Lipid Disorders

TOPLINE:

Intermittent hypoxemia prompted higher postprandial plasma triglyceride levels in men than in women compared with normoxia.

METHODOLOGY:

• Potential gender differences in the impact of intermittent hypoxemia on triglycerides have not been well studied, despite the increased risk for metabolic comorbidities in obstructive sleep apnea (OSA).
• The researchers recruited 24 healthy young adults with a mean age of 23.3 years for the 12 men and 21.3 years for the 12 women.
• Participants consumed a high-fat meal followed by 6 hours of exposure to intermittent hypoxemia or ambient air; the primary outcome was changes in postprandial plasma triglyceride levels.

TAKEAWAY:

• Intermittent hypoxemia was associated with significantly higher postprandial triglycerides in men but not in women.
• Women had lower levels of total triglycerides as well as denser triglyceride-rich lipoprotein triglycerides (TRL-TG) and buoyant TRL-TG in both normoxia and hypoxemia conditions compared with men.
• Glucose levels were significantly higher in men and significantly lower in women during intermittent hypoxemia compared with normoxia (P < .001 for both sexes).

IN PRACTICE:

“Although there is a need for larger confirmatory studies in individuals living with obstructive sleep apnea, this study demonstrates that intermittent hypoxemia alters triglyceride metabolism differently between men and women,” the researchers wrote.

SOURCE:

The lead author of the study was Nicholas Goulet, MD, of the University of Ottawa, Ottawa, Ontario, Canada. The study was published online in The Journal of Physiology on January 29, 2024.

LIMITATIONS:

Limitations of the study included the experimental design with simulated OSA, the small and homogeneous study population, the use of a specific profile for intermittent hypoxemia, and the use of a specific high-fat meal.

DISCLOSURES:

The study was supported by the Natural Sciences and Engineering Research Council of Canada and the Association Médicale Universitaire de l’Hôpital Montfort. The researchers had no financial conflicts to disclose.

A version of this article appeared on Medscape.com.

TOPLINE:

Intermittent hypoxemia prompted higher postprandial plasma triglyceride levels in men than in women compared with normoxia.

METHODOLOGY:

• Potential gender differences in the impact of intermittent hypoxemia on triglycerides have not been well studied, despite the increased risk for metabolic comorbidities in obstructive sleep apnea (OSA).
• The researchers recruited 24 healthy young adults with a mean age of 23.3 years for the 12 men and 21.3 years for the 12 women.
• Participants consumed a high-fat meal followed by 6 hours of exposure to intermittent hypoxemia or ambient air; the primary outcome was changes in postprandial plasma triglyceride levels.

TAKEAWAY:

• Intermittent hypoxemia was associated with significantly higher postprandial triglycerides in men but not in women.
• Women had lower levels of total triglycerides as well as denser triglyceride-rich lipoprotein triglycerides (TRL-TG) and buoyant TRL-TG in both normoxia and hypoxemia conditions compared with men.
• Glucose levels were significantly higher in men and significantly lower in women during intermittent hypoxemia compared with normoxia (P < .001 for both sexes).

IN PRACTICE:

“Although there is a need for larger confirmatory studies in individuals living with obstructive sleep apnea, this study demonstrates that intermittent hypoxemia alters triglyceride metabolism differently between men and women,” the researchers wrote.

SOURCE:

The lead author of the study was Nicholas Goulet, MD, of the University of Ottawa, Ottawa, Ontario, Canada. The study was published online in The Journal of Physiology on January 29, 2024.

LIMITATIONS:

Limitations of the study included the experimental design with simulated OSA, the small and homogeneous study population, the use of a specific profile for intermittent hypoxemia, and the use of a specific high-fat meal.

DISCLOSURES:

The study was supported by the Natural Sciences and Engineering Research Council of Canada and the Association Médicale Universitaire de l’Hôpital Montfort. The researchers had no financial conflicts to disclose.

A version of this article appeared on Medscape.com.

TOPLINE:

Intermittent hypoxemia prompted higher postprandial plasma triglyceride levels in men than in women compared with normoxia.

METHODOLOGY:

• Potential gender differences in the impact of intermittent hypoxemia on triglycerides have not been well studied, despite the increased risk for metabolic comorbidities in obstructive sleep apnea (OSA).
• The researchers recruited 24 healthy young adults with a mean age of 23.3 years for the 12 men and 21.3 years for the 12 women.
• Participants consumed a high-fat meal followed by 6 hours of exposure to intermittent hypoxemia or ambient air; the primary outcome was changes in postprandial plasma triglyceride levels.

TAKEAWAY:

• Intermittent hypoxemia was associated with significantly higher postprandial triglycerides in men but not in women.
• Women had lower levels of total triglycerides as well as denser triglyceride-rich lipoprotein triglycerides (TRL-TG) and buoyant TRL-TG in both normoxia and hypoxemia conditions compared with men.
• Glucose levels were significantly higher in men and significantly lower in women during intermittent hypoxemia compared with normoxia (P < .001 for both sexes).

IN PRACTICE:

“Although there is a need for larger confirmatory studies in individuals living with obstructive sleep apnea, this study demonstrates that intermittent hypoxemia alters triglyceride metabolism differently between men and women,” the researchers wrote.

SOURCE:

The lead author of the study was Nicholas Goulet, MD, of the University of Ottawa, Ottawa, Ontario, Canada. The study was published online in The Journal of Physiology on January 29, 2024.

LIMITATIONS:

Limitations of the study included the experimental design with simulated OSA, the small and homogeneous study population, the use of a specific profile for intermittent hypoxemia, and the use of a specific high-fat meal.

DISCLOSURES:

The study was supported by the Natural Sciences and Engineering Research Council of Canada and the Association Médicale Universitaire de l’Hôpital Montfort. The researchers had no financial conflicts to disclose.

A version of this article appeared on Medscape.com.

TOPLINE:

Persistent hypertriglyceridemia is linked to an increased risk for type 2 diabetes (T2D) in young adults, independent of lifestyle factors.

METHODOLOGY:

• This prospective study analyzed the data of 1,840,251 individuals aged 20-39 years from the South Korean National Health Insurance Service database (mean age 34 years, 71% male).
• The individuals had undergone four consecutive annual health checkups between 2009 and 2012 and had no history of T2D.
• The individuals were sorted into five groups indicating the number of hypertriglyceridemia diagnoses over four consecutive years: 0, 1, 2, 3, and 4, defined as serum fasting triglyceride levels of 150 mg/dL or higher.
• Data on lifestyle-related risk factors, such as smoking status and heavy alcohol consumption, were collected through self-reported questionnaires.
• The primary outcome was newly diagnosed cases of T2D. Over a mean follow-up of 6.53 years, a total of 40,286 individuals developed T2D.

TAKEAWAY:

• The cumulative incidence of T2D increased with an increase in exposure scores for hypertriglyceridemia (log-rank test, P < .001), independent of lifestyle-related factors.
• The incidence rate per 1000 person-years was 1.25 for participants with an exposure score of 0 and 11.55 for those with a score of 4.
• For individuals with exposure scores of 1, 2, 3, and 4, the adjusted hazard ratios for incident diabetes were 1.674 (95% CI, 1.619-1.732), 2.192 (2.117-2.269), 2.637 (2.548-2.73), and 3.715 (3.6-3.834), respectively, vs those with an exposure score of 0.
• Exploratory subgroup analyses suggested the risk for T2D in persistent hypertriglyceridemia were more pronounced among people in their 20s than in their 30s and in women.

IN PRACTICE:

“Identification of individuals at higher risk based on triglyceride levels and management strategies for persistent hypertriglyceridemia in young adults could potentially reduce the burden of young-onset type 2 diabetes and enhance long-term health outcomes,” the authors wrote.

SOURCE:

The study, led by Min-Kyung Lee, Division of Endocrinology and Metabolism, Department of Internal Medicine, Myongji Hospital, Hanyang University College of Medicine, Seoul, Republic of Korea, was published online in Diabetes Research and Clinical Practice.

LIMITATIONS:

The scoring system based on fasting triglyceride levels of ≥ 150 mg/dL may have limitations, as the cumulative incidence of T2D also varied significantly for mean triglyceride levels. Moreover, relying on a single annual health checkup for hypertriglyceridemia diagnosis might not capture short-term fluctuations. Despite sufficient cases and a high follow-up rate, the study might have underestimated the incidence of T2D.

DISCLOSURES:

This work was supported by the National Research Foundation of Korea grant funded by the Korean Government and the faculty grant of Myongji Hospital. The authors declared no conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

Persistent hypertriglyceridemia is linked to an increased risk for type 2 diabetes (T2D) in young adults, independent of lifestyle factors.

METHODOLOGY:

• This prospective study analyzed the data of 1,840,251 individuals aged 20-39 years from the South Korean National Health Insurance Service database (mean age 34 years, 71% male).
• The individuals had undergone four consecutive annual health checkups between 2009 and 2012 and had no history of T2D.
• The individuals were sorted into five groups indicating the number of hypertriglyceridemia diagnoses over four consecutive years: 0, 1, 2, 3, and 4, defined as serum fasting triglyceride levels of 150 mg/dL or higher.
• Data on lifestyle-related risk factors, such as smoking status and heavy alcohol consumption, were collected through self-reported questionnaires.
• The primary outcome was newly diagnosed cases of T2D. Over a mean follow-up of 6.53 years, a total of 40,286 individuals developed T2D.

TAKEAWAY:

• The cumulative incidence of T2D increased with an increase in exposure scores for hypertriglyceridemia (log-rank test, P < .001), independent of lifestyle-related factors.
• The incidence rate per 1000 person-years was 1.25 for participants with an exposure score of 0 and 11.55 for those with a score of 4.
• For individuals with exposure scores of 1, 2, 3, and 4, the adjusted hazard ratios for incident diabetes were 1.674 (95% CI, 1.619-1.732), 2.192 (2.117-2.269), 2.637 (2.548-2.73), and 3.715 (3.6-3.834), respectively, vs those with an exposure score of 0.
• Exploratory subgroup analyses suggested the risk for T2D in persistent hypertriglyceridemia were more pronounced among people in their 20s than in their 30s and in women.

IN PRACTICE:

“Identification of individuals at higher risk based on triglyceride levels and management strategies for persistent hypertriglyceridemia in young adults could potentially reduce the burden of young-onset type 2 diabetes and enhance long-term health outcomes,” the authors wrote.

SOURCE:

The study, led by Min-Kyung Lee, Division of Endocrinology and Metabolism, Department of Internal Medicine, Myongji Hospital, Hanyang University College of Medicine, Seoul, Republic of Korea, was published online in Diabetes Research and Clinical Practice.

LIMITATIONS:

The scoring system based on fasting triglyceride levels of ≥ 150 mg/dL may have limitations, as the cumulative incidence of T2D also varied significantly for mean triglyceride levels. Moreover, relying on a single annual health checkup for hypertriglyceridemia diagnosis might not capture short-term fluctuations. Despite sufficient cases and a high follow-up rate, the study might have underestimated the incidence of T2D.

DISCLOSURES:

This work was supported by the National Research Foundation of Korea grant funded by the Korean Government and the faculty grant of Myongji Hospital. The authors declared no conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

Persistent hypertriglyceridemia is linked to an increased risk for type 2 diabetes (T2D) in young adults, independent of lifestyle factors.

METHODOLOGY:

• This prospective study analyzed the data of 1,840,251 individuals aged 20-39 years from the South Korean National Health Insurance Service database (mean age 34 years, 71% male).
• The individuals had undergone four consecutive annual health checkups between 2009 and 2012 and had no history of T2D.
• The individuals were sorted into five groups indicating the number of hypertriglyceridemia diagnoses over four consecutive years: 0, 1, 2, 3, and 4, defined as serum fasting triglyceride levels of 150 mg/dL or higher.
• Data on lifestyle-related risk factors, such as smoking status and heavy alcohol consumption, were collected through self-reported questionnaires.
• The primary outcome was newly diagnosed cases of T2D. Over a mean follow-up of 6.53 years, a total of 40,286 individuals developed T2D.

TAKEAWAY:

• The cumulative incidence of T2D increased with an increase in exposure scores for hypertriglyceridemia (log-rank test, P < .001), independent of lifestyle-related factors.
• The incidence rate per 1000 person-years was 1.25 for participants with an exposure score of 0 and 11.55 for those with a score of 4.
• For individuals with exposure scores of 1, 2, 3, and 4, the adjusted hazard ratios for incident diabetes were 1.674 (95% CI, 1.619-1.732), 2.192 (2.117-2.269), 2.637 (2.548-2.73), and 3.715 (3.6-3.834), respectively, vs those with an exposure score of 0.
• Exploratory subgroup analyses suggested the risk for T2D in persistent hypertriglyceridemia were more pronounced among people in their 20s than in their 30s and in women.

IN PRACTICE:

“Identification of individuals at higher risk based on triglyceride levels and management strategies for persistent hypertriglyceridemia in young adults could potentially reduce the burden of young-onset type 2 diabetes and enhance long-term health outcomes,” the authors wrote.

SOURCE:

The study, led by Min-Kyung Lee, Division of Endocrinology and Metabolism, Department of Internal Medicine, Myongji Hospital, Hanyang University College of Medicine, Seoul, Republic of Korea, was published online in Diabetes Research and Clinical Practice.

LIMITATIONS:

The scoring system based on fasting triglyceride levels of ≥ 150 mg/dL may have limitations, as the cumulative incidence of T2D also varied significantly for mean triglyceride levels. Moreover, relying on a single annual health checkup for hypertriglyceridemia diagnosis might not capture short-term fluctuations. Despite sufficient cases and a high follow-up rate, the study might have underestimated the incidence of T2D.

DISCLOSURES:

This work was supported by the National Research Foundation of Korea grant funded by the Korean Government and the faculty grant of Myongji Hospital. The authors declared no conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

Higher high-density lipoprotein cholesterol (HDL-C) levels show a positive association with prediabetes reversal to normoglycemia in Chinese adults, but only up to a certain threshold.

METHODOLOGY:

• Researchers examined the correlation between HDL-C levels and the reversion of people with prediabetes to normoglycemia in a secondary analysis of data from a population-based cohort study.
• The analysis included 15,420 Chinese patients with prediabetes who underwent health screening between 2010 and 2016 (mean age, 51 ± 13 years; 5414 (35%) women).
• The outcome measure, reversion to normoglycemia, was determined by no self-reported diabetic event and fasting plasma glucose < 5.6 mmol/L at follow-up.
• They categorized the adults into four groups on the basis of HDL-C quartiles.
• They used multiple statistical models to investigate the association between HDL-C levels and reversion from prediabetes, assess the linearity of the association, and account for independent variables and confounding factors.

TAKEAWAY:

• After a median follow-up of nearly 3 years, 6627 (43%) of patients with prediabetes had a reversion to normoglycemia.
• The groups with higher HDL-C levels had a higher likelihood of prediabetes reversal to normoglycemia (adjusted hazard ratio [HR], 1.90; P < .001).
• They found a nonlinear association and threshold effect: The probability of reversal from prediabetes to normoglycemia stabilized rather than continued to increase at an inflection point (1.54 mmol/L in men, 1.62 mmol/L in women).
• A significant positive correlation with reversal to normoglycemia was observed below the HDL-C threshold (men: HR, 2.78; 95% CI, 2.37-3.26; women: HR, 2.22; 95% CI, 1.80-2.73).

IN PRACTICE:

“Keeping HDL-C levels near the inflection point in patients with prediabetes may greatly increase the likelihood of reversion from prediabetes to normoglycemia,” the authors wrote.

SOURCE:

The study, with lead author Zihe Mo, Department of Physical Examination, Dongguan Tungwah Hospital, Dongguan, China, was published online in Scientific Reports.

LIMITATIONS:

The study included individuals of Chinese descent, necessitating more studies into the HDL-C and normoglycemia relationship across diverse genetic backgrounds. The study relied solely on fasting plasma glucose measurements and was unable to capture the entirety of prediabetes complexity. As a secondary analysis of previously published data, the study faces limitations in managing unmeasured variables not initially included in the dataset. The observational study cannot determine a causal relationship between HDL-C and reversion from prediabetes to normoglycemia.

DISCLOSURES:

The study was supported by the Natural Science Funding of China. The authors declared no conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

Higher high-density lipoprotein cholesterol (HDL-C) levels show a positive association with prediabetes reversal to normoglycemia in Chinese adults, but only up to a certain threshold.

METHODOLOGY:

• Researchers examined the correlation between HDL-C levels and the reversion of people with prediabetes to normoglycemia in a secondary analysis of data from a population-based cohort study.
• The analysis included 15,420 Chinese patients with prediabetes who underwent health screening between 2010 and 2016 (mean age, 51 ± 13 years; 5414 (35%) women).
• The outcome measure, reversion to normoglycemia, was determined by no self-reported diabetic event and fasting plasma glucose < 5.6 mmol/L at follow-up.
• They categorized the adults into four groups on the basis of HDL-C quartiles.
• They used multiple statistical models to investigate the association between HDL-C levels and reversion from prediabetes, assess the linearity of the association, and account for independent variables and confounding factors.

TAKEAWAY:

• After a median follow-up of nearly 3 years, 6627 (43%) of patients with prediabetes had a reversion to normoglycemia.
• The groups with higher HDL-C levels had a higher likelihood of prediabetes reversal to normoglycemia (adjusted hazard ratio [HR], 1.90; P < .001).
• They found a nonlinear association and threshold effect: The probability of reversal from prediabetes to normoglycemia stabilized rather than continued to increase at an inflection point (1.54 mmol/L in men, 1.62 mmol/L in women).
• A significant positive correlation with reversal to normoglycemia was observed below the HDL-C threshold (men: HR, 2.78; 95% CI, 2.37-3.26; women: HR, 2.22; 95% CI, 1.80-2.73).

IN PRACTICE:

“Keeping HDL-C levels near the inflection point in patients with prediabetes may greatly increase the likelihood of reversion from prediabetes to normoglycemia,” the authors wrote.

SOURCE:

The study, with lead author Zihe Mo, Department of Physical Examination, Dongguan Tungwah Hospital, Dongguan, China, was published online in Scientific Reports.

LIMITATIONS:

The study included individuals of Chinese descent, necessitating more studies into the HDL-C and normoglycemia relationship across diverse genetic backgrounds. The study relied solely on fasting plasma glucose measurements and was unable to capture the entirety of prediabetes complexity. As a secondary analysis of previously published data, the study faces limitations in managing unmeasured variables not initially included in the dataset. The observational study cannot determine a causal relationship between HDL-C and reversion from prediabetes to normoglycemia.

DISCLOSURES:

The study was supported by the Natural Science Funding of China. The authors declared no conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

Higher high-density lipoprotein cholesterol (HDL-C) levels show a positive association with prediabetes reversal to normoglycemia in Chinese adults, but only up to a certain threshold.

METHODOLOGY:

• Researchers examined the correlation between HDL-C levels and the reversion of people with prediabetes to normoglycemia in a secondary analysis of data from a population-based cohort study.
• The analysis included 15,420 Chinese patients with prediabetes who underwent health screening between 2010 and 2016 (mean age, 51 ± 13 years; 5414 (35%) women).
• The outcome measure, reversion to normoglycemia, was determined by no self-reported diabetic event and fasting plasma glucose < 5.6 mmol/L at follow-up.
• They categorized the adults into four groups on the basis of HDL-C quartiles.
• They used multiple statistical models to investigate the association between HDL-C levels and reversion from prediabetes, assess the linearity of the association, and account for independent variables and confounding factors.

TAKEAWAY:

• After a median follow-up of nearly 3 years, 6627 (43%) of patients with prediabetes had a reversion to normoglycemia.
• The groups with higher HDL-C levels had a higher likelihood of prediabetes reversal to normoglycemia (adjusted hazard ratio [HR], 1.90; P < .001).
• They found a nonlinear association and threshold effect: The probability of reversal from prediabetes to normoglycemia stabilized rather than continued to increase at an inflection point (1.54 mmol/L in men, 1.62 mmol/L in women).
• A significant positive correlation with reversal to normoglycemia was observed below the HDL-C threshold (men: HR, 2.78; 95% CI, 2.37-3.26; women: HR, 2.22; 95% CI, 1.80-2.73).

IN PRACTICE:

“Keeping HDL-C levels near the inflection point in patients with prediabetes may greatly increase the likelihood of reversion from prediabetes to normoglycemia,” the authors wrote.

SOURCE:

The study, with lead author Zihe Mo, Department of Physical Examination, Dongguan Tungwah Hospital, Dongguan, China, was published online in Scientific Reports.

LIMITATIONS:

The study included individuals of Chinese descent, necessitating more studies into the HDL-C and normoglycemia relationship across diverse genetic backgrounds. The study relied solely on fasting plasma glucose measurements and was unable to capture the entirety of prediabetes complexity. As a secondary analysis of previously published data, the study faces limitations in managing unmeasured variables not initially included in the dataset. The observational study cannot determine a causal relationship between HDL-C and reversion from prediabetes to normoglycemia.

DISCLOSURES:

The study was supported by the Natural Science Funding of China. The authors declared no conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

While low-density lipoprotein (LDL) particles are much more abundant than lipoprotein(a) [Lp(a)] particles and carry the greatest overall risk for coronary heart disease (CHD), on a per-particle basis, Lp(a) is associated with about six times the atherogenic risk for LDL, new observational research suggested.

METHODOLOGY:

• To compare the atherogenicity of Lp(a) relative to LDL on a per-particle basis, researchers used a genetic analysis because Lp(a) and LDL both contain one apolipoprotein B (apoB) per particle.
• In a genome-wide association study of 502,413 UK Biobank participants, they identified genetic variants uniquely affecting plasma levels of either Lp(a) or LDL particles.
• For these two genetic clusters, they related the change in apoB to the respective change in CHD risk, which allowed them to directly compare the atherogenicity of LDL and Lp(a), particle to particle.

TAKEAWAY:

• The odds ratio for CHD for a 50 nmol/L higher Lp(a)-apoB was 1.28 (95% CI, 1.24-1.33) compared with 1.04 (95% CI, 1.03-1.05) for the same increment in LDL-apoB.
• Additional supporting evidence was provided by using polygenic scores to rank participants according to the difference in Lp(a)-apoB vs LDL-apoB, which revealed a greater risk for CHD per 50 nmol/L apoB for the Lp(a) cluster (hazard ratio [HR], 1.47; 95% CI, 1.36-1.58) than the LDL cluster (HR, 1.04; 95% CI, 1.02-1.05).
• Based on the data, the researchers estimate that the atherogenicity of Lp(a) is roughly sixfold greater (point estimate of 6.6; 95% CI, 5.1-8.8) than that of LDL on a per-particle basis.

IN PRACTICE:

“There are two clinical implications. First, to completely characterize atherosclerotic cardiovascular disease risk, it is imperative to measure Lp(a) in all adult patients at least once. Second, these studies provide a rationale that targeting Lp(a) with potent and specific drugs may lead to clinically meaningful benefit,” wrote the authors of an accompanying commentary on the study.

SOURCE:

The study, with first author Elias Björnson, PhD, University of Gothenburg, Gothenburg, Sweden, and an editorial by Sotirios Tsimikas, MD, University of California, San Diego, and Vera Bittner, MD, University of Alabama at Birmingham, was published in the Journal of the American College of Cardiology.

LIMITATIONS:

The UK Biobank consists primarily of a Caucasian population, and confirmatory studies in more diverse samples are needed. The working range for the Lp(a) assay used in the study did not cover the full range of Lp(a) values seen in the population. Variations in Lp(a)-apoB and LDL-apoB were estimated from genetic analysis and not measured specifically in biochemical assays.

DISCLOSURES:

The study had no commercial funding. Some authors received honoraria from the pharmaceutical industry. A complete list of author disclosures is available with the original article.

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

TOPLINE:

While low-density lipoprotein (LDL) particles are much more abundant than lipoprotein(a) [Lp(a)] particles and carry the greatest overall risk for coronary heart disease (CHD), on a per-particle basis, Lp(a) is associated with about six times the atherogenic risk for LDL, new observational research suggested.

METHODOLOGY:

• To compare the atherogenicity of Lp(a) relative to LDL on a per-particle basis, researchers used a genetic analysis because Lp(a) and LDL both contain one apolipoprotein B (apoB) per particle.
• In a genome-wide association study of 502,413 UK Biobank participants, they identified genetic variants uniquely affecting plasma levels of either Lp(a) or LDL particles.
• For these two genetic clusters, they related the change in apoB to the respective change in CHD risk, which allowed them to directly compare the atherogenicity of LDL and Lp(a), particle to particle.

TAKEAWAY:

• The odds ratio for CHD for a 50 nmol/L higher Lp(a)-apoB was 1.28 (95% CI, 1.24-1.33) compared with 1.04 (95% CI, 1.03-1.05) for the same increment in LDL-apoB.
• Additional supporting evidence was provided by using polygenic scores to rank participants according to the difference in Lp(a)-apoB vs LDL-apoB, which revealed a greater risk for CHD per 50 nmol/L apoB for the Lp(a) cluster (hazard ratio [HR], 1.47; 95% CI, 1.36-1.58) than the LDL cluster (HR, 1.04; 95% CI, 1.02-1.05).
• Based on the data, the researchers estimate that the atherogenicity of Lp(a) is roughly sixfold greater (point estimate of 6.6; 95% CI, 5.1-8.8) than that of LDL on a per-particle basis.

IN PRACTICE:

“There are two clinical implications. First, to completely characterize atherosclerotic cardiovascular disease risk, it is imperative to measure Lp(a) in all adult patients at least once. Second, these studies provide a rationale that targeting Lp(a) with potent and specific drugs may lead to clinically meaningful benefit,” wrote the authors of an accompanying commentary on the study.

SOURCE:

The study, with first author Elias Björnson, PhD, University of Gothenburg, Gothenburg, Sweden, and an editorial by Sotirios Tsimikas, MD, University of California, San Diego, and Vera Bittner, MD, University of Alabama at Birmingham, was published in the Journal of the American College of Cardiology.

LIMITATIONS:

The UK Biobank consists primarily of a Caucasian population, and confirmatory studies in more diverse samples are needed. The working range for the Lp(a) assay used in the study did not cover the full range of Lp(a) values seen in the population. Variations in Lp(a)-apoB and LDL-apoB were estimated from genetic analysis and not measured specifically in biochemical assays.

DISCLOSURES:

The study had no commercial funding. Some authors received honoraria from the pharmaceutical industry. A complete list of author disclosures is available with the original article.

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

TOPLINE:

While low-density lipoprotein (LDL) particles are much more abundant than lipoprotein(a) [Lp(a)] particles and carry the greatest overall risk for coronary heart disease (CHD), on a per-particle basis, Lp(a) is associated with about six times the atherogenic risk for LDL, new observational research suggested.

METHODOLOGY:

• To compare the atherogenicity of Lp(a) relative to LDL on a per-particle basis, researchers used a genetic analysis because Lp(a) and LDL both contain one apolipoprotein B (apoB) per particle.
• In a genome-wide association study of 502,413 UK Biobank participants, they identified genetic variants uniquely affecting plasma levels of either Lp(a) or LDL particles.
• For these two genetic clusters, they related the change in apoB to the respective change in CHD risk, which allowed them to directly compare the atherogenicity of LDL and Lp(a), particle to particle.

TAKEAWAY:

• The odds ratio for CHD for a 50 nmol/L higher Lp(a)-apoB was 1.28 (95% CI, 1.24-1.33) compared with 1.04 (95% CI, 1.03-1.05) for the same increment in LDL-apoB.
• Additional supporting evidence was provided by using polygenic scores to rank participants according to the difference in Lp(a)-apoB vs LDL-apoB, which revealed a greater risk for CHD per 50 nmol/L apoB for the Lp(a) cluster (hazard ratio [HR], 1.47; 95% CI, 1.36-1.58) than the LDL cluster (HR, 1.04; 95% CI, 1.02-1.05).
• Based on the data, the researchers estimate that the atherogenicity of Lp(a) is roughly sixfold greater (point estimate of 6.6; 95% CI, 5.1-8.8) than that of LDL on a per-particle basis.

IN PRACTICE:

“There are two clinical implications. First, to completely characterize atherosclerotic cardiovascular disease risk, it is imperative to measure Lp(a) in all adult patients at least once. Second, these studies provide a rationale that targeting Lp(a) with potent and specific drugs may lead to clinically meaningful benefit,” wrote the authors of an accompanying commentary on the study.

SOURCE:

The study, with first author Elias Björnson, PhD, University of Gothenburg, Gothenburg, Sweden, and an editorial by Sotirios Tsimikas, MD, University of California, San Diego, and Vera Bittner, MD, University of Alabama at Birmingham, was published in the Journal of the American College of Cardiology.

LIMITATIONS:

The UK Biobank consists primarily of a Caucasian population, and confirmatory studies in more diverse samples are needed. The working range for the Lp(a) assay used in the study did not cover the full range of Lp(a) values seen in the population. Variations in Lp(a)-apoB and LDL-apoB were estimated from genetic analysis and not measured specifically in biochemical assays.

DISCLOSURES:

The study had no commercial funding. Some authors received honoraria from the pharmaceutical industry. A complete list of author disclosures is available with the original article.

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

The relationship between lipid levels and the development of dementia is an evolving but confusing landscape.

“This is an incredibly complex area, and there really isn’t a clear consensus on this subject because different lipid classes reflect different things,” according to Betsy Mills, PhD, assistant director of aging and Alzheimer’s prevention at the Alzheimer’s Drug Discovery Foundation.

Some studies suggest that excessive lipid levels may increase the risk of developing dementia and Alzheimer’s disease (AD). Others imply that elevated low-density lipoprotein (LDL) cholesterol or even triglycerides may offer some protection against subsequent dementia whereas higher levels of high-density lipoprotein (HDL) cholesterol, hitherto thought to be protective, may have a deleterious effect.

“It depends on what lipids you’re measuring, what you’re using to measure those lipids, what age the person is, and multiple other factors,” Dr. Mills told this news organization.

Teasing out the variables and potential mechanisms for the association between lipids and dementia risk necessitates understanding the role that lipids play in the healthy brain, the negative impact of brain lipid dysregulation, and the interplay between cholesterol in the central nervous system (CNS) and the cholesterol in the rest of the body.

 

Beyond Amyloid

The role of lipids in AD risk has historically been “overlooked,” says Scott Hansen, PhD, associate professor, Department of Molecular Medicine, Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, Florida.

“The common narrative is that amyloid is the culprit in AD and certainly that’s the case in familial AD,” he told this news organization. “It’s been assumed that because amyloid deposits are also found in the brains of people with late-onset AD — which is the vast majority of cases — amyloid is the cause, but that’s not clear at all.”

The “limited clinical success” of aducanumab, its “extremely small efficacy” — despite its obvious success in eradicating the amyloid plaques — suggests there’s “much more to the story than amyloid.”

He and a growing community of scientists recognize the role of inflammation and lipids. “The major finding of my lab is that cholesterol actually drives the synthesis of amyloid via inflammation. In other words, amyloid is downstream of cholesterol. Cholesterol drives the inflammation, and the inflammation drives amyloid,” he said.
 

‘Lipid Invasion Model’

Because the brain is an incredibly lipid-rich organ, Dr. Mills said that “any dysregulation in lipid homeostasis will impact the brain because cholesterol is needed for the myelin sheaths, cell membranes, and other functions.”

A healthy brain relies upon healthy lipid regulation, and “since the first description of AD over 100 years ago, the disease has been associated with altered lipids in the brain,” Dr. Hansen noted.

He cited the “ lipid invasion model” as a way of understanding brain lipid dysregulation. This hypothesis posits that AD is driven by external lipids that enter the brain as a result of damage to the blood-brain barrier (BBB).

“Cholesterol in the brain and cholesterol in the periphery — meaning, in the rest of the body, outside the brain — are separate,” Dr. Hansen explained. “The brain produces its own cholesterol and keeps tight control of it.”

Under normal circumstances, cholesterol from the diet doesn’t enter the brain. “Each pool of cholesterol — in the brain and in the periphery — has its own distinct regulatory mechanisms, target cells, and transport mechanisms.”

When the BBB has been compromised, it becomes permeable, allowing LDL cholesterol to enter the brain, said Dr. Hansen. Then the brain’s own lipoproteins transport the invading cholesterol, allowing it to be taken up by neurons. In turn, this causes neuronal amyloid levels to rise, ultimately leading to the creation of amyloid-b plaques. It also plays a role in tau phosphorylation. Both are key features of AD pathology.

Elevated levels of cholesterol and other lipids have been found in amyloid plaques, Dr. Hansen noted. Moreover, studies of brains of patients with AD have pointed to BBB damage.

And the risk factors for AD overlap with the risk factors for damage to the BBB (such as, aging, brain trauma, hypertension, stress, sleep deprivation, smoking, excess alcohol, obesity, diabetes, and APOE4 genotype), according to the lipid invasion model paper cited by Dr. Hansen.
 

‘Chicken and Egg’

“There is a strong link between the brain and the heart, and we know that cardiovascular risk factors have an overlap with dementia risk factors — especially vascular dementia,” said Dr. Mills. 

She explained that an atherogenic lipid profile results in narrowing of the arteries, with less blood reaching the brain. “This can lead to stress in the brain, which drives inflammation and pathology.”

But cholesterol itself plays an important role in inflammation, Dr. Hansen said. In the periphery, it is “part of an integral response to tissue damage and infection.”

In the brain, once cholesterol is synthesized by the astrocytes, it is transported to neurons via the apolipoprotein E (APOE) protein, which plays a role in brain cholesterol homeostasis, Dr. Mills explained. Those with the ε4 allele of APOE (APOE4) tend to have faultier transport and storage of lipids in the brain, relative to the other APOE variants.

It’s known that individuals with APOE4 are particularly vulnerable to late-onset AD, Dr. Hansen observed. By contrast, APOE2 has a more protective effect. “Most people have APOE3, which is ‘in between,’ ” he said.

When there is neuronal uptake of “invading cholesterol,” not only is amyloid produced but also neuroinflammatory cytokines, further driving inflammation. A vicious cycle ensues: Cholesterol induces cytokine release; and cytokine release, in turn, induces cholesterol synthesis — which “suggests an autocatalytic function of cholesterol in the escalation of inflammation,” Dr. Hansen suggested. He noted that permeability of the BBB also allows inflammatory cytokines from elsewhere in the body to invade the brain, further driving inflammation.

Dr. Mills elaborated: “We know that generally, in dementia, there appear to be some changes in cholesterol metabolism in the brain, but it’s a chicken-and-egg question. We know that as the disease progresses, neurons are dying and getting remodeled. Do these changes have to do with the degenerative process, or are the changes in the cholesterol metabolism actually driving the degenerative disease process? It’s probably a combination, but it’s unclear at this point.”
 

Lipids in Plasma vs CSF

Dr. Mills explained that HDL particles in the brain differ from those in the periphery. “In the CNS, you have ‘HDL-like particles,’ which are similar in size and composition [to HDL in the periphery] but aren’t the same particles.” The brain itself generates HDL-like lipoproteins, which are produced by astrocytes and other glial cells and found in cerebrospinal fluid (CSF).

Dyslipidemia in the periphery can be a marker for cardiovascular pathology. In the brain, “it can be an indication that there is active damage going on, depending on which compartment you’re looking at.”

She noted that plasma lipid levels and brain CSF lipid levels are “very different.” Research suggests that HDL in the CSF exhibits similar heterogeneity to plasma HDL, but these CSF lipoproteins present at 100-fold lower concentrations, compared to plasma HDL and have unique combinations of protein subpopulations. Lipidomics analysis studies show that these compartments “get very different readings, in terms of the predominant lipid disease state, and they are regulated differently from the way lipids in the periphery are regulated.” 

In the brain, the cholesterol “needs to get shuttled from glial cells to neurons,” so defects in the transport process can disrupt overall brain homeostasis, said Dr. Mills. But since the brain system is separate from the peripheral system, measuring plasma lipids is more likely to point to cardiovascular risks, while changes reflected in CSF lipids are “more indicative of alteration in lipid homeostasis in the brain.”
 

HDL and Triglycerides: A Complicated Story

Dr. Mills noted that HDL in the periphery is “very complicated,” and the idea that HDL, as a measure on its own, is “necessarily ‘good’ isn’t particularly informative.” Rather, HDL is “extremely heterogeneous, very diverse, has different lipid compositions, different classes, and different modifications.” For example, like oxidized LDL, oxidized HDL is also “bad,” preventing the HDL from having protective functions.

Similarly, the apolipoproteins associated with HDL can affect the function of the HDL. “Our understanding of the HDL-like particles in the CNS is limited, but we do understand the APOE4 link,” Dr. Mills said. “It seems that the HDL-like particles containing APOE2 or APOE3 are larger and are more effective at transferring the lipids and cholesterol linked to them relative to APOE4-containing particles.” 

Because HDL is more complex than simply being “good,” measuring HDL doesn’t “give you the full story,” said Dr. Mills. She speculates that this may be why there are studies suggesting that high levels of HDL might not have protective benefits and might even be detrimental. This makes it difficult to look at population studies, where the different subclasses of HDL are not necessarily captured in depth. 

Dr. Mills pointed to another confounding factor, which is that much of the risk for the development of AD appears to be related to the interaction of HDL, LDL, and triglycerides. “When you look at each of these individually, you get a lot of heterogeneity, and it’s unclear what’s driving what,” she said.

An advantage of observational studies is that they give information about which of these markers are associated with trends and disease risks in specific groups vs others. 

“For example, higher levels of triglycerides are associated with cardiovascular risk more in women, relative to men,” she said. And the triglyceride-to-HDL ratio seems “particularly robust” as a measure of cardiovascular health and risk. 

The interpretation of associations with triglycerides can be “tricky” and “confusing” because results differ so much between studies, she said. “There are differences between middle age and older age, which have to do with age-related changes in metabolism and lipid metabolism and not necessarily that the markers are indicating something different,” she said.

Some research has suggested that triglycerides may have a protective effect against dementia, noted Uma Naidoo, MD, director of nutritional and lifestyle psychiatry, Massachusetts General Hospital, and director of nutritional psychiatry at MGH Academy.

This may be because the brain “runs mostly on energy from burning triglycerides,” suggested Dr. Naidoo, author of the books Calm Your Mind With Food and This Is Your Brain on Food.

In addition, having higher levels of triglycerides may be linked with having overall healthier behaviors, Dr. Naidoo told this news organization.

Dr. Mills said that in middle-aged individuals, high levels of LDL-C and triglycerides are “often indicative of more atherogenic particles and risk to cardiovascular health, which is a generally negative trajectory. But in older individuals, things become more complicated because there are differences in terms of clearance of some of these particles, tissue clearance and distribution, and nutrient status. So for older individuals, it seems that fluctuations in either direction—either too high or too low—tend to be more informative that some overall dysregulation is going on the system.” 

She emphasized that, in this “emerging area, looking at only one or two studies is confusing. But if you look at the spectrum of studies, you can see a pattern, which is that the regulation gets ‘off,’ as people age.”

 

The Potential Role of Statins

Dr. Mills speculated that there may be “neuroprotective benefits for some of the statins which appear to be related to cardiovascular benefits. But at this point, we don’t have any clear data whether statins actually directly impact brain cholesterol, since it’s a separate pool.”

They could help “by increasing blood flow and reducing narrowing of the arteries, but any direct impact on the brain is still under investigation.”

Dr. Hansen pointed to research suggesting statins taken at midlife appear to be cardioprotective and may be protective of brain health as well, whereas statins initiated in older age do not appear to have these benefits.

He speculated that one reason statins seem less helpful when initiated later in life is that the BBB has already been damaged by systemic inflammation in the periphery, and the neuroinflammatory process resulting in neuronal destruction is already underway. “I think statins aren’t going to fix that problem, so although lowering cholesterol can be helpful in some respects, it might be too late to affect cognition because the nerves have already died and won’t grow back.”
 

Can Dietary Approaches Help?

Dr. Naidoo said that when looking at neurologic and psychiatric disease, “it’s important to think about the ‘long game’ — how can we improve our blood and cardiovascular health earlier in life to help potentiate healthy aging?”

From a nutritional psychiatry standpoint, Dr. Naidoo focuses on nourishing the gut microbiome and decreasing inflammation. “A healthy and balanced microbiome supports cognition, while the composition of gut bacteria is actually drastically different in patients with neurological diseases, such as AD.” 

She recommends a nutrient-dense, anti-inflammatory diet including probiotic-rich foods (such as kimchi, sauerkraut, plain yogurt, and miso). Moreover, “the quality and structure of our fatty acids may be relevant as well: Increasing our intake of polyunsaturated fatty acids and avoiding processed fats like trans fats and hydrogenated oils may benefit our overall brain health.”

Dr. Naidoo recommends extra-virgin olive oil as a source of healthy fat. Its consumption is linked to lower incidence of AD by way of encouraging autophagy, which she calls “our own process of “cellular cleanup.’”

Dr. Naidoo believes that clinicians’ guidance to patients should “focus on healthy nutrition and other lifestyle practices, such as exercise, outdoor time, good sleep, and stress reduction.” 

Dr. Mills notes the importance of omega-3 fatty acids, such as docosahexaenoic acid (DHA) , for brain health. “DHA is a major lipid component of neuronal membranes,” she said. “Because of inefficiencies in metabolism with APOE4, people tend to metabolize more of the lipids on the membranes themselves, so they have higher lipid membrane turnover and a greater need to supplement. Supplementing particularly through diet, with foods such as fatty fish rich in omega-3, can help boost the levels to help keep neuronal membranes intact.”
 

What This Means for the Clinician

“At this point, we see all of these associations between lipids and dementia, but we haven’t worked out exactly what it means on the individual level for an individual patient,” said Dr. Mills. Certainly, the picture is complex, and the understanding is growing and shifting. “The clinical applications remain unclear.”

One potential clinical take-home is that clinicians might consider tracking lipid levels over time. “If you follow a patient and see an increase or decrease [in lipid levels], that can be informative.” Looking at ratios of lipids might be more useful than looking only at a change in a single measure. “If you see trends in a variety of measures that track with one another, it might be more of a sign that something is potentially wrong.” 

Whether the patient should first try a lifestyle intervention or might need medication is a “personalized clinical decision, depending on the individual, their risk factors, and how their levels are going,” said Dr. Mills. 

Dr. Mills, Dr. Hansen, and Dr. Naidoo declared no relevant financial relationships.
 

A version of this article appeared on Medscape.com.

The relationship between lipid levels and the development of dementia is an evolving but confusing landscape.

“This is an incredibly complex area, and there really isn’t a clear consensus on this subject because different lipid classes reflect different things,” according to Betsy Mills, PhD, assistant director of aging and Alzheimer’s prevention at the Alzheimer’s Drug Discovery Foundation.

Some studies suggest that excessive lipid levels may increase the risk of developing dementia and Alzheimer’s disease (AD). Others imply that elevated low-density lipoprotein (LDL) cholesterol or even triglycerides may offer some protection against subsequent dementia whereas higher levels of high-density lipoprotein (HDL) cholesterol, hitherto thought to be protective, may have a deleterious effect.

“It depends on what lipids you’re measuring, what you’re using to measure those lipids, what age the person is, and multiple other factors,” Dr. Mills told this news organization.

Teasing out the variables and potential mechanisms for the association between lipids and dementia risk necessitates understanding the role that lipids play in the healthy brain, the negative impact of brain lipid dysregulation, and the interplay between cholesterol in the central nervous system (CNS) and the cholesterol in the rest of the body.

 

Beyond Amyloid

The role of lipids in AD risk has historically been “overlooked,” says Scott Hansen, PhD, associate professor, Department of Molecular Medicine, Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, Florida.

“The common narrative is that amyloid is the culprit in AD and certainly that’s the case in familial AD,” he told this news organization. “It’s been assumed that because amyloid deposits are also found in the brains of people with late-onset AD — which is the vast majority of cases — amyloid is the cause, but that’s not clear at all.”

The “limited clinical success” of aducanumab, its “extremely small efficacy” — despite its obvious success in eradicating the amyloid plaques — suggests there’s “much more to the story than amyloid.”

He and a growing community of scientists recognize the role of inflammation and lipids. “The major finding of my lab is that cholesterol actually drives the synthesis of amyloid via inflammation. In other words, amyloid is downstream of cholesterol. Cholesterol drives the inflammation, and the inflammation drives amyloid,” he said.
 

‘Lipid Invasion Model’

Because the brain is an incredibly lipid-rich organ, Dr. Mills said that “any dysregulation in lipid homeostasis will impact the brain because cholesterol is needed for the myelin sheaths, cell membranes, and other functions.”

A healthy brain relies upon healthy lipid regulation, and “since the first description of AD over 100 years ago, the disease has been associated with altered lipids in the brain,” Dr. Hansen noted.

He cited the “ lipid invasion model” as a way of understanding brain lipid dysregulation. This hypothesis posits that AD is driven by external lipids that enter the brain as a result of damage to the blood-brain barrier (BBB).

“Cholesterol in the brain and cholesterol in the periphery — meaning, in the rest of the body, outside the brain — are separate,” Dr. Hansen explained. “The brain produces its own cholesterol and keeps tight control of it.”

Under normal circumstances, cholesterol from the diet doesn’t enter the brain. “Each pool of cholesterol — in the brain and in the periphery — has its own distinct regulatory mechanisms, target cells, and transport mechanisms.”

When the BBB has been compromised, it becomes permeable, allowing LDL cholesterol to enter the brain, said Dr. Hansen. Then the brain’s own lipoproteins transport the invading cholesterol, allowing it to be taken up by neurons. In turn, this causes neuronal amyloid levels to rise, ultimately leading to the creation of amyloid-b plaques. It also plays a role in tau phosphorylation. Both are key features of AD pathology.

Elevated levels of cholesterol and other lipids have been found in amyloid plaques, Dr. Hansen noted. Moreover, studies of brains of patients with AD have pointed to BBB damage.

And the risk factors for AD overlap with the risk factors for damage to the BBB (such as, aging, brain trauma, hypertension, stress, sleep deprivation, smoking, excess alcohol, obesity, diabetes, and APOE4 genotype), according to the lipid invasion model paper cited by Dr. Hansen.
 

‘Chicken and Egg’

“There is a strong link between the brain and the heart, and we know that cardiovascular risk factors have an overlap with dementia risk factors — especially vascular dementia,” said Dr. Mills. 

She explained that an atherogenic lipid profile results in narrowing of the arteries, with less blood reaching the brain. “This can lead to stress in the brain, which drives inflammation and pathology.”

But cholesterol itself plays an important role in inflammation, Dr. Hansen said. In the periphery, it is “part of an integral response to tissue damage and infection.”

In the brain, once cholesterol is synthesized by the astrocytes, it is transported to neurons via the apolipoprotein E (APOE) protein, which plays a role in brain cholesterol homeostasis, Dr. Mills explained. Those with the ε4 allele of APOE (APOE4) tend to have faultier transport and storage of lipids in the brain, relative to the other APOE variants.

It’s known that individuals with APOE4 are particularly vulnerable to late-onset AD, Dr. Hansen observed. By contrast, APOE2 has a more protective effect. “Most people have APOE3, which is ‘in between,’ ” he said.

When there is neuronal uptake of “invading cholesterol,” not only is amyloid produced but also neuroinflammatory cytokines, further driving inflammation. A vicious cycle ensues: Cholesterol induces cytokine release; and cytokine release, in turn, induces cholesterol synthesis — which “suggests an autocatalytic function of cholesterol in the escalation of inflammation,” Dr. Hansen suggested. He noted that permeability of the BBB also allows inflammatory cytokines from elsewhere in the body to invade the brain, further driving inflammation.

Dr. Mills elaborated: “We know that generally, in dementia, there appear to be some changes in cholesterol metabolism in the brain, but it’s a chicken-and-egg question. We know that as the disease progresses, neurons are dying and getting remodeled. Do these changes have to do with the degenerative process, or are the changes in the cholesterol metabolism actually driving the degenerative disease process? It’s probably a combination, but it’s unclear at this point.”
 

Lipids in Plasma vs CSF

Dr. Mills explained that HDL particles in the brain differ from those in the periphery. “In the CNS, you have ‘HDL-like particles,’ which are similar in size and composition [to HDL in the periphery] but aren’t the same particles.” The brain itself generates HDL-like lipoproteins, which are produced by astrocytes and other glial cells and found in cerebrospinal fluid (CSF).

Dyslipidemia in the periphery can be a marker for cardiovascular pathology. In the brain, “it can be an indication that there is active damage going on, depending on which compartment you’re looking at.”

She noted that plasma lipid levels and brain CSF lipid levels are “very different.” Research suggests that HDL in the CSF exhibits similar heterogeneity to plasma HDL, but these CSF lipoproteins present at 100-fold lower concentrations, compared to plasma HDL and have unique combinations of protein subpopulations. Lipidomics analysis studies show that these compartments “get very different readings, in terms of the predominant lipid disease state, and they are regulated differently from the way lipids in the periphery are regulated.” 

In the brain, the cholesterol “needs to get shuttled from glial cells to neurons,” so defects in the transport process can disrupt overall brain homeostasis, said Dr. Mills. But since the brain system is separate from the peripheral system, measuring plasma lipids is more likely to point to cardiovascular risks, while changes reflected in CSF lipids are “more indicative of alteration in lipid homeostasis in the brain.”
 

HDL and Triglycerides: A Complicated Story

Dr. Mills noted that HDL in the periphery is “very complicated,” and the idea that HDL, as a measure on its own, is “necessarily ‘good’ isn’t particularly informative.” Rather, HDL is “extremely heterogeneous, very diverse, has different lipid compositions, different classes, and different modifications.” For example, like oxidized LDL, oxidized HDL is also “bad,” preventing the HDL from having protective functions.

Similarly, the apolipoproteins associated with HDL can affect the function of the HDL. “Our understanding of the HDL-like particles in the CNS is limited, but we do understand the APOE4 link,” Dr. Mills said. “It seems that the HDL-like particles containing APOE2 or APOE3 are larger and are more effective at transferring the lipids and cholesterol linked to them relative to APOE4-containing particles.” 

Because HDL is more complex than simply being “good,” measuring HDL doesn’t “give you the full story,” said Dr. Mills. She speculates that this may be why there are studies suggesting that high levels of HDL might not have protective benefits and might even be detrimental. This makes it difficult to look at population studies, where the different subclasses of HDL are not necessarily captured in depth. 

Dr. Mills pointed to another confounding factor, which is that much of the risk for the development of AD appears to be related to the interaction of HDL, LDL, and triglycerides. “When you look at each of these individually, you get a lot of heterogeneity, and it’s unclear what’s driving what,” she said.

An advantage of observational studies is that they give information about which of these markers are associated with trends and disease risks in specific groups vs others. 

“For example, higher levels of triglycerides are associated with cardiovascular risk more in women, relative to men,” she said. And the triglyceride-to-HDL ratio seems “particularly robust” as a measure of cardiovascular health and risk. 

The interpretation of associations with triglycerides can be “tricky” and “confusing” because results differ so much between studies, she said. “There are differences between middle age and older age, which have to do with age-related changes in metabolism and lipid metabolism and not necessarily that the markers are indicating something different,” she said.

Some research has suggested that triglycerides may have a protective effect against dementia, noted Uma Naidoo, MD, director of nutritional and lifestyle psychiatry, Massachusetts General Hospital, and director of nutritional psychiatry at MGH Academy.

This may be because the brain “runs mostly on energy from burning triglycerides,” suggested Dr. Naidoo, author of the books Calm Your Mind With Food and This Is Your Brain on Food.

In addition, having higher levels of triglycerides may be linked with having overall healthier behaviors, Dr. Naidoo told this news organization.

Dr. Mills said that in middle-aged individuals, high levels of LDL-C and triglycerides are “often indicative of more atherogenic particles and risk to cardiovascular health, which is a generally negative trajectory. But in older individuals, things become more complicated because there are differences in terms of clearance of some of these particles, tissue clearance and distribution, and nutrient status. So for older individuals, it seems that fluctuations in either direction—either too high or too low—tend to be more informative that some overall dysregulation is going on the system.” 

She emphasized that, in this “emerging area, looking at only one or two studies is confusing. But if you look at the spectrum of studies, you can see a pattern, which is that the regulation gets ‘off,’ as people age.”

 

The Potential Role of Statins

Dr. Mills speculated that there may be “neuroprotective benefits for some of the statins which appear to be related to cardiovascular benefits. But at this point, we don’t have any clear data whether statins actually directly impact brain cholesterol, since it’s a separate pool.”

They could help “by increasing blood flow and reducing narrowing of the arteries, but any direct impact on the brain is still under investigation.”

Dr. Hansen pointed to research suggesting statins taken at midlife appear to be cardioprotective and may be protective of brain health as well, whereas statins initiated in older age do not appear to have these benefits.

He speculated that one reason statins seem less helpful when initiated later in life is that the BBB has already been damaged by systemic inflammation in the periphery, and the neuroinflammatory process resulting in neuronal destruction is already underway. “I think statins aren’t going to fix that problem, so although lowering cholesterol can be helpful in some respects, it might be too late to affect cognition because the nerves have already died and won’t grow back.”
 

Can Dietary Approaches Help?

Dr. Naidoo said that when looking at neurologic and psychiatric disease, “it’s important to think about the ‘long game’ — how can we improve our blood and cardiovascular health earlier in life to help potentiate healthy aging?”

From a nutritional psychiatry standpoint, Dr. Naidoo focuses on nourishing the gut microbiome and decreasing inflammation. “A healthy and balanced microbiome supports cognition, while the composition of gut bacteria is actually drastically different in patients with neurological diseases, such as AD.” 

She recommends a nutrient-dense, anti-inflammatory diet including probiotic-rich foods (such as kimchi, sauerkraut, plain yogurt, and miso). Moreover, “the quality and structure of our fatty acids may be relevant as well: Increasing our intake of polyunsaturated fatty acids and avoiding processed fats like trans fats and hydrogenated oils may benefit our overall brain health.”

Dr. Naidoo recommends extra-virgin olive oil as a source of healthy fat. Its consumption is linked to lower incidence of AD by way of encouraging autophagy, which she calls “our own process of “cellular cleanup.’”

Dr. Naidoo believes that clinicians’ guidance to patients should “focus on healthy nutrition and other lifestyle practices, such as exercise, outdoor time, good sleep, and stress reduction.” 

Dr. Mills notes the importance of omega-3 fatty acids, such as docosahexaenoic acid (DHA) , for brain health. “DHA is a major lipid component of neuronal membranes,” she said. “Because of inefficiencies in metabolism with APOE4, people tend to metabolize more of the lipids on the membranes themselves, so they have higher lipid membrane turnover and a greater need to supplement. Supplementing particularly through diet, with foods such as fatty fish rich in omega-3, can help boost the levels to help keep neuronal membranes intact.”
 

What This Means for the Clinician

“At this point, we see all of these associations between lipids and dementia, but we haven’t worked out exactly what it means on the individual level for an individual patient,” said Dr. Mills. Certainly, the picture is complex, and the understanding is growing and shifting. “The clinical applications remain unclear.”

One potential clinical take-home is that clinicians might consider tracking lipid levels over time. “If you follow a patient and see an increase or decrease [in lipid levels], that can be informative.” Looking at ratios of lipids might be more useful than looking only at a change in a single measure. “If you see trends in a variety of measures that track with one another, it might be more of a sign that something is potentially wrong.” 

Whether the patient should first try a lifestyle intervention or might need medication is a “personalized clinical decision, depending on the individual, their risk factors, and how their levels are going,” said Dr. Mills. 

Dr. Mills, Dr. Hansen, and Dr. Naidoo declared no relevant financial relationships.
 

A version of this article appeared on Medscape.com.

The relationship between lipid levels and the development of dementia is an evolving but confusing landscape.

“This is an incredibly complex area, and there really isn’t a clear consensus on this subject because different lipid classes reflect different things,” according to Betsy Mills, PhD, assistant director of aging and Alzheimer’s prevention at the Alzheimer’s Drug Discovery Foundation.

Some studies suggest that excessive lipid levels may increase the risk of developing dementia and Alzheimer’s disease (AD). Others imply that elevated low-density lipoprotein (LDL) cholesterol or even triglycerides may offer some protection against subsequent dementia whereas higher levels of high-density lipoprotein (HDL) cholesterol, hitherto thought to be protective, may have a deleterious effect.

“It depends on what lipids you’re measuring, what you’re using to measure those lipids, what age the person is, and multiple other factors,” Dr. Mills told this news organization.

Teasing out the variables and potential mechanisms for the association between lipids and dementia risk necessitates understanding the role that lipids play in the healthy brain, the negative impact of brain lipid dysregulation, and the interplay between cholesterol in the central nervous system (CNS) and the cholesterol in the rest of the body.

 

Beyond Amyloid

The role of lipids in AD risk has historically been “overlooked,” says Scott Hansen, PhD, associate professor, Department of Molecular Medicine, Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, Florida.

“The common narrative is that amyloid is the culprit in AD and certainly that’s the case in familial AD,” he told this news organization. “It’s been assumed that because amyloid deposits are also found in the brains of people with late-onset AD — which is the vast majority of cases — amyloid is the cause, but that’s not clear at all.”

The “limited clinical success” of aducanumab, its “extremely small efficacy” — despite its obvious success in eradicating the amyloid plaques — suggests there’s “much more to the story than amyloid.”

He and a growing community of scientists recognize the role of inflammation and lipids. “The major finding of my lab is that cholesterol actually drives the synthesis of amyloid via inflammation. In other words, amyloid is downstream of cholesterol. Cholesterol drives the inflammation, and the inflammation drives amyloid,” he said.
 

‘Lipid Invasion Model’

Because the brain is an incredibly lipid-rich organ, Dr. Mills said that “any dysregulation in lipid homeostasis will impact the brain because cholesterol is needed for the myelin sheaths, cell membranes, and other functions.”

A healthy brain relies upon healthy lipid regulation, and “since the first description of AD over 100 years ago, the disease has been associated with altered lipids in the brain,” Dr. Hansen noted.

He cited the “ lipid invasion model” as a way of understanding brain lipid dysregulation. This hypothesis posits that AD is driven by external lipids that enter the brain as a result of damage to the blood-brain barrier (BBB).

“Cholesterol in the brain and cholesterol in the periphery — meaning, in the rest of the body, outside the brain — are separate,” Dr. Hansen explained. “The brain produces its own cholesterol and keeps tight control of it.”

Under normal circumstances, cholesterol from the diet doesn’t enter the brain. “Each pool of cholesterol — in the brain and in the periphery — has its own distinct regulatory mechanisms, target cells, and transport mechanisms.”

When the BBB has been compromised, it becomes permeable, allowing LDL cholesterol to enter the brain, said Dr. Hansen. Then the brain’s own lipoproteins transport the invading cholesterol, allowing it to be taken up by neurons. In turn, this causes neuronal amyloid levels to rise, ultimately leading to the creation of amyloid-b plaques. It also plays a role in tau phosphorylation. Both are key features of AD pathology.

Elevated levels of cholesterol and other lipids have been found in amyloid plaques, Dr. Hansen noted. Moreover, studies of brains of patients with AD have pointed to BBB damage.

And the risk factors for AD overlap with the risk factors for damage to the BBB (such as, aging, brain trauma, hypertension, stress, sleep deprivation, smoking, excess alcohol, obesity, diabetes, and APOE4 genotype), according to the lipid invasion model paper cited by Dr. Hansen.
 

‘Chicken and Egg’

“There is a strong link between the brain and the heart, and we know that cardiovascular risk factors have an overlap with dementia risk factors — especially vascular dementia,” said Dr. Mills. 

She explained that an atherogenic lipid profile results in narrowing of the arteries, with less blood reaching the brain. “This can lead to stress in the brain, which drives inflammation and pathology.”

But cholesterol itself plays an important role in inflammation, Dr. Hansen said. In the periphery, it is “part of an integral response to tissue damage and infection.”

In the brain, once cholesterol is synthesized by the astrocytes, it is transported to neurons via the apolipoprotein E (APOE) protein, which plays a role in brain cholesterol homeostasis, Dr. Mills explained. Those with the ε4 allele of APOE (APOE4) tend to have faultier transport and storage of lipids in the brain, relative to the other APOE variants.

It’s known that individuals with APOE4 are particularly vulnerable to late-onset AD, Dr. Hansen observed. By contrast, APOE2 has a more protective effect. “Most people have APOE3, which is ‘in between,’ ” he said.

When there is neuronal uptake of “invading cholesterol,” not only is amyloid produced but also neuroinflammatory cytokines, further driving inflammation. A vicious cycle ensues: Cholesterol induces cytokine release; and cytokine release, in turn, induces cholesterol synthesis — which “suggests an autocatalytic function of cholesterol in the escalation of inflammation,” Dr. Hansen suggested. He noted that permeability of the BBB also allows inflammatory cytokines from elsewhere in the body to invade the brain, further driving inflammation.

Dr. Mills elaborated: “We know that generally, in dementia, there appear to be some changes in cholesterol metabolism in the brain, but it’s a chicken-and-egg question. We know that as the disease progresses, neurons are dying and getting remodeled. Do these changes have to do with the degenerative process, or are the changes in the cholesterol metabolism actually driving the degenerative disease process? It’s probably a combination, but it’s unclear at this point.”
 

Lipids in Plasma vs CSF

Dr. Mills explained that HDL particles in the brain differ from those in the periphery. “In the CNS, you have ‘HDL-like particles,’ which are similar in size and composition [to HDL in the periphery] but aren’t the same particles.” The brain itself generates HDL-like lipoproteins, which are produced by astrocytes and other glial cells and found in cerebrospinal fluid (CSF).

Dyslipidemia in the periphery can be a marker for cardiovascular pathology. In the brain, “it can be an indication that there is active damage going on, depending on which compartment you’re looking at.”

She noted that plasma lipid levels and brain CSF lipid levels are “very different.” Research suggests that HDL in the CSF exhibits similar heterogeneity to plasma HDL, but these CSF lipoproteins present at 100-fold lower concentrations, compared to plasma HDL and have unique combinations of protein subpopulations. Lipidomics analysis studies show that these compartments “get very different readings, in terms of the predominant lipid disease state, and they are regulated differently from the way lipids in the periphery are regulated.” 

In the brain, the cholesterol “needs to get shuttled from glial cells to neurons,” so defects in the transport process can disrupt overall brain homeostasis, said Dr. Mills. But since the brain system is separate from the peripheral system, measuring plasma lipids is more likely to point to cardiovascular risks, while changes reflected in CSF lipids are “more indicative of alteration in lipid homeostasis in the brain.”
 

HDL and Triglycerides: A Complicated Story

Dr. Mills noted that HDL in the periphery is “very complicated,” and the idea that HDL, as a measure on its own, is “necessarily ‘good’ isn’t particularly informative.” Rather, HDL is “extremely heterogeneous, very diverse, has different lipid compositions, different classes, and different modifications.” For example, like oxidized LDL, oxidized HDL is also “bad,” preventing the HDL from having protective functions.

Similarly, the apolipoproteins associated with HDL can affect the function of the HDL. “Our understanding of the HDL-like particles in the CNS is limited, but we do understand the APOE4 link,” Dr. Mills said. “It seems that the HDL-like particles containing APOE2 or APOE3 are larger and are more effective at transferring the lipids and cholesterol linked to them relative to APOE4-containing particles.” 

Because HDL is more complex than simply being “good,” measuring HDL doesn’t “give you the full story,” said Dr. Mills. She speculates that this may be why there are studies suggesting that high levels of HDL might not have protective benefits and might even be detrimental. This makes it difficult to look at population studies, where the different subclasses of HDL are not necessarily captured in depth. 

Dr. Mills pointed to another confounding factor, which is that much of the risk for the development of AD appears to be related to the interaction of HDL, LDL, and triglycerides. “When you look at each of these individually, you get a lot of heterogeneity, and it’s unclear what’s driving what,” she said.

An advantage of observational studies is that they give information about which of these markers are associated with trends and disease risks in specific groups vs others. 

“For example, higher levels of triglycerides are associated with cardiovascular risk more in women, relative to men,” she said. And the triglyceride-to-HDL ratio seems “particularly robust” as a measure of cardiovascular health and risk. 

The interpretation of associations with triglycerides can be “tricky” and “confusing” because results differ so much between studies, she said. “There are differences between middle age and older age, which have to do with age-related changes in metabolism and lipid metabolism and not necessarily that the markers are indicating something different,” she said.

Some research has suggested that triglycerides may have a protective effect against dementia, noted Uma Naidoo, MD, director of nutritional and lifestyle psychiatry, Massachusetts General Hospital, and director of nutritional psychiatry at MGH Academy.

This may be because the brain “runs mostly on energy from burning triglycerides,” suggested Dr. Naidoo, author of the books Calm Your Mind With Food and This Is Your Brain on Food.

In addition, having higher levels of triglycerides may be linked with having overall healthier behaviors, Dr. Naidoo told this news organization.

Dr. Mills said that in middle-aged individuals, high levels of LDL-C and triglycerides are “often indicative of more atherogenic particles and risk to cardiovascular health, which is a generally negative trajectory. But in older individuals, things become more complicated because there are differences in terms of clearance of some of these particles, tissue clearance and distribution, and nutrient status. So for older individuals, it seems that fluctuations in either direction—either too high or too low—tend to be more informative that some overall dysregulation is going on the system.” 

She emphasized that, in this “emerging area, looking at only one or two studies is confusing. But if you look at the spectrum of studies, you can see a pattern, which is that the regulation gets ‘off,’ as people age.”

 

The Potential Role of Statins

Dr. Mills speculated that there may be “neuroprotective benefits for some of the statins which appear to be related to cardiovascular benefits. But at this point, we don’t have any clear data whether statins actually directly impact brain cholesterol, since it’s a separate pool.”

They could help “by increasing blood flow and reducing narrowing of the arteries, but any direct impact on the brain is still under investigation.”

Dr. Hansen pointed to research suggesting statins taken at midlife appear to be cardioprotective and may be protective of brain health as well, whereas statins initiated in older age do not appear to have these benefits.

He speculated that one reason statins seem less helpful when initiated later in life is that the BBB has already been damaged by systemic inflammation in the periphery, and the neuroinflammatory process resulting in neuronal destruction is already underway. “I think statins aren’t going to fix that problem, so although lowering cholesterol can be helpful in some respects, it might be too late to affect cognition because the nerves have already died and won’t grow back.”
 

Can Dietary Approaches Help?

Dr. Naidoo said that when looking at neurologic and psychiatric disease, “it’s important to think about the ‘long game’ — how can we improve our blood and cardiovascular health earlier in life to help potentiate healthy aging?”

From a nutritional psychiatry standpoint, Dr. Naidoo focuses on nourishing the gut microbiome and decreasing inflammation. “A healthy and balanced microbiome supports cognition, while the composition of gut bacteria is actually drastically different in patients with neurological diseases, such as AD.” 

She recommends a nutrient-dense, anti-inflammatory diet including probiotic-rich foods (such as kimchi, sauerkraut, plain yogurt, and miso). Moreover, “the quality and structure of our fatty acids may be relevant as well: Increasing our intake of polyunsaturated fatty acids and avoiding processed fats like trans fats and hydrogenated oils may benefit our overall brain health.”

Dr. Naidoo recommends extra-virgin olive oil as a source of healthy fat. Its consumption is linked to lower incidence of AD by way of encouraging autophagy, which she calls “our own process of “cellular cleanup.’”

Dr. Naidoo believes that clinicians’ guidance to patients should “focus on healthy nutrition and other lifestyle practices, such as exercise, outdoor time, good sleep, and stress reduction.” 

Dr. Mills notes the importance of omega-3 fatty acids, such as docosahexaenoic acid (DHA) , for brain health. “DHA is a major lipid component of neuronal membranes,” she said. “Because of inefficiencies in metabolism with APOE4, people tend to metabolize more of the lipids on the membranes themselves, so they have higher lipid membrane turnover and a greater need to supplement. Supplementing particularly through diet, with foods such as fatty fish rich in omega-3, can help boost the levels to help keep neuronal membranes intact.”
 

What This Means for the Clinician

“At this point, we see all of these associations between lipids and dementia, but we haven’t worked out exactly what it means on the individual level for an individual patient,” said Dr. Mills. Certainly, the picture is complex, and the understanding is growing and shifting. “The clinical applications remain unclear.”

One potential clinical take-home is that clinicians might consider tracking lipid levels over time. “If you follow a patient and see an increase or decrease [in lipid levels], that can be informative.” Looking at ratios of lipids might be more useful than looking only at a change in a single measure. “If you see trends in a variety of measures that track with one another, it might be more of a sign that something is potentially wrong.” 

Whether the patient should first try a lifestyle intervention or might need medication is a “personalized clinical decision, depending on the individual, their risk factors, and how their levels are going,” said Dr. Mills. 

Dr. Mills, Dr. Hansen, and Dr. Naidoo declared no relevant financial relationships.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Light physical activity during childhood may lower blood cholesterol levels more effectively than moderate to vigorous physical activity, regardless of body fat mass.

METHODOLOGY:

• Researchers analyzed the data of 792 children (58% females) from the Avon Longitudinal Study of Parents and Children (ALSPAC) UK birth cohort.
• The measures included accelerometer-based sedentary time, light physical activity, and moderate to vigorous physical activity at ages 11, 15, and 24 years.
• The children had complete measurements of fasting high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglyceride, and total cholesterol levels at ages 15 , 17, and 24 years.
• Data also included measures of body mass, composition (fat and lean mass), insulin resistance, inflammation, and other cardiometabolic, socioeconomic, and lifestyle factors.
• The researchers conducted two types of analyses: Mediation path, to examine how fat and lean body mass affected longitudinal associations of activity level with blood lipids over 13 years, and temporal path, to look at temporal relationships between activity and lipid levels at ages 15 and 24 years only.

TAKEAWAY:

• Higher cumulative light physical activity from childhood through young adulthood was associated with a fivefold to eightfold decrease in total cholesterol, while total body fat mass decreased the impact of light physical activity on total cholesterol by 6%.
• Higher cumulative moderate to vigorous physical activity over 13 years led to a modest decrease in total cholesterol, an effect reduced to nonsignificance by the presence of higher fat mass.
• More cumulative sedentary time was associated with increasing total cholesterol.

IN PRACTICE:

“Light physical activity provides an opportunity for persons with obesity to follow a path to potentially benefit from the lipid-lowering effect of mild exercise,» wrote the author.

SOURCE:

Andrew O. Agbaje, from the Institute of Public Health and Clinical Nutrition, School of Medicine, University of Eastern Finland, Kuopio, Finland, conducted this study. It was published online December 14, 2023, in the Journal of Clinical Endocrinology and Metabolism.

LIMITATIONS:

The study included mostly White participants, so the findings might not apply to diverse racial and ethnic groups. The accelerometer data were gathered using a 60-second epoch, a duration known to underestimate moderate to vigorous physical activity in pediatric populations. There were no measures of fasting plasma lipids at age 11 years. The study also lacked data on participants’ dietary habits, alcohol intake, and menstrual cycle.

DISCLOSURES:

The ALSPAC UK birth cohort is funded by the UK Medical Research Council, the Wellcome Trust, and the University of Bristol. The author is funded by multiple foundations. No conflicts of interest were reported.

A version of this article appeared on Medscape.com.

TOPLINE:

Light physical activity during childhood may lower blood cholesterol levels more effectively than moderate to vigorous physical activity, regardless of body fat mass.

METHODOLOGY:

• Researchers analyzed the data of 792 children (58% females) from the Avon Longitudinal Study of Parents and Children (ALSPAC) UK birth cohort.
• The measures included accelerometer-based sedentary time, light physical activity, and moderate to vigorous physical activity at ages 11, 15, and 24 years.
• The children had complete measurements of fasting high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglyceride, and total cholesterol levels at ages 15 , 17, and 24 years.
• Data also included measures of body mass, composition (fat and lean mass), insulin resistance, inflammation, and other cardiometabolic, socioeconomic, and lifestyle factors.
• The researchers conducted two types of analyses: Mediation path, to examine how fat and lean body mass affected longitudinal associations of activity level with blood lipids over 13 years, and temporal path, to look at temporal relationships between activity and lipid levels at ages 15 and 24 years only.

TAKEAWAY:

• Higher cumulative light physical activity from childhood through young adulthood was associated with a fivefold to eightfold decrease in total cholesterol, while total body fat mass decreased the impact of light physical activity on total cholesterol by 6%.
• Higher cumulative moderate to vigorous physical activity over 13 years led to a modest decrease in total cholesterol, an effect reduced to nonsignificance by the presence of higher fat mass.
• More cumulative sedentary time was associated with increasing total cholesterol.

IN PRACTICE:

“Light physical activity provides an opportunity for persons with obesity to follow a path to potentially benefit from the lipid-lowering effect of mild exercise,» wrote the author.

SOURCE:

Andrew O. Agbaje, from the Institute of Public Health and Clinical Nutrition, School of Medicine, University of Eastern Finland, Kuopio, Finland, conducted this study. It was published online December 14, 2023, in the Journal of Clinical Endocrinology and Metabolism.

LIMITATIONS:

The study included mostly White participants, so the findings might not apply to diverse racial and ethnic groups. The accelerometer data were gathered using a 60-second epoch, a duration known to underestimate moderate to vigorous physical activity in pediatric populations. There were no measures of fasting plasma lipids at age 11 years. The study also lacked data on participants’ dietary habits, alcohol intake, and menstrual cycle.

DISCLOSURES:

The ALSPAC UK birth cohort is funded by the UK Medical Research Council, the Wellcome Trust, and the University of Bristol. The author is funded by multiple foundations. No conflicts of interest were reported.

A version of this article appeared on Medscape.com.

TOPLINE:

Light physical activity during childhood may lower blood cholesterol levels more effectively than moderate to vigorous physical activity, regardless of body fat mass.

METHODOLOGY:

• Researchers analyzed the data of 792 children (58% females) from the Avon Longitudinal Study of Parents and Children (ALSPAC) UK birth cohort.
• The measures included accelerometer-based sedentary time, light physical activity, and moderate to vigorous physical activity at ages 11, 15, and 24 years.
• The children had complete measurements of fasting high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglyceride, and total cholesterol levels at ages 15 , 17, and 24 years.
• Data also included measures of body mass, composition (fat and lean mass), insulin resistance, inflammation, and other cardiometabolic, socioeconomic, and lifestyle factors.
• The researchers conducted two types of analyses: Mediation path, to examine how fat and lean body mass affected longitudinal associations of activity level with blood lipids over 13 years, and temporal path, to look at temporal relationships between activity and lipid levels at ages 15 and 24 years only.

TAKEAWAY:

• Higher cumulative light physical activity from childhood through young adulthood was associated with a fivefold to eightfold decrease in total cholesterol, while total body fat mass decreased the impact of light physical activity on total cholesterol by 6%.
• Higher cumulative moderate to vigorous physical activity over 13 years led to a modest decrease in total cholesterol, an effect reduced to nonsignificance by the presence of higher fat mass.
• More cumulative sedentary time was associated with increasing total cholesterol.

IN PRACTICE:

“Light physical activity provides an opportunity for persons with obesity to follow a path to potentially benefit from the lipid-lowering effect of mild exercise,» wrote the author.

SOURCE:

Andrew O. Agbaje, from the Institute of Public Health and Clinical Nutrition, School of Medicine, University of Eastern Finland, Kuopio, Finland, conducted this study. It was published online December 14, 2023, in the Journal of Clinical Endocrinology and Metabolism.

LIMITATIONS:

The study included mostly White participants, so the findings might not apply to diverse racial and ethnic groups. The accelerometer data were gathered using a 60-second epoch, a duration known to underestimate moderate to vigorous physical activity in pediatric populations. There were no measures of fasting plasma lipids at age 11 years. The study also lacked data on participants’ dietary habits, alcohol intake, and menstrual cycle.

DISCLOSURES:

The ALSPAC UK birth cohort is funded by the UK Medical Research Council, the Wellcome Trust, and the University of Bristol. The author is funded by multiple foundations. No conflicts of interest were reported.

A version of this article appeared on Medscape.com.

PARIS — Although metabolic liver diseases are mainly seen in patients with obesity or type 2 diabetes, studies have shown that non-alcoholic fatty liver disease, recently renamed metabolic dysfunction-associated steatotic liver disease (MASLD), also affects slim patients. Moreover, the condition could be particularly severe in this population. 

A recent study carried out using data from the French Constance cohort showed that of the 25,753 patients with MASLD, 16.3% were lean (BMI of less than 25 kg/m²). In addition, 50% of these patients had no metabolic risk factors. 

These slim patients with MASLD were most often young patients, for the most part female, and less likely to present with symptoms of metabolic syndrome. Asian patients were overrepresented in this group. 

“These patients probably have genetic and/or environmental risk factors,” commented senior author Lawrence Serfaty, MD, PhD, head of the metabolic liver unit at the new Strasbourg public hospital, during a press conference at the Paris NASH meeting. 

The disease was more severe in slim subjects. Overall, 3.6% of the slim subjects had advanced fibrosis (Forns index > 6.9) vs 1.7% of patients with overweight or obesity (P < .001), regardless of demographic variables, metabolic risk factors, and lifestyle. They also had higher alanine aminotransferase levels. 

In addition, over the course of a mean follow-up of 3.8 years, liver events (eg, cirrhosis, decompensated cirrhosis, and liver cancer), chronic kidney diseases, and all-cause mortality were much more common in these patients than in patients with overweight or obesity (adjusted hazard ratios of 5.84, 2.49, and 3.01, respectively). It should be noted that these clinical results were linked to fibrosis severity in both slim and overweight subjects with MASLD. 

Nonetheless, cardiovascular events remained more common in patients with overweight or obesity, suggesting that obesity itself is a major risk factor for cardiovascular diseases, regardless of MASLD. 

“Armed with these results, which confirm those obtained from other studies, we must seek to understand the pathogenesis of the disease in slim patients and study the role of the microbiota, genetics, and diet, as well as determining the effects of alcohol and tobacco, consumption of which was slightly more common in this subpopulation,” said Dr. Serfaty. 

According to the study authors, sarcopenia and bile acids could also be involved in the pathogenesis of MASLD in slim patients. The researchers concluded that “due to the relatively low rate of MASLD in slim subjects, screening should target patients presenting with metabolic anomalies and/or unexplained cytolysis.”
 

This article was translated from the Medscape French edition.

PARIS — Although metabolic liver diseases are mainly seen in patients with obesity or type 2 diabetes, studies have shown that non-alcoholic fatty liver disease, recently renamed metabolic dysfunction-associated steatotic liver disease (MASLD), also affects slim patients. Moreover, the condition could be particularly severe in this population. 

A recent study carried out using data from the French Constance cohort showed that of the 25,753 patients with MASLD, 16.3% were lean (BMI of less than 25 kg/m²). In addition, 50% of these patients had no metabolic risk factors. 

These slim patients with MASLD were most often young patients, for the most part female, and less likely to present with symptoms of metabolic syndrome. Asian patients were overrepresented in this group. 

“These patients probably have genetic and/or environmental risk factors,” commented senior author Lawrence Serfaty, MD, PhD, head of the metabolic liver unit at the new Strasbourg public hospital, during a press conference at the Paris NASH meeting. 

The disease was more severe in slim subjects. Overall, 3.6% of the slim subjects had advanced fibrosis (Forns index > 6.9) vs 1.7% of patients with overweight or obesity (P < .001), regardless of demographic variables, metabolic risk factors, and lifestyle. They also had higher alanine aminotransferase levels. 

In addition, over the course of a mean follow-up of 3.8 years, liver events (eg, cirrhosis, decompensated cirrhosis, and liver cancer), chronic kidney diseases, and all-cause mortality were much more common in these patients than in patients with overweight or obesity (adjusted hazard ratios of 5.84, 2.49, and 3.01, respectively). It should be noted that these clinical results were linked to fibrosis severity in both slim and overweight subjects with MASLD. 

Nonetheless, cardiovascular events remained more common in patients with overweight or obesity, suggesting that obesity itself is a major risk factor for cardiovascular diseases, regardless of MASLD. 

“Armed with these results, which confirm those obtained from other studies, we must seek to understand the pathogenesis of the disease in slim patients and study the role of the microbiota, genetics, and diet, as well as determining the effects of alcohol and tobacco, consumption of which was slightly more common in this subpopulation,” said Dr. Serfaty. 

According to the study authors, sarcopenia and bile acids could also be involved in the pathogenesis of MASLD in slim patients. The researchers concluded that “due to the relatively low rate of MASLD in slim subjects, screening should target patients presenting with metabolic anomalies and/or unexplained cytolysis.”
 

This article was translated from the Medscape French edition.

PARIS — Although metabolic liver diseases are mainly seen in patients with obesity or type 2 diabetes, studies have shown that non-alcoholic fatty liver disease, recently renamed metabolic dysfunction-associated steatotic liver disease (MASLD), also affects slim patients. Moreover, the condition could be particularly severe in this population. 

A recent study carried out using data from the French Constance cohort showed that of the 25,753 patients with MASLD, 16.3% were lean (BMI of less than 25 kg/m²). In addition, 50% of these patients had no metabolic risk factors. 

These slim patients with MASLD were most often young patients, for the most part female, and less likely to present with symptoms of metabolic syndrome. Asian patients were overrepresented in this group. 

“These patients probably have genetic and/or environmental risk factors,” commented senior author Lawrence Serfaty, MD, PhD, head of the metabolic liver unit at the new Strasbourg public hospital, during a press conference at the Paris NASH meeting. 

The disease was more severe in slim subjects. Overall, 3.6% of the slim subjects had advanced fibrosis (Forns index > 6.9) vs 1.7% of patients with overweight or obesity (P < .001), regardless of demographic variables, metabolic risk factors, and lifestyle. They also had higher alanine aminotransferase levels. 

In addition, over the course of a mean follow-up of 3.8 years, liver events (eg, cirrhosis, decompensated cirrhosis, and liver cancer), chronic kidney diseases, and all-cause mortality were much more common in these patients than in patients with overweight or obesity (adjusted hazard ratios of 5.84, 2.49, and 3.01, respectively). It should be noted that these clinical results were linked to fibrosis severity in both slim and overweight subjects with MASLD. 

Nonetheless, cardiovascular events remained more common in patients with overweight or obesity, suggesting that obesity itself is a major risk factor for cardiovascular diseases, regardless of MASLD. 

“Armed with these results, which confirm those obtained from other studies, we must seek to understand the pathogenesis of the disease in slim patients and study the role of the microbiota, genetics, and diet, as well as determining the effects of alcohol and tobacco, consumption of which was slightly more common in this subpopulation,” said Dr. Serfaty. 

According to the study authors, sarcopenia and bile acids could also be involved in the pathogenesis of MASLD in slim patients. The researchers concluded that “due to the relatively low rate of MASLD in slim subjects, screening should target patients presenting with metabolic anomalies and/or unexplained cytolysis.”
 

This article was translated from the Medscape French edition.

TOPLINE: 

Compared with a healthy omnivore diet, a healthy vegan diet led to significant improvement in  low-density lipoprotein cholesterol (LDL-C) as well as fasting insulin and weight loss in a randomized controlled trial of identical twins. 

METHODOLOGY:  

• Researchers randomly assigned 22 pairs of healthy adult identical twins (34 women, mean age 39 years, mean body mass index 25.9) to a healthy vegan or omnivore diet (1 twin per pair) for 8 weeks.
• For the first 4 weeks, diet-specific meals were provided via a meal delivery service. For the final 4 weeks, participants prepared their own diet-appropriate meals/snacks.
• The primary outcome was change in LDL-C; secondary outcomes included changes in body weight and fasting insulin. 

TAKEAWAY:

• After 8 weeks, twins eating a vegan diet showed a significant mean decrease of 13.9 mg/dL in LDL-C compared with twins eating an omnivorous diet.
• The vegan diet also led to a significant mean decrease of 2.9 Times New RomanμIU/mL in fasting insulin and 1.9 kg in body weight after 8 weeks compared with the omnivore diet, although weight loss was observed in both diet groups. 
• The vegan diet group also had a larger but nonsignificant absolute median decrease in fasting HDL-C  triglycerides , vitamin B12, glucose, and trimethylamine N-oxide levels at 8 weeks.

IN PRACTICE: 

“Our results corroborate a previous finding showing that eating a vegan diet can improve cardiovascular health. Clinicians may consider recommending plant-based diets to reduce cardiometabolic risk factors, as well as aligning with environmental benefits,” the researchers concluded. 

SOURCE: 

The study, with first author Matthew J. Landry, PhD, RDN, Stanford Prevention Research Center, Stanford University School of Medicine, California, was published online November 30 in  JAMA Network Open. 

LIMITATIONS: 

The adult twin population was generally healthy and findings may not be generalizable to other populations. The sample size was small, and the duration of intervention was short and there was no follow-up period, which limits insights on stability and sustainability of the diets. 

DISCLOSURES: 

Funding was provided by the Vogt Foundation, and grants from Stanford University and the National Heart, Lung, and Blood Institute. Dr. Landry has no relevant disclosures. One author reported receiving funding from Beyond Meat outside of this study. 

A version of this article appeared on Medscape.com.

TOPLINE: 

Compared with a healthy omnivore diet, a healthy vegan diet led to significant improvement in  low-density lipoprotein cholesterol (LDL-C) as well as fasting insulin and weight loss in a randomized controlled trial of identical twins. 

METHODOLOGY:  

• Researchers randomly assigned 22 pairs of healthy adult identical twins (34 women, mean age 39 years, mean body mass index 25.9) to a healthy vegan or omnivore diet (1 twin per pair) for 8 weeks.
• For the first 4 weeks, diet-specific meals were provided via a meal delivery service. For the final 4 weeks, participants prepared their own diet-appropriate meals/snacks.
• The primary outcome was change in LDL-C; secondary outcomes included changes in body weight and fasting insulin. 

TAKEAWAY:

• After 8 weeks, twins eating a vegan diet showed a significant mean decrease of 13.9 mg/dL in LDL-C compared with twins eating an omnivorous diet.
• The vegan diet also led to a significant mean decrease of 2.9 Times New RomanμIU/mL in fasting insulin and 1.9 kg in body weight after 8 weeks compared with the omnivore diet, although weight loss was observed in both diet groups. 
• The vegan diet group also had a larger but nonsignificant absolute median decrease in fasting HDL-C  triglycerides , vitamin B12, glucose, and trimethylamine N-oxide levels at 8 weeks.

IN PRACTICE: 

“Our results corroborate a previous finding showing that eating a vegan diet can improve cardiovascular health. Clinicians may consider recommending plant-based diets to reduce cardiometabolic risk factors, as well as aligning with environmental benefits,” the researchers concluded. 

SOURCE: 

The study, with first author Matthew J. Landry, PhD, RDN, Stanford Prevention Research Center, Stanford University School of Medicine, California, was published online November 30 in  JAMA Network Open. 

LIMITATIONS: 

The adult twin population was generally healthy and findings may not be generalizable to other populations. The sample size was small, and the duration of intervention was short and there was no follow-up period, which limits insights on stability and sustainability of the diets. 

DISCLOSURES: 

Funding was provided by the Vogt Foundation, and grants from Stanford University and the National Heart, Lung, and Blood Institute. Dr. Landry has no relevant disclosures. One author reported receiving funding from Beyond Meat outside of this study. 

A version of this article appeared on Medscape.com.

TOPLINE: 

Compared with a healthy omnivore diet, a healthy vegan diet led to significant improvement in  low-density lipoprotein cholesterol (LDL-C) as well as fasting insulin and weight loss in a randomized controlled trial of identical twins. 

METHODOLOGY:  

• Researchers randomly assigned 22 pairs of healthy adult identical twins (34 women, mean age 39 years, mean body mass index 25.9) to a healthy vegan or omnivore diet (1 twin per pair) for 8 weeks.
• For the first 4 weeks, diet-specific meals were provided via a meal delivery service. For the final 4 weeks, participants prepared their own diet-appropriate meals/snacks.
• The primary outcome was change in LDL-C; secondary outcomes included changes in body weight and fasting insulin. 

TAKEAWAY:

• After 8 weeks, twins eating a vegan diet showed a significant mean decrease of 13.9 mg/dL in LDL-C compared with twins eating an omnivorous diet.
• The vegan diet also led to a significant mean decrease of 2.9 Times New RomanμIU/mL in fasting insulin and 1.9 kg in body weight after 8 weeks compared with the omnivore diet, although weight loss was observed in both diet groups. 
• The vegan diet group also had a larger but nonsignificant absolute median decrease in fasting HDL-C  triglycerides , vitamin B12, glucose, and trimethylamine N-oxide levels at 8 weeks.

IN PRACTICE: 

“Our results corroborate a previous finding showing that eating a vegan diet can improve cardiovascular health. Clinicians may consider recommending plant-based diets to reduce cardiometabolic risk factors, as well as aligning with environmental benefits,” the researchers concluded. 

SOURCE: 

The study, with first author Matthew J. Landry, PhD, RDN, Stanford Prevention Research Center, Stanford University School of Medicine, California, was published online November 30 in  JAMA Network Open. 

LIMITATIONS: 

The adult twin population was generally healthy and findings may not be generalizable to other populations. The sample size was small, and the duration of intervention was short and there was no follow-up period, which limits insights on stability and sustainability of the diets. 

DISCLOSURES: 

Funding was provided by the Vogt Foundation, and grants from Stanford University and the National Heart, Lung, and Blood Institute. Dr. Landry has no relevant disclosures. One author reported receiving funding from Beyond Meat outside of this study. 

A version of this article appeared on Medscape.com.

TOPLINE:

Changes in statin prescribing guidelines in 2013 had little effect on statin use for patients who are at risk for atherosclerotic cardiovascular disease (ASCVD), according to a study published Dec. 5 in the Annals of Internal Medicine. 

METHODOLOGY:

• Statins lower cholesterol and can reduce the risk for heart and circulatory disease.
• In 2013, the American College of Cardiology and the American Heart Association (ACC/AHA) expanded indications for which clinicians could prescribe statins to adults for primary prevention, including risk scores for ASCVD above a certain threshold. 
• Researchers studied trends in statin use between 1999 and 2018 using National Health and Nutrition Examination Survey data for 21,961 adults older than 20 years who did not have ASCVD. 
• They analyzed data from before and after implementation of the 2013 guidelines.

TAKEAWAY:

• Statin usage increased since 1999 but peaked at 35% in 2013 despite the expanded ACC/AHA guidelines.
• No changes in usage were observed for the proportion of adults who were newly eligible for statins. 
• Statin use among patients with diabetes increased by 31.1 percentage points between 1999 and 2014 but then remained stagnant from 2014 to 2018.
• Statin use among those with ASCVD risk of more than 20% increased by 23.1 percentage points between 1999 and 2013 but did not increase between 2013 and 2018.

IN PRACTICE:

“Although the ACC/AHA guidelines expanded indications for primary prevention, they also increased decision-making complexity, requiring new multistep risk calculation… Many clinicians do not routinely use cardiovascular risk calculators because of a lack of time, input availability, or buy-in. Electronic health record tools that calculate ASCVD risks show promise, but they are not routinely implemented and do not address other barriers, such as competing patient priorities and limited time for shared decision-making.“

SOURCE:

The study was led by Timothy S. Anderson, MD, MAS, Division of General Internal Medicine, at the University of Pittsburgh. The research was funded by the National Institute on Aging of the National Institutes of Health.

LIMITATIONS:

Data on whether patients had previously been offered and declined statins were not available. Risk score data for baseline ASCVD, which affects risk classification, were also not available.

DISCLOSURES:

The authors report no disclosures.

A version of this article appeared on Medscape.com.

TOPLINE:

Changes in statin prescribing guidelines in 2013 had little effect on statin use for patients who are at risk for atherosclerotic cardiovascular disease (ASCVD), according to a study published Dec. 5 in the Annals of Internal Medicine. 

METHODOLOGY:

• Statins lower cholesterol and can reduce the risk for heart and circulatory disease.
• In 2013, the American College of Cardiology and the American Heart Association (ACC/AHA) expanded indications for which clinicians could prescribe statins to adults for primary prevention, including risk scores for ASCVD above a certain threshold. 
• Researchers studied trends in statin use between 1999 and 2018 using National Health and Nutrition Examination Survey data for 21,961 adults older than 20 years who did not have ASCVD. 
• They analyzed data from before and after implementation of the 2013 guidelines.

TAKEAWAY:

• Statin usage increased since 1999 but peaked at 35% in 2013 despite the expanded ACC/AHA guidelines.
• No changes in usage were observed for the proportion of adults who were newly eligible for statins. 
• Statin use among patients with diabetes increased by 31.1 percentage points between 1999 and 2014 but then remained stagnant from 2014 to 2018.
• Statin use among those with ASCVD risk of more than 20% increased by 23.1 percentage points between 1999 and 2013 but did not increase between 2013 and 2018.

IN PRACTICE:

“Although the ACC/AHA guidelines expanded indications for primary prevention, they also increased decision-making complexity, requiring new multistep risk calculation… Many clinicians do not routinely use cardiovascular risk calculators because of a lack of time, input availability, or buy-in. Electronic health record tools that calculate ASCVD risks show promise, but they are not routinely implemented and do not address other barriers, such as competing patient priorities and limited time for shared decision-making.“

SOURCE:

The study was led by Timothy S. Anderson, MD, MAS, Division of General Internal Medicine, at the University of Pittsburgh. The research was funded by the National Institute on Aging of the National Institutes of Health.

LIMITATIONS:

Data on whether patients had previously been offered and declined statins were not available. Risk score data for baseline ASCVD, which affects risk classification, were also not available.

DISCLOSURES:

The authors report no disclosures.

A version of this article appeared on Medscape.com.

TOPLINE:

Changes in statin prescribing guidelines in 2013 had little effect on statin use for patients who are at risk for atherosclerotic cardiovascular disease (ASCVD), according to a study published Dec. 5 in the Annals of Internal Medicine. 

METHODOLOGY:

• Statins lower cholesterol and can reduce the risk for heart and circulatory disease.
• In 2013, the American College of Cardiology and the American Heart Association (ACC/AHA) expanded indications for which clinicians could prescribe statins to adults for primary prevention, including risk scores for ASCVD above a certain threshold. 
• Researchers studied trends in statin use between 1999 and 2018 using National Health and Nutrition Examination Survey data for 21,961 adults older than 20 years who did not have ASCVD. 
• They analyzed data from before and after implementation of the 2013 guidelines.

TAKEAWAY:

• Statin usage increased since 1999 but peaked at 35% in 2013 despite the expanded ACC/AHA guidelines.
• No changes in usage were observed for the proportion of adults who were newly eligible for statins. 
• Statin use among patients with diabetes increased by 31.1 percentage points between 1999 and 2014 but then remained stagnant from 2014 to 2018.
• Statin use among those with ASCVD risk of more than 20% increased by 23.1 percentage points between 1999 and 2013 but did not increase between 2013 and 2018.

IN PRACTICE:

“Although the ACC/AHA guidelines expanded indications for primary prevention, they also increased decision-making complexity, requiring new multistep risk calculation… Many clinicians do not routinely use cardiovascular risk calculators because of a lack of time, input availability, or buy-in. Electronic health record tools that calculate ASCVD risks show promise, but they are not routinely implemented and do not address other barriers, such as competing patient priorities and limited time for shared decision-making.“

SOURCE:

The study was led by Timothy S. Anderson, MD, MAS, Division of General Internal Medicine, at the University of Pittsburgh. The research was funded by the National Institute on Aging of the National Institutes of Health.

LIMITATIONS:

Data on whether patients had previously been offered and declined statins were not available. Risk score data for baseline ASCVD, which affects risk classification, were also not available.

DISCLOSURES:

The authors report no disclosures.

A version of this article appeared on Medscape.com.

PHILADELPHIA – An investigational PCSK9 inhibitor that can be injected every 1-3 months as add-on therapy for patients with stubbornly high low-density lipoprotein (LDL) cholesterol has demonstrated cholesterol lowering for up to a year, in a clinical trial.

The results are from the phase 3 Recaticimab Add-On Therapy in Patients With Non-Familial Hypercholesterolemia and Mixed Hyperlipidemia (REMAIN-2) trial.

“It’s a new antibody that has a long half-life so each treatment can be prolonged,” investigator Xin Du, MD, professor of cardiology at Beijing Anzhen Hospital and the Capital Medical University, said in an interview. “Previous drugs like alirocumab and evolocumab have to be given every 2 weeks or every 4 weeks, and this new drug can be given even every 12 weeks, so it can get a very strong effect of LDL cholesterol lowering even when given every 3 months.”

Recaticimab has demonstrated a half-life of 18.6 to 27.4 days vs. 11 to 17 days for alirocumab and evolocumab, she said.

Richard Mark Kirkner/MDedge News

“Currently a high proportion of patients prescribed the PCSK9 inhibitors withdraw from therapy,” Dr. Du said. “After 36 months, only half of them are still on that therapy.”

Dr. Du presented the trial results at the annual scientific sessions of the American Heart Association.
 

Trial design and results

REMAIN-2 randomly assigned 692 patients to one of three recaticimab dosing arms vs. placebo: 150 mg/kg every 4 weeks; 300 mg/kg every 8 weeks; and 450 mg/kg every 12 weeks. The study was conducted from June 2021 to March 2023. The average age of the participants was 56 years and 64% were men. A high percentage of patients, 87% to 93.5%, completed the study across all groups. All participants had high LDL-C levels despite statin therapy: ≥ 70 mg/dL for those with cardiovascular disease and ≥ 100 mg/dL for those without.

Recaticimab enhanced LDL-C reduction by 53.4% to 62% vs. placebo at 24 weeks with a similar effect across all dosing regimens, Dr. Du said. That level of reduction was sustained out to 48 weeks, she said, at 48.4% to 64%.

At week 24, 86% to 94.5% of all patients across the three dosing arms achieved their LDL-C goal. The treatment had a positive impact on other lipid levels as well, Dr. Du said. Levels of non-HDL-C declined 55% to 47%. Apolipoprotein B (ApoB) levels fell 53% to 42% and lipoprotein (a), or Lp(a) readings declined 39.5% to 29%. The placebo arms had no change or small increases in non-HDL-C and ApoB levels and modest reductions in Lp(a).

The trial demonstrated acceptable safety and tolerability of recaticimab, Dr. Du said. At 48 weeks, the rates of injection site reactions were 3.9% in the treatment arms vs. 1.3% in the placebo arms. Common adverse events with a frequency ≥ 5% in patients receiving recaticimab were upper respiratory tract infection, hyperuricemia, urinary tract infection, increased blood creatine phosphokinase – a marker of damage to the heart – COVID-19 infection, and increased alanine transferase and aspartate transferase, both of which are markers of liver damage.
 

Larger, longer studies needed

Longer-term studies of recaticimab are still needed to determine its ability produce durable LDL-C reduction in a cost-effective manner, said discussant Stephen Nicholls, MD, director of Victorian Heart Institute and professor at Monash University in Australia. “It is important to note that these are still relatively short studies and the short treatment period cannot exclude the formation of neutralizing antibodies that have undermined development of other humanized antibodies,” he told attendees.

Victorian Heart Institute

The every-12-week dosing, Dr. Nicholls said in an interview, “provides a dosing regimen that may be palatable to many patients.”

Besides the potential for the development of antibodies, Dr. Nicholls foresaw potential challenges with recaticimab. “The reality will lie in longer-term data,” he said. “If they can achieve durable lipid lowering without such neutralizing antibodies that would be very good.”

Dr. Nicholls added, “There’s a lot going on in the PCSK9 inhibitor space and the challenge for any new therapeutic, including this one, is where will it fit in given the space is getting crowded. So, data is important and clinical uptake will be equally important.”

Dr. Du disclosed relationships with Sanofi, AstraZeneca and Bayer. Dr. Nicholls disclosed relationships with AstraZeneca, Akcea, Amarin, Amgen, Anthera, Boehringer Ingelheim, Cerenis, CSL Behring, Eli Lilly, Esperion, Novartis,  LipoScience, The Medicines Company, Merck, New Amsterdam Pharma, Omthera, Resverlogix, InfraReDx, Roche, Sanofi-Regeneron, Takeda, Vaxxinity, and Seqirus.

PHILADELPHIA – An investigational PCSK9 inhibitor that can be injected every 1-3 months as add-on therapy for patients with stubbornly high low-density lipoprotein (LDL) cholesterol has demonstrated cholesterol lowering for up to a year, in a clinical trial.

The results are from the phase 3 Recaticimab Add-On Therapy in Patients With Non-Familial Hypercholesterolemia and Mixed Hyperlipidemia (REMAIN-2) trial.

“It’s a new antibody that has a long half-life so each treatment can be prolonged,” investigator Xin Du, MD, professor of cardiology at Beijing Anzhen Hospital and the Capital Medical University, said in an interview. “Previous drugs like alirocumab and evolocumab have to be given every 2 weeks or every 4 weeks, and this new drug can be given even every 12 weeks, so it can get a very strong effect of LDL cholesterol lowering even when given every 3 months.”

Recaticimab has demonstrated a half-life of 18.6 to 27.4 days vs. 11 to 17 days for alirocumab and evolocumab, she said.

Richard Mark Kirkner/MDedge News

“Currently a high proportion of patients prescribed the PCSK9 inhibitors withdraw from therapy,” Dr. Du said. “After 36 months, only half of them are still on that therapy.”

Dr. Du presented the trial results at the annual scientific sessions of the American Heart Association.
 

Trial design and results

REMAIN-2 randomly assigned 692 patients to one of three recaticimab dosing arms vs. placebo: 150 mg/kg every 4 weeks; 300 mg/kg every 8 weeks; and 450 mg/kg every 12 weeks. The study was conducted from June 2021 to March 2023. The average age of the participants was 56 years and 64% were men. A high percentage of patients, 87% to 93.5%, completed the study across all groups. All participants had high LDL-C levels despite statin therapy: ≥ 70 mg/dL for those with cardiovascular disease and ≥ 100 mg/dL for those without.

Recaticimab enhanced LDL-C reduction by 53.4% to 62% vs. placebo at 24 weeks with a similar effect across all dosing regimens, Dr. Du said. That level of reduction was sustained out to 48 weeks, she said, at 48.4% to 64%.

At week 24, 86% to 94.5% of all patients across the three dosing arms achieved their LDL-C goal. The treatment had a positive impact on other lipid levels as well, Dr. Du said. Levels of non-HDL-C declined 55% to 47%. Apolipoprotein B (ApoB) levels fell 53% to 42% and lipoprotein (a), or Lp(a) readings declined 39.5% to 29%. The placebo arms had no change or small increases in non-HDL-C and ApoB levels and modest reductions in Lp(a).

The trial demonstrated acceptable safety and tolerability of recaticimab, Dr. Du said. At 48 weeks, the rates of injection site reactions were 3.9% in the treatment arms vs. 1.3% in the placebo arms. Common adverse events with a frequency ≥ 5% in patients receiving recaticimab were upper respiratory tract infection, hyperuricemia, urinary tract infection, increased blood creatine phosphokinase – a marker of damage to the heart – COVID-19 infection, and increased alanine transferase and aspartate transferase, both of which are markers of liver damage.
 

Larger, longer studies needed

Longer-term studies of recaticimab are still needed to determine its ability produce durable LDL-C reduction in a cost-effective manner, said discussant Stephen Nicholls, MD, director of Victorian Heart Institute and professor at Monash University in Australia. “It is important to note that these are still relatively short studies and the short treatment period cannot exclude the formation of neutralizing antibodies that have undermined development of other humanized antibodies,” he told attendees.

Victorian Heart Institute

The every-12-week dosing, Dr. Nicholls said in an interview, “provides a dosing regimen that may be palatable to many patients.”

Besides the potential for the development of antibodies, Dr. Nicholls foresaw potential challenges with recaticimab. “The reality will lie in longer-term data,” he said. “If they can achieve durable lipid lowering without such neutralizing antibodies that would be very good.”

Dr. Nicholls added, “There’s a lot going on in the PCSK9 inhibitor space and the challenge for any new therapeutic, including this one, is where will it fit in given the space is getting crowded. So, data is important and clinical uptake will be equally important.”

Dr. Du disclosed relationships with Sanofi, AstraZeneca and Bayer. Dr. Nicholls disclosed relationships with AstraZeneca, Akcea, Amarin, Amgen, Anthera, Boehringer Ingelheim, Cerenis, CSL Behring, Eli Lilly, Esperion, Novartis,  LipoScience, The Medicines Company, Merck, New Amsterdam Pharma, Omthera, Resverlogix, InfraReDx, Roche, Sanofi-Regeneron, Takeda, Vaxxinity, and Seqirus.

PHILADELPHIA – An investigational PCSK9 inhibitor that can be injected every 1-3 months as add-on therapy for patients with stubbornly high low-density lipoprotein (LDL) cholesterol has demonstrated cholesterol lowering for up to a year, in a clinical trial.

The results are from the phase 3 Recaticimab Add-On Therapy in Patients With Non-Familial Hypercholesterolemia and Mixed Hyperlipidemia (REMAIN-2) trial.

“It’s a new antibody that has a long half-life so each treatment can be prolonged,” investigator Xin Du, MD, professor of cardiology at Beijing Anzhen Hospital and the Capital Medical University, said in an interview. “Previous drugs like alirocumab and evolocumab have to be given every 2 weeks or every 4 weeks, and this new drug can be given even every 12 weeks, so it can get a very strong effect of LDL cholesterol lowering even when given every 3 months.”

Recaticimab has demonstrated a half-life of 18.6 to 27.4 days vs. 11 to 17 days for alirocumab and evolocumab, she said.

Richard Mark Kirkner/MDedge News

“Currently a high proportion of patients prescribed the PCSK9 inhibitors withdraw from therapy,” Dr. Du said. “After 36 months, only half of them are still on that therapy.”

Dr. Du presented the trial results at the annual scientific sessions of the American Heart Association.
 

Trial design and results

REMAIN-2 randomly assigned 692 patients to one of three recaticimab dosing arms vs. placebo: 150 mg/kg every 4 weeks; 300 mg/kg every 8 weeks; and 450 mg/kg every 12 weeks. The study was conducted from June 2021 to March 2023. The average age of the participants was 56 years and 64% were men. A high percentage of patients, 87% to 93.5%, completed the study across all groups. All participants had high LDL-C levels despite statin therapy: ≥ 70 mg/dL for those with cardiovascular disease and ≥ 100 mg/dL for those without.

Recaticimab enhanced LDL-C reduction by 53.4% to 62% vs. placebo at 24 weeks with a similar effect across all dosing regimens, Dr. Du said. That level of reduction was sustained out to 48 weeks, she said, at 48.4% to 64%.

At week 24, 86% to 94.5% of all patients across the three dosing arms achieved their LDL-C goal. The treatment had a positive impact on other lipid levels as well, Dr. Du said. Levels of non-HDL-C declined 55% to 47%. Apolipoprotein B (ApoB) levels fell 53% to 42% and lipoprotein (a), or Lp(a) readings declined 39.5% to 29%. The placebo arms had no change or small increases in non-HDL-C and ApoB levels and modest reductions in Lp(a).

The trial demonstrated acceptable safety and tolerability of recaticimab, Dr. Du said. At 48 weeks, the rates of injection site reactions were 3.9% in the treatment arms vs. 1.3% in the placebo arms. Common adverse events with a frequency ≥ 5% in patients receiving recaticimab were upper respiratory tract infection, hyperuricemia, urinary tract infection, increased blood creatine phosphokinase – a marker of damage to the heart – COVID-19 infection, and increased alanine transferase and aspartate transferase, both of which are markers of liver damage.
 

Larger, longer studies needed

Longer-term studies of recaticimab are still needed to determine its ability produce durable LDL-C reduction in a cost-effective manner, said discussant Stephen Nicholls, MD, director of Victorian Heart Institute and professor at Monash University in Australia. “It is important to note that these are still relatively short studies and the short treatment period cannot exclude the formation of neutralizing antibodies that have undermined development of other humanized antibodies,” he told attendees.

Victorian Heart Institute

The every-12-week dosing, Dr. Nicholls said in an interview, “provides a dosing regimen that may be palatable to many patients.”

Besides the potential for the development of antibodies, Dr. Nicholls foresaw potential challenges with recaticimab. “The reality will lie in longer-term data,” he said. “If they can achieve durable lipid lowering without such neutralizing antibodies that would be very good.”

Dr. Nicholls added, “There’s a lot going on in the PCSK9 inhibitor space and the challenge for any new therapeutic, including this one, is where will it fit in given the space is getting crowded. So, data is important and clinical uptake will be equally important.”

Dr. Du disclosed relationships with Sanofi, AstraZeneca and Bayer. Dr. Nicholls disclosed relationships with AstraZeneca, Akcea, Amarin, Amgen, Anthera, Boehringer Ingelheim, Cerenis, CSL Behring, Eli Lilly, Esperion, Novartis,  LipoScience, The Medicines Company, Merck, New Amsterdam Pharma, Omthera, Resverlogix, InfraReDx, Roche, Sanofi-Regeneron, Takeda, Vaxxinity, and Seqirus.