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Akira Endo, the Father of Statins, Dies
Akira Endo, PhD, the Japanese microbiologist and biochemist known as the father of statins, died at the age of 90 on June 5. His research led to the discovery and rise of a class of drugs that revolutionized the prevention and treatment of cardiovascular diseases. This scientific journey began over half a century ago.
Inspired by Alexander Fleming
Born into a family of farmers in northern Japan, Dr. Endo was fascinated by natural sciences from a young age and showed a particular interest in fungi and molds. At the age of 10, he already knew he wanted to become a scientist.
He studied in Japan and the United States, conducting research at the Albert Einstein College of Medicine in New York City. He was struck by the high number of elderly and overweight individuals in the United States and realized the importance of developing a drug to combat cholesterol. It was upon his return to Japan, when he joined the Sankyo laboratory, that the development of statins began.
Inspired by Alexander Fleming, who discovered penicillin in the mold Penicillium, he hypothesized that fungi could produce antibiotics inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the enzyme that produces cholesterol precursors.
After a year of research on nearly 3800 strains, his team found a known substance, citrinin, that strongly inhibited HMG-CoA reductase and lowered serum cholesterol levels in rats. The research was halted because of its toxicity to the rodents’ kidneys. “Nevertheless, the experience with citrinin gave us hope and courage to quickly discover much more effective active substances,” said Dr. Endo in an article dedicated to the discovery of statins.
First Statin Discovered
In the summer of 1972, researchers discovered a second active culture broth, Penicillium citrinum Pen-51, which was isolated from a sample of rice collected in a grain store in Kyoto.
In July 1973, they isolated three active metabolites from this mold, one of which was compactin, which had structural similarities to HMG-CoA, the substrate of the HMG-CoA reductase reaction.
In 1976, they published two articles reporting the discovery and characterization of compactin (mevastatin), the first statin.
Several Setbacks
Unfortunately, when Sankyo biologists assessed the effectiveness of compactin by giving rats a diet supplemented with compactin for 7 days, no reduction in serum cholesterol was observed.
Only later did an unpublished study show that the statin significantly decreased plasma cholesterol after a month of treatment in laying hens. The hypocholesterolemic effects of compactin were then demonstrated in dogs and monkeys.
However, researchers faced a second challenge in April 1977. Microcrystalline structures were detected in the liver cells of rats that had been fed extremely high amounts of compactin (over 500 mg/kg per day for 5 weeks). Initially deemed toxic, the structures were ultimately found to be nontoxic.
A phase 2 trial began in the summer of 1979 with very encouraging preliminary results, but in August 1980, clinical development of compactin was halted, as the drug was suspected of causing lymphomas in dogs given very high doses: 100 or 200 mg/kg per day for 2 years.
This suspicion also led to the termination of trials on another statin, the closely related lovastatin, which was discovered simultaneously from different fungi by the Merck laboratory and Dr. Endo in February 1979.
First Statin Marketed
It was confirmed that the drug significantly reduced cholesterol levels and was well tolerated. No tumors were detected.
Lovastatin received approval from the Food and Drug Administration to become the first marketed statin in September 1987.
Dr. Endo received numerous awards for his work, including the Albert Lasker Award for Clinical Medical Research in 2008 and the Outstanding Achievement Award from the International Atherosclerosis Society in 2009.
This story was translated from the Medscape French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.
A version of this article appeared on Medscape.com.
Akira Endo, PhD, the Japanese microbiologist and biochemist known as the father of statins, died at the age of 90 on June 5. His research led to the discovery and rise of a class of drugs that revolutionized the prevention and treatment of cardiovascular diseases. This scientific journey began over half a century ago.
Inspired by Alexander Fleming
Born into a family of farmers in northern Japan, Dr. Endo was fascinated by natural sciences from a young age and showed a particular interest in fungi and molds. At the age of 10, he already knew he wanted to become a scientist.
He studied in Japan and the United States, conducting research at the Albert Einstein College of Medicine in New York City. He was struck by the high number of elderly and overweight individuals in the United States and realized the importance of developing a drug to combat cholesterol. It was upon his return to Japan, when he joined the Sankyo laboratory, that the development of statins began.
Inspired by Alexander Fleming, who discovered penicillin in the mold Penicillium, he hypothesized that fungi could produce antibiotics inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the enzyme that produces cholesterol precursors.
After a year of research on nearly 3800 strains, his team found a known substance, citrinin, that strongly inhibited HMG-CoA reductase and lowered serum cholesterol levels in rats. The research was halted because of its toxicity to the rodents’ kidneys. “Nevertheless, the experience with citrinin gave us hope and courage to quickly discover much more effective active substances,” said Dr. Endo in an article dedicated to the discovery of statins.
First Statin Discovered
In the summer of 1972, researchers discovered a second active culture broth, Penicillium citrinum Pen-51, which was isolated from a sample of rice collected in a grain store in Kyoto.
In July 1973, they isolated three active metabolites from this mold, one of which was compactin, which had structural similarities to HMG-CoA, the substrate of the HMG-CoA reductase reaction.
In 1976, they published two articles reporting the discovery and characterization of compactin (mevastatin), the first statin.
Several Setbacks
Unfortunately, when Sankyo biologists assessed the effectiveness of compactin by giving rats a diet supplemented with compactin for 7 days, no reduction in serum cholesterol was observed.
Only later did an unpublished study show that the statin significantly decreased plasma cholesterol after a month of treatment in laying hens. The hypocholesterolemic effects of compactin were then demonstrated in dogs and monkeys.
However, researchers faced a second challenge in April 1977. Microcrystalline structures were detected in the liver cells of rats that had been fed extremely high amounts of compactin (over 500 mg/kg per day for 5 weeks). Initially deemed toxic, the structures were ultimately found to be nontoxic.
A phase 2 trial began in the summer of 1979 with very encouraging preliminary results, but in August 1980, clinical development of compactin was halted, as the drug was suspected of causing lymphomas in dogs given very high doses: 100 or 200 mg/kg per day for 2 years.
This suspicion also led to the termination of trials on another statin, the closely related lovastatin, which was discovered simultaneously from different fungi by the Merck laboratory and Dr. Endo in February 1979.
First Statin Marketed
It was confirmed that the drug significantly reduced cholesterol levels and was well tolerated. No tumors were detected.
Lovastatin received approval from the Food and Drug Administration to become the first marketed statin in September 1987.
Dr. Endo received numerous awards for his work, including the Albert Lasker Award for Clinical Medical Research in 2008 and the Outstanding Achievement Award from the International Atherosclerosis Society in 2009.
This story was translated from the Medscape French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.
A version of this article appeared on Medscape.com.
Akira Endo, PhD, the Japanese microbiologist and biochemist known as the father of statins, died at the age of 90 on June 5. His research led to the discovery and rise of a class of drugs that revolutionized the prevention and treatment of cardiovascular diseases. This scientific journey began over half a century ago.
Inspired by Alexander Fleming
Born into a family of farmers in northern Japan, Dr. Endo was fascinated by natural sciences from a young age and showed a particular interest in fungi and molds. At the age of 10, he already knew he wanted to become a scientist.
He studied in Japan and the United States, conducting research at the Albert Einstein College of Medicine in New York City. He was struck by the high number of elderly and overweight individuals in the United States and realized the importance of developing a drug to combat cholesterol. It was upon his return to Japan, when he joined the Sankyo laboratory, that the development of statins began.
Inspired by Alexander Fleming, who discovered penicillin in the mold Penicillium, he hypothesized that fungi could produce antibiotics inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the enzyme that produces cholesterol precursors.
After a year of research on nearly 3800 strains, his team found a known substance, citrinin, that strongly inhibited HMG-CoA reductase and lowered serum cholesterol levels in rats. The research was halted because of its toxicity to the rodents’ kidneys. “Nevertheless, the experience with citrinin gave us hope and courage to quickly discover much more effective active substances,” said Dr. Endo in an article dedicated to the discovery of statins.
First Statin Discovered
In the summer of 1972, researchers discovered a second active culture broth, Penicillium citrinum Pen-51, which was isolated from a sample of rice collected in a grain store in Kyoto.
In July 1973, they isolated three active metabolites from this mold, one of which was compactin, which had structural similarities to HMG-CoA, the substrate of the HMG-CoA reductase reaction.
In 1976, they published two articles reporting the discovery and characterization of compactin (mevastatin), the first statin.
Several Setbacks
Unfortunately, when Sankyo biologists assessed the effectiveness of compactin by giving rats a diet supplemented with compactin for 7 days, no reduction in serum cholesterol was observed.
Only later did an unpublished study show that the statin significantly decreased plasma cholesterol after a month of treatment in laying hens. The hypocholesterolemic effects of compactin were then demonstrated in dogs and monkeys.
However, researchers faced a second challenge in April 1977. Microcrystalline structures were detected in the liver cells of rats that had been fed extremely high amounts of compactin (over 500 mg/kg per day for 5 weeks). Initially deemed toxic, the structures were ultimately found to be nontoxic.
A phase 2 trial began in the summer of 1979 with very encouraging preliminary results, but in August 1980, clinical development of compactin was halted, as the drug was suspected of causing lymphomas in dogs given very high doses: 100 or 200 mg/kg per day for 2 years.
This suspicion also led to the termination of trials on another statin, the closely related lovastatin, which was discovered simultaneously from different fungi by the Merck laboratory and Dr. Endo in February 1979.
First Statin Marketed
It was confirmed that the drug significantly reduced cholesterol levels and was well tolerated. No tumors were detected.
Lovastatin received approval from the Food and Drug Administration to become the first marketed statin in September 1987.
Dr. Endo received numerous awards for his work, including the Albert Lasker Award for Clinical Medical Research in 2008 and the Outstanding Achievement Award from the International Atherosclerosis Society in 2009.
This story was translated from the Medscape French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.
A version of this article appeared on Medscape.com.
Study Finds Mace Risk Remains High in Patients with Psoriasis, Dyslipidemia
Over a period of 5 years, the, even after adjusting for covariates, results from a large retrospective study showed.
“It is well-established that psoriasis is an independent risk factor for the development of MACE, with cardiometabolic risk factors being more prevalent and incident among patients with psoriasis,” the study’s first author Ana Ormaza Vera, MD, a dermatology research fellow at Eastern Virginia Medical School, Norfolk, said in an interview after the annual meeting of the Society for Investigational Dermatology, where the study was presented during a late-breaking abstract session.
Current guidelines from the joint American Academy of Dermatology/National Psoriasis Foundation and the American Academy of Cardiology/American Heart Association Task Force recommend statins, a lipid-lowering and anti-inflammatory therapy, “for patients with psoriasis who have additional risk-enhancing factors, similar to recommendations made for the general population without psoriasis,” she noted. But how the incidence of MACE differs between patients with and without psoriasis while on statin therapy “has not been explored in real-world settings,” she added.
To address this question, the researchers used real-world data from the TriNetX health research network to identify individuals aged 18-90 years with a diagnosis of both psoriasis and lipid disorders who were undergoing treatment with statins. Those with a prior history of MACE were excluded from the analysis. Patients with lipid disorders on statin therapy, but without psoriatic disease, were matched 1:1 by age, sex, race, ethnicity, common risk factors for MACE, and medications shown to reduce MACE risk. The researchers then assessed the cohorts 5 years following their first statin prescription and used the TriNetX analytics tool to calculate the odds ratio (OR) with 95% CI to evaluate the likelihood of MACE in the presence of statin therapy.
Dr. Ormaza Vera and colleagues identified 20,660 patients with psoriasis and 2,768,429 patients without psoriasis who met the criteria for analysis. After propensity score matching, each cohort included 20,660 patients with a mean age of 60 years. During the 5-year observation period, 2725 patients in the psoriasis cohort experienced MACE compared with 2203 patients in the non-psoriasis cohort (OR, 1.40; 95% CI, 1.317-1.488).
“This was an unexpected outcome that challenges the current understanding and highlights the need for further research into tailored treatments for cardiovascular risk in psoriasis patients,” Dr. Ormaza Vera told this news organization.
She acknowledged certain limitations of the study, including its retrospective design, the inherent limitations of an observational study, and the use of electronic medical record data.
Lawrence J. Green, MD, clinical professor of dermatology, George Washington University, Washington, who was asked to comment on the study results, said that the findings imply that there is more than statin use alone to protect someone with psoriasis from having an increased risk for MACE. “This is not really surprising because statin use alone is only part of a prevention strategy in someone with psoriasis who usually has multiple comorbidities,” Dr. Green said. “On the other hand, the study only went out for 5 years and cardiovascular disease is a long accumulating process, so it could also be too early to demonstrate MACE prevention.”
The study was funded by a grant from the American Skin Association. Dr. Ormaza Vera and her coauthors reported having no relevant disclosures. Dr. Green disclosed that he is a speaker, consultant, or investigator for many pharmaceutical companies.
A version of this article appeared on Medscape.com .
Over a period of 5 years, the, even after adjusting for covariates, results from a large retrospective study showed.
“It is well-established that psoriasis is an independent risk factor for the development of MACE, with cardiometabolic risk factors being more prevalent and incident among patients with psoriasis,” the study’s first author Ana Ormaza Vera, MD, a dermatology research fellow at Eastern Virginia Medical School, Norfolk, said in an interview after the annual meeting of the Society for Investigational Dermatology, where the study was presented during a late-breaking abstract session.
Current guidelines from the joint American Academy of Dermatology/National Psoriasis Foundation and the American Academy of Cardiology/American Heart Association Task Force recommend statins, a lipid-lowering and anti-inflammatory therapy, “for patients with psoriasis who have additional risk-enhancing factors, similar to recommendations made for the general population without psoriasis,” she noted. But how the incidence of MACE differs between patients with and without psoriasis while on statin therapy “has not been explored in real-world settings,” she added.
To address this question, the researchers used real-world data from the TriNetX health research network to identify individuals aged 18-90 years with a diagnosis of both psoriasis and lipid disorders who were undergoing treatment with statins. Those with a prior history of MACE were excluded from the analysis. Patients with lipid disorders on statin therapy, but without psoriatic disease, were matched 1:1 by age, sex, race, ethnicity, common risk factors for MACE, and medications shown to reduce MACE risk. The researchers then assessed the cohorts 5 years following their first statin prescription and used the TriNetX analytics tool to calculate the odds ratio (OR) with 95% CI to evaluate the likelihood of MACE in the presence of statin therapy.
Dr. Ormaza Vera and colleagues identified 20,660 patients with psoriasis and 2,768,429 patients without psoriasis who met the criteria for analysis. After propensity score matching, each cohort included 20,660 patients with a mean age of 60 years. During the 5-year observation period, 2725 patients in the psoriasis cohort experienced MACE compared with 2203 patients in the non-psoriasis cohort (OR, 1.40; 95% CI, 1.317-1.488).
“This was an unexpected outcome that challenges the current understanding and highlights the need for further research into tailored treatments for cardiovascular risk in psoriasis patients,” Dr. Ormaza Vera told this news organization.
She acknowledged certain limitations of the study, including its retrospective design, the inherent limitations of an observational study, and the use of electronic medical record data.
Lawrence J. Green, MD, clinical professor of dermatology, George Washington University, Washington, who was asked to comment on the study results, said that the findings imply that there is more than statin use alone to protect someone with psoriasis from having an increased risk for MACE. “This is not really surprising because statin use alone is only part of a prevention strategy in someone with psoriasis who usually has multiple comorbidities,” Dr. Green said. “On the other hand, the study only went out for 5 years and cardiovascular disease is a long accumulating process, so it could also be too early to demonstrate MACE prevention.”
The study was funded by a grant from the American Skin Association. Dr. Ormaza Vera and her coauthors reported having no relevant disclosures. Dr. Green disclosed that he is a speaker, consultant, or investigator for many pharmaceutical companies.
A version of this article appeared on Medscape.com .
Over a period of 5 years, the, even after adjusting for covariates, results from a large retrospective study showed.
“It is well-established that psoriasis is an independent risk factor for the development of MACE, with cardiometabolic risk factors being more prevalent and incident among patients with psoriasis,” the study’s first author Ana Ormaza Vera, MD, a dermatology research fellow at Eastern Virginia Medical School, Norfolk, said in an interview after the annual meeting of the Society for Investigational Dermatology, where the study was presented during a late-breaking abstract session.
Current guidelines from the joint American Academy of Dermatology/National Psoriasis Foundation and the American Academy of Cardiology/American Heart Association Task Force recommend statins, a lipid-lowering and anti-inflammatory therapy, “for patients with psoriasis who have additional risk-enhancing factors, similar to recommendations made for the general population without psoriasis,” she noted. But how the incidence of MACE differs between patients with and without psoriasis while on statin therapy “has not been explored in real-world settings,” she added.
To address this question, the researchers used real-world data from the TriNetX health research network to identify individuals aged 18-90 years with a diagnosis of both psoriasis and lipid disorders who were undergoing treatment with statins. Those with a prior history of MACE were excluded from the analysis. Patients with lipid disorders on statin therapy, but without psoriatic disease, were matched 1:1 by age, sex, race, ethnicity, common risk factors for MACE, and medications shown to reduce MACE risk. The researchers then assessed the cohorts 5 years following their first statin prescription and used the TriNetX analytics tool to calculate the odds ratio (OR) with 95% CI to evaluate the likelihood of MACE in the presence of statin therapy.
Dr. Ormaza Vera and colleagues identified 20,660 patients with psoriasis and 2,768,429 patients without psoriasis who met the criteria for analysis. After propensity score matching, each cohort included 20,660 patients with a mean age of 60 years. During the 5-year observation period, 2725 patients in the psoriasis cohort experienced MACE compared with 2203 patients in the non-psoriasis cohort (OR, 1.40; 95% CI, 1.317-1.488).
“This was an unexpected outcome that challenges the current understanding and highlights the need for further research into tailored treatments for cardiovascular risk in psoriasis patients,” Dr. Ormaza Vera told this news organization.
She acknowledged certain limitations of the study, including its retrospective design, the inherent limitations of an observational study, and the use of electronic medical record data.
Lawrence J. Green, MD, clinical professor of dermatology, George Washington University, Washington, who was asked to comment on the study results, said that the findings imply that there is more than statin use alone to protect someone with psoriasis from having an increased risk for MACE. “This is not really surprising because statin use alone is only part of a prevention strategy in someone with psoriasis who usually has multiple comorbidities,” Dr. Green said. “On the other hand, the study only went out for 5 years and cardiovascular disease is a long accumulating process, so it could also be too early to demonstrate MACE prevention.”
The study was funded by a grant from the American Skin Association. Dr. Ormaza Vera and her coauthors reported having no relevant disclosures. Dr. Green disclosed that he is a speaker, consultant, or investigator for many pharmaceutical companies.
A version of this article appeared on Medscape.com .
FROM SID 2024
Another Reason to Control Lp(a): To Protect the Kidneys Too
LYON, FRANCE — High levels of lipoprotein(a) [Lp(a)] in the blood are associated with a significantly increased risk for chronic kidney disease, report investigators who are studying the link in a two-part study of more than 100,000 people.
There is already genetic evidence showing that Lp(a) can cause cardiovascular conditions, including myocardial infarction, aortic valve stenosis, peripheral artery disease, and ischemic stroke.
Now, researchers presenting at the European Atherosclerosis Society (EAS) 2024 Congress are adding new organs – the kidneys – to the list of those that can be damaged by elevated Lp(a).
“This is very important,” said lead investigator Anne Langsted, MD, PhD, DMSc, from the Department of Clinical Biochemistry at the Rigshospitalet in Denmark. And “hopefully, we’ll have a treatment for Lp(a) on the market very soon. Until then, I think individuals who have kidney disease would benefit a lot from reducing other risk factors, if they also have high levels” of Lp(a).
Using data gathered from the Copenhagen General Population Study, the study involved 108,439 individuals who had a range of tests including estimated glomerular filtration rate (eGFR), plasma Lp(a) levels, and LPA genotyping. The patients were then linked to a series of national registries to study outcomes.
The researchers conducted two separate analyses: an observational study of Lp(a) levels in 70,040 individuals and a Mendelian randomization study of LPA kringle IV–type 2 domain repeats in 106,624 individuals. The number of those repeats is inversely associated with median Lp(a) plasma levels.
The observational study showed that eGFR decreased with increasing median plasma Lp(a) levels; the Mendelian randomization study indicated that eGFR decreased KIV-2 repeat numbers dropped.
Across both parts of the study, it was found that each 50 mg/dL increase in plasma Lp(a) levels was associated with an increased risk of at least 25% for chronic kidney disease.
Lp(a) and Chronic Kidney Disease
When high plasma levels of Lp(a) have been spotted before in patients with kidney disease, “we’ve kind of assumed that it was probably the kidney disease that caused the higher levels,” Dr. Langsted said. But her team hypothesized that the opposite was at play and that Lp(a) levels are genetically determined, and increased plasma Lp(a) levels may be causally associated with rising risk for chronic kidney disease.
Gerald F. Watts, MD, PhD, DSc, Winthrop Professor of cardiometabolic and internal medicine at the University of Western Australia in Perth, and co-chair of the study, said in an interview that “although Mendelian randomization is a technique that allows you to infer causality, it’s probably a little bit more complex than that in reality,” adding that there is likely a bidirectional relationship between Lp(a) and chronic kidney disease.
Having increased Lp(a) levels on their own is not sufficient to trigger chronic kidney disease. “You probably need another event and then you get into a vicious cycle,” Dr. Watts said.
The mechanism linking Lp(a) with chronic kidney disease remains unclear, but Dr. Watts explained that the lipoprotein probably damages the renal tubes when it is reabsorbed after it dissociates from low-density lipoprotein cholesterol.
The next step will be to identify the people who are most susceptible to this and figure out what treatment might help. Dr. Watts suggested that gene silencing, in which Lp(a) is “completely obliterated,” will lead to an improvement in renal function.
A version of this article appeared on Medscape.com.
LYON, FRANCE — High levels of lipoprotein(a) [Lp(a)] in the blood are associated with a significantly increased risk for chronic kidney disease, report investigators who are studying the link in a two-part study of more than 100,000 people.
There is already genetic evidence showing that Lp(a) can cause cardiovascular conditions, including myocardial infarction, aortic valve stenosis, peripheral artery disease, and ischemic stroke.
Now, researchers presenting at the European Atherosclerosis Society (EAS) 2024 Congress are adding new organs – the kidneys – to the list of those that can be damaged by elevated Lp(a).
“This is very important,” said lead investigator Anne Langsted, MD, PhD, DMSc, from the Department of Clinical Biochemistry at the Rigshospitalet in Denmark. And “hopefully, we’ll have a treatment for Lp(a) on the market very soon. Until then, I think individuals who have kidney disease would benefit a lot from reducing other risk factors, if they also have high levels” of Lp(a).
Using data gathered from the Copenhagen General Population Study, the study involved 108,439 individuals who had a range of tests including estimated glomerular filtration rate (eGFR), plasma Lp(a) levels, and LPA genotyping. The patients were then linked to a series of national registries to study outcomes.
The researchers conducted two separate analyses: an observational study of Lp(a) levels in 70,040 individuals and a Mendelian randomization study of LPA kringle IV–type 2 domain repeats in 106,624 individuals. The number of those repeats is inversely associated with median Lp(a) plasma levels.
The observational study showed that eGFR decreased with increasing median plasma Lp(a) levels; the Mendelian randomization study indicated that eGFR decreased KIV-2 repeat numbers dropped.
Across both parts of the study, it was found that each 50 mg/dL increase in plasma Lp(a) levels was associated with an increased risk of at least 25% for chronic kidney disease.
Lp(a) and Chronic Kidney Disease
When high plasma levels of Lp(a) have been spotted before in patients with kidney disease, “we’ve kind of assumed that it was probably the kidney disease that caused the higher levels,” Dr. Langsted said. But her team hypothesized that the opposite was at play and that Lp(a) levels are genetically determined, and increased plasma Lp(a) levels may be causally associated with rising risk for chronic kidney disease.
Gerald F. Watts, MD, PhD, DSc, Winthrop Professor of cardiometabolic and internal medicine at the University of Western Australia in Perth, and co-chair of the study, said in an interview that “although Mendelian randomization is a technique that allows you to infer causality, it’s probably a little bit more complex than that in reality,” adding that there is likely a bidirectional relationship between Lp(a) and chronic kidney disease.
Having increased Lp(a) levels on their own is not sufficient to trigger chronic kidney disease. “You probably need another event and then you get into a vicious cycle,” Dr. Watts said.
The mechanism linking Lp(a) with chronic kidney disease remains unclear, but Dr. Watts explained that the lipoprotein probably damages the renal tubes when it is reabsorbed after it dissociates from low-density lipoprotein cholesterol.
The next step will be to identify the people who are most susceptible to this and figure out what treatment might help. Dr. Watts suggested that gene silencing, in which Lp(a) is “completely obliterated,” will lead to an improvement in renal function.
A version of this article appeared on Medscape.com.
LYON, FRANCE — High levels of lipoprotein(a) [Lp(a)] in the blood are associated with a significantly increased risk for chronic kidney disease, report investigators who are studying the link in a two-part study of more than 100,000 people.
There is already genetic evidence showing that Lp(a) can cause cardiovascular conditions, including myocardial infarction, aortic valve stenosis, peripheral artery disease, and ischemic stroke.
Now, researchers presenting at the European Atherosclerosis Society (EAS) 2024 Congress are adding new organs – the kidneys – to the list of those that can be damaged by elevated Lp(a).
“This is very important,” said lead investigator Anne Langsted, MD, PhD, DMSc, from the Department of Clinical Biochemistry at the Rigshospitalet in Denmark. And “hopefully, we’ll have a treatment for Lp(a) on the market very soon. Until then, I think individuals who have kidney disease would benefit a lot from reducing other risk factors, if they also have high levels” of Lp(a).
Using data gathered from the Copenhagen General Population Study, the study involved 108,439 individuals who had a range of tests including estimated glomerular filtration rate (eGFR), plasma Lp(a) levels, and LPA genotyping. The patients were then linked to a series of national registries to study outcomes.
The researchers conducted two separate analyses: an observational study of Lp(a) levels in 70,040 individuals and a Mendelian randomization study of LPA kringle IV–type 2 domain repeats in 106,624 individuals. The number of those repeats is inversely associated with median Lp(a) plasma levels.
The observational study showed that eGFR decreased with increasing median plasma Lp(a) levels; the Mendelian randomization study indicated that eGFR decreased KIV-2 repeat numbers dropped.
Across both parts of the study, it was found that each 50 mg/dL increase in plasma Lp(a) levels was associated with an increased risk of at least 25% for chronic kidney disease.
Lp(a) and Chronic Kidney Disease
When high plasma levels of Lp(a) have been spotted before in patients with kidney disease, “we’ve kind of assumed that it was probably the kidney disease that caused the higher levels,” Dr. Langsted said. But her team hypothesized that the opposite was at play and that Lp(a) levels are genetically determined, and increased plasma Lp(a) levels may be causally associated with rising risk for chronic kidney disease.
Gerald F. Watts, MD, PhD, DSc, Winthrop Professor of cardiometabolic and internal medicine at the University of Western Australia in Perth, and co-chair of the study, said in an interview that “although Mendelian randomization is a technique that allows you to infer causality, it’s probably a little bit more complex than that in reality,” adding that there is likely a bidirectional relationship between Lp(a) and chronic kidney disease.
Having increased Lp(a) levels on their own is not sufficient to trigger chronic kidney disease. “You probably need another event and then you get into a vicious cycle,” Dr. Watts said.
The mechanism linking Lp(a) with chronic kidney disease remains unclear, but Dr. Watts explained that the lipoprotein probably damages the renal tubes when it is reabsorbed after it dissociates from low-density lipoprotein cholesterol.
The next step will be to identify the people who are most susceptible to this and figure out what treatment might help. Dr. Watts suggested that gene silencing, in which Lp(a) is “completely obliterated,” will lead to an improvement in renal function.
A version of this article appeared on Medscape.com.
Counting Steps or Watching the Clock for a Longer Life?
Exercise recommendations typically focus on the duration of physical activity. For example, the World Health Organization advises at least 150 minutes of moderate physical activity per week. A new analysis of data from the Women’s Health Study, published in JAMA Internal Medicine, suggested that step count could also be a useful metric. For some, such a recommendation might be easier to follow.
“It’s not so easy to keep track of how long you’ve been moderately active in a given week,” Cary P. Gross, MD, from the Department of Medicine at Yale University in New Haven, Connecticut, wrote in an editorial. “Counting steps might be easier for some people, especially since most carry a phone that can serve as a pedometer.”
The 10,000-Step Recommendation
However, there are no well-founded recommendations for step counts, partly due to a lack of scientific evidence linking steps with mortality and cardiovascular diseases. The often-cited 10,000 steps per day originated from a marketing campaign in Japan in the 1960s.
The research team led by Rikuta Hamaya, MD, from the Division of Preventive Medicine at Brigham and Women’s Hospital in Boston, analyzed data from participants in the Women’s Health Study. This clinical trial in the United States from 1992 to 2004 investigated the use of aspirin and vitamin E for cancer and cardiovascular disease prevention.
The current analysis included 14,399 women who were aged ≥ 62 years and had not developed cardiovascular disease or cancer. Between 2011 and 2015, they measured their physical activity and step count over 7 days using an accelerometer. They were followed-up for an average of 9 years.
Risk Reduction With Both Parameters
Moderate physical activity among the participants amounted to a median of 62 minutes per week, with a median daily step count of 5183. Hamaya and his colleagues found that both physical activity parameters were associated with lower mortality and reduced risk for cardiovascular diseases.
Participants who engaged in more than the recommended 150 minutes of moderate-intensity activity per week had a 32% lower mortality risk than those who were the least physically active. Women with > 7000 steps per day had a 42% lower mortality risk than those with the lowest daily step count.
Women in the top three quartiles of physical activity outlived those in the lowest quartile by an average of 2.22 months (time) or 2.36 months (steps), according to Hamaya and his team. The survival advantage was independent of body mass index.
For the endpoint of cardiovascular diseases (heart attack, stroke, and cardiovascular mortality), the researchers observed similar results as for mortality.
More Ways to Reach the Goal
Dr. Hamaya emphasized the importance of offering multiple ways to meet exercise recommendations: “For some, especially younger people, physical activity includes sports like tennis, soccer, walking, or jogging. All these can be tracked well with step counting. But for others, activity means cycling or swimming, which is easier to measure by duration.”
For Dr. Gross, the new findings provide a basis for using step counts to set physical activity goals — both in individual patient counseling and in formal guidelines. However, he stressed that further studies are necessary.
“The results need to be replicated in various populations, not just among men and younger people but also among ethnic minorities and lower-income populations, who often have less time and space for structured physical activity.”
This story was translated from Medscape German edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
Exercise recommendations typically focus on the duration of physical activity. For example, the World Health Organization advises at least 150 minutes of moderate physical activity per week. A new analysis of data from the Women’s Health Study, published in JAMA Internal Medicine, suggested that step count could also be a useful metric. For some, such a recommendation might be easier to follow.
“It’s not so easy to keep track of how long you’ve been moderately active in a given week,” Cary P. Gross, MD, from the Department of Medicine at Yale University in New Haven, Connecticut, wrote in an editorial. “Counting steps might be easier for some people, especially since most carry a phone that can serve as a pedometer.”
The 10,000-Step Recommendation
However, there are no well-founded recommendations for step counts, partly due to a lack of scientific evidence linking steps with mortality and cardiovascular diseases. The often-cited 10,000 steps per day originated from a marketing campaign in Japan in the 1960s.
The research team led by Rikuta Hamaya, MD, from the Division of Preventive Medicine at Brigham and Women’s Hospital in Boston, analyzed data from participants in the Women’s Health Study. This clinical trial in the United States from 1992 to 2004 investigated the use of aspirin and vitamin E for cancer and cardiovascular disease prevention.
The current analysis included 14,399 women who were aged ≥ 62 years and had not developed cardiovascular disease or cancer. Between 2011 and 2015, they measured their physical activity and step count over 7 days using an accelerometer. They were followed-up for an average of 9 years.
Risk Reduction With Both Parameters
Moderate physical activity among the participants amounted to a median of 62 minutes per week, with a median daily step count of 5183. Hamaya and his colleagues found that both physical activity parameters were associated with lower mortality and reduced risk for cardiovascular diseases.
Participants who engaged in more than the recommended 150 minutes of moderate-intensity activity per week had a 32% lower mortality risk than those who were the least physically active. Women with > 7000 steps per day had a 42% lower mortality risk than those with the lowest daily step count.
Women in the top three quartiles of physical activity outlived those in the lowest quartile by an average of 2.22 months (time) or 2.36 months (steps), according to Hamaya and his team. The survival advantage was independent of body mass index.
For the endpoint of cardiovascular diseases (heart attack, stroke, and cardiovascular mortality), the researchers observed similar results as for mortality.
More Ways to Reach the Goal
Dr. Hamaya emphasized the importance of offering multiple ways to meet exercise recommendations: “For some, especially younger people, physical activity includes sports like tennis, soccer, walking, or jogging. All these can be tracked well with step counting. But for others, activity means cycling or swimming, which is easier to measure by duration.”
For Dr. Gross, the new findings provide a basis for using step counts to set physical activity goals — both in individual patient counseling and in formal guidelines. However, he stressed that further studies are necessary.
“The results need to be replicated in various populations, not just among men and younger people but also among ethnic minorities and lower-income populations, who often have less time and space for structured physical activity.”
This story was translated from Medscape German edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
Exercise recommendations typically focus on the duration of physical activity. For example, the World Health Organization advises at least 150 minutes of moderate physical activity per week. A new analysis of data from the Women’s Health Study, published in JAMA Internal Medicine, suggested that step count could also be a useful metric. For some, such a recommendation might be easier to follow.
“It’s not so easy to keep track of how long you’ve been moderately active in a given week,” Cary P. Gross, MD, from the Department of Medicine at Yale University in New Haven, Connecticut, wrote in an editorial. “Counting steps might be easier for some people, especially since most carry a phone that can serve as a pedometer.”
The 10,000-Step Recommendation
However, there are no well-founded recommendations for step counts, partly due to a lack of scientific evidence linking steps with mortality and cardiovascular diseases. The often-cited 10,000 steps per day originated from a marketing campaign in Japan in the 1960s.
The research team led by Rikuta Hamaya, MD, from the Division of Preventive Medicine at Brigham and Women’s Hospital in Boston, analyzed data from participants in the Women’s Health Study. This clinical trial in the United States from 1992 to 2004 investigated the use of aspirin and vitamin E for cancer and cardiovascular disease prevention.
The current analysis included 14,399 women who were aged ≥ 62 years and had not developed cardiovascular disease or cancer. Between 2011 and 2015, they measured their physical activity and step count over 7 days using an accelerometer. They were followed-up for an average of 9 years.
Risk Reduction With Both Parameters
Moderate physical activity among the participants amounted to a median of 62 minutes per week, with a median daily step count of 5183. Hamaya and his colleagues found that both physical activity parameters were associated with lower mortality and reduced risk for cardiovascular diseases.
Participants who engaged in more than the recommended 150 minutes of moderate-intensity activity per week had a 32% lower mortality risk than those who were the least physically active. Women with > 7000 steps per day had a 42% lower mortality risk than those with the lowest daily step count.
Women in the top three quartiles of physical activity outlived those in the lowest quartile by an average of 2.22 months (time) or 2.36 months (steps), according to Hamaya and his team. The survival advantage was independent of body mass index.
For the endpoint of cardiovascular diseases (heart attack, stroke, and cardiovascular mortality), the researchers observed similar results as for mortality.
More Ways to Reach the Goal
Dr. Hamaya emphasized the importance of offering multiple ways to meet exercise recommendations: “For some, especially younger people, physical activity includes sports like tennis, soccer, walking, or jogging. All these can be tracked well with step counting. But for others, activity means cycling or swimming, which is easier to measure by duration.”
For Dr. Gross, the new findings provide a basis for using step counts to set physical activity goals — both in individual patient counseling and in formal guidelines. However, he stressed that further studies are necessary.
“The results need to be replicated in various populations, not just among men and younger people but also among ethnic minorities and lower-income populations, who often have less time and space for structured physical activity.”
This story was translated from Medscape German edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
Discussing a Silent Problem: Communicating Effectively About Lipid Risks and Management
This transcript has been edited for clarity.
Jorge Plutzky, MD: Hi. I'm Dr Jorge Plutzky, director of preventive cardiology at the Brigham and Women's Hospital, and in that setting I direct our lipid clinic. I'm pleased to be here today to talk about how we communicate about cholesterol. And I'm pleased to be able to do that today with a patient of mine, Brian McMahon.
Brian, thank you for being here.
Brian McMahon: Thank you, Doctor.
Plutzky: Why don't you tell people listening how we came to connect in the first place.
McMahon: Well, it was around statins. I had been prescribed one probably 10 years ago, and I had an adverse reaction to it — a violent reaction. And the doctor just told me to stop taking it. So I did. And I never asked another question.
And then 10 years later, my GP in Connecticut said, "You should go get a calcium score exam. Insurance doesn't cover it. It's 90 bucks, and it'll be the best 90 bucks you ever spent." And then the numbers were not good. That led me to come and talk to you about what do I do now? What are my options? I had an adverse reaction to statins. I didn't think I could even take them.
Plutzky: That's so important. Really, the failure was in your physician not getting that initial follow-up: Okay, so you had this reaction; what are the potential explanations for that, and what could be the next steps?
It really should not fall upon you as a patient to have to push that. But in fact, when people are better educated about the issues in our system, sometimes you do have to be your own advocate and ask, "What's next?" And it's important for us in communicating these issues during that first encounter, which might be with a primary care physician or a cardiologist, but more often it's with a primary care physician.
We're more motivated when someone's already had an event — secondary prevention. Let's not have another one because the patient has now been through something scary: a heart attack or a stent or even bypass surgery or a stroke. Those really motivate people. But even in that setting, we often find that patients don't necessarily stay on treatment or don't necessarily get treated aggressively enough to the right LDL level.
So that becomes important to set the stage early about why we are doing this, and let's come up with options that are safe, usually well tolerated, and have been extensively studied.
McMahon: I think the key is that it is a silent killer, so you don't feel bad, you don't have a rash, you don't have a scratch. It's not painful, but it could kill you. But the very fact that it's just that the statin doesn't agree with you — that was a real mess, in my estimation.
Plutzky: Often in settings of primary prevention, you're trying to conjure up the future for someone, saying, "You know what? If we don't do something, we're going to run into issues." But those patients don't feel bad. You're right that it is silent, but that's where the huge opportunity exists: early intervention — identifying what that risk is and how many different options we have, like if someone doesn't succeed on or has an issue with a statin. We know that's uncommon, but people often do well with some of these other alternatives, including just a different statin, which was the case with you.
McMahon: Right. And I had no idea that that was even available to me. That was an eye-opener, that there are options available to me, that I can find different things that work; but for goodness' sake, you should be on it.
Plutzky: Yes, we often have patients do well on a statin. Some patients really can't take a statin.
We'll go through a couple different options. I often will lay out for people who think they're having an issue with the statin that there are three possibilities: One, it's not the statin, because in the clinical trials we see people who quit the placebo as often as they quit the statin. Sharing that with patients matters. It's possible that what one felt wasn't even related to the statin. Two, sometimes reactions are statin specific. We try a different statin and then someone does well. Sometimes that may be influenced by the fact that we've laid out the data and explained to a patient, "We know that statins are safe, effective, and well tolerated, and here's the benefit for you down the road."
Is that part of why that second statin now works? It's hard to know. I've had many physician patients who say, "I didn't feel great on that one, but now I'm on a different statin and I'm feeling, much better." So, everyone reacts differently.
McMahon: I love that you walked me into it too. It wasn't just, "Here's 20 mg. We started at 5 mg, then we went to 10 mg, now we're at 20 mg." You took the time to say, "I hear you and I heard what happened to you. So, let's walk into this." I lost 10 years of taking statins, which would have put me in a different place.
Plutzky: The fact is that the first dose of the statin has the biggest impact on reducing your LDL. And then as you titrate it up, which we do all the time — we have with you — the effect on the lowering of LDL is less impactful. That's why it can be a way in with people to say, "Let's start with this low dose." At least they're on something. And people often say, "Wow! I really feel completely fine on this." There are people who either just can't take a statin at all or who, once they're on the statin, aren't getting to a low enough or appropriate LDL number, and it's good to have those alternatives.
One of them is specifically theoretically designed for people who think they've had muscle issues with statin. Your issues were different, but bempedoic acid is an alternative. And even going beyond that, we now have injectable medicines that really are very effective at bringing down LDL.
When people hear injections, they're like, "Oh my gosh, I don't want to take an injection," but explain to people how easy it is to do those injections. It's basically just a pen against your skin. That really reduces their fear and their anxiety. But it's important to realize that we do have many tools for lowering LDL. If someone runs into a problem with the statin that you can't overcome, then it's important to move on.
So we should recognize how important it is to lower LDL. Realizing how many tools we have allows people to begin working through the process where the objective is: I want to get my LDL down, and if we can do it with a statin, then we're taking advantage of all this data we have about their benefits. But if that turns out not to work for a given patient, even after trying and explaining things, then let's move on. But let's get to that ultimate goal of lowering LDL as one component of risk.
I think there's nothing more empowering for the person you're dealing with than to share with them what it is that you know; that you know, based upon medical science and clinical trials, what that rationale is, because no one is trying to hurt themselves. If someone comes in who doesn't want to take a statin, it's not because they're trying to have a heart attack. They're not trying to hurt themselves. There's some barrier to what's motivating them, to what's keeping them from this therapy. We just have to better communicate what the goal is and what the basis is for pursuing this, and then finding your way through the woods of saying, "Well, that worked great and we've made it" vs "We've run into something, so let's go on a different path."
McMahon: I think that to me was the light-bulb moment, which was that experience with statin: Don't take it anymore. And then 10 years go by and now I'm in trouble. And then I find out that there is a wealth of opportunities. There are so many arrows in your quiver — not to make a Cupid joke, but there are so many arrows available to fix this, and I didn't know it. Now I do.
Plutzky: Yes, it's empowering. I think there's a challenge for us as caregivers to more broadly share what we know so that people are motivated and empowered to say, "I want to get treated. I want to do better. And I understand the extent to which this is a risk for me if I don't do better."
McMahon: Right.
Plutzky: So often there's a family history associated with that, too. Sometimes when I'm communicating with patients the idea of "You need to do this," especially patients with young kids, I'm communicating, "How you eat and your activity level is sending a very powerful message to your kids."
McMahon: Yes.
Plutzky: We're trying to eat healthy. We're more oriented toward vegetables. We're being active. Let's go for a walk. Let's go for a family run. Let's have a sport that we do together. Or even just the kids seeing you leave the house to say, "I'm off." "Where are you going, Dad?" "I'm going to play tennis." "Can I come with you?" And then…
McMahon: It creates a lifestyle.
Plutzky: Yes.
McMahon: Well, it comes back to: You have one heart.
Plutzky: Yes. Well, it's been a pleasure to have a chance to discuss what are really important topics. I mean, this is really impactful. Far beyond just your experience, it's the chance for other people to realize that these are issues that need to be recognized, dealt with; that people need to be empowered; and that ultimately it comes down to us about how to better communicate.
I'm always very focused on how can a patient know what I know and what I think matters based upon evidence, data, clinical trials. How do we share that and share that in very limited time windows? It's been a privilege to work with you, Brian, in a clinical setting, and I'm very appreciative of your taking the time to join us today.
McMahon: Thank you for getting me on the right path. I'm grateful.
Plutzky: Well, you've done that for yourself. Good talking to you.
McMahon: Likewise.
Jorge Plutzky, MD, has disclosed the following relevant financial relationships:
Serve(d) as a consultant for: Altimmune; Boehringer Ingelheim; Esperion; New Amsterdam; Novo Nordisk
Received research grant from: Boehringer Ingelheim; Novartis
Serve(d) on clinical trial committee for: Esperion; Novo Nordisk
Brian McMahon has disclosed no relevant financial relationships.
This transcript has been edited for clarity.
Jorge Plutzky, MD: Hi. I'm Dr Jorge Plutzky, director of preventive cardiology at the Brigham and Women's Hospital, and in that setting I direct our lipid clinic. I'm pleased to be here today to talk about how we communicate about cholesterol. And I'm pleased to be able to do that today with a patient of mine, Brian McMahon.
Brian, thank you for being here.
Brian McMahon: Thank you, Doctor.
Plutzky: Why don't you tell people listening how we came to connect in the first place.
McMahon: Well, it was around statins. I had been prescribed one probably 10 years ago, and I had an adverse reaction to it — a violent reaction. And the doctor just told me to stop taking it. So I did. And I never asked another question.
And then 10 years later, my GP in Connecticut said, "You should go get a calcium score exam. Insurance doesn't cover it. It's 90 bucks, and it'll be the best 90 bucks you ever spent." And then the numbers were not good. That led me to come and talk to you about what do I do now? What are my options? I had an adverse reaction to statins. I didn't think I could even take them.
Plutzky: That's so important. Really, the failure was in your physician not getting that initial follow-up: Okay, so you had this reaction; what are the potential explanations for that, and what could be the next steps?
It really should not fall upon you as a patient to have to push that. But in fact, when people are better educated about the issues in our system, sometimes you do have to be your own advocate and ask, "What's next?" And it's important for us in communicating these issues during that first encounter, which might be with a primary care physician or a cardiologist, but more often it's with a primary care physician.
We're more motivated when someone's already had an event — secondary prevention. Let's not have another one because the patient has now been through something scary: a heart attack or a stent or even bypass surgery or a stroke. Those really motivate people. But even in that setting, we often find that patients don't necessarily stay on treatment or don't necessarily get treated aggressively enough to the right LDL level.
So that becomes important to set the stage early about why we are doing this, and let's come up with options that are safe, usually well tolerated, and have been extensively studied.
McMahon: I think the key is that it is a silent killer, so you don't feel bad, you don't have a rash, you don't have a scratch. It's not painful, but it could kill you. But the very fact that it's just that the statin doesn't agree with you — that was a real mess, in my estimation.
Plutzky: Often in settings of primary prevention, you're trying to conjure up the future for someone, saying, "You know what? If we don't do something, we're going to run into issues." But those patients don't feel bad. You're right that it is silent, but that's where the huge opportunity exists: early intervention — identifying what that risk is and how many different options we have, like if someone doesn't succeed on or has an issue with a statin. We know that's uncommon, but people often do well with some of these other alternatives, including just a different statin, which was the case with you.
McMahon: Right. And I had no idea that that was even available to me. That was an eye-opener, that there are options available to me, that I can find different things that work; but for goodness' sake, you should be on it.
Plutzky: Yes, we often have patients do well on a statin. Some patients really can't take a statin.
We'll go through a couple different options. I often will lay out for people who think they're having an issue with the statin that there are three possibilities: One, it's not the statin, because in the clinical trials we see people who quit the placebo as often as they quit the statin. Sharing that with patients matters. It's possible that what one felt wasn't even related to the statin. Two, sometimes reactions are statin specific. We try a different statin and then someone does well. Sometimes that may be influenced by the fact that we've laid out the data and explained to a patient, "We know that statins are safe, effective, and well tolerated, and here's the benefit for you down the road."
Is that part of why that second statin now works? It's hard to know. I've had many physician patients who say, "I didn't feel great on that one, but now I'm on a different statin and I'm feeling, much better." So, everyone reacts differently.
McMahon: I love that you walked me into it too. It wasn't just, "Here's 20 mg. We started at 5 mg, then we went to 10 mg, now we're at 20 mg." You took the time to say, "I hear you and I heard what happened to you. So, let's walk into this." I lost 10 years of taking statins, which would have put me in a different place.
Plutzky: The fact is that the first dose of the statin has the biggest impact on reducing your LDL. And then as you titrate it up, which we do all the time — we have with you — the effect on the lowering of LDL is less impactful. That's why it can be a way in with people to say, "Let's start with this low dose." At least they're on something. And people often say, "Wow! I really feel completely fine on this." There are people who either just can't take a statin at all or who, once they're on the statin, aren't getting to a low enough or appropriate LDL number, and it's good to have those alternatives.
One of them is specifically theoretically designed for people who think they've had muscle issues with statin. Your issues were different, but bempedoic acid is an alternative. And even going beyond that, we now have injectable medicines that really are very effective at bringing down LDL.
When people hear injections, they're like, "Oh my gosh, I don't want to take an injection," but explain to people how easy it is to do those injections. It's basically just a pen against your skin. That really reduces their fear and their anxiety. But it's important to realize that we do have many tools for lowering LDL. If someone runs into a problem with the statin that you can't overcome, then it's important to move on.
So we should recognize how important it is to lower LDL. Realizing how many tools we have allows people to begin working through the process where the objective is: I want to get my LDL down, and if we can do it with a statin, then we're taking advantage of all this data we have about their benefits. But if that turns out not to work for a given patient, even after trying and explaining things, then let's move on. But let's get to that ultimate goal of lowering LDL as one component of risk.
I think there's nothing more empowering for the person you're dealing with than to share with them what it is that you know; that you know, based upon medical science and clinical trials, what that rationale is, because no one is trying to hurt themselves. If someone comes in who doesn't want to take a statin, it's not because they're trying to have a heart attack. They're not trying to hurt themselves. There's some barrier to what's motivating them, to what's keeping them from this therapy. We just have to better communicate what the goal is and what the basis is for pursuing this, and then finding your way through the woods of saying, "Well, that worked great and we've made it" vs "We've run into something, so let's go on a different path."
McMahon: I think that to me was the light-bulb moment, which was that experience with statin: Don't take it anymore. And then 10 years go by and now I'm in trouble. And then I find out that there is a wealth of opportunities. There are so many arrows in your quiver — not to make a Cupid joke, but there are so many arrows available to fix this, and I didn't know it. Now I do.
Plutzky: Yes, it's empowering. I think there's a challenge for us as caregivers to more broadly share what we know so that people are motivated and empowered to say, "I want to get treated. I want to do better. And I understand the extent to which this is a risk for me if I don't do better."
McMahon: Right.
Plutzky: So often there's a family history associated with that, too. Sometimes when I'm communicating with patients the idea of "You need to do this," especially patients with young kids, I'm communicating, "How you eat and your activity level is sending a very powerful message to your kids."
McMahon: Yes.
Plutzky: We're trying to eat healthy. We're more oriented toward vegetables. We're being active. Let's go for a walk. Let's go for a family run. Let's have a sport that we do together. Or even just the kids seeing you leave the house to say, "I'm off." "Where are you going, Dad?" "I'm going to play tennis." "Can I come with you?" And then…
McMahon: It creates a lifestyle.
Plutzky: Yes.
McMahon: Well, it comes back to: You have one heart.
Plutzky: Yes. Well, it's been a pleasure to have a chance to discuss what are really important topics. I mean, this is really impactful. Far beyond just your experience, it's the chance for other people to realize that these are issues that need to be recognized, dealt with; that people need to be empowered; and that ultimately it comes down to us about how to better communicate.
I'm always very focused on how can a patient know what I know and what I think matters based upon evidence, data, clinical trials. How do we share that and share that in very limited time windows? It's been a privilege to work with you, Brian, in a clinical setting, and I'm very appreciative of your taking the time to join us today.
McMahon: Thank you for getting me on the right path. I'm grateful.
Plutzky: Well, you've done that for yourself. Good talking to you.
McMahon: Likewise.
Jorge Plutzky, MD, has disclosed the following relevant financial relationships:
Serve(d) as a consultant for: Altimmune; Boehringer Ingelheim; Esperion; New Amsterdam; Novo Nordisk
Received research grant from: Boehringer Ingelheim; Novartis
Serve(d) on clinical trial committee for: Esperion; Novo Nordisk
Brian McMahon has disclosed no relevant financial relationships.
This transcript has been edited for clarity.
Jorge Plutzky, MD: Hi. I'm Dr Jorge Plutzky, director of preventive cardiology at the Brigham and Women's Hospital, and in that setting I direct our lipid clinic. I'm pleased to be here today to talk about how we communicate about cholesterol. And I'm pleased to be able to do that today with a patient of mine, Brian McMahon.
Brian, thank you for being here.
Brian McMahon: Thank you, Doctor.
Plutzky: Why don't you tell people listening how we came to connect in the first place.
McMahon: Well, it was around statins. I had been prescribed one probably 10 years ago, and I had an adverse reaction to it — a violent reaction. And the doctor just told me to stop taking it. So I did. And I never asked another question.
And then 10 years later, my GP in Connecticut said, "You should go get a calcium score exam. Insurance doesn't cover it. It's 90 bucks, and it'll be the best 90 bucks you ever spent." And then the numbers were not good. That led me to come and talk to you about what do I do now? What are my options? I had an adverse reaction to statins. I didn't think I could even take them.
Plutzky: That's so important. Really, the failure was in your physician not getting that initial follow-up: Okay, so you had this reaction; what are the potential explanations for that, and what could be the next steps?
It really should not fall upon you as a patient to have to push that. But in fact, when people are better educated about the issues in our system, sometimes you do have to be your own advocate and ask, "What's next?" And it's important for us in communicating these issues during that first encounter, which might be with a primary care physician or a cardiologist, but more often it's with a primary care physician.
We're more motivated when someone's already had an event — secondary prevention. Let's not have another one because the patient has now been through something scary: a heart attack or a stent or even bypass surgery or a stroke. Those really motivate people. But even in that setting, we often find that patients don't necessarily stay on treatment or don't necessarily get treated aggressively enough to the right LDL level.
So that becomes important to set the stage early about why we are doing this, and let's come up with options that are safe, usually well tolerated, and have been extensively studied.
McMahon: I think the key is that it is a silent killer, so you don't feel bad, you don't have a rash, you don't have a scratch. It's not painful, but it could kill you. But the very fact that it's just that the statin doesn't agree with you — that was a real mess, in my estimation.
Plutzky: Often in settings of primary prevention, you're trying to conjure up the future for someone, saying, "You know what? If we don't do something, we're going to run into issues." But those patients don't feel bad. You're right that it is silent, but that's where the huge opportunity exists: early intervention — identifying what that risk is and how many different options we have, like if someone doesn't succeed on or has an issue with a statin. We know that's uncommon, but people often do well with some of these other alternatives, including just a different statin, which was the case with you.
McMahon: Right. And I had no idea that that was even available to me. That was an eye-opener, that there are options available to me, that I can find different things that work; but for goodness' sake, you should be on it.
Plutzky: Yes, we often have patients do well on a statin. Some patients really can't take a statin.
We'll go through a couple different options. I often will lay out for people who think they're having an issue with the statin that there are three possibilities: One, it's not the statin, because in the clinical trials we see people who quit the placebo as often as they quit the statin. Sharing that with patients matters. It's possible that what one felt wasn't even related to the statin. Two, sometimes reactions are statin specific. We try a different statin and then someone does well. Sometimes that may be influenced by the fact that we've laid out the data and explained to a patient, "We know that statins are safe, effective, and well tolerated, and here's the benefit for you down the road."
Is that part of why that second statin now works? It's hard to know. I've had many physician patients who say, "I didn't feel great on that one, but now I'm on a different statin and I'm feeling, much better." So, everyone reacts differently.
McMahon: I love that you walked me into it too. It wasn't just, "Here's 20 mg. We started at 5 mg, then we went to 10 mg, now we're at 20 mg." You took the time to say, "I hear you and I heard what happened to you. So, let's walk into this." I lost 10 years of taking statins, which would have put me in a different place.
Plutzky: The fact is that the first dose of the statin has the biggest impact on reducing your LDL. And then as you titrate it up, which we do all the time — we have with you — the effect on the lowering of LDL is less impactful. That's why it can be a way in with people to say, "Let's start with this low dose." At least they're on something. And people often say, "Wow! I really feel completely fine on this." There are people who either just can't take a statin at all or who, once they're on the statin, aren't getting to a low enough or appropriate LDL number, and it's good to have those alternatives.
One of them is specifically theoretically designed for people who think they've had muscle issues with statin. Your issues were different, but bempedoic acid is an alternative. And even going beyond that, we now have injectable medicines that really are very effective at bringing down LDL.
When people hear injections, they're like, "Oh my gosh, I don't want to take an injection," but explain to people how easy it is to do those injections. It's basically just a pen against your skin. That really reduces their fear and their anxiety. But it's important to realize that we do have many tools for lowering LDL. If someone runs into a problem with the statin that you can't overcome, then it's important to move on.
So we should recognize how important it is to lower LDL. Realizing how many tools we have allows people to begin working through the process where the objective is: I want to get my LDL down, and if we can do it with a statin, then we're taking advantage of all this data we have about their benefits. But if that turns out not to work for a given patient, even after trying and explaining things, then let's move on. But let's get to that ultimate goal of lowering LDL as one component of risk.
I think there's nothing more empowering for the person you're dealing with than to share with them what it is that you know; that you know, based upon medical science and clinical trials, what that rationale is, because no one is trying to hurt themselves. If someone comes in who doesn't want to take a statin, it's not because they're trying to have a heart attack. They're not trying to hurt themselves. There's some barrier to what's motivating them, to what's keeping them from this therapy. We just have to better communicate what the goal is and what the basis is for pursuing this, and then finding your way through the woods of saying, "Well, that worked great and we've made it" vs "We've run into something, so let's go on a different path."
McMahon: I think that to me was the light-bulb moment, which was that experience with statin: Don't take it anymore. And then 10 years go by and now I'm in trouble. And then I find out that there is a wealth of opportunities. There are so many arrows in your quiver — not to make a Cupid joke, but there are so many arrows available to fix this, and I didn't know it. Now I do.
Plutzky: Yes, it's empowering. I think there's a challenge for us as caregivers to more broadly share what we know so that people are motivated and empowered to say, "I want to get treated. I want to do better. And I understand the extent to which this is a risk for me if I don't do better."
McMahon: Right.
Plutzky: So often there's a family history associated with that, too. Sometimes when I'm communicating with patients the idea of "You need to do this," especially patients with young kids, I'm communicating, "How you eat and your activity level is sending a very powerful message to your kids."
McMahon: Yes.
Plutzky: We're trying to eat healthy. We're more oriented toward vegetables. We're being active. Let's go for a walk. Let's go for a family run. Let's have a sport that we do together. Or even just the kids seeing you leave the house to say, "I'm off." "Where are you going, Dad?" "I'm going to play tennis." "Can I come with you?" And then…
McMahon: It creates a lifestyle.
Plutzky: Yes.
McMahon: Well, it comes back to: You have one heart.
Plutzky: Yes. Well, it's been a pleasure to have a chance to discuss what are really important topics. I mean, this is really impactful. Far beyond just your experience, it's the chance for other people to realize that these are issues that need to be recognized, dealt with; that people need to be empowered; and that ultimately it comes down to us about how to better communicate.
I'm always very focused on how can a patient know what I know and what I think matters based upon evidence, data, clinical trials. How do we share that and share that in very limited time windows? It's been a privilege to work with you, Brian, in a clinical setting, and I'm very appreciative of your taking the time to join us today.
McMahon: Thank you for getting me on the right path. I'm grateful.
Plutzky: Well, you've done that for yourself. Good talking to you.
McMahon: Likewise.
Jorge Plutzky, MD, has disclosed the following relevant financial relationships:
Serve(d) as a consultant for: Altimmune; Boehringer Ingelheim; Esperion; New Amsterdam; Novo Nordisk
Received research grant from: Boehringer Ingelheim; Novartis
Serve(d) on clinical trial committee for: Esperion; Novo Nordisk
Brian McMahon has disclosed no relevant financial relationships.
Roche Blood Test for Lp(a) Designated Breakthrough Device
The Tina-quant Lp(a) RxDx assay, developed by Roche in partnership with Amgen, is designed to identify adults with elevated Lp(a) levels who may benefit from lipid-lowering therapies currently in development.
Lp(a) is a type of lipoprotein that is genetically inherited. Elevated levels have been associated with an increased risk for heart disease, stroke, and other blood vessel diseases.
Worldwide, about 1 in 5 people have high Lp(a) levels that are not significantly affected by lifestyle changes, such as diet and exercise. Elevated Lp(a) is particularly prevalent among women and people of African descent.
Lp(a) testing is “an important tool for clinicians, enabling them to make a more accurate assessment of [cardiovascular] risk, and it is expected to become a part of regular diagnostic testing in the coming years,” Roche said in a news release announcing the breakthrough designation for the Lp(a) blood test.
If approved, the Tina-quant Lp(a) RxDx assay will be available on select Roche cobas platforms, the company reported.
Although low-density-lipoprotein (LDL) cholesterol particles are much more abundant than Lp(a) particles and carry the greatest overall risk for heart disease, on a per-particle basis, atherogenic risk associated with Lp(a) is about six times higher than that associated with LDL cholesterol, a recent study showed.
There currently are no approved pharmacologic therapies to lower Lp(a) levels in the United States, but several hopefuls are in development.
One is zerlasiran (Silence Therapeutics), a short interfering RNA (siRNA) agent, or “gene silencing” therapy, which binds to and temporarily blocks the action of the LPA gene, which encodes for apolipoprotein A, a dominant and rate-limiting component in the hepatic synthesis of the Lp(a) particle.
Treatment with zerlasiran produced significant and sustained reductions in Lp(a) concentrations in adults with elevated Lp(a) in the phase 1 APOLLO trial and the phase 2 ALPACAR-360 trial.
Other siRNA agents in development to lower Lp(a) levels include pelacarsen, lepodisiran, olpasiran, and muvalaplin.
A version of this article appeared on Medscape.com.
The Tina-quant Lp(a) RxDx assay, developed by Roche in partnership with Amgen, is designed to identify adults with elevated Lp(a) levels who may benefit from lipid-lowering therapies currently in development.
Lp(a) is a type of lipoprotein that is genetically inherited. Elevated levels have been associated with an increased risk for heart disease, stroke, and other blood vessel diseases.
Worldwide, about 1 in 5 people have high Lp(a) levels that are not significantly affected by lifestyle changes, such as diet and exercise. Elevated Lp(a) is particularly prevalent among women and people of African descent.
Lp(a) testing is “an important tool for clinicians, enabling them to make a more accurate assessment of [cardiovascular] risk, and it is expected to become a part of regular diagnostic testing in the coming years,” Roche said in a news release announcing the breakthrough designation for the Lp(a) blood test.
If approved, the Tina-quant Lp(a) RxDx assay will be available on select Roche cobas platforms, the company reported.
Although low-density-lipoprotein (LDL) cholesterol particles are much more abundant than Lp(a) particles and carry the greatest overall risk for heart disease, on a per-particle basis, atherogenic risk associated with Lp(a) is about six times higher than that associated with LDL cholesterol, a recent study showed.
There currently are no approved pharmacologic therapies to lower Lp(a) levels in the United States, but several hopefuls are in development.
One is zerlasiran (Silence Therapeutics), a short interfering RNA (siRNA) agent, or “gene silencing” therapy, which binds to and temporarily blocks the action of the LPA gene, which encodes for apolipoprotein A, a dominant and rate-limiting component in the hepatic synthesis of the Lp(a) particle.
Treatment with zerlasiran produced significant and sustained reductions in Lp(a) concentrations in adults with elevated Lp(a) in the phase 1 APOLLO trial and the phase 2 ALPACAR-360 trial.
Other siRNA agents in development to lower Lp(a) levels include pelacarsen, lepodisiran, olpasiran, and muvalaplin.
A version of this article appeared on Medscape.com.
The Tina-quant Lp(a) RxDx assay, developed by Roche in partnership with Amgen, is designed to identify adults with elevated Lp(a) levels who may benefit from lipid-lowering therapies currently in development.
Lp(a) is a type of lipoprotein that is genetically inherited. Elevated levels have been associated with an increased risk for heart disease, stroke, and other blood vessel diseases.
Worldwide, about 1 in 5 people have high Lp(a) levels that are not significantly affected by lifestyle changes, such as diet and exercise. Elevated Lp(a) is particularly prevalent among women and people of African descent.
Lp(a) testing is “an important tool for clinicians, enabling them to make a more accurate assessment of [cardiovascular] risk, and it is expected to become a part of regular diagnostic testing in the coming years,” Roche said in a news release announcing the breakthrough designation for the Lp(a) blood test.
If approved, the Tina-quant Lp(a) RxDx assay will be available on select Roche cobas platforms, the company reported.
Although low-density-lipoprotein (LDL) cholesterol particles are much more abundant than Lp(a) particles and carry the greatest overall risk for heart disease, on a per-particle basis, atherogenic risk associated with Lp(a) is about six times higher than that associated with LDL cholesterol, a recent study showed.
There currently are no approved pharmacologic therapies to lower Lp(a) levels in the United States, but several hopefuls are in development.
One is zerlasiran (Silence Therapeutics), a short interfering RNA (siRNA) agent, or “gene silencing” therapy, which binds to and temporarily blocks the action of the LPA gene, which encodes for apolipoprotein A, a dominant and rate-limiting component in the hepatic synthesis of the Lp(a) particle.
Treatment with zerlasiran produced significant and sustained reductions in Lp(a) concentrations in adults with elevated Lp(a) in the phase 1 APOLLO trial and the phase 2 ALPACAR-360 trial.
Other siRNA agents in development to lower Lp(a) levels include pelacarsen, lepodisiran, olpasiran, and muvalaplin.
A version of this article appeared on Medscape.com.
Statins Show ‘Remarkable’ CVD Benefit in Oldest Patients
Patients at least 75 years old saw a reduced risk of overall cardiovascular incidence with statin therapy without increased risk of severe adverse effects in a study published in Annals of Internal Medicine.
“Of note, the benefits and safety of statin therapy were consistently found in adults aged 85 years or older,” wrote the authors, led by Wanchun Xu, a PhD student with the Department of Family Medicine and Primary Care, Li Ka Shing Faculty of Medicine, The University of Hong Kong, in the Special Administrative Region, China.
Geriatrician Jerry H. Gurwitz, MD, the Dr. John Meyers Professor in Primary Care Medicine at UMass Chan Medical School in Boston, said he found the results of this trial “remarkable,” but is awaiting the results of the much-anticipated randomized, controlled PREVENTABLE trial years from now for more definitive evidence.
Little Consensus on Statins for This Age Group
Prescribing statins for primary prevention of CVD in the most senior patient groups has been controversial. There is little consensus as patients in this age group have been underrepresented in randomized controlled trials.
Major guidelines for use of statins in the primary prevention of CVD, including the US Preventive Services Task Force, exclude specific guidance for statin use in patients older than 75, citing insufficient evidence.
Ms. Xu and colleagues used territory-wide electronic health records in a sequential target trial emulation comparing matched cohorts that did or did not start statins. There were 42,680 matched person-trials in the group of patients aged 75-84 years and 5,390 matched person-trials in the 85 and older group. The average follow-up was 5.3 years and people with CVDs at baseline, such as coronary heart disease, were excluded. Patients who met indications for statin initiation from January 2008 to December 2015 were included.
Risk Reduction Seen in Both Senior Groups
Of the 42,680 matched person-trials in the 75-84 age group, 9676 developed cardiovascular disease; of the 5390 in the 85-plus group, 1600 developed CVD.
In the younger cohort, the 5-year reduced risk for overall CVD incidence when statin therapy was initiated was 1.20% (95% CI, 0.57%-1.82%) in the intention-to-treat (ITT) analysis; 5.00% (95% CI, 1.11%-8.89%) in the per protocol (PP) analysis.
Reduced risk for overall CVD incidence in the 85-and-older group when statins were initiated was 4.44% in the ITT analysis (95% CI, 1.40%-7.48%); and 12.50% in the PP analysis (95% CI, 4.33%-20.66%). There was no significantly increased risk for liver dysfunction or myopathies in either age group, the authors stated.
One of the biggest strengths of the study is the use of population-based data over a long period. One of the limitations was that the researchers were not able to measure lifestyle factors such as diet and physical activity in their analysis.
Dr. Gurwitz, who has done drug research in older adults for decades, said “the results are very compelling,” and in the oldest group “almost too compelling. Wow.”
Numbers Needed to Treat Are Strikingly Low
He noted that the authors thoroughly acknowledge limitations of the trial. But he also pointed to the impressive number needed to treat reported by the researchers.
The authors stated: “[O]n the basis of the estimated absolute risk reduction in the PP analysis, the number needed to treat [NNT] to prevent 1 CVD event in 5 years was 20 (95% CI, 11-90) in those aged 75-84 years and 8 (95% CI, 5-23) in those aged 85 years or older.”
For perspective, he said, “Sometimes you’re seeing numbers needed to treat for vaccinations of 400 to prevent one hospitalization. They are using real-world information and they are seeing this remarkable effect. If it’s that good in the real world, it’s going to be even better in a clinical trial. That’s why I have some reservations about whether it’s really that good.”
Dr. Gurwitz said, “I’m not ready to start an 87-year-old on statin therapy who hasn’t been on it before for primary prevention, despite the results of this very well done study.” He will await the findings of PREVENTABLE, which aims to enroll 20,000 people at least 75 years old to look at statin use. But in the meantime, he will discuss the Xu et al. results and other evidence with patients if they request statins and may prescribe them as part of shared decision making.
He said the question of whether to use statins in primary prevention is similar to the question of whether to use aspirin as primary prevention for CVD in older adults.
Originally, “Most of us thought, yes, it’s probably a good thing,” he said, but now “there have been a lot of deprescribing efforts to get older people off of aspirin.
“In the United States, believe it or not, 48% of people 75 and older are on statins already,” Dr. Gurwitz said. “Maybe that’s good,” he said, but added physicians won’t know for sure until PREVENTABLE results are in.
“If I didn’t already know the PREVENTABLE trial was going on, and it was never going to happen, I would find this [Xu et al. study] very influential,” Dr. Gurwitz said. “I’m willing to wait.”
The study was funded by the Health and Medical Research Fund, Health Bureau, the Government of Hong Kong Special Administrative Region, China, and the National Natural Science Foundation of China. Coauthors reported grants from the Kerry Group Kuok Foundation, the Malaysian College of Family Physicians, and the International Association of Chinese Nephrologists in Hong Kong. Dr. Gurwitz reported no relevant financial relationships.
Patients at least 75 years old saw a reduced risk of overall cardiovascular incidence with statin therapy without increased risk of severe adverse effects in a study published in Annals of Internal Medicine.
“Of note, the benefits and safety of statin therapy were consistently found in adults aged 85 years or older,” wrote the authors, led by Wanchun Xu, a PhD student with the Department of Family Medicine and Primary Care, Li Ka Shing Faculty of Medicine, The University of Hong Kong, in the Special Administrative Region, China.
Geriatrician Jerry H. Gurwitz, MD, the Dr. John Meyers Professor in Primary Care Medicine at UMass Chan Medical School in Boston, said he found the results of this trial “remarkable,” but is awaiting the results of the much-anticipated randomized, controlled PREVENTABLE trial years from now for more definitive evidence.
Little Consensus on Statins for This Age Group
Prescribing statins for primary prevention of CVD in the most senior patient groups has been controversial. There is little consensus as patients in this age group have been underrepresented in randomized controlled trials.
Major guidelines for use of statins in the primary prevention of CVD, including the US Preventive Services Task Force, exclude specific guidance for statin use in patients older than 75, citing insufficient evidence.
Ms. Xu and colleagues used territory-wide electronic health records in a sequential target trial emulation comparing matched cohorts that did or did not start statins. There were 42,680 matched person-trials in the group of patients aged 75-84 years and 5,390 matched person-trials in the 85 and older group. The average follow-up was 5.3 years and people with CVDs at baseline, such as coronary heart disease, were excluded. Patients who met indications for statin initiation from January 2008 to December 2015 were included.
Risk Reduction Seen in Both Senior Groups
Of the 42,680 matched person-trials in the 75-84 age group, 9676 developed cardiovascular disease; of the 5390 in the 85-plus group, 1600 developed CVD.
In the younger cohort, the 5-year reduced risk for overall CVD incidence when statin therapy was initiated was 1.20% (95% CI, 0.57%-1.82%) in the intention-to-treat (ITT) analysis; 5.00% (95% CI, 1.11%-8.89%) in the per protocol (PP) analysis.
Reduced risk for overall CVD incidence in the 85-and-older group when statins were initiated was 4.44% in the ITT analysis (95% CI, 1.40%-7.48%); and 12.50% in the PP analysis (95% CI, 4.33%-20.66%). There was no significantly increased risk for liver dysfunction or myopathies in either age group, the authors stated.
One of the biggest strengths of the study is the use of population-based data over a long period. One of the limitations was that the researchers were not able to measure lifestyle factors such as diet and physical activity in their analysis.
Dr. Gurwitz, who has done drug research in older adults for decades, said “the results are very compelling,” and in the oldest group “almost too compelling. Wow.”
Numbers Needed to Treat Are Strikingly Low
He noted that the authors thoroughly acknowledge limitations of the trial. But he also pointed to the impressive number needed to treat reported by the researchers.
The authors stated: “[O]n the basis of the estimated absolute risk reduction in the PP analysis, the number needed to treat [NNT] to prevent 1 CVD event in 5 years was 20 (95% CI, 11-90) in those aged 75-84 years and 8 (95% CI, 5-23) in those aged 85 years or older.”
For perspective, he said, “Sometimes you’re seeing numbers needed to treat for vaccinations of 400 to prevent one hospitalization. They are using real-world information and they are seeing this remarkable effect. If it’s that good in the real world, it’s going to be even better in a clinical trial. That’s why I have some reservations about whether it’s really that good.”
Dr. Gurwitz said, “I’m not ready to start an 87-year-old on statin therapy who hasn’t been on it before for primary prevention, despite the results of this very well done study.” He will await the findings of PREVENTABLE, which aims to enroll 20,000 people at least 75 years old to look at statin use. But in the meantime, he will discuss the Xu et al. results and other evidence with patients if they request statins and may prescribe them as part of shared decision making.
He said the question of whether to use statins in primary prevention is similar to the question of whether to use aspirin as primary prevention for CVD in older adults.
Originally, “Most of us thought, yes, it’s probably a good thing,” he said, but now “there have been a lot of deprescribing efforts to get older people off of aspirin.
“In the United States, believe it or not, 48% of people 75 and older are on statins already,” Dr. Gurwitz said. “Maybe that’s good,” he said, but added physicians won’t know for sure until PREVENTABLE results are in.
“If I didn’t already know the PREVENTABLE trial was going on, and it was never going to happen, I would find this [Xu et al. study] very influential,” Dr. Gurwitz said. “I’m willing to wait.”
The study was funded by the Health and Medical Research Fund, Health Bureau, the Government of Hong Kong Special Administrative Region, China, and the National Natural Science Foundation of China. Coauthors reported grants from the Kerry Group Kuok Foundation, the Malaysian College of Family Physicians, and the International Association of Chinese Nephrologists in Hong Kong. Dr. Gurwitz reported no relevant financial relationships.
Patients at least 75 years old saw a reduced risk of overall cardiovascular incidence with statin therapy without increased risk of severe adverse effects in a study published in Annals of Internal Medicine.
“Of note, the benefits and safety of statin therapy were consistently found in adults aged 85 years or older,” wrote the authors, led by Wanchun Xu, a PhD student with the Department of Family Medicine and Primary Care, Li Ka Shing Faculty of Medicine, The University of Hong Kong, in the Special Administrative Region, China.
Geriatrician Jerry H. Gurwitz, MD, the Dr. John Meyers Professor in Primary Care Medicine at UMass Chan Medical School in Boston, said he found the results of this trial “remarkable,” but is awaiting the results of the much-anticipated randomized, controlled PREVENTABLE trial years from now for more definitive evidence.
Little Consensus on Statins for This Age Group
Prescribing statins for primary prevention of CVD in the most senior patient groups has been controversial. There is little consensus as patients in this age group have been underrepresented in randomized controlled trials.
Major guidelines for use of statins in the primary prevention of CVD, including the US Preventive Services Task Force, exclude specific guidance for statin use in patients older than 75, citing insufficient evidence.
Ms. Xu and colleagues used territory-wide electronic health records in a sequential target trial emulation comparing matched cohorts that did or did not start statins. There were 42,680 matched person-trials in the group of patients aged 75-84 years and 5,390 matched person-trials in the 85 and older group. The average follow-up was 5.3 years and people with CVDs at baseline, such as coronary heart disease, were excluded. Patients who met indications for statin initiation from January 2008 to December 2015 were included.
Risk Reduction Seen in Both Senior Groups
Of the 42,680 matched person-trials in the 75-84 age group, 9676 developed cardiovascular disease; of the 5390 in the 85-plus group, 1600 developed CVD.
In the younger cohort, the 5-year reduced risk for overall CVD incidence when statin therapy was initiated was 1.20% (95% CI, 0.57%-1.82%) in the intention-to-treat (ITT) analysis; 5.00% (95% CI, 1.11%-8.89%) in the per protocol (PP) analysis.
Reduced risk for overall CVD incidence in the 85-and-older group when statins were initiated was 4.44% in the ITT analysis (95% CI, 1.40%-7.48%); and 12.50% in the PP analysis (95% CI, 4.33%-20.66%). There was no significantly increased risk for liver dysfunction or myopathies in either age group, the authors stated.
One of the biggest strengths of the study is the use of population-based data over a long period. One of the limitations was that the researchers were not able to measure lifestyle factors such as diet and physical activity in their analysis.
Dr. Gurwitz, who has done drug research in older adults for decades, said “the results are very compelling,” and in the oldest group “almost too compelling. Wow.”
Numbers Needed to Treat Are Strikingly Low
He noted that the authors thoroughly acknowledge limitations of the trial. But he also pointed to the impressive number needed to treat reported by the researchers.
The authors stated: “[O]n the basis of the estimated absolute risk reduction in the PP analysis, the number needed to treat [NNT] to prevent 1 CVD event in 5 years was 20 (95% CI, 11-90) in those aged 75-84 years and 8 (95% CI, 5-23) in those aged 85 years or older.”
For perspective, he said, “Sometimes you’re seeing numbers needed to treat for vaccinations of 400 to prevent one hospitalization. They are using real-world information and they are seeing this remarkable effect. If it’s that good in the real world, it’s going to be even better in a clinical trial. That’s why I have some reservations about whether it’s really that good.”
Dr. Gurwitz said, “I’m not ready to start an 87-year-old on statin therapy who hasn’t been on it before for primary prevention, despite the results of this very well done study.” He will await the findings of PREVENTABLE, which aims to enroll 20,000 people at least 75 years old to look at statin use. But in the meantime, he will discuss the Xu et al. results and other evidence with patients if they request statins and may prescribe them as part of shared decision making.
He said the question of whether to use statins in primary prevention is similar to the question of whether to use aspirin as primary prevention for CVD in older adults.
Originally, “Most of us thought, yes, it’s probably a good thing,” he said, but now “there have been a lot of deprescribing efforts to get older people off of aspirin.
“In the United States, believe it or not, 48% of people 75 and older are on statins already,” Dr. Gurwitz said. “Maybe that’s good,” he said, but added physicians won’t know for sure until PREVENTABLE results are in.
“If I didn’t already know the PREVENTABLE trial was going on, and it was never going to happen, I would find this [Xu et al. study] very influential,” Dr. Gurwitz said. “I’m willing to wait.”
The study was funded by the Health and Medical Research Fund, Health Bureau, the Government of Hong Kong Special Administrative Region, China, and the National Natural Science Foundation of China. Coauthors reported grants from the Kerry Group Kuok Foundation, the Malaysian College of Family Physicians, and the International Association of Chinese Nephrologists in Hong Kong. Dr. Gurwitz reported no relevant financial relationships.
FROM ANNALS OF INTERNAL MEDICINE
Statin Use May Extend Life for Early Breast Cancer Patients
Previous research examining the association between cholesterol and breast cancer metabolism suggests that cholesterol-lowering medications such as statins may improve outcomes in breast cancer patients, Sixten Harborg, a medical student and PhD student at Aarhus University, Denmark, said in a presentation at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress.
In addition, cardiovascular-related death is the second most common cause of death for breast cancer survivors, and given the survival rates in early breast cancer, there is a demand for cardioprotective initiatives and maintenance of cardioprotective drugs after diagnosis, he said in an interview.
What Is Known About Statins and Breast Cancer?
Statins are the most common drugs used to lower cholesterol and may deprive tumor cells of the cholesterol needed for cell membrane synthesis, Mr. Harborg said in his presentation.
Data from a randomized trial published in the Journal of Clinical Oncology in 2017 showed significantly improved disease-free survival, breast cancer–free interval, and distant recurrence–free interval in early stage breast cancer patients randomized to cholesterol-lowering medication vs. those who did not receive cholesterol-lowering medication.
The 2017 study prompted the creation of the MASTER study, a randomized, multicenter, double-blind, placebo-controlled trial comparing standard adjuvant therapy plus placebo to standard adjuvant therapy plus atorvastatin in patients with early breast cancer (NCT04601116), Mr. Harborg said. The MASTER trial is currently recruiting patients in Denmark.
How Was the Current Study Designed?
To provide preliminary analysis, Mr. Harborg and colleagues used an emulation trial design based on electronic health care data from 110,160 females with a diagnosis of stage I, II, or III breast cancer who were part of the Danish Breast Cancer Group, a national clinical registry in Denmark, between 2000 and 2020.
As defined in the European Journal of Epidemiology in 2017, target trial emulation involves application of randomized trial designs to observational data with the goal of improving the quality of observational epidemiology when a comparator trial is not yet available.
The researchers created a cohort of patients based on electronic health care data to simulate a target trial of the use of atorvastatin after breast cancer diagnosis. Patients were randomized to one of two treatment strategies: starting to use statins within 36 months of diagnosis, or not using statins. The primary outcome was death from breast cancer. The follow-up for the MASTER study starts with inclusion and ends with death, emigration from Denmark, end of clinical follow-up, or 10 years of follow-up (whichever comes first); the follow-up was the same in the current study.
The researchers calculated hazard ratios (HR) of breast cancer mortality in statin users vs. non–statin users and used a technique known as inverse-probability of censoring-weighting (IPCW) to estimate the effects of statin use based on prognostic factors.
What Did the Results Show?
The results favored statin use for improved survival in early breast cancer patients, Mr. Harborg said. Overall, the hazard ratio for breast cancer mortality was 0.96 in statin users compared with non–statin users, and was similar in both a Cox regression analysis (HR 0.81), and in a 10-year landmark analysis (HR 0.86).
The difference in mortality between statin and non–statin users was even stronger in patients who were receiving adjuvant chemotherapy (HR 0.94, 0.64, and 0.76 on the IPCW, Cox, and landmark analyses, respectively).
The results were in line with previous reports of statins’ effect on breast cancer survival, Mr. Harborg said in an interview.
“We believe the results encourage the continuous effort of the currently enrolling MASTER trial,” he said.
The results also suggest that deprescribing statins at the time of breast cancer diagnosis is not recommended, and that statin treatment can safely be prescribed to breast cancer patients with increased cardiovascular disease risk and/or dyslipidemia, Mr. Harborg said in the interview.
What Is the Takeaway Message for Clinical Practice?
“The clinical takeaway from our study is that statin use is associated with reduced risk of dying from breast cancer, but that it is not possible to determine the true effect of statins on breast cancer survival without a randomized, placebo-controlled trial,” Mr. Harborg told this publication. “Statins are inexpensive and well-tolerated drugs and may have a beneficial effect in terms of survival for breast cancer patients. However, with the current level of evidence [because the MASTER study is ongoing], we still cannot recommend that oncologists prescribe statins to prevent mortality from breast cancer,” he said.
What Are the Next Steps for Research?
The findings were limited by the study design, and real-world data are needed, Dr. Harborg said. Other limitations include the presence of residual bias, and the use of data based on prescription codes, but these were not considered to have an effect on the main conclusion of the study, Mr. Harborg said in the interview.
However, the results suggest that the addition of statins may improve outcomes for early breast cancer patients, especially when used with chemotherapy, and support the value of the ongoing MASTER study, he concluded.
Ultimately, the MASTER study will provide a more definitive answer to the question of whether statins should be added to the adjuvant treatment regimen of breast cancer to improve breast cancer outcomes, he said.
What Do Clinicians Think of the Study?
The current study is timely and highlights the need for phase 3 trials to examine the potential of statin use for breast cancer outcomes, Malinda T. West, MD, a medical oncologist and breast oncologist at the University of Wisconsin Carbone Cancer Center, Madison, said in an interview.
Questions for future research include whether statins can be used in combination with adjuvant abemaciclib if indicated, or how to best sequence these agents, said Dr. West, who was not involved in the study. Other questions raised by the current study include whether other cholesterol-lowering agents have a potential adjuvant benefit in reducing breast cancer recurrent and/or mortality, and whether the addition of statins would benefit subgroups such as HER2+ and triple negative breast cancer, she said.
“I was not surprised to see another study reporting benefit with statins and reduced risk of breast cancer recurrence and/or mortality, but I think the larger question is defining the subgroups who benefit the most, and identifying predictors for benefit or resistance,” Dr. West said in an interview.
Previous studies have shown that cholesterol elevation, specifically LDL levels, can be linked to increased tumor growth in breast cancer, so the lower mortality risk associated with lipid-lowering therapies in the current study was consistent, Peyton L. Reves, MD, a hematology/oncology fellow, also at the University of Wisconsin, said in an interview. In practice, data from the current study and previous research could be especially useful for patients with elevated LDL levels, said Dr. Reves, who was not involved in the study.
“These results could impact clinical practice in many ways, including leading to routine cholesterol monitoring in breast cancer patients on adjuvant therapy as well as the addition of lipid-lowering therapy with statins in these patients,” Dr. Reves said.
The findings showing particular benefit for patients on adjuvant chemotherapy highlight the need for more research on this specific population and the effect of statins on overall breast cancer mortality, to explore the extent to which the results of the current study were driven by the benefit seen in patients receiving adjuvant chemotherapy, Dr. Reves said.
The study was supported by Director Michael Hermann Nielsen’s Memorial Grant, Manufacturer Einar Willumsen’s Memorial Grant, Astrid Thaysen’s Grant for Medical Basic Research, Eva and Henry Fraenkel’s Memorial Fund, and the Novo Nordisk Foundation.
The researchers had no financial conflicts to disclose. Dr. West and Dr. Reves had no financial conflicts to disclose.
Previous research examining the association between cholesterol and breast cancer metabolism suggests that cholesterol-lowering medications such as statins may improve outcomes in breast cancer patients, Sixten Harborg, a medical student and PhD student at Aarhus University, Denmark, said in a presentation at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress.
In addition, cardiovascular-related death is the second most common cause of death for breast cancer survivors, and given the survival rates in early breast cancer, there is a demand for cardioprotective initiatives and maintenance of cardioprotective drugs after diagnosis, he said in an interview.
What Is Known About Statins and Breast Cancer?
Statins are the most common drugs used to lower cholesterol and may deprive tumor cells of the cholesterol needed for cell membrane synthesis, Mr. Harborg said in his presentation.
Data from a randomized trial published in the Journal of Clinical Oncology in 2017 showed significantly improved disease-free survival, breast cancer–free interval, and distant recurrence–free interval in early stage breast cancer patients randomized to cholesterol-lowering medication vs. those who did not receive cholesterol-lowering medication.
The 2017 study prompted the creation of the MASTER study, a randomized, multicenter, double-blind, placebo-controlled trial comparing standard adjuvant therapy plus placebo to standard adjuvant therapy plus atorvastatin in patients with early breast cancer (NCT04601116), Mr. Harborg said. The MASTER trial is currently recruiting patients in Denmark.
How Was the Current Study Designed?
To provide preliminary analysis, Mr. Harborg and colleagues used an emulation trial design based on electronic health care data from 110,160 females with a diagnosis of stage I, II, or III breast cancer who were part of the Danish Breast Cancer Group, a national clinical registry in Denmark, between 2000 and 2020.
As defined in the European Journal of Epidemiology in 2017, target trial emulation involves application of randomized trial designs to observational data with the goal of improving the quality of observational epidemiology when a comparator trial is not yet available.
The researchers created a cohort of patients based on electronic health care data to simulate a target trial of the use of atorvastatin after breast cancer diagnosis. Patients were randomized to one of two treatment strategies: starting to use statins within 36 months of diagnosis, or not using statins. The primary outcome was death from breast cancer. The follow-up for the MASTER study starts with inclusion and ends with death, emigration from Denmark, end of clinical follow-up, or 10 years of follow-up (whichever comes first); the follow-up was the same in the current study.
The researchers calculated hazard ratios (HR) of breast cancer mortality in statin users vs. non–statin users and used a technique known as inverse-probability of censoring-weighting (IPCW) to estimate the effects of statin use based on prognostic factors.
What Did the Results Show?
The results favored statin use for improved survival in early breast cancer patients, Mr. Harborg said. Overall, the hazard ratio for breast cancer mortality was 0.96 in statin users compared with non–statin users, and was similar in both a Cox regression analysis (HR 0.81), and in a 10-year landmark analysis (HR 0.86).
The difference in mortality between statin and non–statin users was even stronger in patients who were receiving adjuvant chemotherapy (HR 0.94, 0.64, and 0.76 on the IPCW, Cox, and landmark analyses, respectively).
The results were in line with previous reports of statins’ effect on breast cancer survival, Mr. Harborg said in an interview.
“We believe the results encourage the continuous effort of the currently enrolling MASTER trial,” he said.
The results also suggest that deprescribing statins at the time of breast cancer diagnosis is not recommended, and that statin treatment can safely be prescribed to breast cancer patients with increased cardiovascular disease risk and/or dyslipidemia, Mr. Harborg said in the interview.
What Is the Takeaway Message for Clinical Practice?
“The clinical takeaway from our study is that statin use is associated with reduced risk of dying from breast cancer, but that it is not possible to determine the true effect of statins on breast cancer survival without a randomized, placebo-controlled trial,” Mr. Harborg told this publication. “Statins are inexpensive and well-tolerated drugs and may have a beneficial effect in terms of survival for breast cancer patients. However, with the current level of evidence [because the MASTER study is ongoing], we still cannot recommend that oncologists prescribe statins to prevent mortality from breast cancer,” he said.
What Are the Next Steps for Research?
The findings were limited by the study design, and real-world data are needed, Dr. Harborg said. Other limitations include the presence of residual bias, and the use of data based on prescription codes, but these were not considered to have an effect on the main conclusion of the study, Mr. Harborg said in the interview.
However, the results suggest that the addition of statins may improve outcomes for early breast cancer patients, especially when used with chemotherapy, and support the value of the ongoing MASTER study, he concluded.
Ultimately, the MASTER study will provide a more definitive answer to the question of whether statins should be added to the adjuvant treatment regimen of breast cancer to improve breast cancer outcomes, he said.
What Do Clinicians Think of the Study?
The current study is timely and highlights the need for phase 3 trials to examine the potential of statin use for breast cancer outcomes, Malinda T. West, MD, a medical oncologist and breast oncologist at the University of Wisconsin Carbone Cancer Center, Madison, said in an interview.
Questions for future research include whether statins can be used in combination with adjuvant abemaciclib if indicated, or how to best sequence these agents, said Dr. West, who was not involved in the study. Other questions raised by the current study include whether other cholesterol-lowering agents have a potential adjuvant benefit in reducing breast cancer recurrent and/or mortality, and whether the addition of statins would benefit subgroups such as HER2+ and triple negative breast cancer, she said.
“I was not surprised to see another study reporting benefit with statins and reduced risk of breast cancer recurrence and/or mortality, but I think the larger question is defining the subgroups who benefit the most, and identifying predictors for benefit or resistance,” Dr. West said in an interview.
Previous studies have shown that cholesterol elevation, specifically LDL levels, can be linked to increased tumor growth in breast cancer, so the lower mortality risk associated with lipid-lowering therapies in the current study was consistent, Peyton L. Reves, MD, a hematology/oncology fellow, also at the University of Wisconsin, said in an interview. In practice, data from the current study and previous research could be especially useful for patients with elevated LDL levels, said Dr. Reves, who was not involved in the study.
“These results could impact clinical practice in many ways, including leading to routine cholesterol monitoring in breast cancer patients on adjuvant therapy as well as the addition of lipid-lowering therapy with statins in these patients,” Dr. Reves said.
The findings showing particular benefit for patients on adjuvant chemotherapy highlight the need for more research on this specific population and the effect of statins on overall breast cancer mortality, to explore the extent to which the results of the current study were driven by the benefit seen in patients receiving adjuvant chemotherapy, Dr. Reves said.
The study was supported by Director Michael Hermann Nielsen’s Memorial Grant, Manufacturer Einar Willumsen’s Memorial Grant, Astrid Thaysen’s Grant for Medical Basic Research, Eva and Henry Fraenkel’s Memorial Fund, and the Novo Nordisk Foundation.
The researchers had no financial conflicts to disclose. Dr. West and Dr. Reves had no financial conflicts to disclose.
Previous research examining the association between cholesterol and breast cancer metabolism suggests that cholesterol-lowering medications such as statins may improve outcomes in breast cancer patients, Sixten Harborg, a medical student and PhD student at Aarhus University, Denmark, said in a presentation at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress.
In addition, cardiovascular-related death is the second most common cause of death for breast cancer survivors, and given the survival rates in early breast cancer, there is a demand for cardioprotective initiatives and maintenance of cardioprotective drugs after diagnosis, he said in an interview.
What Is Known About Statins and Breast Cancer?
Statins are the most common drugs used to lower cholesterol and may deprive tumor cells of the cholesterol needed for cell membrane synthesis, Mr. Harborg said in his presentation.
Data from a randomized trial published in the Journal of Clinical Oncology in 2017 showed significantly improved disease-free survival, breast cancer–free interval, and distant recurrence–free interval in early stage breast cancer patients randomized to cholesterol-lowering medication vs. those who did not receive cholesterol-lowering medication.
The 2017 study prompted the creation of the MASTER study, a randomized, multicenter, double-blind, placebo-controlled trial comparing standard adjuvant therapy plus placebo to standard adjuvant therapy plus atorvastatin in patients with early breast cancer (NCT04601116), Mr. Harborg said. The MASTER trial is currently recruiting patients in Denmark.
How Was the Current Study Designed?
To provide preliminary analysis, Mr. Harborg and colleagues used an emulation trial design based on electronic health care data from 110,160 females with a diagnosis of stage I, II, or III breast cancer who were part of the Danish Breast Cancer Group, a national clinical registry in Denmark, between 2000 and 2020.
As defined in the European Journal of Epidemiology in 2017, target trial emulation involves application of randomized trial designs to observational data with the goal of improving the quality of observational epidemiology when a comparator trial is not yet available.
The researchers created a cohort of patients based on electronic health care data to simulate a target trial of the use of atorvastatin after breast cancer diagnosis. Patients were randomized to one of two treatment strategies: starting to use statins within 36 months of diagnosis, or not using statins. The primary outcome was death from breast cancer. The follow-up for the MASTER study starts with inclusion and ends with death, emigration from Denmark, end of clinical follow-up, or 10 years of follow-up (whichever comes first); the follow-up was the same in the current study.
The researchers calculated hazard ratios (HR) of breast cancer mortality in statin users vs. non–statin users and used a technique known as inverse-probability of censoring-weighting (IPCW) to estimate the effects of statin use based on prognostic factors.
What Did the Results Show?
The results favored statin use for improved survival in early breast cancer patients, Mr. Harborg said. Overall, the hazard ratio for breast cancer mortality was 0.96 in statin users compared with non–statin users, and was similar in both a Cox regression analysis (HR 0.81), and in a 10-year landmark analysis (HR 0.86).
The difference in mortality between statin and non–statin users was even stronger in patients who were receiving adjuvant chemotherapy (HR 0.94, 0.64, and 0.76 on the IPCW, Cox, and landmark analyses, respectively).
The results were in line with previous reports of statins’ effect on breast cancer survival, Mr. Harborg said in an interview.
“We believe the results encourage the continuous effort of the currently enrolling MASTER trial,” he said.
The results also suggest that deprescribing statins at the time of breast cancer diagnosis is not recommended, and that statin treatment can safely be prescribed to breast cancer patients with increased cardiovascular disease risk and/or dyslipidemia, Mr. Harborg said in the interview.
What Is the Takeaway Message for Clinical Practice?
“The clinical takeaway from our study is that statin use is associated with reduced risk of dying from breast cancer, but that it is not possible to determine the true effect of statins on breast cancer survival without a randomized, placebo-controlled trial,” Mr. Harborg told this publication. “Statins are inexpensive and well-tolerated drugs and may have a beneficial effect in terms of survival for breast cancer patients. However, with the current level of evidence [because the MASTER study is ongoing], we still cannot recommend that oncologists prescribe statins to prevent mortality from breast cancer,” he said.
What Are the Next Steps for Research?
The findings were limited by the study design, and real-world data are needed, Dr. Harborg said. Other limitations include the presence of residual bias, and the use of data based on prescription codes, but these were not considered to have an effect on the main conclusion of the study, Mr. Harborg said in the interview.
However, the results suggest that the addition of statins may improve outcomes for early breast cancer patients, especially when used with chemotherapy, and support the value of the ongoing MASTER study, he concluded.
Ultimately, the MASTER study will provide a more definitive answer to the question of whether statins should be added to the adjuvant treatment regimen of breast cancer to improve breast cancer outcomes, he said.
What Do Clinicians Think of the Study?
The current study is timely and highlights the need for phase 3 trials to examine the potential of statin use for breast cancer outcomes, Malinda T. West, MD, a medical oncologist and breast oncologist at the University of Wisconsin Carbone Cancer Center, Madison, said in an interview.
Questions for future research include whether statins can be used in combination with adjuvant abemaciclib if indicated, or how to best sequence these agents, said Dr. West, who was not involved in the study. Other questions raised by the current study include whether other cholesterol-lowering agents have a potential adjuvant benefit in reducing breast cancer recurrent and/or mortality, and whether the addition of statins would benefit subgroups such as HER2+ and triple negative breast cancer, she said.
“I was not surprised to see another study reporting benefit with statins and reduced risk of breast cancer recurrence and/or mortality, but I think the larger question is defining the subgroups who benefit the most, and identifying predictors for benefit or resistance,” Dr. West said in an interview.
Previous studies have shown that cholesterol elevation, specifically LDL levels, can be linked to increased tumor growth in breast cancer, so the lower mortality risk associated with lipid-lowering therapies in the current study was consistent, Peyton L. Reves, MD, a hematology/oncology fellow, also at the University of Wisconsin, said in an interview. In practice, data from the current study and previous research could be especially useful for patients with elevated LDL levels, said Dr. Reves, who was not involved in the study.
“These results could impact clinical practice in many ways, including leading to routine cholesterol monitoring in breast cancer patients on adjuvant therapy as well as the addition of lipid-lowering therapy with statins in these patients,” Dr. Reves said.
The findings showing particular benefit for patients on adjuvant chemotherapy highlight the need for more research on this specific population and the effect of statins on overall breast cancer mortality, to explore the extent to which the results of the current study were driven by the benefit seen in patients receiving adjuvant chemotherapy, Dr. Reves said.
The study was supported by Director Michael Hermann Nielsen’s Memorial Grant, Manufacturer Einar Willumsen’s Memorial Grant, Astrid Thaysen’s Grant for Medical Basic Research, Eva and Henry Fraenkel’s Memorial Fund, and the Novo Nordisk Foundation.
The researchers had no financial conflicts to disclose. Dr. West and Dr. Reves had no financial conflicts to disclose.
FROM ESMO BREAST CANCER 2024
What Health Risks Do Microplastics Pose?
The annual production of plastic worldwide has increased exponentially from about 2 million tons in 1950 to 460 million tons in 2019, and current levels are expected to triple by 2060.
Plastic contains more than 10,000 chemicals, including carcinogenic substances and endocrine disruptors. Plastic and associated chemicals are responsible for widespread pollution, contaminating aquatic (marine and freshwater), terrestrial, and atmospheric environments globally.
Atmospheric concentrations of plastic particles are on the rise, to the extent that in a remote station in the Eastern Alps in Austria, the contribution of micro- and nanoplastics (MNPs) to organic matter was comparable to data collected at an urban site.
The ocean is the ultimate destination for much of the plastic. All oceans, on the surface and in the depths, contain plastic, which is even found in polar sea ice. Many plastics seem to resist decomposition in the ocean and could persist in the environment for decades. Macro- and microplastic (MP) particles have been identified in hundreds of marine species, including species consumed by humans.
The quantity and fate of MP particles (> 10 µm) and smaller nanoplastics (< 10 µm) in aquatic environments are poorly understood, but what is most concerning is their ability to cross biologic barriers and the potential harm associated with their mobility in biologic systems.
MNP Exposure
MNPs can originate from a wide variety of sources, including food, beverages, and food product packaging. Water bottles represent a significant source of ingestible MNPs for people in their daily lives. Recent estimates, using stimulated Raman scattering imaging, documented a concentration of MNP of approximately 2.4 ± 1.3 × 105 particles per liter of bottled water. Around 90% are nanoplastics, which is two to three orders of magnitude higher than previously reported results for larger MPs.
MNPs enter the body primarily through ingestion or inhalation. For example, MNPs can be ingested by drinking liquids or eating food that has been stored or heated in plastic containers from which they have leaked or by using toothpaste that contains them. Infants are exposed to MPs from artificial milk preparation in polypropylene baby bottles, with higher levels than previously detected and ranging from 14,600 to 4,550,000 particles per capita per day.
MNP and Biologic Systems
The possible formation of hetero-aggregates between nanoplastics and natural organic matter has long been recognized as a potential challenge in the analysis of nanoplastics and can influence toxicologic results in biologic exposure. The direct visualization of such hetero-aggregates in real-world samples supports these concerns, but the analysis of MNPs with traditional techniques remains challenging. Unlike engineered nanoparticles (prepared in the laboratory as model systems), the nanoplastics in the environment are label-free and exhibit significant heterogeneity in chemical composition and morphology.
A systematic analysis of evidence on the toxic effects of MNPs on murine models, however, showed that 52.78% of biologic endpoints (related to glucose metabolism, reproduction, oxidative stress, and lipid metabolism) were significantly affected by MNP exposure.
Between Risk and Toxicity
MNP can enter the body in vivo through the digestive tract, respiratory tract, and skin contact. On average, humans could ingest from 0.1 to 5 g of MNP per week through various exposure routes.
MNPs are a potential risk factor for cardiovascular diseases, as suggested by a recent study on 257 patients with carotid atheromatous plaques. In 58.4% of cases, polyvinyl chloride was detected in the carotid artery plaque, with an average level of 5.2 ± 2.4 μg/mg of plaque. Patients with MNPs inside the atheroma had a higher risk (relative risk, 4.53) for a composite cardiovascular event of myocardial infarction, stroke, or death from any cause at 34 months of follow-up than participants where MNPs were not detectable inside the atheromatous plaque.
The potential link between inflammatory bowel disease (IBD) and MPs has been hypothesized by a study that reported a higher fecal MP concentration in patients with IBD than in healthy individuals. Fecal MP level was correlated with disease severity.
However, these studies have not demonstrated a causal relationship between MNPs and disease, and the way MNPs may influence cellular functions and induce stress responses is not yet well understood.
Future Scenarios
Current evidence confirms the fragmentation of plastic beyond the micrometer level and has unequivocally detected nanoplastics in real samples. As with many other particle distributions of the same size in the natural world, there are substantially more nanoplastics, despite their invisibility with conventional imaging techniques, than particles larger than the micron size.
The initial results of studies on MNPs in humans will stimulate future research on the amounts of MNPs that accumulate in tissue over a person’s lifetime. Researchers also will examine how the particles’ characteristics, including their chemical composition, size, and shape, can influence organs and tissues.
The way MNPs can cause harm, including through effects on the immune system and microbiome, will need to be clarified by investigating possible direct cytotoxic effects, consistent with the introductory statement of the Organization for Economic Cooperation and Development global policy forum on plastics, which states, “Plastic pollution is one of the great environmental challenges of the 21st century, causing wide-ranging damage to ecosystems and human health.”
This story was translated from Univadis Italy, which is part of the Medscape professional network, using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
The annual production of plastic worldwide has increased exponentially from about 2 million tons in 1950 to 460 million tons in 2019, and current levels are expected to triple by 2060.
Plastic contains more than 10,000 chemicals, including carcinogenic substances and endocrine disruptors. Plastic and associated chemicals are responsible for widespread pollution, contaminating aquatic (marine and freshwater), terrestrial, and atmospheric environments globally.
Atmospheric concentrations of plastic particles are on the rise, to the extent that in a remote station in the Eastern Alps in Austria, the contribution of micro- and nanoplastics (MNPs) to organic matter was comparable to data collected at an urban site.
The ocean is the ultimate destination for much of the plastic. All oceans, on the surface and in the depths, contain plastic, which is even found in polar sea ice. Many plastics seem to resist decomposition in the ocean and could persist in the environment for decades. Macro- and microplastic (MP) particles have been identified in hundreds of marine species, including species consumed by humans.
The quantity and fate of MP particles (> 10 µm) and smaller nanoplastics (< 10 µm) in aquatic environments are poorly understood, but what is most concerning is their ability to cross biologic barriers and the potential harm associated with their mobility in biologic systems.
MNP Exposure
MNPs can originate from a wide variety of sources, including food, beverages, and food product packaging. Water bottles represent a significant source of ingestible MNPs for people in their daily lives. Recent estimates, using stimulated Raman scattering imaging, documented a concentration of MNP of approximately 2.4 ± 1.3 × 105 particles per liter of bottled water. Around 90% are nanoplastics, which is two to three orders of magnitude higher than previously reported results for larger MPs.
MNPs enter the body primarily through ingestion or inhalation. For example, MNPs can be ingested by drinking liquids or eating food that has been stored or heated in plastic containers from which they have leaked or by using toothpaste that contains them. Infants are exposed to MPs from artificial milk preparation in polypropylene baby bottles, with higher levels than previously detected and ranging from 14,600 to 4,550,000 particles per capita per day.
MNP and Biologic Systems
The possible formation of hetero-aggregates between nanoplastics and natural organic matter has long been recognized as a potential challenge in the analysis of nanoplastics and can influence toxicologic results in biologic exposure. The direct visualization of such hetero-aggregates in real-world samples supports these concerns, but the analysis of MNPs with traditional techniques remains challenging. Unlike engineered nanoparticles (prepared in the laboratory as model systems), the nanoplastics in the environment are label-free and exhibit significant heterogeneity in chemical composition and morphology.
A systematic analysis of evidence on the toxic effects of MNPs on murine models, however, showed that 52.78% of biologic endpoints (related to glucose metabolism, reproduction, oxidative stress, and lipid metabolism) were significantly affected by MNP exposure.
Between Risk and Toxicity
MNP can enter the body in vivo through the digestive tract, respiratory tract, and skin contact. On average, humans could ingest from 0.1 to 5 g of MNP per week through various exposure routes.
MNPs are a potential risk factor for cardiovascular diseases, as suggested by a recent study on 257 patients with carotid atheromatous plaques. In 58.4% of cases, polyvinyl chloride was detected in the carotid artery plaque, with an average level of 5.2 ± 2.4 μg/mg of plaque. Patients with MNPs inside the atheroma had a higher risk (relative risk, 4.53) for a composite cardiovascular event of myocardial infarction, stroke, or death from any cause at 34 months of follow-up than participants where MNPs were not detectable inside the atheromatous plaque.
The potential link between inflammatory bowel disease (IBD) and MPs has been hypothesized by a study that reported a higher fecal MP concentration in patients with IBD than in healthy individuals. Fecal MP level was correlated with disease severity.
However, these studies have not demonstrated a causal relationship between MNPs and disease, and the way MNPs may influence cellular functions and induce stress responses is not yet well understood.
Future Scenarios
Current evidence confirms the fragmentation of plastic beyond the micrometer level and has unequivocally detected nanoplastics in real samples. As with many other particle distributions of the same size in the natural world, there are substantially more nanoplastics, despite their invisibility with conventional imaging techniques, than particles larger than the micron size.
The initial results of studies on MNPs in humans will stimulate future research on the amounts of MNPs that accumulate in tissue over a person’s lifetime. Researchers also will examine how the particles’ characteristics, including their chemical composition, size, and shape, can influence organs and tissues.
The way MNPs can cause harm, including through effects on the immune system and microbiome, will need to be clarified by investigating possible direct cytotoxic effects, consistent with the introductory statement of the Organization for Economic Cooperation and Development global policy forum on plastics, which states, “Plastic pollution is one of the great environmental challenges of the 21st century, causing wide-ranging damage to ecosystems and human health.”
This story was translated from Univadis Italy, which is part of the Medscape professional network, using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
The annual production of plastic worldwide has increased exponentially from about 2 million tons in 1950 to 460 million tons in 2019, and current levels are expected to triple by 2060.
Plastic contains more than 10,000 chemicals, including carcinogenic substances and endocrine disruptors. Plastic and associated chemicals are responsible for widespread pollution, contaminating aquatic (marine and freshwater), terrestrial, and atmospheric environments globally.
Atmospheric concentrations of plastic particles are on the rise, to the extent that in a remote station in the Eastern Alps in Austria, the contribution of micro- and nanoplastics (MNPs) to organic matter was comparable to data collected at an urban site.
The ocean is the ultimate destination for much of the plastic. All oceans, on the surface and in the depths, contain plastic, which is even found in polar sea ice. Many plastics seem to resist decomposition in the ocean and could persist in the environment for decades. Macro- and microplastic (MP) particles have been identified in hundreds of marine species, including species consumed by humans.
The quantity and fate of MP particles (> 10 µm) and smaller nanoplastics (< 10 µm) in aquatic environments are poorly understood, but what is most concerning is their ability to cross biologic barriers and the potential harm associated with their mobility in biologic systems.
MNP Exposure
MNPs can originate from a wide variety of sources, including food, beverages, and food product packaging. Water bottles represent a significant source of ingestible MNPs for people in their daily lives. Recent estimates, using stimulated Raman scattering imaging, documented a concentration of MNP of approximately 2.4 ± 1.3 × 105 particles per liter of bottled water. Around 90% are nanoplastics, which is two to three orders of magnitude higher than previously reported results for larger MPs.
MNPs enter the body primarily through ingestion or inhalation. For example, MNPs can be ingested by drinking liquids or eating food that has been stored or heated in plastic containers from which they have leaked or by using toothpaste that contains them. Infants are exposed to MPs from artificial milk preparation in polypropylene baby bottles, with higher levels than previously detected and ranging from 14,600 to 4,550,000 particles per capita per day.
MNP and Biologic Systems
The possible formation of hetero-aggregates between nanoplastics and natural organic matter has long been recognized as a potential challenge in the analysis of nanoplastics and can influence toxicologic results in biologic exposure. The direct visualization of such hetero-aggregates in real-world samples supports these concerns, but the analysis of MNPs with traditional techniques remains challenging. Unlike engineered nanoparticles (prepared in the laboratory as model systems), the nanoplastics in the environment are label-free and exhibit significant heterogeneity in chemical composition and morphology.
A systematic analysis of evidence on the toxic effects of MNPs on murine models, however, showed that 52.78% of biologic endpoints (related to glucose metabolism, reproduction, oxidative stress, and lipid metabolism) were significantly affected by MNP exposure.
Between Risk and Toxicity
MNP can enter the body in vivo through the digestive tract, respiratory tract, and skin contact. On average, humans could ingest from 0.1 to 5 g of MNP per week through various exposure routes.
MNPs are a potential risk factor for cardiovascular diseases, as suggested by a recent study on 257 patients with carotid atheromatous plaques. In 58.4% of cases, polyvinyl chloride was detected in the carotid artery plaque, with an average level of 5.2 ± 2.4 μg/mg of plaque. Patients with MNPs inside the atheroma had a higher risk (relative risk, 4.53) for a composite cardiovascular event of myocardial infarction, stroke, or death from any cause at 34 months of follow-up than participants where MNPs were not detectable inside the atheromatous plaque.
The potential link between inflammatory bowel disease (IBD) and MPs has been hypothesized by a study that reported a higher fecal MP concentration in patients with IBD than in healthy individuals. Fecal MP level was correlated with disease severity.
However, these studies have not demonstrated a causal relationship between MNPs and disease, and the way MNPs may influence cellular functions and induce stress responses is not yet well understood.
Future Scenarios
Current evidence confirms the fragmentation of plastic beyond the micrometer level and has unequivocally detected nanoplastics in real samples. As with many other particle distributions of the same size in the natural world, there are substantially more nanoplastics, despite their invisibility with conventional imaging techniques, than particles larger than the micron size.
The initial results of studies on MNPs in humans will stimulate future research on the amounts of MNPs that accumulate in tissue over a person’s lifetime. Researchers also will examine how the particles’ characteristics, including their chemical composition, size, and shape, can influence organs and tissues.
The way MNPs can cause harm, including through effects on the immune system and microbiome, will need to be clarified by investigating possible direct cytotoxic effects, consistent with the introductory statement of the Organization for Economic Cooperation and Development global policy forum on plastics, which states, “Plastic pollution is one of the great environmental challenges of the 21st century, causing wide-ranging damage to ecosystems and human health.”
This story was translated from Univadis Italy, which is part of the Medscape professional network, using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
Is Red Meat Healthy? Multiverse Analysis Has Lessons Beyond Meat
Observational studies on red meat consumption and lifespan are prime examples of attempts to find signal in a sea of noise.
Randomized controlled trials are the best way to sort cause from mere correlation. But these are not possible in most matters of food consumption. So, we look back and observe groups with different exposures.
My most frequent complaint about these nonrandom comparison studies has been the chance that the two groups differ in important ways, and it’s these differences — not the food in question — that account for the disparate outcomes.
But selection biases are only one issue. There is also the matter of analytic flexibility. Observational studies are born from large databases. Researchers have many choices in how to analyze all these data.
A few years ago, Brian Nosek, PhD, and colleagues elegantly showed that analytic choices can affect results. His Many Analysts, One Data Set study had little uptake in the medical community, perhaps because he studied a social science question.
Multiple Ways to Slice the Data
Recently, a group from McMaster University, led by Dena Zeraatkar, PhD, has confirmed the analytic choices problem, using the question of red meat consumption and mortality.
Their idea was simple: Because there are many plausible and defensible ways to analyze a dataset, we should not choose one method; rather, we should choose thousands, combine the results, and see where the truth lies.
You might wonder how there could be thousands of ways to analyze a dataset. I surely did.
The answer stems from the choices that researchers face. For instance, there is the selection of eligible participants, the choice of analytic model (logistic, Poisson, etc.), and covariates for which to adjust. Think exponents when combining possible choices.
Dr. Zeraatkar and colleagues are research methodologists, so, sadly, they are comfortable with the clunky name of this approach: specification curve analysis. Don’t be deterred. It means that they analyze the data in thousands of ways using computers. Each way is a specification. In the end, the specifications give rise to a curve of hazard ratios for red meat and mortality. Another name for this approach is multiverse analysis.
For their paper in the Journal of Clinical Epidemiology, aptly named “Grilling the Data,” they didn’t just conjure up the many analytic ways to study the red meat–mortality question. Instead, they used a published systematic review of 15 studies on unprocessed red meat and early mortality. The studies included in this review reported 70 unique ways to analyze the association.
Is Red Meat Good or Bad?
Their first finding was that this analysis yielded widely disparate effect estimates, from 0.63 (reduced risk for early death) to 2.31 (a higher risk). The median hazard ratio was 1.14 with an interquartile range (IQR) of 1.02-1.23. One might conclude from this that eating red meat is associated with a slightly higher risk for early mortality.
Their second step was to calculate how many ways (specifications) there were to analyze the data by totaling all possible combinations of choices in the 70 ways found in the systematic review.
They calculated a total of 10 quadrillion possible unique analyses. A quadrillion is 1 with 15 zeros. Computing power cannot handle that amount of analyses yet. So, they generated 20 random unique combinations of covariates, which narrowed the number of analyses to about 1400. About 200 of these were excluded due to implausibly wide confidence intervals.
Voilà. They now had about 1200 different ways to analyze a dataset; they chose an NHANES longitudinal cohort study from 2007-2014. They deemed each of the more than 1200 approaches plausible because they were derived from peer-reviewed papers written by experts in epidemiology.
Specification Curve Analyses Results
Each analysis (or specification) yielded a hazard ratio for red meat exposure and death.
- The median HR was 0.94 (IQR, 0.83-1.05) for the effect of red meat on all-cause mortality — ie, not significant.
- The range of hazard ratios was large. They went from 0.51 — a 49% reduced risk for early mortality — to 1.75: a 75% increase in early mortality.
- Among all analyses, 36% yielded hazard ratios above 1.0 and 64% less than 1.0.
- As for statistical significance, defined as P ≤.05, only 4% (or 48 specifications) met this threshold. Zeraatkar reminded me that this is what you’d expect if unprocessed red meat has no effect on longevity.
- Of the 48 analyses deemed statistically significant, 40 indicated that red meat consumption reduced early death and eight indicated that eating red meat led to higher mortality.
- Nearly half the analyses yielded unexciting point estimates, with hazard ratios between 0.90 and 1.10.
Paradigm Changing
As a user of evidence, I find this a potentially paradigm-changing study. Observational studies far outnumber randomized trials. For many medical questions, observational data are all we have.
Now think about every observational study published. The authors tell you — post hoc — which method they used to analyze the data. The key point is that it is one method.
Dr. Zeraatkar and colleagues have shown that there are thousands of plausible ways to analyze the data, and this can lead to very different findings. In the specific question of red meat and mortality, their many analyses yielded a null result.
Now imagine other cases where the researchers did many analyses of a dataset and chose to publish only the significant ones. Observational studies are rarely preregistered, so a reader cannot know how a result would vary depending on analytic choices. A specification curve analysis of a dataset provides a much broader picture. In the case of red meat, you see some significant results, but the vast majority hover around null.
What about the difficulty in analyzing a dataset 1000 different ways? Dr. Zeraatkar told me that it is harder than just choosing one method, but it’s not impossible.
The main barrier to adopting this multiverse approach to data, she noted, was not the extra work but the entrenched belief among researchers that there is a best way to analyze data.
I hope you read this paper and think about it every time you read an observational study that finds a positive or negative association between two things. Ask: What if the researchers were as careful as Dr. Zeraatkar and colleagues and did multiple different analyses? Would the finding hold up to a series of plausible analytic choices?
Nutritional epidemiology would benefit greatly from this approach. But so would any observational study of an exposure and outcome. I suspect that the number of “positive” associations would diminish. And that would not be a bad thing.
Dr. Mandrola, a clinical electrophysiologist at Baptist Medical Associates, Louisville, Kentucky, disclosed no relevant financial relationships.
A version of this article appeared on Medscape.com.
Observational studies on red meat consumption and lifespan are prime examples of attempts to find signal in a sea of noise.
Randomized controlled trials are the best way to sort cause from mere correlation. But these are not possible in most matters of food consumption. So, we look back and observe groups with different exposures.
My most frequent complaint about these nonrandom comparison studies has been the chance that the two groups differ in important ways, and it’s these differences — not the food in question — that account for the disparate outcomes.
But selection biases are only one issue. There is also the matter of analytic flexibility. Observational studies are born from large databases. Researchers have many choices in how to analyze all these data.
A few years ago, Brian Nosek, PhD, and colleagues elegantly showed that analytic choices can affect results. His Many Analysts, One Data Set study had little uptake in the medical community, perhaps because he studied a social science question.
Multiple Ways to Slice the Data
Recently, a group from McMaster University, led by Dena Zeraatkar, PhD, has confirmed the analytic choices problem, using the question of red meat consumption and mortality.
Their idea was simple: Because there are many plausible and defensible ways to analyze a dataset, we should not choose one method; rather, we should choose thousands, combine the results, and see where the truth lies.
You might wonder how there could be thousands of ways to analyze a dataset. I surely did.
The answer stems from the choices that researchers face. For instance, there is the selection of eligible participants, the choice of analytic model (logistic, Poisson, etc.), and covariates for which to adjust. Think exponents when combining possible choices.
Dr. Zeraatkar and colleagues are research methodologists, so, sadly, they are comfortable with the clunky name of this approach: specification curve analysis. Don’t be deterred. It means that they analyze the data in thousands of ways using computers. Each way is a specification. In the end, the specifications give rise to a curve of hazard ratios for red meat and mortality. Another name for this approach is multiverse analysis.
For their paper in the Journal of Clinical Epidemiology, aptly named “Grilling the Data,” they didn’t just conjure up the many analytic ways to study the red meat–mortality question. Instead, they used a published systematic review of 15 studies on unprocessed red meat and early mortality. The studies included in this review reported 70 unique ways to analyze the association.
Is Red Meat Good or Bad?
Their first finding was that this analysis yielded widely disparate effect estimates, from 0.63 (reduced risk for early death) to 2.31 (a higher risk). The median hazard ratio was 1.14 with an interquartile range (IQR) of 1.02-1.23. One might conclude from this that eating red meat is associated with a slightly higher risk for early mortality.
Their second step was to calculate how many ways (specifications) there were to analyze the data by totaling all possible combinations of choices in the 70 ways found in the systematic review.
They calculated a total of 10 quadrillion possible unique analyses. A quadrillion is 1 with 15 zeros. Computing power cannot handle that amount of analyses yet. So, they generated 20 random unique combinations of covariates, which narrowed the number of analyses to about 1400. About 200 of these were excluded due to implausibly wide confidence intervals.
Voilà. They now had about 1200 different ways to analyze a dataset; they chose an NHANES longitudinal cohort study from 2007-2014. They deemed each of the more than 1200 approaches plausible because they were derived from peer-reviewed papers written by experts in epidemiology.
Specification Curve Analyses Results
Each analysis (or specification) yielded a hazard ratio for red meat exposure and death.
- The median HR was 0.94 (IQR, 0.83-1.05) for the effect of red meat on all-cause mortality — ie, not significant.
- The range of hazard ratios was large. They went from 0.51 — a 49% reduced risk for early mortality — to 1.75: a 75% increase in early mortality.
- Among all analyses, 36% yielded hazard ratios above 1.0 and 64% less than 1.0.
- As for statistical significance, defined as P ≤.05, only 4% (or 48 specifications) met this threshold. Zeraatkar reminded me that this is what you’d expect if unprocessed red meat has no effect on longevity.
- Of the 48 analyses deemed statistically significant, 40 indicated that red meat consumption reduced early death and eight indicated that eating red meat led to higher mortality.
- Nearly half the analyses yielded unexciting point estimates, with hazard ratios between 0.90 and 1.10.
Paradigm Changing
As a user of evidence, I find this a potentially paradigm-changing study. Observational studies far outnumber randomized trials. For many medical questions, observational data are all we have.
Now think about every observational study published. The authors tell you — post hoc — which method they used to analyze the data. The key point is that it is one method.
Dr. Zeraatkar and colleagues have shown that there are thousands of plausible ways to analyze the data, and this can lead to very different findings. In the specific question of red meat and mortality, their many analyses yielded a null result.
Now imagine other cases where the researchers did many analyses of a dataset and chose to publish only the significant ones. Observational studies are rarely preregistered, so a reader cannot know how a result would vary depending on analytic choices. A specification curve analysis of a dataset provides a much broader picture. In the case of red meat, you see some significant results, but the vast majority hover around null.
What about the difficulty in analyzing a dataset 1000 different ways? Dr. Zeraatkar told me that it is harder than just choosing one method, but it’s not impossible.
The main barrier to adopting this multiverse approach to data, she noted, was not the extra work but the entrenched belief among researchers that there is a best way to analyze data.
I hope you read this paper and think about it every time you read an observational study that finds a positive or negative association between two things. Ask: What if the researchers were as careful as Dr. Zeraatkar and colleagues and did multiple different analyses? Would the finding hold up to a series of plausible analytic choices?
Nutritional epidemiology would benefit greatly from this approach. But so would any observational study of an exposure and outcome. I suspect that the number of “positive” associations would diminish. And that would not be a bad thing.
Dr. Mandrola, a clinical electrophysiologist at Baptist Medical Associates, Louisville, Kentucky, disclosed no relevant financial relationships.
A version of this article appeared on Medscape.com.
Observational studies on red meat consumption and lifespan are prime examples of attempts to find signal in a sea of noise.
Randomized controlled trials are the best way to sort cause from mere correlation. But these are not possible in most matters of food consumption. So, we look back and observe groups with different exposures.
My most frequent complaint about these nonrandom comparison studies has been the chance that the two groups differ in important ways, and it’s these differences — not the food in question — that account for the disparate outcomes.
But selection biases are only one issue. There is also the matter of analytic flexibility. Observational studies are born from large databases. Researchers have many choices in how to analyze all these data.
A few years ago, Brian Nosek, PhD, and colleagues elegantly showed that analytic choices can affect results. His Many Analysts, One Data Set study had little uptake in the medical community, perhaps because he studied a social science question.
Multiple Ways to Slice the Data
Recently, a group from McMaster University, led by Dena Zeraatkar, PhD, has confirmed the analytic choices problem, using the question of red meat consumption and mortality.
Their idea was simple: Because there are many plausible and defensible ways to analyze a dataset, we should not choose one method; rather, we should choose thousands, combine the results, and see where the truth lies.
You might wonder how there could be thousands of ways to analyze a dataset. I surely did.
The answer stems from the choices that researchers face. For instance, there is the selection of eligible participants, the choice of analytic model (logistic, Poisson, etc.), and covariates for which to adjust. Think exponents when combining possible choices.
Dr. Zeraatkar and colleagues are research methodologists, so, sadly, they are comfortable with the clunky name of this approach: specification curve analysis. Don’t be deterred. It means that they analyze the data in thousands of ways using computers. Each way is a specification. In the end, the specifications give rise to a curve of hazard ratios for red meat and mortality. Another name for this approach is multiverse analysis.
For their paper in the Journal of Clinical Epidemiology, aptly named “Grilling the Data,” they didn’t just conjure up the many analytic ways to study the red meat–mortality question. Instead, they used a published systematic review of 15 studies on unprocessed red meat and early mortality. The studies included in this review reported 70 unique ways to analyze the association.
Is Red Meat Good or Bad?
Their first finding was that this analysis yielded widely disparate effect estimates, from 0.63 (reduced risk for early death) to 2.31 (a higher risk). The median hazard ratio was 1.14 with an interquartile range (IQR) of 1.02-1.23. One might conclude from this that eating red meat is associated with a slightly higher risk for early mortality.
Their second step was to calculate how many ways (specifications) there were to analyze the data by totaling all possible combinations of choices in the 70 ways found in the systematic review.
They calculated a total of 10 quadrillion possible unique analyses. A quadrillion is 1 with 15 zeros. Computing power cannot handle that amount of analyses yet. So, they generated 20 random unique combinations of covariates, which narrowed the number of analyses to about 1400. About 200 of these were excluded due to implausibly wide confidence intervals.
Voilà. They now had about 1200 different ways to analyze a dataset; they chose an NHANES longitudinal cohort study from 2007-2014. They deemed each of the more than 1200 approaches plausible because they were derived from peer-reviewed papers written by experts in epidemiology.
Specification Curve Analyses Results
Each analysis (or specification) yielded a hazard ratio for red meat exposure and death.
- The median HR was 0.94 (IQR, 0.83-1.05) for the effect of red meat on all-cause mortality — ie, not significant.
- The range of hazard ratios was large. They went from 0.51 — a 49% reduced risk for early mortality — to 1.75: a 75% increase in early mortality.
- Among all analyses, 36% yielded hazard ratios above 1.0 and 64% less than 1.0.
- As for statistical significance, defined as P ≤.05, only 4% (or 48 specifications) met this threshold. Zeraatkar reminded me that this is what you’d expect if unprocessed red meat has no effect on longevity.
- Of the 48 analyses deemed statistically significant, 40 indicated that red meat consumption reduced early death and eight indicated that eating red meat led to higher mortality.
- Nearly half the analyses yielded unexciting point estimates, with hazard ratios between 0.90 and 1.10.
Paradigm Changing
As a user of evidence, I find this a potentially paradigm-changing study. Observational studies far outnumber randomized trials. For many medical questions, observational data are all we have.
Now think about every observational study published. The authors tell you — post hoc — which method they used to analyze the data. The key point is that it is one method.
Dr. Zeraatkar and colleagues have shown that there are thousands of plausible ways to analyze the data, and this can lead to very different findings. In the specific question of red meat and mortality, their many analyses yielded a null result.
Now imagine other cases where the researchers did many analyses of a dataset and chose to publish only the significant ones. Observational studies are rarely preregistered, so a reader cannot know how a result would vary depending on analytic choices. A specification curve analysis of a dataset provides a much broader picture. In the case of red meat, you see some significant results, but the vast majority hover around null.
What about the difficulty in analyzing a dataset 1000 different ways? Dr. Zeraatkar told me that it is harder than just choosing one method, but it’s not impossible.
The main barrier to adopting this multiverse approach to data, she noted, was not the extra work but the entrenched belief among researchers that there is a best way to analyze data.
I hope you read this paper and think about it every time you read an observational study that finds a positive or negative association between two things. Ask: What if the researchers were as careful as Dr. Zeraatkar and colleagues and did multiple different analyses? Would the finding hold up to a series of plausible analytic choices?
Nutritional epidemiology would benefit greatly from this approach. But so would any observational study of an exposure and outcome. I suspect that the number of “positive” associations would diminish. And that would not be a bad thing.
Dr. Mandrola, a clinical electrophysiologist at Baptist Medical Associates, Louisville, Kentucky, disclosed no relevant financial relationships.
A version of this article appeared on Medscape.com.