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Foreign We've got another great issue this month of Diabetes core update. I'm Dr. Neal Skolnick, professor of Family and Community Medicine at the Sidney Kimmel Medical College of Thomas Jefferson University. And joining me as always is my
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co host and I'm John Russell, Political professor of Family and Community Medicine also at Thomas Jefferson University, the Sidney Kimmel Medical School. It's great to be with you tonight,
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Neil Shawn, we really have another great addition, beginning with an article from the New England Journal of Medicine, a placebo controlled trial of the oral PCSK9 inhibitor enlistide. This is going to be potentially a big deal. Going to be a very interesting article. Then an article from Diabetes Care, estimated optimal individualized diabetes risk prediction from preventive interventions in the US General population, followed by a discussion of another article from Diabetes Care on the impact of bariatric surgery on weight loss and glycemic control in adults with type 1 diabetes. Then another article from the New England Journal on phenurenon and type 1 diabetes and chronic kidney disease. And finally from Diabetes Care, the effect of SGLT2 use on mortality, amputation and healing in patients with diabetic foot ulcers. John will jump right in to the article from the New England Journal and that is a placebo controlled trial of the oral PCSK9 inhibitor. Enlistide elicitide is an oral PCSK9 inhibitor that has been shown in phase 2 trials to reduce LDL cholesterol level and therefore they then did this much larger, multinational, double blind, randomized, placebo controlled phase three trial that enrolled adults with a history of major ASCVD disease that would be MI, stroke, peripheral vascular disease with an LDL cholesterol level of 55 or higher, and individuals who were at risk for first ASCVD event with an LDL cholesterol level of 70 or higher, people who had, for instance, diabetes and risk factors. Participants were assigned in a 2 to 1 ratio to receive enlistide at a dose of 20 milligrams or placebo daily for 52 weeks. The primary endpoint was the mean percent change in LDL cholesterol level from baseline to week 24. Key secondary endpoints were the mean percent change in LDL cholesterol at week 52 and the mean percent change in levels of non HDL lipoproteins, apoprotein b, and the percent change in lipoprotein A at week 24. There were over 2,900 participants. Mean age was 63. Approximately 40% were women. Mean LDL at baseline entry was 96. The mean percent change in LDL cholesterol levels at week 24 was A was negative 57% with an elicitide and 3% increase with placebo. This was a P value of less than 0.001. The mean percent change in LDL cholesterol level at week 52. The percent change in non HDL cholesterol and APOB levels at week 24 as well as lipo a week were all significantly better with enlicitide than with placebo. P values being less than 0.001. And specifically APOA decreased 28%.
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John so Neil, pretty interesting article and first kind of starting with this study. So this study probably looked at the population we'd want it to look at. So 90 some percent of the people were on a high or mid potency statin. So you know, this wouldn't be in, in, in substitution for people being on a statin. And certainly we would want to start people on a statin. So it's a population we care about.
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It's probably the appropriate population that we
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would use this medicine on. And this medicine showed that it decreased LDL by 57%. So pretty strong, really very good at getting people's LDLs down to lower levels. Now the caveats is it showed that it lowered LDL, but it did not show mortality benefit. We've certainly seen that with the PCSK9 injectable medications that we've had and maybe it won't happen, but I'm going to assume that that does happen. I think the interesting thing for this is going to be kind of what's its price point. So 70% of the people in the United States are not at an LDL goal we would like them to be at. And, and there's probably lots of reasons on for that. When you go back a couple incantations ago of LDL guidelines, high risk people were 70, you know, medium risk people were 100, low risk people might be 130. So you and I in practice at least could kind of say we're putting you in category A, B or C and this is where your LDL goal should be. And they kind of changed it generically that you should be on a high potency or a potency mid to high potency statin and kind of kind of threw up their hands and then all these other medicines showed up. So I think that that's going to be interesting things and why those 70% of people, you know, injectable PCSK9s can range in that $500 a month to $1,200 a month range. It's a lot of money, you know, and a lot of people have donut holes, have a lot of reasons that they can't afford something even if they have insurance. I think, I think doctors are kind of scared off on prior authorizations and it's certainly easier to get, you know, the injectable PCSK9s than it once was. But I think for a lot of people, you know, prior authorization is the dirtiest word out there. So I think one of the interesting things is kind of what's going to be the price point of these medicines, if they do have mortality benefit, if they do have a 55% reduction, you know, how much is this going to cost our patients? And what's going to be kind of the return on investment, you know, for that. So I think that that's going to be interesting. So that's part one in this study. Really excited about to see where it goes. So the other part of this is kind of what else is happening in the lipid kind of realm. So if you also look in the New England journal at the March 28 edition, there was a study, the Easy Pave trial, that really looked about getting people at high, high risk an LDL below 55 versus under 70 and really showed a pretty significant difference in mortality, about a 67% mortality of that of someone who has an LDL 70. So that certainly sets the tone for what's going on. We have new guidelines from our acc aha brethren who, who now have gone back to a number. So we should be below 70 for our high risk patients. Maybe that's going to change to 55, 100 for our other patients. Everyone should have a lipoprotein A checked once. So I think a lot of these things are going to change and I think it's going to be kind of very interesting what we are doing going forward. So I think something that had just become kind of a shoulder shrug type thing, of course you should be on a statin and you should be on one of these potent ones is now going to have, you know, certainly more nuance. And I think all care should be individualized. And I think we're going to be kind of having discussions on patients on kind of adding something to their regimen that they might not be on. And then 55 might be the new 70. Our next article is from Diabetes Care and it looked at estimated optimal individualized diabetes risk prediction from preventive interventions in the US general population. So the design of the study was to calculate A three year predicted risk for diabetes with a model that included individualized preventive intervention effects for metformin therapy and intensive lifestyle among US adults with prediabetes. So the study looked at over 2,700 participants who had prediabetes from the NHANES trial between 2015 and 2020.
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The researchers used a validated type 2
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diabetes risk prediction model and they calculated predicted risk and summarized the optimal prevention studies. So which of these would be best for which individual patient. The mean predicted risk in the sample was 18.4% for standard lifestyle recommendations which would be the placebo group, 14.4% for metformin, 8% for intensive lifestyle and 7.6% for participants respective optimal intervention. The optimal intervention strategy was intensive lifestyle for 91% of the patients.
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Neil John Ordinarily I would say I love this trial because I'm a believer in lifestyle interventions and you and I have talked so many times about that Granddaddy of Preventive Trials Diabetes Preventive Program Trial DPPT New England Journal 2002 there's no doubt that it's a good idea to have an intensive lifestyle program and that it works in that study twice as good as metformin to decrease progression from prediabetes to diabetes. And this trial said what if we looked at that at the population at large and 90% of the people did better with lifestyle, that's as expected and potentially that could decrease 12 million people in the United States over three years from progressing to diabetes from prediabetes. But that's no longer the world that we solely live in. We have all of these other powerful medicines that we choose from now when we see people who have obesity and prediabetes and we talked about a couple of years ago already on our podcast, the trial of Tirzepatide for Obesity Treatment and Diabetes Prevention and what they did there to remind our listeners in the surmount trial, which was the large trial of tirzepatide for obesity, they looked at the people who also had prediabetes and they continued following them on medicine versus placebo for a total of 176 weeks. The results were really phenomenal. Tirzepatide versus placebo in terms of progression from prediabetes to diabetes, 1.3% versus 13.5%. That is a 93% decrease in progression to diabetes from prediabetes in people with obesity, obviously statistically very significant. Really the world we live in now is one, when someone is at high risk and they have prediabetes particularly if they also have obesity. We really are thinking, as we should, very strongly about GLP1s, which have, in this case the dual agonist that we mentioned that have really good evidence of decrease in progression. And we live in a world of ends and lifestyle modification because we feel healthier and we do better when we treat both with a medicine, in this case to decrease progression and diet that is healthy and sufficient exercise. Our next article from Diabetes Care is on the impact of metabolic bariatric surgery on weight loss and glycemic control in adults with type 1 diabetes. This was a multicenter retrospective cohort study. The goals were to see the effect of bariatric surgery in people with type 1 diabetes and obesity. This was a retrospective study of 162 people living with type 1 and obesity. One year after surgery, the mean total weight loss percentage was 29.7%. Insulin requirements dropped from 0.75 units per kilo per day to 0.32. So more than half units per kilo per day. And A1C went from 8% to 7.6%. LDL, HDL, total cholesterol and triglyceride levels significantly improved as well. All significantly.
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John Neal, Some of the, some of the questions of this particular study wouldn't necessarily be weight loss, right? So if you did a bariatric procedure on someone who's overweight, you would expect, you know, three quarters of them would lose a significant amount of their excess weight. With having a bariatric procedure, I think the big question is someone's insulin requirement. And if someone is completely insulin dependent, you know, are you going to see that decrease in insulin requirement? And you certainly do in this. So people will be able to achieve the same glycemic control with a lot less insulin. I think one of the caveats of this is something that I kind of found looking back in the research, and when they've looked at research on people who had type 1 diabetes who had a bariatric procedure, 15% of them had ketoacidosis in this one study in the postoperative period. But I think the one takeaway point is we should have a little bit more trepidation in the perioperative space for someone who's going to have a bariatric surgery who has type 1 diabetes with that caveat. And certainly something that can be kept an eye on and prevented. And remember that the big takeaway point, and I've seen residents make this mistake over the years, everyone with type 1 diabetes needs some insulin every day. So you don't really truly make someone, someone who's npo. You don't give them zero amount of insulin that day. So people are going to need some. So I think there is going to be some nuance in the perioperative period, but otherwise this paper follows along with what we would expect. Our next article is from the New
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England Journal of Medicine and it looked at phenerinone in type 1 diabetes and chronic kidney disease. So the researchers conducted a phase 3 trial involving adults who had type 1 diabetes CKD with a GFR somewhere between 25 to 90 and albuminoria somewhere in
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the 200 to less than 5000 range.
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The patients were already receiving an ACE or an arbitrary Patients were randomly assigned to receive phenarinone 10 or 20 milligrams per day depending on what the GFR was or a matching placebo. The primary outcome was a relative change in the urinary album to creatinine ratio of a period of over six months. So a total of 242 participants underwent randomization. The mean urinary albumin d acratini ratio decreased from 574at baseline to 373at six months among all the participants assigned to receive phenerinone and from 506 to 475among those who were assigned to receive placebo. Over a period of six months, the album of creatinine ratio decreased by 34% with phenerinone and 12% with placebo. That corresponded to a 25% greater reduction with phenerinone than placebo. The most common adverse events was hyperc kalemia which happened in 12 participants were 10.3% of the patients with phenarinone and 4 or 3.3% in the patients with placebo. Two participants are 1.7% overall discontinued funarinone because of this hyperkalemia. At six months the change in GFR was a decrease in 5.6 mls per minute with pheneronone and a decrease in 2.7 mls per minute with placebo and the GFR values approach baseline levels during the washout period.
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John this was a much needed study and really exciting to see. So we know that the CADIGO guidelines talk about pillars of care in treatment of chronic kidney disease and for people with type 2 diabetes. That's ACEs and ARBs, SGLT2s, phenurenon, GLP1s and they all work through different mechanisms. Chronic kidney disease is also a big deal for people with type 1 diabetes, but there's only been one pillar of care available to that group. Aces and arbs and you know, SGLT2s, while sometimes used off label, carry with them a significant increase in the risk of euglycemic dka, which we've talked about before here. So there's been a real need for treatment for people with ckd in type 1. And phenirenone now has evidence to support its use as a non steroidal mra. It is one of those pillars that with the amount of decrease in albuminuria that we saw here, one expects that that will likely also lead and hopefully there'll be other studies to show that that leads to a slowing in the progression of EGFR decline. Now I just want to touch on one other thing that you said and that was that the change in EGFR was greater over six months negative 5.6 with phenerinon than it was with placebo, negative 2.7. And it's important for our audience to understand that this is not a negative effect of Pheneridon. This is what we see when we begin ACEs or ARBs or SGLT2s. You and I have talked a lot about this, this EGFR dip that is not due to nephron damage but rather due to a hemodynamic effect when you decrease hyperfiltration that often people with chronic kidney disease have. So when people are followed out further, and we see this really dramatically when you look at Those graphs of ACEs and ARBs and SGLT2s as well as type 2 diabetes with pheneuron, when you follow the graphs out, we see this initial, what's called the EGFR dip and then a return and then eventually improved EGFRS on treatment drug compared to placebo. So in summary, I think this is an exciting advance that is much needed for people with type 1 diabetes. John our final article for this month from Diabetes Care is the effect of SGLT2 use on mortality, amputee amputation and healing in people with diabetic foot ulcers. We know that diabetic foot ulcers are a leading cause, are the leading cause of non traumatic lower limb amputation. The impact of SGLT2 use though on lower limb amputation has been debated. There was some concern in initial studies or in one of these studies on Canagulaflos and that was not seen in other studies that the aim of this study was to determine specifically in patients with diabetic foot ulcers if the use of SGLT2s would influence amputation and wound healing. This was a retrospective Study conducted in a French specialized diabetic foot center. All patients treated for new diabetic foot ulcers between January 2022 and May 24 and who had at least a year of follow up were included. The primary endpoint was one year amputation rate. There were 452 patients in the study. 94 were treated with an SGLT2 inhibitor. 358 were not. The mean age was 70 years. 77% of the patients were men. In the adjusted statistical model there was no significant association between the one year amputation rate and SGLT use. The six month healing rate was not significantly different between patients treated or not treated with SGLT2 inhibitors. 54% versus 44%. Healing time was significantly less in people treated with SGLT2s with a mean difference of 44 days. That's from 136 days versus 181 days. And the one year mortality rate was significantly lower in the SGLT2 inhibitor group. 1.1% versus 9.2% with a P value of 0.009.
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John so now I think that, you know, an interesting article that doesn't completely kind of blaze new trails because I think the people in the know would say that there really is not this association. But I, but for me I think it kind of strikes a couple different things. So study on canagula flows and early on said maybe it's associated with an increased amputation rate. Right. And, and that that kind of has been carried a little bit as a scarlet letter through many many years now. And people can't completely get away from this correlation is not causation. So two things that often happen in the same space. Right. So our patients with diabetes are much more likely to have peripheral vascular disease that leads to bad complications. Right. And just because someone might be taking an SGLT2 so what's the harm of just avoiding those medicines in people with peripheral vascular disease? We spend an awful lot of time talking about all the benefits of SGLT2s that really are not their glycemic benefits. SGLT2 is very much are the lipid lowering agents of the 90s. Right. So they, they help in so many different areas in our patients with diabetes and it would be really harmful to exclude patients. People with peripheral vascular disease die of Mace. Right. So I think instead of kind of chasing this ghost that doesn't really exist for the SDLT2, maybe we should turn our peripheral arterial disease attention to that fact.
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For more information and links to the articles that we discussed in this issue just go to diabetesjournal.org until next month. Keep listening and keep learning.
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Sam.