Cardiology

Adults with high cholesterol taking statins may have a significantly higher risk of developing glaucoma than those not taking the cholesterol-lowering drugs, an observational study of a large research database found.

The study, published in Ophthalmology Glaucoma, analyzed electronic health records of 79,742 adults with hyperlipidemia in the All of Us Research Program database from 2017 to 2022. The repository is maintained by the National Institutes of Health and provides data for research into precision medicine.

The 6365 statin users in the study population had a 47% greater unadjusted prevalence of glaucoma than nonusers of the drugs (P < .001) and a 13% greater prevalence in models that adjusted for potential confounding variables (P = .02). The researchers also found statin users had significantly higher levels of low-density lipoprotein cholesterol (LDL-C), but even patients with optimal levels of LDL-C had higher rates of glaucoma.

 

‘A Little Unusual’

Drawing any clinically relevant conclusions from this latest study would be premature, said Victoria Tseng, MD, PhD, an assistant professor at UCLA Stein Eye Institute and Doheny Eye Centers UCLA, and the senior author of the study. “I certainly would not be telling my patients on statins to stop their statins.”

Tseng acknowledged her group’s finding runs counter to previous studies that found statins may help prevent glaucoma or at least have no effect on the eye disease, although the association between cholesterol and glaucoma has been well established.

A 2019 analysis of nearly 137,000 participants in three population studies found no connection between statin use and the risk for primary open-angle glaucoma. A 2012 study of more than 500,000 people with high cholesterol found statin use was associated with a significant reduction in the risk for open-angle glaucoma.

“It’s a little unusual that we found the opposite,” Tseng said in an interview.

One explanation is the observational nature of the AoU analysis Tseng’s group conducted. “We don’t know what these people look like or how well the data were collected, so we’re going off of what’s there in the database,” she said.

Another explanation could be the nature of hyperlipidemia itself, she said. “There have definitely been studies that suggest increased cholesterol levels are associated with an increased risk of glaucoma. Presumably, you’re not going to be taking a statin unless your cholesterol is a little worse.”

While the study analysis attempted to control for cholesterol levels, Tseng noted, “there could be some residual confounding from that.”

Statin users in the study had an average LDL-C level of 144.9 mg/dL vs 136.3 mg/dL in the population not taking any cholesterol medication (P < .001). Statin users with optimal LDL-C, defined as less than 100 mg/dL, had a 39% greater adjusted prevalence of glaucoma (P = .02), while those with high LDL-C (160-189 mg/dL) had a 37% greater adjusted prevalence (P = .005).

Age was another factor in the risk for glaucoma, the study found. Statin users aged 60-69 years had an adjusted rate of glaucoma 28% greater than that for nonusers (P = .05).

Laboratory studies may help clarify the relationships between statins and glaucoma, Tseng said. That could include putting statins directly on the optic nerve of laboratory mice and further investigating how statins affect the mechanisms that influence eye pressure, a key driver of glaucoma. From a population study perspective, a randomized trial of glaucoma patients comparing the effect of statins and other cholesterol-lowering medications with nonuse may provide answers.

 

Database Strengths and Limitations

The study “adds to the somewhat mixed literature on the potential association between statins and glaucoma,” Sophia Wang, MD, MS, a glaucoma specialist at Stanford Byers Eye Institute in Palo Alto, California, said in an interview.

The AoU research cohort is a “notable strength” of the new paper, added Wang, who has used the AoU database to study the relationship between blood pressure, blood pressure medications, and glaucoma.

“The population is especially large and diverse, with a large proportion of participants from backgrounds that are traditionally underrepresented in research,” she said. And The inclusion of both medical records and survey data means the health information on the cohort is detailed and longitudinal.

“The authors make excellent use here of the data by including in their analyses results of laboratory investigations — LDL-C, notably — which wouldn’t be readily available in other types of datasets such as claims datasets,” she said.

However, the database has limitations as well, including its reliance on coding, which is prone to errors, to determine glaucoma diagnosis and missing information on eye examinations. In addition, the study used one LDL-C measurement rather than multiple measurements, Wang pointed out, “and we know that LDL-C can vary over time.”

The study was funded by Research to Prevent Blindness. Tseng and Wang reported no relevant financial relationships to disclose.

A version of this article first appeared on Medscape.com.

Adults with high cholesterol taking statins may have a significantly higher risk of developing glaucoma than those not taking the cholesterol-lowering drugs, an observational study of a large research database found.

The study, published in Ophthalmology Glaucoma, analyzed electronic health records of 79,742 adults with hyperlipidemia in the All of Us Research Program database from 2017 to 2022. The repository is maintained by the National Institutes of Health and provides data for research into precision medicine.

The 6365 statin users in the study population had a 47% greater unadjusted prevalence of glaucoma than nonusers of the drugs (P < .001) and a 13% greater prevalence in models that adjusted for potential confounding variables (P = .02). The researchers also found statin users had significantly higher levels of low-density lipoprotein cholesterol (LDL-C), but even patients with optimal levels of LDL-C had higher rates of glaucoma.

 

‘A Little Unusual’

Drawing any clinically relevant conclusions from this latest study would be premature, said Victoria Tseng, MD, PhD, an assistant professor at UCLA Stein Eye Institute and Doheny Eye Centers UCLA, and the senior author of the study. “I certainly would not be telling my patients on statins to stop their statins.”

Tseng acknowledged her group’s finding runs counter to previous studies that found statins may help prevent glaucoma or at least have no effect on the eye disease, although the association between cholesterol and glaucoma has been well established.

A 2019 analysis of nearly 137,000 participants in three population studies found no connection between statin use and the risk for primary open-angle glaucoma. A 2012 study of more than 500,000 people with high cholesterol found statin use was associated with a significant reduction in the risk for open-angle glaucoma.

“It’s a little unusual that we found the opposite,” Tseng said in an interview.

One explanation is the observational nature of the AoU analysis Tseng’s group conducted. “We don’t know what these people look like or how well the data were collected, so we’re going off of what’s there in the database,” she said.

Another explanation could be the nature of hyperlipidemia itself, she said. “There have definitely been studies that suggest increased cholesterol levels are associated with an increased risk of glaucoma. Presumably, you’re not going to be taking a statin unless your cholesterol is a little worse.”

While the study analysis attempted to control for cholesterol levels, Tseng noted, “there could be some residual confounding from that.”

Statin users in the study had an average LDL-C level of 144.9 mg/dL vs 136.3 mg/dL in the population not taking any cholesterol medication (P < .001). Statin users with optimal LDL-C, defined as less than 100 mg/dL, had a 39% greater adjusted prevalence of glaucoma (P = .02), while those with high LDL-C (160-189 mg/dL) had a 37% greater adjusted prevalence (P = .005).

Age was another factor in the risk for glaucoma, the study found. Statin users aged 60-69 years had an adjusted rate of glaucoma 28% greater than that for nonusers (P = .05).

Laboratory studies may help clarify the relationships between statins and glaucoma, Tseng said. That could include putting statins directly on the optic nerve of laboratory mice and further investigating how statins affect the mechanisms that influence eye pressure, a key driver of glaucoma. From a population study perspective, a randomized trial of glaucoma patients comparing the effect of statins and other cholesterol-lowering medications with nonuse may provide answers.

 

Database Strengths and Limitations

The study “adds to the somewhat mixed literature on the potential association between statins and glaucoma,” Sophia Wang, MD, MS, a glaucoma specialist at Stanford Byers Eye Institute in Palo Alto, California, said in an interview.

The AoU research cohort is a “notable strength” of the new paper, added Wang, who has used the AoU database to study the relationship between blood pressure, blood pressure medications, and glaucoma.

“The population is especially large and diverse, with a large proportion of participants from backgrounds that are traditionally underrepresented in research,” she said. And The inclusion of both medical records and survey data means the health information on the cohort is detailed and longitudinal.

“The authors make excellent use here of the data by including in their analyses results of laboratory investigations — LDL-C, notably — which wouldn’t be readily available in other types of datasets such as claims datasets,” she said.

However, the database has limitations as well, including its reliance on coding, which is prone to errors, to determine glaucoma diagnosis and missing information on eye examinations. In addition, the study used one LDL-C measurement rather than multiple measurements, Wang pointed out, “and we know that LDL-C can vary over time.”

The study was funded by Research to Prevent Blindness. Tseng and Wang reported no relevant financial relationships to disclose.

A version of this article first appeared on Medscape.com.

Adults with high cholesterol taking statins may have a significantly higher risk of developing glaucoma than those not taking the cholesterol-lowering drugs, an observational study of a large research database found.

The study, published in Ophthalmology Glaucoma, analyzed electronic health records of 79,742 adults with hyperlipidemia in the All of Us Research Program database from 2017 to 2022. The repository is maintained by the National Institutes of Health and provides data for research into precision medicine.

The 6365 statin users in the study population had a 47% greater unadjusted prevalence of glaucoma than nonusers of the drugs (P < .001) and a 13% greater prevalence in models that adjusted for potential confounding variables (P = .02). The researchers also found statin users had significantly higher levels of low-density lipoprotein cholesterol (LDL-C), but even patients with optimal levels of LDL-C had higher rates of glaucoma.

 

‘A Little Unusual’

Drawing any clinically relevant conclusions from this latest study would be premature, said Victoria Tseng, MD, PhD, an assistant professor at UCLA Stein Eye Institute and Doheny Eye Centers UCLA, and the senior author of the study. “I certainly would not be telling my patients on statins to stop their statins.”

Tseng acknowledged her group’s finding runs counter to previous studies that found statins may help prevent glaucoma or at least have no effect on the eye disease, although the association between cholesterol and glaucoma has been well established.

A 2019 analysis of nearly 137,000 participants in three population studies found no connection between statin use and the risk for primary open-angle glaucoma. A 2012 study of more than 500,000 people with high cholesterol found statin use was associated with a significant reduction in the risk for open-angle glaucoma.

“It’s a little unusual that we found the opposite,” Tseng said in an interview.

One explanation is the observational nature of the AoU analysis Tseng’s group conducted. “We don’t know what these people look like or how well the data were collected, so we’re going off of what’s there in the database,” she said.

Another explanation could be the nature of hyperlipidemia itself, she said. “There have definitely been studies that suggest increased cholesterol levels are associated with an increased risk of glaucoma. Presumably, you’re not going to be taking a statin unless your cholesterol is a little worse.”

While the study analysis attempted to control for cholesterol levels, Tseng noted, “there could be some residual confounding from that.”

Statin users in the study had an average LDL-C level of 144.9 mg/dL vs 136.3 mg/dL in the population not taking any cholesterol medication (P < .001). Statin users with optimal LDL-C, defined as less than 100 mg/dL, had a 39% greater adjusted prevalence of glaucoma (P = .02), while those with high LDL-C (160-189 mg/dL) had a 37% greater adjusted prevalence (P = .005).

Age was another factor in the risk for glaucoma, the study found. Statin users aged 60-69 years had an adjusted rate of glaucoma 28% greater than that for nonusers (P = .05).

Laboratory studies may help clarify the relationships between statins and glaucoma, Tseng said. That could include putting statins directly on the optic nerve of laboratory mice and further investigating how statins affect the mechanisms that influence eye pressure, a key driver of glaucoma. From a population study perspective, a randomized trial of glaucoma patients comparing the effect of statins and other cholesterol-lowering medications with nonuse may provide answers.

 

Database Strengths and Limitations

The study “adds to the somewhat mixed literature on the potential association between statins and glaucoma,” Sophia Wang, MD, MS, a glaucoma specialist at Stanford Byers Eye Institute in Palo Alto, California, said in an interview.

The AoU research cohort is a “notable strength” of the new paper, added Wang, who has used the AoU database to study the relationship between blood pressure, blood pressure medications, and glaucoma.

“The population is especially large and diverse, with a large proportion of participants from backgrounds that are traditionally underrepresented in research,” she said. And The inclusion of both medical records and survey data means the health information on the cohort is detailed and longitudinal.

“The authors make excellent use here of the data by including in their analyses results of laboratory investigations — LDL-C, notably — which wouldn’t be readily available in other types of datasets such as claims datasets,” she said.

However, the database has limitations as well, including its reliance on coding, which is prone to errors, to determine glaucoma diagnosis and missing information on eye examinations. In addition, the study used one LDL-C measurement rather than multiple measurements, Wang pointed out, “and we know that LDL-C can vary over time.”

The study was funded by Research to Prevent Blindness. Tseng and Wang reported no relevant financial relationships to disclose.

A version of this article first appeared on Medscape.com.

This transcript has been edited for clarity. 

Michelle L. O’Donoghue, MD, MPH: I’m here at the American Heart Association Scientific Sessions. It’s a very exciting meeting, but one of the interesting topics that we’re going to be talking about is lipoprotein(a) [Lp(a)] . It’s definitely one of the hottest sessions of the meeting.

Joining me to discuss this topic is Dr Steve Nicholls, who is arguably one of the leading experts in the world on lipids. He’s a professor of medicine at Monash University in Australia. Welcome. Thanks, Steve. 

Stephen J. Nicholls, MBBS, PhD: Thanks for having me. 

O’Donoghue: There are two phase 2 studies that we’ll circle back to that are being presented here at the American Heart Association meeting. These are for novel therapeutics that lower Lp(a). Perhaps taking a step back, we know that there’s a large body of evidence to support the concept that Lp(a) plays a causal role in heart disease and atherogenesis, but to date we haven’t had any effective therapies to really lower it.

Thinking about the therapeutics specifically that are on the horizon, perhaps we could start there. Which one is furthest along in development, and how does that look in terms of its ability to lower Lp(a)?

 

Pelacarsen, an ASO

Nicholls: Most of the therapies are injectable. Most of them are nucleic acid–based therapies, and the one that’s most advanced is an agent called pelacarsen. Pelacarsen is an antisense oligonucleotide (ASO), and it has gone all the way through its early phase 2 studies. It has a fully enrolled cardiovascular outcome trial.

We’re all eagerly awaiting the results of that study sometime in the next year or so. That will be the first large-scale clinical trial that will give us some clinical validation to ask the question of whether substantive lowering of Lp(a) will lower cardiovascular risk, with an agent that in early studies looks like it lowers Lp(a) about 80%.

O’Donoghue: Which is tremendous, because again, we really don’t have any effective therapies right now. I guess one of the big questions is, how much do we need to lower Lp(a) for that to translate into meaningful clinical benefit? What’s your sense there? 

Nicholls: Well, we simply don’t know. We’ve tried to look to genetics to try and give us some sort of sense in terms of what that looks like. Lp(a) is a little tricky because the assays and the numbers that get spit out can be tricky in terms of trying to compare apples and apples in different studies. 

We think that it’s probably at least a 50- to 75-mg/dL lowering of Lp(a) using the old units. We think that pelacarsen would hit that, and so our hope is that that would translate to a 15%-20% reduction in major cardiovascular events, but again, we’ve never asked this question before. 

We have data from PCSK9 inhibitor trials showing that lesser reductions in Lp(a) of 25%-30% with both evolocumab and alirocumab contributed to the clinical benefit that we saw in those studies. Those agents were really good at lowering low-density lipoprotein (LDL) cholesterol, but Lp(a) lowering seemed to matter. One would be very hopeful that if a 25%-30% lowering of Lp(a) is useful, then an 80% or greater lowering of Lp(a) should be really useful. 

 

The siRNAs

O’Donoghue: In addition to the ASO pelacarsen that you mentioned, there are several therapeutics in the pipeline, including three small interfering (si) RNAs that are at least in phase 2 and phase 3 testing at this point in time. There’s olpasiran, which in phase 2 testing led to more than a 95% reduction in Lp(a), and then lepodisiran , which has now moved into phase 3  testing, albeit we haven’t seen yet the phase 2  results. 

What is your sense of lepodisiran and its efficacy? 

Nicholls: What’s been really quite striking about the siRNAs is the even more profound degree of lowering of Lp(a) that we’re seeing. We’re seeing 90% and greater lowering of Lp(a) in all of those programs. We’re seeing some differences between the programs in terms of the durability of that effect. 

I think it would be fair to say that with zerlasiran we’re starting to see perhaps that lowering effect starts to taper off a little bit more quickly than the other two. I think that may have some implications in terms of what dosing regimens may look like in the future. 

Even so, we’re talking about therapies that may be dosed 3- to 6-monthly, or even with the potential for being less frequent than that with lepodisiran. Again, I think the phase 2 data will be really important in terms of giving us more information.

O’Donoghue: For the lepodisiran results, I was really quite struck that even though it was small numbers, single dose administered, it really looked like the duration of effect persisted at the higher doses up to about a year. 

Nicholls: It looks pretty promising. We’ve launched the ACCLAIM study, the large cardiovascular outcome trial of lepodisiran, with a 6-monthly regimen. We are hopeful that more information may be able to give us the opportunity for even less frequent administration. 

That has really important implications for patients where adherence is a particular issue. They may just simply want to come into the clinic. You know, once or twice a year, very much like we’re seeing with inclisiran, and that may be a really effective approach for many patients. 

O’Donoghue: You alluded to the zerlasiran results, which were presented here at the American Heart Association meeting, and that even though it led to a robust reduction in Lp(a), it looked like the durability component was maybe a little bit shorter than for some of the other siRNAs that are currently being evaluated.

What’s your sense of that? 

Nicholls: It probably is. The implications clinically, at least in an outcome trial when they ultimately get to that point, probably aren’t that important. They’ll probably just have slightly more frequent administration. That may become a bigger issue when it gets out into the clinic.

The nice thing is that if all of these agents appear to be effective, are well tolerated, and get out to the clinic, then clinicians and patients are going to have a lot of choice. 

O’Donoghue: I think more competition is always good news for the field, ultimately. I think to your point, especially for a drug that might be self-administered, ultimately, whether it’s once a month or once every 3 months, it doesn’t probably make much difference. I think different choices are needed for different patients. 

Perhaps that’s a perfect segue to talk about the oral Lp(a) inhibitor that is also being developed. You presented these results for muvalaplin. 

 

Muvalaplin, an Oral Small Molecule

Nicholls: In terms of frequency of administration, we’re talking about a daily oral therapeutic. For patients who don’t want an injectable and are happy to take a tablet every day, muvalaplin has the potential to be a really good option for them. 

Muvalaplin is an oral small-molecule inhibitor. It essentially prevents apolipoprotein(a) [apo(a)] from binding to apolipoprotein B (apo B). We presented phase 1 data  at the European Society of Cardiology meeting last year, showing probably Lp(a) lowering on the order of about 65%. Here, we’re going to show that that’s a little bit more. It looks like it’s probably at least 70% lowering using a standard Lp(a) assay. Using an assay that looks specifically at intact Lp(a) particles, it’s probably well in excess of 80%.

Those are really good results. The safety and tolerability with muvalaplin look really good. Again, we’ll need to see that agent move forward into a large outcome trial and we’ve yet to hear about that, at least for now. 

O’Donoghue: It’s an interesting challenge that you faced in terms of the assay because, as you say, it really disrupts the apo(a) from binding to the apo B particle, and hence, a traditional assay that just measures apo(a), regardless of whether or not it’s bound to an apo B particle, may be a conservative estimate.

Nicholls: It may, in particular, because we know that apo(a) ultimately then binds to the drug. That assay is measuring what we think is nonfunctional apo(a) in addition to functional apo(a). It’s measuring functional apo(a) that’s still on an actual Lp(a) particle, but if it’s bound to muvalaplin, we think to some degree that’s probably unfair to count that. That’s why trying to develop other assays to try and understand the full effect of the drug is really important in terms of trying to understand how we develop that and move that forward.

O’Donoghue: Is there any evidence yet that the apo(a) particle that is not bound to apo B is in fact nonfunctional as you described it? 

Nicholls: We think that’s likely to be the case, but I think there continues to be research in that space to try and settle that question once and for all. 

O’Donoghue: Again, I think it’s a really exciting time in this field. Right now, we have three ongoing phase 3 trials. We have the pelacarsen trial that is still in follow-up, and fingers crossed, maybe will report out next year. Olpasiran is also in phase 3 testing, completed enrollment, and also is in the follow-up period. We also have lepodisiran, the ACCLAIM trial, as you mentioned. For people who are perhaps watching and looking to enroll their patients, this trial is still ongoing right now in terms of enrollment. 

Nicholls: It is, and what’s nice about the ACCLAIM study is that it includes both primary and secondary prevention patients. For the first time in a big outcome trial, patients with high Lp(a) levels but who have yet to have a clinical event can actually get into a clinical trial.

I’m sure, like you, my clinic is full of patients with high Lp(a) who are really desperate to get into these trials. Many of those primary prevention patients just simply haven’t qualified, so that’s really good news. 

The step beyond that, if we’re talking about even less frequent administration, is gene editing. We’re seeing those studies with CRISPR move forward to try to evaluate whether a single gene-editing approach at Lp(a) will be all that you need, which is even a more amazing concept, but that’s a study that needs more work. 

O’Donoghue: An exciting space though, for sure. As a final thought, you mentioned the patients in your clinic who you have identified as having high Lp(a). What are you doing right now in your practice for managing those patients? I think there are many practitioners out there who struggle with whether they should really measure their patients’ Lp(a), and whether they want to know that information.

Nicholls: Yeah, it’s really hard. The answer is yes, we do want to know it. We know it’s a great risk enhancer. We know that a patient with a high Lp(a) is somebody whom I want to more intensively treat their other risk factors. I’m aiming for a lower LDL. I’m being much tighter with blood pressure control.

I think there’s some argument from observational data at least that aspirin remains a consideration, particularly in patients where you think there’s a particularly high risk associated with that high Lp(a). I think there are things we absolutely can do today, but we can’t do anything if you don’t know the numbers.

It starts with testing, and then we can move on to what we can do today, and then hopefully in the not-too-distant future, we’ll have specific therapies that really enable for us to address Lp(a) quite definitively. 

O’Donoghue: Thanks again for taking the time. This was a very helpful discussion.

 

Michelle O’Donoghue is a cardiologist at Brigham and Women’s Hospital and senior investigator with the TIMI Study Group. A strong believer in evidence-based medicine, she relishes discussions about the published literature. A native Canadian, Michelle loves spending time outdoors with her family but admits with shame that she’s never strapped on hockey skates. Dr O’Donoghue, Senior Investigator, TIMI Study Group; Associate Professor of Medicine, Harvard Medical School; Associate Physician, Brigham and Women’s Hospital, Boston, Massachusetts, disclosed ties to Janssen; Novartis; CVS Minute Clinic; Merck & Co.; GlaxoSmithKline; Eisai Inc.; AstraZeneca Pharmaceuticals LP; Janssen Pharmaceuticals; Medicines Company; and Amgen. The opinions expressed in this article do not necessarily reflect the views and opinions of Brigham and Women’s Hospital. Stephen J. Nicholls, MBBS, PhD, Director, Victorian Heart Institute, Monash University; Director, Victorian Heart Hospital, Monash Health, Melbourne, Australia, has disclosed ties with Akcea Therapeutics; Amgen; AstraZeneca; Boehringer Ingelheim; CSL Behring; Eli Lilly and Company; Esperion Therapeutics; Kowa Pharmaceuticals; Merck; Novo Nordisk; Pfizer; Sanofi Regeneron; Daichii Sankyo; Vaxxinity; Cyclarity; CSL Sequirus; Takeda; Anthera Pharmaceuticals; Cerenis Therapeutics; Infraredx; New Amsterdam Pharma; Novartis; and Resverlogix.

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity. 

Michelle L. O’Donoghue, MD, MPH: I’m here at the American Heart Association Scientific Sessions. It’s a very exciting meeting, but one of the interesting topics that we’re going to be talking about is lipoprotein(a) [Lp(a)] . It’s definitely one of the hottest sessions of the meeting.

Joining me to discuss this topic is Dr Steve Nicholls, who is arguably one of the leading experts in the world on lipids. He’s a professor of medicine at Monash University in Australia. Welcome. Thanks, Steve. 

Stephen J. Nicholls, MBBS, PhD: Thanks for having me. 

O’Donoghue: There are two phase 2 studies that we’ll circle back to that are being presented here at the American Heart Association meeting. These are for novel therapeutics that lower Lp(a). Perhaps taking a step back, we know that there’s a large body of evidence to support the concept that Lp(a) plays a causal role in heart disease and atherogenesis, but to date we haven’t had any effective therapies to really lower it.

Thinking about the therapeutics specifically that are on the horizon, perhaps we could start there. Which one is furthest along in development, and how does that look in terms of its ability to lower Lp(a)?

 

Pelacarsen, an ASO

Nicholls: Most of the therapies are injectable. Most of them are nucleic acid–based therapies, and the one that’s most advanced is an agent called pelacarsen. Pelacarsen is an antisense oligonucleotide (ASO), and it has gone all the way through its early phase 2 studies. It has a fully enrolled cardiovascular outcome trial.

We’re all eagerly awaiting the results of that study sometime in the next year or so. That will be the first large-scale clinical trial that will give us some clinical validation to ask the question of whether substantive lowering of Lp(a) will lower cardiovascular risk, with an agent that in early studies looks like it lowers Lp(a) about 80%.

O’Donoghue: Which is tremendous, because again, we really don’t have any effective therapies right now. I guess one of the big questions is, how much do we need to lower Lp(a) for that to translate into meaningful clinical benefit? What’s your sense there? 

Nicholls: Well, we simply don’t know. We’ve tried to look to genetics to try and give us some sort of sense in terms of what that looks like. Lp(a) is a little tricky because the assays and the numbers that get spit out can be tricky in terms of trying to compare apples and apples in different studies. 

We think that it’s probably at least a 50- to 75-mg/dL lowering of Lp(a) using the old units. We think that pelacarsen would hit that, and so our hope is that that would translate to a 15%-20% reduction in major cardiovascular events, but again, we’ve never asked this question before. 

We have data from PCSK9 inhibitor trials showing that lesser reductions in Lp(a) of 25%-30% with both evolocumab and alirocumab contributed to the clinical benefit that we saw in those studies. Those agents were really good at lowering low-density lipoprotein (LDL) cholesterol, but Lp(a) lowering seemed to matter. One would be very hopeful that if a 25%-30% lowering of Lp(a) is useful, then an 80% or greater lowering of Lp(a) should be really useful. 

 

The siRNAs

O’Donoghue: In addition to the ASO pelacarsen that you mentioned, there are several therapeutics in the pipeline, including three small interfering (si) RNAs that are at least in phase 2 and phase 3 testing at this point in time. There’s olpasiran, which in phase 2 testing led to more than a 95% reduction in Lp(a), and then lepodisiran , which has now moved into phase 3  testing, albeit we haven’t seen yet the phase 2  results. 

What is your sense of lepodisiran and its efficacy? 

Nicholls: What’s been really quite striking about the siRNAs is the even more profound degree of lowering of Lp(a) that we’re seeing. We’re seeing 90% and greater lowering of Lp(a) in all of those programs. We’re seeing some differences between the programs in terms of the durability of that effect. 

I think it would be fair to say that with zerlasiran we’re starting to see perhaps that lowering effect starts to taper off a little bit more quickly than the other two. I think that may have some implications in terms of what dosing regimens may look like in the future. 

Even so, we’re talking about therapies that may be dosed 3- to 6-monthly, or even with the potential for being less frequent than that with lepodisiran. Again, I think the phase 2 data will be really important in terms of giving us more information.

O’Donoghue: For the lepodisiran results, I was really quite struck that even though it was small numbers, single dose administered, it really looked like the duration of effect persisted at the higher doses up to about a year. 

Nicholls: It looks pretty promising. We’ve launched the ACCLAIM study, the large cardiovascular outcome trial of lepodisiran, with a 6-monthly regimen. We are hopeful that more information may be able to give us the opportunity for even less frequent administration. 

That has really important implications for patients where adherence is a particular issue. They may just simply want to come into the clinic. You know, once or twice a year, very much like we’re seeing with inclisiran, and that may be a really effective approach for many patients. 

O’Donoghue: You alluded to the zerlasiran results, which were presented here at the American Heart Association meeting, and that even though it led to a robust reduction in Lp(a), it looked like the durability component was maybe a little bit shorter than for some of the other siRNAs that are currently being evaluated.

What’s your sense of that? 

Nicholls: It probably is. The implications clinically, at least in an outcome trial when they ultimately get to that point, probably aren’t that important. They’ll probably just have slightly more frequent administration. That may become a bigger issue when it gets out into the clinic.

The nice thing is that if all of these agents appear to be effective, are well tolerated, and get out to the clinic, then clinicians and patients are going to have a lot of choice. 

O’Donoghue: I think more competition is always good news for the field, ultimately. I think to your point, especially for a drug that might be self-administered, ultimately, whether it’s once a month or once every 3 months, it doesn’t probably make much difference. I think different choices are needed for different patients. 

Perhaps that’s a perfect segue to talk about the oral Lp(a) inhibitor that is also being developed. You presented these results for muvalaplin. 

 

Muvalaplin, an Oral Small Molecule

Nicholls: In terms of frequency of administration, we’re talking about a daily oral therapeutic. For patients who don’t want an injectable and are happy to take a tablet every day, muvalaplin has the potential to be a really good option for them. 

Muvalaplin is an oral small-molecule inhibitor. It essentially prevents apolipoprotein(a) [apo(a)] from binding to apolipoprotein B (apo B). We presented phase 1 data  at the European Society of Cardiology meeting last year, showing probably Lp(a) lowering on the order of about 65%. Here, we’re going to show that that’s a little bit more. It looks like it’s probably at least 70% lowering using a standard Lp(a) assay. Using an assay that looks specifically at intact Lp(a) particles, it’s probably well in excess of 80%.

Those are really good results. The safety and tolerability with muvalaplin look really good. Again, we’ll need to see that agent move forward into a large outcome trial and we’ve yet to hear about that, at least for now. 

O’Donoghue: It’s an interesting challenge that you faced in terms of the assay because, as you say, it really disrupts the apo(a) from binding to the apo B particle, and hence, a traditional assay that just measures apo(a), regardless of whether or not it’s bound to an apo B particle, may be a conservative estimate.

Nicholls: It may, in particular, because we know that apo(a) ultimately then binds to the drug. That assay is measuring what we think is nonfunctional apo(a) in addition to functional apo(a). It’s measuring functional apo(a) that’s still on an actual Lp(a) particle, but if it’s bound to muvalaplin, we think to some degree that’s probably unfair to count that. That’s why trying to develop other assays to try and understand the full effect of the drug is really important in terms of trying to understand how we develop that and move that forward.

O’Donoghue: Is there any evidence yet that the apo(a) particle that is not bound to apo B is in fact nonfunctional as you described it? 

Nicholls: We think that’s likely to be the case, but I think there continues to be research in that space to try and settle that question once and for all. 

O’Donoghue: Again, I think it’s a really exciting time in this field. Right now, we have three ongoing phase 3 trials. We have the pelacarsen trial that is still in follow-up, and fingers crossed, maybe will report out next year. Olpasiran is also in phase 3 testing, completed enrollment, and also is in the follow-up period. We also have lepodisiran, the ACCLAIM trial, as you mentioned. For people who are perhaps watching and looking to enroll their patients, this trial is still ongoing right now in terms of enrollment. 

Nicholls: It is, and what’s nice about the ACCLAIM study is that it includes both primary and secondary prevention patients. For the first time in a big outcome trial, patients with high Lp(a) levels but who have yet to have a clinical event can actually get into a clinical trial.

I’m sure, like you, my clinic is full of patients with high Lp(a) who are really desperate to get into these trials. Many of those primary prevention patients just simply haven’t qualified, so that’s really good news. 

The step beyond that, if we’re talking about even less frequent administration, is gene editing. We’re seeing those studies with CRISPR move forward to try to evaluate whether a single gene-editing approach at Lp(a) will be all that you need, which is even a more amazing concept, but that’s a study that needs more work. 

O’Donoghue: An exciting space though, for sure. As a final thought, you mentioned the patients in your clinic who you have identified as having high Lp(a). What are you doing right now in your practice for managing those patients? I think there are many practitioners out there who struggle with whether they should really measure their patients’ Lp(a), and whether they want to know that information.

Nicholls: Yeah, it’s really hard. The answer is yes, we do want to know it. We know it’s a great risk enhancer. We know that a patient with a high Lp(a) is somebody whom I want to more intensively treat their other risk factors. I’m aiming for a lower LDL. I’m being much tighter with blood pressure control.

I think there’s some argument from observational data at least that aspirin remains a consideration, particularly in patients where you think there’s a particularly high risk associated with that high Lp(a). I think there are things we absolutely can do today, but we can’t do anything if you don’t know the numbers.

It starts with testing, and then we can move on to what we can do today, and then hopefully in the not-too-distant future, we’ll have specific therapies that really enable for us to address Lp(a) quite definitively. 

O’Donoghue: Thanks again for taking the time. This was a very helpful discussion.

 

Michelle O’Donoghue is a cardiologist at Brigham and Women’s Hospital and senior investigator with the TIMI Study Group. A strong believer in evidence-based medicine, she relishes discussions about the published literature. A native Canadian, Michelle loves spending time outdoors with her family but admits with shame that she’s never strapped on hockey skates. Dr O’Donoghue, Senior Investigator, TIMI Study Group; Associate Professor of Medicine, Harvard Medical School; Associate Physician, Brigham and Women’s Hospital, Boston, Massachusetts, disclosed ties to Janssen; Novartis; CVS Minute Clinic; Merck & Co.; GlaxoSmithKline; Eisai Inc.; AstraZeneca Pharmaceuticals LP; Janssen Pharmaceuticals; Medicines Company; and Amgen. The opinions expressed in this article do not necessarily reflect the views and opinions of Brigham and Women’s Hospital. Stephen J. Nicholls, MBBS, PhD, Director, Victorian Heart Institute, Monash University; Director, Victorian Heart Hospital, Monash Health, Melbourne, Australia, has disclosed ties with Akcea Therapeutics; Amgen; AstraZeneca; Boehringer Ingelheim; CSL Behring; Eli Lilly and Company; Esperion Therapeutics; Kowa Pharmaceuticals; Merck; Novo Nordisk; Pfizer; Sanofi Regeneron; Daichii Sankyo; Vaxxinity; Cyclarity; CSL Sequirus; Takeda; Anthera Pharmaceuticals; Cerenis Therapeutics; Infraredx; New Amsterdam Pharma; Novartis; and Resverlogix.

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity. 

Michelle L. O’Donoghue, MD, MPH: I’m here at the American Heart Association Scientific Sessions. It’s a very exciting meeting, but one of the interesting topics that we’re going to be talking about is lipoprotein(a) [Lp(a)] . It’s definitely one of the hottest sessions of the meeting.

Joining me to discuss this topic is Dr Steve Nicholls, who is arguably one of the leading experts in the world on lipids. He’s a professor of medicine at Monash University in Australia. Welcome. Thanks, Steve. 

Stephen J. Nicholls, MBBS, PhD: Thanks for having me. 

O’Donoghue: There are two phase 2 studies that we’ll circle back to that are being presented here at the American Heart Association meeting. These are for novel therapeutics that lower Lp(a). Perhaps taking a step back, we know that there’s a large body of evidence to support the concept that Lp(a) plays a causal role in heart disease and atherogenesis, but to date we haven’t had any effective therapies to really lower it.

Thinking about the therapeutics specifically that are on the horizon, perhaps we could start there. Which one is furthest along in development, and how does that look in terms of its ability to lower Lp(a)?

 

Pelacarsen, an ASO

Nicholls: Most of the therapies are injectable. Most of them are nucleic acid–based therapies, and the one that’s most advanced is an agent called pelacarsen. Pelacarsen is an antisense oligonucleotide (ASO), and it has gone all the way through its early phase 2 studies. It has a fully enrolled cardiovascular outcome trial.

We’re all eagerly awaiting the results of that study sometime in the next year or so. That will be the first large-scale clinical trial that will give us some clinical validation to ask the question of whether substantive lowering of Lp(a) will lower cardiovascular risk, with an agent that in early studies looks like it lowers Lp(a) about 80%.

O’Donoghue: Which is tremendous, because again, we really don’t have any effective therapies right now. I guess one of the big questions is, how much do we need to lower Lp(a) for that to translate into meaningful clinical benefit? What’s your sense there? 

Nicholls: Well, we simply don’t know. We’ve tried to look to genetics to try and give us some sort of sense in terms of what that looks like. Lp(a) is a little tricky because the assays and the numbers that get spit out can be tricky in terms of trying to compare apples and apples in different studies. 

We think that it’s probably at least a 50- to 75-mg/dL lowering of Lp(a) using the old units. We think that pelacarsen would hit that, and so our hope is that that would translate to a 15%-20% reduction in major cardiovascular events, but again, we’ve never asked this question before. 

We have data from PCSK9 inhibitor trials showing that lesser reductions in Lp(a) of 25%-30% with both evolocumab and alirocumab contributed to the clinical benefit that we saw in those studies. Those agents were really good at lowering low-density lipoprotein (LDL) cholesterol, but Lp(a) lowering seemed to matter. One would be very hopeful that if a 25%-30% lowering of Lp(a) is useful, then an 80% or greater lowering of Lp(a) should be really useful. 

 

The siRNAs

O’Donoghue: In addition to the ASO pelacarsen that you mentioned, there are several therapeutics in the pipeline, including three small interfering (si) RNAs that are at least in phase 2 and phase 3 testing at this point in time. There’s olpasiran, which in phase 2 testing led to more than a 95% reduction in Lp(a), and then lepodisiran , which has now moved into phase 3  testing, albeit we haven’t seen yet the phase 2  results. 

What is your sense of lepodisiran and its efficacy? 

Nicholls: What’s been really quite striking about the siRNAs is the even more profound degree of lowering of Lp(a) that we’re seeing. We’re seeing 90% and greater lowering of Lp(a) in all of those programs. We’re seeing some differences between the programs in terms of the durability of that effect. 

I think it would be fair to say that with zerlasiran we’re starting to see perhaps that lowering effect starts to taper off a little bit more quickly than the other two. I think that may have some implications in terms of what dosing regimens may look like in the future. 

Even so, we’re talking about therapies that may be dosed 3- to 6-monthly, or even with the potential for being less frequent than that with lepodisiran. Again, I think the phase 2 data will be really important in terms of giving us more information.

O’Donoghue: For the lepodisiran results, I was really quite struck that even though it was small numbers, single dose administered, it really looked like the duration of effect persisted at the higher doses up to about a year. 

Nicholls: It looks pretty promising. We’ve launched the ACCLAIM study, the large cardiovascular outcome trial of lepodisiran, with a 6-monthly regimen. We are hopeful that more information may be able to give us the opportunity for even less frequent administration. 

That has really important implications for patients where adherence is a particular issue. They may just simply want to come into the clinic. You know, once or twice a year, very much like we’re seeing with inclisiran, and that may be a really effective approach for many patients. 

O’Donoghue: You alluded to the zerlasiran results, which were presented here at the American Heart Association meeting, and that even though it led to a robust reduction in Lp(a), it looked like the durability component was maybe a little bit shorter than for some of the other siRNAs that are currently being evaluated.

What’s your sense of that? 

Nicholls: It probably is. The implications clinically, at least in an outcome trial when they ultimately get to that point, probably aren’t that important. They’ll probably just have slightly more frequent administration. That may become a bigger issue when it gets out into the clinic.

The nice thing is that if all of these agents appear to be effective, are well tolerated, and get out to the clinic, then clinicians and patients are going to have a lot of choice. 

O’Donoghue: I think more competition is always good news for the field, ultimately. I think to your point, especially for a drug that might be self-administered, ultimately, whether it’s once a month or once every 3 months, it doesn’t probably make much difference. I think different choices are needed for different patients. 

Perhaps that’s a perfect segue to talk about the oral Lp(a) inhibitor that is also being developed. You presented these results for muvalaplin. 

 

Muvalaplin, an Oral Small Molecule

Nicholls: In terms of frequency of administration, we’re talking about a daily oral therapeutic. For patients who don’t want an injectable and are happy to take a tablet every day, muvalaplin has the potential to be a really good option for them. 

Muvalaplin is an oral small-molecule inhibitor. It essentially prevents apolipoprotein(a) [apo(a)] from binding to apolipoprotein B (apo B). We presented phase 1 data  at the European Society of Cardiology meeting last year, showing probably Lp(a) lowering on the order of about 65%. Here, we’re going to show that that’s a little bit more. It looks like it’s probably at least 70% lowering using a standard Lp(a) assay. Using an assay that looks specifically at intact Lp(a) particles, it’s probably well in excess of 80%.

Those are really good results. The safety and tolerability with muvalaplin look really good. Again, we’ll need to see that agent move forward into a large outcome trial and we’ve yet to hear about that, at least for now. 

O’Donoghue: It’s an interesting challenge that you faced in terms of the assay because, as you say, it really disrupts the apo(a) from binding to the apo B particle, and hence, a traditional assay that just measures apo(a), regardless of whether or not it’s bound to an apo B particle, may be a conservative estimate.

Nicholls: It may, in particular, because we know that apo(a) ultimately then binds to the drug. That assay is measuring what we think is nonfunctional apo(a) in addition to functional apo(a). It’s measuring functional apo(a) that’s still on an actual Lp(a) particle, but if it’s bound to muvalaplin, we think to some degree that’s probably unfair to count that. That’s why trying to develop other assays to try and understand the full effect of the drug is really important in terms of trying to understand how we develop that and move that forward.

O’Donoghue: Is there any evidence yet that the apo(a) particle that is not bound to apo B is in fact nonfunctional as you described it? 

Nicholls: We think that’s likely to be the case, but I think there continues to be research in that space to try and settle that question once and for all. 

O’Donoghue: Again, I think it’s a really exciting time in this field. Right now, we have three ongoing phase 3 trials. We have the pelacarsen trial that is still in follow-up, and fingers crossed, maybe will report out next year. Olpasiran is also in phase 3 testing, completed enrollment, and also is in the follow-up period. We also have lepodisiran, the ACCLAIM trial, as you mentioned. For people who are perhaps watching and looking to enroll their patients, this trial is still ongoing right now in terms of enrollment. 

Nicholls: It is, and what’s nice about the ACCLAIM study is that it includes both primary and secondary prevention patients. For the first time in a big outcome trial, patients with high Lp(a) levels but who have yet to have a clinical event can actually get into a clinical trial.

I’m sure, like you, my clinic is full of patients with high Lp(a) who are really desperate to get into these trials. Many of those primary prevention patients just simply haven’t qualified, so that’s really good news. 

The step beyond that, if we’re talking about even less frequent administration, is gene editing. We’re seeing those studies with CRISPR move forward to try to evaluate whether a single gene-editing approach at Lp(a) will be all that you need, which is even a more amazing concept, but that’s a study that needs more work. 

O’Donoghue: An exciting space though, for sure. As a final thought, you mentioned the patients in your clinic who you have identified as having high Lp(a). What are you doing right now in your practice for managing those patients? I think there are many practitioners out there who struggle with whether they should really measure their patients’ Lp(a), and whether they want to know that information.

Nicholls: Yeah, it’s really hard. The answer is yes, we do want to know it. We know it’s a great risk enhancer. We know that a patient with a high Lp(a) is somebody whom I want to more intensively treat their other risk factors. I’m aiming for a lower LDL. I’m being much tighter with blood pressure control.

I think there’s some argument from observational data at least that aspirin remains a consideration, particularly in patients where you think there’s a particularly high risk associated with that high Lp(a). I think there are things we absolutely can do today, but we can’t do anything if you don’t know the numbers.

It starts with testing, and then we can move on to what we can do today, and then hopefully in the not-too-distant future, we’ll have specific therapies that really enable for us to address Lp(a) quite definitively. 

O’Donoghue: Thanks again for taking the time. This was a very helpful discussion.

 

Michelle O’Donoghue is a cardiologist at Brigham and Women’s Hospital and senior investigator with the TIMI Study Group. A strong believer in evidence-based medicine, she relishes discussions about the published literature. A native Canadian, Michelle loves spending time outdoors with her family but admits with shame that she’s never strapped on hockey skates. Dr O’Donoghue, Senior Investigator, TIMI Study Group; Associate Professor of Medicine, Harvard Medical School; Associate Physician, Brigham and Women’s Hospital, Boston, Massachusetts, disclosed ties to Janssen; Novartis; CVS Minute Clinic; Merck & Co.; GlaxoSmithKline; Eisai Inc.; AstraZeneca Pharmaceuticals LP; Janssen Pharmaceuticals; Medicines Company; and Amgen. The opinions expressed in this article do not necessarily reflect the views and opinions of Brigham and Women’s Hospital. Stephen J. Nicholls, MBBS, PhD, Director, Victorian Heart Institute, Monash University; Director, Victorian Heart Hospital, Monash Health, Melbourne, Australia, has disclosed ties with Akcea Therapeutics; Amgen; AstraZeneca; Boehringer Ingelheim; CSL Behring; Eli Lilly and Company; Esperion Therapeutics; Kowa Pharmaceuticals; Merck; Novo Nordisk; Pfizer; Sanofi Regeneron; Daichii Sankyo; Vaxxinity; Cyclarity; CSL Sequirus; Takeda; Anthera Pharmaceuticals; Cerenis Therapeutics; Infraredx; New Amsterdam Pharma; Novartis; and Resverlogix.

A version of this article appeared on Medscape.com.

An electronic nudge explaining the cardiovascular benefits of the influenza vaccine increased vaccination rates, particularly among people who had previously had a heart attack, showed the NUDGE FLU series of clinical trials.

Influenza has the potential to be a dangerous infection on its own, but it increases the risk for cardiovascular events among people with a history of heart attack, said the study’s lead author, Ankeet Bhatt, MD, a cardiologist at Kaiser Permanente San Francisco Medical Center, San Francisco.

“Yearly influenza vaccines help prevent influenza infection and, in patients with a heart attack, are potentially cardioprotective,” he said during his presentation at the American Heart Association (AHA) Scientific Sessions 2024 in Chicago. The NUDGE FLU results were simultaneously published online in JAMA Cardiology.

In Denmark, where the trials were conducted, about 80% of older adults get flu shots, but only about 40% of younger adults with chronic diseases do, Bhatt reported. In the United States, about 45% of adults and 55% of children received at least one dose of the flu vaccine in the 2023/24 flu season, according to the US Centers for Disease Control and Prevention (CDC).

 

The NUDGE FLU Trials

Bhatt and his colleagues conducted three related clinical trials during the 2022/23 and 2023/24 flu seasons: NUDGE-FLU and NUDGE-FLU-2 targeted older adults, whereas NUDGE-FLU-CHRONIC targeted younger adults with chronic diseases. Nearly 2 million people were involved in the three trials.

Participants were randomized to receive one of a series of different behavioral-science-informed letters, delivered through a government-run electronic communication system, or no reminder.

People who received any of the nudges had higher rates of vaccination; among heart attack survivors, there was a 1.8% improvement and among adults without a history of heart attack, there was a 1.3% improvement. But a nudge that explained the potential cardiovascular benefits of flu shots was even more effective, leading to a 3.9% increase among people with a history of heart attack and a 2% increase among those with no heart attack history.

“A simple sentence resulted in a durable improvement in the vaccination rate,” said Bhatt.

The effect was even greater among those who had not been vaccinated in the previous flu season. Among heart attack survivors, nearly 14% more people got the vaccine compared with just 1.5% more survivors who were previously vaccinated. And it was most effective among younger adults who had experienced a recent heart attack, resulting in a 26% increase.

“The impact was larger in patients with a history of acute myocardial infarction, in those who were vaccine-hesitant, and in younger people” — all groups with the most to gain from vaccination in terms of cardiovascular protection — Bhatt reported.

About 25% of people in the United States are unsure about whether to get a flu shot, said Orly Vardeny, PharmD, professor of medicine at the University of Minnesota Medical School in Minneapolis, who was not involved in the study. The fact that previously unvaccinated people were convinced by the nudges is reassuring. “That’s the group where this intervention is most likely to move the needle,” she said.

Around half of all people hospitalized for flu in the United States have cardiovascular disease, CDC data showed, so “even a small increase in the number of patients who get vaccinated has substantial public health benefits,” Vardeny said.

The NUDGE FLU series showed that nudges like this should be employed as a simple tool to improve vaccination rates, but the system would be much more difficult to implement in the United States, Bhatt said.

Denmark has a national health service and a preexisting government electronic communication system, whereas the US system is privately run and more fractured. It would be possible to make it work, he pointed out, but would take some effort.

A version of this article first appeared on Medscape.com.

An electronic nudge explaining the cardiovascular benefits of the influenza vaccine increased vaccination rates, particularly among people who had previously had a heart attack, showed the NUDGE FLU series of clinical trials.

Influenza has the potential to be a dangerous infection on its own, but it increases the risk for cardiovascular events among people with a history of heart attack, said the study’s lead author, Ankeet Bhatt, MD, a cardiologist at Kaiser Permanente San Francisco Medical Center, San Francisco.

“Yearly influenza vaccines help prevent influenza infection and, in patients with a heart attack, are potentially cardioprotective,” he said during his presentation at the American Heart Association (AHA) Scientific Sessions 2024 in Chicago. The NUDGE FLU results were simultaneously published online in JAMA Cardiology.

In Denmark, where the trials were conducted, about 80% of older adults get flu shots, but only about 40% of younger adults with chronic diseases do, Bhatt reported. In the United States, about 45% of adults and 55% of children received at least one dose of the flu vaccine in the 2023/24 flu season, according to the US Centers for Disease Control and Prevention (CDC).

 

The NUDGE FLU Trials

Bhatt and his colleagues conducted three related clinical trials during the 2022/23 and 2023/24 flu seasons: NUDGE-FLU and NUDGE-FLU-2 targeted older adults, whereas NUDGE-FLU-CHRONIC targeted younger adults with chronic diseases. Nearly 2 million people were involved in the three trials.

Participants were randomized to receive one of a series of different behavioral-science-informed letters, delivered through a government-run electronic communication system, or no reminder.

People who received any of the nudges had higher rates of vaccination; among heart attack survivors, there was a 1.8% improvement and among adults without a history of heart attack, there was a 1.3% improvement. But a nudge that explained the potential cardiovascular benefits of flu shots was even more effective, leading to a 3.9% increase among people with a history of heart attack and a 2% increase among those with no heart attack history.

“A simple sentence resulted in a durable improvement in the vaccination rate,” said Bhatt.

The effect was even greater among those who had not been vaccinated in the previous flu season. Among heart attack survivors, nearly 14% more people got the vaccine compared with just 1.5% more survivors who were previously vaccinated. And it was most effective among younger adults who had experienced a recent heart attack, resulting in a 26% increase.

“The impact was larger in patients with a history of acute myocardial infarction, in those who were vaccine-hesitant, and in younger people” — all groups with the most to gain from vaccination in terms of cardiovascular protection — Bhatt reported.

About 25% of people in the United States are unsure about whether to get a flu shot, said Orly Vardeny, PharmD, professor of medicine at the University of Minnesota Medical School in Minneapolis, who was not involved in the study. The fact that previously unvaccinated people were convinced by the nudges is reassuring. “That’s the group where this intervention is most likely to move the needle,” she said.

Around half of all people hospitalized for flu in the United States have cardiovascular disease, CDC data showed, so “even a small increase in the number of patients who get vaccinated has substantial public health benefits,” Vardeny said.

The NUDGE FLU series showed that nudges like this should be employed as a simple tool to improve vaccination rates, but the system would be much more difficult to implement in the United States, Bhatt said.

Denmark has a national health service and a preexisting government electronic communication system, whereas the US system is privately run and more fractured. It would be possible to make it work, he pointed out, but would take some effort.

A version of this article first appeared on Medscape.com.

An electronic nudge explaining the cardiovascular benefits of the influenza vaccine increased vaccination rates, particularly among people who had previously had a heart attack, showed the NUDGE FLU series of clinical trials.

Influenza has the potential to be a dangerous infection on its own, but it increases the risk for cardiovascular events among people with a history of heart attack, said the study’s lead author, Ankeet Bhatt, MD, a cardiologist at Kaiser Permanente San Francisco Medical Center, San Francisco.

“Yearly influenza vaccines help prevent influenza infection and, in patients with a heart attack, are potentially cardioprotective,” he said during his presentation at the American Heart Association (AHA) Scientific Sessions 2024 in Chicago. The NUDGE FLU results were simultaneously published online in JAMA Cardiology.

In Denmark, where the trials were conducted, about 80% of older adults get flu shots, but only about 40% of younger adults with chronic diseases do, Bhatt reported. In the United States, about 45% of adults and 55% of children received at least one dose of the flu vaccine in the 2023/24 flu season, according to the US Centers for Disease Control and Prevention (CDC).

 

The NUDGE FLU Trials

Bhatt and his colleagues conducted three related clinical trials during the 2022/23 and 2023/24 flu seasons: NUDGE-FLU and NUDGE-FLU-2 targeted older adults, whereas NUDGE-FLU-CHRONIC targeted younger adults with chronic diseases. Nearly 2 million people were involved in the three trials.

Participants were randomized to receive one of a series of different behavioral-science-informed letters, delivered through a government-run electronic communication system, or no reminder.

People who received any of the nudges had higher rates of vaccination; among heart attack survivors, there was a 1.8% improvement and among adults without a history of heart attack, there was a 1.3% improvement. But a nudge that explained the potential cardiovascular benefits of flu shots was even more effective, leading to a 3.9% increase among people with a history of heart attack and a 2% increase among those with no heart attack history.

“A simple sentence resulted in a durable improvement in the vaccination rate,” said Bhatt.

The effect was even greater among those who had not been vaccinated in the previous flu season. Among heart attack survivors, nearly 14% more people got the vaccine compared with just 1.5% more survivors who were previously vaccinated. And it was most effective among younger adults who had experienced a recent heart attack, resulting in a 26% increase.

“The impact was larger in patients with a history of acute myocardial infarction, in those who were vaccine-hesitant, and in younger people” — all groups with the most to gain from vaccination in terms of cardiovascular protection — Bhatt reported.

About 25% of people in the United States are unsure about whether to get a flu shot, said Orly Vardeny, PharmD, professor of medicine at the University of Minnesota Medical School in Minneapolis, who was not involved in the study. The fact that previously unvaccinated people were convinced by the nudges is reassuring. “That’s the group where this intervention is most likely to move the needle,” she said.

Around half of all people hospitalized for flu in the United States have cardiovascular disease, CDC data showed, so “even a small increase in the number of patients who get vaccinated has substantial public health benefits,” Vardeny said.

The NUDGE FLU series showed that nudges like this should be employed as a simple tool to improve vaccination rates, but the system would be much more difficult to implement in the United States, Bhatt said.

Denmark has a national health service and a preexisting government electronic communication system, whereas the US system is privately run and more fractured. It would be possible to make it work, he pointed out, but would take some effort.

A version of this article first appeared on Medscape.com.

New questions about the landmark trial that launched the antiplatelet drug ticagrelor worldwide are being raised after an investigation uncovered more information about how the PLATO study was conducted.

Peter Doshi, PhD, senior editor at The BMJ, obtained primary records for the trial and unpublished data through a Freedom of Information Act request, and has detailed inconsistencies and omissions in data reporting from the 2009 trial originally published in The New England Journal of Medicine (NEJM). The new investigation into the Platelet Inhibition and Patient Outcomes (PLATO) trial is published in The BMJ.

The findings come as generic versions of ticagrelor (Brilinta) are expected to become available soon in the United States. Ticagrelor is the only P2Y12 inhibitor still under patent, and in 2022, the United States spent more than $750 million on it, according to the report.

PLATO, sponsored by ticagrelor manufacturer AstraZeneca, included more than 18,000 patients in 43 countries. Investigators reported that ticagrelor reduced deaths from vascular causes, heart attack, or stroke compared with clopidogrel (Plavix). However, in a subgroup analysis, among US patients, there were more deaths in the ticagrelor group, and AstraZeneca failed its first bid for approval from the US Food and Drug Administration (FDA).

 

Failed First Bid for FDA Approval

AstraZeneca resubmitted its application, which was met with objections by some FDA staff members, including medical officer Thomas Marciniak, who called the resubmission “the worst in my experience regarding completeness of the submissions and the sponsor responding completely and accurately to requests,” Doshi reports.

Despite the objections, the FDA in 2011 approved ticagrelor for acute coronary syndrome, kicking off intense controversy over the trial, as several other studies have failed to replicate PLATO’s positive results.

Doubts have grown about its apparent advantage over cheaper, off-patent P2Y12 inhibitors such as clopidogrel and prasugrel.

“Critics said it was noteworthy that ticagrelor failed in the US,” Doshi writes, “the only high enrolling country where sites were not monitored by the sponsor itself.” Doshi’s report points out that critics of the trial “highlight that AstraZeneca itself carried out the data monitoring for PLATO except for sites that were monitored by third party contract research organizations. In the four countries exclusively monitored by non-sponsor personnel—Georgia, Israel, Russia, and the US—ticagrelor fared worse.”

Victor Serebruany, MD, from Johns Hopkins University, said he was initially impressed by the trial results but became skeptical after noticing inconsistencies and anomalies in the data. He filed a complaint with the US District Court in the District of Columbia, suggesting that the cardiovascular events in the study “may have been manipulated.”

 

US Department of Justice Investigation

The US Department of Justice (DOJ) opened an investigation in 2013 and closed it in 2014 with no further action. Serebruany continues to publish critiques of the trial 15 years later but told The BMJ he has little hope that the questions will be resolved unless the DOJ re-engages with an investigation.

Doshi also points out discrepancies in the data reported. In the 2009 paper, published as an intent-to-treat analysis, investigators said there were 905 total deaths from any cause among all randomized patients. “An internal company report states, however, that 983 patients had died at this point. While 33 deaths occurred after the follow-up period, the NEJM tally still leaves out 45 deaths ‘discovered after withdrawal of consent,’” he reports.

The NEJM responded to Doshi that while it didn’t dispute the error in the number of deaths, it was uncertain about publishing a correction, citing new — not yet published — guidelines from the International Committee of Medical Journal Editors. NEJM Editor-in-Chief Eric Rubin told The BMJ that “for older manuscripts, correction is not necessarily appropriate unless there would be an effect on clinical practice.”

Doshi’s investigation includes an interview with Eric Bates, MD, professor of internal medicine at the University of Michigan in Ann Arbor, and a co-author of the US guidelines that recommend ticagrelor, who said he was “increasingly disturbed by how trial after trial came out as being not dramatically positive in any way.” Bates is now calling for a review of ticagrelor’s recommendation in guidelines, according to the report.

AstraZeneca declined to be interviewed for the BMJ investigation, according to Doshi, and a spokesperson from the company told the journal by email that they have “nothing to add,” directing editors to its 2014 public statement after the DOJ’s investigation into PLATO. The BMJ said PLATO trial co-chairs Robert A. Harrington, MD, and Lars Wallentin, MD, did not respond to The BMJ’s requests for comment.

 

Will the Guidelines Be Changed Now?

“I know and have worked with Drs Wallentin and Harrington,” Bates told Medscape Medical News, “and find them to be honest, intelligent clinical scientists with the highest ethical standards who manage conflicts of interest as well as can be done in the clinical research arena, where industry support is required to develop new knowledge,” he said.

“If there is a concern that AstraZeneca was manipulating the dataset and FDA submission, that is an important issue,” Bates said. “The US paradox and the failure of any other antiplatelet trial to find a comparative mortality advantage are two unexplained issues with PLATO that provide good fodder for conspiracy theories. I agree with the NEJM that this trial is 15 years old and may not be worth readjudicating in the current treatment era.”

Other calls for revisiting guidelines have come after disappointing postlicensure studies have repeatedly demonstrated that ticagrelor has “similar efficacy to clopidogrel but with increased bleeding and [dyspnea],” Doshi reports.

“My concern is the marketing spin by AstraZeneca and the promotion of ticagrelor by six to eight ‘thought leaders’ consistently funded by AstraZeneca over the past 10 years,” said Bates. “They have flooded the literature with supportive subset and post hoc analyses, review articles, and ‘meta-analyses’ flawed by selection and intellectual bias, and public interviews that consistently discount the findings of the many subsequent randomized controlled trials that have not supported the superiority of ticagrelor over clopidogrel or prasugrel.”

A version of this article first appeared on Medscape.com.

New questions about the landmark trial that launched the antiplatelet drug ticagrelor worldwide are being raised after an investigation uncovered more information about how the PLATO study was conducted.

Peter Doshi, PhD, senior editor at The BMJ, obtained primary records for the trial and unpublished data through a Freedom of Information Act request, and has detailed inconsistencies and omissions in data reporting from the 2009 trial originally published in The New England Journal of Medicine (NEJM). The new investigation into the Platelet Inhibition and Patient Outcomes (PLATO) trial is published in The BMJ.

The findings come as generic versions of ticagrelor (Brilinta) are expected to become available soon in the United States. Ticagrelor is the only P2Y12 inhibitor still under patent, and in 2022, the United States spent more than $750 million on it, according to the report.

PLATO, sponsored by ticagrelor manufacturer AstraZeneca, included more than 18,000 patients in 43 countries. Investigators reported that ticagrelor reduced deaths from vascular causes, heart attack, or stroke compared with clopidogrel (Plavix). However, in a subgroup analysis, among US patients, there were more deaths in the ticagrelor group, and AstraZeneca failed its first bid for approval from the US Food and Drug Administration (FDA).

 

Failed First Bid for FDA Approval

AstraZeneca resubmitted its application, which was met with objections by some FDA staff members, including medical officer Thomas Marciniak, who called the resubmission “the worst in my experience regarding completeness of the submissions and the sponsor responding completely and accurately to requests,” Doshi reports.

Despite the objections, the FDA in 2011 approved ticagrelor for acute coronary syndrome, kicking off intense controversy over the trial, as several other studies have failed to replicate PLATO’s positive results.

Doubts have grown about its apparent advantage over cheaper, off-patent P2Y12 inhibitors such as clopidogrel and prasugrel.

“Critics said it was noteworthy that ticagrelor failed in the US,” Doshi writes, “the only high enrolling country where sites were not monitored by the sponsor itself.” Doshi’s report points out that critics of the trial “highlight that AstraZeneca itself carried out the data monitoring for PLATO except for sites that were monitored by third party contract research organizations. In the four countries exclusively monitored by non-sponsor personnel—Georgia, Israel, Russia, and the US—ticagrelor fared worse.”

Victor Serebruany, MD, from Johns Hopkins University, said he was initially impressed by the trial results but became skeptical after noticing inconsistencies and anomalies in the data. He filed a complaint with the US District Court in the District of Columbia, suggesting that the cardiovascular events in the study “may have been manipulated.”

 

US Department of Justice Investigation

The US Department of Justice (DOJ) opened an investigation in 2013 and closed it in 2014 with no further action. Serebruany continues to publish critiques of the trial 15 years later but told The BMJ he has little hope that the questions will be resolved unless the DOJ re-engages with an investigation.

Doshi also points out discrepancies in the data reported. In the 2009 paper, published as an intent-to-treat analysis, investigators said there were 905 total deaths from any cause among all randomized patients. “An internal company report states, however, that 983 patients had died at this point. While 33 deaths occurred after the follow-up period, the NEJM tally still leaves out 45 deaths ‘discovered after withdrawal of consent,’” he reports.

The NEJM responded to Doshi that while it didn’t dispute the error in the number of deaths, it was uncertain about publishing a correction, citing new — not yet published — guidelines from the International Committee of Medical Journal Editors. NEJM Editor-in-Chief Eric Rubin told The BMJ that “for older manuscripts, correction is not necessarily appropriate unless there would be an effect on clinical practice.”

Doshi’s investigation includes an interview with Eric Bates, MD, professor of internal medicine at the University of Michigan in Ann Arbor, and a co-author of the US guidelines that recommend ticagrelor, who said he was “increasingly disturbed by how trial after trial came out as being not dramatically positive in any way.” Bates is now calling for a review of ticagrelor’s recommendation in guidelines, according to the report.

AstraZeneca declined to be interviewed for the BMJ investigation, according to Doshi, and a spokesperson from the company told the journal by email that they have “nothing to add,” directing editors to its 2014 public statement after the DOJ’s investigation into PLATO. The BMJ said PLATO trial co-chairs Robert A. Harrington, MD, and Lars Wallentin, MD, did not respond to The BMJ’s requests for comment.

 

Will the Guidelines Be Changed Now?

“I know and have worked with Drs Wallentin and Harrington,” Bates told Medscape Medical News, “and find them to be honest, intelligent clinical scientists with the highest ethical standards who manage conflicts of interest as well as can be done in the clinical research arena, where industry support is required to develop new knowledge,” he said.

“If there is a concern that AstraZeneca was manipulating the dataset and FDA submission, that is an important issue,” Bates said. “The US paradox and the failure of any other antiplatelet trial to find a comparative mortality advantage are two unexplained issues with PLATO that provide good fodder for conspiracy theories. I agree with the NEJM that this trial is 15 years old and may not be worth readjudicating in the current treatment era.”

Other calls for revisiting guidelines have come after disappointing postlicensure studies have repeatedly demonstrated that ticagrelor has “similar efficacy to clopidogrel but with increased bleeding and [dyspnea],” Doshi reports.

“My concern is the marketing spin by AstraZeneca and the promotion of ticagrelor by six to eight ‘thought leaders’ consistently funded by AstraZeneca over the past 10 years,” said Bates. “They have flooded the literature with supportive subset and post hoc analyses, review articles, and ‘meta-analyses’ flawed by selection and intellectual bias, and public interviews that consistently discount the findings of the many subsequent randomized controlled trials that have not supported the superiority of ticagrelor over clopidogrel or prasugrel.”

A version of this article first appeared on Medscape.com.

New questions about the landmark trial that launched the antiplatelet drug ticagrelor worldwide are being raised after an investigation uncovered more information about how the PLATO study was conducted.

Peter Doshi, PhD, senior editor at The BMJ, obtained primary records for the trial and unpublished data through a Freedom of Information Act request, and has detailed inconsistencies and omissions in data reporting from the 2009 trial originally published in The New England Journal of Medicine (NEJM). The new investigation into the Platelet Inhibition and Patient Outcomes (PLATO) trial is published in The BMJ.

The findings come as generic versions of ticagrelor (Brilinta) are expected to become available soon in the United States. Ticagrelor is the only P2Y12 inhibitor still under patent, and in 2022, the United States spent more than $750 million on it, according to the report.

PLATO, sponsored by ticagrelor manufacturer AstraZeneca, included more than 18,000 patients in 43 countries. Investigators reported that ticagrelor reduced deaths from vascular causes, heart attack, or stroke compared with clopidogrel (Plavix). However, in a subgroup analysis, among US patients, there were more deaths in the ticagrelor group, and AstraZeneca failed its first bid for approval from the US Food and Drug Administration (FDA).

 

Failed First Bid for FDA Approval

AstraZeneca resubmitted its application, which was met with objections by some FDA staff members, including medical officer Thomas Marciniak, who called the resubmission “the worst in my experience regarding completeness of the submissions and the sponsor responding completely and accurately to requests,” Doshi reports.

Despite the objections, the FDA in 2011 approved ticagrelor for acute coronary syndrome, kicking off intense controversy over the trial, as several other studies have failed to replicate PLATO’s positive results.

Doubts have grown about its apparent advantage over cheaper, off-patent P2Y12 inhibitors such as clopidogrel and prasugrel.

“Critics said it was noteworthy that ticagrelor failed in the US,” Doshi writes, “the only high enrolling country where sites were not monitored by the sponsor itself.” Doshi’s report points out that critics of the trial “highlight that AstraZeneca itself carried out the data monitoring for PLATO except for sites that were monitored by third party contract research organizations. In the four countries exclusively monitored by non-sponsor personnel—Georgia, Israel, Russia, and the US—ticagrelor fared worse.”

Victor Serebruany, MD, from Johns Hopkins University, said he was initially impressed by the trial results but became skeptical after noticing inconsistencies and anomalies in the data. He filed a complaint with the US District Court in the District of Columbia, suggesting that the cardiovascular events in the study “may have been manipulated.”

 

US Department of Justice Investigation

The US Department of Justice (DOJ) opened an investigation in 2013 and closed it in 2014 with no further action. Serebruany continues to publish critiques of the trial 15 years later but told The BMJ he has little hope that the questions will be resolved unless the DOJ re-engages with an investigation.

Doshi also points out discrepancies in the data reported. In the 2009 paper, published as an intent-to-treat analysis, investigators said there were 905 total deaths from any cause among all randomized patients. “An internal company report states, however, that 983 patients had died at this point. While 33 deaths occurred after the follow-up period, the NEJM tally still leaves out 45 deaths ‘discovered after withdrawal of consent,’” he reports.

The NEJM responded to Doshi that while it didn’t dispute the error in the number of deaths, it was uncertain about publishing a correction, citing new — not yet published — guidelines from the International Committee of Medical Journal Editors. NEJM Editor-in-Chief Eric Rubin told The BMJ that “for older manuscripts, correction is not necessarily appropriate unless there would be an effect on clinical practice.”

Doshi’s investigation includes an interview with Eric Bates, MD, professor of internal medicine at the University of Michigan in Ann Arbor, and a co-author of the US guidelines that recommend ticagrelor, who said he was “increasingly disturbed by how trial after trial came out as being not dramatically positive in any way.” Bates is now calling for a review of ticagrelor’s recommendation in guidelines, according to the report.

AstraZeneca declined to be interviewed for the BMJ investigation, according to Doshi, and a spokesperson from the company told the journal by email that they have “nothing to add,” directing editors to its 2014 public statement after the DOJ’s investigation into PLATO. The BMJ said PLATO trial co-chairs Robert A. Harrington, MD, and Lars Wallentin, MD, did not respond to The BMJ’s requests for comment.

 

Will the Guidelines Be Changed Now?

“I know and have worked with Drs Wallentin and Harrington,” Bates told Medscape Medical News, “and find them to be honest, intelligent clinical scientists with the highest ethical standards who manage conflicts of interest as well as can be done in the clinical research arena, where industry support is required to develop new knowledge,” he said.

“If there is a concern that AstraZeneca was manipulating the dataset and FDA submission, that is an important issue,” Bates said. “The US paradox and the failure of any other antiplatelet trial to find a comparative mortality advantage are two unexplained issues with PLATO that provide good fodder for conspiracy theories. I agree with the NEJM that this trial is 15 years old and may not be worth readjudicating in the current treatment era.”

Other calls for revisiting guidelines have come after disappointing postlicensure studies have repeatedly demonstrated that ticagrelor has “similar efficacy to clopidogrel but with increased bleeding and [dyspnea],” Doshi reports.

“My concern is the marketing spin by AstraZeneca and the promotion of ticagrelor by six to eight ‘thought leaders’ consistently funded by AstraZeneca over the past 10 years,” said Bates. “They have flooded the literature with supportive subset and post hoc analyses, review articles, and ‘meta-analyses’ flawed by selection and intellectual bias, and public interviews that consistently discount the findings of the many subsequent randomized controlled trials that have not supported the superiority of ticagrelor over clopidogrel or prasugrel.”

A version of this article first appeared on Medscape.com.

TOPLINE:

Elevated levels of N-terminal pro–B-type natriuretic peptide (NT-proBNP), a key biomarker for diagnosing heart failure, show a nearly fourfold increased risk for atrial fibrillation (AF) in at-risk individuals. The utility of this biomarker was particularly evident in older adults and when serum-based measurements were used.

METHODOLOGY:

• Researchers conducted a meta-analysis of prospective cohort, case-cohort, or nested case-control studies to examine the association between NT-proBNP and the incidence of AF.
• They also explored the potential of NT-proBNP in improving risk prediction models for AF.
• Overall, 136,089 adults were included from 16 cohorts, and 8017 cases of incident AF were reported over a median follow-up of 4-20 years.
• Most of the included cohorts were from Europe (n = 12), followed by America (n = 3) and Asia (n = 1).
• The accuracy of the risk prediction models was evaluated using C-indexes, with values in the range of 0.50-0.70, low accuracy; 0.70-0.90, moderate accuracy; and > 0.90, high accuracy.

TAKEAWAY:

• Elevated NT-proBNP levels showed a strong association with the risk for AF, with individuals in the highest quintile of NT-proBNP facing a 3.84-fold higher risk for incident AF (pooled relative risk [RR], 3.84; 95% CI, 3.03-4.87) than those in the lowest quintile.
• The risk increased by 9% for each 10 pg/mL increase in NT-proBNP (RR, 1.09; 95% CI, 1.04-1.14), with a significant nonlinear dose-response association found between NT-proBNP and the risk for AF (P for nonlinearity < .001).
• The association was stronger in the subgroups of older adults and when the biomarker was measured in serum samples.
• The addition of NT-proBNP to traditional risk prediction models for AF may improve predictive accuracy, with the ΔC-indexes ranging from 0.010 to 0.060.

IN PRACTICE:

“The significance of NT-proBNP in enhancing AF risk stratification deserves greater attention, with potential expansion to routine health screening,” the authors wrote.

SOURCE:

The study was led by Wanyue Wang, Department of Epidemiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China, and was published online on December 06, 2024, in Heart.

LIMITATIONS:

Significant heterogeneity was observed in this meta-analysis, with the subgroup articles only providing exploratory and indicative findings. Due to the observational nature of this study, residual confounding could not be excluded. None of the prospective studies included differentiated subtypes of AF, such as paroxysmal and asymptomatic forms, which might have influenced the observed outcomes.

DISCLOSURES:

This study was supported by grants from the National Key Research and Development Program of China, Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, National Natural Science Foundation of China, and National High Level Hospital Clinical Research Funding. The authors declared no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Elevated levels of N-terminal pro–B-type natriuretic peptide (NT-proBNP), a key biomarker for diagnosing heart failure, show a nearly fourfold increased risk for atrial fibrillation (AF) in at-risk individuals. The utility of this biomarker was particularly evident in older adults and when serum-based measurements were used.

METHODOLOGY:

• Researchers conducted a meta-analysis of prospective cohort, case-cohort, or nested case-control studies to examine the association between NT-proBNP and the incidence of AF.
• They also explored the potential of NT-proBNP in improving risk prediction models for AF.
• Overall, 136,089 adults were included from 16 cohorts, and 8017 cases of incident AF were reported over a median follow-up of 4-20 years.
• Most of the included cohorts were from Europe (n = 12), followed by America (n = 3) and Asia (n = 1).
• The accuracy of the risk prediction models was evaluated using C-indexes, with values in the range of 0.50-0.70, low accuracy; 0.70-0.90, moderate accuracy; and > 0.90, high accuracy.

TAKEAWAY:

• Elevated NT-proBNP levels showed a strong association with the risk for AF, with individuals in the highest quintile of NT-proBNP facing a 3.84-fold higher risk for incident AF (pooled relative risk [RR], 3.84; 95% CI, 3.03-4.87) than those in the lowest quintile.
• The risk increased by 9% for each 10 pg/mL increase in NT-proBNP (RR, 1.09; 95% CI, 1.04-1.14), with a significant nonlinear dose-response association found between NT-proBNP and the risk for AF (P for nonlinearity < .001).
• The association was stronger in the subgroups of older adults and when the biomarker was measured in serum samples.
• The addition of NT-proBNP to traditional risk prediction models for AF may improve predictive accuracy, with the ΔC-indexes ranging from 0.010 to 0.060.

IN PRACTICE:

“The significance of NT-proBNP in enhancing AF risk stratification deserves greater attention, with potential expansion to routine health screening,” the authors wrote.

SOURCE:

The study was led by Wanyue Wang, Department of Epidemiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China, and was published online on December 06, 2024, in Heart.

LIMITATIONS:

Significant heterogeneity was observed in this meta-analysis, with the subgroup articles only providing exploratory and indicative findings. Due to the observational nature of this study, residual confounding could not be excluded. None of the prospective studies included differentiated subtypes of AF, such as paroxysmal and asymptomatic forms, which might have influenced the observed outcomes.

DISCLOSURES:

This study was supported by grants from the National Key Research and Development Program of China, Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, National Natural Science Foundation of China, and National High Level Hospital Clinical Research Funding. The authors declared no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Elevated levels of N-terminal pro–B-type natriuretic peptide (NT-proBNP), a key biomarker for diagnosing heart failure, show a nearly fourfold increased risk for atrial fibrillation (AF) in at-risk individuals. The utility of this biomarker was particularly evident in older adults and when serum-based measurements were used.

METHODOLOGY:

• Researchers conducted a meta-analysis of prospective cohort, case-cohort, or nested case-control studies to examine the association between NT-proBNP and the incidence of AF.
• They also explored the potential of NT-proBNP in improving risk prediction models for AF.
• Overall, 136,089 adults were included from 16 cohorts, and 8017 cases of incident AF were reported over a median follow-up of 4-20 years.
• Most of the included cohorts were from Europe (n = 12), followed by America (n = 3) and Asia (n = 1).
• The accuracy of the risk prediction models was evaluated using C-indexes, with values in the range of 0.50-0.70, low accuracy; 0.70-0.90, moderate accuracy; and > 0.90, high accuracy.

TAKEAWAY:

• Elevated NT-proBNP levels showed a strong association with the risk for AF, with individuals in the highest quintile of NT-proBNP facing a 3.84-fold higher risk for incident AF (pooled relative risk [RR], 3.84; 95% CI, 3.03-4.87) than those in the lowest quintile.
• The risk increased by 9% for each 10 pg/mL increase in NT-proBNP (RR, 1.09; 95% CI, 1.04-1.14), with a significant nonlinear dose-response association found between NT-proBNP and the risk for AF (P for nonlinearity < .001).
• The association was stronger in the subgroups of older adults and when the biomarker was measured in serum samples.
• The addition of NT-proBNP to traditional risk prediction models for AF may improve predictive accuracy, with the ΔC-indexes ranging from 0.010 to 0.060.

IN PRACTICE:

“The significance of NT-proBNP in enhancing AF risk stratification deserves greater attention, with potential expansion to routine health screening,” the authors wrote.

SOURCE:

The study was led by Wanyue Wang, Department of Epidemiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China, and was published online on December 06, 2024, in Heart.

LIMITATIONS:

Significant heterogeneity was observed in this meta-analysis, with the subgroup articles only providing exploratory and indicative findings. Due to the observational nature of this study, residual confounding could not be excluded. None of the prospective studies included differentiated subtypes of AF, such as paroxysmal and asymptomatic forms, which might have influenced the observed outcomes.

DISCLOSURES:

This study was supported by grants from the National Key Research and Development Program of China, Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, National Natural Science Foundation of China, and National High Level Hospital Clinical Research Funding. The authors declared no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

The question may seem simple: Could paying for weight loss medications — especially the pricey glucagon-like peptide 1 receptor agonists (GLP-1s), tirzepatide (Zepbound) and semaglutide (Wegovy) — be more cost-effective than paying for obesity care and the complications of obesity, such as cardiovascular disease and diabetes?

It’s a question that’s getting an increased amount of attention.

And for good reason — more than two in five US adults have obesity, according to the Centers for Disease Control and Prevention, and costs to treat obesity, in 2019 dollars, approached $173 billion, including productivity losses. Adults with obesity have annual healthcare costs of $1861 more than those at healthier weights.

Among recent developments:

• A proposed new rule, announced on November 26 by the Biden administration, expands coverage of anti-obesity medication for Americans who have Medicare and Medicaid. If it takes effect, an estimated 3.4 million Medicare recipients and about 4 million adult Medicaid enrollees could get access to the medications.
• As Medicare coverage goes, private insurers often follow. Observers predict that if the Centers for Medicare & Medicaid Services (CMS) covers anti-obesity drugs, more private employers may soon do the same. Recently, however, some private plans have done the opposite and dropped coverage of the pricey GLP-1s, which can cost $1000 a month or more out-of-pocket, citing excess costs for their company.
• Among the analyses about the value of weight loss on healthcare cost savings is a report published on December 5 in JAMA Network Open. Emory University experts looked at privately insured adults and adult Medicare beneficiaries with a body mass index (BMI) of ≥ 25 (classified as overweight). The conclusion: Projected annual savings from weight loss among US adults with obesity were substantial for both employee-based insurance and Medicare recipients.
• Besides helping obesity and obesity-related conditions, access to GLP-1s could have a favorable effect on productivity, others claim. That’s one focus of a 5-year partnership between the University of Manchester in England, and Eli Lilly and Company. Called SURMOUNT-REAL UK, the study will evaluate the effectiveness of tirzepatide in weight loss, diabetes prevention, and prevention of obesity-related complications in adults with obesity. It also aims to look at changes in health-related quality of life with weight loss and with changes in employment status and sick days.

CMS Proposal

In a statement announcing the proposal for Medicare and Medicaid to offer weight loss drugs, the White House noted that “tens of millions of Americans struggle with obesity” but that currently Medicare only covers the anti-obesity medications for certain conditions such as diabetes. The new proposal would expand that access to those with obesity. As of August, just 13 states cover GLP-1s in Medicaid programs, and North Carolina was the latest to do so.

Organizations advocating for health equity and recognition that obesity is a chronic disease came out in strong support of the proposal.

Kenneth E. Thorpe, PhD, a health policy expert at Emory University in Atlanta, who coauthored the recent analysis finding that weight loss offsets healthcare costs on an individual basis, told this news organization: “If finalized, this broad new coverage [by Medicare and Medicaid] would have a profound impact on the ability of Americans to access these novel medications that could significantly reduce obesity-related healthcare spending and improve overall health.”

The proposal “is modernizing the coverage of Medicare and Medicaid for obesity treatment,” agreed John Cawley, PhD, professor of economics and public policy at Cornell University in Ithaca, New York, who has researched the direct medical costs of obesity in the United States. “In this HHS rule, they talk about the scientific and medical consensus that having obesity is a chronic condition.”

The proposal requires a 60-day comment period that ends January 27, 2025, taking the timeline into the beginning of the Trump administration. Cawley and others pointed out that Trump’s pick for Health and Human Services Secretary, Robert F. Kennedy Jr, has been an outspoken opponent of the anti-obesity medicines, suggesting instead that Americans simply eat better.

 

Expert Analyses: Emory, Cornell, Southern California

So would paying for the pricey GLP-1s be smart in the long term? Analyses don’t agree.

Weight loss among those with obesity produces healthcare cost savings, said Thorpe and Peter Joski, MSPH, an associate research professor at Emory University. The two compared annual healthcare spending among privately insured adults and adult Medicare beneficiaries with a BMI of ≥ 25, using data from the Medical Expenditure Panel Survey — Household Component from April 1 to June 20, 2024.

The researchers looked at 3774 adults insured with Medicare and 13,435 with employer-sponsored insurance. Overall, those with private insurance with a weight loss of 5% spent an estimated average of $670 less on healthcare. Those with a weight loss of 25% spent an estimated $2849 less on healthcare. Among those with Medicare who had one or more comorbidities, a 5% weight loss reduced spending by $1262 on average; a 25% loss reduced it by an estimated $5442, or 31%.

Thorpe called the savings substantial. In an email interview, Thorpe said, “So yes, weight loss for people living with obesity does lower healthcare costs, as my research shows, but it also lowers other costs as well.”

These include costs associated with disability, workers’ compensation, presenteeism/absenteeism, and everyday costs, he said. He contends that “those other costs should factor into decisions about preventing and treating obesity of payors and policymakers and enhance the case for cost-effectiveness of treating obesity.”

Other research suggests it’s important to target the use of the anti-obesity medications to the BMI range that would get the most benefit. For people just barely above the BMI threshold of 30, no cost savings are expected, Cawley found in his research. But he has found substantial cost reduction if the BMI was 35-40.

However, as Cawley pointed out, as the drugs get cheaper and more options become available, the entire scenario is expected to shift.

 

The Congressional Budget Office View

In October, the nonpartisan Congressional Budget Office issued a report, “How Would Authorizing Medicare to Cover Anti-Obesity Medications Affect the Federal Budget?” Among the conclusions: Covering the anti-obesity medications would increase federal spending, on net, by about $35 billion from 2026 to 2034. Total direct federal costs of covering the medication would increase from $1.6 billion in 2026 to $7.1 billion in 2034. And it said total savings from improved health of the beneficiaries would be small, less than $50 million in 2026 and rising to $1 billion in 2034.

Covering the medications would cost $5600 per user in 2026, then down to $4300 in 2034. The offset of savings per user would be about $50 in 2026, then $650 in 2034.

 

Expert Analysis: USC Schaeffer Center

“The costs offsets come over time,” said Alison Sexton Ward, PhD, an economist at the University of Southern California’s Leonard D. Schaeffer Center, Los Angeles, and an expert on the topic. “If we look at the average annual medical cost over a lifetime, we do see cost offsets there.”

However, treating obesity means people will live longer, “and living longer costs more,” she said.

She took issue with some of the calculations in the CBO report, such as not considering the effect of semaglutide’s patent expiring in 2033.

In a white paper published in April 2023, Sexton Ward and her coauthors modeled potential social benefits and medical cost offsets from granting access to the newer weight loss drugs. The cumulative social benefits of providing coverage over the next decade would reach nearly $1 trillion, they said. Benefits would increase if private insurance expanded coverage. “In the first 10 years alone, covering weight loss therapies would save Medicare $175 billion-$245 billion, depending on whether private insurance joins Medicare in providing coverage for younger populations.”

While much focus is on Medicare coverage, Sexton Ward and others pointed out the need to expand coverage to younger ages, with the aim of preventing or delaying obesity-related complications.

 

Lilly UK Trial

A spokesperson for Lilly declined to comment further on the UK study, explaining that the study was just launching.

Besides tracking weight loss, researchers will evaluate the effect of the weight loss on sick days from work and employment. Obesity is shown to affect a person’s ability to work, leading to more absenteeism, so treating the obesity may improve productivity.

 

Beyond Health: The Value of Weight Loss

“I love the idea of studying whether access to obesity medications helps people stay employed and do their job,” said Cristy Gallagher, associate director of Research and Policy at STOP Obesity Alliance at the Milken Institute School of Public Health, George Washington University, Washington, DC. The alliance includes more than 50 organizations advocating for adult obesity treatment.

“One of our big arguments is [that] access to care, and to obesity care, will also help other conditions — comorbidities like heart disease and diabetes.”

However, access to the anti-obesity medications, by itself, is not enough, Gallagher said. Other components, such as intensive behavioral therapy and guidance about diet and exercise, are needed, she said. So, too, for those who need it, is access to bariatric surgery, she said. And medication access should include other options besides the GLP-1s, she said. “Not every medication is right for everybody.”

Cawley, Gallagher, Thorpe, and Sexton Ward had no disclosures.
 

A version of this article appeared on Medscape.com.

The question may seem simple: Could paying for weight loss medications — especially the pricey glucagon-like peptide 1 receptor agonists (GLP-1s), tirzepatide (Zepbound) and semaglutide (Wegovy) — be more cost-effective than paying for obesity care and the complications of obesity, such as cardiovascular disease and diabetes?

It’s a question that’s getting an increased amount of attention.

And for good reason — more than two in five US adults have obesity, according to the Centers for Disease Control and Prevention, and costs to treat obesity, in 2019 dollars, approached $173 billion, including productivity losses. Adults with obesity have annual healthcare costs of $1861 more than those at healthier weights.

Among recent developments:

• A proposed new rule, announced on November 26 by the Biden administration, expands coverage of anti-obesity medication for Americans who have Medicare and Medicaid. If it takes effect, an estimated 3.4 million Medicare recipients and about 4 million adult Medicaid enrollees could get access to the medications.
• As Medicare coverage goes, private insurers often follow. Observers predict that if the Centers for Medicare & Medicaid Services (CMS) covers anti-obesity drugs, more private employers may soon do the same. Recently, however, some private plans have done the opposite and dropped coverage of the pricey GLP-1s, which can cost $1000 a month or more out-of-pocket, citing excess costs for their company.
• Among the analyses about the value of weight loss on healthcare cost savings is a report published on December 5 in JAMA Network Open. Emory University experts looked at privately insured adults and adult Medicare beneficiaries with a body mass index (BMI) of ≥ 25 (classified as overweight). The conclusion: Projected annual savings from weight loss among US adults with obesity were substantial for both employee-based insurance and Medicare recipients.
• Besides helping obesity and obesity-related conditions, access to GLP-1s could have a favorable effect on productivity, others claim. That’s one focus of a 5-year partnership between the University of Manchester in England, and Eli Lilly and Company. Called SURMOUNT-REAL UK, the study will evaluate the effectiveness of tirzepatide in weight loss, diabetes prevention, and prevention of obesity-related complications in adults with obesity. It also aims to look at changes in health-related quality of life with weight loss and with changes in employment status and sick days.

CMS Proposal

In a statement announcing the proposal for Medicare and Medicaid to offer weight loss drugs, the White House noted that “tens of millions of Americans struggle with obesity” but that currently Medicare only covers the anti-obesity medications for certain conditions such as diabetes. The new proposal would expand that access to those with obesity. As of August, just 13 states cover GLP-1s in Medicaid programs, and North Carolina was the latest to do so.

Organizations advocating for health equity and recognition that obesity is a chronic disease came out in strong support of the proposal.

Kenneth E. Thorpe, PhD, a health policy expert at Emory University in Atlanta, who coauthored the recent analysis finding that weight loss offsets healthcare costs on an individual basis, told this news organization: “If finalized, this broad new coverage [by Medicare and Medicaid] would have a profound impact on the ability of Americans to access these novel medications that could significantly reduce obesity-related healthcare spending and improve overall health.”

The proposal “is modernizing the coverage of Medicare and Medicaid for obesity treatment,” agreed John Cawley, PhD, professor of economics and public policy at Cornell University in Ithaca, New York, who has researched the direct medical costs of obesity in the United States. “In this HHS rule, they talk about the scientific and medical consensus that having obesity is a chronic condition.”

The proposal requires a 60-day comment period that ends January 27, 2025, taking the timeline into the beginning of the Trump administration. Cawley and others pointed out that Trump’s pick for Health and Human Services Secretary, Robert F. Kennedy Jr, has been an outspoken opponent of the anti-obesity medicines, suggesting instead that Americans simply eat better.

 

Expert Analyses: Emory, Cornell, Southern California

So would paying for the pricey GLP-1s be smart in the long term? Analyses don’t agree.

Weight loss among those with obesity produces healthcare cost savings, said Thorpe and Peter Joski, MSPH, an associate research professor at Emory University. The two compared annual healthcare spending among privately insured adults and adult Medicare beneficiaries with a BMI of ≥ 25, using data from the Medical Expenditure Panel Survey — Household Component from April 1 to June 20, 2024.

The researchers looked at 3774 adults insured with Medicare and 13,435 with employer-sponsored insurance. Overall, those with private insurance with a weight loss of 5% spent an estimated average of $670 less on healthcare. Those with a weight loss of 25% spent an estimated $2849 less on healthcare. Among those with Medicare who had one or more comorbidities, a 5% weight loss reduced spending by $1262 on average; a 25% loss reduced it by an estimated $5442, or 31%.

Thorpe called the savings substantial. In an email interview, Thorpe said, “So yes, weight loss for people living with obesity does lower healthcare costs, as my research shows, but it also lowers other costs as well.”

These include costs associated with disability, workers’ compensation, presenteeism/absenteeism, and everyday costs, he said. He contends that “those other costs should factor into decisions about preventing and treating obesity of payors and policymakers and enhance the case for cost-effectiveness of treating obesity.”

Other research suggests it’s important to target the use of the anti-obesity medications to the BMI range that would get the most benefit. For people just barely above the BMI threshold of 30, no cost savings are expected, Cawley found in his research. But he has found substantial cost reduction if the BMI was 35-40.

However, as Cawley pointed out, as the drugs get cheaper and more options become available, the entire scenario is expected to shift.

 

The Congressional Budget Office View

In October, the nonpartisan Congressional Budget Office issued a report, “How Would Authorizing Medicare to Cover Anti-Obesity Medications Affect the Federal Budget?” Among the conclusions: Covering the anti-obesity medications would increase federal spending, on net, by about $35 billion from 2026 to 2034. Total direct federal costs of covering the medication would increase from $1.6 billion in 2026 to $7.1 billion in 2034. And it said total savings from improved health of the beneficiaries would be small, less than $50 million in 2026 and rising to $1 billion in 2034.

Covering the medications would cost $5600 per user in 2026, then down to $4300 in 2034. The offset of savings per user would be about $50 in 2026, then $650 in 2034.

 

Expert Analysis: USC Schaeffer Center

“The costs offsets come over time,” said Alison Sexton Ward, PhD, an economist at the University of Southern California’s Leonard D. Schaeffer Center, Los Angeles, and an expert on the topic. “If we look at the average annual medical cost over a lifetime, we do see cost offsets there.”

However, treating obesity means people will live longer, “and living longer costs more,” she said.

She took issue with some of the calculations in the CBO report, such as not considering the effect of semaglutide’s patent expiring in 2033.

In a white paper published in April 2023, Sexton Ward and her coauthors modeled potential social benefits and medical cost offsets from granting access to the newer weight loss drugs. The cumulative social benefits of providing coverage over the next decade would reach nearly $1 trillion, they said. Benefits would increase if private insurance expanded coverage. “In the first 10 years alone, covering weight loss therapies would save Medicare $175 billion-$245 billion, depending on whether private insurance joins Medicare in providing coverage for younger populations.”

While much focus is on Medicare coverage, Sexton Ward and others pointed out the need to expand coverage to younger ages, with the aim of preventing or delaying obesity-related complications.

 

Lilly UK Trial

A spokesperson for Lilly declined to comment further on the UK study, explaining that the study was just launching.

Besides tracking weight loss, researchers will evaluate the effect of the weight loss on sick days from work and employment. Obesity is shown to affect a person’s ability to work, leading to more absenteeism, so treating the obesity may improve productivity.

 

Beyond Health: The Value of Weight Loss

“I love the idea of studying whether access to obesity medications helps people stay employed and do their job,” said Cristy Gallagher, associate director of Research and Policy at STOP Obesity Alliance at the Milken Institute School of Public Health, George Washington University, Washington, DC. The alliance includes more than 50 organizations advocating for adult obesity treatment.

“One of our big arguments is [that] access to care, and to obesity care, will also help other conditions — comorbidities like heart disease and diabetes.”

However, access to the anti-obesity medications, by itself, is not enough, Gallagher said. Other components, such as intensive behavioral therapy and guidance about diet and exercise, are needed, she said. So, too, for those who need it, is access to bariatric surgery, she said. And medication access should include other options besides the GLP-1s, she said. “Not every medication is right for everybody.”

Cawley, Gallagher, Thorpe, and Sexton Ward had no disclosures.
 

A version of this article appeared on Medscape.com.

The question may seem simple: Could paying for weight loss medications — especially the pricey glucagon-like peptide 1 receptor agonists (GLP-1s), tirzepatide (Zepbound) and semaglutide (Wegovy) — be more cost-effective than paying for obesity care and the complications of obesity, such as cardiovascular disease and diabetes?

It’s a question that’s getting an increased amount of attention.

And for good reason — more than two in five US adults have obesity, according to the Centers for Disease Control and Prevention, and costs to treat obesity, in 2019 dollars, approached $173 billion, including productivity losses. Adults with obesity have annual healthcare costs of $1861 more than those at healthier weights.

Among recent developments:

• A proposed new rule, announced on November 26 by the Biden administration, expands coverage of anti-obesity medication for Americans who have Medicare and Medicaid. If it takes effect, an estimated 3.4 million Medicare recipients and about 4 million adult Medicaid enrollees could get access to the medications.
• As Medicare coverage goes, private insurers often follow. Observers predict that if the Centers for Medicare & Medicaid Services (CMS) covers anti-obesity drugs, more private employers may soon do the same. Recently, however, some private plans have done the opposite and dropped coverage of the pricey GLP-1s, which can cost $1000 a month or more out-of-pocket, citing excess costs for their company.
• Among the analyses about the value of weight loss on healthcare cost savings is a report published on December 5 in JAMA Network Open. Emory University experts looked at privately insured adults and adult Medicare beneficiaries with a body mass index (BMI) of ≥ 25 (classified as overweight). The conclusion: Projected annual savings from weight loss among US adults with obesity were substantial for both employee-based insurance and Medicare recipients.
• Besides helping obesity and obesity-related conditions, access to GLP-1s could have a favorable effect on productivity, others claim. That’s one focus of a 5-year partnership between the University of Manchester in England, and Eli Lilly and Company. Called SURMOUNT-REAL UK, the study will evaluate the effectiveness of tirzepatide in weight loss, diabetes prevention, and prevention of obesity-related complications in adults with obesity. It also aims to look at changes in health-related quality of life with weight loss and with changes in employment status and sick days.

CMS Proposal

In a statement announcing the proposal for Medicare and Medicaid to offer weight loss drugs, the White House noted that “tens of millions of Americans struggle with obesity” but that currently Medicare only covers the anti-obesity medications for certain conditions such as diabetes. The new proposal would expand that access to those with obesity. As of August, just 13 states cover GLP-1s in Medicaid programs, and North Carolina was the latest to do so.

Organizations advocating for health equity and recognition that obesity is a chronic disease came out in strong support of the proposal.

Kenneth E. Thorpe, PhD, a health policy expert at Emory University in Atlanta, who coauthored the recent analysis finding that weight loss offsets healthcare costs on an individual basis, told this news organization: “If finalized, this broad new coverage [by Medicare and Medicaid] would have a profound impact on the ability of Americans to access these novel medications that could significantly reduce obesity-related healthcare spending and improve overall health.”

The proposal “is modernizing the coverage of Medicare and Medicaid for obesity treatment,” agreed John Cawley, PhD, professor of economics and public policy at Cornell University in Ithaca, New York, who has researched the direct medical costs of obesity in the United States. “In this HHS rule, they talk about the scientific and medical consensus that having obesity is a chronic condition.”

The proposal requires a 60-day comment period that ends January 27, 2025, taking the timeline into the beginning of the Trump administration. Cawley and others pointed out that Trump’s pick for Health and Human Services Secretary, Robert F. Kennedy Jr, has been an outspoken opponent of the anti-obesity medicines, suggesting instead that Americans simply eat better.

 

Expert Analyses: Emory, Cornell, Southern California

So would paying for the pricey GLP-1s be smart in the long term? Analyses don’t agree.

Weight loss among those with obesity produces healthcare cost savings, said Thorpe and Peter Joski, MSPH, an associate research professor at Emory University. The two compared annual healthcare spending among privately insured adults and adult Medicare beneficiaries with a BMI of ≥ 25, using data from the Medical Expenditure Panel Survey — Household Component from April 1 to June 20, 2024.

The researchers looked at 3774 adults insured with Medicare and 13,435 with employer-sponsored insurance. Overall, those with private insurance with a weight loss of 5% spent an estimated average of $670 less on healthcare. Those with a weight loss of 25% spent an estimated $2849 less on healthcare. Among those with Medicare who had one or more comorbidities, a 5% weight loss reduced spending by $1262 on average; a 25% loss reduced it by an estimated $5442, or 31%.

Thorpe called the savings substantial. In an email interview, Thorpe said, “So yes, weight loss for people living with obesity does lower healthcare costs, as my research shows, but it also lowers other costs as well.”

These include costs associated with disability, workers’ compensation, presenteeism/absenteeism, and everyday costs, he said. He contends that “those other costs should factor into decisions about preventing and treating obesity of payors and policymakers and enhance the case for cost-effectiveness of treating obesity.”

Other research suggests it’s important to target the use of the anti-obesity medications to the BMI range that would get the most benefit. For people just barely above the BMI threshold of 30, no cost savings are expected, Cawley found in his research. But he has found substantial cost reduction if the BMI was 35-40.

However, as Cawley pointed out, as the drugs get cheaper and more options become available, the entire scenario is expected to shift.

 

The Congressional Budget Office View

In October, the nonpartisan Congressional Budget Office issued a report, “How Would Authorizing Medicare to Cover Anti-Obesity Medications Affect the Federal Budget?” Among the conclusions: Covering the anti-obesity medications would increase federal spending, on net, by about $35 billion from 2026 to 2034. Total direct federal costs of covering the medication would increase from $1.6 billion in 2026 to $7.1 billion in 2034. And it said total savings from improved health of the beneficiaries would be small, less than $50 million in 2026 and rising to $1 billion in 2034.

Covering the medications would cost $5600 per user in 2026, then down to $4300 in 2034. The offset of savings per user would be about $50 in 2026, then $650 in 2034.

 

Expert Analysis: USC Schaeffer Center

“The costs offsets come over time,” said Alison Sexton Ward, PhD, an economist at the University of Southern California’s Leonard D. Schaeffer Center, Los Angeles, and an expert on the topic. “If we look at the average annual medical cost over a lifetime, we do see cost offsets there.”

However, treating obesity means people will live longer, “and living longer costs more,” she said.

She took issue with some of the calculations in the CBO report, such as not considering the effect of semaglutide’s patent expiring in 2033.

In a white paper published in April 2023, Sexton Ward and her coauthors modeled potential social benefits and medical cost offsets from granting access to the newer weight loss drugs. The cumulative social benefits of providing coverage over the next decade would reach nearly $1 trillion, they said. Benefits would increase if private insurance expanded coverage. “In the first 10 years alone, covering weight loss therapies would save Medicare $175 billion-$245 billion, depending on whether private insurance joins Medicare in providing coverage for younger populations.”

While much focus is on Medicare coverage, Sexton Ward and others pointed out the need to expand coverage to younger ages, with the aim of preventing or delaying obesity-related complications.

 

Lilly UK Trial

A spokesperson for Lilly declined to comment further on the UK study, explaining that the study was just launching.

Besides tracking weight loss, researchers will evaluate the effect of the weight loss on sick days from work and employment. Obesity is shown to affect a person’s ability to work, leading to more absenteeism, so treating the obesity may improve productivity.

 

Beyond Health: The Value of Weight Loss

“I love the idea of studying whether access to obesity medications helps people stay employed and do their job,” said Cristy Gallagher, associate director of Research and Policy at STOP Obesity Alliance at the Milken Institute School of Public Health, George Washington University, Washington, DC. The alliance includes more than 50 organizations advocating for adult obesity treatment.

“One of our big arguments is [that] access to care, and to obesity care, will also help other conditions — comorbidities like heart disease and diabetes.”

However, access to the anti-obesity medications, by itself, is not enough, Gallagher said. Other components, such as intensive behavioral therapy and guidance about diet and exercise, are needed, she said. So, too, for those who need it, is access to bariatric surgery, she said. And medication access should include other options besides the GLP-1s, she said. “Not every medication is right for everybody.”

Cawley, Gallagher, Thorpe, and Sexton Ward had no disclosures.
 

A version of this article appeared on Medscape.com.

TOPLINE:

The beneficial effect of clopidogrel monotherapy over aspirin monotherapy in patients who underwent percutaneous coronary intervention (PCI) and remained event free for 6-18 months on dual antiplatelet therapy (DAPT) is consistent, regardless of bleeding risk or PCI complexity, according to a post hoc analysis of the HOST-EXAM trial.

METHODOLOGY:

• The HOST-EXAM Extended study conducted across 37 sites in South Korea included patients who underwent PCI with drug-eluting stents and remained free of clinical events for 6-18 months post-PCI, while receiving DAPT.
• This post hoc analysis of the HOST-EXAM Extended study compared the effectiveness of long-term daily clopidogrel (75 mg) with that of aspirin monotherapy (100 mg) after PCI, according to bleeding risk and procedural complexity in 3974 patients (mean age, 63 years; 75% men) who were followed for up to 5.9 years.
• High bleeding risk was reported in 866 patients, and 849 patients underwent complex PCI.
• Patients were classified into four distinct risk groups: No bleeding risk and noncomplex PCI, no bleeding risk and complex PCI, high bleeding risk and noncomplex PCI, and high bleeding risk and complex PCI.
• The co-primary endpoints were thrombotic composite events (cardiovascular death, nonfatal myocardial infarction, stroke, readmission due to acute coronary syndrome, and definite/probable stent thrombosis) and any bleeding event.

TAKEAWAY:

• Thrombotic composite events (hazard ratio [HR], 2.15; P < .001) and any bleeding event (HR, 3.64; P < .001) were more frequent in patients with a high bleeding risk than in those without.
• However, there was no difference in the risk for thrombotic composite events or any bleeding event by PCI complexity.
• The long-term benefits of clopidogrel monotherapy over aspirin monotherapy were seen in all patients, regardless of bleeding risks (P for interaction = .38 for thrombotic composite events and P for interaction = .20 for any bleeding event) or PCI complexity (P for interaction = .12 for thrombotic composite events and P for interaction = .62 for any bleeding event).
• The greatest risk reduction in thrombotic composite events with clopidogrel monotherapy occurred in patients with a high bleeding risk who underwent complex PCI (HR, 0.46; P = .03).

IN PRACTICE:

“[In this study], no significant interaction was found between treatment arms and risk groups, denoting that the beneficial impact of clopidogrel monotherapy was consistent regardless of HBR [high bleeding risk] or PCI complexity,” the authors wrote.

SOURCE:

This study was led by Jeehoon Kang, MD, Seoul National University College of Medicine and Seoul National University Hospital, Seoul, Republic of Korea. It was published online on November 27, 2024, in JAMA Cardiology.

LIMITATIONS:

As this study is a post hoc analysis, the findings should be considered primarily hypothesis generating. This study was conducted exclusively in an East Asian population and may not be generalizable to other ethnic groups. The definitions of high bleeding risk and complex PCI used in this analysis were not prespecified in the study protocol of the HOST-EXAM trial. Certain criteria defining high bleeding risk were not analyzed as they fell under the exclusion criteria of the HOST-EXAM trial or were not recorded in the study case report form.

DISCLOSURES:

This study was supported by grants from the Patient-Centered Clinical Research Coordinating Center and Seoul National University Hospital. One author reported receiving grants and personal fees from various pharmaceutical companies outside the submitted work.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

The beneficial effect of clopidogrel monotherapy over aspirin monotherapy in patients who underwent percutaneous coronary intervention (PCI) and remained event free for 6-18 months on dual antiplatelet therapy (DAPT) is consistent, regardless of bleeding risk or PCI complexity, according to a post hoc analysis of the HOST-EXAM trial.

METHODOLOGY:

• The HOST-EXAM Extended study conducted across 37 sites in South Korea included patients who underwent PCI with drug-eluting stents and remained free of clinical events for 6-18 months post-PCI, while receiving DAPT.
• This post hoc analysis of the HOST-EXAM Extended study compared the effectiveness of long-term daily clopidogrel (75 mg) with that of aspirin monotherapy (100 mg) after PCI, according to bleeding risk and procedural complexity in 3974 patients (mean age, 63 years; 75% men) who were followed for up to 5.9 years.
• High bleeding risk was reported in 866 patients, and 849 patients underwent complex PCI.
• Patients were classified into four distinct risk groups: No bleeding risk and noncomplex PCI, no bleeding risk and complex PCI, high bleeding risk and noncomplex PCI, and high bleeding risk and complex PCI.
• The co-primary endpoints were thrombotic composite events (cardiovascular death, nonfatal myocardial infarction, stroke, readmission due to acute coronary syndrome, and definite/probable stent thrombosis) and any bleeding event.

TAKEAWAY:

• Thrombotic composite events (hazard ratio [HR], 2.15; P < .001) and any bleeding event (HR, 3.64; P < .001) were more frequent in patients with a high bleeding risk than in those without.
• However, there was no difference in the risk for thrombotic composite events or any bleeding event by PCI complexity.
• The long-term benefits of clopidogrel monotherapy over aspirin monotherapy were seen in all patients, regardless of bleeding risks (P for interaction = .38 for thrombotic composite events and P for interaction = .20 for any bleeding event) or PCI complexity (P for interaction = .12 for thrombotic composite events and P for interaction = .62 for any bleeding event).
• The greatest risk reduction in thrombotic composite events with clopidogrel monotherapy occurred in patients with a high bleeding risk who underwent complex PCI (HR, 0.46; P = .03).

IN PRACTICE:

“[In this study], no significant interaction was found between treatment arms and risk groups, denoting that the beneficial impact of clopidogrel monotherapy was consistent regardless of HBR [high bleeding risk] or PCI complexity,” the authors wrote.

SOURCE:

This study was led by Jeehoon Kang, MD, Seoul National University College of Medicine and Seoul National University Hospital, Seoul, Republic of Korea. It was published online on November 27, 2024, in JAMA Cardiology.

LIMITATIONS:

As this study is a post hoc analysis, the findings should be considered primarily hypothesis generating. This study was conducted exclusively in an East Asian population and may not be generalizable to other ethnic groups. The definitions of high bleeding risk and complex PCI used in this analysis were not prespecified in the study protocol of the HOST-EXAM trial. Certain criteria defining high bleeding risk were not analyzed as they fell under the exclusion criteria of the HOST-EXAM trial or were not recorded in the study case report form.

DISCLOSURES:

This study was supported by grants from the Patient-Centered Clinical Research Coordinating Center and Seoul National University Hospital. One author reported receiving grants and personal fees from various pharmaceutical companies outside the submitted work.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

The beneficial effect of clopidogrel monotherapy over aspirin monotherapy in patients who underwent percutaneous coronary intervention (PCI) and remained event free for 6-18 months on dual antiplatelet therapy (DAPT) is consistent, regardless of bleeding risk or PCI complexity, according to a post hoc analysis of the HOST-EXAM trial.

METHODOLOGY:

• The HOST-EXAM Extended study conducted across 37 sites in South Korea included patients who underwent PCI with drug-eluting stents and remained free of clinical events for 6-18 months post-PCI, while receiving DAPT.
• This post hoc analysis of the HOST-EXAM Extended study compared the effectiveness of long-term daily clopidogrel (75 mg) with that of aspirin monotherapy (100 mg) after PCI, according to bleeding risk and procedural complexity in 3974 patients (mean age, 63 years; 75% men) who were followed for up to 5.9 years.
• High bleeding risk was reported in 866 patients, and 849 patients underwent complex PCI.
• Patients were classified into four distinct risk groups: No bleeding risk and noncomplex PCI, no bleeding risk and complex PCI, high bleeding risk and noncomplex PCI, and high bleeding risk and complex PCI.
• The co-primary endpoints were thrombotic composite events (cardiovascular death, nonfatal myocardial infarction, stroke, readmission due to acute coronary syndrome, and definite/probable stent thrombosis) and any bleeding event.

TAKEAWAY:

• Thrombotic composite events (hazard ratio [HR], 2.15; P < .001) and any bleeding event (HR, 3.64; P < .001) were more frequent in patients with a high bleeding risk than in those without.
• However, there was no difference in the risk for thrombotic composite events or any bleeding event by PCI complexity.
• The long-term benefits of clopidogrel monotherapy over aspirin monotherapy were seen in all patients, regardless of bleeding risks (P for interaction = .38 for thrombotic composite events and P for interaction = .20 for any bleeding event) or PCI complexity (P for interaction = .12 for thrombotic composite events and P for interaction = .62 for any bleeding event).
• The greatest risk reduction in thrombotic composite events with clopidogrel monotherapy occurred in patients with a high bleeding risk who underwent complex PCI (HR, 0.46; P = .03).

IN PRACTICE:

“[In this study], no significant interaction was found between treatment arms and risk groups, denoting that the beneficial impact of clopidogrel monotherapy was consistent regardless of HBR [high bleeding risk] or PCI complexity,” the authors wrote.

SOURCE:

This study was led by Jeehoon Kang, MD, Seoul National University College of Medicine and Seoul National University Hospital, Seoul, Republic of Korea. It was published online on November 27, 2024, in JAMA Cardiology.

LIMITATIONS:

As this study is a post hoc analysis, the findings should be considered primarily hypothesis generating. This study was conducted exclusively in an East Asian population and may not be generalizable to other ethnic groups. The definitions of high bleeding risk and complex PCI used in this analysis were not prespecified in the study protocol of the HOST-EXAM trial. Certain criteria defining high bleeding risk were not analyzed as they fell under the exclusion criteria of the HOST-EXAM trial or were not recorded in the study case report form.

DISCLOSURES:

This study was supported by grants from the Patient-Centered Clinical Research Coordinating Center and Seoul National University Hospital. One author reported receiving grants and personal fees from various pharmaceutical companies outside the submitted work.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Among pregnant patients with chronic hypertension, delivery at 39 weeks of gestation provides an optimal balance between stillbirth risk and neonatal outcomes. Analysis of 227,977 term singleton deliveries shows consistent findings across different patient subgroups.

METHODOLOGY:

• A population-based retrospective cohort study analyzed 227,977 nonanomalous singleton term births in the United States from 2014 to 2018 among patients with chronic hypertension.
• Researchers excluded pregnancies with superimposed preeclampsia, eclampsia, pregestational diabetes, and deliveries occurring before 37 weeks or at 43 or more weeks of gestation.
• Analysis compared rates of stillbirth, infant death within 1 year of life, and neonatal morbidity at each week of term pregnancy.
• Neonatal morbidity was defined as a composite of neonatal intensive care unit admission, ventilation for 6 hours or longer, a low 5-minute Apgar score (≤ 3), and seizures.

TAKEAWAY:

• The rate of stillbirth per 10,000 ongoing pregnancies increased with gestational age and was lowest at 38 weeks (6.5; 95% CI, 5.4-7.7).
• Rates of infant death and neonatal morbidity were lowest at 40 weeks (18.0/10,000 live births; 95% CI, 13.7-23.6) and 39 weeks (637/10,000 live births; 95% CI, 619-654), respectively.
• At 39 weeks of gestation, the risk for delivery was lower (651/10,000; 95% CI, 633-670) than the composite risk for expectant management (750/10,000; 95% CI, 720-781).
• According to the authors, findings were consistent for non-Hispanic Black patients and pregnancies complicated by fetal growth restriction.

IN PRACTICE:

“To prevent one case of stillbirth, infant death, or neonatal morbidity, an estimated 101 patients with chronic hypertension would need to deliver at 39 weeks of gestation as opposed to 40 weeks. Given the approximately 45,000 patients with chronic hypertension who deliver at term each year in the United States, a policy of delivery at 39 weeks of gestation theoretically would prevent 450 adverse perinatal events per year,” wrote the authors of the study.

SOURCE:

The study was led by Ira Hamilton, James Liu, Labeena Wajahat, and Robert Rossi, University of Cincinnati College of Medicine in Cincinnati. It was published online in O&G Open.

LIMITATIONS:

According to the authors, the study could not stratify chronic hypertension based on medication use, number of medications, or degree of control. The researchers note that exact timing of delivery in weeks and days was not reported, limiting precise understanding of optimal delivery timing. Additionally, the study could not examine rates of neonatal morbidity and mortality in patients who developed superimposed preeclampsia during expectant management.

DISCLOSURES:

The authors did not report any potential conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Among pregnant patients with chronic hypertension, delivery at 39 weeks of gestation provides an optimal balance between stillbirth risk and neonatal outcomes. Analysis of 227,977 term singleton deliveries shows consistent findings across different patient subgroups.

METHODOLOGY:

• A population-based retrospective cohort study analyzed 227,977 nonanomalous singleton term births in the United States from 2014 to 2018 among patients with chronic hypertension.
• Researchers excluded pregnancies with superimposed preeclampsia, eclampsia, pregestational diabetes, and deliveries occurring before 37 weeks or at 43 or more weeks of gestation.
• Analysis compared rates of stillbirth, infant death within 1 year of life, and neonatal morbidity at each week of term pregnancy.
• Neonatal morbidity was defined as a composite of neonatal intensive care unit admission, ventilation for 6 hours or longer, a low 5-minute Apgar score (≤ 3), and seizures.

TAKEAWAY:

• The rate of stillbirth per 10,000 ongoing pregnancies increased with gestational age and was lowest at 38 weeks (6.5; 95% CI, 5.4-7.7).
• Rates of infant death and neonatal morbidity were lowest at 40 weeks (18.0/10,000 live births; 95% CI, 13.7-23.6) and 39 weeks (637/10,000 live births; 95% CI, 619-654), respectively.
• At 39 weeks of gestation, the risk for delivery was lower (651/10,000; 95% CI, 633-670) than the composite risk for expectant management (750/10,000; 95% CI, 720-781).
• According to the authors, findings were consistent for non-Hispanic Black patients and pregnancies complicated by fetal growth restriction.

IN PRACTICE:

“To prevent one case of stillbirth, infant death, or neonatal morbidity, an estimated 101 patients with chronic hypertension would need to deliver at 39 weeks of gestation as opposed to 40 weeks. Given the approximately 45,000 patients with chronic hypertension who deliver at term each year in the United States, a policy of delivery at 39 weeks of gestation theoretically would prevent 450 adverse perinatal events per year,” wrote the authors of the study.

SOURCE:

The study was led by Ira Hamilton, James Liu, Labeena Wajahat, and Robert Rossi, University of Cincinnati College of Medicine in Cincinnati. It was published online in O&G Open.

LIMITATIONS:

According to the authors, the study could not stratify chronic hypertension based on medication use, number of medications, or degree of control. The researchers note that exact timing of delivery in weeks and days was not reported, limiting precise understanding of optimal delivery timing. Additionally, the study could not examine rates of neonatal morbidity and mortality in patients who developed superimposed preeclampsia during expectant management.

DISCLOSURES:

The authors did not report any potential conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Among pregnant patients with chronic hypertension, delivery at 39 weeks of gestation provides an optimal balance between stillbirth risk and neonatal outcomes. Analysis of 227,977 term singleton deliveries shows consistent findings across different patient subgroups.

METHODOLOGY:

• A population-based retrospective cohort study analyzed 227,977 nonanomalous singleton term births in the United States from 2014 to 2018 among patients with chronic hypertension.
• Researchers excluded pregnancies with superimposed preeclampsia, eclampsia, pregestational diabetes, and deliveries occurring before 37 weeks or at 43 or more weeks of gestation.
• Analysis compared rates of stillbirth, infant death within 1 year of life, and neonatal morbidity at each week of term pregnancy.
• Neonatal morbidity was defined as a composite of neonatal intensive care unit admission, ventilation for 6 hours or longer, a low 5-minute Apgar score (≤ 3), and seizures.

TAKEAWAY:

• The rate of stillbirth per 10,000 ongoing pregnancies increased with gestational age and was lowest at 38 weeks (6.5; 95% CI, 5.4-7.7).
• Rates of infant death and neonatal morbidity were lowest at 40 weeks (18.0/10,000 live births; 95% CI, 13.7-23.6) and 39 weeks (637/10,000 live births; 95% CI, 619-654), respectively.
• At 39 weeks of gestation, the risk for delivery was lower (651/10,000; 95% CI, 633-670) than the composite risk for expectant management (750/10,000; 95% CI, 720-781).
• According to the authors, findings were consistent for non-Hispanic Black patients and pregnancies complicated by fetal growth restriction.

IN PRACTICE:

“To prevent one case of stillbirth, infant death, or neonatal morbidity, an estimated 101 patients with chronic hypertension would need to deliver at 39 weeks of gestation as opposed to 40 weeks. Given the approximately 45,000 patients with chronic hypertension who deliver at term each year in the United States, a policy of delivery at 39 weeks of gestation theoretically would prevent 450 adverse perinatal events per year,” wrote the authors of the study.

SOURCE:

The study was led by Ira Hamilton, James Liu, Labeena Wajahat, and Robert Rossi, University of Cincinnati College of Medicine in Cincinnati. It was published online in O&G Open.

LIMITATIONS:

According to the authors, the study could not stratify chronic hypertension based on medication use, number of medications, or degree of control. The researchers note that exact timing of delivery in weeks and days was not reported, limiting precise understanding of optimal delivery timing. Additionally, the study could not examine rates of neonatal morbidity and mortality in patients who developed superimposed preeclampsia during expectant management.

DISCLOSURES:

The authors did not report any potential conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Atherosclerotic cardiovascular disease (ASCVD) risk is higher with cutaneous lupus erythematosus (CLE) or systemic lupus erythematosus (SLE) than with psoriasis.

METHODOLOGY:

• A retrospective matched longitudinal study compared the incidence and prevalence of ASCVD of 8138 individuals with CLE; 24,675 with SLE; 192,577 with psoriasis; and 81,380 control individuals.
• The disease-free control population was matched in a 10:1 ratio to the CLE population on the basis of age, sex, insurance type, and enrollment duration.
• Prevalent ASCVD was defined as coronary artery disease, prior myocardial infarction, or cerebrovascular accident, with ASCVD incidence assessed by number of hospitalizations over 3 years.

TAKEAWAY:

• Persons with CLE had higher ASCVD risk than control individuals (odds ratio [OR], 1.72; P < .001), similar to those with SLE (OR, 2.41; P < .001) but unlike those with psoriasis (OR, 1.03; P = .48).
• ASCVD incidence at 3 years was 24.8 per 1000 person-years for SLE, 15.2 per 1000 person-years for CLE, 14.0 per 1000 person-years for psoriasis, and 10.3 per 1000 person-years for controls.
• Multivariable Cox proportional regression modeling showed ASCVD risk was highest in those with SLE (hazard ratio [HR], 2.23; P < .001) vs CLE (HR, 1.32; P < .001) and psoriasis (HR, 1.06; P = .09).
• ASCVD prevalence was higher in individuals with CLE receiving systemic therapy (2.7%) than in those receiving no therapy (1.6%), suggesting a potential link between disease severity and CVD risk.

IN PRACTICE:

“Persons with CLE are at higher risk for ASCVD, and guidelines for the evaluation and management of ASCVD may improve their quality of care,” the authors wrote.

SOURCE:

The study was led by Henry W. Chen, MD, Department of Dermatology, University of Texas Southwestern Medical Center, Dallas. It was published online on December 4, 2024, in JAMA Dermatology.

LIMITATIONS: 

The study was limited by its relatively young population (median age, 49 years) and the exclusion of adults aged > 65 years on Medicare insurance plans. The database lacked race and ethnicity data, and the analysis was restricted to a shorter 3-year period. The study could not fully evaluate detailed risk factors such as blood pressure levels, cholesterol measurements, or glycemic control, nor could it accurately assess smoking status.

DISCLOSURES:

The research was supported by the Department of Dermatology at the University of Texas Southwestern Medical Center and a grant from the National Institutes of Health. Several authors reported receiving grants or personal fees from various pharmaceutical companies. One author reported being a deputy editor for diversity, equity, and inclusion at JAMA Cardiology. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Atherosclerotic cardiovascular disease (ASCVD) risk is higher with cutaneous lupus erythematosus (CLE) or systemic lupus erythematosus (SLE) than with psoriasis.

METHODOLOGY:

• A retrospective matched longitudinal study compared the incidence and prevalence of ASCVD of 8138 individuals with CLE; 24,675 with SLE; 192,577 with psoriasis; and 81,380 control individuals.
• The disease-free control population was matched in a 10:1 ratio to the CLE population on the basis of age, sex, insurance type, and enrollment duration.
• Prevalent ASCVD was defined as coronary artery disease, prior myocardial infarction, or cerebrovascular accident, with ASCVD incidence assessed by number of hospitalizations over 3 years.

TAKEAWAY:

• Persons with CLE had higher ASCVD risk than control individuals (odds ratio [OR], 1.72; P < .001), similar to those with SLE (OR, 2.41; P < .001) but unlike those with psoriasis (OR, 1.03; P = .48).
• ASCVD incidence at 3 years was 24.8 per 1000 person-years for SLE, 15.2 per 1000 person-years for CLE, 14.0 per 1000 person-years for psoriasis, and 10.3 per 1000 person-years for controls.
• Multivariable Cox proportional regression modeling showed ASCVD risk was highest in those with SLE (hazard ratio [HR], 2.23; P < .001) vs CLE (HR, 1.32; P < .001) and psoriasis (HR, 1.06; P = .09).
• ASCVD prevalence was higher in individuals with CLE receiving systemic therapy (2.7%) than in those receiving no therapy (1.6%), suggesting a potential link between disease severity and CVD risk.

IN PRACTICE:

“Persons with CLE are at higher risk for ASCVD, and guidelines for the evaluation and management of ASCVD may improve their quality of care,” the authors wrote.

SOURCE:

The study was led by Henry W. Chen, MD, Department of Dermatology, University of Texas Southwestern Medical Center, Dallas. It was published online on December 4, 2024, in JAMA Dermatology.

LIMITATIONS: 

The study was limited by its relatively young population (median age, 49 years) and the exclusion of adults aged > 65 years on Medicare insurance plans. The database lacked race and ethnicity data, and the analysis was restricted to a shorter 3-year period. The study could not fully evaluate detailed risk factors such as blood pressure levels, cholesterol measurements, or glycemic control, nor could it accurately assess smoking status.

DISCLOSURES:

The research was supported by the Department of Dermatology at the University of Texas Southwestern Medical Center and a grant from the National Institutes of Health. Several authors reported receiving grants or personal fees from various pharmaceutical companies. One author reported being a deputy editor for diversity, equity, and inclusion at JAMA Cardiology. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Atherosclerotic cardiovascular disease (ASCVD) risk is higher with cutaneous lupus erythematosus (CLE) or systemic lupus erythematosus (SLE) than with psoriasis.

METHODOLOGY:

• A retrospective matched longitudinal study compared the incidence and prevalence of ASCVD of 8138 individuals with CLE; 24,675 with SLE; 192,577 with psoriasis; and 81,380 control individuals.
• The disease-free control population was matched in a 10:1 ratio to the CLE population on the basis of age, sex, insurance type, and enrollment duration.
• Prevalent ASCVD was defined as coronary artery disease, prior myocardial infarction, or cerebrovascular accident, with ASCVD incidence assessed by number of hospitalizations over 3 years.

TAKEAWAY:

• Persons with CLE had higher ASCVD risk than control individuals (odds ratio [OR], 1.72; P < .001), similar to those with SLE (OR, 2.41; P < .001) but unlike those with psoriasis (OR, 1.03; P = .48).
• ASCVD incidence at 3 years was 24.8 per 1000 person-years for SLE, 15.2 per 1000 person-years for CLE, 14.0 per 1000 person-years for psoriasis, and 10.3 per 1000 person-years for controls.
• Multivariable Cox proportional regression modeling showed ASCVD risk was highest in those with SLE (hazard ratio [HR], 2.23; P < .001) vs CLE (HR, 1.32; P < .001) and psoriasis (HR, 1.06; P = .09).
• ASCVD prevalence was higher in individuals with CLE receiving systemic therapy (2.7%) than in those receiving no therapy (1.6%), suggesting a potential link between disease severity and CVD risk.

IN PRACTICE:

“Persons with CLE are at higher risk for ASCVD, and guidelines for the evaluation and management of ASCVD may improve their quality of care,” the authors wrote.

SOURCE:

The study was led by Henry W. Chen, MD, Department of Dermatology, University of Texas Southwestern Medical Center, Dallas. It was published online on December 4, 2024, in JAMA Dermatology.

LIMITATIONS: 

The study was limited by its relatively young population (median age, 49 years) and the exclusion of adults aged > 65 years on Medicare insurance plans. The database lacked race and ethnicity data, and the analysis was restricted to a shorter 3-year period. The study could not fully evaluate detailed risk factors such as blood pressure levels, cholesterol measurements, or glycemic control, nor could it accurately assess smoking status.

DISCLOSURES:

The research was supported by the Department of Dermatology at the University of Texas Southwestern Medical Center and a grant from the National Institutes of Health. Several authors reported receiving grants or personal fees from various pharmaceutical companies. One author reported being a deputy editor for diversity, equity, and inclusion at JAMA Cardiology. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, lipid-lowering drugs, were associated with a 22% lower risk for nonmelanoma skin cancer (NMSC) in patients with atherosclerotic cardiovascular disease (ASCVD), an effect that was particularly significant among men, those older than 65 years, and those with immunosuppression.

METHODOLOGY:

• To evaluate the risk for NMSC — basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) — in patients with ASCVD on PCSK9 inhibitors, researchers analyzed data from the US Collaborative Network in the TriNetX database of adults aged ≥ 40 years with ASCVD who received statin therapy between 2016 and 2022.
• A total of 73,636 patients were included, divided equally between those receiving a PCSK9 inhibitor (evolocumab, alirocumab, or inclisiran) plus statin therapy and the control group (those on statin therapy only).
• The analysis used propensity score matching for head-to-head comparisons, with hazard ratios (HRs) estimated using Cox proportional hazard models.
• Stratified analyses examined outcomes by age, sex, Fitzpatrick skin type, and immune status. (Immunosuppressed patients were those treated with immunosuppressants for more than 90 days in the year before the index date — the date when exposed patients were first prescribed a PCSK9 inhibitor, which was also index date for matched patients in the statin-only group.)

TAKEAWAY:

• Patients with ASCVD in the PCSK9 group showed significantly lower risks for NMSC (HR, 0.78; 95% CI, 0.71-0.87), BCC (HR, 0.78; 95% CI, 0.69-0.89), and SCC (HR, 0.79; 95% CI, 0.67-0.93) than control individuals on a statin only (P < .001 for all three).
• Both evolocumab and alirocumab demonstrated similar protective effects against the development of NMSC.
• The reduced risk for NMSC was particularly notable among patients aged 65-79 years (HR, 0.75; 95% CI, 0.66-0.86) and those aged ≥ 80 years (HR, 0.74; 95% CI, 0.60-0.91).
• Men showed a more pronounced reduction in the risk for NMSC (HR, 0.73; 95% CI, 0.64-0.83) than women (HR, 0.93; 95% CI, 0.78-1.11). The effect on lowering NMSC risk was also evident among immunosuppressed patients in the PCSK9 group (HR, 0.68; 95% CI, 0.60-0.75).

IN PRACTICE:

“The findings suggest the promising pleiotropic effect of PCSK9 inhibitors on the chemoprevention of NMSC,” the study authors wrote. Referring to previous studies that “provided mechanistic clues to our findings,” they added that “further studies are required to investigate the underlying mechanisms and establish causality.”

SOURCE:

The study was led by Cheng-Yuan Li, Taipei Veterans General Hospital, Taipei, Taiwan, and was published online in The British Journal of Dermatology.

LIMITATIONS:

Electronic health records lack information on sun protection habits, family history of skin cancer, diet, body mass index, and air pollution exposure, risk factors for NMSC. The study also lacked detailed information on enrollees’ lipid profiles and was focused mostly on patients in the United States, limiting the generalizability of the findings to other regions.

DISCLOSURES:

The study was supported by grants from Taipei Veterans General Hospital and the Ministry of Science and Technology, Taiwan. The authors reported no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, lipid-lowering drugs, were associated with a 22% lower risk for nonmelanoma skin cancer (NMSC) in patients with atherosclerotic cardiovascular disease (ASCVD), an effect that was particularly significant among men, those older than 65 years, and those with immunosuppression.

METHODOLOGY:

• To evaluate the risk for NMSC — basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) — in patients with ASCVD on PCSK9 inhibitors, researchers analyzed data from the US Collaborative Network in the TriNetX database of adults aged ≥ 40 years with ASCVD who received statin therapy between 2016 and 2022.
• A total of 73,636 patients were included, divided equally between those receiving a PCSK9 inhibitor (evolocumab, alirocumab, or inclisiran) plus statin therapy and the control group (those on statin therapy only).
• The analysis used propensity score matching for head-to-head comparisons, with hazard ratios (HRs) estimated using Cox proportional hazard models.
• Stratified analyses examined outcomes by age, sex, Fitzpatrick skin type, and immune status. (Immunosuppressed patients were those treated with immunosuppressants for more than 90 days in the year before the index date — the date when exposed patients were first prescribed a PCSK9 inhibitor, which was also index date for matched patients in the statin-only group.)

TAKEAWAY:

• Patients with ASCVD in the PCSK9 group showed significantly lower risks for NMSC (HR, 0.78; 95% CI, 0.71-0.87), BCC (HR, 0.78; 95% CI, 0.69-0.89), and SCC (HR, 0.79; 95% CI, 0.67-0.93) than control individuals on a statin only (P < .001 for all three).
• Both evolocumab and alirocumab demonstrated similar protective effects against the development of NMSC.
• The reduced risk for NMSC was particularly notable among patients aged 65-79 years (HR, 0.75; 95% CI, 0.66-0.86) and those aged ≥ 80 years (HR, 0.74; 95% CI, 0.60-0.91).
• Men showed a more pronounced reduction in the risk for NMSC (HR, 0.73; 95% CI, 0.64-0.83) than women (HR, 0.93; 95% CI, 0.78-1.11). The effect on lowering NMSC risk was also evident among immunosuppressed patients in the PCSK9 group (HR, 0.68; 95% CI, 0.60-0.75).

IN PRACTICE:

“The findings suggest the promising pleiotropic effect of PCSK9 inhibitors on the chemoprevention of NMSC,” the study authors wrote. Referring to previous studies that “provided mechanistic clues to our findings,” they added that “further studies are required to investigate the underlying mechanisms and establish causality.”

SOURCE:

The study was led by Cheng-Yuan Li, Taipei Veterans General Hospital, Taipei, Taiwan, and was published online in The British Journal of Dermatology.

LIMITATIONS:

Electronic health records lack information on sun protection habits, family history of skin cancer, diet, body mass index, and air pollution exposure, risk factors for NMSC. The study also lacked detailed information on enrollees’ lipid profiles and was focused mostly on patients in the United States, limiting the generalizability of the findings to other regions.

DISCLOSURES:

The study was supported by grants from Taipei Veterans General Hospital and the Ministry of Science and Technology, Taiwan. The authors reported no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, lipid-lowering drugs, were associated with a 22% lower risk for nonmelanoma skin cancer (NMSC) in patients with atherosclerotic cardiovascular disease (ASCVD), an effect that was particularly significant among men, those older than 65 years, and those with immunosuppression.

METHODOLOGY:

• To evaluate the risk for NMSC — basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) — in patients with ASCVD on PCSK9 inhibitors, researchers analyzed data from the US Collaborative Network in the TriNetX database of adults aged ≥ 40 years with ASCVD who received statin therapy between 2016 and 2022.
• A total of 73,636 patients were included, divided equally between those receiving a PCSK9 inhibitor (evolocumab, alirocumab, or inclisiran) plus statin therapy and the control group (those on statin therapy only).
• The analysis used propensity score matching for head-to-head comparisons, with hazard ratios (HRs) estimated using Cox proportional hazard models.
• Stratified analyses examined outcomes by age, sex, Fitzpatrick skin type, and immune status. (Immunosuppressed patients were those treated with immunosuppressants for more than 90 days in the year before the index date — the date when exposed patients were first prescribed a PCSK9 inhibitor, which was also index date for matched patients in the statin-only group.)

TAKEAWAY:

• Patients with ASCVD in the PCSK9 group showed significantly lower risks for NMSC (HR, 0.78; 95% CI, 0.71-0.87), BCC (HR, 0.78; 95% CI, 0.69-0.89), and SCC (HR, 0.79; 95% CI, 0.67-0.93) than control individuals on a statin only (P < .001 for all three).
• Both evolocumab and alirocumab demonstrated similar protective effects against the development of NMSC.
• The reduced risk for NMSC was particularly notable among patients aged 65-79 years (HR, 0.75; 95% CI, 0.66-0.86) and those aged ≥ 80 years (HR, 0.74; 95% CI, 0.60-0.91).
• Men showed a more pronounced reduction in the risk for NMSC (HR, 0.73; 95% CI, 0.64-0.83) than women (HR, 0.93; 95% CI, 0.78-1.11). The effect on lowering NMSC risk was also evident among immunosuppressed patients in the PCSK9 group (HR, 0.68; 95% CI, 0.60-0.75).

IN PRACTICE:

“The findings suggest the promising pleiotropic effect of PCSK9 inhibitors on the chemoprevention of NMSC,” the study authors wrote. Referring to previous studies that “provided mechanistic clues to our findings,” they added that “further studies are required to investigate the underlying mechanisms and establish causality.”

SOURCE:

The study was led by Cheng-Yuan Li, Taipei Veterans General Hospital, Taipei, Taiwan, and was published online in The British Journal of Dermatology.

LIMITATIONS:

Electronic health records lack information on sun protection habits, family history of skin cancer, diet, body mass index, and air pollution exposure, risk factors for NMSC. The study also lacked detailed information on enrollees’ lipid profiles and was focused mostly on patients in the United States, limiting the generalizability of the findings to other regions.

DISCLOSURES:

The study was supported by grants from Taipei Veterans General Hospital and the Ministry of Science and Technology, Taiwan. The authors reported no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.