And welcome to the DSN Year in Review for Diabetes. My name is Cecilia Lo Wong. I am the chair of the DSN Diabetes for ACE this year. And with me is Dr. Rivka Schulman-Rosenbaum, who's a vice chair of the DSN in Diabetes. So we're very, very happy to give you this kind of our take on the Year in Review for Diabetes. And Dr. Schulman-Rosenbaum will start with about half of the topics and the articles that she chose for that, and then I'll finish. The way that we did this, because this is definitely a bit subjective, there's a lot going on every year in diabetes, was that we came up with a list of 10 topics, and then we tried to choose at least an article or two that we felt highlighted that area for the year. So we tried to cover a breadth of topics, but didn't really go a lot in depth to a number of different articles for every topic. So that's our disclaimer. So I have the pleasure of introducing Dr. Schulman-Rosenbaum, who's going to give the first half. So she is the director of inpatient diabetes at Long Island Jewish Medical Center, Northwell Health in New Hyde Park, New York, and an associate professor of medicine at the Zucker School of Medicine at Hofstra Northwell. She received her medical degree from SUNY Downstate College of Medicine, and she trained in internal medicine and was a chief resident at the Long Island Jewish Medical Center. She did her fellowship training in endocrinology and metabolism at the Icahn School of Medicine at Mount Sinai. She specializes in the management of inpatient diabetes and inpatient endocrinology. Right now, her research focuses on areas related to inpatient diabetes, including hyperglycemia due to COVID-19 and endocrine interventions in the emergency department. She was the recipient of the Saltzman Award for Excellence in Quality for Northwell Health, and I'm very, very happy to have her start off our session. But I'm going to introduce Dr. Cecilia Lo Wang, just so we get the introductions out of the way. And it is my pleasure to be able to introduce Dr. Lo Wang, who is an endocrinologist and professor of medicine at the University of Colorado School of Medicine, the director of the glucose management team at the University of Colorado Hospital, director of the CU Diabetes Fellowship Training Program, and clinician scientist at the CPC Clinical Research. She earned her medical degree at the University of Rochester and did her residency and chief residency in internal medicine at the University of Utah. She completed her fellowship in endocrinology at the University of Colorado and joined the CU faculty. Dr. Lo Wang sees patients in the endocrine clinic with a focus on diabetes and metabolic disorders, on the endocrine consult service, on the glucose management consult service, and the general medical wards at the University of Colorado Hospital. Dr. Lo Wang currently chairs the FDA Endocrinologic and Metabolic Drugs Advisory Committee. She's involved in clinical research and clinical trials and current projects related to hospital dysglycemia, hospital use of CGM, community-based trials in digital technology and cardio-oncology, and stem cell therapy for diabetic foot ulcers. She is a member of the Academy of Medical Educators at CU. She serves on committees for the Endocrine Society and chairs the ACE Diabetes Disease State Network. So we look forward to hearing from Dr. Lo Wang halfway through. Oh, there we go. Okay, so the learning objectives for our talk today will be highlighting key areas of diabetes research discoveries over the past year, including topics such as diabetes pharmacotherapy, cardiovascular and renal outcomes, inpatient diabetes, diabetes technology, and access to healthcare, as well as other key areas in diabetology. Here are our disclosures. So I'll be starting with the topic of type 1 diabetes prevention. As we all know, the diagnosis of type 1 diabetes carries with it a heavy burden and a lifelong disease, and anything that could potentially prevent it or delay it is very valuable. I'll be reviewing an article that was published in 2021 in Science Translational Medicine, looking at the use of teplizumab to prevent onset of clinical type 1 diabetes in patients who are high risk. Now, this was actually the extension of the original study, which was published in 2019. So teplizumab is an anti-CD3 monoclonal antibody. It binds to the T-cell co-receptor CD3 as a partial agonist, and it's administered as a 30-minute IV infusion, typically over 14 days, in an outpatient research center. To go over a little bit about the original study from the New England Journal by Harold and colleagues in 2019, it was a multi-centered, multinational, double-blinded, randomized controlled trial. There was 76 participants, and they were relatives of patients who had type 1 diabetes, and they were considered high risk for type 1. Now, this was determined in the following way. There are preclinical stages for the diagnosis of type 1 diabetes, stage one being autoimmune positivity of antibodies, stage two being a dysglycemia on the oral glucose tolerance test, but not overtly with diabetes, stage three being overt diabetes. So the patients in this study had to be at stage two, so they had positive autoantibodies and some element of dysglycemia on the oral glucose tolerance test, and they were a relative of a patient who already had type 1 diabetes. It was a median follow-up of 742 days, and in that study, they found that there was a reduced rate of type 1 diabetes diagnosis in the teplizumab group, down to 14.9% diagnosed per year compared to 35.9% in the placebo group, and if you look at the bottom right figure, the teplizumab group had a median time to diagnosis of type 1 diabetes of 48.4 months, whereas the placebo group, 24.4 months. So there was a delay in the diagnosis of type 1 diabetes by two years. The current study was an extension of the original study. It was the same population, just followed for a longer period of time. It was a 923-day median follow-up, and again, it was teplizumab versus placebo, which was just a saline infusion. 44 patients received teplizumab, and 32 patients received placebo. Here you can see the Kaplan-Meier curve, and in red is the teplizumab group, and in black, the placebo group, and as you see, this is measuring the proportion of time that a patient is free of type 1 diabetes. So the teplizumab group had a hazard ratio for development of type 1 diabetes at 0.457, which was statistically significant. The median time to diagnosis of type 1 diabetes in the teplizumab group in this extension study was 59.6 months, and the placebo group, 27.1 months, which was actually a difference of 32.5 months of time that the patient did not develop type 1 diabetes. And at the conclusion of the study, the teplizumab group, 50% still did not have type 1 diabetes, they were still free of type 1 diabetes, but in the placebo group, only 22% did not have type 1. Here you can see the trends in the C-peptide levels, again, for the teplizumab in red and the placebo in black. So at the start of the infusion for teplizumab, the C-peptide levels went up, and they maintained at a higher level compared to the placebo group throughout the study. And interestingly, the change in the C-peptide level was associated with increased levels of one particular type of memory CD8 positive T-cell, which is called the KLRG1 positive TIGIT positive T-cell, and it's thought that this may play into the mechanism of benefit from this drug. Unfortunately, in July of 2021, the FDA declined approval for teplizumab. At this point, citing a small sample size and the need for additional pharmacokinetic data. Moving on, diabetes technology. There was a very extensive lecture this morning. I will not be reviewing all of diabetes technology, but I selected out one study that I thought was very interesting. So the study looked at the use of hybrid closed-loop insulin pump therapy in an older type 1 diabetes population. And the elderly patients with type 1 diabetes or older patients, they are a unique population because they do have a longer, typically a longer duration of diabetes, higher rates of diabetes complications. They often have a higher burden of hypoglycemia unawareness. There is potentially associated concerns with hearing impairment, dexterity, mobility, cognition that may not be the case for younger patients. And the traditional approach for this population has been to raise the glucose target to help prevent hypoglycemia since hypoglycemia is very dangerous. So this article by Bowton and colleagues was published in the Lancet Healthy Longevity earlier this year. It was an open-label, multi-center in the UK and Austria, randomized crossover study. To be included, patients had to be at least 60 years old with type 1 diabetes for at least 12 months and using pump therapy for at least three months prior to the study. There were two 16-week periods and it was a crossover study, so they each got to try the two groups. One was a hybrid closed-loop group and one was a sensor-augmented pump therapy group. The equipment used for the study was the Cambridge Hybrid Closed-Loop Algorithm which was on the CAM Apps FX app on an Android smartphone, a Dexcom G6 and a Dana Diabetes Care RS insulin pump. Now the two groups, both the sensor-augmented and the hybrid closed-loop, had all the same equipment but their auto mode was disabled in the sensor-augmented group. So the sensor-augmented group still had the CGM, they still had the pump, they just didn't have the interaction of the two. Now the primary endpoint was looking at the time and range, 3.9 to 10 millimoles per liter or 70 to 180 milligrams per deciliter. And there was 37 patients enrolled in the study, 20 in the closed-loop first group and 17 in the sensor-augmented pump first group. And if you look at the table for the characteristics of the patients in the study, they were a median of 68 years old. There was a vast majority of white patients in the group, around 97%. They had had diabetes for a long time, a median of 38 years and been on pump therapy for a very long time of about 10 years. Their rates of diabetes complications were comparable to the general type 1 population in a type 1 diabetes exchange. And their hemoglobin A1C at baseline was 7.4%, which for the elderly population is considered fair or ECHL depending. So looking at the results of this study, so for primary endpoint, time and range, so in a closed-loop group, it was 79.9%. In the sensor-augmented group, 71.4%. That was 8.6% higher time and range in the hybrid closed-loop group, and that was a statistically significant finding. For secondary endpoints, there was also statistically significant findings towards the closed-loop group for time in the hyperglycemia range, mean glucose and hemoglobin A1C, which was 6.7 at the end of the study for the closed-loop group and 6.9 in the sensor-augmented group. Importantly, the hypoglycemia rate, there was not a statistically significant difference between the two groups. So the patients had better time and range, lower A1C, but not more hypoglycemia. And if you look at the bottom table, looking at severe hypoglycemia events, there was two events in the sensor-augmented group and no events in the closed-loop group. Here you can see the median sensor glucose concentration and interquartile ranges during the closed-loop insulin delivery in red and during the sensor-augmented pump therapy in blue. And as you can see, that the red group is consistently lower than the blue group throughout the times of the day and not approaching any hypoglycemia, staying within the dotted lines very consistently. In summary, this study shows that it is possible to achieve excellent glycemic control with a hybrid closed-loop system without increasing the risk of hypoglycemia in an elderly type 1 diabetes population. Moving on to healthcare equity, diabetes and access to care. So I'd like to review a study that was published in the JCENM earlier this year entitled Inequity and Adoption of Advanced Diabetes Technologies Among Medicare Fee-for-Service Beneficiaries. So this study by Wery and colleagues, it was an observational study. The nice thing is that it's a national database of Medicare population, so there was uniform insurance for all the patients. They were all Medicare A and B, so there's no difference in insurance. It looked back at 2017 to 2019 time period. They utilized ICD-10 codes and insurance claims to determine patients with type 1 diabetes and who were prescribed insulin pump therapy and or CGM therapy. And it was identifying if the race ethnicity was known for the patients. They were only included in the study if they had known race or ethnicity, and that was self-reported data that the patients would give to Social Security. So I said it was an observational study and the primary outcome was diabetes technology used by race ethnicity groups. In the end, there was 13,796 patients in the final cohort. So this table breaks it down by the three years that they looked at the data, 2017, 2018, and 2019. And as you can see, the very large majority of the patients overall were white. And it breaks it down by prevalence of pump use, CGM use, and general technology use. And you'll notice a lot of significant P values there. It'll be easier to see this on the next slide. So starting on the top left, you can see the trends for insulin pump usage. So in blue, that's the white population. The black population was in orange and other minority groups were put together in the gray as other. So comparing from 2017 to 2019, insulin pump use in the white population increased from 14% to 18.2% among type one diabetes patients on Medicare. If you look at the black and the other group, they remain quite low, all below 5% throughout the various years and without much increase over that time period. If you look at the top right, CGM therapy, the blue line, again, the white population increased from 3.2% in 2017 all the way up to 24.9% in 2019. And the black and other population, while it did increase, the gap between the white and the black and other groups did widen over this time period. So more patients went on CGM overall, but the gap in care definitely widened. And if you look at the bottom tables, there are similar trends on the left looking at any technology and on the bottom right looking at both use of CGM and pump. So similar trends were noted. So the authors of the study cite potential barriers for diabetes technology adoption among minorities in the United States. One might be insurance, although in this particular study, like I said, they all had the same insurance, so that wouldn't be a barrier. Lower income, cultural barriers, language barriers, health numeracy or literacy challenges, limited access to resources, provider-patient relationships, IT usability issues, perception that there may be cost involved, and also there may be potential implicit bias in the physician or providers. And there is an absence of standard guidelines for determining and selecting which patients should have diabetes technology. And traditionally it was thought to give these therapies to more adherent patients, patients with able to lower their A1C, and we may need to revisit and have more clear criteria to make sure that it's more fairly distributed. So reducing health inequity is definitely a major public health goal, and improving quality of diabetes care may reduce complication rates and healthcare costs. Moving on to COVID-19 and diabetes. So as I'm sure you all recall, we had this thing happen over the last few years, and the pandemic really hit the hospitals terribly, and then with the use of dexamethasone, which did help reduce mortality, we had very high rates of hyperglycemia in the hospital. Despite the major challenge and the need for all of us to cope with this, very little was published towards the management of COVID-related steroid hyperglycemia. So I wanted to highlight an article published in Endocrine Practice later last year, which was the first study to examine effectiveness of a steroid-induced hyperglycemia management protocol for COVID-19. This was a retrospective study. It looked at COVID-19 patients receiving dexamethasone who had either diabetes or hyperglycemia or both. It was in the non-critically ill population. It was performed at a single tertiary center in Saudi Arabia in 2020, and what happened was they put together a protocol of recommendations of how to manage the hyperglycemia. They distributed to two out of four of the units that cared for the COVID patients, and the other units were the control group. They just had standard therapy. However, the doctors wanted to manage it. So there was 116 patients under the protocol group and 47 in the control group. So this is the protocol that was distributed to the two teams in the intervention group. So it's very busy, but just to kind of give you some of the highlights. So patients had a hemoglobin A1C measured, point-of-care glucose checks. The frequency varied based on if they had a history of diabetes or not. If they did not, then they might start with only two finger sticks per day to minimize contact with COVID. If they had a history of diabetes, they went straight to a pre-meal and bedtime point-of-care glucose. The teams were given guidance on selecting a customized correctional scale based on clinical criteria listed, and they recommended basic labs to screen for DKA. Now, if the patient was on basal insulin at home, they were started on basal insulin right away, and they would either use the home dose or 0.1 units per kg per day. Then they recommended following the glucose trends and they gave advice on how to up titrate the basal insulin and if the prandial glucoses were elevated to add the pre-meal insulin at 0.1 units per kg per meal, so 0.3 units per kg per day. There was also advice in the protocol given as to how to handle discharge when the patients were ready to go home, what to send them home on, mainly based on their A1C, but also some other clinical criteria. So what they did was they looked at the time in the target glucose range of 70 to 180 at the various time points that were checked, typically in the hospital. So fasting glucose, pre-lunch glucose, pre-dinner glucose, bedtime glucose. And the brown is showing the protocol group, time and range. And the blue is showing the control group, which is standard of care. So just looking at it, you can see that the brown bars are all pretty consistently higher than the blue bars. And the significant values are noted. So for fasting glucose, there was a significantly higher time and range for day four, day five, and discharge day. For pre-lunch, it was significant at discharge day. For pre-dinner, at day three, five, and discharge day. And for bedtime glucose, it was significant on day one only. And the authors do suggest that they might have gone a little too low on their starting basal insulin dose, which they did with the 0.1 units per kg, which they did out of fear, given the COVID isolation protocols, and that the nurses would not be checking on the patients for fear of hypoglycemia. They suggest that might be why it took until day four to have significance for the fasting glucose in the intervention group, and to consider if they're not high risk for hypoglycemia, potentially starting at a higher weight-based calculation, such as 0.2 units per kg per day. Interestingly, this study also looked at in-hospital mortality, and in-hospital mortality was significantly lower in the protocol group at 12.9% compared to the control group, 29.9%. Moving on to another topic within COVID-19, the question has come up, does COVID cause diabetes? So I know this has been kind of a hot topic. Before I get into the article, I just wanted to briefly review the pathophysiology of COVID-19 and diabetes. So ACE2 is the main entry receptor for SARS-CoV-2 with expression in the pancreatic islet cells, and is associated with reduced numbers of insulin secretory granules in the beta cells, as well as impaired insulin secretion. SARS-CoV-2 is also associated with adipose tissue dysfunction, which may lead to insulin resistance, as well as pro-inflammatory pathways, such as cytokine storm, which can lead to insulin resistance and also lead to impaired insulin secretion. Superimpose on this dexamethasone and the metabolic effects of glucocorticoids, and you have a bit of a mess with hyperglycemia. Well, getting back to our study. So Rothman and colleagues published an article in Diabetologia in 2022, and they were looking to examine the incidence of type 2 diabetes after the recovery from COVID-19. This was a retrospective cohort analysis performed in Germany of 1,171 primary care practices, and it represented over 8 million patients overall. And they identified which patients had COVID-19, and they used as the control an acute upper respiratory infection that was not COVID-19. So acute URI or COVID-19. And the study was done from 2020 to 2021. The median follow-up for the COVID group was 119 days, and for the URI group, 161 days. They said in their article, they were not looking for type 1 diabetes because the incidence was low. So they only tested for type 2 diabetes and what was called other types of diabetes based on the ICD-10 codes. They excluded patients who had received corticosteroid use within 30 days of the index date. And in the end, there was over 35,000 patients in the COVID group and the acute URI group. So if you look in the table, basically for the type 2 diabetes, there was a significantly noted incidence rate ratio of 1.28. The other diabetes group was not significant. So here's the Kaplan-Meier curve for type 2 diabetes. And as you can see, the COVID group is in blue. The URI group is in red. And there was a statistically significant higher incidence of type 2 diabetes diagnosis in patients who had previously had COVID-19. In conclusion, there was an increased incidence of DM2 after COVID-19 recovery. This was based on a nationwide primary care database. Limitations include that hospitalization data was not available as this was a primary care study. And if confirmed, that the need for diabetes screening in patients who had even mild cases of COVID-19 may be appropriate. Now, this was a retrospective study, so it does not imply causation. And there was actually another study, which I don't have any slides on, that came out in diabetes care recently in a VA population. There was also a retrospective cohort study showing a similar finding of a higher incidence in type 2 diabetes after recovery from COVID, but the findings were only significant in men, and it was not significant in women. But of note, the much larger portion of the population in the VA studied was men. All right, and finally, a word on type 1 diabetes after COVID. So it's really unclear if COVID-19 can cause type 1 diabetes, but there was one article in JAMA Pediatrics by Gottesman and colleagues, and they had noticed this was the main pediatric tertiary care center in San Diego, and they're the only pediatric tertiary care center in the area. So they get pretty much all of the referrals for new onset type 1. And they had noticed that in the year, the first year of the pandemic, there was a much higher incidence of new onset type 1, so then they decided to study this as a cross-sectional study. And they looked back the five years prior to the pandemic year, and they noted that there are normally seasonal variations of type 1 diabetes, so they wanted to make sure to look back over time to kind of see if there was really a change. And what they found was that in the first pandemic year, 187 children were admitted with new onset type 1 versus 119 in the prior year, which was an increase of 57%, which they found was higher than the predicted amount based on the 95% confidence interval. They also noticed that there was a higher rate of DKA in these patients, so they were sicker patients. This does not imply causality at all and needs to be further studied, but is definitely of interest and would be very useful to study further. And with that, I will call up Dr. Lo Wang for her section of the talk. Thank you, Rivka. So now we'll turn our attention to the last five topics or so for the rest of our hour, and I'll go over a few cardiovascular and renal trials in diabetes. And one thing I wanted to say is that actually the first line of this slide was rendered obsolete about a couple of hours ago when we got the announcement that tirzapatide was approved by the FDA. So it's been approved as an adjunct to diet and exercise for glucose lowering in type 2 diabetes. So the trade name is Moonjaro, and I'm sure we'll hear a lot more about it. So tirzapatide's been mentioned several times at this conference, and there's been a buzz in the late press, and then it's been also presented at other conferences. But just to lay the foundation, it's a dual glucose-dependent insulinotropic polypeptide, so GIP, and GLP-1 receptor agonist. So it's a dual agonist, and there are a number of different dual and triple agonists that are under study. It's a once-weekly subcutaneous injection, and the structure is based on the GIP amino acid sequence plus a C20 fatty acid moiety. And so the surpassed series of clinical trials have studied the use of tirzapatide in type 2 diabetes and really had astounding results, so there's a lot of interest. And one of the big questions is why? Why is tirzapatide so incredibly efficacious to lower body weight and lower A1C? And so this is a study that I wanted to highlight starting to look at protein structure and try to come up with some answers as to why. And so these were cryo-electron microscopic structures of tirzapatide bound to the transmembrane domain of the GIP receptor on the left and the GLP-1 receptor on the right. And so tirzapatide is in that pinkish color, so you can kind of see how people are studying to try to figure out whether or not we can replicate this in other new drugs. So just one caveat is that we don't have cardiovascular or renal outcome data yet for tirzapatide. So this first trial I'd like to highlight is SURPASS-5. So this is a trial of tirzapatide added to titrated insulin glargine in patients with type 2 diabetes. Three different doses of weekly tirzapatide. And so you can see that it was a small trial of about 600 patients, half men and half women, and who had inadequate glycemic control receiving insulin glargine. The mean age was 61 years. This was done worldwide in 45 different research centers. And the 475 patients were randomized about evenly to the three different doses of tirzapatide versus placebo in addition to baseline glargine. And the primary outcome was the change in glycated hemoglobin A1C from baseline to 40 weeks. And so what was found is that there is a marked decrease in A1C on all three doses of tirzapatide as compared to placebo. I wouldn't call that quite a dose response. You can actually see quite a decrease in A1C with the lowest dose, 5 milligrams, and then about even with 10 and 15 milligrams. The weight change ranged from minus 5.4 to minus 8.8 kilograms in the 5 to 15 milligram dose ranges. This is versus a weight gain of 1.6 kilograms in the placebo group. The most common treatment emergent adverse events were diarrhea, which ranged between 12 to 21% in terms of incidence versus 10% on placebo, and then nausea, which ranged from 13 to 18% versus 3%. So you can see those adverse GI side effects with tirzapatide as well. This is SURPASS-2, which was a randomized open-label phase three non-inferiority trial in patients on tirzapatide versus semaglutide. So it was almost 2,000 adults with inadequately controlled type 2 diabetes with a mean A1C that was over 8% and had had type 2 diabetes for almost nine years. You can see the average BMI there and the weight. And so patients were randomized one to one to one on three different doses of tirzapatide versus semaglutide one milligram. This duration was also 40 weeks. And you can see that the adverse events leading to discontinuation of the study medications occurred in about 6.8% of patients. And it was maybe 50% higher to double in the tirzapatide group compared to the semaglutide group. So what did they find? So on the left side, you can see the starting hemoglobin A1C in the entire group. And then in the different curves, you can see that the black dotted line is the semaglutide group. And the other three are the tirzapatide groups. And you can see that the A1C decreased from an average of about 8.3% down to as low as below 6% on the highest dose of tirzapatide after 40 weeks. In terms of the percent of patients who met the weight loss target, you can see this is also fairly standard presentation of at least 5%, at least 10%, at least 15% weight loss. And on all the different doses of tirzapatide, we see higher percentages of patients who met those weight loss targets. So really remarkable findings. So turning now to another question that we'll often ask ourselves, which is that many of these cardiovascular outcome trials were done in patients on a background of metformin. So will we see these same beneficial effects to reduce cardiovascular events in patients without metformin? And so this was a post-hoc analysis of dulaglutide in patients with type 2 diabetes in Rewind with ASCVD versus those at high risk with or without metformin. So remember, Rewind had almost 10,000 patients and about a third had ASCVD. And this trial was looking at dulaglutide 1.5 milligrams weekly versus placebo on top of standard of care. And so about 19% of patients were not on metformin at baseline. So those patients were older, they had a slightly lower BMI, higher percentage of women and prior CV events, heart failure, as well as renal disease. And the primary outcome, remember, of Rewind was first event of a composite of non-fatal MI, non-fatal stroke, cardiovascular or unknown death. And so what the authors found is that there was no difference in that primary outcome, the composite cardiovascular outcome in patients on metformin versus not on metformin. So I think that's pretty important for all of us who are wondering. This is, I think, validation of the standards of care guidelines out there about starting these agents that have great data for lowering cardiovascular risk in patients with or without metformin, so regardless of whether or not they're on metformin. And so the question also was, were there certain subgroups where this was true? And so you can see that actually probably not. And so dulagletide reduced this primary outcome whether patients were on or off, and then this was divided into various different endpoints, MACE, microvascular, all-cause mortality, and heart failure. So turning then to finarinone, which we've also heard about a few times during this conference, finarinone use in type 2 diabetes and CKD. So just a reminder that this is a selective mineralocorticoid receptor antagonist with a non-steroidal structure. There's little affinity for non-mineralocorticoid receptors. And so the main contraindications are concomitant use with strong CYP3A3 inhibitors or adrenal insufficiency. So Fidelity was a pooled analysis of Fidelio and Figaro DKD, and it's great because it was an individual patient-level pre-specified pooled analysis of two phase three trials, and this was across a spectrum of CKD. So the total number of patients studied was 13,000, over 13,000, with a median follow-up of about three years. And there were about 40% of patients in this population who had a GFR of over 60, but those patients had albuminuria. So here's a diagram that kind of goes through an overview of the trial. So the inclusion-exclusion criteria, type two diabetes plus CKD, GFR of 25 or greater, serum potassium had to be 4.8 or lower, and they needed to be on a maximally tolerated labeled dose of a RAS inhibitor. And so any patients with New York Heart Association class two through four heart failure were excluded. So the protocol included, randomized a total of over 13,000 patients, as I mentioned. Phenerenone was at two doses, 10 milligrams or 20 milligrams versus placebo, and the median follow-up was about three years. And the outcomes, there was a cardiovascular composite outcome of time to cardiovascular death, non-fatal MI, non-fatal stroke, or hospitalization for heart failure. There was also a kidney composite outcome that was a composite of time to kidney failure, a sustained 57% or greater decrease in GFR or renal death. So of the trial population, the baseline characteristics median age was about 65, with two thirds were men and 30% were women. 99.8% of the subjects were on RAS inhibitors and about 72% were on statins. The mean A1C was 7.7% with blood pressure 137 over 76, and prior heart failure, actually 7.7%. So you can see the breakdown of subjects in the trial and what their GFRs were. I mentioned that about 40% had a GFR of 60 or above, and the urine, albumin, creatinine ratio was very, very high. So two thirds of the subjects in this combined analysis had urine, albumin, creatinine ratio of 300 or greater, so grade three. And in the end, there were very few hyperkalemia rates related to discontinuations. So this is the discontinuation rate per 100 patient years. So in the intervention group, it was 0.66, in the placebo group, 0.22. And in the end, the primary outcomes were positive. And so the endpoint of the cardiovascular composite, there's a decreased, 14% decreased risk of the cardiovascular composite outcome, and 23% decrease in risk of the kidney composite outcome. So really, really great data. And then in terms of risk for dialysis, 20% decrease. So finarinone on top of standard of care actually reduced the risk of clinically meaningful cardiovascular and kidney outcomes in patients with type two and CKD. So now let's switch gears to lifestyle. So I've included a couple of trials here. So one is looking at the replacement of dietary saturated fat with polyunsaturated fat or carbohydrate. And so one of the questions that's come up is, does this reduce your risk of cardiovascular disease in type two? And so this was a systematic review and meta-analysis that was published in the European Journal of Nutrition in 2021. And it included five prospective observational studies plus one randomized control trial. And unfortunately, that RCT only had a sample size of 14. So the overall quality of evidence was low to very low. So unfortunately, this was, this is true of many of our nutrition studies, unfortunately. So the end was over 22,000 average duration, about 10 years. And so one of the questions that was looked at was when you replace 2% of the calories from saturated fat with polyunsaturated fat or 5% of the calories from saturated fat with carbohydrate, does that reduce the occurrence of cardiovascular disease? So it looks like when you replace the saturated fat with polyunsaturated fat, you do reduce the risk. So it just barely doesn't touch one. So it has a relative risk of 0.87. With carbohydrates, it actually does touch one. So it's a little more questionable. When you look at the ratio of polyunsaturated fat to saturated fat intake, that was associated with a reduced risk of cardiovascular disease with a relative risk of 0.75. But again, the quality of the study, the studies overall was very low. What about looking at, kind of relooking at the results of Lookahead? So I think Lookahead was, the results were disappointing because we didn't see what we expected, which was a reduction in cardiovascular risk in patients with type 2 diabetes and intensive lifestyle intervention. So one of the questions that came up is were there subgroups within Lookahead that benefited or didn't benefit? And so remember that Lookahead included over 5,000 patients with type 2 diabetes and overweight or obesity who were randomly assigned to intensive lifestyle intervention or control, which was diabetes support and education. The duration of follow-up was about 10 years. And the goal, this is a typo, was to achieve and maintain 7% weight loss through caloric restriction and physical activity. So the primary outcome of cardiovascular disease wasn't significant. So initially, that primary outcome was MACE, or major adverse cardiovascular events. A couple of years into the trial, it was discovered that the incidence of these outcomes was extremely low. So they actually added hospitalization for angina to try to get to enough events and find some degree of significance. But overall, the trial was stopped early because the primary outcome was not significant for futility. And the primary outcome was not found to be significant. So then, subgroup analyses were performed to try to figure out whether the risk of cardiovascular outcomes varied by subgroups. So that's the paper I'd like to show you today. So this was published by Banks et al. in Diabetes Care in 2021. And so this group of investigators divided the look-ahead population into four different groups. So patients who had older onset of type 2, patients who had poor glucose control, people who had severe obesity, and people who had younger onset diabetes. And so you can see the breakdown in the percentages of those subgroups within look-ahead and the differences in age, BMI, A1C, percentage of white, as well as median diabetes duration, insulin use, and prior cardiovascular disease. So what was found is that in the subgroup of patients with type 2 diabetes with poor glucose, that diabetes support and education was more beneficial than an intensive lifestyle intervention. So I thought this was incredibly interesting. So you can see that in these subgroups, so these subgroups are divided up into the four, and then looking at the primary outcome, as well as different secondary outcomes. And on all of these secondary outcomes except the last, the subgroup with poor glucose control did worse. And so this is broken down on the right, where you can see the actual numbers. And the risk was actually even possibly increased in the subjects with poor glucose control. So this might tell us that there is a subgroup of patients with type 2 diabetes that we should be thinking about a different approach. So this, again, points to needing to individualize our approach to our patients with type 2 diabetes, even with lifestyle interventions. So I'd like to turn next to diabetes health literacy and health numeracy. So even though there haven't been new papers published on this in the last year, I wanted to highlight it because it became a new section within the ADA standards of care for diabetes. And I think this is incredibly important. So all of us who take care of patients with diabetes know how important health literacy is and numeracy to be able to adequately take care of diabetes. And I think that we understand that we think that we understand that our patients who have lower health literacy, lower numeracy, may have a harder time and face greater challenges. And so this section now is in that section one, improving care and promoting health and populations in the standards of medical care for diabetes. And so just a couple of definitions. Health literacy. So this is the degree to which individuals have the capacity to obtain, process, and understand basic health information and services they need to make appropriate decisions. And this is strongly associated with patients being able to engage in complex disease management and self-care, which is true of all of our chronic diseases, but maybe especially diabetes. Health numeracy needs primary numeric skills, applied health numeracy, and interpretive health numeracy. So you have to know how to do addition. You need to know how to apply that and how to interpret your numbers. And there's also an emotional component that affects the ability to understand the concepts of risk, probability, and the communication of scientific evidence. So I just thought this was really important, very fascinating, especially in these days. And so both of these, health literacy and health numeracy, are needed for effective communication, developing a treatment regimen, and making diabetes self-management task decisions. And so it's estimated that about 80 million adults in the US have limited or low health literacy. So this is an incredibly important issue to study and to understand and figure out treatment for. So this is a study that came out in 2018. And it was looking at effective self-management interventions in populations with low income or low health literacy. So the group divided self-management into these five core skills, taking action, problem-solving, partnership, decision-making, and resource utilization. So it's a systematic review of 23 studies. And the interventions that were the most effective were the ones that included four of five skills, especially taking action plus partnership and problem solving. And so there were significant outcomes with empowerment or self-efficacy and disease-specific quality of life. The other thing that's important is that we have to have literacy-sensitive communication intervention to decrease med non-adherence. So as one of our prior leaders in government health had mentioned, medications don't work if you don't take them. And so this particular study is of about 400 adults with type 2 diabetes in 10 public health clinics, of which 96% were uninsured. The mean A1C was 9.6%, with a mean age of 50, and about 2 thirds were female. And so there is a random assignment by clinic to training in effective health communication versus educational material without that health communication training. And so what did the training include? How to work with low health literacy populations, how to improve communication, so teaching back, goal-setting, reducing jargon, motivational interviewing, effective use of medical interpreters, and then use of a diabetes toolkit for patients with limited literacy and numeracy skills. And this was over the course of two years. And so use of that training in effective health communication significantly improved med adherence as well as treatment satisfaction. So I think that we have some methods that are starting to be studied now that can help with this problem of health literacy and numeracy. So I wanted to end with one last slide. So this is just looking at FDA novel drug approvals in diabetes and metabolic disorders for 2021. So far, there have been none in diabetes and metabolism, except for today, in 2022. So it includes evanacumab, which is an angiopoietin-like 3 inhibitor for homozygous familial hypercholesterolemia, dazaglucagon, a glucagon receptor agonist for severe hypoglycemia, of course, finaranone, which I've already mentioned, the non-steroidal selective mineralic corticoid receptor antagonist. And that's to reduce the risk of CKD, as well as end-stage renal disease, cardiovascular death, non-fatal MI, hospitalization for heart failure, and sustained GFR decline in CKD associated with type 2, and in glycerin. So I'd like to end with some take-home points. It was a big year for diabetes, and a big day for diabetes today, I would say. So teplizumab for a delayed onset of type 1 did not receive FDA approval, as Dr. Shulman-Rosenbaum mentioned. And hybrid closed-loop therapy was found to be safe in older adults with type 1. We need to address health inequities. So the selection for and access to diabetes technology is an ongoing issue that we need to address. Treatment of dexamethasone-associated hyperglycemia and COVID-19 infection has become more common, and we need to know better ways to treat this. There is a possible increased risk for type 2, and possibly even type 1 after COVID-19 infection. Terzapatide for type 2 diabetes now FDA-approved, and the data are really remarkable, but we don't have cardiovascular or renal outcomes. We now know that dulaglatide reduces cardiovascular outcomes in type 2 on or off metformin in a post-hoc analysis. Phenerenone looks to be a very promising agent, not for hypertension, but for CKD and type 2 diabetes. But where it should play a role in is a little bit unclear, although it has been suggested to be used as the next line after SGLT2 inhibitors. There's a subgroup in Lookahead in which the intensive lifestyle intervention is not effective and may even increase cardiovascular risk, and that's the group with poor glucose control. Health literacy and numeracy are important, so literacy-sensitive communication through training can improve self-efficacy and diabetes-specific quality of life. And lastly, we went over a few of the new FDA approvals in 2021. So thank you so much for your attention, and I wanted to bring Dr. Schulman Rosenbaum back on the stage for any questions. Well, we can hear you just fine. My name is Fabiano Rosenbaum from Long Island, New Brunswick. Anyway, a couple of comments. One of them had to do with the Rathbun article concerning the development of diabetes in COVID patients. I think we viewed the article the same way, but I'm wondering if you could talk a little bit about what you saw in the article. So, I'm going to turn it over to you, Fabiano, and then I'm going to turn it over to you, Dr. Rosenbaum. Thank you. I think we viewed the article the same way. I thought it would be kind of interesting, and I wonder if there was subset analysis that may have been conducted in those that were treated with steroids and those who were not. Because not everyone received steroids as part of the protocol. So, this study excluded patients who had received steroids within 30 days of the index date. But again, it was a primary care study, so they didn't have all the hospitalization data. And it was focusing more on COVID that was treated in the outpatient setting. So, I don't think we have the full answer to that question. But yeah, it is definitely an important issue to look into. And the other comment was, look ahead. So, I mean, it was a pretty interesting study in intensive lifestyle intervention in diabetics. But the critique for that particular trial was that it wasn't conducted long enough. People feel that perhaps if it were extended for a longer period of time, maybe the outcomes would have been a little bit more favorable. But it was a pretty interesting study and I guess the money ran out. That's a great comment. So, I think there's been a lot of speculation about why look ahead wasn't positive. And so, one is maybe we didn't study people long enough. Of course, I think cost was definitely an issue. Another question was maybe we need more weight loss than 8% in order to see the reduction in cardiovascular outcomes. Although, really the study was not for amount of weight loss. So, hard to know what the reasons are. But at least the mix went up. Next question. Hello, this is Kendra Salah from the University of Alabama at Birmingham. Thank you for the review. I have questions. I see many patients with diabetes and on stage 1 and 2 basically patients with type 1 diabetes. I want to know if you are aware if there is any upcoming clinical trials for these patients. I was able to refer one of them to Vanderbilt because they are working on allopurinol. But I don't know if you are aware if there is something coming in regards of if they can apply for clinical trials. I mean, it's definitely a very important area to get better clarity on given the fact that we now have evidence that this immune therapy did have some prevention by two or three years of the onset. In terms of the exact information for the other trials, I would have to get it back to you. But I believe there is some ongoing. Do you have any recommendations? Because when you see these patients how do you do something or put them on the forming or what's your approach? I know there is not a strong literature but I just want to know how you guys practice when you see these type of patients on stage 1 or stage 2 of type 1 diabetes. I mean I think monitoring is definitely one approach depending on the level if they have dysglycemia on the glucose tolerance test and other features but I don't think it's completely clear what we are supposed to do with these patients so I think it is a great idea to potentially refer them for clinical trials so we can get a better handle on it. I don't know if there is anyone but there have been a number of failed trials over the years over the past 15, 20 or more years and people have looked at early insulin use, etc. So there is a lot of ongoing research, a lot of small molecules that are being looked at, methotrexate all sorts of things so I think for now just screening and then targeting people who have two or more auto-antibodies for early detection of type 1 I think is in order to prevent DKA as the first presentation I think is really where we are trying to move those efforts in addition to the ongoing research. Preventing DKA that's a good suggestion perhaps as a conversation we should talk to them if we identify them. Thank you. Sudhir Bansal from Rhode Island enjoyed your presentations I think the comment I would have is despite the interesting outcome in organ prevention we are still lacking in implementation at least in 2021 both the Grigham group and the veterans trials, both with the GLP-1 and the SGLT-2 data, it's very demeaning that, I mean though they complimented themselves on 8% of the people who are being managed by endocrinologists who are put on these medications. To me it's what the hell are the 92% people doing who are being seen by the endocrinologists so though we compliment on ourselves and say that ACE is approaching the primary care group we as endocrinologists and I find that in practice are not doing the right jobs with these group of people so when we talk about for example the SGLT-2 most of the trials were stopped the placebo arm were felt to be you know we were threatening the placebo arm so most of these trials were stopped ahead of time but yet we find that in clinical practice we are doing worse than the placebo arm of the trials yeah thanks for your comment I think there's a lot of work to do thanks for those presentations it was really interesting one comment and one question just addressing the ethnic disparity in terms of technology we've actually looked in the VA population at CGM use both in type 1 and type 2 diabetes patients and so we're talking about 25,000 patients who were initiated on CGM and we found actually the same thing there was this racial ethnic disparity percentages were surprisingly low in the hispanic and african american group so I think that data supports which I think was reported in the article and the reasons are obviously complicated as you pointed out and just like the article that you mentioned they're all part of the VA same concept welcome to get the type of care that is available and this is national of course suggests that this is a country wide problem regarding the look ahead study it's really quite interesting did they look to see whether this increased risk in those with hyperglycemia baseline did this wane over time to suggesting that part of this was perhaps overcoming the years of hyperglycemia induced damage that maybe have occurred also those individuals are more likely to be at risk for hyperglycemia potentially and I'm wondering if that was at all looked at do you have any sense about sort of the potential mediating actors in that relationship so the question about look ahead and kind of why the subgroup did worse I don't know but I assume that's going to be studied further so I don't know thanks Peter nice talk just a question I have I was interested in the slide you put up regarding the substitution of polyunsaturated fats and carbs for fats do you when you're doing clinical practice because this is a question I think we all get do you have a specific recommendation for your patients a low carb diet or do you have a specific recommendation for a low fat diet or the Mediterranean diet or do you just kind of say whatever diet you are most likely to adhere to choose that people come to me all the time are carbs good or bad for you and I'm never sure how to answer them yeah no thanks for your question so I definitely think that all carbs are not the same but many of these studies were done with complex carbohydrates with higher fiber so I have an entire dot phrase that I use for dietary recommendations for all of my patients and so I don't recommend any specific carbohydrate amounts or percentages and I really think that people need to make these small changes in their diets and try to make sustainable changes and there's a subset of patients who want to do everything all at once that's really not a huge percentage but for them I might recommend something like following the Mediterranean diet or the DASH diet but for most other people once you go through a list of what did you eat for breakfast this morning or what did you eat for dinner last night what do you drink then you can find some places where people can make these changes that make a huge difference but I don't tell people that they should eat a certain percentage of carbohydrates thanks for your question and just to add in a lot of times we'll focus on a carb consistent diet especially if they're on insulin therapy to avoid fluctuations if they're on like let's say set doses of insulin go over the plate method which is like an easy way to kind of review the diet breaking it down by the plate method so just to tack on thank you Hi, Dr. Whitmer from Cleveland Clinic just a comment question on the hybrid closed loop therapy that was found to be safe in older adults we've had a lot of patients go into DKA on after an insulin pump start in our older population and so in that study it seemed like the patients that were successful had been on insulin pump therapy for 10 years, is that right? So the study population had been on insulin pump therapy for a median of 10 years that was the population being studied so what are your thoughts on that insulin pump start this was also a population that had an A1C at the start of 7.4 the median age of 68 so not 92 so I guess you know your point is well taken that it needs to be clarified like the specific patient and if they're appropriate, if they can't handle then that may be a complicating factor but if they're a good elderly able to really comprehend technology well enough then it does appear safe and I don't know if the patients you had used it in were on the hybrid closed loop or if they were just on the pump therapy they were new to insulin pump therapy and that's my point that these patients seem to be very experienced and so one of the criteria for this study is they had to be on the pump therapy for at least 3 months but the median was 10 years yeah alright thank you so much for attending our session alright

diabetes

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type 1 diabetes prevention

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COVID-19 and diabetes

cardiovascular outcomes

renal outcomes

lifestyle interventions

FDA approval

clinical trials