In a new world of pharmaceutical abundance, treating diabetes properly means matching meds to individual needs. Endocrinologist Robert J. Rushakoff, MD, helps providers get up to speed on the latest drugs, explaining benefits, crucial caveats, and factors ranging from expense to nonadherence. Breaking down a convoluted glucose-lowering algorithm, he delivers straightforward pearls of wisdom based on research and experience.
Today we're gonna be talking about medications for type two diabetes. Trying to help figure out which drugs maybe for appropriate for which patients. I have no conflicts to disclose. So today we're gonna talk a little bit about goals. How they keep changing will discuss some a little bit about diabetes medications. A few general updates about them. The reasons for where they show up in the current algorithm and we'll put it all together. Look at the algorithm that's changed significantly in 2019. And again in 2021 talk about what's new and give you a few real world warnings at the end. Um Treating Type two diabetes used to be really simple. Your choices weren't so great. You had just a couple of medications and that was it. People would just argue back and forth whether you should have loose control or tight control. And this was actually centered in san Francisco, loose control was how they thought things should be over at the bia and tight control was at the main campus at UCSF Parnassus and eventually for things sort of swung the type control. But uh it's going back and forth even a few times since then we'll talk about that. I think it's important to understand where we've been. So you know why we're going where we're going. So this is looking at the historical and Background on treatments and goals and so forth. So this is over the past 40 years When we look back in the 1980s, all we had were sultan areas and insulin average hemoglobin A one C. When people monitored was about 9%. This was before a big trials in the CCP and the U. K. P. S. There were no algorithms out there that were official. Although we all have our own informal algorithms, there are no official goals. We have really complex glucose meters at the time. And if I were giving a lecture back then we'd be talking about first, the second phase insulin production, which I guarantee you none of you have ever heard of and care is all about because it really made no difference whatsoever. And of course salt and urea is that were then all we talked about our probably 3rd, 4th or fifth line drugs at this point. By the 19 nineties we had the diabetes control and complications trial and type one diabetes average hemoglobin A one C. Was 8% that foreman was available again. No real algorithms. Generally the goal was the hemoglobin. A one C under eight meters were simpler. And the main concern back then was lactic acidosis with metformin. Something we now no almost never occurs. And it has remained basically the first drug or treatment of diabetes. But the question we need to ask towards the end here is how long is that going to be the case? Right. Mhm. Then by the 1997 we had the fizzling dion's Can see at Hemoglobin. England see nationally with 7 9 we now have the D. C. C. And the United Kingdom prospective diabetes study. Still no official algorithms out their goals tend to be ever lower 6.5 7. And now everything was about Feisal indians, everything was insulin resistance because they treated insulin resistance. These were the first or second line then now they're probably six or seventh line or not used whatsoever. Again this is the point out. We get really excited about new things and then suddenly not so much over time. By 2000 and six average hemoglobin A one C. With some two people were talking about a goal of six. We had the in cretins who were being released. Still no official algorithms. You had a lot of meters now we talked about in pretends and whether they were we had decreased levels of in pretends and these drugs were being given second or third and now maybe there are first line drugs. By 2013 we had the SdlP too. So we're being given out goals were now whatever is appropriate for that particular patient. We have lots of algorithms out here. The goals. No one was really clear what the right goals. We started having continuous glucose monitoring And SQL T2 inhibitors are now good for everything and maybe their first line but maybe there's still some caution. We'll be talking. Yeah. So over time we've had these big landmark studies you KPBS in type two D CCP in type one accord advanced V. A. D. T. That what specifically a cardiovascular disease. Type two. What's universal is at lowering blood sugars, decreases risk for micro vascular disease. I don't think anyone can argue with that. The issue has been that people don't generally die from micro vascular disease will die from cardiovascular and with that all the studies that were short term didn't really show any benefit of lowering blood sugar. Whether it was a yes or a court advance would be a DT. But these were all short term studies, longer term studies when we had a follow up can go up to now three years in the D. C. C. T. A little bit less for the UK. Yeah. Show that long term initial control of blood sugars will lead to decreased cardiovascular disease and perhaps decrease mortality. There was the one study the accord study that showed increased mortality. But that's really the outlier. And yes turns out the patients who have increased mortality were actually people who, despite all the treatment interventions remain having hyper. So it was definitely an out wire route. The key thing here is that it takes a long time to see benefit from glucose is on cardiovascular. It is they won't talk about that again. So, when you look at goals, the question is, what's the appropriate goal? Any single picture Because just having a goal of 65 or seven or 7.5 doesn't tell us something because every patient really is somewhere else on this scale. So perhaps they've had diabetes for a long time. They have a lot of risk for high publicity in your other problems for medications. They have a very short life expectancy. Clearly less control. Less. Stringent control would be appropriate. But if patients have a long life expectancy, then I've already started to mention that improving uh medications and control that will help cardiovascular disease will be really important. We know that the patient doesn't have any micro vascular disease and there are 85 years old. The chances are going to develop it is very, very small. So I think we have to keep that all into um our thought process as we move ahead on what goal is appropriate patient. We look specifically for quote older patients. We can all sit here and argue what's an older patient? Um, No people have different goals. And I think you can see that, you know, generally, if someone is considered to be healthy and very functional, a reasonable goal is still fairly tight. So it can be anywhere from under 7 to 7.5 as patients have more complex chronic diseases or are there are older and with more complex problems, the goals become less stringent. So when someone really has late or end stage disease, you don't really care what the human woman anyone see is, we just want to keep them in a point where the high blood sugars aren't taxing on. So what does that mean? No past targets were 6.5-7. Now we all talk about personalization. But this still little guidance to really help us on anything patient. We talk about time and range now because we can do continuous glucose monitoring. And while this is something that we'll be talking a lot more about in the future, no one has data on what range is appropriate, what data we should be following. This is still to be determined in the next few years. What is clear is we now are much more interested about cardiovascular disease. Overall, the cardiovascular diseases I mentioned is lower in people who have had longer, lower glucose is generally it takes at least five years to see that effect. So improving blood sugar today is not going to suddenly decrease someone's cardiovascular tomorrow. Um but this time frame actually may be completely changed with GLP one agonist. Mm So you know, we have to kind of figure this out over time. So if we kind of put this together, we still have to remember that there are issues with short term for poor control. We have adverse events such as urinary frequency urinary incontinence infections of all types patients can have high publicity weight loss, muscle law, tired having rocked it. All these things can be present from short term for control. So we do we can't just say, oh, let the blood sugar be anything. We have to do glucose and arrange to keep these things from half. So as we put it together and start looking at all these medications that are available. We have a lot of places where there are abnormalities that cause the abnormal glucose tablets. Obviously patients with diabetes will have changes in insulin secretion and their multiple drugs that improve that there is alteration and glue do not. And multiple drugs that changed that Obviously there is an increase of paddock glucose production and medications like Metformin will reduce the glucose production, insulin resistance of skeletal muscle and mainly five solution dion's metformin to a little bit will improve um insulin resistance and muscle. But we also have issues with appetite control, issues with glucose reabsorption where there's an increased reabsorption of glucose in Type two diabetes and SlB two inhibitors that reverse that. We have a lot of places where medications will impact all these abnormalities. Yes. Now this isn't one of my favorite little studies from a long time ago. Just to start pointing out why all the drugs can decrease glucose is all the drugs can decrease microvascular disease. But all the drugs aren't the same. This is something that we can all actually see this is looking at weight changes with different drugs. This is a while ago and it's just looking at one year in the Kaiser system where patients had one new drug at it during that time. So they were quote stable on one extra drop. And if a cell phone your real were added, they gained on average £4 metformin. They lost an average of £5 or so. They put it started on the thighs Celine Dion and they gained almost £11 and insulin about seven. So right off the bat, there are major differences in what happened. Think what we're mainly going to be talking about diabetes, cardiovascular disease. Now. Historically, I think they're all aware that most patients with diabetes have attention that diabetes is associated with 2 to 4 fold, increase risks growth, an increased risk and cardiovascular debt. What we're really even more interested in these days this heart failure because of the close relationship between diabetes and heart failure and in fact, heart failure is the second most common initial presentation of pretty vascular disease in diabetes And among patients hospitalized for heart failure, the prevalence of diabetes actually 40%. So this is where we see a high percentage of our diabetes patients in the hospital. Now, as I mentioned, there was the court studied many years ago that showed an increase in the death rate. Um, for patients that had type control. There are other studies that have been done over time where patients were put on Newer Medications, size 11 Diane's at some studies showed an increased risk for death from being honest by a Celine Dione. Generally, those studies have been discredited. But nevertheless, what came out of those studies is the FDA mandated cardiovascular outcome. So, these are all the cardiovascular outcome trials that have been done to date and pretty much encompass all the ones that of that are going to be done a thing. So, we have no studies on all the newer classes of medications. Look at what's the effect these drugs on cardiac disease. Now, these studies were performed to say, oh, are they good? They were really done to make sure that they're not causing an increased risk of cardiovascular disease and death. So, um, with that we'll be talking about a few of those studies. So when we put those studies together with all the other information on our medications, what we're going to be talking about is trying to figure out What's right about one drug versus another. So, when you look at the drugs, we look at the efficacy of lowering glucose and most of them are relatively the same risk for hypoglycemia, which there's complete difference between different classes. Yes. The adverse effects costs and insurance coverage, which are completely different also between different groups, whether there's weight gain or weight loss with patients will actually take it, especially after they look it up on the internet. And then whether there's cardiovascular and renal safety or actual benefits. You can see where these new drugs have come onto the market. No way back when we have insulin Soften your area since the 1950s, By Guana in United States, 1994, although they've been around the world since 90 mates. And this would have been way over here and then the increase in the newer drugs as guilty to inhibitors and so forth the last few years. Let's talk a little bit about these medications. I'm not going to go through everything about all the different drugs, just a few important things. Again, mainly about cardiovascular issues. And then as we get to the end, I'll kind of go through um specifics on some of the medications, what's important to in mind. Yeah. Um so this is a study looking at Metformin, congestive heart failure. Because I'm sure if you look at the um DDR No, it'll talk about Metformin and not using congestive heart failure. This is actually showing that impatient to a pad, congestive heart failure and diabetes being on Metformin is actually beneficial. Good name, fewer people die there on that foreman, fewer people are hospitalized, fewer people are hospitalized for any cause, not just for congestive heart. This is just being on old Met foreman. That's been around since my yeah, this is comparing heart failure, hospitalizations. People on the foreman versus a self Maria. And there are fewer patients hospitalized with Metformin for heart failure, he cared to assault Maria. And if you look across subgroups for that study. This goes across basically all the subgroups think of race age history of heart failure. So finally, there's an old maid analysis because any studies on Metformin are gonna be old at this point because there are no new studies on that foreman really. Um so they had 40 trials that compared with any other treatment or a placebo. And the bottom line was Metformin was associated with a significant decrease in cardiovascular mortality overall. Although I could find you studies on both sides of this that are are generally well done. So but when you put them all together, they just seem to be a creative faster and more. What about self and your Diaz? It's a steady from Canada but it makes a makes a point quite nicely looking at mortality and cardiovascular arrest in salt Maria's and Canadians. And specifically in this case south asian and chinese uh for in Canada. And can. The key point is mortality and um cardiovascular outcomes were higher in patients who are on sulfa Maria's with a hazard rate of two. This was even more so in the chinese and south asian patients we've been given. So the bottom line from this really quite large a study show considering the wide use of self Maria's, there was a significant signal there or increased mortality in all patients who were on self Maria. Um This is one of the reasons that's possible. This is looking at hypoglycemia and I think this is obvious to everyone. I'm listening right now that patients were only on self injurious versus met foreman. The risk for hypoglycemia on the medication like self Maria is going to be increased, really doesn't cause high football. You're right employment. Um again, just making the point, this is where patients are comparing the rape, the risk of hypoglycemia of met foreman and glitches I'd versus metformin and a before inhibitor sacks of Clifton. And as you would expect, there's really very little risk for hypoglycemia with a deep before metformin and at significant risk of hyperglycemia with salt Maria. I mean, when patients have poor control and self care is not doing anything, it won't cause hyperglycemia. The blood sugars are high and the medication is not doing anything when people give it to someone in good control. There is a high risk behind uh, this is looking at again, another made analysis looking at salt Maria's and the risk of cardiovascular events. In a newer evaluation of old medication class. In fact, they only could find six studies that didn't have major design biases. The bottom line was mortality in five of these studies was increased with self nuclear. Now it's still controversial. So even though people have been talking about cardiovascular uh, for outcomes for the last 40 years with cellphone Maria's, Not everyone completely believes that. And there are discussions on both sides where sometimes you can some studies will show that it does, Some study shows that they don't. Um, and just to give you, there were two new studies, the Carolina study that compared the mcbrides that before and equipment and I'll show you the sack. and then the grade study grade study is a study that chest was completed. Um, and it shows and this was a study that it show the comparative effect of all the different classes of medication when added to metformin. Unfortunately, they didn't add in the best guilty to inhibitors. And the study is already considered worthless because of that because it doesn't have one of the newest major groups. But nevertheless, it did show, you know, the data has been completely analyzed that really there's not so much difference in outcome, consult Maria is and other drugs except for GLP ones and improve out. So I think this hasn't been published yet in any of the journal they study was mentioning comparative vinegar, Leptin, Angloma, Pride. Bottom line was there was no difference in cardiovascular outcomes between the groups. This would go since. Generally, studies have showed Leonard Lipton across the board has been neutral for cardiovascular disease. This would tend to say, well, using a self Noriega Mcbride is equal to the neutral in neglect. Don't leave it up to you decide where this fits as we go Feisal in diane's so fizzle and die owns or a lot of positive things to the TDS, reduced blood pressure, blood sugar, crp levels, reduces bad liver and liver tests. Abner Mountain reduces stent failure. All sorts of great things, but Generally people gain between five and £12 within the first year of taking it. Others patients will have a severe peripheral oedema to 30% of the time it's unresponsive diuretics. And again, just to be fair, there are the important improvements and cardiac index, growth volume and so forth. But what is the help for our overall outcomes? The studies are old. This was back in 2005 proactive study with glitter zone and it generally showed that and improve cardiovascular outcomes and d and put off the need to start insulin. Um So this was an early study is it? And we'll come back to that. This is a study looking at rosie Glinda zone that was taken off the market for a while because of the main analysis that started to worsen cardiovascular disease. And the bottom line was a new maid analysis where they looked at all the old raw data, 33 trials of every 100 patients showed an increase in the restaurant and that's the bottom line for the Feisal and jones. They increase the risk for heart. Um in fact, overall there was a 33% increased risk versus control with the files one guy owns for M My heart failure and cardiovascular death. But this was entirely due to heart felt In cretins. So we have the DPP four inhibitors used have been out for a long time. Now I'm sure you're all well aware of these medications. These were the cardiovascular outcomes trial For the DPP four inhibitors. So the main basically they didn't show very much. Um They were non inferior to placebo. We looked at heart failure. Um There was no change with alec Clifton was Siddig Lipton with sacks uplift. In the initial study, it showed an increased risk for heart failure. But the follow up kind of larger retrospective studies have not shown this. Um so basically they're pretty much a neutral group of drugs for cardiovascular disease. They generally don't make anything worse, but they don't make anything better Again, keep in mind that the cardiovascular outcome trials were designed to look for worsened problems. They weren't designed to look for improving cardiovascular health over safety. This is looking at some of blue tide. New data from just a few months ago. This was looking at the drug or weight loss. So I think everyone probably has seen the headlines for this. So they gave semi glue, type 2.4 mg dose that we have generally had for Type two diabetes is point to 5.5 mg a week. This is 2.4 mg a week. And this is what it showed. It showed in people with um with diabetes and obesity that if you go here, this is a percent body weight change was about 10% with the high dose, here's a one mg dose. This is currently available for treatment of type two diabetes with the usual doses that we use. This is placebo. Up here, we look at waist circumference. Can waist circumference down nine cm with the big dose about seven cm with the one mg dose used for diabetes as far as going up to the higher dose for improving blood sugar control. There is really no difference. Once you get past the one mg a dose. So it higher than that it's helpful for weight loss but not particularly for hemoglobin. England. See but this is a fairly dramatic drop. Anyone see it? See this is again looking at some glue tied and looking at cardiovascular disease outcome. So this would be one of those trials. And what we see is for primary outcome that there is a decrease it's in risk for the primary outcomes of cardiovascular death, non feeling in mind on stroke compared to placebo. Um And if we look specifically what where the help is, there is a slight decrease in non fatal am I? But that's a region the value of note and there is a decrease in non fatal throat that does the significance no change in death. Are you've asked for what kind of summer where the GPS GLP once go. They decrease stroke. So people on GLP ones um whether it's some glue type here, this is the laboratory type, there is a decrease in nonfatal stroke and stroke and fatal stroke. The Sette two inhibitors again on the market for quite a while now. Same kind of outcome studies. So this is an outcome study looking at hospitalization for heart failure. This is all the news of course. If you look on a Graph that has goes to 100%, it's hard to see the difference when you start looking at it blowing up a bit. You can see that there is a decrease in um in hospitalization for heart failure and this begins relatively quickly after the patients are started on the medication. Um This is one of the real world studies. So now we have a randomized studies then we have the retrospective real world studies where they just collect all the insurance company data or national medical record data. And this is from mainly from europe and look retrospectively and looked at patients who had initiation of invincibility inhibitor versus other Glucose lowering drugs. And with L two inhibitors there is a 39% lower incidence of heart failure and 51% risk lower rate of all cause death. So this is what has people so excited what cardiologists are giving this patient renal doctors are getting agents as well talk about because of all the impressive data lower on lowering risk for disease. So, if we look at heart failure overall, DPP four inhibitors don't do so much for heart failure at all. GLP one agonist, don't do anything heart failure. The STL T two inhibitors reduce heart failure, hospitalization, right, What about net profit? The so this is like the Niagara Fox in and kidney outcome renal outcomes and type two diabetes. Um And it shows that when patients are put on Magdala Fox in in this case it S. B. Two inhibitor, you have a decrease in the progression of any kidney disease. Can see the album. The cramping ratio is better with managua flocks in and this is pretty typical looking at G. F. R. Changes, there's an immediate drop in E. G. F. R. But then it flattened out a bit compared to placebo. This is something to keep in mind when you put patients on this initially there E. F. R. Can look um suspicious. Uh But that is short and here's another study that shows up again. The patients are put on GLP one. Let me ask you to. They're big car drops again. It returns close to baseline compared to the patients weren't put on it first. So these drugs have um become the drug that people are talking about so much. If you look they'll say there's no there are some risks like urinary tract infection. General yeast infections, but don't worry about This is a study of over 2,200,000 patients and compared born with the L. one and they headline was sclC inhibitor is not associated with increased risk for U. T. I. That's great. But it's total nonsense because what did they do? They excluded all patients with a history of the UTI. Are or were at high risk for U. T. So they excluded patients would have sepsis chronic kidney disease but enlarge prostate and so forth. So basically a lot of the patients we take care of, they excluded from this because those are the patients and end up with urinary tract infections. So you do need to be really careful with these tracks and pick your patients um with care because there are risks and they often seem to be overlooked. Finally with the SDLP two's uh we have the risk for you guys seem like a It doesn't happen so much in type two diabetes but it can so in these drugs do cause some ketosis begin with. And then if patients are fasting for some reason for what or have general anesthesia, they can go into utilizing it. DK A. Um and generally the place we see it as pre operatively. So patients will come in the hospital and ho stop their blood sugar looks fine. But they're assad attic they go into a prolonged encephalopathy with this. You guys make a until they're treated for a few days. Um You can see it in patients undergoing colonoscopy. I had one of my patients before that to me after after the fact. Um and this was a publication about this last year. So patients on the medication, they go through their whole prep for a colonoscopy and then they go and their blood sugars are fine but now they're vomiting and have utilizing a and get into trouble. So what we've long instituted here is for any procedure we use our pre op program which you can look at. UCSF dot logic, Calm and in there we have the patients stop these medications at least three days before the procedure. That's not 100%. But it should keep almost all patients from developing university. Mhm. The other thing about these drugs is that they are improved non alcoholic hepatitis um and actually improve your gas levels and decrease the risk for gout. So a couple I've added little benefits the medication. So thinking back on our little chart here when we start looking at all these drugs which drug for which patients uh we can start getting a little more specific. No, I have some charts here. You can I'm sure look at these. If you are given. If you want to look at this after the fact just going to go through a few high so self and your E. A agents it can cause hypoglycemia, cause weight gain. Probably neutral cardiovascular disease. Probably neutral for renal effects. Um matt foreman, no hypoglycemia generally neutral. Or wait, maybe some potential benefits party of vascular disease. No gent no effect on renal disease. But it's contraindicated. If E G. F. R. Is under 30 you get down to probably 30 to 45. You should decrease the dose From 1000 twice a day to 500 twice a day. Remember to screen for the 12 deficiency because metformin can cause of 12 deficiency. and any of the patients who are on extended release. We've had all sorts of issues as of the DNA. That's in some of these preparations and the drugs getting taken off the market on all these drugs we don't use almost at all. So I'm not spend time one in The VLT two inhibitors. Again, no hypoglycemia. No, they have some weight loss. There's benefit for cardiovascular disease and heart failure, benefit for real disease. Generally the FDA says don't use it for under 45 but usually we use it down to it EGFR 30. Some people use it even lower but generally 30s are cut off. You have to worry about you basement thank you. The infections utilizing the PKK and again it needs to be they need to be stopped 3-4 days before any procedure. The GLP ones for the in cretins. No hypoglycemia significant weight loss. Um Probably some benefit for cardiovascular disease neutral for heart failure. They decreased albumin urea you have to be cautious with patients with renal disease because if they start having nausea and vomiting that go into complete renal failure. Um And finally the before inhibitors. No hypoglycemia that it's neutral for just about everything. So no wait effects. No cardiovascular renal this is the current algorithm looks really complicated. And of course I'm sure you can see every detail of this on your screen right now. But this is the 2021 algorithm and it finally actually makes some sense believe it or not? It used to be that the algorithms from the major organizations were start with Metformin and then give whatever you want. Um That's no longer the so basically we start with patients um who have high risk for cardiovascular disease or kidneys is and in that case everyone theoretically has started on the foreman and diet and exercise. And then if we look at patients who have heart disease pretty straightforward. They started on generally a GLP one or an SD LT two A one CS remain above target. You add the other one. So patients go from that form and a GLP one or an SLT two and then the other one is added. If patients have heart failure, the STL T2 is definitely a drug of choice at that point. If patients have kidney disease generally it's the S. G. L. T. Two's. Uh if they don't um if their renal function is okay it can be on a GLP one or an S. Um If you add semi glue tied to s guilty to inhibit her, you can see what happens. This is semi blue tied one mg a week plus. And yes you open to adding the um GLP one gave another point and a half decreasing a one C. And almost support kilograms. Now what if there's no clear cardiovascular disease or renal disease. So it's now it depends. Are you trying to reduce the risk for hypoglycemia in that case. No, A DPP four GOP one stld too. Even A T. ZD theoretically won't add hypoglycemia to the rest of the patient on the foreman. If those don't work, you add one of the others. If the patient has to minimize weight gain or promote weight loss. And I think that that's what most of our time twos again, this is getting repetitive. A GLP one or an SLT to those fail the other one is added. And if cost is a major issue obviously everything I've already said is thrown out the patients on Metformin and then you use a salt Maria or easy d um and then consider adding a low cost basilan's. So we have the medical benefits of all these new drugs cost. Move it. The drugs have come actually give us much medical um This isn't really to go through this chart. It's just to point out that when you fail with these oral agents or injectable GOP one's we move to other treatment. In this case it's moving to basil insulin that's added, Starting it generally about 10 minutes a day high traded and worry about over visualization. The patients are getting more than half a unit per kilogram because remember basil insulin should be covering basil requirements too often? We end up giving basil insulin? And it's trying to control the meal requirements and the patients just get hungry and eat more and gain weight. So we have um this is just to point out which basil insulin should use generally doesn't make so much difference. Here is just one new study that showed if you give large jean um and or did amir that it was associated with less hypoglycemia than NPH. And if the A one C. Is still above target, you can then move aah or twice a day or premixed insulin twice a day or basil bullets insulin as appropriate. And obviously if the patients on a premixed insulin or premium incident, the patient no longer needs the secretive. So just to get near to tying this all up a couple last things, that's the show that everything I just mentioned isn't always correct. Remember if you have a new patient who is symptomatic, has high blood sugars, generally they have glucose toxicity present. So the high blood sugars themselves turn off insulin reduction. So bad ideas for a first drug would be Metformin because the patients probably dehydrated. That could be a patient who with greater risk for lack of acidosis. The worst drug given would be an sdlp to their blood sugars are already high. They have high glucose is in europe. And maybe these patients are even at a greater risk for a DK which we've seen at times when people have done this on SNl G two when they're out of control and begin with. So old fashioned south Korea and never go wrong starting a patient on in someone, they're totally out of control cost. Since I've mentioned that a few times now. Can see cost is crazy. Self Maria's can be $4 a month. That foreman $4 a month. You get to know blah blah tied or laura vela tied. You know as they just go up in price. Just four years ago It was $515, not $729, insulin costs go up. Everything keeps going up for no apparent reason Managua flocks and You can see was $300 back in 2014. Now nearly $600 a month. Uh For noah Now the gyms are open 24 hour business is $35. Uh Personal trainer in San Francisco is probably $1,000 a month and a pellet time. It's about $39 plus the bike. And it's interesting when you talk to patients at by video you see their pelican bikes in the back room and talk about just to finish up. This all sounds really good. But the patients actually take any of these medicines giving them all these drugs. This is looking at urine samples to see if patients actually take your drugs. This wasn't so bad. I mean 21 we're not adhering to anti diabetic, antihypertensive lipid drugs, They actually did pretty well where oral hypoglycemic non appearance is only 9%. But a new study that just came out showed that um in Canada, the majority of people who were given Metformin for their first line drugs As monotherapy, 90%. Almost half were not adherent over the first year, And 1/3 of those who started metformin discontinued it on their own in the 1st 3 miles. So the point of all this is given you a whole lot of information on where things have been with diabetes, where we're going, how things are changing. How the new drugs that cost a lot of money also appear to have a lot of benefits. But we thought that was the case in the past. It hasn't true. So I hope I've left you with some information. Probably a lot of questions that you can think about with your patients and options are going forward.