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- [00:03]
Dr. Neal Skolnick
Welcome to Diabetes Core Update January 2026. I'm your host, Dr. Neal Skolnick and joining me is my co host Dr. John Russell. And we have another excellent series of articles this month, beginning with an article from the New England journal on the PCSK9 IVlocumab in patients without previous MIS or strokes and the effect on mace. Then an article from JAMA on SGLT2 inhibitors and kidney outcomes looked at by EGFR and albuminuria. Then from diabetes care, continuous SGLT2 GLP1 receptor agonists and their effect on frailty progression in older adults with type 2 diabetes, an incredibly important issue. Then an article from JAMA on The effects of SGLT2 inhibitors by diabetes status and level of albuminuria. Then we're going to talk about an important article in Diabetes Care on tirzepatide in adults with type 1 diabetes. And this is a phase 2 randomized placebo controlled trial. And finally a fascinating article from Diabetes Care titled Listening. Yes, I said listening to hypoglycemia and this is using voice as a biomarker for detection of medical emergencies of hypoglycemia using a machine learning algorithm.
- [01:58]
Dr. John Russell
Let's jump in our first three articles from the New England Journal of Medicine and it looked at evoloquimab in patients without a previous MI or stroke. So in this particular study it was an international double blind randomized placebo controlled trial of evolocumab in patients with atherosclerosis or diabetes without a previous MI or stroke who had an LDL of at least 90 milligrams per deciliter. Patients were randomly assigned in one to one ratio to receive either the evolocumab at a dose of 140mg every two weeks or placebo. The two primary endpoints were a composite of death from coronary heart disease, myocardial infarction or ischemic stroke. That would be a three point MACE or composite of three point MACE or ischemic driven arterial vascularization, which would be a four point mace. There were over 12,000 patients who were randomly assigned to receive either evolocumab or placebo and they were included in efficacy analysis. The median age of the patients was 66 years of age, 43% were women and 93% of the patients were white. The median follow up was 4.6 years. A three point MACE event occurred in 336 patients, or 6.2% in the evolocamab group, as compared with 443 or 8% in the placebo group with a hazard ratio of 0.75. A four point MACE event occurred in 747 patients or 13% in the evolocumab group as opposed to 907, which would be 16.2% in the placebo group with a Hazard Ratio of 0.81. There was no evidence of between group difference seen in the incidence of safety events. Neil?
- [03:53]
Dr. Neal Skolnick
John, this is such an important trial. Recent guidelines have talked about lower and lower LDL goals and we'll talk about them in a moment. But for people at high risk and high risk have been defined as people with diabetes and people with existent underlying atherosclerotic disease. Most of these trials, at least in the PCSK 9s, all of the trials were in people who had had events. It is so helpful now to be able to know from the evidence that we can help people substantially who have significant elevated risk by virtue of either atherosclerotic disease that is established by something as simple as something John, you and I are doing every week, which are calcium scores. A calcium score over 100 opted someone in to this study as having underlying atherosclerotic disease. And the other group that's very common that we see in the office all the time are people with high, high risk diabetes. The other thing that's interesting, in this trial, in addition to a 25% decrease in mace, there was a 20% decrease in death from any cause and that was 7.9% in the treated group, 9.7% in the placebo group. That was a hazard ratio of 0.8 and it had a confidence interval of 0.70 to 0.91. Now you see that doesn't pass unity. If this wasn't low on the hierarchical analysis level, where one of the ones above it didn't meet statistical significance, this would have opted in for statistical significance. But because of the way statistics are done in clinical trials, where things are predefined, which is very important, this can only be thought thought of as hypothesis generating. Nonetheless, this is a powerful effect. Death from any cause and in all likelihood represents truth. So what does this tell us? Well, guidelines have recommended progressively lower levels for LDL with a cholesterol less than 70. Now recommended by the American Diabetes association for people with diabetes and by the American heart association in 2022 less than 55 for at very high risk. You usually can't get there with a statin alone. You sometimes get there with statin plus ezetimab. I think we are way underutilizing PCSK9s and this trial is going to be important in putting that to the forefront of our attention and establishing the evidence base to treat more people with PCSK9s who don't have LDLs below those low goals. Our next article from JAMA is a Meta analysis of SGLT2 outcomes and the importance of this trial was that SGLT2 inhibitors reduce CKD progression in individuals with type 2 diabetes, CKD or heart failure. However, their effects in people with stage 4 CKD or who have little to no albuminuria remains unclear. They assessed in this trial a large Meta analysis of SGLT2 inhibitor trials from the Cardiorenal Trialist Consortium. These were all randomized double blind placebo controlled trials and what they found among over 70,000 participants average age 65 years of age in 10 randomized trials, 3.3% experienced CKD progression and 1.4% reached kidney failure. SGLT2 inhibitors reduced the risk of CKD progression with a hazard ratio of approximately 0.56, that is a 40% decrease irrespective of baseline EGFR and irrespective of baseline albuminuria. Although the magnitude of protection varied, SGLT2 inhibitors reduced the annual rate of EGFR decline across all EGFR and UACR subgroups, including participants with and without diabetes.
- [08:48]
Dr. John Russell
John so Neil, I think this is kind of an interesting article. You know the first thing it's a meta analysis and anytime you look at a meta analysis it's really as good as the studies that are included and the studies that are excluded. This seems to be a study that seems to included a lot of the right studies and has 70,000 people in it. So probably we can infer from that large amount analysis probably a little bit of light on the subject. The Cadigo guidelines of 2024 talk about not necessarily starting a SGLT2 in those who don't have albuminoria and have a GFR above 45. In this particular study they really looked at different GFR subgroups, different albuminoria subgroups, and basically the takeaway from this study is in every instance that someone has CKD attached to them as a diagnosis, regardless of which of all the categories on the heat map you go into, they would recommend that people get put on an SGLT2 and really decreasing progression. And you kind of talked about all these numbers that live that hazard ratio that living in that 30 to 40% decrease. So pretty powerful. Certainly we'd like people to not progress into having kidney failure or needing dialysis. The one thing Also in thinking about this is, boy, this kind of opens up about fivefold the people that we're going to put on medications. Well, the Pagliflozin has moved into the generic space, so. And I think the other SGLT2s are soon going to start moving into that. So again, it's going to be something that's become a little bit more affordable for patients that we can use to prevent them from progression to kidney disease, which certainly is very expensive. There's a site called kidneyfailurerisk.com where you can plug in someone's GFR and their abnimicinine ratio and actually look at various drugs and see how much it will decrease progression. And certainly SGLT2s are kind of part of that equation in Pennsylvania. Our next article is from Diabetes Care and It looked at SGLT2 inhibitors, GLP1 receptor agonists and fertility progression in older adults with type 2 diabetes. So older adults with type 2 diabetes are at high risk for frailty. And this study looked at the effect of GLP1s and SGLT2s on frailty. So this study used a 7% random sample of Medicare data and the researchers compared new users of DPP4S, GLP1, SGLT2S and sulfony areas on a one year frailty progression measured by claims based frailty index with the range of 0 per 1, with higher scores indicating greater frailty. Mediation analysis assessed whether cardiovascular safety events explain the differences in frailty progression. Compared with the DPP4 users. The mean claims based frailty index change was significantly lower for the GLP1s, a decrease of 0.011. SDLT2 also had a decrease of 0.005. There was no difference found for sulfonylurea users. These associations were minimally mediated by cardiovascular or safety events.
- [12:44]
Dr. Neal Skolnick
Neil John, I really like this study because I think frailty is a really important issue. As you know, I'm also boarded in geriatrics and spend a good deal of time taking care of older adults. And I always worry with all sorts of medicines whether or not the effect that we're seeing in younger, more vigorous people in whom most of these medicines are studied, whether the effect is actually the same in older adults. One of the things that I thought was wonderful with dapagliflozin in the deliver trial, looking at heart failure with preserved ejection fraction, they actually did a subgroup analysis, they did a frailty index on everybody and they looked at, and this was published in the journal Circulation. They looked at whether or not Topagliflozin had a different effect on outcomes based on frailty index, and it didn't. And in fact there was a suggestion of more benefit in those who were most frail. I've always thought that that's a model for how clinical trials ought to be done. Moving forward, when we talk about medicines that are often considered for the elderly, I've worried about the effect of GLP1s on our older adults. That is an age where normally there's decreased muscle mass over time. With that decrease in muscle mass, there's increased frailty. Well, what this trial does is reassure me immensely that GLP1s are safe. SGLT2s are safe, and not only safe in these older adults, but might actually be diminish the movement toward frailty. Yes, in the study they gave some reasons. Maybe they protect by reducing cellular senescence and improving mitochondrial function and inflammation and oxidative stress and on and on. I'm not sure that we know why and clinically I'm not as convinced that it reduces frailty. But this trial just nails it in saying, yes, I can feel comfortable in using these two classes of medicines in my older adults without worry about inducing frailty. Our next trial is from JAMA and it is titled the effects of SGLT2s by diabetes status and level of Albuminuria. It is a meta analysis guidelines offer different strengths of recommendation based on diabetes status in uacr. The objective of this trial was to assess the relative and absolute effects of SGLT2 inhibitors across efficacy and serious safety outcomes in individuals stratified by diabetes status and UICR either above or below 200. It included eight randomized clinical trials for a total of over 58,000 participants with a mean age of 64 years. There were about 49,000 with diabetes and almost 10,000 without. They compared in all of the trials. SGLT2 inhibitors versus placebo Allocation to an SGLT2 inhibitor produced a lower rate of kidney disease progression with a hazard ratio of 0.65 in those with diabetes and a hazard ratio of 0.74 in those without diabetes. A lower rate of acute kidney injury with a hazard ratio of 0.77 in those with diabetes and 0.72 without a lower rate of any hospitalization. Again, these are all going to be about the same in people with and without diabete lower rate of any death as well. Diabetes specific hazard ratios were similar in participants with a UACR greater than 200 and with a UACR less than 200. When analyzed separately, a UACR of 200 or greater meant a larger estimated absolute benefit with regard to effect on kidney disease progression.
- [17:21]
Dr. John Russell
JOHN so Neil, I find this to be interesting and this is actually a companion piece in the same journal that the previous article that I talked about was. So one is this kind of echoes what we saw in the last study is really any abuminoria is going to benefit from an SGLT2. So I think that this is easy. If we have kind of two urine albumin to creatinine ratios separated by a couple months apart, that we could kind of feel confident that we could start a patient on one of these medications and they're going to do better. So I think it doesn't really say a whole lot that we didn't say before. That said, it also didn't show a difference, absolute huge difference between people had diabetes and didn't have diabetes. And I think if you look at kind of what is going to be a big part of primary care over the next 10 years is probably preventing the progression of kidney disease, not only should we be screening our patients for diabetic kidney disease with doing once or twice a year urine album and creatinine ratio, also our patients with hypertension, also our patients with borderline kidney disease, for some other reason, we should be following urine aminocretin ratios regularly, just like we would do with our patients with diabetes. So if you look at the standard of care for the average person who's gonna see you and I in the office, who might get a metabolic panel and a lipid panel, we probably need to start getting a urine album to creatinine ratio and if it is abnormal on more than two events, that we should have a very low threshold for starting someone on an SGLT2 because we can prevent a lot of downstream misery. Our next article is from Diabetes Care and it looked at tirzepatide in adults, patients with type 1 diabetes, a phase 2 randomized placebo controlled trial. So in this particular study, the researchers looked at adding tirzepatide to insulin in adults with type 1 diabetes. So overweight and obesity are prevalent in patients who have type 1 diabetes and contribute to their overall cardiovascular risk. But tirzepatide has not been studied in type 1 diabetes. So this was the turtle 1 trial, which was a phase 212 week double blind placebo controlled trial in which adults with type 1 diabetes and a BMI greater than 30 were randomized 1 to 1 to once weekly subcutaneous tirzepatide, 2.5 milligrams for four weeks, 5 milligrams for eight weeks or a placebo injection. The primary endpoint was a change in body weight at 12 weeks. What they found is after 12 weeks adjuvant tirzepatide versus placebo had an additional decrease of 8.7 kilos or an 8.8% weight loss. Other things that they measured which were not the primary endpoint was a decrease in a 1C of 0.4%, a 35.1% decrease in total insulin use, a 49% decrease in bolus insulin use and a 25% decrease in basal insulin use, all while having no significant adverse effects.
- [20:58]
Dr. Neal Skolnick
Neil John this is a wonderful trial to see. There have been four other trials for GLP1s two with liraglutide, two with slightly semaglutide, all of which is shown in different versions of the same thing, meaning a decrease in weight and improvement in a 1C along with decrease in insulin needs here. Wow. You had about a 30% decrease in total daily insulin. That's impressive. An improvement of 0.4 in a 1C and a substantial weight loss. We often don't think about Type one as needing these medicines, but when we stand back from things we recognize that almost 80% of adults with type 1 diabetes aren't achieving their glycemic targets and in fact over time about 2/3 of adults with type 1 also have overweight or obesity. So there's a real need for additional medicines or hopefully some of these will move forward to be FDA approved because it clearly is an area of need where there is off label use and now increasingly good data to support their use. Again, recognizing that this particular trial was quite small and we do want larger trials in people with type 1. Our final trial is a fascinating trial in diabetes care titled Listening to Hypoglycemia Voice as a Biomarker for Detection of a Medical Emergency using Machine Learning and the authors got this idea here to develop a machine learning approach for non invasive hypoglycemia detection using people's voices. They collected Voice data over 500 recordings with a smartphone in a standardized fashion in people with euglycemia and hypoglycemia in two sequential studies of people who had type 1 diabetes. Using this data, they trained and evaluated a machine learning approach to detect hypoglycemia solely based on the sound and cadence of these people's voices. There are 22 individuals who were included in the trial. Half were female, average age 37, average A1C was 7.1 and it turned out the machine learning approach was able to detect hypoglycemia with a high degree of accuracy.
- [23:52]
Dr. John Russell
JOHN so, Neil, thinking about this study, I hearken back to some of kind of the early days with some of the digital thermometers that would go in someone's ear or against someone's forehead. And when they originally came out, they were about as accurate as your mom putting her hand on your forehead to detect whether you had a of fever. And certainly a lot of the science of that has come a long way in this kind of 25, 30 years. So in thinking about the study, I feel that this is a little bit of that 20, 30 years ago. And you know, if we aren't, well, our mom or our dad or someone in our family or someone who cares about us can say something's wrong. I hear it in your voice, right? And you know, and, and maybe as we become a little bit more disconnected society, maybe not everyone is going to have the benefit of that person in their house to say, you don't sound right. And if you think there are more and more things in all of our homes that we ask it to change the channel or play a favorite song or things like that, will it get to that point? Now, hypoglycemia is a pretty important thing, so you would really like, if you're going to rely solely on the sound of someone's voice for it to be awful, awful, awful good. And I think this is interesting, but I don't think it's at the point that it's awful, awful, awful good. So we certainly don't want to throw away our CGMs and our other things that are those real markers for hypoglycemia. But you could imagine a time probably in the not too distant future that your cell phone that's going to know you real well. Although it sure seems like we text into our cell phones a lot more than we talk into our cell phones. That said that we could get to a point that the devices in our home might be able to be like our mom and say, you know, Neil, something doesn't sound right as you have a little bit of a upper respiratory tract infection. As we record this ep, I know you real well and say this is not your, this is not what you normally sound like. So I think this is an interesting thing in the future. We're probably just not at this point just yet.
- [26:24]
Dr. Neal Skolnick
For more information and links to the articles that we discussed in this issue, just go to diabetesjournal.org until next month.
- [26:36]
Dr. John Russell
Keep listening and keep learning.
- [26:38]
Dr. Neal Skolnick
SAM.