Good morning. Thank you very much for inviting me to speak at this year’s conference, update in internal medicine. And as was said, I will talk to you about what may not be moving targets in diabetes and I think things are pretty much what they were but there have been some confusion that sort of entered the equation in recent years and I hope that I will settle that for you.
So what I want to do is in the next 30-35 minutes or so, is just review what the guidelines for glycemic control are, look at the message for achieving glycemic control and maybe this is where some of the controversy is. Review some of the barriers both regarding glycemic targets and some of the concerns that seems to keep popping up in the newspapers as well as the literature about creating fear about using some of the drugs that are basic drugs in the armamentarium against diabetes. And there have been some shifting targets in lipids and blood pressure management as well that I will review for you briefly and then I just want to leave you with some take home points.
So let’s start with glycemic targets for non-pregnant adults. And this could apply to children as well and it applies to Type I as well as Type II although I think most of my comments this morning will be directed to people with Type II diabetes. But these have been the established goals now for years, to try to maintain preprandial blood sugars between 70 and 130 which gives some leeway to the clinician taken care of someone with diabetes as to whether this is someone you feel comfortable allowing to have very intense glycemic control such as a young person with Type I diabetes, no other complications recently diagnosed versus someone with Type II diabetes who might be a little
bit older, have other comorbidities and you’re more comfortable keeping a fasting glucose between 100 and 110. So there’s leeway in these guidelines.
We try to keep postprandial glucose less than 180, we really don’t have guidelines for patients monitoring postprandial blood sugars. But if you do have someone monitor a postprandial glucose it should be 2 hours after eating rather than 10 minutes or 30 minutes after eating when levels are going to be higher because we still don’t have the skill at really controlling those postprandial peaks quite so well with the medications that we have. And then to maintain the A1C level at or about 7 which corresponds to an average glucose of about 150. But I want you to pay attention to this little line here down at the bottom is that more or less stringent goals may be appropriate for individual patients. And even though we live in this age of CT scans and MRI scans and every possible scan or test we could imagine which in a way kind of robbed us of our clinical judgement and we really wanted to sort of see things in front of us, clinical judgement is still very much part of what’s involved in the care of someone with diabetes.
So when we talk about controversies regarding glycemic targets I think the stick of dynamite around the heart is where the controversy exists, is looking at what increases the risk of cardiovascular disease and cardiovascular outcomes have become the standard for almost every drug. That if increases risk for cardiovascular disease it becomes something that we shouldn’t be using. But let’s take a closer look.
So I’m not going to go through all the studies, I’ve done this in prior years but I do want to results of the Accord Study that now has been published about three years ago. As you recall this was a very large study of people with Type II diabetes that was stopped early because of a nonsignificant increase in mortality, cardiovascular mortality and the intensively treated group. It was felt it was not safe to continue the study, the study was abruptly stopped, they did follow people through to the end point, there was a blood pressure arm and a lipid arm that I’ll talk about later as well.
A couple of things to call your attention to is Accord did identify a risk group who was at risk for cardiovascular with intensive therapy. If you look to the left of this line here means that intensive therapy was better, if you look to the right of the line it means the conventional therapy was better. The groups that did better or did more poorly depending on how you want to look at it with intensive therapy were those who had prior cardiovascular events where they fall to the right of the line, those who has A1C levels above 8 percent and there were some racial differences here as well that I will not focus on. Everyone else although almost all of the events except for those who did not have a previous cardiovascular event did better with intensive therapy. All the other lines pretty much cross zero meaning that there was really no significant difference. But the intensive therapy was better for those who had no prior cardiovascular event and who had A1Cs of less than 8 percent.
Now when we look at these trials so Accord kind of got grouped in with the VA trial and an Advance trial all of which were very large clinical trials, all of which showed no overall benefit on cardiovascular mortality with intensive versus conventional therapy. But there are two very
important points to make. So these studies were done in response to the UKPDS but the United Kingdom Perspective Diabetes Study was actually performed in patients with newly diagnosed Type II diabetes so they were at the time of diagnosis in comparison to all three of these trials where patients had diabetes from anywhere from 7 to 10 years.
The other issue, so why the target really hasn’t changed, is the glycemic target as recommended by the American Diabetes Association has always been to try to achieve a goal of less than 7 percent. Each of these studies aimed for glycemic targets of A1Cs of less than 6.5 or less than 6, much tighter than what the overall goals would be. So in fact the goals did not change, the goals stayed the same meaning that we are not in a situation where we should be pushing for more and more intense levels of glycemic control particularly in people with well-established diabetes or particularly in people who have a lot of premorbidities.
This was reviewed by nicely in one of the meta analyses from the study in the Annals of Internal Medicine where she actually looked at the, the first doctor is a she, looked at the UKPDS separately from the other studies and then grouped them altogether in terms of risks for nonfatal MIs, fatal MI, nonfatal stroke, fatal stroke and peripheral arterial disease and as you can see everything sort of falls on the line of zero meaning no significant difference except for nonfatal MI where there was a reduction with intensive therapy. But certainly the trend is that things fall to the right of the line towards intensive rather than conventional therapy.
One of the other issues though that raises a concern was that of hypoglycemia. That the more intensive the therapy the more likely it was for patients to have hypoglycemia and in many of these studies there did seem to be a link between the incidence of severe hypoglycemia defined as needing outside assistance and cardiovascular events. And so here almost all the studies with the exception of the Metformin component of the UKPDS all fall the right of the line meaning that intensive therapy was associated with a higher risk for hypoglycemia. So keep that in mind when we talk about the drugs that were used in pushing to these goals later on.
So the summary of this meta analysis is that number one, compared with conventional therapy, intensive glucose control did reduce the risk for nonfatal MI but not cardiovascular death or mortality. And similarly intensive therapy was associated with a higher risk for hypoglycemia and similarly what I didn’t put here is that the intensive therapy trials particularly Accord where they really drove those A1Cs down, there was a significant amount of weight gain. And the way they looked at weight gain at least in the original publication was the percent of subjects gaining more than 10 kilos. And that’s a lot of weight gain.
So there have been a couple of other ways – people have taken different approaches to looking at this association between glycemic control and morbidities and this is an Italian study that I really liked the way they did it. I think it really makes the point that was made earlier that if you look at patients with diabetes according to the total illness burden index which is this TIBI here. Those will low illness burden indices meaning relatively healthy patients did have a cardiovascular mortality benefit
by having an AIC of less than 6.5 compared to those with higher A1Cs. However, in those who had higher levels of disease burden other than diabetes, there was really no cardiovascular mortality benefit with AICs of less than 6.5. This was sort of a retrospective review not a randomized control clinical trial. But I think it makes the point that there are some patients who we should be driving down and others not.
So here we are, we’re back to the same target. So now let’s look at those. Qualifications for these glycemic targets. These goals should be individualized based on duration of diabetes, the life expectancy of your patient, the presence of comorbid conditions, the presence of cardiovascular disease or advanced complications whether or not they’re able to detect their hypoglycemic episodes and at what point the detect their hypoglycemic episodes as well as individual patient considerations. Some patients just don’t want to have their blood sugars tightly controlled. They’re going to say I don’t feel well if my blood sugars are below 120 to 130 and you can prescribe away in the office but they’re not going to go, they’re not going to go there. They’re going to stay where they’re comfortable.
So I want to just turn the page now and look at methods for achieving glycemic control. Certainly medical nutrition therapy is part of all of our therapies, exercise should be encouraged, home glucose monitoring helps people see where they’re at. Glucose sensors are a bit more advanced therapy and then there’s the pharmacologic therapy. And as I mentioned if we look at these three large clinical trials, if we look at intensive groups versus conventionally treated groups, there was a high
percentage of patients in Accord and the VA trial that were on insulin, actually in both the intensively treated and conventionally treated groups and the use of thiazolidinediones that I’ll talk about a little bit more this morning was also very high with almost 100 percent of patients in Accord being on a TZD and the drug that was used in most of these trials was Rosiglitazone which is now effectively off the market. Whether or not we want to go through all that data again is another point but I know we’ve done that here in the past.
The other point about this slide where no differences were seen in cardiovascular outcomes is that other preventive measures where in place with an equal percentages of patients being on statins, aspirin, very low incidences of smoking and blood pressure control was reasonably obtained and achieved.
So there’s a long list of medications now for treating diabetes, for treating Type II diabetes. We have sulfonylureas and the short acting insulin secretogogue. We have Metformin and thiazolidinedione. The new class on the market is the dipeptidyl peptidase 4 inhibitors which prolong the actions of endogenously secreted GLP-1. Alpha glucosidase inhibitors has been awhile, these two new drugs are very weak glucose lowering agents but they are FDA approved for treating Type II diabetes. And we have injectable medications, the glucagon like peptide agonist, the two of which we have are exenatide and liraglutide and Amylin agonists which is Pramlintide and as always we have insulin.
But then you read the newspaper and you think well I’m afraid to use any drug in my patients, we read that oh well rosiglitazone is effectively off the market, it’s approved but you have to have your patient sign a waiver in order to be able to prescribe is and I’m not going to have anybody sign a waiver regardless of what I think. Bladder cancer is the latest one in patients treated with pioglitazone that’s raised concerns. Cancer-related mortality in patients using sulfonylureas or insulin, Byetta causing renal failure or pancreatitis, so what do we do?
Well let me just review first the algorithm by the American Diabetes Association for approach to treatment for diabetes and I have modified a bit in light of some of the news that has come along. But this is - algorithm based on published data and probably will be updated soon. At the time of diagnosis lifestyle plus Metformin, so early initiation of Metformin and I’ll go through why that’s a reasonable approach. Step 2, meaning the AIC stays above 7 percent in someone that you want to have a lower AIC, Tier I therapies reflect those that have been around for a long time, we know these drugs, we know what their safety is, we know how to use them, we know what their long term effects are, would be to address the insulin secretory defect in Type II diabetes by adding either a basal insulin or sulfonylurea or if you would like a short acting insulin secretogogue. Tier II therapies less well, less well studied, less well-known, no real outcomes data yet would be to add a GLP agent such as a GLP-1 agonist or a DPP 4 inhibitor. Pioglitazone used to be more robust in this tier but I think in light of some of the data that’s come out about bladder cancer in addition to other issues such as reductions in bone density and weight gain, it’s sort of falling out of favor as a tier 2 agent, Step 2 agent.
And then finally in patients if their A1C stays above 7 certainly if they’ve been on a basal insulin, insulin can be intensified. If they’re not yet on a basal insulin, a basal insulin can be added and Pramlintide would only be advanced if they have significant postprandial hyperglycemia.
Other therapies that really don’t fall in here but can be used are the alphaglucosidase inhibitors which seems to be infrequently used in the United States and the bio acid sequestrant, I usually only add the bio acid sequestrant if I want it for lipid lowering properties and hope that it will also approve the glycemic control.
So let’s look at this issue of pancreatitis with use of the GLC-1 therapies. So there’s been several reports and concerns about pancreatitis that have appeared in newspapers, on the web and in the FDA watch. There’s now been several studies, this is just one of several studies that have done claims based investigations of insurance data bases that are subject to their own limitations but thousands of patients, hundreds of thousands of patients are in these databases. And there’s several of these that are published now. This is one that grouped patients according to age so the orange bars are patients without diabetes, blue bars are patients with diabetes. So grouped according to age, people with diabetes are always at higher risk for pancreatitis than those without diabetes. People have also looked, done claims based data reviews looking at the incidence of diabetes or pancreatitis in patients on the GLP-1 agents in comparison to other agents for treating diabetes and the incidence for pancreatitis is identical across all these agents, not lower but identical to what it is with other
therapies. But our attention is on this. However, four patients with a history of pancreatitis, I tend not to prescribe these agents, at least not at this point.
What about bladder cancer? So the first sort of signal that pioglitazone might be associated with bladder cancer came from a study published in the late 1990’s, the Proactive study. In which the incidence of bladder cancer was higher among those who were treated with pioglitazone than those who did not receive pioglitazone. The purpose of that study was a cardiovascular outcomes study that was a relatively negative study anyway. So there’s been signals for this, so this is again another large review, we can see large patient, this comes from the adverse drug reporting system so it really depends on reports but looking at all the drugs, the make the point in this paper that when you get an incidence of just 4 cases and even probably 8 cases you really can’t come away with any clinically meaningful information about that and these odds ratios don’t really mean much.
But pioglitazone did stand out here as at least giving a signal for a higher risk of bladder cancer particularly in men, particularly in men who smoke. So certainly a consideration, another consideration when using this drug but another reason why it’s kind of fallen back a little bit in our armamentarium. Mechanistic studies for why that would be - is I’m not really sure. But it’s a signal that is sort of called our attention to the issue.
But there is a light on the horizon. So we have all these scary headlines which give us headaches but there is a beacon of light and that’s Metformin which has been around for a long time. What are
some of the advantages here with Metformin. Well, it’s weight neutral, it has a low risk of hypoglycemia, it’s the only diabetes agent that has been demonstrated to reduce cardiovascular complications, both morbidity and mortality albeit in a small number of patients, about 300 patients in the UKPDS but the only one that we have the outcome studies for. It’s associated with improved outcomes in patients with CHF. So CHF has really been removed as a contraindication to Metformin. And I know your next lecture is on CHF. It’s low cost, it’s available in generics, it’s effective at delaying the progression from impaired to abnormal glucose tolerance to overt diabetes. Almost every single oral agent that’s approved for use in diabetes has made a combination agent with Metformin. So there must something that people like about Metformin. It’s associated with a reduced risk of cancer, I’ll show you a little bit about that data. But the concerns that have sort of nagged are this requirement for normal renal function and the concern about lactic acidosis but that concern about lactic acidosis really come primarily from Phenformin which has been off the market for decades.
So here’s the followup studies, the study from the UKPDS with a ten year followup study. So the 1997 data, the 2007 data and then the Metformin results. Metformin reduced the risk of myocardial infarction to a greater extent then intensive therapy with sulfonylureas or insulin. Greater reductions in any diabetes related end points whether it be microvascular or macrovascular disease and significant reductions in mortality. So both in the 1997 report and the 2007 study, the 10 year followup showing that there was a legacy effect both with intensive therapy in general but particularly with Metformin therapy. So this is important.
So we’ve seen all these reports about insulin and sulfonylureas and cancer but it’s what we have, it’s more about insulin but no one agent has really sort of come out of the pack to show that there’s a higher risk here and the studies are relatively short term. But what has been shown is that Metformin always seems to be associated with a lower risk of cancer. So these have not made the headlines in the newspaper but certainly they’re making it into the journals. And this is one study from the Netherlands, it’s an epidemiologic review which is looking at patients who were treated with Metformin versus those who were not treated with Metformin and looking at cancer mortality every time and you can see that there’s greater than a 50 percent reduction in risk for cancer mortality. Cardiovascular mortality was not different between these two groups but cancer mortality was. So there seems to be something to this signal.
So now let’s turn to lactic acidosis. Well that’s sort of ___ and we certainly don’t want any of our patients to have lactic acidosis but now there’s been several meta-analyses looking at what the incidence for lactic acidosis in patients treated with Metformin and there’s very little data substantiating that it’s really a risk factor and there’s really no difference in lactic acidosis in patients treated with Metformin compared to treatment with other agents so there’s probably other things that are contributing to it. So there’s really no evidence right now showing that Metformin itself carries higher risk. If someone develops lactic acidosis while they are on Metformin, Metformin gets blamed. Just like if somebody develops pancreatitis while they’re on a GLP-1, the GLP-1 gets blamed. But we just had a patient come in this month with pancreatitis on Metformin and Metformin
doesn’t get blamed so it gets a bye on that one. So I think, sometimes we overplay these risks for some drugs once it gets in our head and maybe underplay it with others.
So one of the questions that always comes up at these conferences is what should we do when the GFR drops below 60, should we stop the drug? I personally have been stopping the drug below 60 but over recent years I’ve been sort of allowing myself a little leeway and letting that GFR maybe b e 50. Or maybe in the high 40’s just trying to get myself a little more comfortable with this. So there’s no approval to use Metformin with GFRs less than 60, I doubt that they will change their labeling to allow it but this is a proposed guideline that was just published on – just a couple of months ago in Diabetes Care by a review group and they actually reviewed guidelines for Metformin use across the world which is in your syllabus. But most of the other countries, Europe, Australia, Canada say that using Metformin to a GFR of approximately 45 mils per minute is pretty safe. Some of them go as low as 30, less than 30 they’re saying not to use it. But I will leave that with you as something to think about within your patients with Metformin. The recommendation would be with GFRs greater than 60 fine, keep using it. GFR between 60 and 45, well you can continue to use but monitor the renal function a little more frequently. If the GFR is less than 45 don’t start Metformin but if somebody’s already on Metformin perhaps reduce the dose by 50 percent and use the maximum dose of a gram per day. And if the GFR is less than 30, stop the Metformin.
So I just want to turn now with the last few minutes to what some other moving targets are in diabetes. So we always talk about glycemic control but obviously it’s a disease, a metabolic disorder
that has hyperglycemia as one of the manifestations but dyslipidemia and abnormal blood pressure are other manifestations. The recommended targets for people with diabetes is to have an LDL lipid profile done at least every year and the target in LDL of less than 100, less than 70 in people with established heart disease. Triglycerides of less than 150 so pay attention to this because that sort of the crux of the Accord lipid-lowering trial and HDLs greater than 50 which is hard to do. There are no approved agents other than niacin and even niacin has come into question.
And that our target blood pressure is less than 130 over 80. So there have been many lipid lowering trials in people with and without diabetes and pretty much across the board, you pick the trial, the list is about this long with acronyms for lipid lowering trials. But you pick the trial, the patients do better on a statin then they do not on a statin. And these are patients with diabetes treated primarily with a atorvastatin or simvastatin in each of these trials, these are relatively risk reductions here in the orange bars and absolute risk reductions here in the blue bars. And so there’s always a reduction in risk, it just depends on what the starting LDL was here. So here are the starting LDLs was 189 so of course you’re going to get the most bang for your money here with lipid lowering where here they started with an LDL of 97 so you see it’s not that it’s a negative study, they just started at a lower LDL level.
So what did Accord do as part of their study? So a substudy in the Accord trial was to take a subgroup of patients in the glucose lowering trial and they’re all on simvastatin already and to add fenofibrate to them to lower the circulating triglycerides. Remember we said the target for
triglycerides is less than 150 although it’s hard to get there in some patients and many of our patients have triglyceride levels of up to 200 and the question is, well should we be adding something to lower the triglycerides in these patients. So this study really answered that question because the average triglycerides here in this part of the figure show that at study entry the average triglyceride level was 160, so not too high of a triglyceride level. So as far as lowering of total cholesterol, LDL cholesterol, HDL cholesterol were fairly similar, the fenofibrate group had a little bit more of an HDL increase than did those on simvastatin alone. And triglyceride came down as would be expected with the addition of a fibrate.
However, absolutely no difference in study outcomes whether you look at it as the primary outcome or just any macrovascular outcome, identical between the two studies. So where does that leave with lipid lowering. Well I think where we were. There was really never a guideline to put patients on an agent for lowering triglycerides unless triglycerides are above 400 in which case we might want to start with fibrates. But still the major, the primary goal for lipid lowering is to go after the LDL. So the recommendation is to start statin therapy in patients with Type II diabetes who have overt cardiovascular disease as soon as that’s known. If they’re above age 40 with one or more risk factors which they all do, consider initiation of statin therapy for patients less than age 40 who have an LDL of greater than 100 with at least one risk factor and that combination therapy with statins and fibrates should be reserved for patients who have true hypertriglyceridemia with triglyceride levels definitely above 200. There was a suggestion of a benefit for patients who had triglycerides above 204 and
HDL less than 34. So those two combinations could go together as well but yet the data is not really in support of that.
What about blood pressure? So there was a blood pressure arm to the Accord trial, again a very large number of patients, patients were randomized to achieve a systolic blood pressure of less than 120 versus less than 140. And as you can see there was a nice spread between the groups, the less than 140 group reached a blood pressure of 133 over 70. Those in the intensively treated arm reached a blood pressure of 119 over 64. Again, the same drugs could be used in both arms. Again, absolutely no difference in outcomes, whether looking – at their composite as the primary outcome of a variety of macrovascular disorders or nonfatal stroke, the differences were the same.
So what should our blood pressure target be? Well, the goal is still less than 130 but it means that if your patients in between 130 and 139, you’re probably okay particularly if you’re on many medications. Diastolic we still aim less than 180 if we can get there. But again, similar to glycemic control just based on patient characteristics in response to therapy, higher or lower targets may be appropriate. So the recommendation is for patients, those who have a systolic greater than 140 or diastolic greater than 90 or anyone with microalbuminuria, they need to be one blood pressure lowering medication right away.
For patients with systolic blood pressure between 130 and 139 or diastolic of 80 to 89 there is this recommendation for a trial of lifestyle therapy for 3 months and I would say lifestyle, start lifestyle
therapy, see if they respond but don’t give up lifestyle therapy. What I’ve learned over the years is this sort of persistent message and I think that’s important, is the persistent message from us about lifestyle and the importance of lifestyle. It comes around but it takes a while for those patients who are going to do it. In 3 months somebody might be just figuring out what kind of exercise they want to do so most of your patients are going to end up on blood pressure lowering. But lifestyle therapy is very important. Keeping a reasonable sodium intake, losing weight if overweight, giving 8 to 10 servings of fresh fruit and vegetables, low fat dairy products and so moderate amounts of alcohol intake is someone does drink and exercise is very important. There was a very nice study that I did not get to make the slide about, it’s really not so much about shifting targets. But it was a large study in Diabetes Care that the only intervention they did for patients with uncontrolled blood pressure on several agents was move the blood pressure medication to bedtime and they followed them for four years it was better control of their blood pressure and a reduction in cardiovascular events. So it was a very nice study so it’s been my latest intervention for people on many medications or even one medication.
So what about clinical care? So comprehensive diabetes care involves treatment of all vascular risk factors. Blood pressure, lipids, use of aspirin, getting people to stop smoking, persistent messages about therapeutic lifestyle changes are all effective strategies for reducing cardiovascular risk. The confusion I think or this confusion about quote moving targets really arises when the guidelines for chronic disease management and for diabetes, they come from the American Diabetes Association. I know other groups publish theirs as well but they’re all pretty close. But when these guidelines are
used for determination of how much we get reimbursed on, you know, and how many patients we have in a certain level and the NSQA is actually taken this information and has revised the guidelines which are printed in your syllabus for the percentage of patients that we can reasonably get to certain targets. So the message is being heard.
So when we look at standards of care, standards of care are different from quality indicators. Standards of care are goals, it’s like, just like we try to be better people in our lives, we try to do the best thing for our patients. They’re meant to provide general treatment goals and tools to evaluate the quality of care and targets that are desirable for most people are what are published but then again clinical judgement has to come in to play.
This is a little grid that was published, they tried to poll all the different studies together in terms of making sense of the guidelines and hopefully you can read this but of course patients who have only mild hyperglycemia, low risk for hypoglycemia, who are young, who have a short disease duration, no other comorbidities and no established vascular complications, we can aim for very low levels of A1C, in contrast to those who are older, who have had diabetes for a long time, you know, just sort of going over the thing. The problem I think for us is people don’t necessarily fit into these categories, we might have somebody who is at high hypoglycemia risk but yet they’re highly motivated for tight control but they have other comorbidities. So how do you sort of move these people around? And that’s judgement, it’s almost no algorithm can tell you that.
So I’ll just leave, I think this whole thing about moving targets was shown in this editorial cartoon that I enjoyed about – just you spin the wheel as to what’s going to scare you or reassure you on any given day and we have to then take this to our patients. So I think I finished with a second to spare.
I think there’s time for one question.
Any questions, yes.
Q: You didn’t talk much about aspirin and a couple of studies that ____ interest in. (inaudible)
That’s a good question so just along with all the other things that we have revisited, the whole issue of aspirin use has been revisited. Where we were putting all of our patients on aspirin and even there - there was some debate about the dose but certainly a baby aspirin was what we used. But now there have been several fairly large trials that have shown that in people at low risk for events which would be women below the ages of 60, men below the age of 50, with Type I and Type II diabetes that the benefit to aspirin therapy do not outweigh the risks. So that we’re waiting for women to sort of become over age 60 or men above the age 50 or they have other risk factors, two or more significant risk factors for cardiovascular disease or being considered at high risk for cardiovascular mortality before using aspirin. So I’ve actually taken quite a few patients off of aspirin for that reason.
