CAD & Atherosclerosis

Progression of chronic kidney disease (CKD) and cardiovascular disease risk in hypertensive adults was significantly slower among those who consumed more fruits and vegetables or oral sodium bicarbonate, compared with controls who received usual care.

A primary focus on pharmacologic strategies has failed to reduced hypertension-related CKD and cardiovascular disease mortality, Nimrit Goraya, MD, of Texas A&M Health Sciences Center College of Medicine, Temple, and colleagues wrote. High-acid diets (those with greater amounts of animal-sourced foods) have been associated with increased incidence and progression of CKD and with increased risk of cardiovascular disease.

Diets high in fruits and vegetables are associated with reduced CKD and cardiovascular disease but are not routinely used as part of hypertension treatment. The researchers hypothesized that dietary acid reduction could slow kidney disease progression and reduce cardiovascular disease risk.

In a study published in The American Journal of Medicine, the researchers randomized 153 adults aged 18-70 years with hypertension and CKD to fruits and vegetables, oral sodium bicarbonate (NaHCO₃), or usual care; 51 to each group. The fruit and vegetable group received 2-4 cups daily of base-producing food items including apples, apricots, oranges, peaches, pears, raisins, strawberries, carrots, cauliflower, eggplant, lettuce, potatoes, spinach, tomatoes, and zucchini. Participants were not instructed how to incorporate these foods into their diets. The sodium bicarbonate group received an average of four to five NaHCO₃ tablets daily (650 mg), divided into two doses.

The mean age of the participants was 48.8 years, 51% were female, and 47% were African American. The primary outcome was CKD progression and cardiovascular disease risk over 5 years. All participants met criteria at baseline for macroalbuminuria (a urine albumin to creatinine ratio of at least 200 mg/g) and were considered at increased risk for CKD progression.

Over the 5-year follow-up, CKD progression was significantly slower in the groups receiving fruits and vegetables and oral sodium bicarbonate, compared with usual care, based on trajectories showing a lower decline of estimated glomerular filtration rates (mean declines of 1.08 and 1.17 for fruits/vegetables and NaHCO₃, respectively, vs 19.4 for usual care, P < .001 for both).

However, systolic blood pressure and subsequent cardiovascular disease risk indicators were lower only in the fruit and vegetable group, compared with both the NaHCO₃ or usual-care groups over the long term. “Specifically, with fruits and vegetables, systolic blood pressure, plasma LDL and Lp(a) cholesterol, and body mass index decreased from baseline, consistent with better cardiovascular disease protection,” the researchers wrote. The protection against cardiovascular disease in the fruits and vegetables group occurred with lower doses of antihypertensive and statin medications and was not affected by baseline differences in medication doses.

The findings were limited by several factors, including the lack of data on compliance with the NaHCO₃ supplements, although urine net acid excretion in this group suggested increased alkali intake similar to that provided by fruits and vegetables, the researchers noted. Other limitations included the focus only on individuals with very high albuminuria.

More basic science studies are needed to explore how the potential vascular injury suggested by albuminuria affects CKD progression and cardiovascular disease, and clinical studies are needed to assess the impact of dietary acid reduction on patients with lower levels of albuminuria that the current study, the researchers said.

However, the results suggest that consuming fruits and vegetables, rather than NaHCO₃, is the preferred strategy for dietary acid reduction for patients with primary hypertension and CKD, they concluded. The findings also support routine measurement of urine albumin-to-creatinine ratios in hypertensive patients to identify CKD and assess risk for progression and subsequent cardiovascular disease.

The study was supported by the Larry and Jane Woirhaye Memorial Endowment in Renal Research at the Texas Tech University Health Sciences Center, the University Medical Center (both in Lubbock, Texas), the Endowment, Academic Operations Division of Baylor Scott & White Health, and the Episcopal Health Foundation. The researchers had no financial conflicts to disclose.

Progression of chronic kidney disease (CKD) and cardiovascular disease risk in hypertensive adults was significantly slower among those who consumed more fruits and vegetables or oral sodium bicarbonate, compared with controls who received usual care.

A primary focus on pharmacologic strategies has failed to reduced hypertension-related CKD and cardiovascular disease mortality, Nimrit Goraya, MD, of Texas A&M Health Sciences Center College of Medicine, Temple, and colleagues wrote. High-acid diets (those with greater amounts of animal-sourced foods) have been associated with increased incidence and progression of CKD and with increased risk of cardiovascular disease.

Diets high in fruits and vegetables are associated with reduced CKD and cardiovascular disease but are not routinely used as part of hypertension treatment. The researchers hypothesized that dietary acid reduction could slow kidney disease progression and reduce cardiovascular disease risk.

In a study published in The American Journal of Medicine, the researchers randomized 153 adults aged 18-70 years with hypertension and CKD to fruits and vegetables, oral sodium bicarbonate (NaHCO₃), or usual care; 51 to each group. The fruit and vegetable group received 2-4 cups daily of base-producing food items including apples, apricots, oranges, peaches, pears, raisins, strawberries, carrots, cauliflower, eggplant, lettuce, potatoes, spinach, tomatoes, and zucchini. Participants were not instructed how to incorporate these foods into their diets. The sodium bicarbonate group received an average of four to five NaHCO₃ tablets daily (650 mg), divided into two doses.

The mean age of the participants was 48.8 years, 51% were female, and 47% were African American. The primary outcome was CKD progression and cardiovascular disease risk over 5 years. All participants met criteria at baseline for macroalbuminuria (a urine albumin to creatinine ratio of at least 200 mg/g) and were considered at increased risk for CKD progression.

Over the 5-year follow-up, CKD progression was significantly slower in the groups receiving fruits and vegetables and oral sodium bicarbonate, compared with usual care, based on trajectories showing a lower decline of estimated glomerular filtration rates (mean declines of 1.08 and 1.17 for fruits/vegetables and NaHCO₃, respectively, vs 19.4 for usual care, P < .001 for both).

However, systolic blood pressure and subsequent cardiovascular disease risk indicators were lower only in the fruit and vegetable group, compared with both the NaHCO₃ or usual-care groups over the long term. “Specifically, with fruits and vegetables, systolic blood pressure, plasma LDL and Lp(a) cholesterol, and body mass index decreased from baseline, consistent with better cardiovascular disease protection,” the researchers wrote. The protection against cardiovascular disease in the fruits and vegetables group occurred with lower doses of antihypertensive and statin medications and was not affected by baseline differences in medication doses.

The findings were limited by several factors, including the lack of data on compliance with the NaHCO₃ supplements, although urine net acid excretion in this group suggested increased alkali intake similar to that provided by fruits and vegetables, the researchers noted. Other limitations included the focus only on individuals with very high albuminuria.

More basic science studies are needed to explore how the potential vascular injury suggested by albuminuria affects CKD progression and cardiovascular disease, and clinical studies are needed to assess the impact of dietary acid reduction on patients with lower levels of albuminuria that the current study, the researchers said.

However, the results suggest that consuming fruits and vegetables, rather than NaHCO₃, is the preferred strategy for dietary acid reduction for patients with primary hypertension and CKD, they concluded. The findings also support routine measurement of urine albumin-to-creatinine ratios in hypertensive patients to identify CKD and assess risk for progression and subsequent cardiovascular disease.

The study was supported by the Larry and Jane Woirhaye Memorial Endowment in Renal Research at the Texas Tech University Health Sciences Center, the University Medical Center (both in Lubbock, Texas), the Endowment, Academic Operations Division of Baylor Scott & White Health, and the Episcopal Health Foundation. The researchers had no financial conflicts to disclose.

Progression of chronic kidney disease (CKD) and cardiovascular disease risk in hypertensive adults was significantly slower among those who consumed more fruits and vegetables or oral sodium bicarbonate, compared with controls who received usual care.

A primary focus on pharmacologic strategies has failed to reduced hypertension-related CKD and cardiovascular disease mortality, Nimrit Goraya, MD, of Texas A&M Health Sciences Center College of Medicine, Temple, and colleagues wrote. High-acid diets (those with greater amounts of animal-sourced foods) have been associated with increased incidence and progression of CKD and with increased risk of cardiovascular disease.

Diets high in fruits and vegetables are associated with reduced CKD and cardiovascular disease but are not routinely used as part of hypertension treatment. The researchers hypothesized that dietary acid reduction could slow kidney disease progression and reduce cardiovascular disease risk.

In a study published in The American Journal of Medicine, the researchers randomized 153 adults aged 18-70 years with hypertension and CKD to fruits and vegetables, oral sodium bicarbonate (NaHCO₃), or usual care; 51 to each group. The fruit and vegetable group received 2-4 cups daily of base-producing food items including apples, apricots, oranges, peaches, pears, raisins, strawberries, carrots, cauliflower, eggplant, lettuce, potatoes, spinach, tomatoes, and zucchini. Participants were not instructed how to incorporate these foods into their diets. The sodium bicarbonate group received an average of four to five NaHCO₃ tablets daily (650 mg), divided into two doses.

The mean age of the participants was 48.8 years, 51% were female, and 47% were African American. The primary outcome was CKD progression and cardiovascular disease risk over 5 years. All participants met criteria at baseline for macroalbuminuria (a urine albumin to creatinine ratio of at least 200 mg/g) and were considered at increased risk for CKD progression.

Over the 5-year follow-up, CKD progression was significantly slower in the groups receiving fruits and vegetables and oral sodium bicarbonate, compared with usual care, based on trajectories showing a lower decline of estimated glomerular filtration rates (mean declines of 1.08 and 1.17 for fruits/vegetables and NaHCO₃, respectively, vs 19.4 for usual care, P < .001 for both).

However, systolic blood pressure and subsequent cardiovascular disease risk indicators were lower only in the fruit and vegetable group, compared with both the NaHCO₃ or usual-care groups over the long term. “Specifically, with fruits and vegetables, systolic blood pressure, plasma LDL and Lp(a) cholesterol, and body mass index decreased from baseline, consistent with better cardiovascular disease protection,” the researchers wrote. The protection against cardiovascular disease in the fruits and vegetables group occurred with lower doses of antihypertensive and statin medications and was not affected by baseline differences in medication doses.

The findings were limited by several factors, including the lack of data on compliance with the NaHCO₃ supplements, although urine net acid excretion in this group suggested increased alkali intake similar to that provided by fruits and vegetables, the researchers noted. Other limitations included the focus only on individuals with very high albuminuria.

More basic science studies are needed to explore how the potential vascular injury suggested by albuminuria affects CKD progression and cardiovascular disease, and clinical studies are needed to assess the impact of dietary acid reduction on patients with lower levels of albuminuria that the current study, the researchers said.

However, the results suggest that consuming fruits and vegetables, rather than NaHCO₃, is the preferred strategy for dietary acid reduction for patients with primary hypertension and CKD, they concluded. The findings also support routine measurement of urine albumin-to-creatinine ratios in hypertensive patients to identify CKD and assess risk for progression and subsequent cardiovascular disease.

The study was supported by the Larry and Jane Woirhaye Memorial Endowment in Renal Research at the Texas Tech University Health Sciences Center, the University Medical Center (both in Lubbock, Texas), the Endowment, Academic Operations Division of Baylor Scott & White Health, and the Episcopal Health Foundation. The researchers had no financial conflicts to disclose.

TOPLINE:

Rates of major adverse cardiovascular events (MACE) do not differ significantly among individual biologics used for psoriasis or psoriatic arthritis (PsA), a database analysis finds. 

METHODOLOGY:

• Data from the TriNetX health records database included 32,758 patients treated with TNF inhibitors (TNFi, 62.9%), interleukin-17 inhibitors (IL-17i, 15.4%), IL-23i (10.7%), and IL-12i/IL-23i (10.7%).
• The researchers calculated time-dependent risk for MACE using multinomial Cox proportional hazard ratios. The reference was TNFi exposure.
• Subset analyses compared MACE in patients with and without existing cardiovascular disease.

TAKEAWAY:

• Compared with TNFi use, there was no difference in the incidence of MACE events in the IL-17i, IL-23i, or IL-12i/IL-23i group.
• There were also no significant differences between biologic groups in the incidence of congestive heart failure, myocardial infarction, or cerebral vascular accident/stroke.

IN PRACTICE:

Despite some concern about increased risk for MACE with TNFi use, this study suggests no special risk for patients with psoriasis or PsA associated with TNFi vs other biologics. “Given our results, as it pertains to MACE, prescribers shouldn’t favor any one biologic class over another,” said lead investigator Shikha Singla, MD, medical director of the Psoriatic Arthritis Program at Medical College of Wisconsin in Milwaukee, Wisconsin.

SOURCE:

Bonit Gill, MD, a second-year fellow at Medical College of Wisconsin, presented the study as a poster at the annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis. 

LIMITATIONS:

The study’s retrospective nature makes it impossible to prove causation and the patients included in the study were from Wisconsin, which may limit generalizability.

DISCLOSURES:

Dr. Gill had no relevant financial disclosures. Other study authors participated in trials or consulted for AbbVie, AstraZeneca, Novartis, Eli Lilly, Janssen, and UCB.

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

TOPLINE:

Rates of major adverse cardiovascular events (MACE) do not differ significantly among individual biologics used for psoriasis or psoriatic arthritis (PsA), a database analysis finds. 

METHODOLOGY:

• Data from the TriNetX health records database included 32,758 patients treated with TNF inhibitors (TNFi, 62.9%), interleukin-17 inhibitors (IL-17i, 15.4%), IL-23i (10.7%), and IL-12i/IL-23i (10.7%).
• The researchers calculated time-dependent risk for MACE using multinomial Cox proportional hazard ratios. The reference was TNFi exposure.
• Subset analyses compared MACE in patients with and without existing cardiovascular disease.

TAKEAWAY:

• Compared with TNFi use, there was no difference in the incidence of MACE events in the IL-17i, IL-23i, or IL-12i/IL-23i group.
• There were also no significant differences between biologic groups in the incidence of congestive heart failure, myocardial infarction, or cerebral vascular accident/stroke.

IN PRACTICE:

Despite some concern about increased risk for MACE with TNFi use, this study suggests no special risk for patients with psoriasis or PsA associated with TNFi vs other biologics. “Given our results, as it pertains to MACE, prescribers shouldn’t favor any one biologic class over another,” said lead investigator Shikha Singla, MD, medical director of the Psoriatic Arthritis Program at Medical College of Wisconsin in Milwaukee, Wisconsin.

SOURCE:

Bonit Gill, MD, a second-year fellow at Medical College of Wisconsin, presented the study as a poster at the annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis. 

LIMITATIONS:

The study’s retrospective nature makes it impossible to prove causation and the patients included in the study were from Wisconsin, which may limit generalizability.

DISCLOSURES:

Dr. Gill had no relevant financial disclosures. Other study authors participated in trials or consulted for AbbVie, AstraZeneca, Novartis, Eli Lilly, Janssen, and UCB.

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

TOPLINE:

Rates of major adverse cardiovascular events (MACE) do not differ significantly among individual biologics used for psoriasis or psoriatic arthritis (PsA), a database analysis finds. 

METHODOLOGY:

• Data from the TriNetX health records database included 32,758 patients treated with TNF inhibitors (TNFi, 62.9%), interleukin-17 inhibitors (IL-17i, 15.4%), IL-23i (10.7%), and IL-12i/IL-23i (10.7%).
• The researchers calculated time-dependent risk for MACE using multinomial Cox proportional hazard ratios. The reference was TNFi exposure.
• Subset analyses compared MACE in patients with and without existing cardiovascular disease.

TAKEAWAY:

• Compared with TNFi use, there was no difference in the incidence of MACE events in the IL-17i, IL-23i, or IL-12i/IL-23i group.
• There were also no significant differences between biologic groups in the incidence of congestive heart failure, myocardial infarction, or cerebral vascular accident/stroke.

IN PRACTICE:

Despite some concern about increased risk for MACE with TNFi use, this study suggests no special risk for patients with psoriasis or PsA associated with TNFi vs other biologics. “Given our results, as it pertains to MACE, prescribers shouldn’t favor any one biologic class over another,” said lead investigator Shikha Singla, MD, medical director of the Psoriatic Arthritis Program at Medical College of Wisconsin in Milwaukee, Wisconsin.

SOURCE:

Bonit Gill, MD, a second-year fellow at Medical College of Wisconsin, presented the study as a poster at the annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis. 

LIMITATIONS:

The study’s retrospective nature makes it impossible to prove causation and the patients included in the study were from Wisconsin, which may limit generalizability.

DISCLOSURES:

Dr. Gill had no relevant financial disclosures. Other study authors participated in trials or consulted for AbbVie, AstraZeneca, Novartis, Eli Lilly, Janssen, and UCB.

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

Replacing meat with plant-based meat alternatives (PBMAs) can improve cardiovascular disease risk factors, including low-density lipoprotein cholesterol (LDL-C), a review of randomized controlled trials suggested.

Long-term randomized controlled trials and prospective cohort studies that evaluate cardiovascular disease events such as myocardial infarction and stroke are needed to draw definitive conclusions, according to the authors.

“Our take-home is that plant-based meats are a healthy alternative to animal meat, based on intermediate cardiovascular endpoints such as lipids, triglycerides, blood pressure, and other cardiovascular disease risk factors,” said senior author Ehud Ur, MB, professor of medicine at the University of British Columbia, Vancouver, in Canada, and an endocrinologist at St. Paul’s Hospital in Vancouver.

“However, we also found that there’s a lack of clinical outcome trials that would determine definitively whether plant-based meats are healthy. But certainly, everything points in the direction of cardiovascular benefit,” said Dr. Ur.

The review was published on June 25 in the Canadian Journal of Cardiology.
 

Ultraprocessed Foods

PBMAs are foods that mimic meats and contain ingredients such as protein derivatives from soy, pea, wheat, and fungi. A growing number of Canadians are limiting meat or excluding it from their diets. Some are opting to eat PBMAs instead.

But most PBMAs are classified as ultraprocessed foods. Such foods are produced primarily from substances extracted from whole food sources, such as sugar, salt, oil, and protein. Alternatively, they may be created in a laboratory using flavor enhancers and food coloring. This classification has caused the public and health professionals to question the potential health implications of PBMAs, said Dr. Ur.

“One of the concerns is that these products are highly processed, and things that are highly processed are considered bad. And so, are you swapping one set of risks for another?” he said.

To shed more light on this question, Dr. Ur’s team, which was led by Matthew Nagra, ND, of the Vancouver Naturopathic Clinic, assessed the literature on PBMAs and their impact on health.

“While the plant-based meat market has experienced significant growth in recent years and more and more Canadians are enjoying plant-based burgers, surprisingly little is known about how these meat alternatives may impact health and, in particular, cardiovascular disease risk,” Dr. Nagra said in a statement. “Thus, we sought to review the available literature on the topic to identify what is currently known and to provide direction for future research.”
 

Less Saturated Fat, Cholesterol

The researchers assessed the literature that was published from 1970 to 2023 on PBMAs, their contents, nutritional profiles, and impact on cardiovascular disease risk factors, such as cholesterol levels and blood pressure.

They found that, compared with meat, PBMAs had less saturated fat, less cholesterol, more fiber, more carbohydrates, fewer calories, less monounsaturated fat, more polyunsaturated fat, and more sodium.

In addition, several randomized controlled trials showed that PBMAs reduced total cholesterol and LDL-C, as well as apolipoprotein B-100, body weight, and waist circumference. PBMAs were not shown to raise blood pressure, despite some products’ high sodium content.

“No currently available evidence suggests that the concerning aspects of PBMAs (eg, food processing and high sodium content) negate the potential cardiovascular benefits,” wrote the researchers.

Unfortunately, no long-term research has evaluated how these alternatives may affect the risk of developing a myocardial infarction or stroke. Similarly, there is little research on the healthfulness of some common components of PBMAs, such as vital wheat gluten.

To shed light on these important issues would require large clinical trials, involving many patients, and great expense, said Dr. Ur. “Drug companies can afford to do large clinical trials, even if they are expensive to do, because they must do them to get approval for their drug. But these plant-based meats are produced by companies that most likely are not able to do clinical outcome trials. Such trials would have to be done by the National Institutes of Health in the United States, or in Canada, the National Research Council,” he said.

There are many reasons to avoid meat, Dr. Ur added. “There are ethical reasons against killing animals. Then there is the issue of global warming. Meat is a very expensive source of food energy. As an individual, the biggest impact you can make on global warming is to not eat meat. Then there is the argument about personal health, which is where our study comes in. For those people who like the taste of meat and who struggle with giving it up, the PBMAs allow them to have a reasonably diverse diet,” he said.
 

Are Eggs Healthy?

Meat substitutes are helpful for people who want to reduce their cardiovascular disease risk, J. David Spence, MD, professor emeritus of neurology and clinical pharmacology at the University of Western Ontario in London, Canada, wrote in an accompanying editorial.

“Eating too much meat and egg yolk increases cardiovascular risk, and it’s a challenge for patients to learn to eat less meat and cut out egg yolks. If we can find good substitutes that are tasty and enjoyable, that’s a good thing,” Dr. Spence told this news organization.

“Besides plant-based meat substitutes, there is great potential for reduction of cardiovascular risk with the use of egg substitutes,” he said.

Dr. Spence pointed out that two large egg yolks contain 474 mg of cholesterol, almost twice the amount contained in a Hardee’s Monster Thickburger (265 mg).

Cholesterol elevates plasma levels of toxic metabolites of the intestinal microbiome, such as trimethylamine N-oxide (TMAO). Plasma levels of TMAO increase in a linear fashion with egg consumption, and TMAO is bad for the arteries, said Dr. Spence.

“Eggs are terrible and should not be eaten by people at risk for cardiovascular disease. But people don’t understand that because the egg marketing propaganda has been so effective. The yolk is terrible. The egg marketing board is extremely effective in persuading people that eggs are healthy, and they’re not.”

Dr. Spence recommends using egg substitutes, such as Egg Beaters or Better’n Eggs, instead of whole eggs, and says it’s never too late to switch. “That’s the mistake people make, but the arteries can actually improve,” he said.

No funding source for the study was reported. Dr. Ur and Dr. Spence reported having no relevant financial relationships.
 

A version of this article appeared on Medscape.com.

Replacing meat with plant-based meat alternatives (PBMAs) can improve cardiovascular disease risk factors, including low-density lipoprotein cholesterol (LDL-C), a review of randomized controlled trials suggested.

Long-term randomized controlled trials and prospective cohort studies that evaluate cardiovascular disease events such as myocardial infarction and stroke are needed to draw definitive conclusions, according to the authors.

“Our take-home is that plant-based meats are a healthy alternative to animal meat, based on intermediate cardiovascular endpoints such as lipids, triglycerides, blood pressure, and other cardiovascular disease risk factors,” said senior author Ehud Ur, MB, professor of medicine at the University of British Columbia, Vancouver, in Canada, and an endocrinologist at St. Paul’s Hospital in Vancouver.

“However, we also found that there’s a lack of clinical outcome trials that would determine definitively whether plant-based meats are healthy. But certainly, everything points in the direction of cardiovascular benefit,” said Dr. Ur.

The review was published on June 25 in the Canadian Journal of Cardiology.
 

Ultraprocessed Foods

PBMAs are foods that mimic meats and contain ingredients such as protein derivatives from soy, pea, wheat, and fungi. A growing number of Canadians are limiting meat or excluding it from their diets. Some are opting to eat PBMAs instead.

But most PBMAs are classified as ultraprocessed foods. Such foods are produced primarily from substances extracted from whole food sources, such as sugar, salt, oil, and protein. Alternatively, they may be created in a laboratory using flavor enhancers and food coloring. This classification has caused the public and health professionals to question the potential health implications of PBMAs, said Dr. Ur.

“One of the concerns is that these products are highly processed, and things that are highly processed are considered bad. And so, are you swapping one set of risks for another?” he said.

To shed more light on this question, Dr. Ur’s team, which was led by Matthew Nagra, ND, of the Vancouver Naturopathic Clinic, assessed the literature on PBMAs and their impact on health.

“While the plant-based meat market has experienced significant growth in recent years and more and more Canadians are enjoying plant-based burgers, surprisingly little is known about how these meat alternatives may impact health and, in particular, cardiovascular disease risk,” Dr. Nagra said in a statement. “Thus, we sought to review the available literature on the topic to identify what is currently known and to provide direction for future research.”
 

Less Saturated Fat, Cholesterol

The researchers assessed the literature that was published from 1970 to 2023 on PBMAs, their contents, nutritional profiles, and impact on cardiovascular disease risk factors, such as cholesterol levels and blood pressure.

They found that, compared with meat, PBMAs had less saturated fat, less cholesterol, more fiber, more carbohydrates, fewer calories, less monounsaturated fat, more polyunsaturated fat, and more sodium.

In addition, several randomized controlled trials showed that PBMAs reduced total cholesterol and LDL-C, as well as apolipoprotein B-100, body weight, and waist circumference. PBMAs were not shown to raise blood pressure, despite some products’ high sodium content.

“No currently available evidence suggests that the concerning aspects of PBMAs (eg, food processing and high sodium content) negate the potential cardiovascular benefits,” wrote the researchers.

Unfortunately, no long-term research has evaluated how these alternatives may affect the risk of developing a myocardial infarction or stroke. Similarly, there is little research on the healthfulness of some common components of PBMAs, such as vital wheat gluten.

To shed light on these important issues would require large clinical trials, involving many patients, and great expense, said Dr. Ur. “Drug companies can afford to do large clinical trials, even if they are expensive to do, because they must do them to get approval for their drug. But these plant-based meats are produced by companies that most likely are not able to do clinical outcome trials. Such trials would have to be done by the National Institutes of Health in the United States, or in Canada, the National Research Council,” he said.

There are many reasons to avoid meat, Dr. Ur added. “There are ethical reasons against killing animals. Then there is the issue of global warming. Meat is a very expensive source of food energy. As an individual, the biggest impact you can make on global warming is to not eat meat. Then there is the argument about personal health, which is where our study comes in. For those people who like the taste of meat and who struggle with giving it up, the PBMAs allow them to have a reasonably diverse diet,” he said.
 

Are Eggs Healthy?

Meat substitutes are helpful for people who want to reduce their cardiovascular disease risk, J. David Spence, MD, professor emeritus of neurology and clinical pharmacology at the University of Western Ontario in London, Canada, wrote in an accompanying editorial.

“Eating too much meat and egg yolk increases cardiovascular risk, and it’s a challenge for patients to learn to eat less meat and cut out egg yolks. If we can find good substitutes that are tasty and enjoyable, that’s a good thing,” Dr. Spence told this news organization.

“Besides plant-based meat substitutes, there is great potential for reduction of cardiovascular risk with the use of egg substitutes,” he said.

Dr. Spence pointed out that two large egg yolks contain 474 mg of cholesterol, almost twice the amount contained in a Hardee’s Monster Thickburger (265 mg).

Cholesterol elevates plasma levels of toxic metabolites of the intestinal microbiome, such as trimethylamine N-oxide (TMAO). Plasma levels of TMAO increase in a linear fashion with egg consumption, and TMAO is bad for the arteries, said Dr. Spence.

“Eggs are terrible and should not be eaten by people at risk for cardiovascular disease. But people don’t understand that because the egg marketing propaganda has been so effective. The yolk is terrible. The egg marketing board is extremely effective in persuading people that eggs are healthy, and they’re not.”

Dr. Spence recommends using egg substitutes, such as Egg Beaters or Better’n Eggs, instead of whole eggs, and says it’s never too late to switch. “That’s the mistake people make, but the arteries can actually improve,” he said.

No funding source for the study was reported. Dr. Ur and Dr. Spence reported having no relevant financial relationships.
 

A version of this article appeared on Medscape.com.

Replacing meat with plant-based meat alternatives (PBMAs) can improve cardiovascular disease risk factors, including low-density lipoprotein cholesterol (LDL-C), a review of randomized controlled trials suggested.

Long-term randomized controlled trials and prospective cohort studies that evaluate cardiovascular disease events such as myocardial infarction and stroke are needed to draw definitive conclusions, according to the authors.

“Our take-home is that plant-based meats are a healthy alternative to animal meat, based on intermediate cardiovascular endpoints such as lipids, triglycerides, blood pressure, and other cardiovascular disease risk factors,” said senior author Ehud Ur, MB, professor of medicine at the University of British Columbia, Vancouver, in Canada, and an endocrinologist at St. Paul’s Hospital in Vancouver.

“However, we also found that there’s a lack of clinical outcome trials that would determine definitively whether plant-based meats are healthy. But certainly, everything points in the direction of cardiovascular benefit,” said Dr. Ur.

The review was published on June 25 in the Canadian Journal of Cardiology.
 

Ultraprocessed Foods

PBMAs are foods that mimic meats and contain ingredients such as protein derivatives from soy, pea, wheat, and fungi. A growing number of Canadians are limiting meat or excluding it from their diets. Some are opting to eat PBMAs instead.

But most PBMAs are classified as ultraprocessed foods. Such foods are produced primarily from substances extracted from whole food sources, such as sugar, salt, oil, and protein. Alternatively, they may be created in a laboratory using flavor enhancers and food coloring. This classification has caused the public and health professionals to question the potential health implications of PBMAs, said Dr. Ur.

“One of the concerns is that these products are highly processed, and things that are highly processed are considered bad. And so, are you swapping one set of risks for another?” he said.

To shed more light on this question, Dr. Ur’s team, which was led by Matthew Nagra, ND, of the Vancouver Naturopathic Clinic, assessed the literature on PBMAs and their impact on health.

“While the plant-based meat market has experienced significant growth in recent years and more and more Canadians are enjoying plant-based burgers, surprisingly little is known about how these meat alternatives may impact health and, in particular, cardiovascular disease risk,” Dr. Nagra said in a statement. “Thus, we sought to review the available literature on the topic to identify what is currently known and to provide direction for future research.”
 

Less Saturated Fat, Cholesterol

The researchers assessed the literature that was published from 1970 to 2023 on PBMAs, their contents, nutritional profiles, and impact on cardiovascular disease risk factors, such as cholesterol levels and blood pressure.

They found that, compared with meat, PBMAs had less saturated fat, less cholesterol, more fiber, more carbohydrates, fewer calories, less monounsaturated fat, more polyunsaturated fat, and more sodium.

In addition, several randomized controlled trials showed that PBMAs reduced total cholesterol and LDL-C, as well as apolipoprotein B-100, body weight, and waist circumference. PBMAs were not shown to raise blood pressure, despite some products’ high sodium content.

“No currently available evidence suggests that the concerning aspects of PBMAs (eg, food processing and high sodium content) negate the potential cardiovascular benefits,” wrote the researchers.

Unfortunately, no long-term research has evaluated how these alternatives may affect the risk of developing a myocardial infarction or stroke. Similarly, there is little research on the healthfulness of some common components of PBMAs, such as vital wheat gluten.

To shed light on these important issues would require large clinical trials, involving many patients, and great expense, said Dr. Ur. “Drug companies can afford to do large clinical trials, even if they are expensive to do, because they must do them to get approval for their drug. But these plant-based meats are produced by companies that most likely are not able to do clinical outcome trials. Such trials would have to be done by the National Institutes of Health in the United States, or in Canada, the National Research Council,” he said.

There are many reasons to avoid meat, Dr. Ur added. “There are ethical reasons against killing animals. Then there is the issue of global warming. Meat is a very expensive source of food energy. As an individual, the biggest impact you can make on global warming is to not eat meat. Then there is the argument about personal health, which is where our study comes in. For those people who like the taste of meat and who struggle with giving it up, the PBMAs allow them to have a reasonably diverse diet,” he said.
 

Are Eggs Healthy?

Meat substitutes are helpful for people who want to reduce their cardiovascular disease risk, J. David Spence, MD, professor emeritus of neurology and clinical pharmacology at the University of Western Ontario in London, Canada, wrote in an accompanying editorial.

“Eating too much meat and egg yolk increases cardiovascular risk, and it’s a challenge for patients to learn to eat less meat and cut out egg yolks. If we can find good substitutes that are tasty and enjoyable, that’s a good thing,” Dr. Spence told this news organization.

“Besides plant-based meat substitutes, there is great potential for reduction of cardiovascular risk with the use of egg substitutes,” he said.

Dr. Spence pointed out that two large egg yolks contain 474 mg of cholesterol, almost twice the amount contained in a Hardee’s Monster Thickburger (265 mg).

Cholesterol elevates plasma levels of toxic metabolites of the intestinal microbiome, such as trimethylamine N-oxide (TMAO). Plasma levels of TMAO increase in a linear fashion with egg consumption, and TMAO is bad for the arteries, said Dr. Spence.

“Eggs are terrible and should not be eaten by people at risk for cardiovascular disease. But people don’t understand that because the egg marketing propaganda has been so effective. The yolk is terrible. The egg marketing board is extremely effective in persuading people that eggs are healthy, and they’re not.”

Dr. Spence recommends using egg substitutes, such as Egg Beaters or Better’n Eggs, instead of whole eggs, and says it’s never too late to switch. “That’s the mistake people make, but the arteries can actually improve,” he said.

No funding source for the study was reported. Dr. Ur and Dr. Spence reported having no relevant financial relationships.
 

A version of this article appeared on Medscape.com.

Should a patient with high lipoprotein (a), or Lp(a), be started on low-dose aspirin?

This is the conundrum facing many physicians and patients, but even getting to that point will require more availability and coverage of tests and a greater appreciation of the risk associated with Lp(a), said cardiologists.
 

Lp(a): The Silent Risk

On Lp(a) Awareness Day, C. Michael Gibson, MD, MA, CEO of the Baim Institute for Clinical Research, Boston, Massachusetts, and PERFUSE took the opportunity to talk about his experiences with testing on X.

The professor of medicine at Harvard Medical School, also in Boston, said he was surprised to find that he had a very high calcium score, despite a low-density lipoprotein (LDL) cholesterol level of just 70 mg/dL. Eventually, he found out that he had a “very, very high Lp(a),” which was particularly concerning because his grandfather died of a heart attack at 45 years of age.

But how much risk does that represent?

A 2022 consensus statement from the European Atherosclerosis Society (EAS) highlighted that epidemiologic and genetic studies “strongly support a causal and continuous association between Lp(a) concentration and cardiovascular outcomes,” even at very low LDL cholesterol levels.

This is because Lp(a) has proinflammatory and proatherosclerotic properties, and high levels are associated with both micro- and macrocalcification of the aortic valve. Findings from a US registry study also suggest the threshold related to increased cardiovascular risk may differ for primary and secondary prevention populations (J Am Coll Cardiol. 2024 Mar 5;83[9]:873-886).

Lp(a) is, however, genetically determined, and there are no drugs available that directly lower levels, although some are on the horizon. In the meantime, the experts behind the consensus statement recommend that all adults be tested at least once in their lifetime.
 

Testing Cost and Availability

This recommendation has been translated into guidelines in “many, many” countries, said lead author Florian Kronenberg, MD, MAE, Institute of Genetic Epidemiology, Medical University of Innsbruck, Innsbruck, Austria, but “we are far away from reaching that goal.”

“We’ve got a real problem,” added Stephen Nicholls, MD, PhD, director of the Victorian Heart Institute and a professor of cardiology at Monash University, Melbourne, Australia, as there is “not a country in the world where there’s good access to Lp(a) testing.”

Dr. Kronenberg said that the consensus statement “created a kind of momentum” toward universal testing.

Ulrich Laufs, MD, PhD, professor and chair, Department of Cardiology, University Hospital Leipzig, Leipzig, Germany, agreed, saying that, overall, Lp(a) testing has “increased dramatically,” albeit from “extremely low levels.”

Dr. Kronenberg believes that “we have to be really patient.” He cited a lack of knowledge among physicians as one of the biggest barriers to greater uptake of testing.

“There is still no appreciation of the role of Lp(a),” agreed Alberico L. Catapano, MD, PhD, director of Cardiovascular Research and of the Lipoproteins and Atherosclerosis Laboratory of IRCCS Multimedica, Milan, Italy, and past president of the EAS.

“That’s why it’s not mentioned” to patients, he said. “What is really needed is to inform physician colleagues that Lp(a) is not only a risk factor but is the cause” of atherosclerotic cardiovascular disease (ASCVD).

Dr. Kronenberg said that the pressure for testing can often come from the patient themselves.

Physicians then question why the patient wants to be tested when there are no medications to treat it, he added. “We really tried very hard when we did the consensus paper to say that we should perform the test and give people advice on what to do.”

Dr. Catapano believes that another major obstacle is the cost of the test, which remains high “because very few people do it,” and there is some debate over which test to use.

Taken together, these issues have meant that “payers are really struggling with the idea of funding Lp(a),” said Dr. Nicholls, adding that “there seems to be this fixation on: ‘Well, if you can’t lower Lp(a), why measure it?’ ”

Rather than blame the payers, he says there is a need to educate about the science behind testing and underline that Lp(a) is an “important risk enhancer” for cardiovascular disease.

“Because if we’re going to make people pay out of pocket, then you’re creating a massive equity issue in that only those who can afford the test have it.”
 

High Lp(a) Now What?

But once the test has been performed, there then comes the question as to what to do about the result.

“Before we get anywhere near an agent that effectively lowers Lp(a) and get it into the clinic, there are lots of things that we can do today,” said Dr. Nicholls.

If someone has an intermediate or high background cardiovascular risk and they have got a high Lp(a) level, they “should be treated more intensively, as we know that high Lp(a) patients do better if their LDL cholesterol and their blood pressure is lower.”

For Dr. Catapano, this means having the “same mindset as you do with [a patient with] high blood pressure, high LDL cholesterol, and so on, because it’s exactly the same thing: It’s interacting with your other risk factors to increase your overall risk.”

Dr. Gibson agreed. Through a range of measures, including weight loss and statin therapy, he was able to reduce his overall cardiovascular risk, and his LDL cholesterol level dropped to just 20 mg/dL.
 

A Role for Aspirin?

However, one debate that has been rolling on in recent months is whether to start patients with elevated Lp(a) on low-dose aspirin.

It gained added momentum when Pablo Corral, MD, a lipidologist and a professor in the School of Medicine, Pharmacology Department, FASTA University, Mar del Plata, Buenos Aires, Argentina, highlighted the issue on X.

He pointed to a recent study, which showed that regular aspirin use was associated with a significantly lower rate of ASCVD mortality in adults without clinical ASCVD but who had elevated Lp(a).

Dr. Nicholls said that, when you “peel away the layers” of the current evidence, there is some suggestion that Lp(a)may be prothrombotic. “So in theory, perhaps aspirin might be maybe more intuitively useful there.”

He noted that the ASPREE primary prevention study found that low-dose aspirin in older adults resulted in a significantly higher risk for major hemorrhage over placebo and did not significantly reduce the risk for cardiovascular disease.

But an analysis he and his colleagues did suggest that aspirin may indeed benefit older individuals if they have elevated Lp(a) genotypes.
 

An Individual Decision

For Dr. Kronenberg and Dr. Laufs, there is currently a lack of appropriate data to make a recommendation either way, particularly for primary prevention.

They warned that the risk for thrombosis in patients with mildly elevated Lp(a) cannot be discounted, and in most cases either “the existing risk of bleeding exceeds the beneficial effects [of aspirin], or it’s not indicated,” said Dr. Laufs.

“When we make a recommendation, we should have evidence-based data,” Dr. Kronenberg said, but, at the moment, people “somehow put their finger in the air and see” which way the wind is blowing.

Dr. Catapano urged patients to talk to their physician, as even low-dose aspirin is “very potent” at inhibiting platelets.

Dr. Gibson agreed, saying that he is in two minds, as the potential benefit has to be weighed against the bleeding risk.

He personally takes low-dose aspirin because “I know I have a low bleeding risk,” but it is a decision “that has to be taken individually between a patient and their physician.”

Dr. Gibson, Dr. Kronenberg, Dr. Nicholls, and Dr. Catapano all reported conflicts of interest with numerous pharmaceutical companies and organizations.

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

Should a patient with high lipoprotein (a), or Lp(a), be started on low-dose aspirin?

This is the conundrum facing many physicians and patients, but even getting to that point will require more availability and coverage of tests and a greater appreciation of the risk associated with Lp(a), said cardiologists.
 

Lp(a): The Silent Risk

On Lp(a) Awareness Day, C. Michael Gibson, MD, MA, CEO of the Baim Institute for Clinical Research, Boston, Massachusetts, and PERFUSE took the opportunity to talk about his experiences with testing on X.

The professor of medicine at Harvard Medical School, also in Boston, said he was surprised to find that he had a very high calcium score, despite a low-density lipoprotein (LDL) cholesterol level of just 70 mg/dL. Eventually, he found out that he had a “very, very high Lp(a),” which was particularly concerning because his grandfather died of a heart attack at 45 years of age.

But how much risk does that represent?

A 2022 consensus statement from the European Atherosclerosis Society (EAS) highlighted that epidemiologic and genetic studies “strongly support a causal and continuous association between Lp(a) concentration and cardiovascular outcomes,” even at very low LDL cholesterol levels.

This is because Lp(a) has proinflammatory and proatherosclerotic properties, and high levels are associated with both micro- and macrocalcification of the aortic valve. Findings from a US registry study also suggest the threshold related to increased cardiovascular risk may differ for primary and secondary prevention populations (J Am Coll Cardiol. 2024 Mar 5;83[9]:873-886).

Lp(a) is, however, genetically determined, and there are no drugs available that directly lower levels, although some are on the horizon. In the meantime, the experts behind the consensus statement recommend that all adults be tested at least once in their lifetime.
 

Testing Cost and Availability

This recommendation has been translated into guidelines in “many, many” countries, said lead author Florian Kronenberg, MD, MAE, Institute of Genetic Epidemiology, Medical University of Innsbruck, Innsbruck, Austria, but “we are far away from reaching that goal.”

“We’ve got a real problem,” added Stephen Nicholls, MD, PhD, director of the Victorian Heart Institute and a professor of cardiology at Monash University, Melbourne, Australia, as there is “not a country in the world where there’s good access to Lp(a) testing.”

Dr. Kronenberg said that the consensus statement “created a kind of momentum” toward universal testing.

Ulrich Laufs, MD, PhD, professor and chair, Department of Cardiology, University Hospital Leipzig, Leipzig, Germany, agreed, saying that, overall, Lp(a) testing has “increased dramatically,” albeit from “extremely low levels.”

Dr. Kronenberg believes that “we have to be really patient.” He cited a lack of knowledge among physicians as one of the biggest barriers to greater uptake of testing.

“There is still no appreciation of the role of Lp(a),” agreed Alberico L. Catapano, MD, PhD, director of Cardiovascular Research and of the Lipoproteins and Atherosclerosis Laboratory of IRCCS Multimedica, Milan, Italy, and past president of the EAS.

“That’s why it’s not mentioned” to patients, he said. “What is really needed is to inform physician colleagues that Lp(a) is not only a risk factor but is the cause” of atherosclerotic cardiovascular disease (ASCVD).

Dr. Kronenberg said that the pressure for testing can often come from the patient themselves.

Physicians then question why the patient wants to be tested when there are no medications to treat it, he added. “We really tried very hard when we did the consensus paper to say that we should perform the test and give people advice on what to do.”

Dr. Catapano believes that another major obstacle is the cost of the test, which remains high “because very few people do it,” and there is some debate over which test to use.

Taken together, these issues have meant that “payers are really struggling with the idea of funding Lp(a),” said Dr. Nicholls, adding that “there seems to be this fixation on: ‘Well, if you can’t lower Lp(a), why measure it?’ ”

Rather than blame the payers, he says there is a need to educate about the science behind testing and underline that Lp(a) is an “important risk enhancer” for cardiovascular disease.

“Because if we’re going to make people pay out of pocket, then you’re creating a massive equity issue in that only those who can afford the test have it.”
 

High Lp(a) Now What?

But once the test has been performed, there then comes the question as to what to do about the result.

“Before we get anywhere near an agent that effectively lowers Lp(a) and get it into the clinic, there are lots of things that we can do today,” said Dr. Nicholls.

If someone has an intermediate or high background cardiovascular risk and they have got a high Lp(a) level, they “should be treated more intensively, as we know that high Lp(a) patients do better if their LDL cholesterol and their blood pressure is lower.”

For Dr. Catapano, this means having the “same mindset as you do with [a patient with] high blood pressure, high LDL cholesterol, and so on, because it’s exactly the same thing: It’s interacting with your other risk factors to increase your overall risk.”

Dr. Gibson agreed. Through a range of measures, including weight loss and statin therapy, he was able to reduce his overall cardiovascular risk, and his LDL cholesterol level dropped to just 20 mg/dL.
 

A Role for Aspirin?

However, one debate that has been rolling on in recent months is whether to start patients with elevated Lp(a) on low-dose aspirin.

It gained added momentum when Pablo Corral, MD, a lipidologist and a professor in the School of Medicine, Pharmacology Department, FASTA University, Mar del Plata, Buenos Aires, Argentina, highlighted the issue on X.

He pointed to a recent study, which showed that regular aspirin use was associated with a significantly lower rate of ASCVD mortality in adults without clinical ASCVD but who had elevated Lp(a).

Dr. Nicholls said that, when you “peel away the layers” of the current evidence, there is some suggestion that Lp(a)may be prothrombotic. “So in theory, perhaps aspirin might be maybe more intuitively useful there.”

He noted that the ASPREE primary prevention study found that low-dose aspirin in older adults resulted in a significantly higher risk for major hemorrhage over placebo and did not significantly reduce the risk for cardiovascular disease.

But an analysis he and his colleagues did suggest that aspirin may indeed benefit older individuals if they have elevated Lp(a) genotypes.
 

An Individual Decision

For Dr. Kronenberg and Dr. Laufs, there is currently a lack of appropriate data to make a recommendation either way, particularly for primary prevention.

They warned that the risk for thrombosis in patients with mildly elevated Lp(a) cannot be discounted, and in most cases either “the existing risk of bleeding exceeds the beneficial effects [of aspirin], or it’s not indicated,” said Dr. Laufs.

“When we make a recommendation, we should have evidence-based data,” Dr. Kronenberg said, but, at the moment, people “somehow put their finger in the air and see” which way the wind is blowing.

Dr. Catapano urged patients to talk to their physician, as even low-dose aspirin is “very potent” at inhibiting platelets.

Dr. Gibson agreed, saying that he is in two minds, as the potential benefit has to be weighed against the bleeding risk.

He personally takes low-dose aspirin because “I know I have a low bleeding risk,” but it is a decision “that has to be taken individually between a patient and their physician.”

Dr. Gibson, Dr. Kronenberg, Dr. Nicholls, and Dr. Catapano all reported conflicts of interest with numerous pharmaceutical companies and organizations.

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

Should a patient with high lipoprotein (a), or Lp(a), be started on low-dose aspirin?

This is the conundrum facing many physicians and patients, but even getting to that point will require more availability and coverage of tests and a greater appreciation of the risk associated with Lp(a), said cardiologists.
 

Lp(a): The Silent Risk

On Lp(a) Awareness Day, C. Michael Gibson, MD, MA, CEO of the Baim Institute for Clinical Research, Boston, Massachusetts, and PERFUSE took the opportunity to talk about his experiences with testing on X.

The professor of medicine at Harvard Medical School, also in Boston, said he was surprised to find that he had a very high calcium score, despite a low-density lipoprotein (LDL) cholesterol level of just 70 mg/dL. Eventually, he found out that he had a “very, very high Lp(a),” which was particularly concerning because his grandfather died of a heart attack at 45 years of age.

But how much risk does that represent?

A 2022 consensus statement from the European Atherosclerosis Society (EAS) highlighted that epidemiologic and genetic studies “strongly support a causal and continuous association between Lp(a) concentration and cardiovascular outcomes,” even at very low LDL cholesterol levels.

This is because Lp(a) has proinflammatory and proatherosclerotic properties, and high levels are associated with both micro- and macrocalcification of the aortic valve. Findings from a US registry study also suggest the threshold related to increased cardiovascular risk may differ for primary and secondary prevention populations (J Am Coll Cardiol. 2024 Mar 5;83[9]:873-886).

Lp(a) is, however, genetically determined, and there are no drugs available that directly lower levels, although some are on the horizon. In the meantime, the experts behind the consensus statement recommend that all adults be tested at least once in their lifetime.
 

Testing Cost and Availability

This recommendation has been translated into guidelines in “many, many” countries, said lead author Florian Kronenberg, MD, MAE, Institute of Genetic Epidemiology, Medical University of Innsbruck, Innsbruck, Austria, but “we are far away from reaching that goal.”

“We’ve got a real problem,” added Stephen Nicholls, MD, PhD, director of the Victorian Heart Institute and a professor of cardiology at Monash University, Melbourne, Australia, as there is “not a country in the world where there’s good access to Lp(a) testing.”

Dr. Kronenberg said that the consensus statement “created a kind of momentum” toward universal testing.

Ulrich Laufs, MD, PhD, professor and chair, Department of Cardiology, University Hospital Leipzig, Leipzig, Germany, agreed, saying that, overall, Lp(a) testing has “increased dramatically,” albeit from “extremely low levels.”

Dr. Kronenberg believes that “we have to be really patient.” He cited a lack of knowledge among physicians as one of the biggest barriers to greater uptake of testing.

“There is still no appreciation of the role of Lp(a),” agreed Alberico L. Catapano, MD, PhD, director of Cardiovascular Research and of the Lipoproteins and Atherosclerosis Laboratory of IRCCS Multimedica, Milan, Italy, and past president of the EAS.

“That’s why it’s not mentioned” to patients, he said. “What is really needed is to inform physician colleagues that Lp(a) is not only a risk factor but is the cause” of atherosclerotic cardiovascular disease (ASCVD).

Dr. Kronenberg said that the pressure for testing can often come from the patient themselves.

Physicians then question why the patient wants to be tested when there are no medications to treat it, he added. “We really tried very hard when we did the consensus paper to say that we should perform the test and give people advice on what to do.”

Dr. Catapano believes that another major obstacle is the cost of the test, which remains high “because very few people do it,” and there is some debate over which test to use.

Taken together, these issues have meant that “payers are really struggling with the idea of funding Lp(a),” said Dr. Nicholls, adding that “there seems to be this fixation on: ‘Well, if you can’t lower Lp(a), why measure it?’ ”

Rather than blame the payers, he says there is a need to educate about the science behind testing and underline that Lp(a) is an “important risk enhancer” for cardiovascular disease.

“Because if we’re going to make people pay out of pocket, then you’re creating a massive equity issue in that only those who can afford the test have it.”
 

High Lp(a) Now What?

But once the test has been performed, there then comes the question as to what to do about the result.

“Before we get anywhere near an agent that effectively lowers Lp(a) and get it into the clinic, there are lots of things that we can do today,” said Dr. Nicholls.

If someone has an intermediate or high background cardiovascular risk and they have got a high Lp(a) level, they “should be treated more intensively, as we know that high Lp(a) patients do better if their LDL cholesterol and their blood pressure is lower.”

For Dr. Catapano, this means having the “same mindset as you do with [a patient with] high blood pressure, high LDL cholesterol, and so on, because it’s exactly the same thing: It’s interacting with your other risk factors to increase your overall risk.”

Dr. Gibson agreed. Through a range of measures, including weight loss and statin therapy, he was able to reduce his overall cardiovascular risk, and his LDL cholesterol level dropped to just 20 mg/dL.
 

A Role for Aspirin?

However, one debate that has been rolling on in recent months is whether to start patients with elevated Lp(a) on low-dose aspirin.

It gained added momentum when Pablo Corral, MD, a lipidologist and a professor in the School of Medicine, Pharmacology Department, FASTA University, Mar del Plata, Buenos Aires, Argentina, highlighted the issue on X.

He pointed to a recent study, which showed that regular aspirin use was associated with a significantly lower rate of ASCVD mortality in adults without clinical ASCVD but who had elevated Lp(a).

Dr. Nicholls said that, when you “peel away the layers” of the current evidence, there is some suggestion that Lp(a)may be prothrombotic. “So in theory, perhaps aspirin might be maybe more intuitively useful there.”

He noted that the ASPREE primary prevention study found that low-dose aspirin in older adults resulted in a significantly higher risk for major hemorrhage over placebo and did not significantly reduce the risk for cardiovascular disease.

But an analysis he and his colleagues did suggest that aspirin may indeed benefit older individuals if they have elevated Lp(a) genotypes.
 

An Individual Decision

For Dr. Kronenberg and Dr. Laufs, there is currently a lack of appropriate data to make a recommendation either way, particularly for primary prevention.

They warned that the risk for thrombosis in patients with mildly elevated Lp(a) cannot be discounted, and in most cases either “the existing risk of bleeding exceeds the beneficial effects [of aspirin], or it’s not indicated,” said Dr. Laufs.

“When we make a recommendation, we should have evidence-based data,” Dr. Kronenberg said, but, at the moment, people “somehow put their finger in the air and see” which way the wind is blowing.

Dr. Catapano urged patients to talk to their physician, as even low-dose aspirin is “very potent” at inhibiting platelets.

Dr. Gibson agreed, saying that he is in two minds, as the potential benefit has to be weighed against the bleeding risk.

He personally takes low-dose aspirin because “I know I have a low bleeding risk,” but it is a decision “that has to be taken individually between a patient and their physician.”

Dr. Gibson, Dr. Kronenberg, Dr. Nicholls, and Dr. Catapano all reported conflicts of interest with numerous pharmaceutical companies and organizations.

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

LYON, FRANCE — The anti-obesity drug semaglutide is associated with significant reductions in the inflammatory marker high-sensitivity C-reactive protein (CRP), even in patients who do not lose substantial amounts of weight with the drug, according to data from the SELECT clinical trial.

The research, presented at the European Atherosclerosis Society 2024, involved over 17,600 patients with overweight or obesity and had established cardiovascular disease but not diabetes.

Those given semaglutide experienced a 38% reduction in high-sensitivity CRP levels compared with placebo regardless of baseline body mass index, statin use, cholesterol levels, and other measures.

“Weight loss was associated with greater high-sensitivity CRP reduction in both treatment groups,” said study presenter Jorge Plutzky, MD, director of Preventive Cardiology at Brigham and Women’s Hospital, Boston, but “with increased high-sensitivity CRP reductions in those receiving semaglutide.”

The drug also “significantly reduced high-sensitivity CRP early,” he said, “prior to major weight loss and in those who did not lose significant amounts of weight.” The reductions reached approximately 12% at 4 weeks and around 20% at 8 weeks, when the weight loss “was still quite modest,” at 2% and 3% of body weight, respectively. Even among patients who achieved weight loss of less than 2% body weight, semaglutide was associated with a reduction in high-sensitivity CRP levels.

In the SELECT trial, semaglutide also resulted in a consistent reduction of around 20% vs placebo in major adverse cardiovascular events such as cardiovascular mortality, nonfatal myocardial infarction, or nonfatal stroke.

But Naveed Sattar, MD, PhD, professor of cardiometabolic medicine at the University of Glasgow, Scotland, said in an interview that body weight “is probably the major driver” of CRP levels in the population, accounting for between 20% and 30% of the variation.

Dr. Sattar, who was not involved in the study, said that because drugs like semaglutide lower weight but also have anti-inflammatory effects, the question becomes: “Could the anti-inflammatory effects be part of the mechanisms by which these drugs affect the risk of major adverse cardiovascular events?”
 

Reducing Cardiovascular Events

The current analysis, however, cannot answer the question, he said. “All it tells us is about associations.”

“What we do know is semaglutide, predominantly by lowering weight, is lowering CRP levels and equally, we know that when you lose weight, you improve blood pressure, you improve lipids, and you reduce the risk of diabetes,” he said.

Dr. Sattar also took issue with the researchers’ conclusion that the high-sensitivity CRP reductions seen in SELECT occurred prior to major weight loss because the “pattern of CRP reduction and weight reduction is almost identical.”

Dr. Sattar also pointed out in a recent editorial that the drug appears to have a direct effect on blood vessels and the heart, which may lead to improvements in systemic inflammation. Consequently, he said, any assertion that semaglutide is genuinely anti-inflammatory is, at this stage, “speculation.”

Dr. Plutzky said that “systemic, chronic inflammation is implicated as a potential mechanism and therapeutic target in atherosclerosis and major adverse cardiovascular events, as well as obesity,” and high-sensitivity CRP levels are an “established biomarker of inflammation and have been shown to predict cardiovascular risk.”

However, the relationship between high-sensitivity CRP, responses to glucagon-like peptide 1 receptor agonists like semaglutide, and cardiovascular outcomes in obesity “remains incompletely understood,” said Dr. Plutzky.
 

A version of this article appeared on Medscape.com.

LYON, FRANCE — The anti-obesity drug semaglutide is associated with significant reductions in the inflammatory marker high-sensitivity C-reactive protein (CRP), even in patients who do not lose substantial amounts of weight with the drug, according to data from the SELECT clinical trial.

The research, presented at the European Atherosclerosis Society 2024, involved over 17,600 patients with overweight or obesity and had established cardiovascular disease but not diabetes.

Those given semaglutide experienced a 38% reduction in high-sensitivity CRP levels compared with placebo regardless of baseline body mass index, statin use, cholesterol levels, and other measures.

“Weight loss was associated with greater high-sensitivity CRP reduction in both treatment groups,” said study presenter Jorge Plutzky, MD, director of Preventive Cardiology at Brigham and Women’s Hospital, Boston, but “with increased high-sensitivity CRP reductions in those receiving semaglutide.”

The drug also “significantly reduced high-sensitivity CRP early,” he said, “prior to major weight loss and in those who did not lose significant amounts of weight.” The reductions reached approximately 12% at 4 weeks and around 20% at 8 weeks, when the weight loss “was still quite modest,” at 2% and 3% of body weight, respectively. Even among patients who achieved weight loss of less than 2% body weight, semaglutide was associated with a reduction in high-sensitivity CRP levels.

In the SELECT trial, semaglutide also resulted in a consistent reduction of around 20% vs placebo in major adverse cardiovascular events such as cardiovascular mortality, nonfatal myocardial infarction, or nonfatal stroke.

But Naveed Sattar, MD, PhD, professor of cardiometabolic medicine at the University of Glasgow, Scotland, said in an interview that body weight “is probably the major driver” of CRP levels in the population, accounting for between 20% and 30% of the variation.

Dr. Sattar, who was not involved in the study, said that because drugs like semaglutide lower weight but also have anti-inflammatory effects, the question becomes: “Could the anti-inflammatory effects be part of the mechanisms by which these drugs affect the risk of major adverse cardiovascular events?”
 

Reducing Cardiovascular Events

The current analysis, however, cannot answer the question, he said. “All it tells us is about associations.”

“What we do know is semaglutide, predominantly by lowering weight, is lowering CRP levels and equally, we know that when you lose weight, you improve blood pressure, you improve lipids, and you reduce the risk of diabetes,” he said.

Dr. Sattar also took issue with the researchers’ conclusion that the high-sensitivity CRP reductions seen in SELECT occurred prior to major weight loss because the “pattern of CRP reduction and weight reduction is almost identical.”

Dr. Sattar also pointed out in a recent editorial that the drug appears to have a direct effect on blood vessels and the heart, which may lead to improvements in systemic inflammation. Consequently, he said, any assertion that semaglutide is genuinely anti-inflammatory is, at this stage, “speculation.”

Dr. Plutzky said that “systemic, chronic inflammation is implicated as a potential mechanism and therapeutic target in atherosclerosis and major adverse cardiovascular events, as well as obesity,” and high-sensitivity CRP levels are an “established biomarker of inflammation and have been shown to predict cardiovascular risk.”

However, the relationship between high-sensitivity CRP, responses to glucagon-like peptide 1 receptor agonists like semaglutide, and cardiovascular outcomes in obesity “remains incompletely understood,” said Dr. Plutzky.
 

A version of this article appeared on Medscape.com.

LYON, FRANCE — The anti-obesity drug semaglutide is associated with significant reductions in the inflammatory marker high-sensitivity C-reactive protein (CRP), even in patients who do not lose substantial amounts of weight with the drug, according to data from the SELECT clinical trial.

The research, presented at the European Atherosclerosis Society 2024, involved over 17,600 patients with overweight or obesity and had established cardiovascular disease but not diabetes.

Those given semaglutide experienced a 38% reduction in high-sensitivity CRP levels compared with placebo regardless of baseline body mass index, statin use, cholesterol levels, and other measures.

“Weight loss was associated with greater high-sensitivity CRP reduction in both treatment groups,” said study presenter Jorge Plutzky, MD, director of Preventive Cardiology at Brigham and Women’s Hospital, Boston, but “with increased high-sensitivity CRP reductions in those receiving semaglutide.”

The drug also “significantly reduced high-sensitivity CRP early,” he said, “prior to major weight loss and in those who did not lose significant amounts of weight.” The reductions reached approximately 12% at 4 weeks and around 20% at 8 weeks, when the weight loss “was still quite modest,” at 2% and 3% of body weight, respectively. Even among patients who achieved weight loss of less than 2% body weight, semaglutide was associated with a reduction in high-sensitivity CRP levels.

In the SELECT trial, semaglutide also resulted in a consistent reduction of around 20% vs placebo in major adverse cardiovascular events such as cardiovascular mortality, nonfatal myocardial infarction, or nonfatal stroke.

But Naveed Sattar, MD, PhD, professor of cardiometabolic medicine at the University of Glasgow, Scotland, said in an interview that body weight “is probably the major driver” of CRP levels in the population, accounting for between 20% and 30% of the variation.

Dr. Sattar, who was not involved in the study, said that because drugs like semaglutide lower weight but also have anti-inflammatory effects, the question becomes: “Could the anti-inflammatory effects be part of the mechanisms by which these drugs affect the risk of major adverse cardiovascular events?”
 

Reducing Cardiovascular Events

The current analysis, however, cannot answer the question, he said. “All it tells us is about associations.”

“What we do know is semaglutide, predominantly by lowering weight, is lowering CRP levels and equally, we know that when you lose weight, you improve blood pressure, you improve lipids, and you reduce the risk of diabetes,” he said.

Dr. Sattar also took issue with the researchers’ conclusion that the high-sensitivity CRP reductions seen in SELECT occurred prior to major weight loss because the “pattern of CRP reduction and weight reduction is almost identical.”

Dr. Sattar also pointed out in a recent editorial that the drug appears to have a direct effect on blood vessels and the heart, which may lead to improvements in systemic inflammation. Consequently, he said, any assertion that semaglutide is genuinely anti-inflammatory is, at this stage, “speculation.”

Dr. Plutzky said that “systemic, chronic inflammation is implicated as a potential mechanism and therapeutic target in atherosclerosis and major adverse cardiovascular events, as well as obesity,” and high-sensitivity CRP levels are an “established biomarker of inflammation and have been shown to predict cardiovascular risk.”

However, the relationship between high-sensitivity CRP, responses to glucagon-like peptide 1 receptor agonists like semaglutide, and cardiovascular outcomes in obesity “remains incompletely understood,” said Dr. Plutzky.
 

A version of this article appeared on Medscape.com.

Glucagon-like peptide 1 (GLP-1) receptor agonists such as semaglutide (marketed as Ozempic and Rybelsus for type 2 diabetes and as Wegovy for obesity) slow down digestion and curb hunger by working on the brain’s dopamine reward center. They are prescribed to promote weight loss, metabolic health in type 2 diabetes, and heart health in coronary artery disease.

Semaglutide can be prescribed in two forms: the brand-name version, which is approved and confirmed as safe and effective by the US Food and Drug Administration (FDA), and the versions that can be obtained from a compounding pharmacy. Compounding pharmacies are permitted by the FDA to produce what is “ essentially a copy” of approved medications when there’s an official shortage, which is currently the case with semaglutide and other GLP-1 receptor agonists.

Patients are often drawn to compounding pharmacies for pricing-related reasons. If semaglutide is prescribed for a clear indication like diabetes and is covered by insurance, the brand-name version is commonly dispensed. However, if it’s not covered, patients need to pay out of pocket for branded versions, which carry a monthly cost of $1000 or more. Alternatively, their doctors can prescribe compounded semaglutide, which some telehealth companies advertise at costs of approximately $150-$300 per month.
 

Potential Issues With Compounded Semaglutide 

Compounding pharmacies produce drugs from raw materials containing active pharmaceutical ingredients (APIs). Although compounders use many of the same ingredients found in brand-name medications, for drugs like semaglutide, they may opt for specific salts that are not identical to those involved in the production of the standard versions. These salts are typically reserved for research purposes and may not be suitable for general use.

In late 2023, the FDA issued a letter asking the public to exercise caution when using compounded products containing semaglutide or semaglutide salts. This was followed in January 2024 by an FDA communication citing adverse events reported with the use of compounded semaglutide and advising patients to avoid these versions if an approved form of the drug is available.
 

Compound Pharmacies: A Closer Look 

Compounding pharmacies have exploded in popularity in the past several decades. The compounding pharmacy market is expected to grow at 7.8% per year over the next decade. 

Historically, compounding pharmacies have filled a niche for specialty vitamins for intravenous administration as well as chemotherapy medications. They also offer controlled substances, such as ketamine lozenges and nasal sprays, which are unavailable or are in short supply from traditional manufacturers.

Compounding pharmacies fall into two categories. First are compounding pharmacies covered under Section 503A of the Federal Food, Drug and Cosmetic Act; these drugs are neither tested nor monitored. Such facilities do not have to report adverse events to the FDA. The second category is Section 503B outsourcing facilities. These pharmacies choose to be tested by, to be inspected by, and to report adverse events to the FDA. 
 

The FDA’s Latest Update on This Issue

This news organization contacted the FDA for an update on the adverse events reported about compounded semaglutide. From August 8, 2021, to March 31, 2024, they received more than 20,000 adverse events reports for FDA-approved semaglutide. Comparatively, there were 210 adverse events reported on compounded semaglutide products. 

The FDA went on to describe that many of the adverse events reported were consistent with known reactions in the labeling, like nausea, diarrhea, and headache. Yet, they added that, “the FDA is unable to determine how, or if, other factors may have contributed to these adverse events, such as differences in ingredients and formulation between FDA-approved and compounded semaglutide products.” They also noted there was variation in the data quality in the reports they have received, which came only from 503B compounding pharmacies.

In conclusion, given the concerns about compounded semaglutide, it is prudent for the prescribing physicians as well as the patients taking the medication to know that risks are “higher” according to the FDA. We eagerly await more specific information from the FDA to better understand reported adverse events. 
 

How to Help Patients Receive Safe Compounded Semaglutide 

For clinicians considering prescribing semaglutide from compounding pharmacies, there are several questions worth asking, according to the Alliance for Pharmacy Compounding. First, find out whether the pharmacy complies with United States Pharmacopeia compounding standards and whether they source their APIs from FDA-registered facilities, the latter being required by federal law. It’s also important to ensure that these facilities undergo periodic third-party testing to verify medication purity and dosing. 

Ask whether the pharmacy is accredited by the Pharmacy Compounding Accreditation Board (PCAB). Accreditation from the PCAB means that pharmacies have been assessed for processes related to continuous quality improvement. In addition, ask whether the pharmacy is designated as a 503B compounder and if not, why.

Finally, interviewing the pharmacist themselves can provide useful information about staffing, training, and their methods of preparing medications. For example, if they are preparing a sterile eye drop, it is important to ask about sterility testing.

Jesse M. Pines, MD, MBA, MSCE, is a clinical professor of emergency medicine at George Washington University in Washington, and a professor in the department of emergency medicine at Drexel University College of Medicine in Philadelphia, Pennsylvania. Dr. Pines is also the chief of clinical innovation at US Acute Care Solutions in Canton, Ohio. Robert D. Glatter, MD, is an assistant professor of emergency medicine at Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York. Dr. Pines reported conflicts of interest with CSL Behring and Abbott Point-of-Care. Dr. Glatter reported no relevant conflicts of interest.
 

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

Glucagon-like peptide 1 (GLP-1) receptor agonists such as semaglutide (marketed as Ozempic and Rybelsus for type 2 diabetes and as Wegovy for obesity) slow down digestion and curb hunger by working on the brain’s dopamine reward center. They are prescribed to promote weight loss, metabolic health in type 2 diabetes, and heart health in coronary artery disease.

Semaglutide can be prescribed in two forms: the brand-name version, which is approved and confirmed as safe and effective by the US Food and Drug Administration (FDA), and the versions that can be obtained from a compounding pharmacy. Compounding pharmacies are permitted by the FDA to produce what is “ essentially a copy” of approved medications when there’s an official shortage, which is currently the case with semaglutide and other GLP-1 receptor agonists.

Patients are often drawn to compounding pharmacies for pricing-related reasons. If semaglutide is prescribed for a clear indication like diabetes and is covered by insurance, the brand-name version is commonly dispensed. However, if it’s not covered, patients need to pay out of pocket for branded versions, which carry a monthly cost of $1000 or more. Alternatively, their doctors can prescribe compounded semaglutide, which some telehealth companies advertise at costs of approximately $150-$300 per month.
 

Potential Issues With Compounded Semaglutide 

Compounding pharmacies produce drugs from raw materials containing active pharmaceutical ingredients (APIs). Although compounders use many of the same ingredients found in brand-name medications, for drugs like semaglutide, they may opt for specific salts that are not identical to those involved in the production of the standard versions. These salts are typically reserved for research purposes and may not be suitable for general use.

In late 2023, the FDA issued a letter asking the public to exercise caution when using compounded products containing semaglutide or semaglutide salts. This was followed in January 2024 by an FDA communication citing adverse events reported with the use of compounded semaglutide and advising patients to avoid these versions if an approved form of the drug is available.
 

Compound Pharmacies: A Closer Look 

Compounding pharmacies have exploded in popularity in the past several decades. The compounding pharmacy market is expected to grow at 7.8% per year over the next decade. 

Historically, compounding pharmacies have filled a niche for specialty vitamins for intravenous administration as well as chemotherapy medications. They also offer controlled substances, such as ketamine lozenges and nasal sprays, which are unavailable or are in short supply from traditional manufacturers.

Compounding pharmacies fall into two categories. First are compounding pharmacies covered under Section 503A of the Federal Food, Drug and Cosmetic Act; these drugs are neither tested nor monitored. Such facilities do not have to report adverse events to the FDA. The second category is Section 503B outsourcing facilities. These pharmacies choose to be tested by, to be inspected by, and to report adverse events to the FDA. 
 

The FDA’s Latest Update on This Issue

This news organization contacted the FDA for an update on the adverse events reported about compounded semaglutide. From August 8, 2021, to March 31, 2024, they received more than 20,000 adverse events reports for FDA-approved semaglutide. Comparatively, there were 210 adverse events reported on compounded semaglutide products. 

The FDA went on to describe that many of the adverse events reported were consistent with known reactions in the labeling, like nausea, diarrhea, and headache. Yet, they added that, “the FDA is unable to determine how, or if, other factors may have contributed to these adverse events, such as differences in ingredients and formulation between FDA-approved and compounded semaglutide products.” They also noted there was variation in the data quality in the reports they have received, which came only from 503B compounding pharmacies.

In conclusion, given the concerns about compounded semaglutide, it is prudent for the prescribing physicians as well as the patients taking the medication to know that risks are “higher” according to the FDA. We eagerly await more specific information from the FDA to better understand reported adverse events. 
 

How to Help Patients Receive Safe Compounded Semaglutide 

For clinicians considering prescribing semaglutide from compounding pharmacies, there are several questions worth asking, according to the Alliance for Pharmacy Compounding. First, find out whether the pharmacy complies with United States Pharmacopeia compounding standards and whether they source their APIs from FDA-registered facilities, the latter being required by federal law. It’s also important to ensure that these facilities undergo periodic third-party testing to verify medication purity and dosing. 

Ask whether the pharmacy is accredited by the Pharmacy Compounding Accreditation Board (PCAB). Accreditation from the PCAB means that pharmacies have been assessed for processes related to continuous quality improvement. In addition, ask whether the pharmacy is designated as a 503B compounder and if not, why.

Finally, interviewing the pharmacist themselves can provide useful information about staffing, training, and their methods of preparing medications. For example, if they are preparing a sterile eye drop, it is important to ask about sterility testing.

Jesse M. Pines, MD, MBA, MSCE, is a clinical professor of emergency medicine at George Washington University in Washington, and a professor in the department of emergency medicine at Drexel University College of Medicine in Philadelphia, Pennsylvania. Dr. Pines is also the chief of clinical innovation at US Acute Care Solutions in Canton, Ohio. Robert D. Glatter, MD, is an assistant professor of emergency medicine at Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York. Dr. Pines reported conflicts of interest with CSL Behring and Abbott Point-of-Care. Dr. Glatter reported no relevant conflicts of interest.
 

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

Glucagon-like peptide 1 (GLP-1) receptor agonists such as semaglutide (marketed as Ozempic and Rybelsus for type 2 diabetes and as Wegovy for obesity) slow down digestion and curb hunger by working on the brain’s dopamine reward center. They are prescribed to promote weight loss, metabolic health in type 2 diabetes, and heart health in coronary artery disease.

Semaglutide can be prescribed in two forms: the brand-name version, which is approved and confirmed as safe and effective by the US Food and Drug Administration (FDA), and the versions that can be obtained from a compounding pharmacy. Compounding pharmacies are permitted by the FDA to produce what is “ essentially a copy” of approved medications when there’s an official shortage, which is currently the case with semaglutide and other GLP-1 receptor agonists.

Patients are often drawn to compounding pharmacies for pricing-related reasons. If semaglutide is prescribed for a clear indication like diabetes and is covered by insurance, the brand-name version is commonly dispensed. However, if it’s not covered, patients need to pay out of pocket for branded versions, which carry a monthly cost of $1000 or more. Alternatively, their doctors can prescribe compounded semaglutide, which some telehealth companies advertise at costs of approximately $150-$300 per month.
 

Potential Issues With Compounded Semaglutide 

Compounding pharmacies produce drugs from raw materials containing active pharmaceutical ingredients (APIs). Although compounders use many of the same ingredients found in brand-name medications, for drugs like semaglutide, they may opt for specific salts that are not identical to those involved in the production of the standard versions. These salts are typically reserved for research purposes and may not be suitable for general use.

In late 2023, the FDA issued a letter asking the public to exercise caution when using compounded products containing semaglutide or semaglutide salts. This was followed in January 2024 by an FDA communication citing adverse events reported with the use of compounded semaglutide and advising patients to avoid these versions if an approved form of the drug is available.
 

Compound Pharmacies: A Closer Look 

Compounding pharmacies have exploded in popularity in the past several decades. The compounding pharmacy market is expected to grow at 7.8% per year over the next decade. 

Historically, compounding pharmacies have filled a niche for specialty vitamins for intravenous administration as well as chemotherapy medications. They also offer controlled substances, such as ketamine lozenges and nasal sprays, which are unavailable or are in short supply from traditional manufacturers.

Compounding pharmacies fall into two categories. First are compounding pharmacies covered under Section 503A of the Federal Food, Drug and Cosmetic Act; these drugs are neither tested nor monitored. Such facilities do not have to report adverse events to the FDA. The second category is Section 503B outsourcing facilities. These pharmacies choose to be tested by, to be inspected by, and to report adverse events to the FDA. 
 

The FDA’s Latest Update on This Issue

This news organization contacted the FDA for an update on the adverse events reported about compounded semaglutide. From August 8, 2021, to March 31, 2024, they received more than 20,000 adverse events reports for FDA-approved semaglutide. Comparatively, there were 210 adverse events reported on compounded semaglutide products. 

The FDA went on to describe that many of the adverse events reported were consistent with known reactions in the labeling, like nausea, diarrhea, and headache. Yet, they added that, “the FDA is unable to determine how, or if, other factors may have contributed to these adverse events, such as differences in ingredients and formulation between FDA-approved and compounded semaglutide products.” They also noted there was variation in the data quality in the reports they have received, which came only from 503B compounding pharmacies.

In conclusion, given the concerns about compounded semaglutide, it is prudent for the prescribing physicians as well as the patients taking the medication to know that risks are “higher” according to the FDA. We eagerly await more specific information from the FDA to better understand reported adverse events. 
 

How to Help Patients Receive Safe Compounded Semaglutide 

For clinicians considering prescribing semaglutide from compounding pharmacies, there are several questions worth asking, according to the Alliance for Pharmacy Compounding. First, find out whether the pharmacy complies with United States Pharmacopeia compounding standards and whether they source their APIs from FDA-registered facilities, the latter being required by federal law. It’s also important to ensure that these facilities undergo periodic third-party testing to verify medication purity and dosing. 

Ask whether the pharmacy is accredited by the Pharmacy Compounding Accreditation Board (PCAB). Accreditation from the PCAB means that pharmacies have been assessed for processes related to continuous quality improvement. In addition, ask whether the pharmacy is designated as a 503B compounder and if not, why.

Finally, interviewing the pharmacist themselves can provide useful information about staffing, training, and their methods of preparing medications. For example, if they are preparing a sterile eye drop, it is important to ask about sterility testing.

Jesse M. Pines, MD, MBA, MSCE, is a clinical professor of emergency medicine at George Washington University in Washington, and a professor in the department of emergency medicine at Drexel University College of Medicine in Philadelphia, Pennsylvania. Dr. Pines is also the chief of clinical innovation at US Acute Care Solutions in Canton, Ohio. Robert D. Glatter, MD, is an assistant professor of emergency medicine at Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York. Dr. Pines reported conflicts of interest with CSL Behring and Abbott Point-of-Care. Dr. Glatter reported no relevant conflicts of interest.
 

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

WASHINGTON – Women with autoimmune liver diseases (AILD) may face increased risks for major adverse cardiovascular outcomes, according to a study presented at the annual Digestive Disease Week^® (DDW).

In particular, women with autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) appear to have higher risks than women without AIH or PBC. Those with primary sclerosing cholangitis (PSC) don’t seem to have increased risks.

“We know that cardiovascular disease remains the number one cause of death, but the mortality rate for women over the last decade has plateaued, whereas in men it’s actually declining due to interventions,” said lead author Rachel Redfield, MD, a transplant hepatology fellow at Thomas Jefferson University Hospital in Philadelphia.

“This is likely because we don’t have adequate risk stratification, especially for women,” she said. “We know that immune-mediated diseases — such as rheumatoid arthritis and psoriasis — carry a higher risk of cardiovascular disease, but there’s not a lot of data on our autoimmune liver disease patients.”

Dr. Redfield

Although being a female can offer protection against some CVD risks, the atherosclerotic cardiovascular disease (ASCVD) 10-year risk score calculator recommended by the American College of Cardiology doesn’t include chronic inflammatory diseases associated with increased CVD risk, including AILD.

Dr. Redfield and colleagues conducted a multicenter, retrospective cohort study of patients with AIH, PBC, and PSC from 1999-2019. Using TriNetX data, the researchers looked at women with AILD who also had diabetes mellitus, hypertension, and hyperlipidemia, as well as a control group of men and women with these same disorders, excluding those who used biologics, immune modulators, and steroids or had other autoimmune disorders.

The research team used 1:1 propensity-score matching for women in the study group and in the control group based on age, race, ethnicity, ASCVD risk factors, and tobacco use. Women in the study group and men in the control group were matched for age, race, ethnicity, and tobacco use.

The primary outcome was summative cardiovascular risk, including unstable angina, acute myocardial infarction, presence of coronary angioplasty implant, coronary artery bypass, percutaneous coronary intervention, and cerebral infarction.

Overall, women with AIH had a significantly higher cardiovascular risk compared to women without AIH, at 25.4% versus 20.6% (P = .0007).

Specifically, women with PBC had a significantly higher cardiovascular risk compared to women without PBC, at 27.05% versus 20.9% (P < .0001).

There wasn’t a significant difference in risk between women with and without PSC, at 27.5% versus 21.8% (P = .27).

When compared to men without disease, women with AIH didn’t have a statistically significant higher risk, at 25.3% versus 24.2% (P = .44). Similarly, there didn’t appear to be a significant difference between women with PBC and men without PBC, at 26.9% versus 25.9% (P = .52), or between women with PSC and men without PSC, at 27.7% versus 26.2% (P = .78).

Dr. Redfield and colleagues then compared the ASCVD-calculated risk versus database risk, finding that in each group of women with AILD — including AIH, PBC, and PSC — the ASCVD-calculated risk was around 11%, compared with database risk scores of 25% for AIH, 27% for PBC, and 28% for PSC. These database risks appeared similar to both the ASCVD and database risk percentages for men.

“So potentially there’s an oversight in women with any kind of inflammatory disease, but specifically here, autoimmune liver diseases,” she said. “We really need to enhance our risk assessment strategies to take into account their risk and optimize patient outcomes.”

Dr. Redfield noted the limitations with using TriNetX data, including coding consistency among providers and healthcare organizations, unknown patient follow-up dates, and the inability to capture various inflammatory disease phenotypes, such as autoimmune hepatitis with multiple flares, which may be associated with higher cardiovascular risks.

As an attendee of the DDW session, Kenneth Kelson, MD, a gastroenterologist with Fremont Medical Group and Washington Hospital Healthcare System in Fremont, California, noted the importance of investigating the effects of different types of statins in these patients. Although the research team looked at top-level differences among statin users, finding that women with AILD were more likely to be on a statin, they didn’t incorporate statin therapy in the propensity-score matching model.

“Lipid-soluble statins are known to cause more liver trouble, even though it’s pretty low,” Dr. Kelson said. “Whereas the water-soluble statins have a lower incidence of liver issues.”

Dr. Redfield and Dr. Kelson reported no relevant disclosures.

WASHINGTON – Women with autoimmune liver diseases (AILD) may face increased risks for major adverse cardiovascular outcomes, according to a study presented at the annual Digestive Disease Week^® (DDW).

In particular, women with autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) appear to have higher risks than women without AIH or PBC. Those with primary sclerosing cholangitis (PSC) don’t seem to have increased risks.

“We know that cardiovascular disease remains the number one cause of death, but the mortality rate for women over the last decade has plateaued, whereas in men it’s actually declining due to interventions,” said lead author Rachel Redfield, MD, a transplant hepatology fellow at Thomas Jefferson University Hospital in Philadelphia.

“This is likely because we don’t have adequate risk stratification, especially for women,” she said. “We know that immune-mediated diseases — such as rheumatoid arthritis and psoriasis — carry a higher risk of cardiovascular disease, but there’s not a lot of data on our autoimmune liver disease patients.”

Dr. Redfield

Although being a female can offer protection against some CVD risks, the atherosclerotic cardiovascular disease (ASCVD) 10-year risk score calculator recommended by the American College of Cardiology doesn’t include chronic inflammatory diseases associated with increased CVD risk, including AILD.

Dr. Redfield and colleagues conducted a multicenter, retrospective cohort study of patients with AIH, PBC, and PSC from 1999-2019. Using TriNetX data, the researchers looked at women with AILD who also had diabetes mellitus, hypertension, and hyperlipidemia, as well as a control group of men and women with these same disorders, excluding those who used biologics, immune modulators, and steroids or had other autoimmune disorders.

The research team used 1:1 propensity-score matching for women in the study group and in the control group based on age, race, ethnicity, ASCVD risk factors, and tobacco use. Women in the study group and men in the control group were matched for age, race, ethnicity, and tobacco use.

The primary outcome was summative cardiovascular risk, including unstable angina, acute myocardial infarction, presence of coronary angioplasty implant, coronary artery bypass, percutaneous coronary intervention, and cerebral infarction.

Overall, women with AIH had a significantly higher cardiovascular risk compared to women without AIH, at 25.4% versus 20.6% (P = .0007).

Specifically, women with PBC had a significantly higher cardiovascular risk compared to women without PBC, at 27.05% versus 20.9% (P < .0001).

There wasn’t a significant difference in risk between women with and without PSC, at 27.5% versus 21.8% (P = .27).

When compared to men without disease, women with AIH didn’t have a statistically significant higher risk, at 25.3% versus 24.2% (P = .44). Similarly, there didn’t appear to be a significant difference between women with PBC and men without PBC, at 26.9% versus 25.9% (P = .52), or between women with PSC and men without PSC, at 27.7% versus 26.2% (P = .78).

Dr. Redfield and colleagues then compared the ASCVD-calculated risk versus database risk, finding that in each group of women with AILD — including AIH, PBC, and PSC — the ASCVD-calculated risk was around 11%, compared with database risk scores of 25% for AIH, 27% for PBC, and 28% for PSC. These database risks appeared similar to both the ASCVD and database risk percentages for men.

“So potentially there’s an oversight in women with any kind of inflammatory disease, but specifically here, autoimmune liver diseases,” she said. “We really need to enhance our risk assessment strategies to take into account their risk and optimize patient outcomes.”

Dr. Redfield noted the limitations with using TriNetX data, including coding consistency among providers and healthcare organizations, unknown patient follow-up dates, and the inability to capture various inflammatory disease phenotypes, such as autoimmune hepatitis with multiple flares, which may be associated with higher cardiovascular risks.

As an attendee of the DDW session, Kenneth Kelson, MD, a gastroenterologist with Fremont Medical Group and Washington Hospital Healthcare System in Fremont, California, noted the importance of investigating the effects of different types of statins in these patients. Although the research team looked at top-level differences among statin users, finding that women with AILD were more likely to be on a statin, they didn’t incorporate statin therapy in the propensity-score matching model.

“Lipid-soluble statins are known to cause more liver trouble, even though it’s pretty low,” Dr. Kelson said. “Whereas the water-soluble statins have a lower incidence of liver issues.”

Dr. Redfield and Dr. Kelson reported no relevant disclosures.

WASHINGTON – Women with autoimmune liver diseases (AILD) may face increased risks for major adverse cardiovascular outcomes, according to a study presented at the annual Digestive Disease Week^® (DDW).

In particular, women with autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) appear to have higher risks than women without AIH or PBC. Those with primary sclerosing cholangitis (PSC) don’t seem to have increased risks.

“We know that cardiovascular disease remains the number one cause of death, but the mortality rate for women over the last decade has plateaued, whereas in men it’s actually declining due to interventions,” said lead author Rachel Redfield, MD, a transplant hepatology fellow at Thomas Jefferson University Hospital in Philadelphia.

“This is likely because we don’t have adequate risk stratification, especially for women,” she said. “We know that immune-mediated diseases — such as rheumatoid arthritis and psoriasis — carry a higher risk of cardiovascular disease, but there’s not a lot of data on our autoimmune liver disease patients.”

Dr. Redfield

Although being a female can offer protection against some CVD risks, the atherosclerotic cardiovascular disease (ASCVD) 10-year risk score calculator recommended by the American College of Cardiology doesn’t include chronic inflammatory diseases associated with increased CVD risk, including AILD.

Dr. Redfield and colleagues conducted a multicenter, retrospective cohort study of patients with AIH, PBC, and PSC from 1999-2019. Using TriNetX data, the researchers looked at women with AILD who also had diabetes mellitus, hypertension, and hyperlipidemia, as well as a control group of men and women with these same disorders, excluding those who used biologics, immune modulators, and steroids or had other autoimmune disorders.

The research team used 1:1 propensity-score matching for women in the study group and in the control group based on age, race, ethnicity, ASCVD risk factors, and tobacco use. Women in the study group and men in the control group were matched for age, race, ethnicity, and tobacco use.

The primary outcome was summative cardiovascular risk, including unstable angina, acute myocardial infarction, presence of coronary angioplasty implant, coronary artery bypass, percutaneous coronary intervention, and cerebral infarction.

Overall, women with AIH had a significantly higher cardiovascular risk compared to women without AIH, at 25.4% versus 20.6% (P = .0007).

Specifically, women with PBC had a significantly higher cardiovascular risk compared to women without PBC, at 27.05% versus 20.9% (P < .0001).

There wasn’t a significant difference in risk between women with and without PSC, at 27.5% versus 21.8% (P = .27).

When compared to men without disease, women with AIH didn’t have a statistically significant higher risk, at 25.3% versus 24.2% (P = .44). Similarly, there didn’t appear to be a significant difference between women with PBC and men without PBC, at 26.9% versus 25.9% (P = .52), or between women with PSC and men without PSC, at 27.7% versus 26.2% (P = .78).

Dr. Redfield and colleagues then compared the ASCVD-calculated risk versus database risk, finding that in each group of women with AILD — including AIH, PBC, and PSC — the ASCVD-calculated risk was around 11%, compared with database risk scores of 25% for AIH, 27% for PBC, and 28% for PSC. These database risks appeared similar to both the ASCVD and database risk percentages for men.

“So potentially there’s an oversight in women with any kind of inflammatory disease, but specifically here, autoimmune liver diseases,” she said. “We really need to enhance our risk assessment strategies to take into account their risk and optimize patient outcomes.”

Dr. Redfield noted the limitations with using TriNetX data, including coding consistency among providers and healthcare organizations, unknown patient follow-up dates, and the inability to capture various inflammatory disease phenotypes, such as autoimmune hepatitis with multiple flares, which may be associated with higher cardiovascular risks.

As an attendee of the DDW session, Kenneth Kelson, MD, a gastroenterologist with Fremont Medical Group and Washington Hospital Healthcare System in Fremont, California, noted the importance of investigating the effects of different types of statins in these patients. Although the research team looked at top-level differences among statin users, finding that women with AILD were more likely to be on a statin, they didn’t incorporate statin therapy in the propensity-score matching model.

“Lipid-soluble statins are known to cause more liver trouble, even though it’s pretty low,” Dr. Kelson said. “Whereas the water-soluble statins have a lower incidence of liver issues.”

Dr. Redfield and Dr. Kelson reported no relevant disclosures.

Beta-blockers are excellent drugs. They’re cheap and effective; feature prominently in hypertension guidelines; and remain a sine qua non for coronary artery disease, myocardial infarction, and heart failure treatment. They’ve been around forever, and we know they work. Good luck finding an adult medicine patient who isn’t on one.

Beta-blockers act by slowing resting heart rate (and blunting the heart rate response to exercise. The latter is a pernicious cause of activity intolerance that often goes unchecked. Even when the adverse effects of beta-blockers are appreciated, providers are loath to alter dosing, much less stop the drug. After all, beta-blockers are an integral part of guideline-directed medical therapy (GDMT), and GDMT saves lives.

Balancing Heart Rate and Stroke Volume Effects

The pulmonologist sees beta-blockers differently. To augment cardiac output and optimize oxygen uptake (VO₂) during exercise, we need the heart rate response. In fact, the heart rate response contributes more to cardiac output than augmenting stroke volume (SV) and more to VO₂ than the increase in arteriovenous (AV) oxygen difference. An inability to increase the heart rate commensurate with physiologic work is called chronotropic incompetence (CI). That’s what beta-blockers do ─ they cause CI.

Physiology dictates that CI will cause activity intolerance. That said, it’s hard to quantify the impact from beta-blockers at the individual patient level. Data suggest the heart rate effect is profound. A study in patients without heart failure found that 22% of participants on beta-blockers had CI, and the investigators used a conservative CI definition (≤ 62% of heart rate reserve used). A recent report published in JAMA Cardiology found that stopping beta-blockers in patients with heart failure allowed for an extra 30 beats/min at max exercise.

Wasserman and Whipp’s textbook, the last word on all things exercise, presents a sample subject who undergoes two separate cardiopulmonary exercise tests (CPETs). Before the first, he’s given a placebo, and before the second, he gets an intravenous beta-blocker. He’s a 23-year-old otherwise healthy male — the perfect test case for isolating beta-blocker impact without confounding by comorbid diseases, other medications, or deconditioning. His max heart rate dropped by 30 beats/min after the beta-blocker, identical to what we saw in the JAMA Cardiology study (with the heart rate increasing by 30 beats/min following withdrawal). Case closed. Stop the beta-blockers on your patients so they can meet their exercise goals and get healthy!

Such pithy enthusiasm discounts physiology’s complexities. When blunting our patient’s heart rate response with beta-blockers, we also increase diastolic filling time, which increases SV. For the 23-year-old in Wasserman and Whipp’s physiology textbook, the beta-blocker increased O₂ pulse (the product of SV and AV difference). Presumably, this is mediated by the increased SV. There was a net reduction in VO₂ peak, but it was nominal, suggesting that the drop in heart rate was largely offset by the increase in O₂ pulse. For the patients in the JAMA Cardiology study, the entire group had a small increase in VO2 peak with beta-blocker withdrawal, but the effect differed by left ventricular function. Across different studies, the beta-blocker effect on heart rate is consistent but the change in overall exercise capacity is not. 

Patient Variability in Beta-Blocker Response

In addition to left ventricular function, there are other factors likely to drive variability at the patient level. We’ve treated the response to beta-blockers as a class effect — an obvious oversimplification. The impact on exercise and the heart will vary by dose and drug (eg, atenolol vs metoprolol vs carvedilol, and so on). Beta-blockers can also affect the lungs, and we’re still debating how cautious to be in the presence of asthma or chronic obstructive pulmonary disease. 

In a world of infinite time, resources, and expertise, we’d CPET everyone before and after beta-blocker use. Our current reality requires the unthinkable: We’ll have to talk to each other and our patients. For example, heart failure guidelines recommend titrating drugs to match the dose from trials that proved efficacy. These doses are quite high. Simple discussion with the cardiologist and the patient may allow for an adjustment back down with careful monitoring and close attention to activity tolerance. With any luck, you’ll preserve the benefits from GDMT while optimizing your patient›s ability to meet their exercise goals.
 

Dr. Holley, professor in the department of medicine, Uniformed Services University, Bethesda, Maryland, and a pulmonary/sleep and critical care medicine physician at MedStar Washington Hospital Center, Washington, disclosed ties with Metapharm, CHEST College, and WebMD.

A version of this article appeared on Medscape.com.

Beta-blockers are excellent drugs. They’re cheap and effective; feature prominently in hypertension guidelines; and remain a sine qua non for coronary artery disease, myocardial infarction, and heart failure treatment. They’ve been around forever, and we know they work. Good luck finding an adult medicine patient who isn’t on one.

Beta-blockers act by slowing resting heart rate (and blunting the heart rate response to exercise. The latter is a pernicious cause of activity intolerance that often goes unchecked. Even when the adverse effects of beta-blockers are appreciated, providers are loath to alter dosing, much less stop the drug. After all, beta-blockers are an integral part of guideline-directed medical therapy (GDMT), and GDMT saves lives.

Balancing Heart Rate and Stroke Volume Effects

The pulmonologist sees beta-blockers differently. To augment cardiac output and optimize oxygen uptake (VO₂) during exercise, we need the heart rate response. In fact, the heart rate response contributes more to cardiac output than augmenting stroke volume (SV) and more to VO₂ than the increase in arteriovenous (AV) oxygen difference. An inability to increase the heart rate commensurate with physiologic work is called chronotropic incompetence (CI). That’s what beta-blockers do ─ they cause CI.

Physiology dictates that CI will cause activity intolerance. That said, it’s hard to quantify the impact from beta-blockers at the individual patient level. Data suggest the heart rate effect is profound. A study in patients without heart failure found that 22% of participants on beta-blockers had CI, and the investigators used a conservative CI definition (≤ 62% of heart rate reserve used). A recent report published in JAMA Cardiology found that stopping beta-blockers in patients with heart failure allowed for an extra 30 beats/min at max exercise.

Wasserman and Whipp’s textbook, the last word on all things exercise, presents a sample subject who undergoes two separate cardiopulmonary exercise tests (CPETs). Before the first, he’s given a placebo, and before the second, he gets an intravenous beta-blocker. He’s a 23-year-old otherwise healthy male — the perfect test case for isolating beta-blocker impact without confounding by comorbid diseases, other medications, or deconditioning. His max heart rate dropped by 30 beats/min after the beta-blocker, identical to what we saw in the JAMA Cardiology study (with the heart rate increasing by 30 beats/min following withdrawal). Case closed. Stop the beta-blockers on your patients so they can meet their exercise goals and get healthy!

Such pithy enthusiasm discounts physiology’s complexities. When blunting our patient’s heart rate response with beta-blockers, we also increase diastolic filling time, which increases SV. For the 23-year-old in Wasserman and Whipp’s physiology textbook, the beta-blocker increased O₂ pulse (the product of SV and AV difference). Presumably, this is mediated by the increased SV. There was a net reduction in VO₂ peak, but it was nominal, suggesting that the drop in heart rate was largely offset by the increase in O₂ pulse. For the patients in the JAMA Cardiology study, the entire group had a small increase in VO2 peak with beta-blocker withdrawal, but the effect differed by left ventricular function. Across different studies, the beta-blocker effect on heart rate is consistent but the change in overall exercise capacity is not. 

Patient Variability in Beta-Blocker Response

In addition to left ventricular function, there are other factors likely to drive variability at the patient level. We’ve treated the response to beta-blockers as a class effect — an obvious oversimplification. The impact on exercise and the heart will vary by dose and drug (eg, atenolol vs metoprolol vs carvedilol, and so on). Beta-blockers can also affect the lungs, and we’re still debating how cautious to be in the presence of asthma or chronic obstructive pulmonary disease. 

In a world of infinite time, resources, and expertise, we’d CPET everyone before and after beta-blocker use. Our current reality requires the unthinkable: We’ll have to talk to each other and our patients. For example, heart failure guidelines recommend titrating drugs to match the dose from trials that proved efficacy. These doses are quite high. Simple discussion with the cardiologist and the patient may allow for an adjustment back down with careful monitoring and close attention to activity tolerance. With any luck, you’ll preserve the benefits from GDMT while optimizing your patient›s ability to meet their exercise goals.
 

Dr. Holley, professor in the department of medicine, Uniformed Services University, Bethesda, Maryland, and a pulmonary/sleep and critical care medicine physician at MedStar Washington Hospital Center, Washington, disclosed ties with Metapharm, CHEST College, and WebMD.

A version of this article appeared on Medscape.com.

Beta-blockers are excellent drugs. They’re cheap and effective; feature prominently in hypertension guidelines; and remain a sine qua non for coronary artery disease, myocardial infarction, and heart failure treatment. They’ve been around forever, and we know they work. Good luck finding an adult medicine patient who isn’t on one.

Beta-blockers act by slowing resting heart rate (and blunting the heart rate response to exercise. The latter is a pernicious cause of activity intolerance that often goes unchecked. Even when the adverse effects of beta-blockers are appreciated, providers are loath to alter dosing, much less stop the drug. After all, beta-blockers are an integral part of guideline-directed medical therapy (GDMT), and GDMT saves lives.

Balancing Heart Rate and Stroke Volume Effects

The pulmonologist sees beta-blockers differently. To augment cardiac output and optimize oxygen uptake (VO₂) during exercise, we need the heart rate response. In fact, the heart rate response contributes more to cardiac output than augmenting stroke volume (SV) and more to VO₂ than the increase in arteriovenous (AV) oxygen difference. An inability to increase the heart rate commensurate with physiologic work is called chronotropic incompetence (CI). That’s what beta-blockers do ─ they cause CI.

Physiology dictates that CI will cause activity intolerance. That said, it’s hard to quantify the impact from beta-blockers at the individual patient level. Data suggest the heart rate effect is profound. A study in patients without heart failure found that 22% of participants on beta-blockers had CI, and the investigators used a conservative CI definition (≤ 62% of heart rate reserve used). A recent report published in JAMA Cardiology found that stopping beta-blockers in patients with heart failure allowed for an extra 30 beats/min at max exercise.

Wasserman and Whipp’s textbook, the last word on all things exercise, presents a sample subject who undergoes two separate cardiopulmonary exercise tests (CPETs). Before the first, he’s given a placebo, and before the second, he gets an intravenous beta-blocker. He’s a 23-year-old otherwise healthy male — the perfect test case for isolating beta-blocker impact without confounding by comorbid diseases, other medications, or deconditioning. His max heart rate dropped by 30 beats/min after the beta-blocker, identical to what we saw in the JAMA Cardiology study (with the heart rate increasing by 30 beats/min following withdrawal). Case closed. Stop the beta-blockers on your patients so they can meet their exercise goals and get healthy!

Such pithy enthusiasm discounts physiology’s complexities. When blunting our patient’s heart rate response with beta-blockers, we also increase diastolic filling time, which increases SV. For the 23-year-old in Wasserman and Whipp’s physiology textbook, the beta-blocker increased O₂ pulse (the product of SV and AV difference). Presumably, this is mediated by the increased SV. There was a net reduction in VO₂ peak, but it was nominal, suggesting that the drop in heart rate was largely offset by the increase in O₂ pulse. For the patients in the JAMA Cardiology study, the entire group had a small increase in VO2 peak with beta-blocker withdrawal, but the effect differed by left ventricular function. Across different studies, the beta-blocker effect on heart rate is consistent but the change in overall exercise capacity is not. 

Patient Variability in Beta-Blocker Response

In addition to left ventricular function, there are other factors likely to drive variability at the patient level. We’ve treated the response to beta-blockers as a class effect — an obvious oversimplification. The impact on exercise and the heart will vary by dose and drug (eg, atenolol vs metoprolol vs carvedilol, and so on). Beta-blockers can also affect the lungs, and we’re still debating how cautious to be in the presence of asthma or chronic obstructive pulmonary disease. 

In a world of infinite time, resources, and expertise, we’d CPET everyone before and after beta-blocker use. Our current reality requires the unthinkable: We’ll have to talk to each other and our patients. For example, heart failure guidelines recommend titrating drugs to match the dose from trials that proved efficacy. These doses are quite high. Simple discussion with the cardiologist and the patient may allow for an adjustment back down with careful monitoring and close attention to activity tolerance. With any luck, you’ll preserve the benefits from GDMT while optimizing your patient›s ability to meet their exercise goals.
 

Dr. Holley, professor in the department of medicine, Uniformed Services University, Bethesda, Maryland, and a pulmonary/sleep and critical care medicine physician at MedStar Washington Hospital Center, Washington, disclosed ties with Metapharm, CHEST College, and WebMD.

A version of this article appeared on Medscape.com.

HOUSTON — Narcolepsy is associated with a significantly increased risk for cardiovascular disease (CVD) and major adverse cardiac events (MACEs), independent of common comorbid conditions and medications commonly used to treat the chronic sleep disorder, according to two new studies.

A nationwide analysis revealed that people with narcolepsy had a 77% higher risk for CVD and an 82% higher risk for MACE than those without the disorder.

“These findings indicate that it is important for clinicians to regularly monitor patients for cardiovascular disease and take this into consideration when recommending specific treatments for narcolepsy,” study investigators Christopher Kaufmann, PhD; Munaza Riaz, PharmD, MPhil; and Rakesh Bhattacharjee, MD, told this news organization.

“Additionally, physicians should consider monitoring the presence of other health conditions as contributing factors to the risk of CVD,” they said. Dr. Kaufmann and Dr. Riaz are with the University of Florida, Gainesville, Florida, and Dr. Bhattacharjee is with the University of California, San Diego.

They presented their research at SLEEP 2024: 38th Annual Meeting of the Associated Professional Sleep Societies.
 

Independent Risk Factor

The National Institute of Neurological Disorders and Stroke reports an estimated 125,000 to 200,000 people in the United States live with narcolepsy. The condition often coexists with other common health conditions including obstructive sleep apnea (OSA), diabetes, and other comorbidities, which can all contribute to the risk for CVD.

This raises doubt as to whether narcolepsy itself directly leads to CVD or if it is the result of these comorbid health conditions. Additionally, some medications used to treat narcolepsy carry their own cardiovascular risks.

Using the IBM MarketScan Commercial and Medicare supplemental databases, the researchers identified 34,562 adults with a diagnosis of narcolepsy and a propensity-matched comparison cohort of 100,405 adults without narcolepsy. The patients had a mean age of 40 years, and 62% were women.

Compared with adults without narcolepsy, those with the chronic sleep disorder that causes overwhelming daytime drowsiness had a 77% increased risk for any CVD (hazard ratio [HR], 1.77) and an 82% increased risk for MACE (HR, 1.82).

They also had an increased risk for stroke (HR, 2.04), heart failure or myocardial infarction (MI; HR, 1.64), and atrial fibrillation (HR, 1.58).

The results were similar in a separate analysis of the same population that also controlled for baseline use of stimulants, oxybates, and wake-promoting agents — medications commonly used to treat excessive daytime sleepiness associated with narcolepsy.

In this analysis, narcolepsy was associated with an 89% higher risk for CVD (HR, 1.89) and a 95% increased risk for MACE (HR, 1.95). The risk for any stroke (HR, 2.06), heart failure (HR, 1.90), atrial fibrillation (HR, 1.66), and MI (HR, 1.93) was also higher in those with narcolepsy.

“Our study found that even after considering the presence of health conditions like obstructive sleep apnea, diabetes, hypertension, hyperlipidemia, and even depression, as well as medication use, there still appears to be an independent relationship between narcolepsy and CVD,” the investigators said.

They cautioned that the mechanisms explaining the link between CVD and narcolepsy are unclear and warrant further study.

“Sleep fragmentation is a hallmark of narcolepsy, and it is speculated that this fragmentation, which may trigger disturbances in autonomic function, predisposes individuals to CVD. In rodent models, a possible link has been observed between hypocretin — a central neurotransmitter that is reduced or deficient in patients with narcolepsy — and atherosclerosis.

“However, it remains uncertain whether this is the primary mechanism related to CVD,” they commented.
 

Compelling Evidence for Higher CVD

Commenting on the findings for this news organization, Shaheen Lakhan, MD, a neurologist and researcher based in Miami, Florida, called for narcolepsy to be recognized as a significant contributor to higher CVD risk.

“Given the compelling evidence linking narcolepsy to a higher incidence of cardiovascular disease, it is crucial that narcolepsy be included in clinical guidelines and risk assessment tools alongside other known risk factors,” said Dr. Lakhan, who was not involved in this research.

“Physicians and health care providers should proactively address the increased cardiovascular risk associated with narcolepsy by incorporating preventive strategies and interventions into the management of patients with this condition,” Dr. Lakhan suggested.

Regular CVD screening, a healthier lifestyle, and targeted therapies could all decrease cardiac risk, Dr. Lakhan added.

“Ultimately, novel disease-modifying therapies for narcolepsy should target the core mechanisms driving the increased cardiovascular risk associated with this condition. By elucidating the specific biological pathways and developing targeted therapies that address the unique challenges faced by narcolepsy patients, we can effectively mitigate the risk,” Dr. Lakhan said.

The studies were funded by the Sleep Research Society Foundation. The authors and Dr. Lakhan had no relevant disclosures.

A version of this article appeared on Medscape.com.

HOUSTON — Narcolepsy is associated with a significantly increased risk for cardiovascular disease (CVD) and major adverse cardiac events (MACEs), independent of common comorbid conditions and medications commonly used to treat the chronic sleep disorder, according to two new studies.

A nationwide analysis revealed that people with narcolepsy had a 77% higher risk for CVD and an 82% higher risk for MACE than those without the disorder.

“These findings indicate that it is important for clinicians to regularly monitor patients for cardiovascular disease and take this into consideration when recommending specific treatments for narcolepsy,” study investigators Christopher Kaufmann, PhD; Munaza Riaz, PharmD, MPhil; and Rakesh Bhattacharjee, MD, told this news organization.

“Additionally, physicians should consider monitoring the presence of other health conditions as contributing factors to the risk of CVD,” they said. Dr. Kaufmann and Dr. Riaz are with the University of Florida, Gainesville, Florida, and Dr. Bhattacharjee is with the University of California, San Diego.

They presented their research at SLEEP 2024: 38th Annual Meeting of the Associated Professional Sleep Societies.
 

Independent Risk Factor

The National Institute of Neurological Disorders and Stroke reports an estimated 125,000 to 200,000 people in the United States live with narcolepsy. The condition often coexists with other common health conditions including obstructive sleep apnea (OSA), diabetes, and other comorbidities, which can all contribute to the risk for CVD.

This raises doubt as to whether narcolepsy itself directly leads to CVD or if it is the result of these comorbid health conditions. Additionally, some medications used to treat narcolepsy carry their own cardiovascular risks.

Using the IBM MarketScan Commercial and Medicare supplemental databases, the researchers identified 34,562 adults with a diagnosis of narcolepsy and a propensity-matched comparison cohort of 100,405 adults without narcolepsy. The patients had a mean age of 40 years, and 62% were women.

Compared with adults without narcolepsy, those with the chronic sleep disorder that causes overwhelming daytime drowsiness had a 77% increased risk for any CVD (hazard ratio [HR], 1.77) and an 82% increased risk for MACE (HR, 1.82).

They also had an increased risk for stroke (HR, 2.04), heart failure or myocardial infarction (MI; HR, 1.64), and atrial fibrillation (HR, 1.58).

The results were similar in a separate analysis of the same population that also controlled for baseline use of stimulants, oxybates, and wake-promoting agents — medications commonly used to treat excessive daytime sleepiness associated with narcolepsy.

In this analysis, narcolepsy was associated with an 89% higher risk for CVD (HR, 1.89) and a 95% increased risk for MACE (HR, 1.95). The risk for any stroke (HR, 2.06), heart failure (HR, 1.90), atrial fibrillation (HR, 1.66), and MI (HR, 1.93) was also higher in those with narcolepsy.

“Our study found that even after considering the presence of health conditions like obstructive sleep apnea, diabetes, hypertension, hyperlipidemia, and even depression, as well as medication use, there still appears to be an independent relationship between narcolepsy and CVD,” the investigators said.

They cautioned that the mechanisms explaining the link between CVD and narcolepsy are unclear and warrant further study.

“Sleep fragmentation is a hallmark of narcolepsy, and it is speculated that this fragmentation, which may trigger disturbances in autonomic function, predisposes individuals to CVD. In rodent models, a possible link has been observed between hypocretin — a central neurotransmitter that is reduced or deficient in patients with narcolepsy — and atherosclerosis.

“However, it remains uncertain whether this is the primary mechanism related to CVD,” they commented.
 

Compelling Evidence for Higher CVD

Commenting on the findings for this news organization, Shaheen Lakhan, MD, a neurologist and researcher based in Miami, Florida, called for narcolepsy to be recognized as a significant contributor to higher CVD risk.

“Given the compelling evidence linking narcolepsy to a higher incidence of cardiovascular disease, it is crucial that narcolepsy be included in clinical guidelines and risk assessment tools alongside other known risk factors,” said Dr. Lakhan, who was not involved in this research.

“Physicians and health care providers should proactively address the increased cardiovascular risk associated with narcolepsy by incorporating preventive strategies and interventions into the management of patients with this condition,” Dr. Lakhan suggested.

Regular CVD screening, a healthier lifestyle, and targeted therapies could all decrease cardiac risk, Dr. Lakhan added.

“Ultimately, novel disease-modifying therapies for narcolepsy should target the core mechanisms driving the increased cardiovascular risk associated with this condition. By elucidating the specific biological pathways and developing targeted therapies that address the unique challenges faced by narcolepsy patients, we can effectively mitigate the risk,” Dr. Lakhan said.

The studies were funded by the Sleep Research Society Foundation. The authors and Dr. Lakhan had no relevant disclosures.

A version of this article appeared on Medscape.com.

HOUSTON — Narcolepsy is associated with a significantly increased risk for cardiovascular disease (CVD) and major adverse cardiac events (MACEs), independent of common comorbid conditions and medications commonly used to treat the chronic sleep disorder, according to two new studies.

A nationwide analysis revealed that people with narcolepsy had a 77% higher risk for CVD and an 82% higher risk for MACE than those without the disorder.

“These findings indicate that it is important for clinicians to regularly monitor patients for cardiovascular disease and take this into consideration when recommending specific treatments for narcolepsy,” study investigators Christopher Kaufmann, PhD; Munaza Riaz, PharmD, MPhil; and Rakesh Bhattacharjee, MD, told this news organization.

“Additionally, physicians should consider monitoring the presence of other health conditions as contributing factors to the risk of CVD,” they said. Dr. Kaufmann and Dr. Riaz are with the University of Florida, Gainesville, Florida, and Dr. Bhattacharjee is with the University of California, San Diego.

They presented their research at SLEEP 2024: 38th Annual Meeting of the Associated Professional Sleep Societies.
 

Independent Risk Factor

The National Institute of Neurological Disorders and Stroke reports an estimated 125,000 to 200,000 people in the United States live with narcolepsy. The condition often coexists with other common health conditions including obstructive sleep apnea (OSA), diabetes, and other comorbidities, which can all contribute to the risk for CVD.

This raises doubt as to whether narcolepsy itself directly leads to CVD or if it is the result of these comorbid health conditions. Additionally, some medications used to treat narcolepsy carry their own cardiovascular risks.

Using the IBM MarketScan Commercial and Medicare supplemental databases, the researchers identified 34,562 adults with a diagnosis of narcolepsy and a propensity-matched comparison cohort of 100,405 adults without narcolepsy. The patients had a mean age of 40 years, and 62% were women.

Compared with adults without narcolepsy, those with the chronic sleep disorder that causes overwhelming daytime drowsiness had a 77% increased risk for any CVD (hazard ratio [HR], 1.77) and an 82% increased risk for MACE (HR, 1.82).

They also had an increased risk for stroke (HR, 2.04), heart failure or myocardial infarction (MI; HR, 1.64), and atrial fibrillation (HR, 1.58).

The results were similar in a separate analysis of the same population that also controlled for baseline use of stimulants, oxybates, and wake-promoting agents — medications commonly used to treat excessive daytime sleepiness associated with narcolepsy.

In this analysis, narcolepsy was associated with an 89% higher risk for CVD (HR, 1.89) and a 95% increased risk for MACE (HR, 1.95). The risk for any stroke (HR, 2.06), heart failure (HR, 1.90), atrial fibrillation (HR, 1.66), and MI (HR, 1.93) was also higher in those with narcolepsy.

“Our study found that even after considering the presence of health conditions like obstructive sleep apnea, diabetes, hypertension, hyperlipidemia, and even depression, as well as medication use, there still appears to be an independent relationship between narcolepsy and CVD,” the investigators said.

They cautioned that the mechanisms explaining the link between CVD and narcolepsy are unclear and warrant further study.

“Sleep fragmentation is a hallmark of narcolepsy, and it is speculated that this fragmentation, which may trigger disturbances in autonomic function, predisposes individuals to CVD. In rodent models, a possible link has been observed between hypocretin — a central neurotransmitter that is reduced or deficient in patients with narcolepsy — and atherosclerosis.

“However, it remains uncertain whether this is the primary mechanism related to CVD,” they commented.
 

Compelling Evidence for Higher CVD

Commenting on the findings for this news organization, Shaheen Lakhan, MD, a neurologist and researcher based in Miami, Florida, called for narcolepsy to be recognized as a significant contributor to higher CVD risk.

“Given the compelling evidence linking narcolepsy to a higher incidence of cardiovascular disease, it is crucial that narcolepsy be included in clinical guidelines and risk assessment tools alongside other known risk factors,” said Dr. Lakhan, who was not involved in this research.

“Physicians and health care providers should proactively address the increased cardiovascular risk associated with narcolepsy by incorporating preventive strategies and interventions into the management of patients with this condition,” Dr. Lakhan suggested.

Regular CVD screening, a healthier lifestyle, and targeted therapies could all decrease cardiac risk, Dr. Lakhan added.

“Ultimately, novel disease-modifying therapies for narcolepsy should target the core mechanisms driving the increased cardiovascular risk associated with this condition. By elucidating the specific biological pathways and developing targeted therapies that address the unique challenges faced by narcolepsy patients, we can effectively mitigate the risk,” Dr. Lakhan said.

The studies were funded by the Sleep Research Society Foundation. The authors and Dr. Lakhan had no relevant disclosures.

A version of this article appeared on Medscape.com.

There has been much hyperbole since the presentation of results from the SELECT cardiovascular outcomes trial (CVOT) at this year’s European Congress on Obesity, which led many to herald semaglutide as the “new statin.”

In the SELECT CVOT, participants with overweight or obesity (body mass index [BMI] ≥ 27), established cardiovascular disease (CVD), and no history of type 2 diabetes were administered the injectable glucagon-like peptide 1 (GLP-1) receptor agonist semaglutide (Wegovy) at a 2.4-mg dose weekly. Treatment resulted in a significant 20% relative risk reduction in major adverse CV events (a composite endpoint comprising CV death, nonfatal myocardial infarction, or nonfatal stroke). Importantly, SELECT was a trial on secondary prevention of CVD. 

The CV benefits of semaglutide were notably independent of baseline weight or amount of weight lost. This suggests that the underlying driver of improved CV outcomes with semaglutide extends beyond simple reduction in obesity and perhaps indicates a direct effect on vasculature and reduction in atherosclerosis, although this remains unproven.
 

Not All Risk Reduction Is Equal 

Much of the sensationalist coverage in the lay press focused on the 20% relative risk reduction figure. This endpoint is often more impressive and headline-grabbing than the absolute risk reduction, which provides a clearer view of a treatment’s real-world impact.

In SELECT, the absolute risk reduction was 1.5 percentage points, which translated into a number needed to treat (NNT) of 67 over 34 months to prevent one primary outcome of a major adverse CV event.

Lower NNTs suggest more effective treatments because fewer people need to be treated to prevent one clinical event, such as the major adverse CV events used in SELECT.
 

Semaglutide vs Statins

How does the clinical effectiveness observed in the SELECT trial compare with that observed in statin trials when it comes to the secondary prevention of CVD?

The seminal 4S study published in 1994 explored the impact of simvastatin on all-cause mortality among people with previous myocardial infarction or angina and hyperlipidemia (mean baseline BMI, 26). After 5.4 years of follow-up, the trial was stopped early owing to a 3.3-percentage point absolute risk reduction in all-cause mortality (NNT, 30; relative risk reduction, 28%). The NNT to prevent one death from CV causes was 31, and the NNT to prevent one major coronary event was lower, at 15.

Other statin secondary prevention trials, such as the LIPID and MIRACL studies, demonstrated similarly low NNTs.

So, you can see that the NNTs for statins in secondary prevention are much lower than with semaglutide in SELECT. Furthermore, the benefits of semaglutide in preventing CVD in people living with overweight/obesity have yet to be elucidated. 

In contrast, we already have published evidence showing the benefits of statins in the primary prevention of CVD, albeit with higher and more variable NNTs than in the statin secondary prevention studies. 

The benefits of statins are also postulated to extend beyond their impact on lowering low-density lipoprotein cholesterol. Statins have been suggested to have anti-inflammatory and plaque-stabilizing effects, among other pleiotropic benefits.

We also currently lack evidence for the cost-effectiveness of semaglutide for CV risk reduction. Assessing economic viability and use in health care systems, such as the UK’s National Health Service, involves comparing the cost of semaglutide against the health care savings from prevented CV events. Health economic studies are vital to determine whether the benefits justify the expense. In contrast, the cost-effectiveness of statins is well established, particularly for high-risk individuals.
 

Advantages of GLP-1s Should Not Be Overlooked

Of course, statins don’t provide the significant weight loss benefits of semaglutide. 

Additional data from SELECT presented at the 2024 European Congress on Obesity demonstrated that participants lost a mean of 10.2% body weight and 7.7 cm from their waist circumference after 4 years. Moreover, after 2 years, 12% of individuals randomized to semaglutide had returned to a normal BMI, and nearly half were no longer living with obesity.

Although the CV benefits of semaglutide were independent of weight reduction, this level of weight loss is clinically meaningful and will reduce the risk of many other cardiometabolic conditions including type 2 diabetes, metabolic dysfunction–associated steatotic liver disease, and obstructive sleep apnea/hypopnea syndrome, as well as improve low mood, depression, and overall quality of life. Additionally, obesity is now a risk factor for 13 different types of cancer, including bowel, breast, and pancreatic cancer, so facilitating a return to a healthier body weight will also mitigate future risk for cancer.
 

Sticking With Our Cornerstone Therapy, For Now

In conclusion, I do not believe that semaglutide is the “new statin.” Statins are the cornerstone of primary and secondary prevention of CVD in a wide range of comorbidities, as evidenced in multiple large and high-quality trials dating back over 30 years.

However, there is no doubt that the GLP-1 receptor agonist class is the most significant therapeutic advance for the management of obesity and comorbidities to date. 

The SELECT CVOT data uniquely position semaglutide as a secondary CVD prevention agent on top of guideline-driven management for people living with overweight/obesity and established CVD. Additionally, the clinically meaningful weight loss achieved with semaglutide will impact the risk of developing many other cardiometabolic conditions, as well as improve mental health and overall quality of life.

Dr. Fernando, GP Partner, North Berwick Health Centre, North Berwick, Scotland, creates concise clinical aide-mémoire for primary and secondary care to make life easier for health care professionals and ultimately to improve the lives of patients. He is very active on social media (X handle @drkevinfernando), where he posts hot topics in type 2 diabetes and CVRM. He recently has forayed into YouTube (@DrKevinFernando) and TikTok (@drkevinfernando) with patient-facing video content. Dr. Fernando has been elected to Fellowship of the Royal College of General Practitioners, the Royal College of Physicians of Edinburgh, and the Academy of Medical Educators for his work in diabetes and medical education. He has disclosed the following relevant financial relationships: Serve(d) as a speaker or a member of a speakers bureau for AstraZeneca; Boehringer Ingelheim; Lilly; Menarini; Bayer; Dexcom; Novartis; Novo Nordisk; Amgen; and Daiichi Sankyo; received income in an amount equal to or greater than $250 from AstraZeneca; Boehringer Ingelheim; Lilly; Menarini; Bayer; Dexcom; Novartis; Novo Nordisk; Amgen; and Daiichi Sankyo.

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

There has been much hyperbole since the presentation of results from the SELECT cardiovascular outcomes trial (CVOT) at this year’s European Congress on Obesity, which led many to herald semaglutide as the “new statin.”

In the SELECT CVOT, participants with overweight or obesity (body mass index [BMI] ≥ 27), established cardiovascular disease (CVD), and no history of type 2 diabetes were administered the injectable glucagon-like peptide 1 (GLP-1) receptor agonist semaglutide (Wegovy) at a 2.4-mg dose weekly. Treatment resulted in a significant 20% relative risk reduction in major adverse CV events (a composite endpoint comprising CV death, nonfatal myocardial infarction, or nonfatal stroke). Importantly, SELECT was a trial on secondary prevention of CVD. 

The CV benefits of semaglutide were notably independent of baseline weight or amount of weight lost. This suggests that the underlying driver of improved CV outcomes with semaglutide extends beyond simple reduction in obesity and perhaps indicates a direct effect on vasculature and reduction in atherosclerosis, although this remains unproven.
 

Not All Risk Reduction Is Equal 

Much of the sensationalist coverage in the lay press focused on the 20% relative risk reduction figure. This endpoint is often more impressive and headline-grabbing than the absolute risk reduction, which provides a clearer view of a treatment’s real-world impact.

In SELECT, the absolute risk reduction was 1.5 percentage points, which translated into a number needed to treat (NNT) of 67 over 34 months to prevent one primary outcome of a major adverse CV event.

Lower NNTs suggest more effective treatments because fewer people need to be treated to prevent one clinical event, such as the major adverse CV events used in SELECT.
 

Semaglutide vs Statins

How does the clinical effectiveness observed in the SELECT trial compare with that observed in statin trials when it comes to the secondary prevention of CVD?

The seminal 4S study published in 1994 explored the impact of simvastatin on all-cause mortality among people with previous myocardial infarction or angina and hyperlipidemia (mean baseline BMI, 26). After 5.4 years of follow-up, the trial was stopped early owing to a 3.3-percentage point absolute risk reduction in all-cause mortality (NNT, 30; relative risk reduction, 28%). The NNT to prevent one death from CV causes was 31, and the NNT to prevent one major coronary event was lower, at 15.

Other statin secondary prevention trials, such as the LIPID and MIRACL studies, demonstrated similarly low NNTs.

So, you can see that the NNTs for statins in secondary prevention are much lower than with semaglutide in SELECT. Furthermore, the benefits of semaglutide in preventing CVD in people living with overweight/obesity have yet to be elucidated. 

In contrast, we already have published evidence showing the benefits of statins in the primary prevention of CVD, albeit with higher and more variable NNTs than in the statin secondary prevention studies. 

The benefits of statins are also postulated to extend beyond their impact on lowering low-density lipoprotein cholesterol. Statins have been suggested to have anti-inflammatory and plaque-stabilizing effects, among other pleiotropic benefits.

We also currently lack evidence for the cost-effectiveness of semaglutide for CV risk reduction. Assessing economic viability and use in health care systems, such as the UK’s National Health Service, involves comparing the cost of semaglutide against the health care savings from prevented CV events. Health economic studies are vital to determine whether the benefits justify the expense. In contrast, the cost-effectiveness of statins is well established, particularly for high-risk individuals.
 

Advantages of GLP-1s Should Not Be Overlooked

Of course, statins don’t provide the significant weight loss benefits of semaglutide. 

Additional data from SELECT presented at the 2024 European Congress on Obesity demonstrated that participants lost a mean of 10.2% body weight and 7.7 cm from their waist circumference after 4 years. Moreover, after 2 years, 12% of individuals randomized to semaglutide had returned to a normal BMI, and nearly half were no longer living with obesity.

Although the CV benefits of semaglutide were independent of weight reduction, this level of weight loss is clinically meaningful and will reduce the risk of many other cardiometabolic conditions including type 2 diabetes, metabolic dysfunction–associated steatotic liver disease, and obstructive sleep apnea/hypopnea syndrome, as well as improve low mood, depression, and overall quality of life. Additionally, obesity is now a risk factor for 13 different types of cancer, including bowel, breast, and pancreatic cancer, so facilitating a return to a healthier body weight will also mitigate future risk for cancer.
 

Sticking With Our Cornerstone Therapy, For Now

In conclusion, I do not believe that semaglutide is the “new statin.” Statins are the cornerstone of primary and secondary prevention of CVD in a wide range of comorbidities, as evidenced in multiple large and high-quality trials dating back over 30 years.

However, there is no doubt that the GLP-1 receptor agonist class is the most significant therapeutic advance for the management of obesity and comorbidities to date. 

The SELECT CVOT data uniquely position semaglutide as a secondary CVD prevention agent on top of guideline-driven management for people living with overweight/obesity and established CVD. Additionally, the clinically meaningful weight loss achieved with semaglutide will impact the risk of developing many other cardiometabolic conditions, as well as improve mental health and overall quality of life.

Dr. Fernando, GP Partner, North Berwick Health Centre, North Berwick, Scotland, creates concise clinical aide-mémoire for primary and secondary care to make life easier for health care professionals and ultimately to improve the lives of patients. He is very active on social media (X handle @drkevinfernando), where he posts hot topics in type 2 diabetes and CVRM. He recently has forayed into YouTube (@DrKevinFernando) and TikTok (@drkevinfernando) with patient-facing video content. Dr. Fernando has been elected to Fellowship of the Royal College of General Practitioners, the Royal College of Physicians of Edinburgh, and the Academy of Medical Educators for his work in diabetes and medical education. He has disclosed the following relevant financial relationships: Serve(d) as a speaker or a member of a speakers bureau for AstraZeneca; Boehringer Ingelheim; Lilly; Menarini; Bayer; Dexcom; Novartis; Novo Nordisk; Amgen; and Daiichi Sankyo; received income in an amount equal to or greater than $250 from AstraZeneca; Boehringer Ingelheim; Lilly; Menarini; Bayer; Dexcom; Novartis; Novo Nordisk; Amgen; and Daiichi Sankyo.

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

There has been much hyperbole since the presentation of results from the SELECT cardiovascular outcomes trial (CVOT) at this year’s European Congress on Obesity, which led many to herald semaglutide as the “new statin.”

In the SELECT CVOT, participants with overweight or obesity (body mass index [BMI] ≥ 27), established cardiovascular disease (CVD), and no history of type 2 diabetes were administered the injectable glucagon-like peptide 1 (GLP-1) receptor agonist semaglutide (Wegovy) at a 2.4-mg dose weekly. Treatment resulted in a significant 20% relative risk reduction in major adverse CV events (a composite endpoint comprising CV death, nonfatal myocardial infarction, or nonfatal stroke). Importantly, SELECT was a trial on secondary prevention of CVD. 

The CV benefits of semaglutide were notably independent of baseline weight or amount of weight lost. This suggests that the underlying driver of improved CV outcomes with semaglutide extends beyond simple reduction in obesity and perhaps indicates a direct effect on vasculature and reduction in atherosclerosis, although this remains unproven.
 

Not All Risk Reduction Is Equal 

Much of the sensationalist coverage in the lay press focused on the 20% relative risk reduction figure. This endpoint is often more impressive and headline-grabbing than the absolute risk reduction, which provides a clearer view of a treatment’s real-world impact.

In SELECT, the absolute risk reduction was 1.5 percentage points, which translated into a number needed to treat (NNT) of 67 over 34 months to prevent one primary outcome of a major adverse CV event.

Lower NNTs suggest more effective treatments because fewer people need to be treated to prevent one clinical event, such as the major adverse CV events used in SELECT.
 

Semaglutide vs Statins

How does the clinical effectiveness observed in the SELECT trial compare with that observed in statin trials when it comes to the secondary prevention of CVD?

The seminal 4S study published in 1994 explored the impact of simvastatin on all-cause mortality among people with previous myocardial infarction or angina and hyperlipidemia (mean baseline BMI, 26). After 5.4 years of follow-up, the trial was stopped early owing to a 3.3-percentage point absolute risk reduction in all-cause mortality (NNT, 30; relative risk reduction, 28%). The NNT to prevent one death from CV causes was 31, and the NNT to prevent one major coronary event was lower, at 15.

Other statin secondary prevention trials, such as the LIPID and MIRACL studies, demonstrated similarly low NNTs.

So, you can see that the NNTs for statins in secondary prevention are much lower than with semaglutide in SELECT. Furthermore, the benefits of semaglutide in preventing CVD in people living with overweight/obesity have yet to be elucidated. 

In contrast, we already have published evidence showing the benefits of statins in the primary prevention of CVD, albeit with higher and more variable NNTs than in the statin secondary prevention studies. 

The benefits of statins are also postulated to extend beyond their impact on lowering low-density lipoprotein cholesterol. Statins have been suggested to have anti-inflammatory and plaque-stabilizing effects, among other pleiotropic benefits.

We also currently lack evidence for the cost-effectiveness of semaglutide for CV risk reduction. Assessing economic viability and use in health care systems, such as the UK’s National Health Service, involves comparing the cost of semaglutide against the health care savings from prevented CV events. Health economic studies are vital to determine whether the benefits justify the expense. In contrast, the cost-effectiveness of statins is well established, particularly for high-risk individuals.
 

Advantages of GLP-1s Should Not Be Overlooked

Of course, statins don’t provide the significant weight loss benefits of semaglutide. 

Additional data from SELECT presented at the 2024 European Congress on Obesity demonstrated that participants lost a mean of 10.2% body weight and 7.7 cm from their waist circumference after 4 years. Moreover, after 2 years, 12% of individuals randomized to semaglutide had returned to a normal BMI, and nearly half were no longer living with obesity.

Although the CV benefits of semaglutide were independent of weight reduction, this level of weight loss is clinically meaningful and will reduce the risk of many other cardiometabolic conditions including type 2 diabetes, metabolic dysfunction–associated steatotic liver disease, and obstructive sleep apnea/hypopnea syndrome, as well as improve low mood, depression, and overall quality of life. Additionally, obesity is now a risk factor for 13 different types of cancer, including bowel, breast, and pancreatic cancer, so facilitating a return to a healthier body weight will also mitigate future risk for cancer.
 

Sticking With Our Cornerstone Therapy, For Now

In conclusion, I do not believe that semaglutide is the “new statin.” Statins are the cornerstone of primary and secondary prevention of CVD in a wide range of comorbidities, as evidenced in multiple large and high-quality trials dating back over 30 years.

However, there is no doubt that the GLP-1 receptor agonist class is the most significant therapeutic advance for the management of obesity and comorbidities to date. 

The SELECT CVOT data uniquely position semaglutide as a secondary CVD prevention agent on top of guideline-driven management for people living with overweight/obesity and established CVD. Additionally, the clinically meaningful weight loss achieved with semaglutide will impact the risk of developing many other cardiometabolic conditions, as well as improve mental health and overall quality of life.

Dr. Fernando, GP Partner, North Berwick Health Centre, North Berwick, Scotland, creates concise clinical aide-mémoire for primary and secondary care to make life easier for health care professionals and ultimately to improve the lives of patients. He is very active on social media (X handle @drkevinfernando), where he posts hot topics in type 2 diabetes and CVRM. He recently has forayed into YouTube (@DrKevinFernando) and TikTok (@drkevinfernando) with patient-facing video content. Dr. Fernando has been elected to Fellowship of the Royal College of General Practitioners, the Royal College of Physicians of Edinburgh, and the Academy of Medical Educators for his work in diabetes and medical education. He has disclosed the following relevant financial relationships: Serve(d) as a speaker or a member of a speakers bureau for AstraZeneca; Boehringer Ingelheim; Lilly; Menarini; Bayer; Dexcom; Novartis; Novo Nordisk; Amgen; and Daiichi Sankyo; received income in an amount equal to or greater than $250 from AstraZeneca; Boehringer Ingelheim; Lilly; Menarini; Bayer; Dexcom; Novartis; Novo Nordisk; Amgen; and Daiichi Sankyo.

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