Welcome. This is a session on personalized treatment for patients with diabetes. I'm gonna introduce my two speakers in a moment, but for those of you who are just getting your seats and those of you who are fellows in the room, I just wanna tell you that when I was a fellow, we had metformin and a sulfonylurea, and personalized medicine meant you gave them a combination pill. So we've come a long way in the last 15 to 20 years with all of the discoveries, and I have to say that the two colleagues sitting to my right here were really instrumental in many of the clinical trials that led to our understanding of outpatient and inpatient care of diabetes. First, I'm gonna introduce Dr. Guillermo Ampirez. He's professor of medicine in endocrinology and clinical director of the Diabetes Metabolism Center at Emory. He's also the president of medicine and science for the American Diabetes Association this year. So welcome, Guillermo. I also wanna introduce Dr. Lawrence Blond, again, a key clinical investigator in outcomes for diabetes. He currently is the director of the Diabetes Clinical Research Unit at Ochsner Medical Center in New Orleans, Louisiana. And again, we really appreciate you being here today for this discussion. So they've put together a case-based approach to talking about personalized pharmacotherapy, and I'm gonna start with the first case. So Dr. Blond has brought a case of a 67-year-old Latina female with a six-year history of type 2 diabetes, and she had a TIA one month ago. She's also treated for hypertension and dyslipidemia, and her current medications include Metformin, 1,500 milligrams, Citagliptin, 100 milligrams, Aspirin, Atorvastatin, 40 milligrams, Olmosartan, 40 milligrams, and Enlodipine, five milligrams. So she's on a large cocktail of medications for her diabetes as well as her comorbidities. On exam, her BMI is overweight at 29. Her blood pressure's well-controlled at 120 over 76. Her A1c is 7.9%, and she has an EGFR of 58. She also has urine albumin at 40 milligrams per gram of creatinine. She is told that she needs to add insulin to her regimen, and she's seeking a second opinion from Dr. Blond. So in this case, in addition to seeing a certified diabetes care and education specialist about improving her lifestyle choices, which of the following would be the best therapeutic option for this patient? A, increase metformin to 2,000 milligrams per day. Add Glargine 100, U100, starting at 10 units at bedtime. Add bedtime starting doses of Glargine U300, or insulin to Gludec. Add an SGLT2 inhibitor, or add a GLP-1 receptor agonist. And I want to let Dr. Blond kind of work us through these choices for this case. Thank you. So this isn't, I think for most of this audience, a very challenging case, but it, I think, raises a number of issues that are worth discussing. And you may see, during the course of this, me getting up and getting closer to the screen. I've reached an age where when I go shopping, half the things in my shopping cart say, for fast relief. And almost everything that I have that doesn't hurt doesn't work. So I'll do the best that I can here. So if you look at a number of studies, this is one, that have looked at the difference from the top dose of metformin to 1,500 or 2,000 milligrams per day, there's only a marginal better glycemic control and association with a higher incidence of GI side effects. What about adding insulin? As the next step, which is what she was told needed to happen. So here are four studies comparing GLP-1 receptor agonists to insulin-glargine U-100. And you can see on the left that in all of them, the reduction in A1c was greater with the GLP-1 receptor agonists. And on the right, the reduction in weight was significantly greater. There was a reduction with the GLP-1 receptor agonists and an increase in weight with insulin. And these greater A1c and weight reductions were statistically significant. So what about adding an SGLT2 inhibitor? So this is sort of a combination of some of the texts from both ACE and the ADA standards of care that says if patients have established or high risk for ASCVD, heart failure and or chronic kidney disease, then independent of glycemic control, glycemic targets and or treatment, including metformin use, a GLP-1 receptor agonist or SGLT2 inhibitor with proven efficacy benefit for the individual patient's condition is recommended as part of the glucose lowering regimen and also as part of the comprehensive cardiovascular risk reduction regimen. And proven benefit usually means that there is, it's an identification by an FDA indication in a medication's prescribing information or label. Although another way would be the primary outcome of a trial demonstrating benefit. So here we're looking at the cardiovascular outcome trials of some of the SGLT2 inhibitors, canagliflozin, empagliflozin, and dapagliflozin and urtigliflozin. And you can see that the reduction in MACE was accomplished only with empagliflozin and canagliflozin. And when you look at a comparison of the components of MACE with those two agents and you look at stroke, in neither of them was there a reduction in the risk for stroke. Now, in fairness, this wasn't the primary outcome. The primary outcome for which the studies were powered were, of course, the composite outcome of MACE. So the fact that this didn't show a decrease doesn't mean that one couldn't use these agents as part of the recommendations. Interestingly, there has been a recent meta-analysis and systematic review of five of the cardiovascular outcome trials with SGLT2 inhibitors. And in none of them did they demonstrate a reduction in the risk for stroke. And even when they looked at all of the components of stroke, fatal, non-fatal, there was no reduction in that risk. They did see a significant reduction of hemorrhagic stroke, although it was a small number of events in that trial. But in general, this supported the other studies that we looked at of not showing a definite benefit for stroke. But that doesn't mean that one might not get it because in most of these trials, the primary outcome was MACE. Let's turn to GLP-1 receptor agonists. And of course, if you were adding those, you'd have to stop the sitagliptin. So which GLP-1 receptor agonists should be used? So here we have the cardiovascular outcome trial results with liraglutide, semaglutide, exenatide extended release, and doulaglutide. And you can see that in three of the four at the very top, there was a reduction in MACE. But for two of them, where the boxes are, there was a significant reduction in the risk for stroke with semaglutide in SUSTAIN-6 and with doulaglutide in the REWIND trial. And this is from the figure in the standards of care that looks at recommendations for patients who have either established or high risk for arteriosclerotic cardiovascular disease, heart failure, and or chronic kidney disease. And we're looking at the one that is focused on arteriosclerotic cardiovascular disease, which recommends a GLP-1 receptor agonist and or a SGLT2 inhibitor. And then if those don't get you to the glycemic goal, then to add the other one that you weren't given. So in other words, if you started with a GLP-1 and you weren't at glycemic goal, you could add an SGLT2 inhibitor. But at the very bottom, they indicate that you could also consider a thiazolidinedione. So this is the IRIS study that I'm sure you're familiar with. This is a trial in people who didn't have type 2 diabetes. They had insulin resistance, but no diabetes. And they had a recent history of ischemic stroke or TIA. And they were randomized to receive pioglitazone or placebo. And there was a 24% reduction in the primary outcome of fatal or non-fatal stroke or MI in the trial with the people who got pioglitazone. There was also a very significant reduction of about 50% of the patients who got pioglitazone had a relative risk reduction of developing type 2 diabetes. And of course, the issue is that pioglitazone is associated with a lower risk of MI and stroke and of development of diabetes in this trial, but a higher risk of developing weight gain, edema, and fracture. So it was interesting to see a very recent post hoc analysis of this trial that looked at the doses, lower doses of pioglitazone in this trial. So compared to 45 milligrams, giving a pool dose of either 15 or 30 milligrams per day was associated with similar reductions in the benefits and less adverse events with the exception of fracture. Now, of course, further studies are needed to confirm these findings, because in actual fact, the percentage of people in this trial who are on these lower doses was much less than the percentage of people who are on 45 milligrams. But in fact, I think it was a very interesting study that suggests a way of taking advantage of some of the benefits. So with that review of how one might deal with a patient like this and concluding that maybe the best choice would be a GLP-1 first, and then if that didn't get you to glycemicol, then adding a SGLT2 inhibitor, or maybe even a TZD. And with that, I'll turn over the slides to Dr. Ampiras. But we didn't know, we don't know what the hemoglobin A1C level is in your patient. What if the hemoglobin A1C is 11 or 12? Will you still use GLP-1 or you will do insulin? So I think that's an interesting question. And clearly when people have A1C values that are that high, many people would give insulin first. There haven't been specific studies that compare, to my knowledge, a GLP-1 receptor agonist and insulin in those sorts of patients, although there are post hoc analyses of some of the comparison trials in which there was a minority of patients who had pretty high glucoses, and there was surprisingly good outcome with the SGLT2 inhibitors. And of course, you raised another, for people who aren't that high, generally both ACE and ADA recommend using a GLP-1 receptor agonist before insulin. But I think you raised, there's clearly gonna be people, particularly if they're very symptomatic, for whom insulin makes the most sense. I would agree, starting with GLP-1. Let me present a simple case from my clinic. 59 year old female, 12 year history of diabetes with chronic kidney disease. And the GFR is 45. But more importantly, the urinary albumin creatinine ratio is greater than 300. So you have a patient who has CKD high protein in the urine. And she had been receiving a combination of metformin and glargine, like a lot of patients in my clinic. The hemoglobin A1C is 8.1, not too bad. And the low glucose range between 98 to 130, and postprandial, all the way up to 200. But this patient has noticed hypoglycemic events during the past month, likely related to CKD. On physical exam, she's overweight, 29. Blood pressure is okay, and she has mild retinopathy. So CKD, urinary albumin creatinine ratio, hypoglycemia with glargine. So the choices are very clear, that's right. Decreased dose of insulin, continued metformin, increased glargine, stopped metformin, increased glargine. Stopped glargine, changed to 70-30, that's something that we never do. Continued metformin, reduced dose of glargine by 20%, and add dapaglifloxacin. We increased metformin and reduced dose of glargine. I'm not sure how would you treat this patient, but I think that following Larry's presentation, I think we should go on to add SGLT2. But I bring this case because of the hypoglycemia with insulin. So we now know that using CGM, we're going to recognize a large number of hypoglycemic events, and especially nocturnal hypoglycemia. 63% of patients with type 1 diabetes and about half of patients with type 2 have unrecognized hypoglycemic events by CGM. 83% of those episodes with CGM are at night. And the question is, why do we have hypoglycemic at night, hypoglycemia at night more often? And there is tons of studies that have shown, especially 10, 20 years ago, that have looked at hypoglycemia is more common at night than during the daytime. We thought that it was because you eat during the day, you are protected. And the answer is not what you eat. The answer is the catecholamine response to hypoglycemia. And when you look in here, to your left is patient with diabetes, and to your right, patient with no diabetes. And they underwent a hypoglycemic clamp at 10 a.m. after a 12-hour period, so overnight fast. And when you're looking here in the dash line, it's nighttime during sleep. And in the continuous, the other, I'm looking at the left here, daytime awake, and nighttime awake. And there is difference in the catecholamine response. If you're sleeping, it doesn't matter if you're young or old, you have less catecholamine response. If you have diabetes to the left, if you don't have diabetes to the right. And that is the main reason why hypoglycemia, you see it all the time at night. So the other thing is that you notice the association with cardiovascular events, that's right, and this clinically is the most important thing. The third thing is what the ADA this year recommend. Please stop just doing serum creatinine or calculating GFR. That is a very late event, and what we'd like to do is to do urinary albumin creatinine ratio. And the recommendation is to do it at least once a year. Because if you have a UACR more than 30, you'll double the risk of cardiovascular events. If you have over 300, you've increased the risk of cardiovascular event by three to five fold. And here, this is a beautiful slide that makes the point why you have to measure urinary albumin creatinine ratio. If you look at the curve for GFR, look, you already have macroalbuminuria for many years. And you have to intervene if you want to reduce cardiovascular events. GFR is a late event. Urinary albumin creatinine ratio is the way to go. And what I mentioned before, if you have somebody with albuminuria, you don't, I mean, I'm sure that you think this patient is going to go to end-state kidney disease. Yeah, a late event. The main reason why you want to do albuminuria is because the association with cardiovascular events and cardiovascular mortality. And these are the recommendations of the combined ADA, KDGO, monitoring at least one time a year. But if you have in the bottom, already albuminuria twice a year. The diagnosis of chronic kidney disease, number one is urinary albumin creatinine ratio. Number two, GFR. The other thing is, why do we care? Because now we have way to treat. For many years, the only thing that we have is ACE inhibitors or ARBs. Now we have much better treatment or combination with other agents, that's right. And what I'm showing here is the residual risk. Yeah, ACE inhibitor, ARB work a little bit, but the residual risk is there. So now we have three type of medication that have been shown to be effective in CKD in patients with diabetes. Larry mentioned about the HCLT2, number one in the list. Number two is GLP-1. Both reduces albuminuria and progression from micro to macro albuminuria. And of course now we have the mineralocorticoid receptor antagonist. We published in the last two years, two large studies that's showing that you can decrease progression and you reduce mortality in patients with diabetes. Metformin, DPP4, TCDs, neutral effects. Insulin doesn't do much to the kidneys. So the recommendation from Kate Deagle, first line, HCLT2, if you have albuminuria. Everybody should be on ACE inhibitors. This is on top of ACE inhibitors of ARBs, HCLT2s. It does, you cannot use it, the alternative to use GLP-1. All of the other medicine have negative or neutral effect on what is progression of kidney disease. And Larry already presented this. All of these trials, EMPA, CAMBA, DECLARE, GERISH, all of them showed an improvement of renal disease. So recommendation number one, Kate Deagle, ADA. At least once a year, if you have a patient with microal, twice a year. And you have to start with this medication because they have been shown to change the progression of diabetic kidney disease. All right, any comments? Thank you very much. So I do have one comment. For the first part of your talk, where you're talking about the importance of hypoglycemia, one of the things I wondered, as more and more people are using CGM, particularly in the type two group, we may finally get an answer to a question that has not really been addressed. Which is, what about people who don't have severe hypoglycemia? Who have mild, how frequent is this? And what are the impact of that on people, how they feel and function? I think that this is probably the only way that you can get an answer to that question with capturing large amounts of people who are using CGM and recording what happens to them. And we have done studies, and in the hospital, 45% are asymptomatic. No symptoms at all. You go in, are you nervous? You feel shaky? You're sweating? Nothing. So hypoglycemia is asymptomatic in at least half of the patients. And with type one and nocturnal hypoglycemia, 70% are asymptomatic. And the question is, in those people, does that predict people who are at increased risk for severe hypoglycemia? Probably. But we don't really have great data among that. And are there other signs and symptoms that people have that we're not identifying? I agree. Okay. So this is Dr. Blond's next case. This is a 73-year-old gentleman with new-onset type two diabetes, being treated for both heart failure and hypertension with furosemide, 40 milligrams once daily, and a combination for hypertension, as well as Carvedilol. BMI is 32.5 with blood pressure of 128 over 85, and A1C is 8.9%. So after initial diabetes education, he and his physician agree target A1C should be initially lowered to less than 7.5%, and eventually less than seven if this could be done safely. Ejection fraction is 36%, with an EGFR of 50, and urine albumin creatinine ratio of 50 milligrams per gram. Other lab values are within normal limits. So the question about how to manage this patient is in addition to a further session about improving his lifestyle interventions, which of the following would be the best anti-hyperglycemic therapeutic option for him? Metformin, DPP-4 inhibitor, GLP-1 receptor agonist, SGLT-2 inhibitor, or a combination metformin, GLP-1 receptor agonist, or combination metformin, SGLT-2 inhibitor? So if one looks at that center part of the ADA's recommendations for people where you're looking at the heart failure pathway, it indicates that when heart failure predominates, one should use an SGLT-2 inhibitor with proven benefit in that population. So empagliflozin and dapagliflozin have proven benefit. I'm gonna quickly show you those studies. Kanagliflozin has proven benefit in those with diabetic nephropathy with albuminuria from the CREDENCE trial. And empagliflozin and dapagliflozin heart failure benefits have now been extended to those with and without type 2 diabetes. And for empagliflozin, and I'll show you in a minute, probably for dapagliflozin, not limited to those who have heart failure with reduced ejection fraction. So I think the answer, and we'll come back to this at the end, is either SGLT-2 inhibitor to start with or a combination of the two agents to start with. And combinations probably are underutilized in a trial that isn't completely relevant to our case because the patient was, in this study, was on metformin plus vildagliptin, a DPP-4 inhibitor that's not available in this country. But initial combination therapy slowed the decline of glycemic control versus metformin alone or versus vildagliptin added after initial metformin. And there was a reduction in initial treatment failure with the combination and a prolongation of good control with that combination. So which SGLT-2 inhibitor should be used? Dr. Ampera has already showed you that in these trials, he was showing you CKD. Here we're looking at hospitalization for heart failure. And in all of these studies with empagliflozin, canagliflozin, dapagliflozin, and erdigliflozin, there was a reduction in hospitalization for heart failure. This came as a surprise initially. There weren't a huge number of people in these studies with known heart failure, but this led to the idea of doing studies where the primary outcome would be the effect on heart failure. And the first of these was the dapagliflozin heart failure study in which they looked at individuals who had heart failure with reduced ejection fraction, less than 40%, and almost 60% of these individuals did not have diabetes. The primary outcome was a composite of cardiovascular death and worsening heart failure, and there was a 26% reduction in that outcome. There was also a marked reduction in worsening of heart failure. The results were similar in those with and without diabetes. And just in the last week or so, there's been a top-line announcement that dapagliflozin met the primary endpoint in the DELIVER phase two trial that looked at people with heart failure with preserved ejection fraction and showed a significant and clinically meaningful reduction in the risk of cardiovascular death or worsening heart failure. So we'll keep that in mind. There was a trial called EMPRO-REDUCE with empagliflozin that was almost identical in terms of the trial design to the DAPA heart failure study and had almost identical results showing a marked reduction in the primary outcome of a composite of cardiovascular death or hospitalization for worsening heart failure. It was a 25% risk reduction, and again, similar in those with and without diabetes. And the also showed, and I'll come back to this in a minute, in a annual rate of EGFR decline was slower with empagliflozin than it was in placebo. This was followed by the first of the studies with EMPRO-PRESERVED with individuals who had heart failure with preserved ejection fraction, the EMPRO-PRESERVED study. And again, individuals with and without diabetes, the primary outcome was a composite of cardiovascular death and hospitalization for heart failure. There was a 21% reduction. There was also a marked reduction in the risk reduction in hospitalization for heart failure itself. And this was the first of the trials that showed the potential benefit in people with heart failure with preserved ejection fraction, a group that is large and for which there's been a paucity of therapeutic options available. The investigators just recently in a letter to the editor ended up showing a prospective patient level pooled analysis of results of these two trial, EMPRO-RESULT-REDUCED and EMPRO-PRESERVED. And what they looked at was the effect on major adverse renal outcomes in those trials. And those were a profound and sustained decrease in EGFR or the need for renal replacement therapy. And they found there was a 51% reduction with empagliflozin in the EMPRO-REDUCED trial and almost no reduction, 5% in the EMPRO-PRESERVED trial. So it looks as though the ejection fraction influenced the effects of empagliflozin on major renal outcomes. So this was a post-hoc sort of, although it was pre-specified study and I think raises some issues that will have to be followed up going forward in these patients. There's also a trial called the IMPULSE trial in which they took patients who were in the hospital with either decompensated chronic heart failure or new onset heart failure. And once they were stable, they randomized them to empagliflozin or placebo and followed them for 90 days. And what they found was the primary outcome, which was a composite of clinical benefit, was significantly improved in those who got empagliflozin. And this really hadn't been looked at in this population. And I think is important and it also appeared to be safe in this study. So the end result is that for this patient, starting an SGLT2 inhibitor or a combination of metformin and an SGLT2 inhibitor looked like the first choice. SGLT2, so which of those would you pick? The last one. Well, you know, I'm the chair of the platform for diabetes at Emory and our primary care, not using SGLT2 as much as we should. And they quote, cost. Expensive, you have to get pre-approval many times, but there is a recent study in diabetes care follow up this patient for type two diabetes, no heart failure and just type two risk factors. If you combine metformin and SGLT2, it's cost saving, it's cost effective. Not because the hemoglobin A1C reduction, but for the reduced admission to the hospital for heart failure and cardiovascular complication. So I've been telling everybody in primary care, don't wait until your heart failure to use an SGLT2 in the way that for many, many patients with cardiovascular risk factor is cost effective. Although you spend more money at the beginning, you save life, you save admission to the hospital. And for some of these, there are single pill combinations that may make it easier to use. And even if one was nervous about starting the combination all at once, one could start with one, see that it was tolerated, and then quickly, rather than waiting to see whether it got people to control, quickly add the other, so. And the ADA this year says that in the standards of care, that if you have a patient who already have heart failure, and you have to decide is metformin needed, metformin doesn't do anything to heart failure. Nothing, zero. So those patients should be treated with an SGLT2. Taking in consideration that the reduction of hemoglobin A1C is just 0.6, 0.8% for most of them. So if you have somebody with hemoglobin A1C of nine, don't start just with SGLT2, combine it with metformin, but you get a reduction of about 2%. And even at lower A1Cs, ACE for a long time has recommended consideration of early combination therapy. I agree. So next case, 45-year-old obese woman, six-year history of type 2, BMI is 33, hemoglobin A1C not too bad, 7.5 to 8.8, currently on metformin. And she's taking Betamir, a basal insulin, 38 units. During the past three years, she have gained 35 pounds, especially during COVID. So despite daily exercise and diet, she's still increasing body weight. So she's concerned about that, which one of these medications should you use? So of course, all of you are going to say GLP-1, that's right, because insulin is associated with increased body weight. All of the oral agents do nothing helping the body weight. So the right answer would be the last one. So let's review the data that I think is very interesting. And then first, what is the impact of obesity in cardiovascular system? I mean, this is when we have a patient with obesity is a disease, that's right, because you have increased risk of stroke, you have hemorrhagic and ischemic stroke, you have increased risk of heart failures and atrial fibrillation. So for each one unit increment in BMI, you're going to get a five, four to 6% increase in all the cardiovascular complications. And we also know that if you improve glycemic control, and you lose body weight, and this is studied from Europe, diabetes goes away, that's right. If you lose somewhere between 10 to 15% of body weight, most people are able to stop insulin if the duration of diabetes is less than five to 10 years, or come down the number of medications. So weight loss is going to be the future. And this is a paper, I don't know if Kalindo is here in this lecture, but this is a beautiful study that is under review, I've been approved, on the trend of utilization of weight gaining and weight losing medication for the type two diabetes. So in the dark red is overall, and you see that there's not much, this goes from 10 to 20 years of diabetes. And if you look at insulin, it's about 25%, that's associated with weight gain. If you look at sulfonylureas, insulin plus sulfonylureas in this country is about 50 to 60% of patients with or without metformin. And if you look at thalasulodendron, well, it's about 4%. These are the weight gaining medications, and to the right is the weight reducing medication. So the GLP-1, SGLT-2s, the utilization is minimal. So at Emory, about 20% of patients, 22% are on GLP-1, SGLT-2s. Doctors are not prescribing, professionals are not prescribing weight losing medication, and you see the trend is very minimal, the increment. So something needs to be done, that's right. And this is the trend utilization according to body weight. And it's the same thing. I mean, minimal changes in the bottom as weight losing medications, in the top of weight gaining. We have not done much. And with respect to race, the story is even, you cry, that's right, because blacks Americans, Latinos Americans are using less of the weight losing medication. They're still being treated with metformin, sulfonylureas, and insulin. Metformin is used in about 60% of patients with type two in this country. Sulfonylureas, about 25%. Insulin, about 27%. With utilization of weight losing medicine, according to Galindo, it's minimal, as shown here in the bottom. And this is for my Spanish speaking people who didn't realize that the slide is in Spanish, but it just shows, just look at the figures. And this is the association between BMI and cardiovascular disease and mortality. In men and women. This is why you have to treat obesity. And now we have two recent reports, that's right. This is the report from the Sustained Forte. And you see here to the right is the change from hemoglobin, from body weight, from baseline. Now we have 2.4 milligrams semaglutide. It's associated with somewhere around 15 to 20% decrease in body weight. And the mean change in hemoglobin A1C, at week 40 of the study, is 2.2%. You don't get this with regular doses of GLT1 or SGLT2s. So I think that now we have a way to treat obesity. And yesterday it was approved, the dual combinations of the GLTs. And this is associated with 2.4% reduction of hemoglobin A1C. And weight loss, similar to what we see after bariatric surgery. Obesity is a disease and needs to be treated aggressively. And I think this is going to be the future of the ADA and AIDS. We have to look at why people develop diabetes over weight obesity. Now we have treatment for them. Excellent. We're going to stop in a minute, but I think this slide is marvelous. For treatment of diabetes, GLT1 has been shown, yeah, to decrease hemoglobin A1C of one to 1.5%. Sure. But for treatment of obesity, we're now using higher doses. For semaglutide 2.4, it's for patients with obesity. For diabetes, now it was approved, semaglutide 2.0 for the treatment of diabetes. And that is associated with significant weight loss. The other thing is liraglutide. You use 1.8 for treatment of diabetes, three milligrams for the use of patients with, for treatment of obesity. And dulaglutide, you use 0.75, 1.5 for treatment of diabetes. But now you can use all the way up to 4.5 milligrams of dulaglutide. Of course, cost is an issue, but if you have somebody that you can use higher doses, you're going to fight both hyperglycemia and diabetes. And I think we have five minutes before we open for comments. It won't even take you five minutes, probably, to show this. So this is something that my group is pushing around. A 64-year-old female, type 2 diabetes, come with pneumonia, right lower lung infiltrate. She's very well controlled on metformin, 400 milligrams twice a day. The blood glucose 164, hemoglobin A1C 7.1, and GFR not too bad, 66. So what would you do with this case? So the current guidelines say, oh, insulin, that's right. So, but if this patient is doing well, can you use metformin? Can you use oral agents in the hospital? So the current recommendations, and we're going to publish the new guidelines for endocrine society and ADA, is going to be presented in June at the Endocrine Society in Atlanta. I'm going to continue with the same story. But Francisco Pascal published this paper a couple months ago in the Annals of Internal Medicine. And what we think, you can use oral agents if there are no contraindications. Can you use metformin? New England Journal of Medicine, a couple months from now is going to say maybe yes. If you have normal kidney function and low risk of lactic acidosis, you can use oral agents. The use of DPP4 had been shown to be effective in patients with glucose less than 200. So you don't have to use basal or basal blotter for everybody. In patients who have low glucose less than 200, hemoglobin A1C less than 7.5, so fairly well controlled by the patient that has sold it to you, you can continue the oral agents, but you have to check for kidney function and make sure there's no risk of contraindications to their use. In patients who have moderate hyperglycemia, glucose in the 200, 300, most people are like that, you are going to use one single dose of basal plus sliding scale or plus a DPP4. And we think that you should reserve the use of basal blotters for those patients who are treated with basal blotters at home, patients that you don't know have type one or type two, this one and a half, basal blotters. Type one diabetes, basal blotters. But for patients with type two, I would reserve basal blotters only for those patients who have significant hyperglycemia with hemoglobin A1C greater than nine. And when they go home, again, oral agents, not associated with hypoglycemia, would be my preferred way to treat these people. So it's a new idea, individualization of treatment according to Pascal is the way to go. Excellent. Well, I want to thank you both for this really robust discussion. And I think we could probably entertain one or two brief questions at the microphones. Excellent talk, just a question. What is the mechanism of improvement in heart failure with the use of SGLT2s? I think that there's a lot about the effects of SGLT2 inhibitor that are not known. There's a lot of postulation about this, but clearly there is a benefit on volume that may play a role, but there are probably lots of other factors that we're still trying to get to the bottom of. It's a dual thing. It decreased the reabsorption of glucose and increased natriuresis. And that has been shown to decrease blood pressure about two to four points. And of course, maybe that has to do with endothelial sympathetic tone. Many reasons why that has been effective. But that effect on the sodium, you would think that if that were the case, that diuretics would have more of an effect than, and compared to SGLT2 inhibitors, there hasn't been that sort of effect. That is true. Hi, sir. Thank you so much for this presentation. One of the common motifs, I think, is the risk of hover basalization that sort of has recurred in some of your cases. And I'm just wondering, especially on the inpatient side, sometimes we see people come in for an elective surgery on 75 units of collagen and that's it, right? And of course, there will be MP overnight and that's fun. So the question is, have we done enough as a community to help our primary care teams sort of transition from this concept of increasing long-acting to really more of a balanced type of approach? I mean, you are 100% correct and you're, I mean, and I'm guilty, number one. I mean, we have done all of these trials suggesting that insulin should be for everybody in the hospital and it's true for type one. It's true for those patients treated with insulin prior to admission that if you have somebody with well control, maybe you don't need much. And if you're going to start insulin, 90% of the patients do very well with a single dose, small doses of basal insulin, 0.2 to 0.25%. And it happened to be an older adult, whatever that means, or you have a GFR less than 60, maybe 1.5, so 20 units, 10 units is more than enough to prevent hyperglycemia in the hospital. So I think that we are changing. It has taken us 15 years of doing clinical trials with insulin to open up to, now we have an NIH, my affidavit from my group has an NIH study and we are treating patients with oral agents in the hospital. No, don't start, compare it to starting insulin. We have about 150 patients in that study, can't tell you what's going to happen. We are going to recruit 250 patients to see if you can use oral agents. I mean, 40% of patients in the UK are treated with oral agents. 60% of patients in Israel are treated with oral agents. And I don't think we have better data than they do. So I think that we are changing to individualized care of the inpatients. So you know, it probably might be a good idea to come up with another term than sliding scale to SSI since it's been so recommended to be avoided in that using something like correcting factor or something would, because I think when people see that, they've been told that they shouldn't use it. So does sliding scale work? Yeah, it works. If you have a patient with low glucose less than 180, 90% do very well. If they're not treated with insulin prior to admission. So if you have a patient with oral agent, let's say metformin DPP4, and you may or may not continue them, can you treat this patient with sliding scale? Yeah. If they have low glucose less than 180, in the Journal of Hospital Medicine a few months ago, Ali Mikdal from my group, they published that 80% do very well. If you have a patient with low glucose equal or greater than 200, please don't use sliding scale. It doesn't work. So maybe 180 is the cut limit that we'll use or not. And I have two daughters who are surgeons. And the youngest one is very outspoken, said, dad, it works. Do these studies. That was about three or four years ago. This is series of 25,000 patients from memory. And it works. It works. So that's why surgeons use sliding scale. And she says, when it doesn't work, I call endo. That's what they do, the surgeons. Been well trained. I think this gentleman over here and then Dr. McGill. In your first presentation, the first case of five years of diabetes, and you indicate the A1C goal of less than 7%, which is the ADA official number, but the ADA, the EASD, AAC, all say in selected patients, an A1C as close to normal as possible may be indicated while avoiding hypoglycemic agents. So considering the legacy effect, why wouldn't you set your A1C goal at less than 5.7? I think it is a good question. In both of these cases, they had other issues going on. And so I think that's one of the reasons to at least pick this to start with. But I think it's a good point. And ACE has always recommended a level of 6.5% or less. So I think you raise a good point. And the American College of Physicians says there is no reason to use less than 7. 7 to 8 will be okay. If you have a young person with no contraindication, you can try to normalize hemoglobin A1C. Knowing that hemoglobin A1C is the way that we adjust therapy may not be the best way to adjust therapy in many patients because it doesn't recognize hypoglycemia. So I think that trying to bring hemoglobin A1C less than 7 or 6.5 like the accord was associated with increased mortality. So I think individualization of care. And if you want to push for 5.7, I think that you shouldn't use just hemoglobin A1C, you should do CGM to recognize the 50% of asymptomatic hypoglycemic events. But in a patient who's not getting a hypoglycemic agent, sulfonylurea or insulin, where you don't have to worry about that, and if you look at the legacy effect, 5.7 came from that Italian study where they showed that that's the point where MI starts to increase. Yeah, and Verify says that if you did, they verified two patients with newly diagnosed diabetes. And the combination of two agents, they got a hemoglobin A1C less than 6.5, as an average was around 6, a little less than 6, and they did very well, so you're right. Dr. McGill, and we'll see how much time we have left after that. Okay, quick. Great, thank you for such a wonderful session. Read all this stuff and I still learn things, so this is wonderful. A little comment though about the timing of insulin. Someone taking Detemir at night and having hypoglycemia at night, first thing I would do is move it to morning. Second thing I would do is ask them how much alcohol they drink. Because, you know, low at night is alcohol, high at night is marijuana. I mean, does anybody else not have these patients? Am I the only one? Didn't know that. Has these patients? The other, in the hospital, you know, all these patients who get steroids or transplant, you know, these morning steroids, they become, especially the low doses, the five milligram, they have a little relative adrenal insufficiency at two in the morning. And then we're giving them Lantus at night. Half of what I do is move the, even the basal insulin to match the steroids in particular. Just, I think timing matters a whole heck of a lot with insulin and it's, you know, standard order sets make this a little challenging. And the new Endocrine Society guidelines, ADA guidelines that are going to be presented at the Endocrine Society, welcome to Atlanta, I live there, is going to, one of the questions that are going to be addressed is the treatment of corticosteroid with insulin therapy. And we're going to recommend, if you, the problem with steroids is that, is there are different patients. So one is, you cannot say a steroid for COPD exacerbation. You just give one dose of prednisone in the morning. But if you have a rejection, you give super high doses, or you have an autoimmune disease, you have high doses. So that's the problem with steroids. And for those patients taking once a day prednisone, or the equivalent, we are going to recommend NPH more than basal insulin. But for high doses of steroids or multiple doses, then you can use basal, basal bolus. In those patients, those high doses are then frequently reduced. So there's a, although there's a longstanding, but there's a day-to-day change as well that you have to deal with. So Endocrine Society is going to address that question very well. I want to thank you, and apologize to our two question askers. You can find our physicians out there. But thank you very much for attending today. Thank you. Thank you. Thank you. Thank you.

personalized treatment options

diabetes

type 2 diabetes

transient ischemic attack

medications

metformin

GLP-1 receptor agonists

SGLT2 inhibitors

weight reduction