How To Help People With Diabetes

Transcription

1 Diabetes Medications and Medication Management Christopher Lamer, PharmD, MHS, BCPS, CDE November 2013 Okay, great. Well, I want to say thank you very much for giving me the opportunity to present and talk today. My name is Chris Lamer and I work for the Office of Information Technology. So, my primary projects over the past couple of years, recent years, have been the Personal Health Record and Meaningful Use. The agenda for today, I d like to start off, anytime I talk about diabetes, to talk about normal pathophysiology of the body so that we can get a sense of where the medications are working and then we get into reviewing the different medications. For each one, sort of have a standard flow of information talking about drug classes and drugs, mechanism of action of each drug, the effects, the dosing, and then some of the notes or comments about the different medications. So the basic first step with diabetes pathophysiology is of course, we look at the intake of energy that we bring into our body with food that goes into the gut and it gets broken down to free fatty acids, simple sugars, and amino acids. As that happens, our body also releases GIP and GLP-1, that s caused by stimulation of the food. This is quickly inactivated by DPP-4. However, the glucose that gets broken down and these two agents stimulate the beta cells to release insulin and amylin and then also inhibit the alpha cells of the pancreas from making glucagon. So they go from a state where we are creating glucose to keep our body going, to shutting that down and finding ways to utilize the abundance of glucose that we re taking in. Insulin gets released from the pancreatic cells. Initially there is what s called first-phase insulin release, and that is when all the vesicles containing insulin, amylin, and c-peptides that are sort of being stored inside the beta cells gets released into the body. The primary reason for this large release of insulin is to quickly circulate throughout the body and tell it, Hey, stop making glucose. It goes to the muscles, to the liver, and stops glucose production and gets ready to begin the body to start utilizing the glucose we take in. And that s second-phase insulin release; this is primarily stimulated by the nucleus in the beta cell. It s a much slower release of insulin that also lasts for a longer period of time. In general, it lasts as long as we are eating and helps to control our blood sugar level. As the insulin gets released, it does a number of things throughout the body. It goes to adipose tissue and it creates adipose tissue from free fatty acids that goes to all of our tissue in our body to promote glucose uptake and utilization. One of the effects is that there is a glucose reabsorption from the kidneys, and insulin will stimulate glycogen production, so we take excess glucose and store it for later and it inhibits gluconeogenesis and decreases glycogenolysis so that would reduce the glucose being made by the liver. Now, we kind of put this all together and we have all the body organs that are involved in metabolism and it s pretty much everything in our body goes into taking in and metabolizing our food. In talking about medications, it s important to point out that nutrition and physical activity are the cornerstones for diabetes management. That is from the very beginning all the way through a patient s life, as we think about normal anatomy and physiology.

2 It s pretty much like weight loss. There are three things that are involved. One is the amount of energy you're bringing in, the amount of energy you're burning up, and how well your body is able to burn that energy. We know in diabetes, our ability to burn energy and utilize it diminishes over time and that is why we need medications. Nutrition with physical activity will certainly help early on and it will continue to help throughout. So it s important to make sure that we don t lose focus on that. But as time goes on, people may need medications to help. As I go through the presentation, I just want to point out that the Division of Diabetes Treatment and Prevention does have a number of diabetes algorithm cards that are available for downloading. This is the one on glucose control, and pretty much everything that I ll talk about today will follow along with this diabetes algorithm card. And as you can see on the left-hand side, we have our flow chart of where our medications should be considered. And right away, there is an emphasis on lifestyle intervention and that s going to be on nutrition and physical activity, initiation of metformin, adding sulfonylurea, adding a basal insulin or thiazolidinedione, and then eventually intensifying insulin therapy. So as I talk today, we will focus on those medications with our primary cornerstones, but those medications aren t for everybody and not everybody is going to be controlled by them. So we do have other medications in the diabetes arsenal that we can look to and we ll talk about those as well. I'm not going to talk much about insulin. Dr. Russell will be presenting about insulin on Wednesday, November 20, and will do a much better job than I could. So I will strongly encourage you to join in on that call. I do want to mention just a couple of things and that is that insulin works. If you look at drug markets, insulins are six of the top-ten selling drugs. So, insulin does work. It is used a lot and it s a high market-use medication. I also want to mention that there are a few new insulins that are coming out to market. One is degludec. It s a new ultra-long acting insulin similar to glargine. It has a long time onset. There is virtually no peak in the insulin, the duration of action much like from the other ultra-long acting insulin that is greater than 24 hours. For this drug, it may be even a little bit longer. One of the things that stands out with this medication is that this insulin can be mixed with the rapid-acting insulin. As we know, the other insulins cannot. Everybody remembers these days, no, these are not the days of the hippies, these are days of the Exubera or inhaled insulin. It was not a big seller, it was rather awkward to use. Nothing like being out in public and using your insulin inhaler and somebody would come in and say, Hey, can I get a hit off of that? A lot of people likened it to just hitting a bong. It s so uncomfortable for people to use out in public. It was very hard to adjust the insulin dose. There are only certain dose levels that you could get to, it s hard to titrate, and they found on the animal studies that animals were having lung-function problem. So, in addition to patients having to use the inhaler, feeling awkward with it, having a hard time adjusting the dose, they also had to go in for pulmonary function testing, which takes a lot of time. You ve got to sit down, you ve got to make your equipment get there, and you blow, blow, blow. It takes a lot of time out of your day. They had to do it fairly frequently and the whole process was very expensive. So, having to pay for everything, Exubera is expensive. Eventually, they withdrew it from the market because it just wasn t catching on. I bring that up only because there is a new inhaled insulin being looked at. It s called Afrezza. It s a short-acting insulin. It is obviously a lot smaller. It looks more like a kazoo than a big bong. It is more titratable. It uses something called TechnoSphere Technology which allows the user to adjust the dose of the insulin much as they would with insulin. They haven t found any clinical differences in pulmonary function testing. They have found that there is an increase in upper respiratory tract infections with its DHHS Indian Health Service Division of Diabetes Treatment and Prevention - November 2013 Page 2 of 11

3 use compared to placebo. It is comparable with insulin as far as glucose control. There s some less hypoglycemia, less weight gain. It s a very short-acting medication, about 45 minutes. So this is still in testing. It hasn t been released to the market, but the company that is creating it is obviously very hopeful for it and that it will appeal to a large market. When to consider insulin? So, if we go back to the diabetes algorithm cards, there are a number of instances when insulin should be considered and those are listed there on the slide, but really the bottom line is that there is no wrong time. Insulin is a good drug, insulin works. It does have some downsides, it does cause weight gain, it can cause hypoglycemia, it does require a monitoring, but in patients, it s probably one of the most effective medications that we can use. The last thing I would just mention is that don t lose sight of insulin pens for some people who may be averse to using insulin because of needles and syringes and getting all that together. Insulin pens are a very attractive alternative. All right! Before I go into talking about the oral medications, I want to bring up the issue of medication adherence. And I think this is important because generally, we see patients, we look at their A1C and see it is trending. If it's staying good, okay, great. If it s getting worse or it is not getting better, well, we tend to add on another medication. We may intensify diet and exercise as well like we should. Typically, the easiest thing is, Okay, let s add a new medication on and see what happens. Well, the Indian Health Service has adopted a group of measures called the Pharmacy Quality Alliance Measures. Within that measure set are a number of measures called proportion of days covered. What that measure looks at is how many people have enough medications? How many people have enough days supply to cover them for at least 292 out of 365 days? The result from that measure consistently across sites and across medications throughout IHS has been about 50%. That means that about half of our patients do not have enough medications to cover them, at least 80% of their days. There are at least 73 or more days that go by where they don t have the medication to take. So we are not even looking in how often they are taking their medications or how consistently they are taking them, just if they have enough medication at home to take. This shows that a lot of people do not have it. So half of our patients go 73 or more days without having their medications, and this is true for metformin, sulfonylureas, thiazolidinediones, statins, ACE inhibitors, calcium channel blockers, and beta blockers. They are all very consistently 50%, do not have enough medication. We also look at the gap in therapy. How many patients go more than 30 days between when their days supply runs out until they get a new prescription. Again, that has been about 50% as well. So before adding medications on for patients, you always want to see how they're taking their medications, if they have enough medications to take, and what barriers they may have if they're not. The immediate way to do that is to pull up their med list, look at the diabetes med, look at when it was last filled and how many days supply it was and see if they should have run out or not. So let s go through the body and talk about the different medications that affect the different organ systems. So here in the gastrointestinal track, we have three drugs that we can look at; the alphaglucosidase inhibitors, the amylin analogue and at least one bile-acid sequestrant. In the Alphaglucosidase inhibitors, we have two drugs, acarbose and miglitol. They have been around for a very long time. Mechanism of action, as we begin to eat our food enzymes generally come in and they break down carbohydrates into simple sugars and water. When this happens, it s a relatively fast process. That glucose gets absorbed into the body and you can see here at the bottom you get sort of a high peak of glucose entering the body that stimulates or cascades our metabolism. DHHS Indian Health Service Division of Diabetes Treatment and Prevention - November 2013 Page 3 of 11

4 Well, if somebody were to take acarbose and miglitol, those drugs block various enzymes. So the carbohydrates have to find a different way to get broken down and bacteria in our gut is hanging around and willing to help do that. Except whenever bacteria breaks down those carbohydrates. Well, on the good side, when bacteria break down the carbohydrates, they re not as efficient as enzymes. So, they work a lot slower. That means that the amount of glucose entering the body is at a lower level. So, the theory behind that is that it s staying below the glucose toxicity threshold and the body is more easily able to manage that glucose load. On the negative side, instead of breaking it down into simple sugars and water, it breaks it down into simple sugars and methane. Methane is a gas and is rather explosive and that is the way that people feel. There s a minimal A1C-lowering effect of about 0.5%. Dosing is acarbose 25 milligrams, three times a day, miglitol 25 milligrams, three times a day, both of them titrating up very slowly to the maximum level, 100 milligrams, three times a day. The main side-effect from these medications is feelings that they are exploding inside, terrible cramping, gas, constipation, very uncomfortable medication. For that reason, there aren t many people who take these medications and not many people who are able to take them long-term and titrate up to a higher effective dose. Next medication is the amylin analogue. Right now, we have one on the market and that is pramlintide, Symlin. Originally it came out only as a vial. Since then, they have already also marketed it as a vial and an insulin for a Symlin pen. It has modest reductions of A1C, about 0.5%. It does decrease the amount of insulin that s needed by about 3%; not a lot, but it can do some reduction. There is a decrease in weight, on average, about 1.5 kilograms. That number ranges from people gaining weight to losing a lot of weight, but on average it s around 1.5 kilograms. That s primarily due to decrease of food intake and it is because one of the effects of this medication is it causes satiety, it makes you feel that you're already full. It is true for both patients with Type 1 and Type 2 diabetes. Amylin is created with insulin in the body, during first-phase insulin release, it s packaged in those vesicles and so a large amount gets released into the body. In people with Type 1 diabetes, that secretion is not there. In Type 1, you are not able to release insulin and you're not releasing the amylin either. In Type 2, the amount is diminished. So there is decreased concentration and that leads to inadequacy of insulin monotherapy leading to the hyperglycemia and weight gain. So the way that amylin works is it replaces, in theory, the amylin that your body would naturally be making and it causes your gastric emptying to be slowly so you ll feel full more quickly and therefore increases satiety. Type 1 dosing, 15 microgram subcutaneously before each meal then you can titrate up to 60 micrograms. Type 2 diabetes, you can be a little bit more aggressive. Type 1 patients tended to be more susceptible to the gastrointestinal effects of the medication. Type 2, you can start off with 60 micrograms before each meal and increase the dose up to 120. You want to make sure that the patient can go up to three to seven days without having any signs or symptoms of severe nausea before sticking at that dose. If they are complaining of feeling terrible and sick, obviously you want to back off down to a dose where they feel a little bit more comfortable, and 120 micrograms is the maximum dose in Type 2 diabetes. It is a subcutaneous injection. It cannot be mixed or given with insulin. It has to be given actually about two inches away from where you're doing the insulin injection. The last I had looked, when you bought the pen, the needles for the pens were not included. You have to order those separately. So I don t know if that s still the case. Hopefully, that no longer is. But at that time, you also had to give the patient a prescription for a 29, 30, or 31-gauge needles. It was good in the refrigerator for up to 30 days just like a vial of insulin. DHHS Indian Health Service Division of Diabetes Treatment and Prevention - November 2013 Page 4 of 11

5 As I mentioned, the GI side effects are the most common; nausea, anorexia, vomiting. Headaches are fairly common with the medication. Then again, I think headaches are common with almost every medication. There were allergic reactions reported in 5% of Type 2 diabetic patients. As I mentioned, there is a decrease in need of insulin when patients are taking amylin and because of that, you want to decrease your mealtime insulin dose by half when you start therapy with the medication because you don t know how drastic that effect is going to be and you don t want the patient to become hypoglycemic. So, you want to cut the insulin dose down by 50%, start off, and then you can titrate the insulin dose back up over time once you know how the amylin is going to affect the patient. Generally, severe hypoglycemia is going to hit if you didn t reduce the dose, it s going to be within the first three hours. It s Pregnancy Category C and is secreted in breast milk, so you want to use caution in somebody who is pregnant or who s breastfeeding and may be good to avoid until you know how it works. There are a number of cautions and contraindications to the medication. If somebody's A1C is way out of control, this isn t a good start of medication for them, they should get their A1C under control first and be participating in their current insulin regimen. If they re not monitoring their blood glucose, this isn t a good option. Again, any medication that s going to cause them to have hypoglycemia, you really need to make sure that the patient is going to be checking their blood sugar, making sure that they re being safe. If the patient has symptoms of hypoglycemia unawareness or they have recurrent hypoglycemia, they shouldn t be getting it either. Any of the medications that are going to slow the GI tract down, you don t want to give to somebody who has GI problems. If patient has gastroparesis and they already had slow motility, you don t want to slow it down anymore or cause any other problem to the patient. So you want to avoid in those patients. Bile acid sequestrant, Welchol, colesevelam, and it s one of the newest bile acid sequestrants to come out in the market and whenever it originally came out it was targeted towards dyslipidemia and who is believed that the Welchol would be much better tolerated than some of the older bile acid sequestrants and not causes much constipation and so forth. What they found is that it actually helped to lower A1C, very similar to some of the other medications that we saw about 0.5%. It lowered the LDL by 18% and increases triglycerides. This is very consistent with the other bile acid sequestrants as far as the cholesterol effects, but with the Welchol, they discovered that there s also A1C-lowering effect and so they ve been marketing it for patients with diabetes. So they intend to get the LDL and the A1C at the same time. The dosing is very similar to dyslipidemia, six 625 mg tablets once a day or you could break it up by three twice a day. There's also a powder that the patient can mix in with their drink. Not surprisingly the symptoms for the medication are very similar to the other bile acid sequestrants; constipation, dyspepsia, and nausea, and there's an increased risk for triglyceride elevation. If the patient already has high triglycerides, you don t want to push these triglycerides up any higher especially if the patient is at risk of pancreatitis. We tend to make that greater than 500. The other thing they re saying is caution if the triglyceride level are greater than 300. DHHS Indian Health Service Division of Diabetes Treatment and Prevention - November 2013 Page 5 of 11

6 Now, we re moving on down the gastrointestinal tract and we can talk about incretin mimetics, the GLP- 1 agonist and the DPP-4 inhibitors. We have two GLP-1 agonists, exenatide or Byetta and liraglutide or Victoza on the market. There are pictures of the pens there on the screen. They suppress glucagon secretion similar to the amylin. They slow gastric emptying and therefore, increase the sense of satiety. So we also want to be careful. So they are the medications that are slowing gastric emptying that it may decrease the absorption of some medications, so some medications that may have a slow absorption rate over time, they pass on out through the body before they get fully absorbed because of it. It s also believed that these agents will promote beta-cell proliferation. In fact when they first came out, one of the thoughts was this was a -- it was going to be a drug that was going to cause your pancreas to possibly regenerate itself. That s never been shown. That was one of the hopes. Effects - has a little bit stronger A1C-lowering effect about half to one percent. We have some information about the fasting glucose, so decrease of 8 to 10 milligrams per deciliter and postprandial 60 to 70 milligrams per deciliter and consistent with other medications. A weight decrease at range of 0.9 to 4 kilograms and this was maintained at two years. So often with medications we find that there may be an early weight loss that is associated with the medications and that goes away over time, but they recently found that even at two years that weight was kept off. Exenatide comes as a prefilled pen. You need to prime it before you use it the first time and just like with the cylinder, the pen needles were not included. It s five micrograms twice a day for 30 days and you want to do that at least 60 minutes before the morning and evening meal. We can increase to 10 micrograms plus a day and up to 20 twice a day. This is a medication that should not be used in end-stage renal disease and, just like insulin, it needs to be stored in the refrigerator and discarded after 30 days. For the most part, all the medications that are in vials and opened are generally recommended that they are eliminated after one month s supply. After release of Exenatide, they come out with a once a weekly dose called Bydureon and it does come with the needle and there s a package of it right there and it s 2 micrograms subcutaneous once a week. Then a health patient should remember to take it which reduces amount of injections that are needed and reduced injections are always a favorable thing for patients. There is also liraglutide, 0.6 micrograms once a day for seven days and 1.2 micrograms once a day up to 1.8 is the max dose. You don t have to worry about it in kidney disease but like anything you want to use it cautiously and it can be stored in your refrigerator, don t freeze it, good for about 30 days. Medications will cause some gastrointestinal side effects and this has been the primary reason for people to quit using it, diarrhea and vomiting. Again, all the medications that are going to slow your gut down are going to make you feel full, but there also is going to be a risk of making you feel sick with these symptoms. The discontinuation rates, what they found was the symptoms will decrease overtime. So if you are going to titrate the patient up, they feel miserable, back down, take your time. As long as the patients have time to get used to it, they re going to do better and they ll be able to stay on the medication and it s recommended that the patient eat slowly. Eating a fast meal will cause more food to dump into the gut quickly causing that nauseous feeling. If they eat more slowly the gut doesn t feel like it's getting overwhelmed. People don t feel the side effects as much. And it should be injected within 15 minutes of a meal. Again, same information about orally administered drugs, slow gastric emptying may reduce the absorption. Safety concerns and this has been in the news a lot, both tabloid-type news and actual literature and then there are perceived risks of cancer with this agent thyroid cancer, pancreatitis cancer. They re not really sure if they re causing anything. DHHS Indian Health Service Division of Diabetes Treatment and Prevention - November 2013 Page 6 of 11

7 Now, it looks like these medications may be associated with different cancers but associations are not cause and effect and so the ACE and AACE, committees of endocrinology, have recently put out a statement that there s just not enough evidence to say that these medications are causing any problems and their recommendation is that to use these medications just as you would normally, but of course look out if the patient has a history of cancer especially in an area where these medications are associated with pancreatic cancer, but careful monitoring of your general patient who doesn t have a history and isn t at risk for this type of cancer is probably all you need to do. The question is well with this medication, how long is it going to take before it actually causes cancer? Some experts say well may not be for 20 to 50 years in which case you have somebody who s 50 years old and they re developing cancer, or they re developing diabetes, how much of a concern is it something that may not cause cancer for 50 more years. But still, the verdict is not out there. The safety is unknown and so the recommendation is to proceed with caution and certainly people with high risk try not to use the medications. There s a lot of other GLP-1 analogues coming out in the market mostly me too drugs. As these things have become popular with the promotion of A1C control, weight loss, really positive things for patients and providers, the use and desire for other drug companies to get a piece of the pie have risen. There are a number of drugs, taspoglutide is one that was started off, they went through a number of marketing and in phase three clinical trials there were just too many GI side effects and so they tossed that one out. There are currently three others that are -- I believe they re still in phase three clinical trials and not been approved yet, albiglutide, lixisenatide, and dulaglutide. All work in their way through the process to get the FDA approval. Next is the DPP-4 inhibitor and there s four of them- sitagliptin, saxagliptin, alogliptin, and linagliptin and they re all linagliptin up to be approved by the FDA. So these ones are all out there and available. You see samples of the bottles down below. They are competitive inhibitors of DPP-4. They don t block it and continue to block it forever, it's a competitive reaction. They lower A1C and reduce weight, just like the other medications. A1C reductions anywhere between 0.5% to 1% and glucose lowering effect 10 to 30, 30 to 60, kind of a bit lower than the average on the other group of drugs but very close, and no weight effect though. No gaining of weight or loss of weight on average observed, although they have been some number of instances and reports of people who have lost weight using the medication. So, I think on average, there s not much would change for people. The dosing, each one is dosed a little bit differently, sitagliptin or Januvia is dosed 100 milligrams a day and then reduction in dose if the patient has kidney disease. Saxigliptin or Onglyza is dosed 2.5 to 5 milligrams a day and reduced for severe kidney disease. Alogliptin, 25 milligrams a day and reduced for kidney disease, and then there s linagliptin or Tradjenta, 5 milligrams a day, one dose, and there s no dose change necessary in renal impairments. So, the one that makes this one stand out is that there s no dose change for renal disease. They are all relatively comparable in their effects. There have been a number of hypersensitivity reactions related to the medications. So if somebody starts complaining of symptoms, you want to make sure that they re targeted and treated aggressively, it can go as far as an anaphylaxis or even Stevens-Johnson syndrome. If you are using a sulfonylurea with the patient already, you may want to lower the dose of the sulfonylurea. They found that adding one of these medications on with the patient who s on glyburide or so and they have relatively decent control, you want to pump them down a little bit more. You start on one of the DPP-4 inhibitors and you can run the risk of getting hypoglycemic. So just like with some variation in insulin. Here you want to cut back a little on your sulfonylurea dose so you see how it s going to affect the patient and then titrate them back up. Odds are you re going to get them back up to the dose they were originally on, but better to be safe and move up, go back slowly than just assume it will be okay. Pregnancy Category B and it is secreted in breast milk. DHHS Indian Health Service Division of Diabetes Treatment and Prevention - November 2013 Page 7 of 11

8 There are still ongoing post-marketing surveillance concerns around pancreatitis for these agents. A lot of this has come from observation and from theory. The theory is that DPP-4 may be a substance that suppresses certain malignancies and when you take these drugs and block the DPP-4, they re no longer suppressing and instead they are enabling the medications to continue on. Here we have some notes that saxagliptin is metabolized by cytochrome P450 3A4 enzyme system, anything that goes through that system always carries the risk of serious adverse drug reaction, and there s a common group of medications here, the conazoles telithromycin and so forth. So, if you are using Saxagliptin just be aware of that, that you need to make sure that you re running the patient s medication through an interactions checker to be on the safe side. Vildagliptin or Galvus is not approved by the FDA yet. It was getting close to being released to the market, but the FDA said that they wanted more information on skin lesions and kidney impairments that were found in animal studies. And then there s another agent called Tenegliptin and that branding was -- I can t remember, but it s been approved in Korea, by the Korean FDA but not yet in the United States. So there are still a number of DPP-4 inhibitors that are trying to make their way on to the market. I'm coming into some familiar territory of sulfonylurea and meglitinides. We ve been using them for many years. Stimulates the beta cells to secrete insulin similar to a first-phase insulin release. They bind to and disassociate from the insulin receptors very rapidly, triggering this reaction. We get stronger A1C-lowering effects of about 1% to 2%. However, because we are increasing the amount of insulin that we re making, we are also increasing the amount of weight that the patient is gaining. A1Clowering effects are little bit less in the meglitinides and that s because they are working for a shorter period of time and a little bit weight loss because they are triggering a little bit less increase in insulin. Here we have a table of all the dosing, glyburide 0.5 to 10 milligrams twice a day. We can sort of skip through all these. We of course have our second generation sulfonylureas, our first generation sulfonylureas are the less specific, require a higher dose and now we have our two meglitinides that are on the market, repaglinide or Prandin and nateglinide or Starlix. Both of these agents are dosed before your meal. These are the choices for people who would benefit from a sulfonylurea but may get hypoglycemic in between meals. So here, in this case, we want to target somebody who is only having problems with their postprandial hypoglycemia. Now, I think it s been found that that s generally not the more common thing to have happen. Generally, sulfonylurea is preferred because it reduces the basal release throughout the day and helps manage the patient's blood sugar over a 24-hour time period getting a better A1C-lowering effect versus dropping it down just postprandially and letting it build up throughout the rest of the day. They re very fast at working. They work within two days, then you start seeing some blood sugar lowering effects. They can be used alone or with other medications. On the downside though, there are two types of sulfonylurea failure. There is primary failure, meaning you take the drug and it doesn t work. So giving this medication to somebody who has Type 1 diabetes who doesn t have the ability to create insulin, you can see primary failure because it s not going to do anything. Secondary failure is when the medication stops working over time. This is observed in a number of patients, anywhere between months to 5 years to 20 years, you never know when it s going to happen. And there are a lot of different theories that as the diabetes progresses and the glucose threshold is being met, the sulfonylurea is no longer able to produce enough insulin to keep up with it and therefore it becomes nonfunctional and that s sort of the theory that we use because at that time, we always want to add on a second medication and what s been found is that when you add on another medication, let s say metformin, you start to get better A1C control than if you were to just switch the patients from sulfonylurea to metformin. So getting the blood sugar back under a little of control helps the sulfonylurea kick back in. DHHS Indian Health Service Division of Diabetes Treatment and Prevention - November 2013 Page 8 of 11

9 Secondary failure is something that s common in the sulfonylureas. They don t seem to work forever. We also see hypoglycemia and it s been broken up into three different types; neuro-hypoglycemia, adrenergic, counter regulatory hormones neuro-glycopenic, and this was already the question with the question with people who were already prescribed a beta blocker. Well, if they re on a beta blocker, they re not going to know if they re having the adrenergic hypoglycemic effects. I don t know that that really holds true. People are going to have their symptoms of hypoglycemia and then they re likely going to feel them unless the receptors or responses are diminished over time with the diabetes. There s always a hypoglycemia treatment; always want to use glucose tablets, orange juice, simple sugars to get in the body quickly. Biguanide, metformin is probably a number one medication for diabetes. It s been around for a long time, it s been used for a long time, shown to be really safe and effective. Theory behind metformin is it may decrease glucose production from the liver and from the muscles thereby the body can continue to make insulin and get better control of the more limited amount of glucose that s being released. The net result is you get a lowering of A1C and you do not get weight gain. In some cases, you ll observe weight loss with the metformin. A1C-lowering effects are about 1% or 2%. We also have a decrease in triglyceride levels and decrease of weight as I mentioned. I think we are all familiar with the metformin dosing. Start low and slowly work your way up as the patient tolerates, up to a maximum dose of 2500 milligrams per day or two grams per day if you're using the extended-release tablets. The common side effects for going up too quickly, are going to be GI effects. Metformin can upset the stomach and frequently does especially if you dose it too aggressively. It can cause an unpleasant metallic taste in some patients and there s the risk of lactic acidosis, very rare and often questioned in the literature and in practice of, Is this something that we really need to worry about? But it is a black box warning and so we do have to worry about it for that reason. As we talked about some of the other medications increasing your risk for developing cancer, there s also some speculation that with metformin there would be a decreased risk in getting certain types of cancer from the medication. Again, it s nothing that s been proven, and preventing cancer should not be an indication for which you are prescribing metformin but there have been some observations and associations with that. Precautions, so here we go into the precautions that say do not use metformin because the risk of lactic acidosis, renal dysfunction, congestive heart failure. Although these days I think there s been enough information in the literature and I think because so many people with diabetes have heart failure, that metformin appears to be very safe in people with heart failure and the incidence of the lactic acidosis is minimal. It s still something to be cautious of. People who are hypoxic, have liver disease, acute or chronic lactic acidosis, alcoholism, or going in for surgery if you add iodinated contrast media, those last cases you want to hold the metformin right before going in. Again, the incidence of lactic acidosis is extremely rare and not much different than the risk of lactic acidosis just for having diabetes, but we have to follow the rules that are out there. Thiazolidinediones improve glucose uptake and utilization. We only have one agent on the market left, pioglitazone or Actos. It s believed that these agents affect PPAR Gamma and they convert visceral adipose tissue into subcutaneous adipose tissue. Subcutaneous adipose tissue, if we go to the apple or pear concept, the fat that we have stored in our subcutaneous tissue, like down in our thighs and so forth, is believed to be more stable and safer. It s not breaking apart and releasing fats into the blood stream and so forth. Visceral adipose tissue is highly lipolytic. It breaks down more easily into free fatty acids. Free fatty acids in the bloodstream can lead to insulin resistance. They can also get circulated back to the liver and increase triglyceride levels. DHHS Indian Health Service Division of Diabetes Treatment and Prevention - November 2013 Page 9 of 11

10 Further, as visceral adipose tissue breaks down, it stimulates a different kind of cytokines which are believed to be inflammatory markers and cause problems throughout the body, a number of different ways. Effects of pioglitazone, decrease in A1C, there is a decrease in triglycerides, which is offset by an increase in LDL. However, that LDL is believed to be a big buoyant LDL versus a small dense and more atherosclerotic LDL. It s believed to have a positive impact by making it into a larger LDL particle. And because thiazolidinediones improve the action of insulin on glucose it leads to increases in weight. Dosing for pioglitazone 15 to 45 milligrams a day, also rosiglitazone or Avandia is listed there. There may still be some patients who are taking rosiglitazone. For the most part it s been pulled from the market. However, there is program that if patient is taking it, they cannot take another TZD and they have good benefit with it. There s a monitoring program whereby the patient can continue to get it, but I think that s extremely rare these days. Some things to consider with the TZDs, it may stimulate ovulation in premenopausal women, especially with insulin resistance. It also may cause fluid retention, exacerbating heart failure, or possibly displaying underlying heart failure. So the patient may have heart failure you just don t know it yet. They take this medication and all of a sudden boom, it hits, you sort of pushed them over the edge. So certainly you want to use caution with patients who already have a diagnosis of heart failure. Number of post-marketing concerns, bone fractures had been observed in people taking the medication, bladder cancer with Actos. Again, it s not clear, it s not definite, but there are observations and associations. And from Avandia we have cardiovascular disease, myocardial infarction, CVA and death. So for these reasons patients must enroll in the program and there was a push to get rid of it and people over to Actos or another agent. We also had mention of the glitazars and these are dual acting peroxisome proliferator-activated receptors. They affect PPAR Alpha and PPAR Gamma. PPAR Gamma it is like a thiazolidinedione. PPAR Alpha is like a fibrate, Gemfibrozil. So the theory behind these medications was great, lowering A1C, improve insulin sensitization, decrease triglycerides by a good amount, you know, it hit the lipids and the blood glucose all at the same time; great potential for people with diabetes. However, they re not having a good turnout rate for these. Muraglitazar was discontinued because they are finding an increased risk of cardiovascular disease. The company didn t want to push this further. They just realized that they had something on their hands that just wasn t going to get through the FDA. Ragaglitazar was discontinued after urinary, bladder tumors in rats and tesaglitazar was discontinued due to increases in the creatinine and decreases in GFR. So, each one of these agents has had a terrible outcome that has caused the drug companies to give up on them. And then we have our newest class of drug, the SGLT2 inhibitors or the sodium-glucose cotransporter enzyme agents. A subtype 2 of sodium-glucose transport protein. It accounts for about 90% of glucose reabsorption by the kidneys. These medications go into the kidney and they block those enzymes so that that glucose will not get reabsorbed. You just go ahead and pee it out and get rid of it. There are number of these agents that are trying to make their way on to the market. Dapagliflozin was not FDA approved, but they re working on it. Invokana was FDA approved. You can see the bottle right there. There are two other ones that are trying to make their way on to market. The dose for these agents is about 100 milligram a day; it can increase up to 300. Decrease that dose if they have renal dysfunction, and if their egfr is less than 45 you don t want to use it all. One of the interesting things that I thought about this medication was they actually had make use of the egfr, the electronic glomerular filtration rate and the dosing requirements versus just the GFR, which is generally indicative a lot of the Cockcroft-Gault equation. So, I thought that was interesting with the medication. And it may interfere with some transferase enzymes in the kidney which may affect the absorption and elimination of couple of different medications such as rifampin, phenobarbital and phenytoin. DHHS Indian Health Service Division of Diabetes Treatment and Prevention - November 2013 Page 10 of 11

11 So again if you re using this medication, you definitely want to talk to your pharmacist about it, and the patient s other medications and run it through an interaction checker to make sure that you re not going to be interfering with these medications, especially something like phenobarbital and phenytoin which you re trying to dose very accurately. Adverse effects, vaginal and yeast infections, interestingly that all I found is affecting women, and also urinary tract infections. It causes hyperkalemia and volume depletion. One of the things that they notified of concern, is there s increase risk of stroke and MI within the first 30 days of therapy. This has been observed. It wasn t statistically significant. That s something that they re going to have to continue to look at. There have also been increases in LDL, but they re quick to point out, but there s also been increases in HDL. So LDL goes up but the HDL goes up so we re in a good balance. However, the FDA said, Okay, we want you to do a five-year post-marketing study to assess for stroke and myocardial infarction with this agent. So those are ongoing now. Then finally, a new therapy is the Fibroblast Growth Factor 21. This is an agent that protects against obesity with a biological agent that boosts action of insulin, decreases LDL and triglycerides, increases HDL. It s a daily injection. There s not a lot published on this at this time and it s still very early on and they re doing very early studies, but it appears to afford a lot of benefits for people with diabetes. One of the negatives to it, being a biological agent is that the body tends to recognize it as a foreign substance and creates antibodies against it. So while it's been working great, initially over time it becomes less effective and in fact, over prolonged use it starts to confer a risk for allergic reaction. So in summary, a very long-winded presentation, but the bottom line is we have some very well validated therapies that have been used for many years that we have incorporated into our internal IHS algorithms, treatment guidelines and recommendations as well into our National P&T formulary considerations and those are metformin, sulfonylureas, and insulin. These agents do work. They are safe when dosed appropriately. And then we have a lot of the less validated therapies, and that s mainly because they re newer or they re clouded by uncertainties and other risks such as thiazolidinediones, GLP-1 agonist, DPP-4 inhibitor, and amylin analogue. As we move on into the future, we have the glitizars. I mentioned the whole slew of them that have not been pursued, but there are still other chemicals that are being evaluated as glitizar-type medications. And the newest agents, the SGLT2 inhibitors and we ll have to see what happens with those over time and if they really do increase the risk of MI and stroke or if they do confer benefit, plus some of the new biological medications that are coming along to the market. So with that I just want to say thank you very much for your time. DHHS Indian Health Service Division of Diabetes Treatment and Prevention - November 2013 Page 11 of 11