two years on the average to add a second medicine. The current study really shows that again, it's important to intensify therapy early. Here they used as a definition of intensification not just adding an additional medicine, but in patients who were uncontrolled on their initial dose of metformin. Did the doctor increase metformin? Did they send the patient to the dietitian or to diabetes education for more intensive of follow up or did they add a medicine or increase the metformin? Basically what it shows is if you intensify therapy early, if you're aggressive early, patients tend to do better. This is not a rocket science conclusion but is rocket science in the process of taking care of patients and making sure that both we and our patients know that our time frame for achieving their A1 goal is short three to six months, not let's add medicine and wait a year or two and see what happens. And that really is the take home point here. Therapeutic inertia occurs both on patients point of view. Patients don't like to add medicines, but also on our end as physicians. Sometimes because we're uncertain what to do next, sometimes because we emotionally feel for a patient and feel like and agree with them that we wish we didn't have to add medicines. But it's important to remember that often we need to. 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.