B (3:07)

Neil John Inpatient management of hyperglycemia is an area that's seen a lot of changes over the last 10 to 15 years, beginning in the early part of the 2000s with a study done in a large surgical ICU setting at a single institution which showed impressive results with intensive blood glucose management, leading to recommendations for IV insulin protocols that were used in many hospitals across the country. What was interesting there is those results were never replicated in other studies that were done. Similar results were not able to be achieved. And then the NICE sugar study, which came out about five years ago, showed in both surgical and medical inpatients worse outcomes with intensive blood sugar control among medical inpatients. This led to recommendations in 2009 from the American Diabetes association to target good but not intensive control of blood sugars among medical inpatients, and that target being aiming for a blood Sugar less than 180 as the target blood sugar for medical inpatients. This study is interesting in possibly putting sitagliptin on the map as an additional agent that might be able to be used in addition to insulin. The results of this study, though, are not that surprising. If you look here, they were careful to include patients who didn't have terrible blood sugars to begin with. The average blood sugar on entry was about 200 milligrams per deciliter, so it's really not that surprising that sitagliptin did as well as largine plus bolus therapy. That said, sitagliptin is a potentially attractive agent for management of inpatient hyperglycemia because of its lack of hypoglycemic effects, which might be the issue that leads to poor outcomes when patients are managed to try to achieve intensive blood sugar control. So we'll look forward to more studies about sitagliptin. For now, I probably wouldn't be using this in place of our usual insulin res, but it's something that's on the map to keep an eye out for future studies. Our next study, published in the November issue of Diabetes Care, is empagliflozin as add on to metformin plus sulfonylurea in patients with type 2 diabetes. This study looked at patients inadequately Controlled on metformin and sulfonylurea with an A1C between 7 and 10%, randomized those patients and treated with once daily empagliflozin 10 milligrams, empagliflozin 25 milligrams or placebo for 24 weeks. In addition, there was an open label group in this study who had A1Cs greater than 10% treated with empagliflozin 25mg at week 24. Adjusted mean changes from baseline in A1C were negative 0.17% for placebo versus negative 0.82% and negative 0.77% from empagliflozin 10mg and 25mg respectively with significant P values. Empagliflozin significantly reduced mean daily glucose, weight and systolic but not diastolic blood pressure versus placebo. In the open label group, the change from baseline A1C at week 24 was negative 2.89%.

C (6:59)

Shawn so this newer class of medicine, the SGLT2 inhibitors I think is an interesting class and this study probably looked at it in the method that I think in primary care we would end up using this medicine and probably as a third line agent added to metformin and something else. So I think it's a study looking at a population that we would care about. So in general, when we look at these new medicines, I think we look at the same rubric we look at at every new medication. So what are some of the categories we want to look at? Well, how much a 1c reduction do we get? About 0.81c reduction. So not necessarily as potent as some other things, not as weak as some other things. What about weight loss? Well, we saw about a five pound weight loss in this particular study. How about hypoglycemia? Well, interesting. This class in monotherapy does not cause hypoglycemia, but when added on to a sulfonylure and metformin did have some instances of hypoglycemia. So how somehow it exacerbates hypoglycemia you might see from a sulfonylurea I think is something we have to keep in mind and then we have to look at side effects. So in this particular side effects there was about a 25% increase in urinary tract infections in women, not an appreciably difference in men. There was a slightly increased rate of genital infections in men and about a four fold increase in genital infections in women. So kind of an increased rate of having a candidal infection is something that we should keep in mind. And I think the last thing we're going to think about is costs and formulary, etc. And not really sure how this medicine is going to fit in, but usually newer medicines are going to be more expensive. So I think this is a category that we are going to be seeing. Not exactly sure what to make with the very, very, very robust A1C reduction we saw in this open label group who had worse control. But perhaps this might be a little bit of a niche for this medicine as well in people who are not necessarily on combination therapy but are more naive to diabetic treatment in general. Our next article is from the November 2013 edition of Diabetes Care and it looked at clinical inertia in patients with type 2 diabetes. This was a retrospective cohort study Based on over 81,000 people who had type 2 diabetes in the United Kingdom. Clinical Practice Research Data Link Patients were entered between January 2004 and December 2006 and were followed until April of 2011. In patients on one oral diabetic agent who had an A1C greater than 7, it was 2.9 years till an additional agent was added. In folks who had an A1C greater than 7.5 it was 1.9 years. In folks who had an A1C greater than 8 it was 1.6 years. When we looked at folks who were on two drugs it was 7.2 years till an additional medicine was added, 7.2 years if they had an A1C greater than seven point five and 6.9 if they had an A1C Greater than 8. When they looked at the time to adding insulin, if someone was on one oral agent it was 7.1 years and they had an average A1C of 8.7. If they were on two oral agents it was 6.1 years and they averaged an A1C of 9.1. If they were already on three oral anti diabetic agents it was six years to add insulin and they had an average A1c of 9.7.

B (10:31)

Neal John, this is really a very important general point and this was first looked at in the era of hypertension where it was shown that people on the average had six or more elevated blood pressure readings before their primary care physician would increase their antihypertopension. And in addition it was shown that in patients who had their antihypertensives increased more often, those patients had better blood pressure control. Here we're seeing a similar thing with regard to diabetic management. And basically for patients who are on a single medicine takes about two years of being out of control until we add a medicine. And for patients who are on two or more oral agents, it's over seven years until an additional oral agent or insulin is added. And clearly that's too long. We could argue about what the cutoff is and we know about, and we've talked in other podcasts about individualization of treatment. But the main point that this study makes, and I think it's an important one, is that we ought to think about adding additional agents. We ought to think about intensifying therapy when someone exceeds their target for a shorter length of time. The average A1C at intensification of therapy in this study was over eight and a half whether someone was on one, two or more agents. So I think the point is a very simple take home point that we try to assess blood sugar control and we don't fool ourselves that further desire will lead to a better outcome. It often requires further changes in medications. For our next article, we're going to depart a little bit from our usual procedure of discussing articles from the American Diabetes association journals because of the high importance to all of our listeners of the new cholesterol guidelines that were just issued. Remember, the background here is that traditionally the NIH has issued the main guidelines on cholesterol, first ATP 1, then 2, then 3. And for the last four years we're going to announce ATP 4, which had been put off regularly. About six months ago, the NIH announced that they were no longer going to be issuing guidelines and handed the data synthesis that had been done to the American Heart Association. So the American Heart Association's guidelines on cholesterol management are now the standard guidelines for management of cholesterol and were published just a week and a half ago in the journal Circulation. The background in terms of the science on which these guidelines were based was that randomized trials have compared either fixed doses of statins with placebo or compared fixed doses of high intensity statins with moderate or lower intensity statins. There have been no studies that actually looked at target levels of LDL and the effect on outcome. Based on that, the American Heart association has essentially recommended four treatment 1 clearly, individuals with clinical atherosclerotic disease, either coronary artery disease, stroke or peripheral vascular disease 2 individuals with primary elevation of LDL cholesterol greater than 190 milligrams per deciliter 3 patients with diabetes aged 40 to 75 years of age with an LDL cholesterol of 70 to 189 milligrams per deciliter, even if they don't have established atherosclerotic disease. And group number four, individuals without established disease or diabetes who have cholesterol levels from 70 to 189 milligrams per deciliter who have an estimated 10 year atherosclerotic cardiovascular disease risk greater than 7.5%. The way that the American Heart association recommends gauging that 10 year risk is not using Framingham as we have traditionally done, but using a new online calculator and equation that is available from their website. Point number three, treatment is recommended primarily with statins and the decision is either to use a moderate intensity statin if someone is not at high risk, or for high risk patients use high potency statins. An important point number four is there are no more LDL targets. We're not aiming for an LDL less than 130 or 170, but rather the decision is to use a moderate potency statin or a high potency stat.

C (15:26)

JOHN so these guidelines are really going to change a lot what we do. And because this is a diabetes forum, I think we should focus a little bit on what this is going to mean for our patients with diabetes. So the answer used to be what patients with diabetes need to be on a statin. It was pretty much all of them. I think right now you would say the answer would be diabetics who are over the age of 40 and have an LDL that is 70 or above. So that is a change from before. So that person who is 35 or that person who has an LDL of 50, you wouldn't necessarily put them on a statin, which is different than from before. There certainly have been plenty of studies that have looked at statins in diabetic patients and have actually found that a more potent statin does better than a less potent statin. I think what it would say to us is if you have someone with diabetes, when they're going to have that would be a significant risk group that you would put them on a high potency statin, expect to get around a 50% reduction, which is going to be a decent dose of atorvastatin or rosuvastatin to get that 50% reduction. So what we would see, but if we, we would no longer be chasing ldl. So that patient who was on a high dose statin who had an LDL of 106, the guidelines no longer say we should put them on some kind of additional therapy to get them below 100. I think the other area of interest with regard to diabetes is the discussion that high potency statins might induce diabetes in a certain population of patients. So if you look at our high potency statins, the incidence of developing diabetes from them is probably about 1 in 200 patients. If you're looking at primary prevention, the chance of decreasing someone's chance of having a cardiovascular event might be only about 2%. So overall you might be wrestling with what to do in primary prevention a certain population. And I might argue that you might want to use one of the less potent potent statins, a pravastatin, a simvastatin at a lower dose in that particular group to decrease the chance of someone developing diabetes who isn't necessarily a high risk patient.

B (17:42)

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.

A (18:07)

Sa.