Lipid Disorders

TOPLINE:

Both low and high levels of high-density lipoprotein (HDL) are associated with an increased risk for age-related macular degeneration (AMD). This study also identified a potential novel single-nucleotide polymorphism linked to an elevated risk for the retina condition.

METHODOLOGY:

• Researchers conducted a cross-sectional retrospective analysis using data from the All of Us research program to assess the association between lipoprotein and the risk for AMD.
• They analyzed data from 2328 patients with AMD (mean age, 75.5 years; 46.7% women; 84.2% White individuals) and 5028 matched controls (mean age, 75.6 years; 52.5% women; 82.9% White individuals).
• Data were extracted for smoking status, history of hyperlipidemia, use of statins (categorized as hepatically and non-hepatically metabolized), and laboratory values for total triglyceride, low-density lipoprotein (LDL), and HDL levels.
• Data for single-nucleotide polymorphisms associated with the dysregulation of LDL and HDL metabolism were extracted using the PLINK toolkit.

TAKEAWAY:

• Both high and low HDL levels were associated with an increased risk for AMD (adjusted odds ratio [aOR], 1.28 for both; both P < .001), whereas low and high levels of triglyceride and LDL did not demonstrate a statistically significant association with the risk for AMD.
• A history of smoking and statin use showed significant associations with an increased risk for AMD (aOR, 1.30 and 1.36, respectively; both P < .001).
• Single-nucleotide polymorphisms in the genes associated with HDL metabolism, ABCA1 and LIPC, were negatively associated with the risk for AMD (aOR, 0.88; P = .04 and aOR, 0.86; P = .001, respectively).
• Lipoprotein(a) or Lp(a) was identified as a novel single nucleotide polymorphism linked to an increased risk for AMD (aOR, 1.37; P = .007).

IN PRACTICE:

“Despite conflicting evidence regarding the relationship with elevated HDL and AMD risk, this is to our knowledge the first time a U-shaped relationship with low and high HDL and AMD has been described. In fact, the presence of a U-shaped relationship may explain inconsistency in prior analyses comparing mean HDL levels in AMD and control populations,” the study authors wrote. 

SOURCE:

The study was led by Jimmy S. Chen, MD, of the Viterbi Family Department of Ophthalmology and Shiley Eye Institute at the University of California, San Diego. It was published online on January 3, 2025, in Ophthalmology.

LIMITATIONS:

The study was limited by the retrospective collection and analysis of data. The use of billing codes for diagnosis extraction may have introduced documentation inaccuracies. The subgroup analysis by severity of AMD was not performed.

DISCLOSURES:

One of the authors was funded by grants from the National Eye Institute (NEI), Research to Prevent Blindness Career Development Award, Robert Machemer MD and International Retinal Research Foundation, and the UC San Diego Academic Senate. Another author reported receiving a grant from the National Heart, Lung, and Blood Institute, while a third author received funding from the National Institutes of Health (NIH), NEI, and Research to Prevent Blindness. The All of Us Research Program was supported by grants from the NIH and other sources. 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 appeared on Medscape.com.

TOPLINE:

Both low and high levels of high-density lipoprotein (HDL) are associated with an increased risk for age-related macular degeneration (AMD). This study also identified a potential novel single-nucleotide polymorphism linked to an elevated risk for the retina condition.

METHODOLOGY:

• Researchers conducted a cross-sectional retrospective analysis using data from the All of Us research program to assess the association between lipoprotein and the risk for AMD.
• They analyzed data from 2328 patients with AMD (mean age, 75.5 years; 46.7% women; 84.2% White individuals) and 5028 matched controls (mean age, 75.6 years; 52.5% women; 82.9% White individuals).
• Data were extracted for smoking status, history of hyperlipidemia, use of statins (categorized as hepatically and non-hepatically metabolized), and laboratory values for total triglyceride, low-density lipoprotein (LDL), and HDL levels.
• Data for single-nucleotide polymorphisms associated with the dysregulation of LDL and HDL metabolism were extracted using the PLINK toolkit.

TAKEAWAY:

• Both high and low HDL levels were associated with an increased risk for AMD (adjusted odds ratio [aOR], 1.28 for both; both P < .001), whereas low and high levels of triglyceride and LDL did not demonstrate a statistically significant association with the risk for AMD.
• A history of smoking and statin use showed significant associations with an increased risk for AMD (aOR, 1.30 and 1.36, respectively; both P < .001).
• Single-nucleotide polymorphisms in the genes associated with HDL metabolism, ABCA1 and LIPC, were negatively associated with the risk for AMD (aOR, 0.88; P = .04 and aOR, 0.86; P = .001, respectively).
• Lipoprotein(a) or Lp(a) was identified as a novel single nucleotide polymorphism linked to an increased risk for AMD (aOR, 1.37; P = .007).

IN PRACTICE:

“Despite conflicting evidence regarding the relationship with elevated HDL and AMD risk, this is to our knowledge the first time a U-shaped relationship with low and high HDL and AMD has been described. In fact, the presence of a U-shaped relationship may explain inconsistency in prior analyses comparing mean HDL levels in AMD and control populations,” the study authors wrote. 

SOURCE:

The study was led by Jimmy S. Chen, MD, of the Viterbi Family Department of Ophthalmology and Shiley Eye Institute at the University of California, San Diego. It was published online on January 3, 2025, in Ophthalmology.

LIMITATIONS:

The study was limited by the retrospective collection and analysis of data. The use of billing codes for diagnosis extraction may have introduced documentation inaccuracies. The subgroup analysis by severity of AMD was not performed.

DISCLOSURES:

One of the authors was funded by grants from the National Eye Institute (NEI), Research to Prevent Blindness Career Development Award, Robert Machemer MD and International Retinal Research Foundation, and the UC San Diego Academic Senate. Another author reported receiving a grant from the National Heart, Lung, and Blood Institute, while a third author received funding from the National Institutes of Health (NIH), NEI, and Research to Prevent Blindness. The All of Us Research Program was supported by grants from the NIH and other sources. 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 appeared on Medscape.com.

TOPLINE:

Both low and high levels of high-density lipoprotein (HDL) are associated with an increased risk for age-related macular degeneration (AMD). This study also identified a potential novel single-nucleotide polymorphism linked to an elevated risk for the retina condition.

METHODOLOGY:

• Researchers conducted a cross-sectional retrospective analysis using data from the All of Us research program to assess the association between lipoprotein and the risk for AMD.
• They analyzed data from 2328 patients with AMD (mean age, 75.5 years; 46.7% women; 84.2% White individuals) and 5028 matched controls (mean age, 75.6 years; 52.5% women; 82.9% White individuals).
• Data were extracted for smoking status, history of hyperlipidemia, use of statins (categorized as hepatically and non-hepatically metabolized), and laboratory values for total triglyceride, low-density lipoprotein (LDL), and HDL levels.
• Data for single-nucleotide polymorphisms associated with the dysregulation of LDL and HDL metabolism were extracted using the PLINK toolkit.

TAKEAWAY:

• Both high and low HDL levels were associated with an increased risk for AMD (adjusted odds ratio [aOR], 1.28 for both; both P < .001), whereas low and high levels of triglyceride and LDL did not demonstrate a statistically significant association with the risk for AMD.
• A history of smoking and statin use showed significant associations with an increased risk for AMD (aOR, 1.30 and 1.36, respectively; both P < .001).
• Single-nucleotide polymorphisms in the genes associated with HDL metabolism, ABCA1 and LIPC, were negatively associated with the risk for AMD (aOR, 0.88; P = .04 and aOR, 0.86; P = .001, respectively).
• Lipoprotein(a) or Lp(a) was identified as a novel single nucleotide polymorphism linked to an increased risk for AMD (aOR, 1.37; P = .007).

IN PRACTICE:

“Despite conflicting evidence regarding the relationship with elevated HDL and AMD risk, this is to our knowledge the first time a U-shaped relationship with low and high HDL and AMD has been described. In fact, the presence of a U-shaped relationship may explain inconsistency in prior analyses comparing mean HDL levels in AMD and control populations,” the study authors wrote. 

SOURCE:

The study was led by Jimmy S. Chen, MD, of the Viterbi Family Department of Ophthalmology and Shiley Eye Institute at the University of California, San Diego. It was published online on January 3, 2025, in Ophthalmology.

LIMITATIONS:

The study was limited by the retrospective collection and analysis of data. The use of billing codes for diagnosis extraction may have introduced documentation inaccuracies. The subgroup analysis by severity of AMD was not performed.

DISCLOSURES:

One of the authors was funded by grants from the National Eye Institute (NEI), Research to Prevent Blindness Career Development Award, Robert Machemer MD and International Retinal Research Foundation, and the UC San Diego Academic Senate. Another author reported receiving a grant from the National Heart, Lung, and Blood Institute, while a third author received funding from the National Institutes of Health (NIH), NEI, and Research to Prevent Blindness. The All of Us Research Program was supported by grants from the NIH and other sources. 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 appeared on Medscape.com.

TOPLINE:

Fragmented sleep — that is, increased wakefulness and reduced sleep efficiency — is a sign of metabolic dysfunction–associated steatotic liver disease (MASLD), a study using actigraphy showed.

METHODOLOGY:

• Researchers assessed sleep-wake rhythms in 35 patients with MASLD (median age, 58 years; 66% were men; 80% with metabolic syndrome) and 16 matched healthy controls (median age, 61 years; 50% were men) using data collected 24/7 via actigraphy for 4 weeks.
• Sub-analyses were conducted with MASLD comparator groups: 16 patients with MASH, 8 with MASH with cirrhosis, and 11 with non-MASH–related cirrhosis.
• All participants visited the clinic at baseline, week 2, and week 4 to undergo a clinical investigation and complete questionnaires about their sleep.
• A standardized sleep hygiene education session was conducted at week 2.

TAKEAWAY:

• Actigraphy data from patients with MASLD did not reveal significant differences in bedtime, sleep-onset latency, sleep duration, wake-up time, or time in bed compared with controls.
• However, compared with controls, those with MASLD woke 55% more often at night (8.5 vs 5.5), lay awake 113% longer after having first fallen asleep (45.4 minutes vs 21.3 minutes), and slept more often and longer during the day (decreased sleep efficiency).
• Subgroup analyses showed that actigraphy-measured sleep patterns and quality were similarly impaired in patients with MASH, MASH with cirrhosis, and non–MASH-related cirrhosis.
• Patients with MASLD self-reported their fragmented sleep as shorter sleep with a delayed onset. In sleep diaries, 32% of patients with MASLD reported sleep disturbances caused by psychological stress, compared with only 6.25% of controls and 9% of patients with cirrhosis.
• The sleep education session did not change the actigraphy measures or the sleep parameters assessed with sleep questionnaires at the end of the study.

IN PRACTICE:

“We concluded from our data that sleep fragmentation plays a role in the pathogenesis of human MASLD. Whether MASLD causes sleep disorders or vice versa remains unknown. The underlying mechanism presumably involves genetics, environmental factors, and the activation of immune responses — ultimately driven by obesity and metabolic syndrome,” said corresponding author.

SOURCE:

The study, led by Sofia Schaeffer, PhD, University of Basel, Switzerland, was published online in Frontiers in Network Physiology.

LIMITATIONS:

The study had several limitations. There was a significant difference in body mass index between patients with MASLD (median, 31) and controls (median, 23.5), representing a potential confounder that could explain the differences in sleep behavior. Undetected obstructive sleep apnea could also be a confounding factor. The small number of participants limited the interpretation and generalization of the data, especially in the MASLD subgroups.

DISCLOSURES:

This study was supported by a grant from the University of Basel. One coauthor received a research grant from the University Center for Gastrointestinal and Liver Diseases, Basel, Switzerland. Another coauthor was employed by NovoLytiX. Schaeffer and the remaining coauthors declared that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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

TOPLINE:

Fragmented sleep — that is, increased wakefulness and reduced sleep efficiency — is a sign of metabolic dysfunction–associated steatotic liver disease (MASLD), a study using actigraphy showed.

METHODOLOGY:

• Researchers assessed sleep-wake rhythms in 35 patients with MASLD (median age, 58 years; 66% were men; 80% with metabolic syndrome) and 16 matched healthy controls (median age, 61 years; 50% were men) using data collected 24/7 via actigraphy for 4 weeks.
• Sub-analyses were conducted with MASLD comparator groups: 16 patients with MASH, 8 with MASH with cirrhosis, and 11 with non-MASH–related cirrhosis.
• All participants visited the clinic at baseline, week 2, and week 4 to undergo a clinical investigation and complete questionnaires about their sleep.
• A standardized sleep hygiene education session was conducted at week 2.

TAKEAWAY:

• Actigraphy data from patients with MASLD did not reveal significant differences in bedtime, sleep-onset latency, sleep duration, wake-up time, or time in bed compared with controls.
• However, compared with controls, those with MASLD woke 55% more often at night (8.5 vs 5.5), lay awake 113% longer after having first fallen asleep (45.4 minutes vs 21.3 minutes), and slept more often and longer during the day (decreased sleep efficiency).
• Subgroup analyses showed that actigraphy-measured sleep patterns and quality were similarly impaired in patients with MASH, MASH with cirrhosis, and non–MASH-related cirrhosis.
• Patients with MASLD self-reported their fragmented sleep as shorter sleep with a delayed onset. In sleep diaries, 32% of patients with MASLD reported sleep disturbances caused by psychological stress, compared with only 6.25% of controls and 9% of patients with cirrhosis.
• The sleep education session did not change the actigraphy measures or the sleep parameters assessed with sleep questionnaires at the end of the study.

IN PRACTICE:

“We concluded from our data that sleep fragmentation plays a role in the pathogenesis of human MASLD. Whether MASLD causes sleep disorders or vice versa remains unknown. The underlying mechanism presumably involves genetics, environmental factors, and the activation of immune responses — ultimately driven by obesity and metabolic syndrome,” said corresponding author.

SOURCE:

The study, led by Sofia Schaeffer, PhD, University of Basel, Switzerland, was published online in Frontiers in Network Physiology.

LIMITATIONS:

The study had several limitations. There was a significant difference in body mass index between patients with MASLD (median, 31) and controls (median, 23.5), representing a potential confounder that could explain the differences in sleep behavior. Undetected obstructive sleep apnea could also be a confounding factor. The small number of participants limited the interpretation and generalization of the data, especially in the MASLD subgroups.

DISCLOSURES:

This study was supported by a grant from the University of Basel. One coauthor received a research grant from the University Center for Gastrointestinal and Liver Diseases, Basel, Switzerland. Another coauthor was employed by NovoLytiX. Schaeffer and the remaining coauthors declared that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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

TOPLINE:

Fragmented sleep — that is, increased wakefulness and reduced sleep efficiency — is a sign of metabolic dysfunction–associated steatotic liver disease (MASLD), a study using actigraphy showed.

METHODOLOGY:

• Researchers assessed sleep-wake rhythms in 35 patients with MASLD (median age, 58 years; 66% were men; 80% with metabolic syndrome) and 16 matched healthy controls (median age, 61 years; 50% were men) using data collected 24/7 via actigraphy for 4 weeks.
• Sub-analyses were conducted with MASLD comparator groups: 16 patients with MASH, 8 with MASH with cirrhosis, and 11 with non-MASH–related cirrhosis.
• All participants visited the clinic at baseline, week 2, and week 4 to undergo a clinical investigation and complete questionnaires about their sleep.
• A standardized sleep hygiene education session was conducted at week 2.

TAKEAWAY:

• Actigraphy data from patients with MASLD did not reveal significant differences in bedtime, sleep-onset latency, sleep duration, wake-up time, or time in bed compared with controls.
• However, compared with controls, those with MASLD woke 55% more often at night (8.5 vs 5.5), lay awake 113% longer after having first fallen asleep (45.4 minutes vs 21.3 minutes), and slept more often and longer during the day (decreased sleep efficiency).
• Subgroup analyses showed that actigraphy-measured sleep patterns and quality were similarly impaired in patients with MASH, MASH with cirrhosis, and non–MASH-related cirrhosis.
• Patients with MASLD self-reported their fragmented sleep as shorter sleep with a delayed onset. In sleep diaries, 32% of patients with MASLD reported sleep disturbances caused by psychological stress, compared with only 6.25% of controls and 9% of patients with cirrhosis.
• The sleep education session did not change the actigraphy measures or the sleep parameters assessed with sleep questionnaires at the end of the study.

IN PRACTICE:

“We concluded from our data that sleep fragmentation plays a role in the pathogenesis of human MASLD. Whether MASLD causes sleep disorders or vice versa remains unknown. The underlying mechanism presumably involves genetics, environmental factors, and the activation of immune responses — ultimately driven by obesity and metabolic syndrome,” said corresponding author.

SOURCE:

The study, led by Sofia Schaeffer, PhD, University of Basel, Switzerland, was published online in Frontiers in Network Physiology.

LIMITATIONS:

The study had several limitations. There was a significant difference in body mass index between patients with MASLD (median, 31) and controls (median, 23.5), representing a potential confounder that could explain the differences in sleep behavior. Undetected obstructive sleep apnea could also be a confounding factor. The small number of participants limited the interpretation and generalization of the data, especially in the MASLD subgroups.

DISCLOSURES:

This study was supported by a grant from the University of Basel. One coauthor received a research grant from the University Center for Gastrointestinal and Liver Diseases, Basel, Switzerland. Another coauthor was employed by NovoLytiX. Schaeffer and the remaining coauthors declared that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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

An individual’s estimated risk of having a heart attack or stroke in the next 10 years is widely used to guide preventative medication prescriptions with statins or antihypertensive drugs in those who have not yet had such an event.

To estimate that risk, doctors use equations that include different risk factors, such as age, cholesterol levels, and blood pressure. The current equations, known as the pooled cohort equations, are considered to be outdated as they were developed in 2013 based on population data from the 1960s and 70s. A new set of risk equations — known as the PREVENT equations — were developed by the American Heart Association (AHA) in 2023, and are based on a more contemporary population. It is anticipated that AHA will recommend these new risk equations be used in clinical practice in the next primary prevention guidelines.

But could these new risk equations do more harm than good?

Two recent studies found that applying the PREVENT risk equations to the US population results in a much lower overall level of risk compared with the pooled cohort equations. And, if the current threshold for starting statin treatment — which is an estimated 7.5% risk of having a heart attack or stroke in the next 10 years — is kept the same, this would result in many fewer patients being eligible for statin treatment.

As cardiovascular risk is also used to guide antihypertensive treatment, the new risk equations would also result in fewer people with borderline high blood pressure being eligible for those medications.

This has raised concerns in the medical community, where there is a widespread view that many more people would benefit from primary prevention treatment, and that anything that may cause fewer people to receive these medications would be harmful. 

“I believe the new equations more accurately predict the risk of the current US population, but we need to be aware of what effect that may have on use of statins,” said Tim Anderson, MD, who studies healthcare delivery at the University of Pittsburgh in Pennsylvania and is lead author of one of the studies evaluating the equations.

Anderson told this news organization that the pooled cohort equations have long been viewed as problematic. 

“Because these equations were based on cohorts from the 1960s and 70s, it is believed they overestimate the current population’s risk of MI and stroke as the burden of disease has shifted in the intervening 50-60 years,” he said.

 

Current Equations Overestimate Risk

The new equations are based on more recent, representative, and diverse cohorts that capture a wider spectrum of the population in terms of race, ethnicity, and socioeconomic status. They also include factors that are now known to be relevant to cardiovascular risk, such as chronic kidney disease.

Anderson compared how the two sets of equations estimated risk of cardiovascular disease in the next 10 years in the US population using the NHANES survey — a large nationally representative survey conducted between 2017 and 2020. 

He found that the pooled cohort equations estimated the population average 10-year risk of cardiovascular disease to be about 8%, but the PREVENT equations estimated it at just over 4%.

“The new equations estimate that the middle-aged US population have almost half the level of risk of MI and stroke over next 10 years compared with the equations used currently. So, we will substantially change risk estimates if the new equations are introduced into practice,” Anderson said. 

The study found that, if the PREVENT equations are adopted in the next set of primary prevention guidelines and the current threshold of a 7.5% risk of having an MI or stroke in the next 10 years is maintained as the starting point for statin treatment, then 17.3 million adults who were previously recommended primary prevention statin therapy would no longer be eligible.

A second, similar study, conducted by a different team of US researchers, estimated that using PREVENT would decrease the number of US adults receiving or recommended for statin therapy by 14.3 million and antihypertensive therapy by 2.62 million.

The researchers, led by James A. Diao, MD, from Harvard Medical School, Boston, Massachusetts, also suggested that over 10 years, reductions in treatment eligibility could result in an estimated 107,000 additional MI or stroke events.

Anderson points out that using the new equations would not affect the highest-risk patients. “They are still going to be high risk whichever equations are used. If you smoke a pack of cigarettes a day, have very high blood pressure or cholesterol and are older, then you are high risk. That part hasn’t changed. These people will qualify for statin treatment many times over with both sets of guidelines,” he said. 

Rather it will be the large population at moderate risk of cardiovascular disease that will be affected, with far fewer of these individuals likely to get statins.

“If you are on the fence about whether to take a statin or not and you’re currently just on the threshold where they might be recommended then these new equations could mean that you’ll be less likely to be offered them,” he said. “Using the new equations may result in a delay of a couple of years to have that conversation.”

 

A Red Flag

Steve Nissen, MD, a cardiologist at the Cleveland Clinic in Ohio, is not a fan of cardiovascular risk equations in general. He points out that less than half of those currently eligible for statins are actually treated. And he believes the studies suggesting fewer people will be eligible with the new risk equations raise a red flag on whether they should be used.

“Anything that may result in fewer people being treated is a huge problem,” he told this news organization. “We have abundant evidence that we should be treating more people, not fewer people. Every study we have done has shown benefit with statins.”

The risk calculators were initially developed to limit use of statins and other medications to high-risk patients, he said, but now that we know more about safety of these drugs, it’s clear that the risks are almost nonexistent. 

“We really need something else to guide the prescription of statins,” said Nissen.

Nissen suggests the risk calculators and guidelines have resulted in undertreatment of the population because they lack nuance and put too much emphasis on age. We should be more interested in reducing the lifetime risk of cardiovascular events, he said. “Calculators don’t do a good job of that. Their time horizons are too short. Young people with a family history of cardiovascular disease may have a low 10-year risk on a risk calculator but their lifetime risk is elevated, and as such, they should be considered for statin treatment. We need to find a more nuanced approach to understanding the lifetime risk of individuals,” he said. 

Nissen said risk calculators can be useful in high-risk patients to help demonstrate their need for treatment. “I can show them the calculator and that they have a 20% chance of an event — that can help convince them to take a statin.” 

But at the lower end of the risk scale, “all it does is keep patients who should be getting treatment from having that treatment.”

Nissen said changing the risk calculator won’t affect how he treats patients. “I use judgment to decide who to treat based on scientific literature and the patient in front of me. We will engage in a discussion and make a shared decision on what is the best course of action. Calculators will never be a substitute for medical judgment,” he said.

 

Equations Don’t Decide

Sadiya Khan, MD, a cardiologist at Northwestern University, Evanston, Illinois, and lead author of the PREVENT equations, told this news organization that it is important to put this discussion into context.

“The two recent papers do a good job of describing differences in predictive risk between the two sets of equations but that’s where they stop,” she said. “The translation from that to the decision on who should or should not be on statins or other medications is a step too far.”

Clinical guidelines will need to be updated to take the PREVENT equations into account, as Khan argued in a JAMA editorial. So it is not clear whether the current 7.5% 10-year risk figure will remain the threshold to start treatment. Khan anticipates the guidelines committee will have to re-evaluate that threshold.

“The 7.5% risk threshold was advised in the 2013 guidelines, based on what we knew then about the balance between benefit and harm and with the knowledge that the risk equations overestimated risk,” she said. “We now have a lot more data on the safety of statin therapy. We see this frequently in preventive care. Treatments often becomes more widespread in time and use expands into lower-risk patients.”

She also pointed out that the current primary prevention guidelines encourage consideration of other factors, not just predictive risk scores, when thinking about starting statins, including very high LDL cholesterol, family history, and apo B and Lp(a) levels.

“The recommendation on who would qualify for statin therapy is not based on one number,” she said. “It is based on many considerations, including both qualitative and quantitative factors, and discussions between the patient and the doctor. It is not a straightforward yes or no based on a 7.5% risk threshold.”

The equations, she said, should only be viewed as the first step in the process, and she said she agrees with Nissen that when applying the equations, doctors need to use additional data from each individual patient to make a judgment. “Equations do not decide who gets treated. Clinical practice guidelines do that.” 

Khan also agreed with Nissen that more effort is needed to identify longer term cardiovascular risk in younger people, and so the PREVENT equations include 30-year risk estimates.

“I totally agree that we need to start earlier in having these prevention conversations. The PREVENT model starts at age 30 which is 10 years earlier than the pooled cohort equations and they add a 30-year time horizon as well as the 10-year period for these discussions on predicted risk estimates,” she said. “We need to make sure we are not missing risk in young adults just because we are waiting for them to get into some arbitrary age category.”

Khan says she believes that, used correctly, the new equations will not limit access to statins or other cardiovascular treatments. “Because they are a more accurate reflection of risk in the contemporary population, the new PREVENT equations should identify the correct patients to be treated, within the confines of knowing that no risk prediction equation is perfect,” she said. “And if everything else is considered as well, not just the numbers in the risk equations, it shouldn’t result in fewer patients being treated.”

Anderson reported receiving grants from the American Heart Association, the American College of Cardiology, and the US Deprescribing Research Network. Nissen is leading a development program for a nonprescription low dose of rosuvastatin. He is also involved in trials of a new cholesterol lowering drug, obicetrapib, and on trials on drugs that lower Lp(a). Khan reported receiving grants from the American Heart Association and National Heart, Lung, and Blood Institute.

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

An individual’s estimated risk of having a heart attack or stroke in the next 10 years is widely used to guide preventative medication prescriptions with statins or antihypertensive drugs in those who have not yet had such an event.

To estimate that risk, doctors use equations that include different risk factors, such as age, cholesterol levels, and blood pressure. The current equations, known as the pooled cohort equations, are considered to be outdated as they were developed in 2013 based on population data from the 1960s and 70s. A new set of risk equations — known as the PREVENT equations — were developed by the American Heart Association (AHA) in 2023, and are based on a more contemporary population. It is anticipated that AHA will recommend these new risk equations be used in clinical practice in the next primary prevention guidelines.

But could these new risk equations do more harm than good?

Two recent studies found that applying the PREVENT risk equations to the US population results in a much lower overall level of risk compared with the pooled cohort equations. And, if the current threshold for starting statin treatment — which is an estimated 7.5% risk of having a heart attack or stroke in the next 10 years — is kept the same, this would result in many fewer patients being eligible for statin treatment.

As cardiovascular risk is also used to guide antihypertensive treatment, the new risk equations would also result in fewer people with borderline high blood pressure being eligible for those medications.

This has raised concerns in the medical community, where there is a widespread view that many more people would benefit from primary prevention treatment, and that anything that may cause fewer people to receive these medications would be harmful. 

“I believe the new equations more accurately predict the risk of the current US population, but we need to be aware of what effect that may have on use of statins,” said Tim Anderson, MD, who studies healthcare delivery at the University of Pittsburgh in Pennsylvania and is lead author of one of the studies evaluating the equations.

Anderson told this news organization that the pooled cohort equations have long been viewed as problematic. 

“Because these equations were based on cohorts from the 1960s and 70s, it is believed they overestimate the current population’s risk of MI and stroke as the burden of disease has shifted in the intervening 50-60 years,” he said.

 

Current Equations Overestimate Risk

The new equations are based on more recent, representative, and diverse cohorts that capture a wider spectrum of the population in terms of race, ethnicity, and socioeconomic status. They also include factors that are now known to be relevant to cardiovascular risk, such as chronic kidney disease.

Anderson compared how the two sets of equations estimated risk of cardiovascular disease in the next 10 years in the US population using the NHANES survey — a large nationally representative survey conducted between 2017 and 2020. 

He found that the pooled cohort equations estimated the population average 10-year risk of cardiovascular disease to be about 8%, but the PREVENT equations estimated it at just over 4%.

“The new equations estimate that the middle-aged US population have almost half the level of risk of MI and stroke over next 10 years compared with the equations used currently. So, we will substantially change risk estimates if the new equations are introduced into practice,” Anderson said. 

The study found that, if the PREVENT equations are adopted in the next set of primary prevention guidelines and the current threshold of a 7.5% risk of having an MI or stroke in the next 10 years is maintained as the starting point for statin treatment, then 17.3 million adults who were previously recommended primary prevention statin therapy would no longer be eligible.

A second, similar study, conducted by a different team of US researchers, estimated that using PREVENT would decrease the number of US adults receiving or recommended for statin therapy by 14.3 million and antihypertensive therapy by 2.62 million.

The researchers, led by James A. Diao, MD, from Harvard Medical School, Boston, Massachusetts, also suggested that over 10 years, reductions in treatment eligibility could result in an estimated 107,000 additional MI or stroke events.

Anderson points out that using the new equations would not affect the highest-risk patients. “They are still going to be high risk whichever equations are used. If you smoke a pack of cigarettes a day, have very high blood pressure or cholesterol and are older, then you are high risk. That part hasn’t changed. These people will qualify for statin treatment many times over with both sets of guidelines,” he said. 

Rather it will be the large population at moderate risk of cardiovascular disease that will be affected, with far fewer of these individuals likely to get statins.

“If you are on the fence about whether to take a statin or not and you’re currently just on the threshold where they might be recommended then these new equations could mean that you’ll be less likely to be offered them,” he said. “Using the new equations may result in a delay of a couple of years to have that conversation.”

 

A Red Flag

Steve Nissen, MD, a cardiologist at the Cleveland Clinic in Ohio, is not a fan of cardiovascular risk equations in general. He points out that less than half of those currently eligible for statins are actually treated. And he believes the studies suggesting fewer people will be eligible with the new risk equations raise a red flag on whether they should be used.

“Anything that may result in fewer people being treated is a huge problem,” he told this news organization. “We have abundant evidence that we should be treating more people, not fewer people. Every study we have done has shown benefit with statins.”

The risk calculators were initially developed to limit use of statins and other medications to high-risk patients, he said, but now that we know more about safety of these drugs, it’s clear that the risks are almost nonexistent. 

“We really need something else to guide the prescription of statins,” said Nissen.

Nissen suggests the risk calculators and guidelines have resulted in undertreatment of the population because they lack nuance and put too much emphasis on age. We should be more interested in reducing the lifetime risk of cardiovascular events, he said. “Calculators don’t do a good job of that. Their time horizons are too short. Young people with a family history of cardiovascular disease may have a low 10-year risk on a risk calculator but their lifetime risk is elevated, and as such, they should be considered for statin treatment. We need to find a more nuanced approach to understanding the lifetime risk of individuals,” he said. 

Nissen said risk calculators can be useful in high-risk patients to help demonstrate their need for treatment. “I can show them the calculator and that they have a 20% chance of an event — that can help convince them to take a statin.” 

But at the lower end of the risk scale, “all it does is keep patients who should be getting treatment from having that treatment.”

Nissen said changing the risk calculator won’t affect how he treats patients. “I use judgment to decide who to treat based on scientific literature and the patient in front of me. We will engage in a discussion and make a shared decision on what is the best course of action. Calculators will never be a substitute for medical judgment,” he said.

 

Equations Don’t Decide

Sadiya Khan, MD, a cardiologist at Northwestern University, Evanston, Illinois, and lead author of the PREVENT equations, told this news organization that it is important to put this discussion into context.

“The two recent papers do a good job of describing differences in predictive risk between the two sets of equations but that’s where they stop,” she said. “The translation from that to the decision on who should or should not be on statins or other medications is a step too far.”

Clinical guidelines will need to be updated to take the PREVENT equations into account, as Khan argued in a JAMA editorial. So it is not clear whether the current 7.5% 10-year risk figure will remain the threshold to start treatment. Khan anticipates the guidelines committee will have to re-evaluate that threshold.

“The 7.5% risk threshold was advised in the 2013 guidelines, based on what we knew then about the balance between benefit and harm and with the knowledge that the risk equations overestimated risk,” she said. “We now have a lot more data on the safety of statin therapy. We see this frequently in preventive care. Treatments often becomes more widespread in time and use expands into lower-risk patients.”

She also pointed out that the current primary prevention guidelines encourage consideration of other factors, not just predictive risk scores, when thinking about starting statins, including very high LDL cholesterol, family history, and apo B and Lp(a) levels.

“The recommendation on who would qualify for statin therapy is not based on one number,” she said. “It is based on many considerations, including both qualitative and quantitative factors, and discussions between the patient and the doctor. It is not a straightforward yes or no based on a 7.5% risk threshold.”

The equations, she said, should only be viewed as the first step in the process, and she said she agrees with Nissen that when applying the equations, doctors need to use additional data from each individual patient to make a judgment. “Equations do not decide who gets treated. Clinical practice guidelines do that.” 

Khan also agreed with Nissen that more effort is needed to identify longer term cardiovascular risk in younger people, and so the PREVENT equations include 30-year risk estimates.

“I totally agree that we need to start earlier in having these prevention conversations. The PREVENT model starts at age 30 which is 10 years earlier than the pooled cohort equations and they add a 30-year time horizon as well as the 10-year period for these discussions on predicted risk estimates,” she said. “We need to make sure we are not missing risk in young adults just because we are waiting for them to get into some arbitrary age category.”

Khan says she believes that, used correctly, the new equations will not limit access to statins or other cardiovascular treatments. “Because they are a more accurate reflection of risk in the contemporary population, the new PREVENT equations should identify the correct patients to be treated, within the confines of knowing that no risk prediction equation is perfect,” she said. “And if everything else is considered as well, not just the numbers in the risk equations, it shouldn’t result in fewer patients being treated.”

Anderson reported receiving grants from the American Heart Association, the American College of Cardiology, and the US Deprescribing Research Network. Nissen is leading a development program for a nonprescription low dose of rosuvastatin. He is also involved in trials of a new cholesterol lowering drug, obicetrapib, and on trials on drugs that lower Lp(a). Khan reported receiving grants from the American Heart Association and National Heart, Lung, and Blood Institute.

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

An individual’s estimated risk of having a heart attack or stroke in the next 10 years is widely used to guide preventative medication prescriptions with statins or antihypertensive drugs in those who have not yet had such an event.

To estimate that risk, doctors use equations that include different risk factors, such as age, cholesterol levels, and blood pressure. The current equations, known as the pooled cohort equations, are considered to be outdated as they were developed in 2013 based on population data from the 1960s and 70s. A new set of risk equations — known as the PREVENT equations — were developed by the American Heart Association (AHA) in 2023, and are based on a more contemporary population. It is anticipated that AHA will recommend these new risk equations be used in clinical practice in the next primary prevention guidelines.

But could these new risk equations do more harm than good?

Two recent studies found that applying the PREVENT risk equations to the US population results in a much lower overall level of risk compared with the pooled cohort equations. And, if the current threshold for starting statin treatment — which is an estimated 7.5% risk of having a heart attack or stroke in the next 10 years — is kept the same, this would result in many fewer patients being eligible for statin treatment.

As cardiovascular risk is also used to guide antihypertensive treatment, the new risk equations would also result in fewer people with borderline high blood pressure being eligible for those medications.

This has raised concerns in the medical community, where there is a widespread view that many more people would benefit from primary prevention treatment, and that anything that may cause fewer people to receive these medications would be harmful. 

“I believe the new equations more accurately predict the risk of the current US population, but we need to be aware of what effect that may have on use of statins,” said Tim Anderson, MD, who studies healthcare delivery at the University of Pittsburgh in Pennsylvania and is lead author of one of the studies evaluating the equations.

Anderson told this news organization that the pooled cohort equations have long been viewed as problematic. 

“Because these equations were based on cohorts from the 1960s and 70s, it is believed they overestimate the current population’s risk of MI and stroke as the burden of disease has shifted in the intervening 50-60 years,” he said.

 

Current Equations Overestimate Risk

The new equations are based on more recent, representative, and diverse cohorts that capture a wider spectrum of the population in terms of race, ethnicity, and socioeconomic status. They also include factors that are now known to be relevant to cardiovascular risk, such as chronic kidney disease.

Anderson compared how the two sets of equations estimated risk of cardiovascular disease in the next 10 years in the US population using the NHANES survey — a large nationally representative survey conducted between 2017 and 2020. 

He found that the pooled cohort equations estimated the population average 10-year risk of cardiovascular disease to be about 8%, but the PREVENT equations estimated it at just over 4%.

“The new equations estimate that the middle-aged US population have almost half the level of risk of MI and stroke over next 10 years compared with the equations used currently. So, we will substantially change risk estimates if the new equations are introduced into practice,” Anderson said. 

The study found that, if the PREVENT equations are adopted in the next set of primary prevention guidelines and the current threshold of a 7.5% risk of having an MI or stroke in the next 10 years is maintained as the starting point for statin treatment, then 17.3 million adults who were previously recommended primary prevention statin therapy would no longer be eligible.

A second, similar study, conducted by a different team of US researchers, estimated that using PREVENT would decrease the number of US adults receiving or recommended for statin therapy by 14.3 million and antihypertensive therapy by 2.62 million.

The researchers, led by James A. Diao, MD, from Harvard Medical School, Boston, Massachusetts, also suggested that over 10 years, reductions in treatment eligibility could result in an estimated 107,000 additional MI or stroke events.

Anderson points out that using the new equations would not affect the highest-risk patients. “They are still going to be high risk whichever equations are used. If you smoke a pack of cigarettes a day, have very high blood pressure or cholesterol and are older, then you are high risk. That part hasn’t changed. These people will qualify for statin treatment many times over with both sets of guidelines,” he said. 

Rather it will be the large population at moderate risk of cardiovascular disease that will be affected, with far fewer of these individuals likely to get statins.

“If you are on the fence about whether to take a statin or not and you’re currently just on the threshold where they might be recommended then these new equations could mean that you’ll be less likely to be offered them,” he said. “Using the new equations may result in a delay of a couple of years to have that conversation.”

 

A Red Flag

Steve Nissen, MD, a cardiologist at the Cleveland Clinic in Ohio, is not a fan of cardiovascular risk equations in general. He points out that less than half of those currently eligible for statins are actually treated. And he believes the studies suggesting fewer people will be eligible with the new risk equations raise a red flag on whether they should be used.

“Anything that may result in fewer people being treated is a huge problem,” he told this news organization. “We have abundant evidence that we should be treating more people, not fewer people. Every study we have done has shown benefit with statins.”

The risk calculators were initially developed to limit use of statins and other medications to high-risk patients, he said, but now that we know more about safety of these drugs, it’s clear that the risks are almost nonexistent. 

“We really need something else to guide the prescription of statins,” said Nissen.

Nissen suggests the risk calculators and guidelines have resulted in undertreatment of the population because they lack nuance and put too much emphasis on age. We should be more interested in reducing the lifetime risk of cardiovascular events, he said. “Calculators don’t do a good job of that. Their time horizons are too short. Young people with a family history of cardiovascular disease may have a low 10-year risk on a risk calculator but their lifetime risk is elevated, and as such, they should be considered for statin treatment. We need to find a more nuanced approach to understanding the lifetime risk of individuals,” he said. 

Nissen said risk calculators can be useful in high-risk patients to help demonstrate their need for treatment. “I can show them the calculator and that they have a 20% chance of an event — that can help convince them to take a statin.” 

But at the lower end of the risk scale, “all it does is keep patients who should be getting treatment from having that treatment.”

Nissen said changing the risk calculator won’t affect how he treats patients. “I use judgment to decide who to treat based on scientific literature and the patient in front of me. We will engage in a discussion and make a shared decision on what is the best course of action. Calculators will never be a substitute for medical judgment,” he said.

 

Equations Don’t Decide

Sadiya Khan, MD, a cardiologist at Northwestern University, Evanston, Illinois, and lead author of the PREVENT equations, told this news organization that it is important to put this discussion into context.

“The two recent papers do a good job of describing differences in predictive risk between the two sets of equations but that’s where they stop,” she said. “The translation from that to the decision on who should or should not be on statins or other medications is a step too far.”

Clinical guidelines will need to be updated to take the PREVENT equations into account, as Khan argued in a JAMA editorial. So it is not clear whether the current 7.5% 10-year risk figure will remain the threshold to start treatment. Khan anticipates the guidelines committee will have to re-evaluate that threshold.

“The 7.5% risk threshold was advised in the 2013 guidelines, based on what we knew then about the balance between benefit and harm and with the knowledge that the risk equations overestimated risk,” she said. “We now have a lot more data on the safety of statin therapy. We see this frequently in preventive care. Treatments often becomes more widespread in time and use expands into lower-risk patients.”

She also pointed out that the current primary prevention guidelines encourage consideration of other factors, not just predictive risk scores, when thinking about starting statins, including very high LDL cholesterol, family history, and apo B and Lp(a) levels.

“The recommendation on who would qualify for statin therapy is not based on one number,” she said. “It is based on many considerations, including both qualitative and quantitative factors, and discussions between the patient and the doctor. It is not a straightforward yes or no based on a 7.5% risk threshold.”

The equations, she said, should only be viewed as the first step in the process, and she said she agrees with Nissen that when applying the equations, doctors need to use additional data from each individual patient to make a judgment. “Equations do not decide who gets treated. Clinical practice guidelines do that.” 

Khan also agreed with Nissen that more effort is needed to identify longer term cardiovascular risk in younger people, and so the PREVENT equations include 30-year risk estimates.

“I totally agree that we need to start earlier in having these prevention conversations. The PREVENT model starts at age 30 which is 10 years earlier than the pooled cohort equations and they add a 30-year time horizon as well as the 10-year period for these discussions on predicted risk estimates,” she said. “We need to make sure we are not missing risk in young adults just because we are waiting for them to get into some arbitrary age category.”

Khan says she believes that, used correctly, the new equations will not limit access to statins or other cardiovascular treatments. “Because they are a more accurate reflection of risk in the contemporary population, the new PREVENT equations should identify the correct patients to be treated, within the confines of knowing that no risk prediction equation is perfect,” she said. “And if everything else is considered as well, not just the numbers in the risk equations, it shouldn’t result in fewer patients being treated.”

Anderson reported receiving grants from the American Heart Association, the American College of Cardiology, and the US Deprescribing Research Network. Nissen is leading a development program for a nonprescription low dose of rosuvastatin. He is also involved in trials of a new cholesterol lowering drug, obicetrapib, and on trials on drugs that lower Lp(a). Khan reported receiving grants from the American Heart Association and National Heart, Lung, and Blood Institute.

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

Estimation of cardiovascular risk (CVR) in individuals living with type 1 diabetes (T1D) was a key topic presented by Sophie Borot, MD, from Besançon University Hospital, Besançon, France, at the 40th congress of the French Society of Endocrinology. Borot highlighted the complexities of this subject, outlining several factors that contribute to its challenges.

A Heterogeneous Disease

T1D is a highly heterogeneous condition, and the patients included in studies reflect this diversity:

• The impact of blood glucose levels on CVR changes depending on diabetes duration, its history, the frequency of hypoglycemic episodes, average A1c levels over several years, and the patient’s age at diagnosis.
• A T1D diagnosis from the 1980s involved different management strategies compared with a diagnosis today.
• Patient profiles also vary based on complications such as nephropathy or cardiac autonomic neuropathy.
• Diffuse and distal arterial damage in T1D leads to more subtle and delayed pathologic events than in type 2 diabetes (T2D).
• Most clinical studies assess CVR over 10 years, but a 20- or 30-year evaluation would be more relevant.
• Patients may share CVR factors with the general population (eg, family history, smoking, sedentary lifestyle, obesity, hypertension, or elevated low-density lipoprotein [LDL] levels), raising questions about possible overlap with metabolic syndrome.
• Study criteria differ, with a focus on outcomes such as cardiovascular death, major adverse cardiovascular events like myocardial infarction and stroke, or other endpoints.
• CVR is measured using either absolute or relative values, with varying units of measurement.

A Recent Awareness

The concept of CVR in T1D is relatively new. Until the publication of the prospective Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study in 2005, it was believed that T1D control had no impact on CVR. However, follow-up results from the same cohort of 50,000 patients, published in 2022 after 30 years of observation, revealed that CVR was 20% higher in patients who received conventional hyperglycemia-targeted treatment than those undergoing intensive treatment. The CVR increases in conjunction with diabetes duration. The study also showed that even well-controlled glycemia in T1D carries CVR (primarily due to microangiopathy), and that the most critical factor for CVR is not A1c control but rather LDL cholesterol levels.

These findings were corroborated by a Danish prospective study, which demonstrated that while CVR increased in conjunction with the number of risk factors, it was 82% higher in patients with T1D than in a control group — even in the absence of risk factors.
 

Key Takeaways

At diagnosis, a fundamental difference exists between T1D and T2D in terms of the urgency to address CVR. In T2D, diabetes may have progressed for years before diagnosis, necessitating immediate CVR reduction efforts. In contrast, T1D is often diagnosed in younger patients with initially low CVR, raising questions about the optimal timing for interventions such as statin prescriptions.

Recommendations

The American Diabetes Association/European Association for the Study of Diabetes guidelines (2024) include the following recommendations:

For adults with T1D, treatment should mirror that for T2D:

• Between ages 20 and 40, statins are recommended if at least one CVR factor is present.
• For children 10 years of age or older with T1D, the LDL target is < 1.0 g/L. Statins are prescribed if LDL exceeds 1.6 g/L without CVR factors or 1.3 g/L with at least one CVR factor.

The European Society of Cardiology guidelines (2023) include the following:

• For the first time, a dedicated chapter addresses T1D. Like the American guidelines, routine statin use after age 40 is recommended.
• Before age 40, statins are prescribed if there is at least one CVR factor (microangiopathy) or a 10-year CVR ≥ 10% (based on a CVR calculator).

The International Society for Pediatric and Adolescent Diabetes guidelines (2022) recommend:

• For children 10 years of age or older, the LDL target is < 1.0 g/L. Statins are recommended if LDL exceeds 1.3 g/L.

CAC Score in High CVR

The French Society of Cardiology and the French-speaking Society of Diabetology recommend incorporating the coronary artery calcium (CAC) score to refine CVR classification in high-risk patients. For those without prior cardiovascular events, LDL targets vary based on CAC and age. For example:

• High-risk patients with a CAC of 0-10 are reclassified as moderate risk, with an LDL target of < 1 g/L.
• A CAC ≥ 400 indicates very high risk, warranting coronary exploration.
• Patients under 50 years of age with a CAC of 11-100 remain high risk, with an LDL target of 0.7 g/L.

Conclusion

CVR in patients with T1D remains challenging to define. However, it is essential to consider long-term outcomes, planning for 30 or 40 years into the future. This involves educating patients about the importance of prevention, even when reassuring numbers are seen in their youth.

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

Estimation of cardiovascular risk (CVR) in individuals living with type 1 diabetes (T1D) was a key topic presented by Sophie Borot, MD, from Besançon University Hospital, Besançon, France, at the 40th congress of the French Society of Endocrinology. Borot highlighted the complexities of this subject, outlining several factors that contribute to its challenges.

A Heterogeneous Disease

T1D is a highly heterogeneous condition, and the patients included in studies reflect this diversity:

• The impact of blood glucose levels on CVR changes depending on diabetes duration, its history, the frequency of hypoglycemic episodes, average A1c levels over several years, and the patient’s age at diagnosis.
• A T1D diagnosis from the 1980s involved different management strategies compared with a diagnosis today.
• Patient profiles also vary based on complications such as nephropathy or cardiac autonomic neuropathy.
• Diffuse and distal arterial damage in T1D leads to more subtle and delayed pathologic events than in type 2 diabetes (T2D).
• Most clinical studies assess CVR over 10 years, but a 20- or 30-year evaluation would be more relevant.
• Patients may share CVR factors with the general population (eg, family history, smoking, sedentary lifestyle, obesity, hypertension, or elevated low-density lipoprotein [LDL] levels), raising questions about possible overlap with metabolic syndrome.
• Study criteria differ, with a focus on outcomes such as cardiovascular death, major adverse cardiovascular events like myocardial infarction and stroke, or other endpoints.
• CVR is measured using either absolute or relative values, with varying units of measurement.

A Recent Awareness

The concept of CVR in T1D is relatively new. Until the publication of the prospective Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study in 2005, it was believed that T1D control had no impact on CVR. However, follow-up results from the same cohort of 50,000 patients, published in 2022 after 30 years of observation, revealed that CVR was 20% higher in patients who received conventional hyperglycemia-targeted treatment than those undergoing intensive treatment. The CVR increases in conjunction with diabetes duration. The study also showed that even well-controlled glycemia in T1D carries CVR (primarily due to microangiopathy), and that the most critical factor for CVR is not A1c control but rather LDL cholesterol levels.

These findings were corroborated by a Danish prospective study, which demonstrated that while CVR increased in conjunction with the number of risk factors, it was 82% higher in patients with T1D than in a control group — even in the absence of risk factors.
 

Key Takeaways

At diagnosis, a fundamental difference exists between T1D and T2D in terms of the urgency to address CVR. In T2D, diabetes may have progressed for years before diagnosis, necessitating immediate CVR reduction efforts. In contrast, T1D is often diagnosed in younger patients with initially low CVR, raising questions about the optimal timing for interventions such as statin prescriptions.

Recommendations

The American Diabetes Association/European Association for the Study of Diabetes guidelines (2024) include the following recommendations:

For adults with T1D, treatment should mirror that for T2D:

• Between ages 20 and 40, statins are recommended if at least one CVR factor is present.
• For children 10 years of age or older with T1D, the LDL target is < 1.0 g/L. Statins are prescribed if LDL exceeds 1.6 g/L without CVR factors or 1.3 g/L with at least one CVR factor.

The European Society of Cardiology guidelines (2023) include the following:

• For the first time, a dedicated chapter addresses T1D. Like the American guidelines, routine statin use after age 40 is recommended.
• Before age 40, statins are prescribed if there is at least one CVR factor (microangiopathy) or a 10-year CVR ≥ 10% (based on a CVR calculator).

The International Society for Pediatric and Adolescent Diabetes guidelines (2022) recommend:

• For children 10 years of age or older, the LDL target is < 1.0 g/L. Statins are recommended if LDL exceeds 1.3 g/L.

CAC Score in High CVR

The French Society of Cardiology and the French-speaking Society of Diabetology recommend incorporating the coronary artery calcium (CAC) score to refine CVR classification in high-risk patients. For those without prior cardiovascular events, LDL targets vary based on CAC and age. For example:

• High-risk patients with a CAC of 0-10 are reclassified as moderate risk, with an LDL target of < 1 g/L.
• A CAC ≥ 400 indicates very high risk, warranting coronary exploration.
• Patients under 50 years of age with a CAC of 11-100 remain high risk, with an LDL target of 0.7 g/L.

Conclusion

CVR in patients with T1D remains challenging to define. However, it is essential to consider long-term outcomes, planning for 30 or 40 years into the future. This involves educating patients about the importance of prevention, even when reassuring numbers are seen in their youth.

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

Estimation of cardiovascular risk (CVR) in individuals living with type 1 diabetes (T1D) was a key topic presented by Sophie Borot, MD, from Besançon University Hospital, Besançon, France, at the 40th congress of the French Society of Endocrinology. Borot highlighted the complexities of this subject, outlining several factors that contribute to its challenges.

A Heterogeneous Disease

T1D is a highly heterogeneous condition, and the patients included in studies reflect this diversity:

• The impact of blood glucose levels on CVR changes depending on diabetes duration, its history, the frequency of hypoglycemic episodes, average A1c levels over several years, and the patient’s age at diagnosis.
• A T1D diagnosis from the 1980s involved different management strategies compared with a diagnosis today.
• Patient profiles also vary based on complications such as nephropathy or cardiac autonomic neuropathy.
• Diffuse and distal arterial damage in T1D leads to more subtle and delayed pathologic events than in type 2 diabetes (T2D).
• Most clinical studies assess CVR over 10 years, but a 20- or 30-year evaluation would be more relevant.
• Patients may share CVR factors with the general population (eg, family history, smoking, sedentary lifestyle, obesity, hypertension, or elevated low-density lipoprotein [LDL] levels), raising questions about possible overlap with metabolic syndrome.
• Study criteria differ, with a focus on outcomes such as cardiovascular death, major adverse cardiovascular events like myocardial infarction and stroke, or other endpoints.
• CVR is measured using either absolute or relative values, with varying units of measurement.

A Recent Awareness

The concept of CVR in T1D is relatively new. Until the publication of the prospective Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study in 2005, it was believed that T1D control had no impact on CVR. However, follow-up results from the same cohort of 50,000 patients, published in 2022 after 30 years of observation, revealed that CVR was 20% higher in patients who received conventional hyperglycemia-targeted treatment than those undergoing intensive treatment. The CVR increases in conjunction with diabetes duration. The study also showed that even well-controlled glycemia in T1D carries CVR (primarily due to microangiopathy), and that the most critical factor for CVR is not A1c control but rather LDL cholesterol levels.

These findings were corroborated by a Danish prospective study, which demonstrated that while CVR increased in conjunction with the number of risk factors, it was 82% higher in patients with T1D than in a control group — even in the absence of risk factors.
 

Key Takeaways

At diagnosis, a fundamental difference exists between T1D and T2D in terms of the urgency to address CVR. In T2D, diabetes may have progressed for years before diagnosis, necessitating immediate CVR reduction efforts. In contrast, T1D is often diagnosed in younger patients with initially low CVR, raising questions about the optimal timing for interventions such as statin prescriptions.

Recommendations

The American Diabetes Association/European Association for the Study of Diabetes guidelines (2024) include the following recommendations:

For adults with T1D, treatment should mirror that for T2D:

• Between ages 20 and 40, statins are recommended if at least one CVR factor is present.
• For children 10 years of age or older with T1D, the LDL target is < 1.0 g/L. Statins are prescribed if LDL exceeds 1.6 g/L without CVR factors or 1.3 g/L with at least one CVR factor.

The European Society of Cardiology guidelines (2023) include the following:

• For the first time, a dedicated chapter addresses T1D. Like the American guidelines, routine statin use after age 40 is recommended.
• Before age 40, statins are prescribed if there is at least one CVR factor (microangiopathy) or a 10-year CVR ≥ 10% (based on a CVR calculator).

The International Society for Pediatric and Adolescent Diabetes guidelines (2022) recommend:

• For children 10 years of age or older, the LDL target is < 1.0 g/L. Statins are recommended if LDL exceeds 1.3 g/L.

CAC Score in High CVR

The French Society of Cardiology and the French-speaking Society of Diabetology recommend incorporating the coronary artery calcium (CAC) score to refine CVR classification in high-risk patients. For those without prior cardiovascular events, LDL targets vary based on CAC and age. For example:

• High-risk patients with a CAC of 0-10 are reclassified as moderate risk, with an LDL target of < 1 g/L.
• A CAC ≥ 400 indicates very high risk, warranting coronary exploration.
• Patients under 50 years of age with a CAC of 11-100 remain high risk, with an LDL target of 0.7 g/L.

Conclusion

CVR in patients with T1D remains challenging to define. However, it is essential to consider long-term outcomes, planning for 30 or 40 years into the future. This involves educating patients about the importance of prevention, even when reassuring numbers are seen in their youth.

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

TOPLINE:

Adults aged 50 years who were born preterm have a higher risk for hypertension but lower risk for cardiovascular events than those born at term, with similar risks for diabetes, prediabetes, and dyslipidemia between groups.

METHODOLOGY:

• The researchers conducted a prospective cohort study of the Auckland Steroid Trial — the first randomized trial of antenatal corticosteroids (betamethasone) for women who were at risk for preterm birth, conducted in Auckland, New Zealand, between December 1969 and February 1974.
• They analyzed 470 participants, including 424 survivors recruited between January 2020 and May 2022 and 46 participants who died after infancy.
• The outcomes for 326 participants born preterm (mean age, 49.4 years) and 144 participants born at term (mean age, 49.2 years) were assessed using either a questionnaire, administrative datasets, or both.
• The primary outcome was a composite of cardiovascular events or risk factors, defined as a history of a major adverse cardiovascular event or the presence of at least one cardiovascular risk factor, including diabetes mellitus, prediabetes, treated dyslipidemia, and treated hypertension.
• The secondary outcomes included respiratory, mental health, educational, and other health outcomes, as well as components of the primary outcomes.

TAKEAWAY:

• The composite of cardiovascular events or risk factors occurred in 34.5% of participants born preterm and 29.9% of participants born at term, with no differences in the risk factor components.
• The risk for cardiovascular events was lower in participants born preterm than in those born at term (adjusted relative risk [aRR], 0.33; P = .013).
• The participants born preterm had a higher risk for high blood pressure (aRR, 1.74; P = .007) and the composite of treated hypertension or self-reported diagnosis of high blood pressure (aRR, 1.63; P = .010) than those born at term.
• From randomization to the 50-year follow-up, death from any cause was more common in those born preterm than in those born at term (aRR, 2.29; P < .0001), whereas the diagnosis or treatment of a mental health disorder was less common (P = .007); no differences were observed between the groups for other outcomes.

IN PRACTICE:

“Those aware of being born preterm also may be more likely to seek preventive treatments, potentially resulting in a reduced risk of cardiovascular disease but a greater prevalence of risk factors if defined by a treatment such as treated dyslipidemia or treated hypertension,” the authors wrote.

“In this cohort, the survival advantage of the term-born control group abated after infancy, with a higher all-cause mortality rate, compared with that of the group born preterm,” wrote Jonathan S. Litt, MD, MPH, ScD, and Henning Tiemeier, MD, PhD, in a related commentary published in Pediatrics.

SOURCE:

The study was led by Anthony G. B. Walters, MBChB, Liggins Institute, Auckland, New Zealand. It was published online on December 16, 2024, in Pediatrics .

LIMITATIONS:

The small sample size limited the ability to detect subtle differences between groups and the validity of subgroup analyses. Attrition bias may have occurred because of low follow-up rates among presumed survivors. Bias could have been introduced because of lack of consent for access to the administrative dataset or from missing data from the participants in the questionnaire. The lack of in-person assessments for blood pressure and blood tests, resulting from geographical dispersion over 50 years, may have led to underestimation of some outcomes. Additionally, as most participants were born moderately or late preterm, with a median gestational age of 34.1 weeks, findings may not be generalizable to those born preterm at earlier gestational ages.

DISCLOSURES:

The study was supported in part by the Aotearoa Foundation, the Auckland Medical Research Foundation, Cure Kids New Zealand, and the Health Research Council of New Zealand. The authors of both the study and the commentary 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 appeared on Medscape.com.

TOPLINE:

Adults aged 50 years who were born preterm have a higher risk for hypertension but lower risk for cardiovascular events than those born at term, with similar risks for diabetes, prediabetes, and dyslipidemia between groups.

METHODOLOGY:

• The researchers conducted a prospective cohort study of the Auckland Steroid Trial — the first randomized trial of antenatal corticosteroids (betamethasone) for women who were at risk for preterm birth, conducted in Auckland, New Zealand, between December 1969 and February 1974.
• They analyzed 470 participants, including 424 survivors recruited between January 2020 and May 2022 and 46 participants who died after infancy.
• The outcomes for 326 participants born preterm (mean age, 49.4 years) and 144 participants born at term (mean age, 49.2 years) were assessed using either a questionnaire, administrative datasets, or both.
• The primary outcome was a composite of cardiovascular events or risk factors, defined as a history of a major adverse cardiovascular event or the presence of at least one cardiovascular risk factor, including diabetes mellitus, prediabetes, treated dyslipidemia, and treated hypertension.
• The secondary outcomes included respiratory, mental health, educational, and other health outcomes, as well as components of the primary outcomes.

TAKEAWAY:

• The composite of cardiovascular events or risk factors occurred in 34.5% of participants born preterm and 29.9% of participants born at term, with no differences in the risk factor components.
• The risk for cardiovascular events was lower in participants born preterm than in those born at term (adjusted relative risk [aRR], 0.33; P = .013).
• The participants born preterm had a higher risk for high blood pressure (aRR, 1.74; P = .007) and the composite of treated hypertension or self-reported diagnosis of high blood pressure (aRR, 1.63; P = .010) than those born at term.
• From randomization to the 50-year follow-up, death from any cause was more common in those born preterm than in those born at term (aRR, 2.29; P < .0001), whereas the diagnosis or treatment of a mental health disorder was less common (P = .007); no differences were observed between the groups for other outcomes.

IN PRACTICE:

“Those aware of being born preterm also may be more likely to seek preventive treatments, potentially resulting in a reduced risk of cardiovascular disease but a greater prevalence of risk factors if defined by a treatment such as treated dyslipidemia or treated hypertension,” the authors wrote.

“In this cohort, the survival advantage of the term-born control group abated after infancy, with a higher all-cause mortality rate, compared with that of the group born preterm,” wrote Jonathan S. Litt, MD, MPH, ScD, and Henning Tiemeier, MD, PhD, in a related commentary published in Pediatrics.

SOURCE:

The study was led by Anthony G. B. Walters, MBChB, Liggins Institute, Auckland, New Zealand. It was published online on December 16, 2024, in Pediatrics .

LIMITATIONS:

The small sample size limited the ability to detect subtle differences between groups and the validity of subgroup analyses. Attrition bias may have occurred because of low follow-up rates among presumed survivors. Bias could have been introduced because of lack of consent for access to the administrative dataset or from missing data from the participants in the questionnaire. The lack of in-person assessments for blood pressure and blood tests, resulting from geographical dispersion over 50 years, may have led to underestimation of some outcomes. Additionally, as most participants were born moderately or late preterm, with a median gestational age of 34.1 weeks, findings may not be generalizable to those born preterm at earlier gestational ages.

DISCLOSURES:

The study was supported in part by the Aotearoa Foundation, the Auckland Medical Research Foundation, Cure Kids New Zealand, and the Health Research Council of New Zealand. The authors of both the study and the commentary 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 appeared on Medscape.com.

TOPLINE:

Adults aged 50 years who were born preterm have a higher risk for hypertension but lower risk for cardiovascular events than those born at term, with similar risks for diabetes, prediabetes, and dyslipidemia between groups.

METHODOLOGY:

• The researchers conducted a prospective cohort study of the Auckland Steroid Trial — the first randomized trial of antenatal corticosteroids (betamethasone) for women who were at risk for preterm birth, conducted in Auckland, New Zealand, between December 1969 and February 1974.
• They analyzed 470 participants, including 424 survivors recruited between January 2020 and May 2022 and 46 participants who died after infancy.
• The outcomes for 326 participants born preterm (mean age, 49.4 years) and 144 participants born at term (mean age, 49.2 years) were assessed using either a questionnaire, administrative datasets, or both.
• The primary outcome was a composite of cardiovascular events or risk factors, defined as a history of a major adverse cardiovascular event or the presence of at least one cardiovascular risk factor, including diabetes mellitus, prediabetes, treated dyslipidemia, and treated hypertension.
• The secondary outcomes included respiratory, mental health, educational, and other health outcomes, as well as components of the primary outcomes.

TAKEAWAY:

• The composite of cardiovascular events or risk factors occurred in 34.5% of participants born preterm and 29.9% of participants born at term, with no differences in the risk factor components.
• The risk for cardiovascular events was lower in participants born preterm than in those born at term (adjusted relative risk [aRR], 0.33; P = .013).
• The participants born preterm had a higher risk for high blood pressure (aRR, 1.74; P = .007) and the composite of treated hypertension or self-reported diagnosis of high blood pressure (aRR, 1.63; P = .010) than those born at term.
• From randomization to the 50-year follow-up, death from any cause was more common in those born preterm than in those born at term (aRR, 2.29; P < .0001), whereas the diagnosis or treatment of a mental health disorder was less common (P = .007); no differences were observed between the groups for other outcomes.

IN PRACTICE:

“Those aware of being born preterm also may be more likely to seek preventive treatments, potentially resulting in a reduced risk of cardiovascular disease but a greater prevalence of risk factors if defined by a treatment such as treated dyslipidemia or treated hypertension,” the authors wrote.

“In this cohort, the survival advantage of the term-born control group abated after infancy, with a higher all-cause mortality rate, compared with that of the group born preterm,” wrote Jonathan S. Litt, MD, MPH, ScD, and Henning Tiemeier, MD, PhD, in a related commentary published in Pediatrics.

SOURCE:

The study was led by Anthony G. B. Walters, MBChB, Liggins Institute, Auckland, New Zealand. It was published online on December 16, 2024, in Pediatrics .

LIMITATIONS:

The small sample size limited the ability to detect subtle differences between groups and the validity of subgroup analyses. Attrition bias may have occurred because of low follow-up rates among presumed survivors. Bias could have been introduced because of lack of consent for access to the administrative dataset or from missing data from the participants in the questionnaire. The lack of in-person assessments for blood pressure and blood tests, resulting from geographical dispersion over 50 years, may have led to underestimation of some outcomes. Additionally, as most participants were born moderately or late preterm, with a median gestational age of 34.1 weeks, findings may not be generalizable to those born preterm at earlier gestational ages.

DISCLOSURES:

The study was supported in part by the Aotearoa Foundation, the Auckland Medical Research Foundation, Cure Kids New Zealand, and the Health Research Council of New Zealand. The authors of both the study and the commentary 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 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.

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.

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.

VANCOUVER, BRITISH COLUMBIA — While polypharmacy is inevitable for patients with multiple chronic diseases, not all medications improve patient-oriented outcomes, members of the Patients, Experience, Evidence, Research (PEER) team, a group of Canadian primary care professionals who develop evidence-based guidelines, told attendees at the Family Medicine Forum (FMF) 2024.

In a thought-provoking presentation called “Axe the Rx: Deprescribing Chronic Medications with PEER,” the panelists gave examples of medications that may be safely stopped or tapered, particularly for older adults “whose pill bag is heavier than their lunch bag.”

 

Curbing Cardiovascular Drugs

The 2021 Canadian Cardiovascular Society Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease in Adults call for reaching an LDL-C < 1.8 mmol/L in secondary cardiovascular prevention by potentially adding on medical therapies such as proprotein convertase subtilisin/kexin type 9 inhibitors or ezetimibe or both if that target is not reached with the maximal dosage of a statin.

But family physicians do not need to follow this guidance for their patients who have had a myocardial infarction, said Ontario family physician Jennifer Young, MD, a physician advisor in the Canadian College of Family Physicians’ Knowledge Experts and Tools Program.

Treating to below 1.8 mmol/L “means lab testing for the patients,” Young told this news organization. “It means increasing doses [of a statin] to try and get to that level.” If the patient is already on the highest dose of a statin, it means adding other medications that lower cholesterol.

“If that was translating into better outcomes like [preventing] death and another heart attack, then all of that extra effort would be worth it,” said Young. “But we don’t have evidence that it actually does have a benefit for outcomes like death and repeated heart attacks,” compared with putting them on a high dose of a potent statin.

 

Tapering Opioids

Before placing patients on an opioid taper, clinicians should first assess them for opioid use disorder (OUD), said Jessica Kirkwood, MD, assistant professor of family medicine at the University of Alberta in Edmonton, Canada. She suggested using the Prescription Opioid Misuse Index questionnaire to do so.

Clinicians should be much more careful in initiating a taper with patients with OUD, said Kirkwood. They must ensure that these patients are motivated to discontinue their opioids. “We’re losing 21 Canadians a day to the opioid crisis. We all know that cutting someone off their opioids and potentially having them seek opioids elsewhere through illicit means can be fatal.”

In addition, clinicians should spend more time counseling patients with OUD than those without, Kirkwood continued. They must explain to these patients how they are being tapered (eg, the intervals and doses) and highlight the benefits of a taper, such as reduced constipation. Opioid agonist therapy (such as methadone or buprenorphine) can be considered in these patients.

Some research has pointed to the importance of patient motivation as a factor in the success of opioid tapers, noted Kirkwood.

 

Deprescribing Benzodiazepines 

Benzodiazepine receptor agonists, too, often can be deprescribed. These drugs should not be prescribed to promote sleep on a long-term basis. Yet clinicians commonly encounter patients who have been taking them for more than a year, said pharmacist Betsy Thomas, assistant adjunct professor of family medicine at the University of Alberta.

The medications “are usually fairly effective for the first couple of weeks to about a month, and then the benefits start to decrease, and we start to see more harms,” she said.

Some of the harms that have been associated with continued use of benzodiazepine receptor agonists include delayed reaction time and impaired cognition, which can affect the ability to drive, the risk for falls, and the risk for hip fractures, she noted. Some research suggests that these drugs are not an option for treating insomnia in patients aged 65 years or older.

Clinicians should encourage tapering the use of benzodiazepine receptor agonists to minimize dependence and transition patients to nonpharmacologic approaches such as cognitive behavioral therapy to manage insomnia, she said. A recent study demonstrated the efficacy of the intervention, and Thomas suggested that family physicians visit the mysleepwell.ca website for more information.

Young, Kirkwood, and Thomas reported no relevant financial relationships.

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

VANCOUVER, BRITISH COLUMBIA — While polypharmacy is inevitable for patients with multiple chronic diseases, not all medications improve patient-oriented outcomes, members of the Patients, Experience, Evidence, Research (PEER) team, a group of Canadian primary care professionals who develop evidence-based guidelines, told attendees at the Family Medicine Forum (FMF) 2024.

In a thought-provoking presentation called “Axe the Rx: Deprescribing Chronic Medications with PEER,” the panelists gave examples of medications that may be safely stopped or tapered, particularly for older adults “whose pill bag is heavier than their lunch bag.”

 

Curbing Cardiovascular Drugs

The 2021 Canadian Cardiovascular Society Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease in Adults call for reaching an LDL-C < 1.8 mmol/L in secondary cardiovascular prevention by potentially adding on medical therapies such as proprotein convertase subtilisin/kexin type 9 inhibitors or ezetimibe or both if that target is not reached with the maximal dosage of a statin.

But family physicians do not need to follow this guidance for their patients who have had a myocardial infarction, said Ontario family physician Jennifer Young, MD, a physician advisor in the Canadian College of Family Physicians’ Knowledge Experts and Tools Program.

Treating to below 1.8 mmol/L “means lab testing for the patients,” Young told this news organization. “It means increasing doses [of a statin] to try and get to that level.” If the patient is already on the highest dose of a statin, it means adding other medications that lower cholesterol.

“If that was translating into better outcomes like [preventing] death and another heart attack, then all of that extra effort would be worth it,” said Young. “But we don’t have evidence that it actually does have a benefit for outcomes like death and repeated heart attacks,” compared with putting them on a high dose of a potent statin.

 

Tapering Opioids

Before placing patients on an opioid taper, clinicians should first assess them for opioid use disorder (OUD), said Jessica Kirkwood, MD, assistant professor of family medicine at the University of Alberta in Edmonton, Canada. She suggested using the Prescription Opioid Misuse Index questionnaire to do so.

Clinicians should be much more careful in initiating a taper with patients with OUD, said Kirkwood. They must ensure that these patients are motivated to discontinue their opioids. “We’re losing 21 Canadians a day to the opioid crisis. We all know that cutting someone off their opioids and potentially having them seek opioids elsewhere through illicit means can be fatal.”

In addition, clinicians should spend more time counseling patients with OUD than those without, Kirkwood continued. They must explain to these patients how they are being tapered (eg, the intervals and doses) and highlight the benefits of a taper, such as reduced constipation. Opioid agonist therapy (such as methadone or buprenorphine) can be considered in these patients.

Some research has pointed to the importance of patient motivation as a factor in the success of opioid tapers, noted Kirkwood.

 

Deprescribing Benzodiazepines 

Benzodiazepine receptor agonists, too, often can be deprescribed. These drugs should not be prescribed to promote sleep on a long-term basis. Yet clinicians commonly encounter patients who have been taking them for more than a year, said pharmacist Betsy Thomas, assistant adjunct professor of family medicine at the University of Alberta.

The medications “are usually fairly effective for the first couple of weeks to about a month, and then the benefits start to decrease, and we start to see more harms,” she said.

Some of the harms that have been associated with continued use of benzodiazepine receptor agonists include delayed reaction time and impaired cognition, which can affect the ability to drive, the risk for falls, and the risk for hip fractures, she noted. Some research suggests that these drugs are not an option for treating insomnia in patients aged 65 years or older.

Clinicians should encourage tapering the use of benzodiazepine receptor agonists to minimize dependence and transition patients to nonpharmacologic approaches such as cognitive behavioral therapy to manage insomnia, she said. A recent study demonstrated the efficacy of the intervention, and Thomas suggested that family physicians visit the mysleepwell.ca website for more information.

Young, Kirkwood, and Thomas reported no relevant financial relationships.

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

VANCOUVER, BRITISH COLUMBIA — While polypharmacy is inevitable for patients with multiple chronic diseases, not all medications improve patient-oriented outcomes, members of the Patients, Experience, Evidence, Research (PEER) team, a group of Canadian primary care professionals who develop evidence-based guidelines, told attendees at the Family Medicine Forum (FMF) 2024.

In a thought-provoking presentation called “Axe the Rx: Deprescribing Chronic Medications with PEER,” the panelists gave examples of medications that may be safely stopped or tapered, particularly for older adults “whose pill bag is heavier than their lunch bag.”

 

Curbing Cardiovascular Drugs

The 2021 Canadian Cardiovascular Society Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease in Adults call for reaching an LDL-C < 1.8 mmol/L in secondary cardiovascular prevention by potentially adding on medical therapies such as proprotein convertase subtilisin/kexin type 9 inhibitors or ezetimibe or both if that target is not reached with the maximal dosage of a statin.

But family physicians do not need to follow this guidance for their patients who have had a myocardial infarction, said Ontario family physician Jennifer Young, MD, a physician advisor in the Canadian College of Family Physicians’ Knowledge Experts and Tools Program.

Treating to below 1.8 mmol/L “means lab testing for the patients,” Young told this news organization. “It means increasing doses [of a statin] to try and get to that level.” If the patient is already on the highest dose of a statin, it means adding other medications that lower cholesterol.

“If that was translating into better outcomes like [preventing] death and another heart attack, then all of that extra effort would be worth it,” said Young. “But we don’t have evidence that it actually does have a benefit for outcomes like death and repeated heart attacks,” compared with putting them on a high dose of a potent statin.

 

Tapering Opioids

Before placing patients on an opioid taper, clinicians should first assess them for opioid use disorder (OUD), said Jessica Kirkwood, MD, assistant professor of family medicine at the University of Alberta in Edmonton, Canada. She suggested using the Prescription Opioid Misuse Index questionnaire to do so.

Clinicians should be much more careful in initiating a taper with patients with OUD, said Kirkwood. They must ensure that these patients are motivated to discontinue their opioids. “We’re losing 21 Canadians a day to the opioid crisis. We all know that cutting someone off their opioids and potentially having them seek opioids elsewhere through illicit means can be fatal.”

In addition, clinicians should spend more time counseling patients with OUD than those without, Kirkwood continued. They must explain to these patients how they are being tapered (eg, the intervals and doses) and highlight the benefits of a taper, such as reduced constipation. Opioid agonist therapy (such as methadone or buprenorphine) can be considered in these patients.

Some research has pointed to the importance of patient motivation as a factor in the success of opioid tapers, noted Kirkwood.

 

Deprescribing Benzodiazepines 

Benzodiazepine receptor agonists, too, often can be deprescribed. These drugs should not be prescribed to promote sleep on a long-term basis. Yet clinicians commonly encounter patients who have been taking them for more than a year, said pharmacist Betsy Thomas, assistant adjunct professor of family medicine at the University of Alberta.

The medications “are usually fairly effective for the first couple of weeks to about a month, and then the benefits start to decrease, and we start to see more harms,” she said.

Some of the harms that have been associated with continued use of benzodiazepine receptor agonists include delayed reaction time and impaired cognition, which can affect the ability to drive, the risk for falls, and the risk for hip fractures, she noted. Some research suggests that these drugs are not an option for treating insomnia in patients aged 65 years or older.

Clinicians should encourage tapering the use of benzodiazepine receptor agonists to minimize dependence and transition patients to nonpharmacologic approaches such as cognitive behavioral therapy to manage insomnia, she said. A recent study demonstrated the efficacy of the intervention, and Thomas suggested that family physicians visit the mysleepwell.ca website for more information.

Young, Kirkwood, and Thomas reported no relevant financial relationships.

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

TOPLINE:

Intermittent calorie restriction (CR) diet is more effective in reducing liver fat content than a standard-of-care diet in patients with metabolic dysfunction–associated steatotic liver disease (MASLD), especially in those with obesity.

METHODOLOGY:

• Intermittent CR, which involves alternating periods of energy restriction and regular energy intake, has been proposed as a dietary intervention for MASLD.
• Researchers conducted a 12-week randomized controlled trial to compare the effects of a 5:2 intermittent CR and standard-of-care diet in nondiabetic patients with MASLD with or without obesity at an outpatient clinic in Korea.
• Intermittent CR comprised a reduced calorie consumption (500 kcal/d for women and 600 kcal/d for men) on 2 nonconsecutive days a week and, on the remaining 5 days/wk, following the Korean Dietary Reference Intakes (2000 kcal/d for women and 2500 kcal/d for men).
• The standard diet involved the consumption of 80% of the recommended calories (1200-1500 kcal/d for women and 1500-1800 kcal/d for men, or reducing 500-1000 kcal/d).
• The primary outcome was a relative reduction of ≥ 30% in the liver fat content measured by MRI-proton density fat fraction after 12 weeks.
• The secondary outcomes included changes in liver fibrosis, body weight, and body composition from baseline to week 12.

TAKEAWAY:

• Researchers enrolled 72 participants (36 patients with obesity and 36 without), with 63 completing the trial; of these, 32 received an intermittent CR diet (median age, 47.0 years; 58.8% men) and 31 received a standard-of-care diet (median age, 53.0 years; 36.4% men).
• A higher proportion of patients in the intermittent CR group achieved a relative reduction of ≥ 30% in the liver fat content at 12 weeks than the standard-of-care group (72.2% vs 44.4%; P = .033).
• These findings were even more prominent among those with obesity (61.1% in the intermittent CR group vs 27.7% in the standard-of-care group; P = .030).
• Patients with obesity in the intermittent CR group also showed a greater relative reduction in body weight than those in the standard-of-care group (–5.5% vs –2.9%; P = .022).
• Intermittent CR had no apparent effects on body composition, liver enzymes, or the lipid and glucose profiles of those with or without obesity.

IN PRACTICE:

“These results support the recommendation of a 5:2 [intermittent CR] diet as a useful dietary strategy for patients with MASLD,” the authors wrote.

SOURCE:

The study, led by Han Ah Lee, PhD, Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul, South Korea, was published online in Clinical Gastroenterology and Hepatology.

LIMITATIONS:

The intervention period of 12 weeks was relatively short, limiting the ability to observe long-term effects. The study did not reveal the effects of intermittent CR on histologic metabolic dysfunction–associated steatohepatitis or significantly advanced fibrosis. The study was conducted at a single center located in an urban, metropolitan area in Korea, which may limit the applicability of the findings to other populations.

DISCLOSURES:

This study was supported in part by a grant from the National Research Foundation of Korea funded by the Ministry of Science and ICT. 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:

Intermittent calorie restriction (CR) diet is more effective in reducing liver fat content than a standard-of-care diet in patients with metabolic dysfunction–associated steatotic liver disease (MASLD), especially in those with obesity.

METHODOLOGY:

• Intermittent CR, which involves alternating periods of energy restriction and regular energy intake, has been proposed as a dietary intervention for MASLD.
• Researchers conducted a 12-week randomized controlled trial to compare the effects of a 5:2 intermittent CR and standard-of-care diet in nondiabetic patients with MASLD with or without obesity at an outpatient clinic in Korea.
• Intermittent CR comprised a reduced calorie consumption (500 kcal/d for women and 600 kcal/d for men) on 2 nonconsecutive days a week and, on the remaining 5 days/wk, following the Korean Dietary Reference Intakes (2000 kcal/d for women and 2500 kcal/d for men).
• The standard diet involved the consumption of 80% of the recommended calories (1200-1500 kcal/d for women and 1500-1800 kcal/d for men, or reducing 500-1000 kcal/d).
• The primary outcome was a relative reduction of ≥ 30% in the liver fat content measured by MRI-proton density fat fraction after 12 weeks.
• The secondary outcomes included changes in liver fibrosis, body weight, and body composition from baseline to week 12.

TAKEAWAY:

• Researchers enrolled 72 participants (36 patients with obesity and 36 without), with 63 completing the trial; of these, 32 received an intermittent CR diet (median age, 47.0 years; 58.8% men) and 31 received a standard-of-care diet (median age, 53.0 years; 36.4% men).
• A higher proportion of patients in the intermittent CR group achieved a relative reduction of ≥ 30% in the liver fat content at 12 weeks than the standard-of-care group (72.2% vs 44.4%; P = .033).
• These findings were even more prominent among those with obesity (61.1% in the intermittent CR group vs 27.7% in the standard-of-care group; P = .030).
• Patients with obesity in the intermittent CR group also showed a greater relative reduction in body weight than those in the standard-of-care group (–5.5% vs –2.9%; P = .022).
• Intermittent CR had no apparent effects on body composition, liver enzymes, or the lipid and glucose profiles of those with or without obesity.

IN PRACTICE:

“These results support the recommendation of a 5:2 [intermittent CR] diet as a useful dietary strategy for patients with MASLD,” the authors wrote.

SOURCE:

The study, led by Han Ah Lee, PhD, Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul, South Korea, was published online in Clinical Gastroenterology and Hepatology.

LIMITATIONS:

The intervention period of 12 weeks was relatively short, limiting the ability to observe long-term effects. The study did not reveal the effects of intermittent CR on histologic metabolic dysfunction–associated steatohepatitis or significantly advanced fibrosis. The study was conducted at a single center located in an urban, metropolitan area in Korea, which may limit the applicability of the findings to other populations.

DISCLOSURES:

This study was supported in part by a grant from the National Research Foundation of Korea funded by the Ministry of Science and ICT. 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:

Intermittent calorie restriction (CR) diet is more effective in reducing liver fat content than a standard-of-care diet in patients with metabolic dysfunction–associated steatotic liver disease (MASLD), especially in those with obesity.

METHODOLOGY:

• Intermittent CR, which involves alternating periods of energy restriction and regular energy intake, has been proposed as a dietary intervention for MASLD.
• Researchers conducted a 12-week randomized controlled trial to compare the effects of a 5:2 intermittent CR and standard-of-care diet in nondiabetic patients with MASLD with or without obesity at an outpatient clinic in Korea.
• Intermittent CR comprised a reduced calorie consumption (500 kcal/d for women and 600 kcal/d for men) on 2 nonconsecutive days a week and, on the remaining 5 days/wk, following the Korean Dietary Reference Intakes (2000 kcal/d for women and 2500 kcal/d for men).
• The standard diet involved the consumption of 80% of the recommended calories (1200-1500 kcal/d for women and 1500-1800 kcal/d for men, or reducing 500-1000 kcal/d).
• The primary outcome was a relative reduction of ≥ 30% in the liver fat content measured by MRI-proton density fat fraction after 12 weeks.
• The secondary outcomes included changes in liver fibrosis, body weight, and body composition from baseline to week 12.

TAKEAWAY:

• Researchers enrolled 72 participants (36 patients with obesity and 36 without), with 63 completing the trial; of these, 32 received an intermittent CR diet (median age, 47.0 years; 58.8% men) and 31 received a standard-of-care diet (median age, 53.0 years; 36.4% men).
• A higher proportion of patients in the intermittent CR group achieved a relative reduction of ≥ 30% in the liver fat content at 12 weeks than the standard-of-care group (72.2% vs 44.4%; P = .033).
• These findings were even more prominent among those with obesity (61.1% in the intermittent CR group vs 27.7% in the standard-of-care group; P = .030).
• Patients with obesity in the intermittent CR group also showed a greater relative reduction in body weight than those in the standard-of-care group (–5.5% vs –2.9%; P = .022).
• Intermittent CR had no apparent effects on body composition, liver enzymes, or the lipid and glucose profiles of those with or without obesity.

IN PRACTICE:

“These results support the recommendation of a 5:2 [intermittent CR] diet as a useful dietary strategy for patients with MASLD,” the authors wrote.

SOURCE:

The study, led by Han Ah Lee, PhD, Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul, South Korea, was published online in Clinical Gastroenterology and Hepatology.

LIMITATIONS:

The intervention period of 12 weeks was relatively short, limiting the ability to observe long-term effects. The study did not reveal the effects of intermittent CR on histologic metabolic dysfunction–associated steatohepatitis or significantly advanced fibrosis. The study was conducted at a single center located in an urban, metropolitan area in Korea, which may limit the applicability of the findings to other populations.

DISCLOSURES:

This study was supported in part by a grant from the National Research Foundation of Korea funded by the Ministry of Science and ICT. 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.